Neuro Flashcards

Question

ADEM - background, diagnosis

Answer 1

1. Epidemiology a. Peak age 4-8 years; slight male preponderance b. 3/4 have antecedent event – infections associated with ADEM include influenza, EBV, CMV, varicella, enterovirus, MMR, HSV, mycoplasma pneumoniae; post vaccination have also been reported 2. Clinical manifestations a. Encephalopathy b. Polysymptomatic i. Motor deficits 80% ii. Ataxia 50-60% iii. Cranial nerve signs in up to 50% (optic neuritis usually bilateral) – check for RAPD iv. Language disturbance (eg. mutism not uncommon) c. Systemic symptoms common i. Fever 50% ii. Vomiting 33% iii. Headache 40-50% d. Seizures in 10-30% e. Concurrent spinal cord involvement in 3-25% 3. Investigations a. MRI = lesions typically bilateral, multifocal but asymmetric, and large in size i. WM abnormalities 90% - subcortical > periventricular WM vii. Concurrent cord involvement in up to 30% b. CSF = abnormal in 70% with pleocytosis or increased protein i. Oligoclonal bands in 0-29% - NOT necessarily indicator of MS ii. Not always done c. EEG = non-specific diffuse or less commonly focal slowing of the background activity i. Epileptiform discharges much less common a. A first clinical attack with presumed inflammatory or demyelinating cause, with acute or subacute onset that affects multifocal areas of the CNS i. The clinical presentation is polysymptomatic AND ii. Must include encephalopathy that may consist of one or more of the following 1. Behavioral change eg. irritability, lethargy 2. Alteration in consciousness eg. somnolence, coma b. Neuroimaging should show focal or multifocal lesions(s), predominantly involving white matter, without radiological evidence of previous destructive white matter changes

Answer 2

5. Treatment a. Spontaneous improvement without treatment is documented b. Steroids – no RCTs, small paediatric case series  IVMP 15 mg/kg/day then oral prednisolone wean over 4 weeks c. Immunoglobulin = used if no response to steroids d. Plasmapheresis = used in severe cases if not responsive to steroids or Ig e. Other = rituximab, cyclophosphamide 6. Outcomes a. Attack should be followed by improvement, either clinically or on MRI or both, but there may be residual deficits b. Clinical symptoms and MRI findings can fluctuate in severity and evolve in the first 3 months following disease c. A ‘second event’ is defined as the development of new symptoms at least 3 months after the incident illness irrespective of steroid use d. 57-89% of children make full recovery e. Mild neurocognitive deficits and behavioural problems not uncommon i. Children affected at <5 years of age higher risk of cognitive deficits as well as social, behavioural and emotional problems f. Risk of subsequent diagnosis of multiple sclerosis is low (2-10%) g. Follow-up imaging i. Most complete or almost complete resolution of lesions after 3-24 months ii. However lesions may persist for up to many years, despite clinical recovery iii. Patients with a diagnosis of monophasic ADEM do not develop a new demyelinating lesion after 3 months

Answer 3

1. Key points a. Inflammatory (demyelinating) lesion of spinal cord b. Lesions usually span multiple vertebral segments ie. Not really ‘transverse’ i. Term ‘transverse’ retained because of importance of spinal sensory level in making diagnosis c. Important to assess for other sites of demyelination i. Encephalopathy (ADEM) ii. Optic neuritis 2. Causes a. Idiopathic ATM b. Neuromyelitis optica (NMO) c. Multiple sclerosis (MS) d. Other systemic disease eg. SLE 3. Clinical manifestations a. Weakness, bilateral, usually severe i. Almost always LL involvement ii. Sometimes UL involvement b. Sensory symptoms (2/3) – sensory level c. Bladder disturbance (2/3) – retention d. Pain common – back, leg, abdominal e. UMN signs (unless spinal shock) – hyperreflexia, clonus, up going plantars f. Absent abdominal reflexes 4. Investigations a. Imaging i. MRI spine – within 24 hours, exclude compressive aetiology 1. MRI usually abnormal, Rarely changes delayed 3. Paediatric idiopathic ATM usually long segment ii. MRI brain – brain lesions b. CSF – MCS, protein, glucose, oligoclonal bands i. 73% pleocytosis, 55% elevated protein c. Bloods i. NMO antibody ii. MOG antibody – particularly associated with phenotypes such as transverse myelitis, NMO, optic neuritis (particularly bilateral), relapsing optic neuritis, relapsing NMO iii. Serology iv. Autoantibodies: ANA etc v. ACE level 5. Treatment a. IV steroids = IVMP 15 mg/kg for 5 days with ranitidine  Oral steroid wean over 4 weeks b. IDC if urinary retention c. Consider plasma exchange in severe cases that fail to respond to high dose corticosteroid treatment 6. Outcome (RCH series) a. 50% normal outcome b. 70-80% normal to good outcome c. Time to independent ambulation 2 weeks 7. What is the risk of further demyelinating episodes? a. Idiopathic ATM = risk of MS diagnosis low i. Up to 10 % in paediatric myelitis cohorts (but is probably less than this)

Answer 4

1. Key points a. Optic neuritis (ON) = inflammatory demyelinating disorder of the optic nerve that causes acute visual loss i. Unilateral OR bilateral b. The pathogenesis of optic neuritis in children is usually demyelinating, but there is a broad DDX c. Optic neuritis may be an isolated feature, or may be a feature of ADEM, MS or NMO i. Bilateral severe or recurrent – think MOG (myelin oligodendrocyte glycoprotein) d. Treatment with steroids hastens visual recovery e. Visual recovery is good in most patients + can continue for up to 2 years f. A proportion of children will go on to develop MS 2. Clinical presentation a. Visual loss is often profound and may be bilateral i. Typically develops over hours-days, peak at 1-2 weeks b. Colour desaturation (especially with red, formally tested with Ishihara (those colour blind circle things)) c. Eye pain – particularly with movement d. Often para-/post-infectious or post-vaccination 3. DDx a. Infective and autoimmune causes of optic neuropathy b. MS c. NMO – consider NMO in children with ON+TM or recurrent ON d. ADEM

Answer 5

4. Clinical assessment a. Elicit symptoms and signs of optic neuritis i. Reduced visual acuity (if cannot read Snellen, check finger perception, light perception) ii. Visual field loss (typically central scotoma, but other defects can occur) 1. Scotoma: An area of partial alteration in the field of vision consisting of a partially diminished or entirely degenerated visual acuity that is surrounded by a field of normal – or relatively well-preserved – vision iii. Colour desaturation (Ishihara) iv. Pain on eye movement (if Retrobulbar neuritis) v. RAPD = paradoxical dilatation as you swing onto the affected eye vi. Papillitis (if anterior portion of nerve involved) b. Disc appearance i. Normal = Retrobulbar ON ii. Abnormal = papillitis (ie. involving optic disc – swollen disc, blurred) iii. Pallor may suggest chronicity c. Consider issues regarding spectrum of demyelinating diseases including history of preceding infection or vaccine, family history of MS, past history of neurological symptoms or visual impairment, additional current symptoms of encephalopathy (seen with ADEM),transverse myelitis and other focal neurologic deficits. d. Look for signs that may suggest alternative diagnoses = fever, headache, meningism, inflammation to other parts of eye, joint swellings, cytopaenias, dry eyes and mouth, dysfunction of other organs, systemic symptoms, weight loss, other cranial neuropathies, recent head injury, PHx radiotherapy, drug exposure, micronutrient deficiencies, associated anaemias, longer duration of symptoms, FHx of similar (LHON = mitochondrial, Kjer's = AD) 5. Investigations a. MRI brain + orbits i. Should occur within 24 hours and before starting steroids – to exclude conditions that may be exacerbated or complicated by steroid therapy (eg. infection, malignancy) b. Opthal = document severity and exclude DDx c. Blood tests: i. Mandatory 1. FBE + film, inflammatory markers (ESR, CRP) 2. ANA 3. Blood cultures +/- PCR 4. Serology (mycoplasma, toxoplasmosis, syphilis, EBV, CMV, bartonella; if unvaccinated, consider measles, mumps and varicella) 5. Lactate 6. Oligoclonal bands (paired with CSF) 7. Vitamin D ii. Consider: 1. dsDNA, ENA, ANCAs 2. ACE level, Ca++ 3. tumour markers (with advice from oncology) 4. vitamin B1, B12 and folate levels 5. testing for mitochondrial mutations 6. NMO antibodies = should be tested if there is a presentation of optic neuritis PLUS transverse myelitis or a recurrent history of either 7. Serum MOG antibody

Answer 6

6. Management a. Our protocol is to treat with steroids unless there is minimal visual impairment (uncommon in children) AND an otherwise normal MRI brain i. IV methylprednisolone 10-15mg/kg/day for 3-5 days THEN ii. Oral prednisolone 1mg/kg/day for 1 week THEN iii. Oral prednisolone 0.5mg/kg/day for 1 week THEN STOP b. PPI for gastroprotection while on steroids c. Blood pressure should be monitored while an inpatient 7. Outcome a. Estimate that ~85% will recover 6/12 vision; recovery can continue for up to 2 years b. Recurrent optic neuritis is reported to occur in 3-31% c. If recurrent – think MS, NMO, MOG d. Progression to MS i. Diagnosis of MS is unlikely to be made at first presentation of optic neuritis unless there is a PHx of neurologic symptoms that can be attributed to demyelination, or unless MRI shows lesions disseminated in space AND time ii. Rates of progression to MS in children vary from 13-46% (OVERALL = 30%) iii. Highest risk is within the first 2 years after diagnosis iv. Estimates of risk vary, but risk in children with a monosymptomatic presentation and an MRI that is normal outside of the optic nerve appears very low 1. Normal MRI brain = 0-7% risk of subsequent MS v. Risk factors 1. Abnormal MRI brain at presentation = strongest risk for developing MS (ie. demyelination outside the visual system) 2. Age > 12 years 3. Presence of oligoclonal bands in the CSF

Answer 7

1. Key points a. Characterised by severe attacks of optic neuritis and myelitis b. Age of onset 31 +/-11 years -> rare in children c. Index event = isolated myelitis or optic neuritis (up to 90%) i. Time to second index event 5-6 months on average d. Relapsing course often leads to severe disability g. Differentiating features from MS i. Recovery of visual and spinal cord function is generally not as compete after each episode ii. ON is more frequently bilateral in NMO than MS 2. Etiology a. Idiopathic, Occasional familial cases, Post infectious NMO – HIV, syphilis, chlamydia, variceal, CMV EBV 3. Clinical manifestation a. Features of TM + ON c. ON and TM may occur simultaneously or separate in time by weeks or years 4. Diagnostic criteria a. Requires optic neuritis AND transverse myelitis, with 2/3 of: i. MRI brain not diagnostic of MS ii. Seropositivity for aquaporin 4Ab iii. Spine MRI with longitudinally extensive TM involving at least 3 segments 5. Investigations a. CSF i. NMO Ig = target aquaporin 4 Ab = 73% sensitive, 91% specific for NMO ii. Also test for MOG Ab iii. Devoid of oligoclonal bands b. MRI brain spine 6. Treatment a. Treat with immunosuppressive agents to prevent relapse b. Methylprednisolone for 3-5 days followed by taper c. Rituximab is effective for preventing relapse 7. Complications a. Fixed neurological defects affecting visual acuity, visual fields, colour vision, motor and sensory function, balance and bladder/bowel function

Answer 8

1. Key points a. Rare – estimated 2-5% of MS patients experiencing first symptom <18 years of age c. Recurrent lesions at a different place in time and space 2. Clinical manifestations a. Dependent on where the demyelinating lesions are located b. Examples: i. Optic neuritis ii. Acute partial TM iii. Ataxia iv. INO (internuclear ophthalmoplegia) 1. A disorder of conjugate lateral gaze in which the affected eye shows impairment of adduction. When an attempt is made to gaze contralaterally (relative to the affected eye), the affected eye adducts minimally, if at all. The contralateral eye abducts, however with nystagmus. Additionally, the divergence of the eyes leads to horizontal diplopia. v. Vertigo vi. Bladder/bowel dysfunction c. Polyregional symptoms reported in 30% of patients d. Encephalopathy is less common: suggests ADEM or possibly NMO 3. Investigations a. MRI spine+brain b. LP i. Normal or exhibit mild pleocytosis ii. Oligoclonal bands maybe present – can be negative in 10-60% of patients 4. Diagnosis a. Definition = recurrent events of demyelination separated in time and space i. Relapsing remitting course most common ii. McDonald criteria for diagnosis 1. Dissemination in time – eg. 2 attacks or 1 clinical attack now and new lesions on MRI 2. Dissemination in space

Answer 9

1. Treatment a. Acute relapse – steroids b. Symptomatic treatment c. Disease-modifying therapies i. First line therapies 1. Interferon-beta a. IFN-beta1a (Rebif, Avonex) b. IFN beta1b (Betaferon) c. AE = flu-like symptoms, leukopenia, LFTs 2. Glatiramer acetate (Copaxone) ii. Second line therapies/ novel therapies 1. Risk of PML (progressive multifocal encephalopathy) from JC virus (John Cunningham virus aka Human Polyomavirus) (natalizumab, fingolimod, dimethyl fumarate) and other opportunistic infections 2. Complications a. Similarly to adults, children can acquire fixed neurological deficits affecting vision and other cranial nerves, motor and sensory function, balance and bowel/bladder function

Answer 10

MS - Age: >10 - Absent: encephalopathy, fever/vomiting - Present: family history - ON: unilateral - Monosymptomatic - CSF: oligoclonal bands - Follow up: new lesions ADEM - Age: <10 - Absent: fam hx - Present: encephalopathy, fever, vomiting - ON: bilateral - Polysymptomatic - CSF: pleocytosis - Follow up: no new lesions

Answer 11

1. Risk factors a. Un-immunised b. Immunodeficiency i. Defects in complement system (C5-8) ii. Defects in properdin iii. Splenic dysfunction or Asplenia iv. T lymphocyte defects – congenital or acquired increased risk of Listeria c. Congenital or acquired CSF leak across a mucocutaneous barrier eg. lumbar dural sinus, cranial or midline facial defects (cribriform plate), and middle ear (stapedial foot plate) or inner ear fistula, base of skull fracture d. Cochlear implant – risk 30x general population 2. Aetiology a. Children >2 months i. Streptococcus pneumoniae ii. Neisseria meningitidis iii. Hib (unimmunized children) b. Children <2 months i. GBS ii. E. coli and other GN bacteria iii. Listeria monocytogenes c. Immunodeficient i. Pseudomonas ii. Staphylococcus aureus, CONS iii. Salmonella, Listeria iv. Fungal – Cryptococcus d. At risk populations i. Lumbosacral dermal sinus and meningomyelocele associated with staphylococcal, anaerobic and Gram negative enteric bacterial meningitis ii. CSF shunt infections increase risk of staphylococcus (especially CONS) 3. Pathogenesis a. Haematogenous = bacterial colonisation of the nasopharynx > bacteraemia > seeding of meninges b. Continugous spread = mastoiditis, sinusitis, otitis media, orbital cellulitis, osteomyelitis

Answer 12

4. Clinical manifestations a. History i. Infants with meningitis frequently present with non-specific symptoms such as fever, irritability, lethargy, poor feeding, vomiting and diarrhoea ii. Older children may complain of headache or photophobia iii. Seizures iv. Prior antibiotics – clinical presentation may be altered by prior use of antibiotics. b. Examination i. In infants, the fontanelle may be full ii. Neck stiffness may or may not be present (not a reliable sign in young children) iii. A purpuric rash is suggestive of meningococcal septicaemia iv. Kernig's sign: hip flexion with an extended knee causes pain in the back and legs v. Brudzinski sign: involuntary flexion of the knees and hips are passive flexion of the neck while supine vi. CSF shunts, spinal and cranial abnormalities (eg dermal sinuses) which may have predisposed a child to meningitis 5. Investigations a. LP – see acute medicine for contraindications b. Blood culture c. FBE, UEC

Answer 13

a. <2 months = cefotaxime 50 mg/kg Q6H + benzylpenicillin 60 mg/kg Q4H (if >1 month) b. >2 months = ceftriaxone 50 mg/kg Q6H + dexamethasone 0.15 mg/kg IV Q6H for 4 days c. If encephalitis suspected = aciclovir 20 mg/kg IV Q8H d. Targeted therapy i. N meningitidis = benpen Q4H for 7 days ii. S pneumoniae = benpen Q4H for 10 days iii. Hib = ceftriaxone IV iv. If an organism is not isolated but CSF pleocytosis is present – minimum 7 days with IV ceftriaxone v. Prolonged IV therapy require for neonatal and GN bacillary meningitis e. Note i. Benzylpenicillin can be substituted with amoxycillin 50mg/kg iv ii. Cefotaxime can be substituted with Ceftriaxone 100 mg/kg (max 2gm) iv daily in children > 1 month iii. Empiric use of vancomycin is not currently recommended for pneumococcal meningitis in Victoria iv. Delay in antibiotics is associated with poorer outcomes. f. Steroids i. Current evidence suggests that steroids may reduce the risk of hearing loss in bacterial meningitis ii. Consider giving Dexamethasone to children > 2 months of age 15 minutes prior to parenteral antibiotics or, if this is not possible, within one hour of receiving their first dose of antibiotics: 0.15mg/kg IV. Consider giving steroids at the time of lumbar puncture if the clinical suspicion of meningitis is high iii. Steroids should be ceased if a decision is made to cease antibiotic treatment for meningitis before 4 days (eg CSF microscopy not suggestive, CSF cultures negative at 48 hours) iv. Steroids are not recommended in neonates due to concern regarding effects on neurodevelopment

Answer 14

7. Complications a. Seizures – manage with BDZ, phenytoin b. Subdural effusion c. Other foci of suppuration d. Parameningeal focus e. DIC f. Severe neurological sequelae 10-20% = hearing loss, mental retardation, recurrent seizure, delay in acquisition of speech, visual impairment & behavioral problems (50% have subtle neurobehavioral issues) i. Sensorineural hearing loss  most common sequelae (30% of pneumococcal infection) ii. Invasive meningococcal disease mortality still 10% 8. Follow-up a. Formal audiology appointment 6-8 weeks after discharge b. Neurodevelopmental surveillance 9. Prophylaxis a. Meningococcal chemoprophylaxis b. Indications i. Index case – if treated only with penicillin ii. All intimate, household or daycare contacts who have been exposed to index case within 10 days of onset iii. Any person who gave mouth to mouth resuscitation c. Drugs i. Rifampicin – discolouration of tears, urine and contact lenses, skin rash, GI disturbance; contraindicated in those with severe liver disease or on OCP (negates the effect) ii. Ceftriaxone or ciprofloxacin

Answer 15

1. Definition a. Febrile illness with clinical signs and symptoms of meningeal irritation b. No associated neurologic dysfunction c. No evidence of bacterial pathogens in the CSF in a patient who has not received antibiotics 2. Aetiology a. Enteroviruses = poliovirus, coxsackievirus, echovirus = most common b. Paraechovirus c. Arboviruses d. Herpesviruses i. HSV 1 – important cause of severe, sporadic encephalitis ii. HSV 2 – neonates who contract virus from mothers iii. VZV – cerebellar ataxia to severe encephalitis iv. CMV – in immunocompromised hosts v. HHV 6 – in immunocompromised hosts 3. Clinical manifestations a. As for meningitis but usually less severe b. Features suggestive of enterovirus = conjunctivitis, pharyngitis, rash, herpangina, hand-foot-mouth disease 4. Treatment a. Treat as bacterial until it has been excluded b. Requires negative CSF culture 5. Prognosis a. Complete recovery b. Some may have fatigue, irritability, decreased concentration, muscle weakness and spasm for a period of time

Answer 16

1. Key points a. >10 eosinophils/mm3 of CSF and/or accounting for >10% of CSF leukocytes 2. Aetiology a. Infection i. Parasites 1. Angiostrongylus cantonesis 2. Baylisascaris procyonis 3. Gnathostoma spinigerum ii. Bacteria iii. Virus iv. Fungus – Coccidioides b. Non-Infection i. Malignancy – NHL, Hodgkin, Eosinophilic leukaemia ii. Drugs – ibuprofen, ciprofloxacin, intraventricular antibiotics iii. Others – VP shunts, hypereosinophilic syndrome 3. Investigations a. CSF i. Normal to high opening pressure ii. Cell count 20-5000 iii. >10% eosinophils iv. Glucose normal v. Protein increased 4. Treatment a. No effective b. Supportive care c. Repeat LP s

Answer 17

• Granulomatous amoebic encephalitis = Acanthomoeba spp and Balamuthia spp o Most often subacute or chronic disease, usually fatal sometime after neurological signs appear • Primary amoebic meningoencephalitis = Naegleria fowleri often rapidly progressive • Presents with – fever, headache, focal neuro signs, behavioural change, lethargy, ataxia, seizures, CN palsy, altered mental status • CSF pleocytosis with lymphocytic predominance, increased protein, low glucose – or can be normal • Cysts and trophozoites may be seen • Biopsy may be required • Treatment not well defined

Answer 18

General principles - "normal" neutrophils = 0 - normal to have a few lymphocytes - "normal" CSF and negative Gram stain does not rule out bacterial meningitis (Gram stain negative in up to 60% even without prior antis) - correcting for RBCs is inaccurate and not validated, if concerns for meningitis need to treat Bacterial (usually) - neuts >100 - lymphocytes <100 - protein high, glucose low Viral (usually) - neuts <100 - lymphs >100 - low protein, normal glucose TB - neuts <100 - lymphs >100 - normal protein, low glucose

Answer 19

1. Key points a. Encephalitis = inflammation of the brain parenchyma associated with neurological dysfunction 2. Aetiology a. Enterovirus (most common) b. HSV c. Other herpesviruses – EBV, CMV, HHV6, VZV d. Arboviruses e. Bacteria, fungi, parasites 3. Clinical manifestations a. Altered conscious state = decreased level of consciousness, lethargy, personality change, unusual behaviour b. Focal neurological signs c. Seizures d. Associated symptoms = fever, headache, nausea, vomiting 4. Investigations a. Blood culture b. CSF c. Urine and serum toxicology, metabolic studies, anti-NMDA = if indicated d. Imaging = temporal lobe localisation in HSV encephalitis e. EEG = temporal lobe slowing in HSV encephalitis 5. Treatment a. Aciclovir b. If proven HSV encephalitis – treatment for 21 days 6. Prognosis a. Poor outcome associated with i. Coma, convulsion or focal neurological findings in acute phase ii. Young age iii. Need for ICU iv. HSV encephalitis v. Diffusion restriction on MRI b. Neurological sequelae – variable

Answer 20

1. Key points a. Occur in children of any age – most common 4-8 years 3. Pathogenesis c. Majority single – 30% multiple d. Pathogenesis unknown in 10-15% of cases e. Day 1-9 – cerebritis with liquefaction f. Day 10-14 – well circumscribed capsule forms g. Direct spread 50% = single abscess i. Infection – most common source 1. OM/mastoiditis/sinusitis = temporal lobe/ cerebellum 2. Meningitis/dental infection/orbital cellulitis = frontal lobe ii. Trauma / foreign body (shunt) iii. Post-operative h. Haematogenous spread 50% = multiple abscesses distribution MCA i. Usually develop at grey-white matter junction where infarction damages BBB ii. Chronic pulmonary infection (lung abscess, empyema) iii. Cyanotic congenital heart disease – especially TOF as blood bypasses phagocytic filtering action of pulmonary capillary bed iv. Bacterial endocarditis 4. Aetiology a. Streptococci (anaerobic and aerobic) – 60-70% 5. Clinical manifestations a. Early stage of cerebritis and abscess formation – low-grade fever, headache, lethargy b. Progress to vomiting, severe headache, seizures, papilledema, focal neurological signs, coma 6. Investigations a. Blood culture b. CSF – rarely positive i. Often contraindicated due to risk of transtentorial herniation c. Imaging = MRI with contrast Ix of choice (differentiate abscess from neoplasm) 7. Treatment a. Antibiotics = if <2cm and <2 weeks in duration, no signs of raised ICP, child neurologically intact i. Metronidazole + ceftriaxone/cefotaxime b. Neurosurgical intervention i. Abscess >2.5 cm ii. Gas is present in the abscess iii. Multiloculated iv. Located in the posterior fossa v. Fungus suspected c. Usually treated with IV antibiotics for 4-6 weeks 8. Mortality = 5-10% 9. Long-term sequelae a. Hemiparesis b. Seizures c. Hydrocephalus d. Cranial nerve abnormalities e. Behaviour and learning problems

Answer 21

1. Key points a. Childhood stroke is more common than brain tumours – top 10 cause of death in childhood b. Often delays in diagnosis as acute neurological deficits may be attributed to stroke mimickers like migraine, encephalitis or seizure related Todd’s paresis - Urgent brain imaging is critical to confirm stroke diagnosis and guide management. - Early involvement of a paediatric Neurology team is essential to guide assessment and acute management of suspected childhood stroke. - Reperfusion therapies are time critical: alteplase within 4.5 hours, and endovascular clot retrieval within 6 hours of symptom onset. - Childhood stroke has a mortality rate of 5-10%. More than half of the survivors have long-term neurological impairment and 10-20% suffer recurrent strokes - Arterial ischaemic stroke is the most common subtype, accounting for just over half of all strokes 2. Subtypes a. Acute arterial ischaemic stroke b. CV sinovenous thrombosis c. Haemorrhagic stroke 3. Aetiology a. Arteriopathies = major cause of arterial stroke (accounting for 50%) b. Cardiac disease (25%) c. Congenital or acquired Thrombophilic disorders d. NOTE: cause of perinatal arterial stroke usually unknown

Answer 22

4. History and examination a. Specifically ask about i. Recent head/neck injury, chiropractic neck manipulation ii. Varicella infection in the last 6-12 months iii. Migraine iv. OCP or illicit drug use in adolescents v. Family history of early onset ( < age 55) stroke, heart attack or venous thrombosis vi. Recent ENT/head and neck infection in suspected sinovenous thrombosis b. Specifically examine for cardiac murmurs, carotid or cranial bruits c. Suspect stroke in newborns with unexplained seizures or focal neurological signs d. Suspect stroke in older infants or children with sudden onset of focal neurological deficits reaching maximal severity within hours. Red flag features Children presenting with sudden onset of the following features are at high risk of stroke and should undergo immediate neurological assessment and be considered for urgent neuroimaging: - Focal limb or facial weakness* - Visual or speech disturbance* - Limb incoordination or ataxia* - Headache with other neurological signs or symptoms^ - Altered mental state^ - Signs of raised intracranial pressure^ - New onset seizures associated with persistent neurological signs or symptoms (*Arterial ishaemic stroke more likely; ^Haemorrhagic stroke more likely) 5. Investigations Brain imaging - In suspected haemorrhagic stroke, urgent non-contrast CT should be performed - In suspected arterial ischaemic stroke, urgent brain MRI and MRA should be performed - Where urgent MRI is not possible within 30 minutes, CT, including CT angiography should be performed Immediate investigations to determine eligibility for reperfusion therapies - FBE, coagulation profile, UEC, glucose, LFTs, blood group and hold Subsequent investigations to identify underlying causes of confirmed stroke - ECG and echocardiography - Prothrombotic markers and serum homocysteine i. Anticardiolipin (ACLA), lupus anticoagulant (antiphospholipid antibodies) ii. Antithrombin, protein C, protein S iii. Activated protein C resistance iv. Factor V Leiden, Prothrombin gene 20210A mutation v. Serum homocysteine

Answer 23

a. Initial stabilisation i. Refer to neurosurgeons if haemorrhage or evidence of posterior circulation or large anterior circulation dissection, or deteriorating conscious state ii. Establish IV access + give IV fluids to maintain BP iii. Avoid hypotension iv. Maintain normoglycaemia v. Prevent hypothermia vi. Load with IV phenytoin if seizures vii. NBM until swallowing assessed viii. Supportive care = avoid distress, hypotension, dehydration and hypocapnoea – particularly important with known arterial stenosis or Moyamoya b. Arterial ischaemic stroke i. Reperfusion therapies (updated 2021) 1. Acute treatment decisions should be coordinated by the Neurology team in consultation with Emergency and Haematology teams 2. Assessment of initial stroke symptom severity using the Pediatric NIH Stroke Scale must be performed in consultation with the Neurology team before reperfusion therapy is commenced 3. Alteplase (recombinant tissue plasminogen activator) may be appropriate in specific children. a. Potential eligibility criteria include: b. 2 to 17 years of age c. radiologically confirmed arterial stroke with absence of haemorrhage d. Pediatric NIH Stroke Scale score >3 and <24, with symptoms that are not improving e. time from symptom onset <4.5 hours 4. Administration: IV infusion - Total dose is 0.9 mg/kg (maximum 90 mg): a. bolus of 0.09 mg/kg b. then 0.81 mg/kg infused over 60 minutes 5. Absolute contraindications a. Known cerebral arterial venous malformation, aneurysm, or CNS neoplasm b. Known allergy to Alteplase ii. Endovascular therapies may be appropriate in some children with radiologically diagnosed ischaemic stroke (discuss with Neurology) Anticoagulant and antithrombotic therapy: - In children with arterial ischaemic stroke in whom reperfusion therapy is not given, or as secondary prevention: - Anticoagulation and antiplatelet therapy are indicated after the exclusion of haemorrhage on brain imaging - Anticoagulation and antiplatelet therapy should not be administered within 24 hours of receiving alteplase iii. Initial management 1. Non-sickle cell disease – UFH (unfractionated heparin) iv. Subsequent management 1. Cardioembolic stroke and dissection excluded: aspirin (1-5 mg/kg/day) for 2 years 2. Cardioembolic stroke and dissection confirmed: anticoagulant therapy with LMWH heparin or warfarin for at least 6 weeks 3. Children with sickle cell disease – IV hydration and exchange transfusion to reduce HbS level to <30% total Hb 4. Moyamoya – referred to neurosurgeon for consideration of revascularization 5. If recurrent strokes or TIAs while on aspirin prophylaxis  clopidogrel, aspirin-dipyrimadole or anticoagulant therapy v. Neonatal 1. Aspirin or anticoagulant for 6-12 weeks for cardio-embolic AIS 2. Anticoagulation or aspirin for non-cardioembolic AIS not recommended unless recurrent events c. Cerebral sinovenous thrombosis i. Without significant intracranial haemorrhage 1. Anticoagulation for 3/12 with UFH, or LMWH and subsequently LMWH or warfarin for 3/12 (aim for INR of 2.5 2. After 3 months of therapy if incomplete radiological canalization of CVST or ongoing symptoms, further 3/12 of anticoagulation ii. Neonatal SVT without significant intracranial haemorrhage 1. Anticoagulation initially with UFH, o LMWH and subsequently LMWH or warfarin for minimum of 6/52 and no longer than 3/12 iii. SVT with significant intracranial haemorrhage 1. Neurosurg referral

Answer 24

1. Key points a. Acute ischaemic stroke (AIS) = focal infarction resulting from occlusion of arteries b. Diagnosis often delayed d. The acute onset of a focal neurological deficit in a child is stroke until proven otherwise 2. Pathogenesis a. Arterial blood reaches brain via anterior (internal carotid) and posterior (vertebrobasilar) circulations converging at the circle of Willis b. Strokes most often involve the MCA territory 3. Risk factors a. Arteriopathy = leading cause of childhood AIS, present in >50% of children i. Transient cerebral arteriopathy ii. Post-varicella and other viruses angiopathy iii. Systemic/secondary vasculitis (eg. Takayasu) iv. Moyamoya disease = idiopathic or associated with other conditions (NF type 1, trisomy 21, Alagille syndrome, sickle cell anaemia, chromosomal deletions/duplications, post-irradiation) v. Fibromuscular dysplasia vi. Traumatic or spontaneous dissection vii. Vasospasm viii. Congenital arterial hypoplasia (PHACE) b. Cardiac = 25% of childhood AIS i. Congenital heart disease 1. PFO – paradoxical venous thromboembolism ii. Cardiac catheterisation + surgery iii. Arrythmia, valvular heart disease, endocarditis, cardiomyopathy iv. Intracardiac lesions (atrial myxoma) c. Haematological i. Sickle cell anaemia ii. Iron deficiency anaemia iii. Inherited prothrombotic = factor V Leiden, prothrombin gene mutation 20210A iv. Acquired prothrombotic = protein C/S deficiency, antithrombin III deficiency, lipoprotein A, APLS, oral contraceptive, pregnancy d. Other i. Acute systemic illness ii. Chronic systemic illness iii. Illicit drugs iv. MANY others

Answer 25

4. Clinical manifestation a. Hemiparesis – most common b. Other presenting features – acute visual, speech, sensory or balance deficits 5. Investigations a. CT = can demonstrate mature AIS and exclude haemorrhage b. MRI = Ix of choice i. Diffusion weighted MRI can demonstrate AIS within minutes of onset up to 7 days post-onset c. MRA = diagnose vascular occlusion and suggest possible arteriopathy 6. Treatment a. Antithrombotic strategies - d/w neuro re thrombolytic option b. Neuroprotective measures = control BG, temperature an seizures c. Disease specific treatments i. Transfusion therapy in sickle cell disease ii. Immunosuppression in vasculitis iii. Revascularization in Moyamoya d. Secondary stroke prevention e. Rehabilitation 7. Prognosis a. Recurrent stroke 10-50% depending on cause, death 6-10% b. Neurological deficit in 60-70%

Answer 26

1. Key points a. Very common, differs from childhood stroke and has 2 distinct clinical presentations b. Acute symptomatic neonatal AIS i. Presents with focal seizures at 24-28 hours of life ii. MRI diffusion abnormalities in an arterial territory confirm recent infarction c. Late presentation i. Infants are asymptomatic at birth and present later in infancy with signs of early hand preference and hemiparesis ii. Hand dominance within the first year of life is abnormal iii. Imaging reveals focal encephalomalacia in an arterial territory, typically large MCA lesion 2. Management a. In acute neonatal AIS seizure control is important b. Antithrombotic agents are rarely required (exception: cardiac thromboembolism) 3. Outcome a. Poor outcome b. Most children have lifelong disability c. Perinatal stroke accounts for most cases of Hemiparetic CP d. Additional morbidity seen in 25% - disorders of language, learning, cognition and behaviour, long-term epilepsy e. Stroke recurrence for both the child and subsequent pregnancies are extremely low

Answer 27

1. Key points a. Cerebral venous drainage occurs via the cerebral sinovenous system b. Includes superficial (cortical veins, superior sagittal sinus) and deep (internal cerebral veins, straight sinus) system that converge at the torcula to exit via the paired transverse and sigmoid sinuses and jugular veins c. Consequences of CVST i. Increased intracranial pressure ii. Cerebral oedema iii. Venous haemorrhage or infarction (50%) d. More common in children than adults e. Most common in neonates f. Clinical presentation typically gradual, variable and nonspecific compared with AIS 2. Risk factors a. Blood coagulation i. Prothrombotic conditions ii. Dehydration (eg. gastro, neonatal FTT) iii. Iron deficiency anaemia iv. Drugs and toxins (eg. L-asparaginase (ALL), oral contraceptives) v. Acute systemic illnesses (eg. sepsis, DIC) vi. Chronic systemic illnesses (eg. IBD, SLE, leukaemia) vii. Nephrotic syndrome viii. Inborn errors of metabolism b. Blood vessel i. Infection/thrombophlebitis 2. Lemierre syndrome 3. Sepsis ii. Trauma = skull fracture, closed head trauma iii. Compression = birth, occipital bone compression in neonates iv. Iatrogenic = neurosurgery, jugular lines, ECMO v. Venous malformation (eg. dural AV fistula) 3. Clinical presentation a. Neonates = encephalopathy and seizures b. Children = symptoms mimicking idiopathic intracranial hypertension i. Progressive headache, papilledema, diplopia secondary to CNVI palsy, or with acute focal deficits ii. Seizures, lethargy and confusion are common 4. Investigations a. CT venography or MR venography = required for diagnosis 5. Management a. Anticoagulation i. UFH or LMWH in most children - 3-6 months (reimage 3 months) v. Children with persistent risk factors may require long-term anticoagulation vi. Note: optic neuropathy secondary to increased ICP is an important and easily missed complication of CVST 1. Regular opthal examination to measure ICP is required 2. Measures to reduce ICP may be required – acetazolamide, serial LP

Answer 28

1. Key points a. HS includes non-traumatic ICH and is classified by the intracranial compartment containing the haemorrhage b. Intraparenchymal bleeds may occur anywhere, IVH may be isolated or an extension of intraparenchymal bleeding c. Bleeding outside the brain may occur in subarachnoid, subdural or epidural space 2. Risk factors a. Vascular disorder (vascular malformations, hereditary haemorrhagic telangiectasia, aneurysm (less common in children), Moyamoya, vasculitis, neoplasm, drugs, cerebral sinovenous thrombosis) b. Blood disorder (ITP, HUS, liver failure and coagulopathy, vit K deficiency, DIC) c. Trauma i. Middle meningeal artery injury – epidural haematoma ii. Bridging vein injury – subdural haematoma iii. SAH iv. Haemorrhagic contusions (coup and contre-coup) v. NAI (subdural haematomas of different ages) vi. Iatrogenic vii. Rupture of arachnoid cyst 3. Clinical presentation a. Varies depending on location, cause and rate of bleeding b. May feature thunder-clap headache, loss of consciousness and nuchal rigidity c. Focal neurological deficit and seizures d. Can be rapidly fatal e. If bleeds associated with vascular malformations – pulsatile tinnitus, cranial bruit, macrocephaly and high output HF may be present 4. Investigations a. CT = highly sensitive to acute HS b. LP = may be required to exclude subarachnoid haemorrhage c. MRI = highly sensitive to small amounts of acute and/or chronic haemorrhage  test of choice d. Angiography by CT or MRI = often required to exclude underlying vascular abnormalities 5. Management = Urgent neurosurgical intervention a. Reversal of anticoagulation (eg. FFP, vitamin K) b. Definitive repair or removal of vascular malformation c. Recurrence risk for those with structural lesions – serial imaging may be required 6. Outcome a. Not well studied – depend on size location and etiology b. Higher mortality than AIS c. Long-term deficits less common

Answer 29

• Cranial USS can detect many neonatal parenchymal bleeds, especially in preterm infant (bleeds usually centrally within the cranium and include germinal matrix bleeding and IVH) o Germinal matrix injury or bleeding may also occur in utero resulting in periventricular venous infarction that becomes symptomatic in later infancy as congenital hemiparesis • Subarachnoid and subdural blood may by imaged in up to 25% of normal term newborns • Term HS is poorly studied • Term IVH is often secondary to deep CVST

Answer 30

Migraine - evolving/marching symptoms, short, complete resolution, personal/fam hx - normal imaging Seizure - positive symptoms, Todds paralysis - normal imaging or underlying cause e.g. malformation Infection - fever, encephalopathy, gradual onset, meningism Demyelination - gradual onset, multifocal, encephalopathy, optic neuritis or TM Hypoglycaemia - risk factors, meals, systemic symptoms HIE (watershed infarction) - risk factors, bilateral - bilateral, symmetric restriction diffusion in border zones between major arteries (watershed zones) ``` Hypertensive encephalopathy (PRES = posterior reversible encephalopathy syndrome) - HTN, bilateral visual symptoms, encephalopathy ``` Vestibulopathy - vertigo, imbalance, no weakness, gradual onset - normal imaging Inborn error metabolism (IEM) - pre-existing delays/regressions, multisystem disease, abnormal biochemical profile Acute cerebellar ataxia - sudden onset bilateral symmetric ataxia, post viral - normal imaging Channelopathy - syndromic, not localised, gradual - normal imaging Alternating hemiplegia - history of contralateral events, choreoathetosis, dystonia - normal imaging

Answer 31

1. Key points a. Conditions that affect the speed, fluency, quality and ease of movement b. Usually affect TONE and POSTURE c. Generally restricted to disorders secondary to pathology in the brain i. Basal ganglia – extrapyramidal [generally pathology in BG referred to as ‘movement disorder’] (involuntary) ii. Corticospinal – pyramidal (voluntary) iii. Cerebellum d. What do BG do? i. Set up the muscle tone and posture upon which voluntary movements can occur ii. Extrapyramidal and pyramidal work together to produce normal movements iii. Basal ganglia also involved with behaviour and cognition ie. psychiatric disturbances may co-exist (think Tourettes/ Huntington’s/ Parkinson’s) 2. Classification a. Abnormal movements may be divided into i. Voluntary and involuntary ii. Positive and negative 3. Neurotransmitters involved a. Acetylcholine b. Dopamine c. GABA d. Glutamine e. Substance P 4. Aetiology a. Infections = primary, parainfectious, autoimmune b. Ischaemia = HIE, stroke c. Trauma d. Tumours = neoplastic, paraneoplastic e. Metabolic = neurotransmitter disorders, mitochondrial, Wilsons, PKAN f. Autoimmune = SLE g. Medications = anticonvulsants, antipsychotics 5. Positive movement disorders (hyperkinetic) - rhythmic = tremors - athetosis (nonrhythmic, slow) - dystonia (nonrhythmic, sustained) - tics (nonrhythmic, rapid, suppressible) - hemiballismus, chorea, myoclonus (nonrhythmic, rapid, nonsuppressible) 6. Negative (bradykinetic) a. Rigidity = inability of the muscles to relax normally b. Akinesia = inability to initiate movement c. Hypokinesia = reduction in the amount of spontaneous movement d. Bradykinesia = slowness of movement

Answer 32

Dyskinesia is a general term for any abnormal involuntary movement. Akinesia means absence of movement. Bradykinesia means slowness of movement. Hypokinesia means decreased amplitude or range of movement. Hyperkinesia refers to an increase in muscular activity that can result in excessive abnormal movements, excessive normal movements or a combination of both. Hyperkinesia is a state of excessive restlessness. Tremor is an oscillation that is usually rhythmical and regular that affects one or more body parts, such as the arms, legs, neck, tongue, chin or vocal cords. Tremor is produced by rhythmic alternating or simultaneous contractions of opposing muscles.

Answer 33

• Frequently accompanied by rigidity, postural instability, and loss of automatic associated movements • Include: o Parkinson disease o Wilson disease o Huntington disease o Neurodegeneration with iron accumulation

Answer 34

1. Key points a. Nonrhythmic, jerky, rapid + nonsuppressible movements, primarily in distal muscles or face. b. Occurs both at rest and with action c. Increase with stress and disappears with sleep d. Primary and secondary causes 2. Causes a. Primary i. Huntington’s disease – rarely presents in childhood ii. Neuroacanthocytosis iii. Ataxia telangiectasia iv. Spinocerebellar ataxia b. Acquired i. Sydenham chorea ii. Autoimmune = SLE, NMDA iii. Endocrine = Hyperthyroidism, hypoparathyroidism iv. Wilson disease v. CNS infections - toxoplasmosis, Neurosyphilis, viral encephalitis vi. Structural lesions in basal ganglia – stroke, mass lesions, multiple sclerosis vii. Toxins viii. Medications – AED, antipsychotics 3. Treatment a. Valproate b. BDZ c. Haloperidol d. Chlorpromazine e. Penicillin

Answer 35

Uptodate: Athetosis is defined as "a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture" and thus represents a form of slow chorea. 1. Key points a. Slow, writhing movements that involve the same body parts b. May occur at rest c. Worsened by voluntary movement d. Usually occurs in conjunction with chorea or dystonia 2. Causes a. HIE (CP) b. PKU c. Metabolic = Wilsons, PKU, Niemann-Pick, PKAN d. Mitochondrial = Leigh disease e. Kernicterus f. Medications

Answer 36

Uptodate: Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both; dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. 1. Key points a. Non-rhythmic, sustained muscle contraction (unbalanced), frequently causing distorted body posture  patterned, twisting, tremulous b. WORSENED by voluntary action 2. Causes a. Primary (inherited dystonias) i. Idiopathic torsion dystonia (DYT1) ii. Paroxysmal torticollis iii. Segawa disease (DRD) (DYT5a, dopamine responsive) iv. Paroxysmal b. Secondary i. HIE - CP -> 10-15% have dyskinetic form with dystonia and chorea rather than spasticity ii. Huntington iii. PKAN iv. Wilson v. Niemann-Pick vi. Glutaric aciduria vii. Medications viii. Hyperthyroidism Metabolic disorders: disorders of monoamine neurotransmitter metabolism, Wilsons, pantothenate kinase associated neurodegeneration (PKAN) Treatment - trial levodopa (?dopamine responsive dystonia -> if effective, continue), if no response: - botox can be used for focal dystonia - anticholinergics (eg benztropine) - can add benzodiazepine (clonazepam, diazepam, baclofen) - surgical options e.g. deep brain stimulation h. When you think functional, think dystonia when you think dystonia, think functional

Answer 37

Dopamine blocking agents, antipsychotics, antiemetics Acute dystonic reactions - within days of starting medication - torticollis, oculogyric crisis (characterized by a prolonged involuntary upward deviation of the eyes), tongue protrusion, laryngospasm Neuroepileptic malignant syndrome - within a few days of starting/increasing or following withdrawal of med - fever, tachycardia, diaphoresis, delirium, dystonia Tardive dyskinesia - chronic (3+ months of use) - much less frequent in children - causes repetitive, involuntary movements, such as grimacing and eye blinking

Answer 38

1. Types a. Static/Resting tremor i. Present at rest, disappears with action ii. Causes: Wilson’s, Parkinson’s, Huntington’s, Hallervorden-Spatz b. Postural tremor i. Most notable when arms outstretched forwards, but can occur through a range of movement/during goal-directed activity ii. Causes: thyrotoxicosis, pheochromocytes, familial/essential tremor, physiological tremor, Wilson’s disease c. Intention tremor i. Marked at end points of movement, but not present during course of movement ii. Causes: cerebellar disease (including Wilson’s disease) 2. Causes a. Benign essential b. Drugs = amphetamines, valproate, TCAs, caffeine, SSRIs i. Amphetamines ii. Valproate iii. TCAs iv. Caffeine v. SSRIs c. Metabolic/endocrine i. Hypoglycaemia, hypocalcaemia, hypoMg, B12 deficiency ii. Hyperthyroidism iii. PKU, galactosaemia d. Degenerative diseases i. Mitochondrial diseases eg. Leigh syndrome ii. Wilson’s disease iii. Ataxia telangiectasia iv. Juvenile PD e. Peripheral neuropathies eg. SMA f. Psychogenic and medically unexplained g. Bobble-headed doll- IIIrd V lesions h. Spasms nutans - episodic abnormal head posturing with nystagmus 3. Treatment a. Beta blockers b. Clonidine Primadone c. DBS (Deep brain stimulation)

Answer 39

Key points - 5% prevalence, 50% AD, variable presentation Manifestations - most commonly affects distal upper extremities - most apparent at end of goal directed activity (drinking glass of water, finger-nose) and disappears at rest - begins in childhood, slowly progressive Diagnosis Core criteria - bilateral action tremor of hands/forearms, not present at rest - absence of other cognitive signs - may have isolated head tremor with no signs of dystonia - seondary criteria: long duration >3 years, positive famhx, beneficial response to alcohol Treatment - propranolol sometimes used

Answer 40

1. Key points a. Non rhythmic, rapid, nonsuppressible shock like twitches b. Can be cortical + subcortical 2. Causes a. Physiological (sleep) b. Epilepsy c. HIE d. Autoimmune i. Opsoclonus/ myoclonus e. Metabolic i. Tay Sachs ii. Wilsons iii. NCL iv. Mitochondrial f. Medications 3. Management a. Benzos b. Valproate c. Keppra

Answer 41

1. Key points a. Idiosyncratic, non-rhythmic, rapid, suppressible and repetitive movements b. Usually diminished in sleep 2. Causes a. Idiopathic i. Simple ii. Tourette = vocal and motor b. Secondary i. Sydenham chorea ii. Post HIE iii. Medications 3. Treatment a. Reassurance b. Clonidine c. Haloperidol d. Pimizoide 4. The main disabilities in tic disorders are not tics

Answer 42

Key points - 5/10,000 M>F, usually presents <7years Diagnosis - multiple vocal and motor tics, nearly every day for >1 year, no more than 3 months tic free Associations - ADHD (50%), OCD (30%), ODD (15%), learning disorder (25%) Treatment - antidopaminergics (fluphenazine, risperidone, tetrabenazine) - alpha adrenergic agonist (clonidine) - topiramate - botox - habit reversal thinking

Answer 43

1. Key points a. Nonrhythmic, rapid, nonsuppressible violent / flinging movements b. Usually unilateral c. Often proximal arm 2. Definitions a. Chorea = ongoing random appearing sequence of movement fragments b. Athetosis = slow continuous involuntary writhing movement c. Ballismus = chorea that effects proximal joints such as the shoulders/ hips  large amplitude movements of the limbs with flinging/ flailing quality 3. Causes a. Physiologic – chorea normal up until 8 months of age b. Cerebral palsy c. Sydenham Chorea: 1-8 months post infection d. Inherited i. Huntington disease ii. Benign hereditary chorea: AD disorder, mutations in NKX2-1 gene iii. Lesch Nyhan syndrome: X linked disorder of purine breakdown, leading to excessive uric acid – choreathetosis, spasticity, chorea, biting and aggressive behaviours

Answer 44

1. Key points a. Ataxia = disturbance in the smooth, accurate coordination of movement i. Most commonly manifested as an unsteady gait b. Usually results from cerebellar dysfunction c. Most common causes i. Acute cerebellar ataxia – most common ii. Drug intoxication iii. Guillain-Barre 2. Aetiology a. Life-threatening i. Tumours – particularly posterior fossa ii. Intracerebral haemorrhage iii. Stroke iv. Infection 1. Cerebellar abscesses (contiguous spread from otitis media or mastoiditis) 2. Brainstem encephalitis – rare cause with high morbidity a. Causes include Listeria monocytogenes, Lyme disease, EBV and HSV 3. ADEM b. Common conditions i. Acute cerebellar ataxia ii. Guillain-Barre syndrome iii. Toxic exposure iv. Labyrinthitis v. Migraine syndromes and BPPV vi. Trauma 3. Evaluation a. History b. Examination i. Bulging anterior fontanelle  raised ICP ii. Ipsilateral head tilt  posterior fossa tumour iii. Nystagmus  vestibular, cerebellar or brainstem disorders; opsoclonus associated with neuroblastoma iv. Otitis media and hearing loss  acute labyrinthitis v. Meningitis  CNS vi. Healing rash/ viral exanthem  antecedent infection vii. Cerebellar signs c. Investigations i. Toxicological screen ii. BSL iii. Metabolic iv. CSF v. Imaging

Answer 45

vii. Cerebellar signs 1. Wide based, unsteady, lurching or staggering gait 2. Dysarthria 3. Difficulty maintaining truncal position – titubation 4. Dysmetria – finger nose 5. Dysdiadochokinesia – difficulty with rapid alternating movements 6. Vermis (midline) = dysarthria, truncal titubation, gait abnormalities 7. Cerebellar hemispheres = ipsilateral limb dysmetria, hypotonia, tremor; veer to the affected side on walking

Answer 46

1. Key points a. Occurs in children 1-3 years of age b. Diagnosis of exclusion; classically i. Rapid onset of symptoms ii. History of prodromal illness iii. Absence of signs suggesting alternative diagnosis c. Thought to represent an autoimmune response affecting the cerebellum 2. Clinical manifestations a. Symptoms i. Often follows a viral illness (eg. varicella, coxsackie) by 2-3 weeks ii. Sudden onset truncal ataxia – child often unable to stand or sit iii. Vomiting may occur initially – fever and nuchal rigidity absent b. Signs i. The gait is typically wide-based, unsteady, lurching, or staggering. ii. Speech abnormalities such as fluctuations in clarity, rhythm/fluency, tone, and volume may occur. iii. Posture while sitting unsupported may be difficult to maintain, with corrections and oscillations (titubation) iv. Coordination and targeting of voluntary movements may be impaired, as seen on finger-nose testing (dysmetria) and during rapid alternating movements (dysdiadochokinesia). v. Hypotonia, action tremor, and end-gaze nystagmus may also occur 3. Investigations a. CSF = usually normal, may have pleocytosis b. Brain imaging indicated if any atypical features 4. Natural history a. Ataxia improves in a few weeks b. May persist for as long as 3 month 5. Treatment a. Supportive b. Steroids and IVIG sometimes given 6. Prognosis a. Resolves without sequelae usually within 2-3 weeks

Answer 47

Ataxia telangiectasia Spinocerebellar ataxias Friedreichs ataxia

Answer 48

Uptodate: Hereditary ataxia has a variety of causes. One cause is an autosomal recessive disorder associated with defective DNA repair mechanisms: ataxia-telangiectasia (AT; MIM 208900). Patients with AT develop progressive cerebellar ataxia, abnormal eye movements, other neurologic abnormalities, oculocutaneous telangiectasias, and immune deficiency. 1. Key points a. Most common degenerative ataxia 2. Genetics + pathogenesis a. Autosomal recessive b. Mutation 12q22.3 – ATM gene (AT mutated) d. ATM is involved in detection of DNA damage and cell cycle progression e. In the absence of the supervisory function of ATM, cells can build up somatic mutations, possibly leading to malignant transformation f. Results in cerebellar atrophy

Answer 49

a. Main features i. Progressive cerebellar ataxia 1. Earliest clinical manifestation 2. Variable age of onset - <2 years 3. Unusually narrow base (cf. other causes of ataxia) 4. Loss of ambulation in adolescence ii. Abnormal eye movements 1. Oculomotor apraxia of horizontal gaze (difficulty fixating smoothly on an object) 2. Strabismus 3. Nystagmus iii. Neurological abnormalities iv. Oculocutaneous telangiectasias 1. Occur by mid-childhood 2. Located on bulbar conjunctivae, bridge of nose and exposed surfaces v. Immune deficiency 1. Cellular and humoral immunity 2. Decreased secretory IgA, diminished IgG2, Ig4 and IgE b. Other features i. Café au lait macules ii. Pulmonary disease 1. Recurrent sinuopulmonary infections and bronchiectasis 2. Interstitial lung disease/ pulmonary fibrosis 3. Neuromuscular disease iii. Malignancy 1. High risk of Lymphoreticular tumours + brain tumours iv. Radiation sensitivity v. Growth retardation vi. Diabetes mellitus

Answer 50

Uptodate: Diagnostic criteria for ataxia-telangiectasia Definitive diagnosis* Male or female patient with either increased radiation-induced chromosomal breakage in cultured cells or progressive cerebellar ataxia and who has disabling mutations on both alleles of ATM. Probable diagnosis* Male or female patient with progressive cerebellar ataxia and three of the following four findings: 1. Ocular or facial telangiectasia. 2. Serum IgA at least 2 SD below normal for age. 3. Alpha fetoprotein at least 2 SD above normal for age. 4. Increased radiation-induced chromosomal breakage in cultured cells. Possible diagnosis* Male or female patient with progressive cerebellar ataxia and at least one of the following four findings: 1. Ocular or facial telangiectasia. 2. Serum IgA at least 2 SD below normal for age. 3. Alpha fetoprotein more than 2 SD above normal for age. 4. Increased chromosomal breakage after exposure to irradiation. The diagnosis is established by identification of pathogenic variants on both alleles for the AT mutated gene (ATM). Another diagnostic method involves a rapid immunoblotting assay for ATM protein, which is severely depleted in most patients with AT. However, this procedure requires a large blood sample and is available in few laboratories.

Answer 51

1. Key points a. Over 30 different types b. Cerebellar ataxia a feature of each type c. 60-70% of individuals have mutations 2. Genetics a. Several types are associated with expansion of CAG repeats d. Results in a toxic ‘gain of function’ protein e. Greater number of alleles the earlier age of onset and more severe disease f. Anticipation occurs 3. Clinical manifestations a. Typically present in middle age with progressive ataxia, neuronal dysfunction + neuronal loss

Answer 52

1. Key points a. Most common hereditary ataxia 2. Genetics + pathogenesis a. AR b. Tripe GAA report in gene encoding for the mitochondrial protein frataxin c. Results in reduction in the production of frataxin protein d. Size of repeat correlates with complications of disease i. Normal <36 ii. Affected = 56-1300 e. Oxidative injury  excessive iron deposits in mitochondria f. Involves spinocerebellar tracts, dorsal columns in the spinal cord, pyramidal tracts 3. Natural history a. Average onset 10-15 years (2 – 60 ) b. Average age at death 37 years 4. Clinical features a. Ataxia i. Onset 10 years of age ii. Involves lower extremities > upper extremities iii. Romberg +ve, absent tendon responses iv. Posterior column dysfunction = marked loss of vibration and position sense v. Upgoing plantars + loss of lower limb reflexes b. Dysarthric speech c. Nystagmus d. Preserved intelligence e. Skeletal malformations – eg pes cavus, hammertoes, kyphoscoliosis f. Hypertrophic cardiomyopathy g. Diabetes mellitis 5. Investigations a. Genetic testing b. Neuroimaging 6. Management a. Antioxidant therapy with coenzyme Q10 b. Vitamin E

Answer 53

1. Key points a. Clinical syndrome that mimics brain tumours and is characterised by: i. Increased ICP = > 250 mmH2O in non-obese, non-sedated children with a normal CSF cell count and protein content ii. Normal to slightly decrease ventricular size iii. Normal CSF cell count and protein content iv. Normal ventricular anatomy and position b. Papilledema is universally present if child old enough to have a closed fontanelle 2. Risk factors a. Recent weight gain b. Medications 3. Aetiology (IDIOPATHIC, but associated with): a. Haematological = Wiskott-Aldrich syndrome, polycythaemia, aplastic anaemia etc b. Infections = acute sinusitis, otitis media etc c. Drugs = tetracyclines, nalidixic acid, doxycycline, nitrofurantoin, isotretinoin, growth hormone etc. d. Renal = nephrotic syndrome e. Nutritional = hypovitaminosis A, vitamin A intoxication f. CT disorders = antiphospholipid syndrome g. Endocrine = menarche, PCOS, hypothyroidism h. Other = dural venous sinus thrombosis, obesity, head trauma i. Possible associations = CF, cystinosis, Down syndrome

Answer 54

Uptodate: Symptoms ●Headache (84 to 92 percent) ●Transient visual obscurations (68 to 72 percent) ●Intracranial noises (pulsatile tinnitus; 52 to 60 percent) ●Photopsia (48 to 54 percent) ●Back pain (53 percent) ●Retrobulbar pain (44 percent) ●Diplopia (18 to 38 percent), typically from nonlocalizing sixth nerve palsy ●Sustained visual loss (26 to 32 percent) ●Neck pain (41 percent) Examination — The most common signs in IIH are: ●Papilledema ●Visual field loss ●Sixth nerve palsy 4. Clinical manifestations a. History i. Chronic (weeks to months), progressive, frontal headache – may worsen with postural change or Valsalva ii. Vomiting – rarely as persistent and insidious as that associated with posterior fossa tumour iii. Transient visual obscuration lasting seconds and diplopia (secondary to dysfunction of the CNVI nerve) iv. Alert, lack constitutional symptoms b. Examination i. Infant – bulging fontanelle and ‘cracked pot sound’ (percussion results in resonant sound) ii. Papilledema – with enlarged blind spot present in those with closed fontanelle iii. Visual field loss – with enlarged blind spot present in those with closed fontanelle 1. Typically peripheral visual field loss 2. Central visual field loss late in the course iv. Visual acuity loss – occurs AFTER visual field loss v. CNVI palsy vi. Focal neurology  prompt Ix to uncover process other than pseudotumour cerebri 5. Investigations Uptodate: MRI, LP, ophthal exam

Answer 55

6. Treatment The treatment of IIH has two major goals: the alleviation of symptoms (usually headache) and the preservation of vision. a. Treat underlying cause i. Weight loss regimen = if obese ii. If drug associated = discontinue offending drug iii. Sinus thrombosis – anticoagulation b. LP = initial LP that follows CT or MRI which is diagnostic is often therapeutic i. Several additional LP and the removal of sufficient CSF to reduce the opening pressure by 50% occasionally leads to effective resolution c. Medications i. Carbonic anhydrase inhibitor: Acetazolamide 10-30 mg/kg/24 hour – effective ii. Corticosteroids – not routinely given, however may be used if severe ICP elevation who is at risk of losing visual function and is awaiting decompression d. Surgery = rarely VP shunt or sub-temporal decompression necessary e. Surveillance i. Serial monitoring of visual function – acuity, colour vision, visual fields ii. Serial optic nerve examination iii. Serial visual-evoked potentials – useful if visual acuity cannot be reliably documented 7. Prognosis a. Can be a self-limited treatment, however optic atrophy and blindness are the most significant complications if left untreated

Answer 56

1. Definition: Childhood primary angiitis of the CNS (cPACNS) = a. Newly acquired focal and or diffuse neurological deficits and/or psychiatric symptoms in a child b. Angiographic and or histological evidence of vasculitis, in the absence of c. Systemic underlying condition known to mimic findings 2. Classification a. Primary CNS vasculitis i. Large/medium vessels = diagnosed on angiography 1. Monophasic 2. Non-progressive (NPcPACNS) 3. Progressive (PcPACNs) ii. Small vessel (SVcPACNS) = angiography negative + brain biopsy positive 1. Progressive illness b. Secondary CNS vasculitis - infectious (viral, bacterial, fungal, parasitic) - systemic vasculitidies - connective tissue disease - drug induced, other inflammatory conditions c. Autoimmune encephalitis i. Intracellular Ag ii. Receptor/cell surface Ag

Answer 57

a. Clinical evaluation = newly acquired symptoms or deficit in previously healthy child i. Focal neurological deficit ii. Seizures or refractory seizure status iii. Diffuse neurological deficit including cognitive decline with loss of higher exectuve function, concentration difficulties, learning/memory problems, behavior or personality changes, loss of social skills iv. Headaches v. Meningitis symptoms, abnormal level of consciousness vi. Pyschiatric symptoms including hallucinations, pseudoseizures vii. DDx – underlying illness known to cause or mimic CNS vasculitis b. Laboratory tests i. Inflammatory markers (CRP, ESR, FBE) ii. Endothelial markers = vWF antigen  proposed biomarker of vasculitis correlating closely with disease activity in cPACNS iii. CSF inflammatory markers and opening pressure iv. DDx 1. Infections/post infectious inflammation – cultures, serology 2. Autoimmune encephalitis – check neuronal antibodies in CSF and blood 3. Systemic inflammation/rheumatic disease – characteristic laboratory markers such as complement, autoantibodies 4. Thromboembolic conditions – procoagulant profile c. Imaging i. Parenchymal imaging on MRI 1. Inflammatory lesions = T2/FLAIR sequence plus gadolinium (contrast enhancement) 2. Ischaemic lesions = diffuse weighted ii. Vessel imaging d. Brain biopsy Small vessel (SvCPACNs): Gender: Girls of all ages Hallmark feature: Seizures Inflammatory markers: Majority mildly raised CSF: Abnormal in 90% Oligoclonal bands: 20% Neuroimaging: MRI lesions in children with SVcPACNs are not restricted to any territories; lesions are primarily inflammatory and may enhance with contrast Vessel wall imaging often normal in SVcPACNs Brain biopsy: Often required - Characteristic findings include intramural and/or perivascular mononuclear infiltrate, evidence of endothelial activation, and reactive astrocyte formation ``` Medium/large vessel cPACNs Gender: Male Hallmark feature: Stroke like features Inflammatory markers: >50% have normal inflammatory markers at presentation CSF: Abnormal in <50% Oligoclonal bands: - Neuroimaging: Evidence of vessel stenosis on angiography confirms large/medium cPACNs Brain biopsy: Not required ```

Answer 58

5. Treatment a. Two aspects i. Corticosteroids = the mainstay of treatment – IV pulse therapy usually given initially ii. Antithrombotic therapy = particularly important for large/medium vessel cPACNs as high risk for recurrent events b. Non-progressive cPACNs = monophasic inflammatory attack with the highest risk of poor outcome i. Vessel wall inflammation causes several proximal stenoses and a high re-stroke risk ii. High dose corticosteroids iii. Second line immunosuppressives often given iv. Antithrombotic therapy essential c. Progressive cPACNs and SVcPACNs = considered chronic vasculitis i. Long-term immunosuppression = high dose corticosteroids  taper; other agents (eg. cyclophosphamide, mycophenolate) also used 6. Prognosis a. Mortality for cPANS has significantly improved b. Children presenting with status epilepticus and SVcPANS have the poorest prognosis

Answer 59

``` HIV Lead Burns (5%, no cause identified, supportive) Hypertensive Radiation Acute necrotising Autoimmune Demyelinating (ADEM) ```

Answer 60

a. Commonly associated with renal disease in children b. Can sometimes be the initial manifestation of renal disease c. Pathogenesis = marked systemic HTN produces vasoconstriction of cerebral vessels  areas of focal edema and haemorrhage d. Clinical features i. Onset can be acute – seizures, coma ii. Or more indolent onset – headache drowsiness and lethargy, nausea and vomiting, blurred vision, transient cortical blindness and hemiparesis iii. Examination may show papilledema and retinal hemorrhage e. Posterior reversible leukoencephalopathy syndrome (PRES) = MRI shows increased signal intensity in the occipital lobe on T2 weighted images i. Can be seen in children without hypertension ii. In all circumstances manifests with generalised motor seizures, headache, mental state changes, visual disturbances

Answer 61

a. More likely in young patients who receive large daily doses b. Acute i. Pathogenesis = excessive injury damages endothelium  enhanced vascular permeability, cerebral edema and hemorrhages ii. Clinical features = Irritability and lethargy, c/o headache, focal neuro signs and symptoms or seizures iii. Treatment = steroids are often helpful in reducing cerebral edema c. Late i. Characterised by headaches and slowly progressive neurologic signs including hemiparesis and seizures ii. Exposure of the brain to radiation for treatment of childhood cancer increases the risk of later CV disease – stroke, Moyamoya disease, aneurysm, vascular malformation, mineralizing microangiopathy, stroke-like migraines iii. Some children with ALL treated with intrathecal MTX develop neurologic signs months or years later

Answer 62

a. Rare, severe encephalopathy b. More common in Asian countries c. Triggered by viral infection – HHV6, influenza d. Genetically susceptible host e. Elevation of hepatic enzymes WITHOUT hyperammonaemia is a unique feature f. Familial recurrent form associated with mutations in RANBP2 gene g. MRI findings are characterised by symmetric lesions in the thalami h. Prognosis is poor i. Treated with steroids + IVIG

Answer 63

1. Background/Overview a. Encephalitis = inflammation of the brain parenchyma b. Classification = infectious vs autoimmune c. Autoimmune encephalitis should be suspected in any persons who present with an acute encephalopathy with behavioural change, seizures, dystonia or dyskinesia d. Clinical manifestation = encephalopathy with persistent ACS, fever, seizures and/or focal neurological deficits e. Early recognition and treatment with immunotherapy shortens illness duration and improves outcome 2. Pathogenesis a. Autoimmune encephalitides = pathogenic autoantibodies target synaptic or cell-surface proteins expressed on neurons within the CNS, disrupting neurotransmission leading to the clinical features observed b. Described syndromes of autoimmune encephalitis have been associated with autoantibodies against: i. N-Methyl-D-Aspartate receptor (NMDAR) ii. Voltage-gated-potassium-channel complex (VGKC), which includes: 1. Leucine-rich glioma inactivated 1(LGI1) 2. Contactin associated protein 2 (CASPR2) iii. Glycine receptor (GlyR) iv. Glutamic acid decarboxylase (GAD) v. AMPA receptor (AMPAR subunits GluR1/2) vi. GABA type B receptor (GABABR1) 5. DDx a. Infection = HSV, VZV, Enterovirus, Mycoplasma pneumoniae, Influenza, EBV, CMV, HHV6, Japanese B encephalitis b. Demyelination = acute disseminated encephalomyelitis c. Rheumatic/post-streptococcal movement disorder (Sydenham's chorea) d. Neurologic manifestations of systemic lupus erythematosus e. Hashimoto's encephalopathy (rare) f. Cerebrovascular event (thromboembolic, haemorrhagic or vasculitic) g. Intracerebral mass/structural lesion

Answer 64

3. Principles of diagnosis a. Phenotypic features allow clinical suspicion but are not sensitive or specific b. Detection of the autoantibody in serum or in CSF confirms diagnosis – CSF more sensitive 4. History and examination a. Important aspects of history i. Tempo and onset of symptoms ii. Behavioural change 1. Younger children: tantrums, irritability, agitation 2. Older children (>12): hallucinations, bizarre behaviour, acute psychosis iii. Abnormal movements noted by parents/carers 1. Dystonic posturing 2. Involuntary movements a. Can persist through sleep b. Can affect face (eg orolingual dyskinesia) or peripheries c. Can be unilateral or bilateral iv. Seizures = temporal lobe (HSV or limbic encephalitis), focal, generalised v. Sleep disturbance = insomnia or hypersomnolence vi. Speech or language difficulties vii. Prodrome = fever, headache, N+V, diarrhoea, upper respiratory symptoms in the preceding 1-2 weeks viii. Toxins exposure ix. Immunodeficiency = at risk for infections including HSV, CMV, EBV, HHV6 b. Important aspects of examination i. Mental state and signs of encephalopathy ii. Movement disorder and dystonic posturing 1. Involuntary movements at rest and during activity 2. Apparent extensor plantar response without fanning of the toes ('Striatal toe') iii. Language, speech and communication 1. Decreased spontaneous speech, perseverating speech iv. Vital signs (Heart rate, blood pressure, respiratory rate) v. Focal neurological deficits vi. The presence of pyramidal signs (voluntary movement

Answer 65

a. Bloods/other i. Basic bloods: FBE, UEC, CMP, LFT, CRP, ESR, coagulation profile ii. Serum oligoclonal bands (paired with CSF oligoclonal bands) iii. Antibodies 1. Anti-NMDAR antibodies and anti-voltage-gated-potassium-channel (VGKC) antibodies 2. Anti-neuronal antibodies 3. ANA 4. Streptococcal serology (ASOT and Anti-DNase B) (follow-up serology required) 5. Other autoantibodies associated with encephalitis: a. anti-GAD Ab, anti-GlyR Ab, anti-AMPAR Ab, Anti-GABABR1 Ab b. Anti-dsDNA, anti-cardiolipin antibody (if ANA positive and lupus suspected). c. Anti-thyroid antibodies, anti-thyroglobulin antibodies, TSH iv. Ammonia, lactate, pyruvate v. Store serum b. Neuroimaging i. Imaging (MRI-brain) should be performed in ALL CHILDREN to exclude differential diagnoses ii. MRI-brain is non-diagnostic in 50-80% c. LP i. Lymphocytic pleocytosis and increased protein is usually seen ii. Also test for: 1. Oligoclonal bands 2. PCR: HSV, Enterovirus, Mycoplasma pneumoniae and others as clinically appropriate. 3. CSF autoantibody assay may be required, particularly if autoantibody not detected in serum d. EEG i. Should be performed if clinically encephalopathy or if seizures present ii. May have no abnormalities at onset, progressing to widespread ictal and interictal epileptiform activity in the early stages  generalised diffuse, dysrhythmic, high amplitude slowing with no clinical correlate iii. An extreme delta brush pattern has been associated with this disorder e. Other = pelvic and abdominal ultrasound = for girls if anti-NMDAR antibodies detected, to exclude presence of an ovarian teratoma (infrequently associated)

Answer 66

7. Treatment a. Specific treatments i. Treatment for infectious encephalitis until proven otherwise (IV antibiotics and antivirals) ii. Immunotherapy once diagnosis confirmed or strongly suspected: 1. IVIG 1 g/kg/day for two days, AND 2. IV Methylprednisolone 30mg/kg/day (maximum 1g/day) for five days  oral pred taper (3 mo) 3. If no response after 10 days, consider: a. IV Rituximab 375mg/m2 (round off to nearest 100mg) weekly for four weeks b. Cyclophosphamide or another immune-modulatory treatment may be considered. iii. Removal of ovarian teratoma if present (within 4 months of presentation) iv. Anticonvulsants should be commenced to manage recurrent seizures v. Sleep disturbance and agitation can be managed by use of melatonin or chloral hydrate vi. Small doses of benzodiazepines and chloral hydrate can be considered for periods of extreme agitation, with consideration of risperidone if ineffective b. General measures i. Behavioural and environmental modification to minimise agitation. ii. Consultation-liaison psychiatry may be involved for management of psychiatric features. iii. Monitor oral intake and nutrition. iv. Appropriate involvement of allied health and rehabilitation specialists. v. Physiotherapy, occupational therapy, speech therapy, social work 8. Outcome a. Improvement can be slow, over months, but complete recovery can occur b. Children should have regular follow up and tumour surveillance annually for 2 years i. Small risk of relapse in 15-20%. ii. Abdominal/pelvic imaging should be considered if there are features of relapse.

Answer 67

a. Pathogenies i. IgG antibodies bind to the NR1 (or less commonly NR2) subunit of NMDAR, prompting the receptors to be internalised into the neuron ii. As neurotransmitters glutamate and glycine can no longer bind to the receptor, the GABAergic neurons are functionally inactivated and excitatory pathways are disinhibited b. Epidemiology i. Most common autoimmune encephalitis affecting both adults and children ii. Considered 2nd most common cause of encephalitis after ADEM iii. Predominates in females (80%) and those >12 years (although in patients <12 years males more common) f. Cause i. Teratoma association 1. 40% of females >12 year have underlying teratoma of ovary (6% of children <12 years) 2. In boys the presence of underlying tumour exceptional 3. MRI abdomen + USS = to screen for teratoma ii. Infections 1. In a small number of patients occurs simultaneously or after infections with a variety of pathogens, including Mycoplasma pneumoniae, HSV, enterovirus and influenza

Answer 68

c. Clinical presentation – based on phase: i. Prodrome in 50% ii. Early phase 1. Frontostriatal features (psychosis, behavioural change, short term memory impairment) 2. Movement disorder (hyperkinetic choreoathetosis or catatonia) 3. Dystonia 4. Seizures 5. Sleep disturbance iii. Late phase 1. Language disintegration (echolalia, mutism) 2. Autonomic instability 3. Breathing dysfunction, hypoventilation 4. Enuresis, urinary incontinence 5. Episodes of tachycardia, hyperthermia, hypertension d. Clinical presentation – based on age: i. Teenagers and young adults 1. Prominent psychiatric manifestations that may include rapidly progressive anxiety, agitation, delusional thoughts, bizarre behavior, labile affect, mood disturbances (mania), catatonic features, memory deficit, language disintegration, aggression, catatonic features, sleep disturbance 2. May be preceded by a few days of prodromal headache, fever or viral like symptoms 3. Can be mis-diagnosed as new onset psychiatric disorder 4. Further symptoms – decreased LOC, seizures (including status), limb or oral dyskinias, choreoathetoid movements, and autonomic instability (tachy, brady, BP fluctuation, hypoventilation, hypertherimia, and Sialorrhoea) ii. Toddlers and infants 1. Motor or complex seizures and movement disorder 2. Psychiatric behavioural features may be missed – may have temper tantrum, agitation, aggression, reduced speech, mutism, autistic-like regression 3. Cerebellar ataxia and hemiparesis 4. Autonomic dysfunction milder and less frequent

Answer 69

e. Investigations i. MRI-B = abnormal in 35% of cases ii. CSF = abnormal in 80%; moderate lymphocytic pleocytosis, less frequently increased protein synthesis and oligoclonal bands iii. EEG = abnormal in all patients, focal or diffuse slowing, characteristic ‘extreme delta brush’ iv. NDMA receptor Ab present in CSF or serum – sensitivity higher in CSF compared with serum (100% vs 85%); level of autoantibodies in the CSF correlate to outcome – may remain detectable after the patient recovers g. Treatment i. Teratoma removal ii. Corticosteroids IVIG, plasma exchange iii. Rituximab – increasingly being used iv. Cyclophosphamide – has also been used h. Prognosis i. Mortality rate 7% ii. Full or substantial recovery in 75-80% 1. Slow recovery, can take as long as 2 years 2. Last symptoms to improve are social interactions, and language and executive function 3. Relapse occurs in 15-25% of patients – respond to immunotherapy

Answer 70

a. Defined by the detection of thyroid peroxidase (TPO) Ab in patients with acute or subacute encephalitis that responds to corticosteroids b. 50% have normal thyroid function c. Clinical features = stroke-like symptoms, tremor, myoclonus, transient aphasia, sleep and behavioral abnormalities, hallucinations, seizures, ataxia d. Investigations i. CSF = elevated protein, less frequent pleocytosis ii. EEG = abnormal with generalised slowing iii. MRI =usually normal iv. TPO antibodies can occur in asymptomatic children

Answer 71

a. Occurs in infants, teenagers and adults b. Infants i. Develops in the first 2 years of life (mean 20 months) ii. 50% have neuroblastoma iii. Clinical presentation = irritability, ataxia, falling, myoclonus, tremor and drooling iv. Additional symptoms = refusal to walk or sit, speech problems, hypotonia, typical features of opsoclonus (rapid, chaotic, multidirectional eye movement without saccadic intervals) v. May be diagnosed as acute cerebellitis vi. CSF = B cell activation and antibodies against neuronal Ag vii. Treatment = immunosuppressive (corticosteroids, IVIG, rituximab, cyclophosphamide) viii. Prognosis 1. Eye movements improve with immunosuppression 2. Residual behavioral, language and cognitive problems 3. Relapse occurs in 50% of patients due to intercurrent infection or drug tapering 4. Removal of tumour should NOT delay immunosuppression c. Teenagers and young adults i. Often considered idiopathic or post-infectious ii. Some patients do have underlying teratoma iii. CSF = pleocytosis and elevated protein iv. Treatment = immunosuppression v. Prognosis = patients usually have a full recovery and if present, removal of teratoma 1. Better prognosis than neuroblastoma associated opsoclonus, OR the paraneoplastic opsoclonus of older patients related to breast, ovarian or lung cancer

Answer 72

i. Inflammatory encephalopathy characterised by progressive refractory partial seizures, cognitive deterioration and focal deficits that occur with gradual atrophy ii. Frequently presents in 6-8 year old children, although adolescents and adults can be affected iii. Etiology unknown iv. Treatment = high dose steroids, IVIG, rituximab v. Only definitive treatment is functional hemispherectomy

Answer 73

i. Affects children who had normal development until 2-4 years of age ii. Develop Hyperphagia, weight gain, abnormal behavior, lethargy, outburst of euphoria and laughing, impaired concentration  autonomic dysfunction (abnormal pupillary responses, thermal dysregulation, GI dysmotility) and central hypoventilation iii. Cause unknown

Answer 74

1. Key points a. Beyond infancy the spinal cord ends at the level of L1 b. The position of the conus BELOW L2 is consistent with a congenital tethered spinal cord c. If the spinal cord is fixed at any point the normal movement is restricted  stretching of nerve roots i. Usually caused from a thickened filum terminale which attaches to the sacrococcygeal region ii. Can also result from occult spinal dysraphism (eg. lipomyelomeningocele, myelocystocele, and diastematomyelia) d. Tethered cord syndrome = severe pain or neurological deterioration associated with fixation 2. Clinical manifestations a. Occult spinal dysraphism b. Asymmetry of feet – smaller foot has a high arch and clawing of toes, no ankle jerk, atrophic calf (neuro-orthopedic syndrome) c. Acute deterioration manifested by urinary urgency, incontinence, deterioration in motor and sensory function, severe back pain 3. Investigations = MRI 4. Treatment = neurosurgery 5. Outcome = generally good outcome

Answer 75

1. Key points a. Rare form of occult spinal dysraphism – spinal cord is divided into 2 halves b. Type 1 = 2 spinal cords each with its own dural tube and separated by a spicule of bone and cartilage c. Type 2 = 2 spinal cords are enclosed in a single dural sac with a fibrous septum 2. Clinical manifestations a. May have subtle signs of neurological involvement – unilateral calf atrophy and a high arch to 1 or both feet b. Manifestations of tethered spinal cord c. May develop loss of bladder and bowel function, sensory and motor difficulties d. Back pain is common e. Cutaneous manifestations of dysraphism present in 90% - large, hairy, midline patch most common 3. Investigation = MRI 4. Treatment = neurosurgical

Answer 76

1. Key points a. Cystic distension of the spinal cord caused by obstruction of the flow of spinal fluid from within the spinal cord b. Classification i. Communicating syringomyelia = ventricular CSF communicates with the fluid within the spinal cord ii. Non-communicating syringomyelia = ventricular CSF does not communicate with the fluid within the spinal cord; occurs in the context of intramedullary tumours and obstructive lesions iii. Post-traumatic syringomyelia = injury followed by softening of the spinal cord c. Associated with Chiari anomalies in patients with EDS 2. Clinical manifestations a. Insidious onset b. Central cord syndrome: Damage to the central spinal cord and the orientation of spinal tracts from proximal to distal leading to selective involvement of upper rather than lower limb i. Numbness beginning in the shoulder in a cape-like distribution ii. Followed by atrophy and weakness of the upper extremities – with trophic ulcers of the hands in advanced cases c. Scoliosis = rapidly progressive d. Urgency and bladder dysfunction 3. Investigations = MRI 4. Treatment a. Determined by the underlying cause

Answer 77

1. Key points a. Rare in children 2. Classification a. Intra-medullary i. Arise within the spinal cord itself ii. 10% are malignant astrocytic tumours iii. Most are grade I or II tumours of glial or ependymal origin iv. Ependymomas in children are frequently associated with NF-2 b. Extra-medullary i. Intra-dural 1. Occur in NF-1 and NF-2 2. Most are nerve sheath tumours – schwannomas (NF1) or neurofibromas (NF2) 3. Intraspinal meningiomas are only found in patients with NF2 ii. Extradural 1. Primary tumour a. Aneurysmal bone cyst b. Langerhans cell histiocytosis c. Giant cell tumours 2. In infants – neuroblastoma or ganglioneuroblastoma 3. Clinical manifestations a. Dependent on site and obstruction of CSF

Answer 78

a. CSF is produced by the choroid plexus – present in lateral, 3rd + 4th ventricles i. Most comes from the lateral ventricles ii. 25% comes from extrachoroidal sources – eg capillary endothelium within brain parenchyma b. Production regulated by nervous system i. Adrenergic system stimulation  CSF production diminishes ii. Cholinergic system stimulation increases CSF production c. Normal pattern of flow i. Lateral ventricles ii. Through the foramen of Munro into the 3rd ventricle iii. Then goes via aqueduct of Silvius (very narrow) into 4th ventricle iv. Exits from 4th ventricle through paired lateral foramina and midline foramen into basal cisterns d. Reabsorption i. Primarily resorbed via arachnoid villi ii. To a lesser extent by lymphatic channels + choroid plexus

Answer 79

Hydrocephalus is a disorder in which an excessive amount of cerebrospinal fluid (CSF) accumulates within the cerebral ventricles and/or subarachnoid spaces, resulting in ventricular dilation and increased intracranial pressure (ICP). 2. Aetiology + Classification a. Obstructive = non-communicating i. Narrowed aqueduct of sylvius – has some rare associations 1. May be sex linked recessive trait 2. May be associated with neurofibromatosis 3. Occasionally have minor neural tube defects ii. Aqueductal gliosis iii. Neonatal meningitis (interrupted ependymal lining  gliosis which obstructs) iv. Intrauterine viral infection v. Vein of Galen malformation vi. Posterior fossa lesions (brain tumours, Chiari malformation, Dandy-Walker syndrome) b. Non-obstructive = communicating (obliteration of cisterns/ arachnoid villi) i. Subarachnoid haemorrhage ii. Pneumococcal/ tuberculous meningitis (may produce exudate that obstructs basal cisterns) 3. Clinical manifestations a. Infants i. Enlarged head ii. Open, bulging anterior fontanelle iii. Dilatation of scalp veins iv. Sunsetting eyes – due to impingement of dilated suprapineal recess on the tectum (midbrain) v. Disruption of corticospinal tracts -> brisk tendon reflexes, spasticity, clonus b. Older children i. Headache, irritability, lethargy

Answer 80

1. Classification a. Primary headaches i. Migraine ii. Tension type headaches iii. Trigeminal autonomic cephalgias b. Secondary i. Sinus ii. Raised ICP 2. Headache red flags a. Acute and severe b. Progressive chronic c. Focal neurology d. Age < 3 years e. Headache/vomiting on waking f. Consistent location g. Unusual location/pattern h. Presence of VP shunt i. Hypertension 3. Consider intracranial imaging in a. Abnormal neurology b. Meningism (consider LP) c. Marked changes in behaviour d. Symptoms of raised intracranial pressure e. Increasing frequency of undiagnosed headaches f. Onset of severe headache 4. Recurrent headaches a. Tension type (~50% incidence) i. Non-pulsatile band ii. Often end of day iii. Few associated symptoms b. Migraines (~25%): i. Pulsing pain ii. Nausea iii. Photophobia iv. Phonophonia v. Often unilateral 6. Red flags a. ‘Unusual headaches’ i. Occipital ii. Atypical auras iii. Trigeminal autonomic cephalgia b. Abnormal/ focal signs or symptoms c. Seizures or very brief auras d. Early morning vomiting e. Migraine present on waiting f. Change with posture / occur with cough/ bending over g. Migraines without a family history

Answer 81

1. Epidemiology a. 10.6% of children between 5-15, 28% of older adolescents b. Without aura more common in children c. 90% have family history 1. Differences in children a. May be shorter (1-72 hors) b. If child falls asleep, this sleep period is considered part of the duration c. More commonly bilateral d. Nausea and vomiting may be more prominent, associated with: i. Recurrent abdominal pain ii. Cyclic vomiting iii. Abdominal migraine iv. Note – children with these syndromes have a propensity to develop migraine

Answer 82

2. Diagnostic criteria a. Migraine without aura i. At least 5 attacks ii. Headaches lasting 4-72 hours (untreated or unsuccessfully treated) iii. Headaches with at least 2 characteristics – unilateral, pulsating, moderate-severe, aggravated by or causing avoidance of physical activity iv. During the headache at least 2 of 1. Nausea and/or vomiting 2. Photophobia or phonophobia v. Not attributed to another disorder b. Migraine with aura, typical i. At least 2 attacks ii. Aura consists of at least 1 of the following, but no motor weakness 1. Fully reversible visual symptoms 2. Fully reversible sensory symptoms 3. Fully reversible dysphasic speech disturbance iii. At least 2 of the following 1. Homonymous visual symptoms and/or unilateral sensory symptoms 2. At least 1 aura symptom develops gradually over >=5 minutes and/or different aura symptoms occur in succession over >= 5 minutes 3. Each symptom lasts >=5 and <=60 minutes iv. Headache as for migraine without aura – begins during aura or follows within 60 minutes v. Not attributed to another disorder 4. Other clinical features: a. Photophobia/ phonophobia may develop as the child ages b. Triggers may be present – skipping meals, dehydration, weather change c. Aura i. Typically lasts 5-60 minutes ii. Occurs within 60 minutes of headache starting iii. Most common aura in children is photopsia (flashes of light) iv. Sensory, dysphasic and atypical (hemiplegia/ vertical/ cranial nerve symptoms and distortion) symptoms are less common

Answer 83

a. Hemiplegic migraine i. Rare form of aura; transient unilateral weakness lasting for few hours-days ii. Associated with at least 3 identified genes b. Basilar type migraine i. Associated with vertigo, tinnitus, diplopia, blurred vision, scotoma (blind spot), ataxia and occipital headache ii. Pupillary dilatation and ptosis c. HaNDL ‘pseudomigraine’ – transient headache with neurologic deficits + CSF pleocytosis d. Childhood periodic syndromes i. Recurrent GI symptoms, sleep disorders ii. May be treated with migraine therapies

Answer 84

7. Investigations a. MRI = best sensitivity for posterior fossa lesions 8. Management a. Acute i. Supportive = hydration, dark room ii. Pharmacological = most effective if given earlier 1. NSAIDs = ibuprofen, naproxen, aspirin (older children) 2. Triptans (if >12 years) 3. Chlorpromazine 0.15 mg/kg IV in 1L normal saline a. Monitor for hypotension 4. Anti-emetics b. Preventative i. Indicated for frequency (> 1 / week) or disabling symptoms ii. Other indications 1. Frequent or long lasting migraine headaches 2. Migraine attacks that cause significant disability or diminished quality of life despite appropriate acute treatment 3. Contraindication to acute therapies 4. Failure of acute therapies 5. Serious adverse effects of acute therapies 6. Risk of medication overuse headache 7. Menstrual migraine iii. Aim is to reduce frequency to < 2 / month iv. Give prophylactic medications for at least 4-6 months then wean: 1. Flunarizine – only agent proven to be effective in trials a. Calcium channel blocker 2. Beta blockers a. Propranolol = the most common choice b. Contraindicated – asthma/ allergy/ depression , particularly effective in basilar type migraine with POTS 3. Cyproheptadine a. Antihistamine and serotonin antagonist with anticholinergic and calcium channel blocking properties b. Often used in young children who cannot take tablets – syrup 4. Amitriptyline 5. Anti-epileptics – few studies in children, Topiramate + valproate in adults v. Biofeedback therapy has been shown to be effective

Answer 85

50% of recurrent headaches 1. Clinical manifestations a. Mild to moderate in nature b. Diffuse in location “non-pulsatile band” c. Not affected by activity, often at the end of the day d. Tend to be ‘constant pressure’, less associated with nausea/photophobia/phonophobia e. CAN be recurrent – needs at least ten, lasting 30 minutes – 7 days 2. Management a. Acute i. Paracetamol ii. Nurofen b. Prevention i. Amitriptyline ii. Biobehavioural intervention

Answer 86

Congenital abnormality of the levator muscle - Levator function: Reduced - Eyelid crease margin: Crease often absent - Often unilateral - Many patients also have amblyopia, strabismus Aponeurotic ptosis - Levator function: Normal - Eyelid crease margin: Often increased - Uni- or bilateral - Isolated finding of ptosis Cranial nerve 3 palsy - Levator function: Reduced - Eyelid creases: Normal - Usually unilateral - Impaired extraocular movement in ipsilateral eye - If ipsilateral pupil dilated, urgent evaluation for aneurysm is required. Horner's syndrome - Levator function: Normal - Eyelid creases: Normal - Usually unilateral - Ipsilateral miotic pupil Myasthenia - Levator function: Reduced - Eyelid creases: Normal - Uni- or bilateral - Variable and fatigable - Diplopia and extraocular movement abnormalities often present Muscle disease - Levator function: Reduced - Eyelid creases: Normal - Usually bilateral - Orbicularis oculi, other extraocular or bulbar muscles may be affected Congenital Ptosis • Most often associated with absence or reduction of striated levator palpebrae superioris muscle • Unilateral (75%), neurologically and non-progressive • Can have a familial association – autosomal dominant trait

Answer 87

1. Key points a. Benign paroxysmal (positional) vertigo (BPV) is a disorder of early childhood manifested by recurrent episodes of brief disequilibrium b. A family history of migraine headaches is frequently present c. The neurologic examination is normal between episodes 2. Clinical manifestations a. During the attacks, the child appears frightened and off balance, often reaching out to steady him or herself b. The events may be associated with nystagmus, diaphoresis, nausea, and vomiting c. Older children will grab nearby persons or furniture for support to prevent falling and may complain of vertigo or dizziness d. Episodes usually last less than a minute and are not associated with an altered consciousness e. They usually recur in clusters, occurring daily for several days in a row, then remitting for several weeks, and recurring again 3. Natural history a. The disorder typically remits spontaneously by five years of age b. Many patients subsequently develop typical migraine headaches

Answer 88

Embryologic structure that becomes the cerebral hemispheres, gyri and sulci

Answer 89

Embryologic structure that becomes the thalamus and hypothalamus

Answer 90

Becomes the midbrain

Answer 91

Becomes the cerebellum and pons

Answer 92

Becomes the medulla

Answer 93

``` FRONTAL LOBE Function • Planning, executive function, inhibition • Precentral gyrus: motor cortex • Broca’s area (expressive speech) Impairment • Primitive reflexes • Anosmia • Gait apraxia • Dysphasia (expressive) ``` ``` PARIETAL LOBE Function • Postcentral gyrus: sensory cortex • Secondary sensory cortices • Speech = fluent, amnestic nominal Impairment • Dysphasia • Acalculia, agraphia, left right disorientation , finger agnosia • Neglect , inattention ``` ``` TEMPORAL LOBE Function • Auditory processing • Wernicke’s area (posterior temporal) • Semantic memory • Relationship to the hippocampus Impairment • Memory loss ``` ``` OCCIPITAL LOBE Function • Vision Impairment • Homonymous hemianopia ``` ``` CEREBELLUM Function • Coordination Impairment • Ataxia • Nystagmus • Dysdiadokinesis ```

Answer 94

HYPOTHALAMUS Function • Connects with the midbrain, limbic system (via anterior and medial temporal cortex) and autonomic nuclei • ‘Regulator’ hormones Impairment • Imbalances in temperature, sleep, salt/ water THALAMUS (Bunch of nuclei: Latera geniculate nuclei, Medial geniculate nuclei, Ventral anterior nucleus, Ventral lateral nucleus) Function • Largest part of the diencephalon • Projects to the cortex: receives input from basal ganglia -> motor cortex • Connect limbic areas of the cerebral cortex Impairment • Mixed • Loss of sensation in contralateral face and limbs ``` BASAL GANGLIA Function • Corpus striatum, substantia nigra (pars compacta and par reticularis), putamen, caudate nucleus • Output: medial globus pallidus, substantia nigra pars reticularis • Posture and movement Input zone Impairment • Choreathetosis • Dystonia, parkinsonism ``` PINEAL GLAND Function • Melatonin • Onset of puberty

Answer 95

Sheet of nerve fibres that extend between the cerebral cortex and subcortical stages

Answer 96

Cause: Tumour in the hypothalamic optic chiasmatic region (low grade glioma or astrocytoma) Features: - FTT, severe emaciation - Normal or increase caloric intake - Locomotor hyperactivity and euphoria - May have optic atrophy, nystagmus, tremor

Answer 97

Cause: pineal tumour Features: - vertical gaze nystagmus - pupils constrict poorly to light but react to examination

Answer 98

1. Key points a. Supply somatic and visceral motor and sensory information to head i. CNIX and X also supply visceral sensory and motor innervation to neck, chest and most abdominal organs b. Each cranial nerve is associated with a specific function or set of functions c. 12 pairs of cranial nerves listed I-XII 2. Anatomy a. Cranial nerve nuclei associated with brainstem are cranial nerves III to XII (I and II are not in brainstem) b. Exit brainstem in order (rostro-caudal) i. Most exit ventral surface except IV 3. Function a. Motor i. CNIII, IV, VI – control eye movements ii. CNXI, XII b. Sensory i. CNI, II, VIII c. Mixed i. CNV, VII, IX, X 4. Rule of 4 a. 4 cranial nerves exit medulla = CNIX, X, XI, XII b. 4 cranial nerves next the pons = CNV, VI, VII, VIII c. 4 exit above the pons = CNI [not in midbrain], II [not in midbrain], III, IV

Answer 99

CNI - olfactory - sensory - smell CNII - optic - sensory - vision CNIII - oculomotor - motor - external eye muscles / eye movement muscles (except superior oblique and lateral rectus) - parasympathetic fibres to ciliary muscle of eyeball for constriction and accommodation CNIV - trochlear - motor - superior oblique eye muscle CNV - trigeminal - mixed - sensory of the face, scalp, nasal/oral cavities - muscles of mastication - tensor tympani muscle CNVI - abducens - motor - lateral rectus muscle of eye CNVII - facial nerve - mixed - sensation: anterior 2/3 tongue taste - motor: muscles facial expression, stapedius - parasympathetic: salivary and lacrimal glands CNVIII - vestibulocochlear - sensory - hearing (cochlea) - proprioception and balance (vestibular apparatus) CNIX - glossopharyngeal - mixed - sensation: eustachian tube/middle ear, carotid body and sinus, pharynx and posterior 1/3 tongue - motor: styropharyngeus (swallowing) - parasympathetic: salivary glands CNX - vagus nerve - mixed - sensory: general thoracic/abdominal viscera + pharynx, larynx, external ear - motor: speech and swallowing -> soft palate, larynx, pharynx, oesophagus - parasympathetic: cardio/resp/GI CNXI - accessory - motor - sterno(cleido)mastoid, trapezius -> shoulder shrug CNXII - hypoglossal - motor - intrinsic/extrinsic muscles of tongue

Answer 100

* Structural = aim to define anatomical abnormalities  USS/ CT/ MRI * Functional = aim is to define areas of normal and abnormal brain (cortical function)  PET, SPECT, fMRI, MRS 1. USS a. Useful until 15 months – anterior fontanelle open b. Quick, easy, portable, no anaesthetic c. Can exclude major abnormalities 2. CT a. Picks up different tissue density b. Use contrast c. CT angiography – image vessels d. Better than MRI for bone 3. MRI a. Magnetic resonance imaging b. Advantage i. Best modality for 1. Structural injury 2. Inflammation 3. Ischaemia/ infarction ii. No bony artefact 1. Cerebellum 2. Brainstem 3. Spinal cord iii. No radiation c. Limitations i. Needs to be immobile ii. Takes longer than CT iii. Inferior to CT for – acute blood, calcium iv. Problems with ferromagnetic radiation d. Specific points i. <3 month – feed and wrap ii. 3m-6y – need anaesthesia or sedation iv. Paediatric brain not fully myelinated until 2 years 5. PET a. 3D image based on positron-emitting Radionucleotide biologically active trace b. FDG = fludeoxyglucose is the most commonly used racer in child neurology – seizure focus hypometabolic

Answer 101

a. T1 i. Best sequence to see anatomy and structure ii. CSF black / water dark iii. Grey matter grey/white matter white b. T2 i. Best sequence to see areas of inflammation/ edema ii. CSF white / water bright iii. Grey matter grey/white matter black (when myelinated) c. FLAIR i. Fluid attenuated inversion recovery ii. T2 with CSF signal suppressed – black iii. Best sequence to see inflammation/ edema close to CSF (eg. near ventricles, sulci) d. Diffusion i. Best sequence to see acute tissue injury ii. Describes in terms of restriction of diffusion iii. Changes within hours iv. Lasts for 10 days v. DWI = qualitative vi. ADC = quantitative f. MR angiography i. Best sequence to see major vessel (MR angio MR veno) ii. INFERIOR to conventional angiography iii. Best sequence to see blood products (but CT superior for acute blood) g. MR spectroscopy i. Metabolites h. Functional MRI i. Echo planar rapid imaging ii. Relies on assumption that neural activity is coupled to blood flow iii. Functional vs rest iv. Signal produced by differences between oxy and Hb and deoxy Hb as deoxy Hb more magnetic than oxy Hb v. BOLD (Blood Oxygen Level Dependent Contrast)

Answer 102

CNIII (oculomotor) Superior rectus: Elevation (maximal on lateral gaze) Inferior rectus: Depression (maximal on lateral gaze) Medial rectus: Adduction Inferior oblique: Excyclotorsion (up+in) CNIV (trochlear) Superior oblique: Incyclotorsion (down+in) CNVI (abducens) Lateral rectus: Abduction

Answer 103

Double vision Impairment of movement of one eye results in projection of image to one side of the macula in the paretic eye (normally projects onto macula, and does in good eye) -> two images perceived If side by side: lateral or medial rectus If one on top of other: obliques/superior/inferior recti False image is ALWAYS outer most (either vertically or horizontally, also usually paler and less distinct At the point of maximal separation, cover one eye: - if lateral image disappears, covered eye is responsible - if medical image disappears, covered eye is normal

Answer 104

1. Anatomy a. Can result from lesions anywhere along its path beween the occulomotor nucleus in the midbrain and the extra-ocular muscles within the orbit b. Third nerve begins in the midbrain – consists of several subnuclei that innervate the individual extraocular muscles, the eyelids and the pupils 2. Function a. Motor i. Levator muscle of eyelid ii. Four extra-ocular muscles – MR, SR, IR, IO b. Parasympathetic = constrict 3. Aetiology a. Usually congenital in paediatrics – associated with developmental anomaly or birth trauma b. Intracranial lesion eg. compressive lesion, aneurysm c. Orbital disease eg. fracture, tumour, infiltration d. CN fibrosis e. Myasthenia gravis – may mimic CNIII palsy

Answer 105

a. History i. Sudden onset binocular, vertical or oblique diplopia ii. Droopy eyelid iii. Children with congenital CNIII palsy – no diplopia as they ignore or suppress the second image or there is superimposed amblyopia (reduced vision in one eye caused by abnormal visual development early in life, AKA lazy eye) b. Examination i. Key features 1. Partial or complete ptosis – more marked than Horner’s syndorme (as supplies levator palpebrae superioris) 2. Eye in a ‘down and out’ position (if complete) 3. Pupil – failure of pupil to constrict with light (parasympathetic) ii. Pupil may be of normal size and normally reactive, dilated and poorly reactive, or dilated and non-reactive to light and near stimulus iii. Defects in 1. Ipsilateral adduction (medial rectus) 2. Elevation (superior rectus, inferior oblique) 3. Depression (inferior rectus) iv. Consider CNIII palsies to be complete if impairment of the majority of function of all the somatic branches is present and ptosis is complete or almost near 1. If the deficit of adduction is significant, a primary position exotropia (eye turned out) worse in gaze toward the paretic medial rectus muscle occurs 2. If the elevator muscles (eg, superior rectus or inferior oblique muscles) are involved, an ipsilateral hypotropia (eye is turned down) occurs 3. If the inferior rectus muscle is more involved, an ipsilateral hypertropia (eye is turned up) occurs 4. Complete third nerve palsies usually are associated with a large-angle exotropia and hypotropia (eye is down and out) c. Lesions of CNIII in cavernous sinus i. Lesions of CNIII in the cavernous sinus and superior orbital fissure often involve other cranial nerves and have the following clinical manifestations 1. Fourth cranial nerve – Vertical diplopia 2. Sixth cranial nerve – Horizontal diplopia; esotropia (inward deviation) 3. First (ophthalmic) branch of the trigeminal nerve — Pain or numbness 4. Oculosympathetic fibers – Horner syndrome 5. Complications a. Amblyopia is the major complication = 50-75% of children i. Caused by ptosis (deprivation amblyopia), loss of accommodation and strabismus

Answer 106

1. Anatomy a. Longest intracranial course – prone to injury from blunt head trauma or compression from changes in intracranial pressure b. Only cranial nerve that has a dorsal exit from the brainstem c. Begins in the midbrain 2. Function a. Pure motor – superior oblique i. Primary action = intorsion of the eye in the primary position ii. Secondary action = depression of the eye in an adducted position iii. Tertiary action = abduction (especially in the abducted position) 3. Aetiology a. Congenital = most common, even those presenting in adulthood b. Acquired i. Trauma = can occur with mild head injuries (cf. CNIII and CNVI) ii. Microvascular disease c. Idiopathic

Answer 107

a. History i. Binocular vertical diplopia and/or subjective tilting of objects (torsional diplopia) ii. Difficulty focusing, blurred vision , dizziness iii. Conscious or unconscious head tilt – torsional and vertical diplopia improve with head tilting to the side OPPOSITE the paralysed muscle b. Examination i. Ipsilateral hypertropia (deviation upward) + excyclotorsion (rotation outward) of the involved eye (as the function is intorsion and depression) ii. Upward deviation greater when gaze is in the direction of the weak muscle (downgaze and contralateral horizontal gaze) iii. Deviation greater in ipsilateral head tilt c. 3 step test i. Which is higher (hypertropic) eye? 1. The determination of the more hypertropic eye narrows the paretic possibilities to four extraocular muscles (the ipsilateral superior oblique or inferior rectus or the contralateral inferior oblique or superior rectus) ii. Is the hypertropia worse in right or left gaze? 1. The determination of which horizontal gaze worsens the hypertropia narrows the possible muscles involved from four to two because only two muscles act in right gaze and two in left gaze 2. The hypertropia is worse in contralateral gaze because that movement is controlled by the paretic muscle 3. Thus, worsening of the hypertropia in right gaze in a patient with left hypertropia implicates either the left superior oblique or the right superior rectus iii. Is the hypertropia worse in right or left head tilt? 1. The determination of which head tilt worsens the hypertropia (Bielschowsky head tilt test) identifies the involved muscle 2. Hyperdeviation is worse in ipsilateral head tilt in a fourth nerve palsy because the intorsion ability of the ipsilateral superior oblique is weak and is compensated for by the other ipsilateral intorter (the superior rectus) 3. Activation of the superior rectus causes elevation of the eye and increases the hypertropia. 4. The deviation improves in contralateral head tilt, the position that typically is adopted by the patient to reduce diplopia 5. Thus, left hypertropia that worsens with right gaze and left head tilt is consistent with a left superior oblique (or fourth nerve) palsy

Answer 108

1. Anatomy a. Sixth nerve nucleus in the dorsal pons contains all of the neurons responsible for ipsilateral horizontal gaze b. They include the motor neurons for the ipsilateral lateral rectus muscle and the interneurons to the contralateral third nerve medial rectus muscle subnucleus in the midbrain i. The interneurons travel through the MLF fasciculus to the contralateral third nerve subnucleus c. It enters the substance of the cavernous sinus lateral to the internal carotid artery and medial to the ophthalmic division of the trigeminal nerve d. The sixth nerve enters the orbit via the superior orbital fissure to innervate the lateral rectus muscle, which abducts the eye 2. Function a. Abduction 3. Aetiology a. MANY causes b. Congenital c. Demyelinating d. Neoplastic e. Traumatic f. Metabolic

Answer 109

a. History i. Binocular horizontal diplopia ii. Worsens with gaze toward the paretic lateral rectus muscle iii. Early – strabismus may be present only in the gaze toward the paralysed side; with time the esotropia (a form of strabismus (eye misalignment) characterized by an inwards turn of one or both eyes) may be present with gazing straight ahead (primary position) iv. Degree of esotropia and abduction deficit are markers of severity b. Examination i. Nuclear lesions 1. Result in an ipsilateral horizontal gaze palsy rather than an isolated abduction deficit alone because of involvement of the interneurons of the medial longitudinal fasciculus 2. These interneurons control contralateral medial rectus function (adduction) during attempted ipsilateral horizontal gaze 3. Ipsilateral facial nerve palsy may occur because of the close proximity of the facial and abducens nerves in the pons 4. Nuclear and fascicular lesions usually are associated with other brainstem signs (eg, hemiparesis, hemisensory loss, central Horner syndrome) ii. Lesions of the subarachnoid space can result in unilateral or bilateral sixth nerve palsies 1. A sixth nerve palsy can occur in these patients as a nonlocalizing sign of increased intracranial pressure (ICP), due to traction of the sixth nerve 2. The sixth nerve is particularly susceptible to this phenomenon because of its long course within the subarachnoid space 3. Other neurologic symptoms (eg, headache, nausea, vomiting) and signs (eg, dorsal midbrain syndrome, papilledema) of increased ICP also may be present

Answer 110

a. CNVII i. Motor = control of all muscles of facial expression (including platysma) 1. Chorda tympani branch of facial nerve  stapedius muscle to dampen sound ii. Sensory = taste sensation to anterior 2/3 of the tongue iii. Other = lacrimation and salivation b. Bell’s palsy = acute unilateral facial nerve palsy i. NOT associated with other cranial neuropathies or brainstem dysfunction c. Usually develops 2/52 post viral infection – HSV, VZV, EBV, Lyme disease, Mumps d. Active or reactivation of HSV or VZV most common cause e. Age of onset i. Idiopathic or post-viral facial palsy uncommon in very young children – especially infants ii. All children <2 years with atypical features should be discussed with neurologist f. Ramsay-Hunt = herpes zoster oticus i. Associated with vesicles in the external auditory canal or auricle and an ipsilateral facial palsy

Answer 111

2. History and examination a. Ask about the evolution of weakness. Bell's palsy usually comes on very quickly (over hours, no more than days) b. Ask about preceding viral infections or trauma to the head or face c. Ask about hyperacusis (increased sensitivity to sound) and altered taste. Both are common in Bell's palsy. d. Ask about facial pain. Mild pain in the face or behind the ear is common in Bell's palsy i. Severe pain suggests that the lesion may be caused by the varicella zoster virus (VZV). e. Confirm that all facial nerve branches are involved diffusely (with particular reference to the muscles of the upper half of the face, which are spared in upper motor neuron lesions). f. Perform a thorough neurological examination (rest of cranial nerves, peripheral power, tone, reflexes and coordination) g. Examine for signs of otitis media, mastoiditis or parotitis. h. Look for skin lesions or blisters on the face or in the ear canal. i. Confirm that blood pressure and temperature are normal. Hypertension may rarely be associated with Bell's palsy. 3. Clinical manifestations a. Upper and lower portions of the face are paretic  corner of mouth droops, unable to close eye involved b. Other features i. Mild acute pain ii. Hyperaccusis iii. Altered taste (anterior 2/3 of tongue – lost in 50%) c. Features NOT consistent with Bell’s palsy i. Numbness and paraesthesia do NOT usually occur – ipsilateral numbness can reportedly occur with viral (especially herpes) or postviral immunological impairment of the trigeminal and the facial nerves

Answer 112

4. Treatment a. Supportive = eye care i. Lubricating ocular drops TDS ii. Pad eye shut at night b. Steroids = unclear role in children, beneficial in adults i. Prednisolone (1 mg/kg/day PO) considered if within 72 hours c. Antivirals = only if vesicular rash present 5. Prognosis a. Most children recover completely; >85% of patients recover spontaneously with no residual weakness b. 10% have mild weakness as sequelae c. 5% have permanent facial weakness d. Other diagnoses should be considered if no recovery

Answer 113

• Usually a compression neuropathy from forceps application – recovers spontaneously • Congenital absence of the depressor angularis oris muscle causes facial asymmetry – often associated with other congenital anomalies especially of the heart o Cosmetic defect that interferes with feeding • Mobius syndrome = rare neurological disorder characterise by weakness or paralysis of multiple facial nerves (most commonly CNVI and CNVII) o Can have bilateral or unilateral facial palsy o Usually caused by symmetrical calcified infarcts in the tegmentum of the pons and medulla during mid-gestation or late fetal life

Answer 114

1. Anatomy a. Centre aspect of the brain, between sphenoid bones and sella turcica b. Receive blood from cerebral veins and ophthalmic veins + emissary veins c. Contents i. Cranial nerves = CNIII, CNIV, CNV (V1, V2), CNVI ii. Internal cerebral artery 2. Aetiology a. Late complication of an infection of the central face and paranasal sinuses b. Bacteraemia c. Trauma d. Infections of ear and maxillary teeth 3. Clinical presentation a. Headache +/- vomiting, papilloedema b. Focal neurological deficit c. Seizures d. Encephalopathy e. CN palsies i. Fourth cranial nerve – Vertical diplopia ii. Sixth cranial nerve – Horizontal diplopia; esotropia (inward deviation) 1. Most commonly affected iii. First (ophthalmic) branch of the trigeminal nerve — Pain or numbness iv. Oculosympathetic fibers – Horner syndrome f. Visual disturbance = orbital pain, chemosis, proptosis 4. Investigation a. MRI brain – abnormal signal in venous sinus

Answer 115

1. Neuroanatomy a. Horner syndrome can result from a lesion anywhere along a three-neuron sympthathetic (adrenergic) pathway that originates in the hypothalamus b. 1st order = descends caudally from the hypothalamus to the first synapse located in the cervical spinal cord (C8-T2) c. 2nd order = travels from the sympathetic trunk  brachial plexus  over the lung apex  ascends to the superior cervical ganglion, located near the angle of the mandible and the bifurcation of the common carotid d. 3rd order = ascends with the internal carotid artery through the cavernous sinus (in close proximity with CNVI); oculosympathetic pathway joins V1 division of CNV i. Oculosympathetic fibers innervate 1. Iris dilator muscle 2. Muller’s muscle (small smooth muscle in the eyelids responsible for a minor portion of the upper lid elevation and lower lid retraction) 2. Classified based on position a. First order = lesions of the brainstem of cervicothoracic spinal cord b. Second order i. Trauma or surgery involving the spinal cord, thoracic outlet or lung apex ii. Malignancy resulting in compression c. Third order = lesion of the internal carotid artery eg. arterial dissection, thrombosis, cavernous sinus thrombosis 3. Aetiology a. ‘Congenital’ = diagnosed within 4 weeks i. Birth related trauma ii. Congenital infections iii. Neuroblastoma iv. Idiopathic b. Acquired i. Malignancy 1. Neuroblastoma 2. Rhabdomyosarcoma 3. Brainstem tumous (glioma) ii. Brainstem vascular malformation iii. Demyelination (brainstem) iv. Carotid artery thormbosis v. Neck trauma vi. Post-surgical vii. Idiopathic

Answer 116

a. Classic triad i. Ptosis = minor (<2mm) 1. Results from paralysis of Muller’s muscle innervated by sympathetic pathway 2. Lower AND upper eyelid affected 3. Levator palpebrae is UNAFFECTED – weakness of this muscle results in more profound upper lid ptosis seen in CNIII palsies ii. Miosis = pupil constricted 1. Degree of anisocoria more marked in dark than light 2. Associated dilation lag – asymmetry in pupillary redilation between the two eyes when the light source is moved away from the eye iii. Anhidrosis 1. Present in central and pre-ganglionic lesions (first or second order) 2. Anhidrosis NOT a feature of post-ganglionic or third-order lesions 3. Sympathetic fibers are responsible for facial sweating and vasodilatation branch off at the superior cervical ganglion from the remainder of oculosympathetic pathway b. Other features i. In infants and children impaired facial flushing (Harlequin sign) often more apparent than anhidrosis ii. Acute features of sympathetic disruption can also include ipsilateral conjunctival injection, nasal stuffiness, and increased near point of accomodation c. Associated neurolgical signs – to identify site of lesion i. Brainstem signs (diplopia, vertigo, ataxia, lateralized weakness) suggest a brainstem localization ii. Myelopathic features (bilateral or ipsilateral weakness, long tract signs, sensory level, bowel and bladder impairment) suggest involvement of the cervicothoracic cord. iii. Arm pain and/or hand weakness typical of brachial plexus lesions suggest a lesion in the lung apex. iv. Ipsilateral extraocular pareses, particularly a sixth nerve palsy, in the absence of other brainstem signs localize the lesion to the cavernous sinus. v. An isolated Horner syndrome accompanied by neck or head pain suggests an internal carotid dissection.

Answer 117

Optic Tract 1. Optic nerve (a purely sensory outpouching of the brain) 2. Optic chiasm – crossing of temporal fibres a. Upper bitemporal hemianopia = lower fibres i. Usually pituitary tumour b. Lower bitemporal hemianopia = upper fibres i. Usually craniopharyngioma 3. Optic tract (after optic chiasm) 4. Lentigeniculate nucleus (in the thalamus) 5. Optic radiation a. Inferior fibres (superior VF) through temporal lobe (Meyer’s loop) b. Superior fibres (inferior VF) through parietal lobe Visual Fields • ‘Nasal’ and ‘temporal fields’ are perceived by different halves of the eye o Fibres perceiving the ‘temporal fields’ cross at the optic chiasm (i.e. nasal retina) o Fibres perceiving the ‘nasal fields’ do not cross (i.e. temporal retina) • This results in the right field of vision being perceived by the left side of the brain, and the left field of vision being perceived by the right side of the brain • Fibres travel via the optic tract to the lateral geniculate body • After the lateral geniculate body, the optic radiation forms o Superior fibres (carrying the inferior visual field) pass through the parietal lobe o Inferior fibres (carrying the superior visual field) pass through the temporal lobe

Answer 118

Glaucoma, retinal abnormalities (chorioretinitis), papilloedema, acute ischaemia

Answer 119

Optic nerve | Unilateral eye disease

Answer 120

Lesion at the optic chiasm Where the medial optic receptors that perceive the ‘temporal fields’ cross Pituitary tumour Craniopharyngioma Suprasellar meningioma

Answer 121

Bilateral lesions affecting uncrossed optic fibre Atheroma

Answer 122

Damage to the optic tract/ radiation  loss of visual field on the contralateral side Note the macular cortical area has some additional blood supply so central vision may be preserved Brain lesion: Tumour Bleed Abscess Upper quadrontopia: Damage to temporal lobe Lower quadrant homonymous hemianopia: Damage to the parietal lobe

Answer 123

``` • Clinically = an enlarged blind spot • Classification o Peripheral = optic nerve lesion  Optic neuritis  Retinal damage – hypertension/ toxic substances  Also – macular degeneration o Central – damage to the macular cortex  Eg occipital contusion ```

Answer 124

Markus Gunn Pupil • Paradoxical dilatation of a pupil when exposed to light: o Swing light from eye to eye o Complete defect – pupil does not constrict w light o Partial – pupil may constrict partially w light, but when light swung to good eye + back, the pupil dilates (as the other pupil dilates with removal of light) • Suggests a sensory defect of the optic nerve • Any lesion in the optic nerve / tract BEFORE light reflex fibres are sent off to the pretectal nucleus (to supply the pupillary reflex) will cause this sign

Answer 125

1. Shoulder a. Abduction [C5, C6] = deltoid axillary nerve b. Adduction [C6, C7, C8] 2. Elbow a. Flexion [C5, C6] = biceps brachii  musculocutaneous nerve b. Extension [C7, C8] = triceps  radial nerve 3. Wrist a. Flexion [C6, C7] b. Extension [C7, C8] 4. Finger a. Flexion [C7, C8] = FDS + FDP  median + ulnar nerve b. Extension[C7, C8] = extensor digitorum  posterior interossei nerve c. Abduction [T1] = dorsal interossei  ulnar nerve d. Adduction [T1] = palmar interossei  ulnar nerve 5. Thumb a. Abduction [T1] = abductor pollicis brevis  median nerve ``` Reflexes • Biceps [C5, C6] • Triceps [C7, C8] • Brachioradialis [C5, C6] • Finger [C8] ```

Answer 126

1. Hip a. Flexion [L2, L3] = iliopsoas muscle  lumbar sacral plexus b. Extension [L4, L5, S1] = gluteus maximus  inferior gluteal nerve c. Abduction [L4, L5, S1] = gluteus medius and minimus  superior gluteal nerve d. Adduction [L2, L3, L4] = adductors  obturator nerve 2. Knee a. Flexion [L3, L4] = quadriceps  femoral nerve b. Extension [L5, S1] = hamstrings  sciatic nerve 3. Ankle a. Dorsiflexion [L4, L5] = tibialis anterior  deep peroneal nerve b. Plantarflexion [S1, 2] = gastrocnemius  posterior tibial nerve c. Inversion [L4, L5] = tibialis posterior  tibial nerve d. Eversion [L5, S1] = peroneus longus and brevis (superficial peroneal nerve) 4. Toe a. Extension [L4, L5, S1] = extensor hallicus longus  deep peroneal nerve Reflexes • Knee [L3, 4]  femoral nerve • Ankle [L1, 2]  tibial nerve • Babinski [L5, S1, S2]

Answer 127

Root C5, 6, 7 Origin Lateral cord Key Landmarks in Course • Pierces coracobrachialis • Descends in the arm between biceps and brachialis • Becomes cutaneous lateral to the tendon of biceps ``` Motor Distribution • Anterior compartment of the arm: 1) coracobrachialis 2) biceps 3) brachialis ``` Sensory distribution • Skin of lateral forearm

Answer 128

Root (C7), C8, T1 Origin Medial cord Landmarks • Behind medial epicondyle • Under cover of FCU • Superficial to flexor retinaculum Motor • FCU and medial half of FDP • All of intrinsic muscles in hand EXCEPT lateral 2 lumbricals and thenar eminence (may share with median nerve) Sensory • Medial 1.5 fingers front and back, and corresponding part of hand

Answer 129

Root C5, 6, 7, 8, T1 Origin Medial and lateral roots from medial and lateral cords Landmarks • Starts lateral or anterior to brachial artery • Crosses artery to become medial to the brachial artery • Passes beneath fibrous arch of FDS • Through carpal tunnel Motor • Anterior compartment of forearm EXCEPT FCU and medial half of FPD (ulnar nerve) • Thenar eminence (share with ulnar nerve) and lateral 2 lumbricals Sensory • Lateral 3.5 digits and corresponding part of the palm • Extending on dorsum of same 3.5 digits (but only to the NAIL BEDS)

Answer 130

Roots C5, 6, 7, 8, T1 Origin Posterior cord ``` Landmarks • Below teres major (triangular space) • Spiral groove of humerus • Under cover of brachioradialis • Over anatomical snuffbox • Posterior inter-osseous branch runs through supinator to reach posterior compartment of forearm ``` Motor • Extensor muscles of arm and forearm (including triceps) Sensory • Posterior and lower lateral arm • Posterior forearm • Posterior lateral hand, especially over 1st web space

Answer 131

Root C5, 6 Origin Posterior cord Landmarks • Above teres major (quadrilateral space) Motor • Deltoid • Teres minor Sensory • Upper lateral arm (regimental badge distribution)

Answer 132

Root L2, 3, 4 Divisions Posterior Landmarks • Lateral to sheath in femoral triangle Motor • Anterior compartment of thigh Sensory • Medial and intermediate cutaneous nerves of thigh • Saphenous nerve (medial side of leg and foot)

Answer 133

Roots L2, 3, 4 Divisions Anterior Landmarks • Side wall of pelvis • Obturator canal Motor • Adductor muscles Sensory • Lower inner thigh

Answer 134

Roots L2, 3 Divisions Posterior Landmarks • On iliacus • Beneath inguinal ligament just next to ASIS Motor NIL Sensory • Lateral side of thigh

Answer 135

Roots L4, 5, S1, 2, 3 Divisions Anterior and posterior Landmarks • Beneath piriformis • Behind the hip • Posterior thigh Motor • Hamstrings (tibial component supplies all but the short head of biceps) and ischial fibres of adductor magnus Sensory NIL

Answer 136

Roots L4, 5, S1, 2, 3 Divisions Anterior Landmarks • Vertically through middle of popliteal fossa (where it is superficial to vessels • Beneath tendinous arch of soleus • On tibialis posterior • Deep to flexor retinaculum behind medial malleolus Motor • Hamstrings (whilst part of sciatic nerve) • Posterior compartment of leg • Sole of foot Sensory • Lateral side of ankle and foot (sural nerve) • Sole of foot

Answer 137

Roots L4, 5, S1, S2 Divisions Posterior Landmarks • Along medial border of biceps in popliteal fossa • Around neck of fibula • Pierces fibularis longus Motor • Short head of biceps (whilst part of sciatic nerve) Sensory • Lateral calf • (Gives a communicating branch to sural nerve off tibial)

Answer 138

Roots L4, 5, S1, 2 Divisions Posterior Landmarks • Descends on interosseous membrane between EHL and tibialis posterior • Deep to extensor retinaculum Motor • Anterior compartment of leg and extensor digitorum brevis on dorsum of foot Sensory • 1st toe cleft

Answer 139

Roots L5, S1, S2 Divisions Posterior Landmarks NIL Motor • Lateral compartment of leg Sensory • Lateral side of leg and dorsum of foot (except first toe clef)

Answer 140

Upper brachial plexus palsy = Erbs palsy Lower brachial plexus palsy = Klumpke paralysis Backpack palsy

Answer 141

= Klumpke Paralysis (think Klumpke Claw, Climbing (falling from tree and catching branch), L for lower) 1. Site of injury = Lower trunk of the brachial plexus. 2. Cause of injury = undue abduction of the arm, as in clutching something with the hand after a fall from a height, or sometimes in birth injury 3. Nerve roots involved = mainly T1 and partly C8. 4. Muscles paralysed a. Intrinsic muscles of the hand (T1) b. Ulnar flexors of the wrist and fingers (C8) 5. Deformity a. Claw hand due to the unopposed action of the long flexors and extensors of the fingers b. In a claw hand there is hyperextension at the metacarpal-phalangeal joints and flexion at the interphalangeal joints. 6. Disability a. Claw hand b. Cutaneous anaesthesia and analgesia in a narrow zone along the ulnar border of the forearm and hand c. Horner's syndrome = ptosis, miosis, anhydrosis, enophthalmos and loss of ciliospinal reflex- may be associated. i. Injury to sympathetic fibres to the head and neck that leave the spinal cord through nerve T1 7. Vasomotor changes a. The skin areas with sensory loss is warner due to arteriolar dilation b. It is also drier due to the absence of sweating as there is loss of sympathetic activity 8. Tropic changes a. Long standing case of paralysis leads to dry and scaly skin b. The nails crack easily with atrophy of the pulp of fingers.

Answer 142

= Erb Palsy 1. Causes of injury a. Undue separation of the head from the shoulder, which is commonly encountered in i. Birth injury ii. Fall on shoulder iii. During anaesthesia 2. Nerve roots involved = mainly C5 and partly C6. 3. Muscles paralysed a. Mainly biceps, deltoid, brachialis and brachioradialis b. Partly supraspinatus, infraspinatus and supinator 4. Deformity a. Arm = Hangs by the side, it is adducted and medially rotated b. Forearm = Extended and pronated c. The deformity is known as "Policeman's tip hand" or "Porter's tip hand" 5. Disability a. Abduction and lateral rotation of the arm (shoulder) b. Flexion and supination of forearm c. Biceps and supinator jerks are lost d. Sensations are lost over a small area over the lower part of the deltoid.

Answer 143

• Upper brachial plexus disorder • Clinical features o Painless arm and/or shoulder weakness (usually unilateral) o Sensory loss in the same distribution o Full recovery over subsequent few months

Answer 144

1. Accessory - mostly due to surgery, innervates trapezius -> impaired shoulder shrug 2. Axillary - due to Fracture, Compression, Anterior dislocation - innervates deltoid and lateral cutaneous space • Impaired abduction (AFTER first 20 degrees because supraspinatus does this) • Deltoid atrophy • Sensory distribution military badge area 3. Long thoracic - due to compression - innervates serratus anterior -> winged scapula 4. Suprascapular - innervates supraspinatus and infraspinatus • Impaired external rotation • Impaired abduction (first 20 degrees)

Answer 145

1. Site = carpal tunnel 2. Aetiology a. Idiopathic b. Associated = hypothyroidism, pregnancy, RA, DM, acromegaly 3. Function = LOAbF a. Lateral two lumbricals b. Opponens pollicis c. Abductor pollicis brevis d. Flexor pollicis brevis 4. Examination a. Appearance = wasting of thenar eminence b. MOTOR = Loss of thumb abduction, opposition, flexion c. SENSORY = Radial 3.5 fingers only (palmar aspect only) d. SPECIAL = Tinel’s sign (tapping over carpal tunnel elicits paraesthesia), Phalen’s sign (The patient is asked to hold their wrists in complete and forced flexion (pushing the dorsal surfaces of both hands together) for 30–60 seconds -> compresses carpal tunnel -> reproduce symptoms)

Answer 146

1. Aetiology = arm draped over chair (Saturday night palsy) 2. Function = Supplies BEST = brachioradialis, extensors, supinator, triceps 3. Examination a. Appearance = wrist drop b. MOTOR i. Loss of wrist extension ( wrist drop) ii. Loss of finger extension ( finger drop) iii. Reflexes = loss of triceps + brachioradialis; biceps intact c. SENSORY i. Loss of sensation in snuff box area

Answer 147

1. Site a. Entrapment most commonly at the elbow, where the nerve is compressed within the olecranon groove within the cubital tunnel, which lies behind the medial epicondyle b. Can also be compressed at other sites within the cubital tunnel eg. between 2 heads of FCU 2. Aetiology a. Fracture b. Prolonged/recurrent pressure 3. Function a. Medial 2 lumbrical = flex the MCP, extend the IP joints of little + ring fingers b. Interossei = abduct and adduct the fingers c. Hypothenar muscles d. Adductor pollicis 4. Examination a. Appearance i. Ulnar claw ii. Wasting of small intrinsic muscles of the hand (except LOAF) b. MOTOR i. Power 1. Weak finger abduction/adduction 2. Weak thumb adductor pollicis  Fromont’s sign 3. Flexion - ulnar only supplies medial half of FDP  flexion normal in other fingers (?) ii. Tone, reflexes, coordination = normal c. SENSORY = Loss of sensation in ulnar 1.5 finger (medial 1.5 fingers) 5. Ulnar claw/paradox a. Ulnar claw = MCP become hyper-extended by unopposed extension from extensor digitorum, and the IP joints are flexed by unopposed flexion from FDP b. Ulnar paradox i. Claw worse for distal lesion ii. Lesion at the wrist = preserved medial FDP  flexes the IP joints of the ring and little finger iii. Lesion at elbow = loss of FDP reducing flexion; therefore the claw is only due to hyperextension at MCP joints

Answer 148

1. Site = where common fibular nerve is compressed as it winds around the fibular head 2. Aetiology = prolonged squatting or leg crossing, tight plaster cast 3. Normal function a. Motor i. Superficial = lateral compartment  fibularis longus, fibularis brevis 1. Results in EVERSION ii. Deep = anterior compartment  tibialis anterior, extensor hallicus longus, extensor digitorum longus 1. Results in dorsiflexion of the foot and extension of toes 4. Examination a. MOTOR i. Gait = foot drop ii. Motor 1. Weak dorsiflexion 2. Weak eversion 3. [NORMAL inversion] b. SENSORY i. Loss of sensation over upper, lateral calf 5. MAIN DDX = L5 nerve root lesion a. This will result in weakness of i. Dorsiflexion ii. Inversion iii. Eversion b. Sensory loss i. Lateral leg ii. Dorsum of foot

Answer 149

a. Common fibular nerve palsy b. Sciatic nerve palsy c. Lumbosacral plexus lesion d. L4, L5 root lesion e. Peripheral motor neuropathy f. Distal myopathy g. MND h. Precentral gyrus lesion i. Spinal cord lesion

Answer 150

1. Epidemiology a. 1/3000 b. Affects all ethnic groups 2. Genetics + pathogenesis a. AD b. Loss of function NF1 gene – tumour suppressor gene encoding neurofibromin (regulates cell signal transduction pathways) c. 30-50% de novo NF1 pathogenic variant d. Variable expressivity + 100% penetrant by 5 years of age

Answer 151

a. Cutaneous i. Café au lait macules 1. Hallmark of NF and present in almost 100% of patients a. Not uncommon to see 1-2 in general population 2. Present at birth but increase in size, number and pigmentation 3. Scattered over body surface – particularly on trunk and extremities, spare face 4. >5mm pre-pubertal, >15 mm postpubertal ii. Axillary or inguinal freckling 1. Skinfold freckling appears between 3-5 years of age 2. Frequency of axillary and inguinal freckling is >80% by 6 years of age b. Eyes i. Iris Lisch nodules = hamartomas located in the iris 1. Best identified with slit lamp – but can sometimes be seen with naked eye 2. Do NOT affect vision 3. Present in >75% of patients with NF-1 (NOT a characteristic of NF-2) 4. Prevalence increases with age a. 5% of children <3 years of age b. 42% of children 3-4 years of age c. >90% of adults >21 years of age

Answer 152

i. Peripheral neurofibromas 1. Most common type of benign tumour - peripheral nerve sheath tumours comprised of Schwann cells, fibroblasts, Perineural cells and mast cells 2. Increase with age – appear in puberty or during pregnancy 3. Neurofibroma = focal growth a. Discrete cutaneous neurofibromas are the most common type b. Do NOT carry increased risk of malignant transformation c. Soft, fleshy, non-tender, mobile d. Benign but cosmetic issue 4. Plexiform neurofibroma = extent longitudinally along a nerve + involve multiple fascicles a. Occur 30% - severe lesion of head or neck 2% b. Located superficially and associated with overgrowth of skin and tissues, OR located deep inside the body c. Majority of disfiguring plexiform neurofibromas evident by 2 years – usually congenital and tend to grow rapidly d. Can undergo malignant transformation (10%) – peripheral nerve sheath tumour (MPNSTs) = neurofibrosarcoma  grow suddenly or become painful i. More likely for deep lesions ii. Highly malignant e. Can compress the airway or spinal cord 5. Nodular neurofibroma = discrete lesions that may grow under the skin, appear as firm, rubbery masses that may be tender or occur deeper inside the body ii. Optic pathway gliomas (IOG) 1. Predominant type of intracranial neoplasm 2. Occur in 15% of children <6 years (2% symptomatic) 3. Rarely occur in older children 4. Typically low-grade pilocytic astrocytoma 5. Usually normal vision – minority develop visual loss + proptosis due to expanding lesion 6. Occasionally compress hypothalamus – results in delayed puberty iii. Other CNS neoplasms 1. Other CNS tumours not very common (but more common than general population) 2. 5x more common in NF-1 than general population 3. Include a. Astrocytomas b. Brainstem gliomas – usually indolent c. Meningiomas d. Non-optic nerve gliomas iv. Soft tissue sarcomas 1. Malignant peripheral nerve sheath tumours a. Usually present with development of significant and constant pain, change in consistency, or rapid growth b. Lifetime risk 5-13% c. Greatest risk for sarcomas 10-20 years after appearance of neurofibromas – therefore frequently detected in 20-50 year olds d. Among children with MPNSTs 20-50% have NF1 2. Rhabdomyosarcoma = often genitourinary, tend to present at early age 3. Gastrointestinal stroma tumours 4. Glomus tumours = arise in tips of fingers and toes under the nail bed and present with pain, tenderness and sensitivity to cold 5. Other tumours = JMML, phaeochromocytoma, Wilm’s tumour, breast cancer

Answer 153

i. Long bone dysplasia and pseudoarthrosis 1. Typically presents in infants or young children with anterolateral bowing of tibia 2. Progresses to narrowing of the medullary canal, cortical thickening and fracture 3. Pseudoarthrosis is a false joint that forms when there is nonunion of bone fragments at the site of long bone fracture – severely compromises function in the affected limb 4. Occur in 5% of patients with NF1 ii. Sphenoid wing dysplasia – can result in facial asymmetry iii. Scoliosis 1. 10-25% of individuals 2. Typically presents age 6-10 years 3. More common in females iv. Other 1. Scalloping caused by dural ectasia 2. Non-ossifying fibromas within long bones 3. Osteoporosis

Answer 154

i. Cognitive deficits and learning difficulties 1. 50% of individuals 2. ID in 5% 3. Mean IQ 90 – about half require special education assistance ii. Autism spectrum disorder iii. Seizures 1. 5% of individuals, any age any type 2. Focal seizures – consider intracranial malignancy iv. Peripheral neuropathy v. Aqueductal stenosis

Answer 155

i. UBO’s = unidentified bright object = hyperintense regions on T2 MRI 1. Cerebellum > brainstem > internal capsule 2. Benign 3. Present in 2/3 - ? should be present in diagnostic criteria 4. Increase in size until 10 years then disappear ii. Macrocephaly 1. Common, relative to stature, or absolute 2. Brain volume increased in NF1 – may correlate with reduced cognition iii. Pubertal disturbance 1. Must consider CNS lesion compressing hypothalamus iv. Hypertension 1. Occurs in 6% - renal artery stenosis 1.5%, phaeochromocytoma 0.7% 2. Frequent finding in adulthood - may develop during childhood 3. Usually essential hypertension – however vascular lesions causing renovascular HTN are more frequent in NF1 patients -> must investigate/exclude v. Short stature 1. 10-15% vi. Hypothalamus 1. Mean age of death 54 M/ /59 F (compared with 70/ 74)

Answer 156

``` Birth – 2 years • Cafe-au-lait spots • Pseudoarthrosis • Sphenoid wing dysplasia • Optic pathway gliomas • Plexiform neurofibromas (rarely) ``` ``` 2 – 6 years • Axillary freckling • Lisch nodules • Optic pathway gliomas • Other CNS tumours • Learning disability or speech delay • Plexiform neurofibromas ``` ``` 6 – 10 years • Learning disabilities • ADHD • Scoliosis • Plexiform neurofibromas • Increased risk of other cancer types eg. rhabdomyosarcoma • Headaches ``` Adolescence • Subcutaneous and cutaneous neurofibromas • Malignant transformation of pre-existing plexiform neurofibromas • Isolated malignant peripheral nerve sheaths • Hypertension

Answer 157

a. Clinical criteria = 2 of 7 of the following criteria i. Six or more café-au-lait macules = >5mm pre-pubertal, >15mm post-pubertal ii. Axillary or inguinal freckling = multiple hyperpigmented 2-3mm iii. Two or more iris Lisch nodules = hamartomas located in the iris iv. Two or more neurofibromas or 1 plexiform neurofibroma v. Distinctive osseous lesion 1. Examples = sphenoid dysplasia (may cause pulsating exophthalmos) or cortical thinning of long bones with or without pseudoarthrosis (eg. tibia) vi. Optic gliomas vii. 1st degree relative with NF-1 b. Molecular testing possible i. For those who do not meet diagnostic criteria ii. If young child has a serious tumour (eg. optic glioma) as it would affect management iii. Prenatal or pre-implantation genetic diagnosis iv. In some patients with spinal NF1 may not meet criteria v. NOTE: 1. Large and heterogenous gene 2. Need to sequence exons of entire NF1 gene and MLPA for deletions 3. Find causative mutation in 95% with clinical diagnosis of NF1 4. Can target testing if know specific mutation

Answer 158

a. Close multidisciplinary follow-up required b. Yearly review c. Surveillance i. Learning evaluation +/- formal psychometric assessment as required ii. Neurological assessment iii. BP iv. Scoliosis review v. Annual opthal examination – particularly in childhood vi. MRI for follow-up of clinically suspected intracranial and other internal tumours – routine neuro-imaging not recommended (controversial) d. Adults i. Neurological assessment ii. BP iii. Ophthalmology only if symptoms (symptomatic optic nerve glioma in adulthood rare) e. Treatment of manifestations i. Surgical excision of malignant nerve sheath tumours ii. Surgery of limited value otherwise not helpful – regrowth iii. Surgical management of scoliosis f. Pharmacological i. Carboplatin for optic glioma ii. New therapy = MEK inhibitor – induces tumour regression 1. RAS-mitogen-activated protein kinase (MAPK) activated in plexiform neurofibromas

Answer 159

a. Legius syndrome i. Multiple café au lait patches ii. Flexural freckling iii. No neurofibromas, optic nerve gliomas, bone lesions iv. Macrocephaly, learning problems can occur v. Cased by SPRED1 mutations vi. Resembles a mild form of NF-1 b. Noon-syndrome with multiple lentigines (NMSL) i. AKA LEOPARD syndrome ii. Key features 1. Lentigines – flat, black-brown macules 2. Hypertrophic cardiomyopathy 3. Short stature 4. Pectus deformity 5. Dysmorphic facial features – widely spaced eyes, ptosis

Answer 160

1. Genetics a. AD b. Loss of function of NF-2 gene – tumour suppressor gene encoding merlin (links between membrane proteins and cell cytoskeleton) c. 50% de novo d. Fully penetrant e. Genotype/phenotype correlation i. Nonsense/frameshift = severe disease ii. Missense = often milder 2. Presenting symptoms a. Unilateral hearing loss 35% b. Focal weakness 12% c. Tinnitus 10% d. Bilateral hearing loss 9% e. Balance dysfunction 8% f. Seizure 8% g. Focal sensory deficit 6% h. Visual loss 1% i. Diagnosis due to family history 11%

Answer 161

a. Vestibular schwannomas – can be bilateral i. Results in tinnitus, hearing loss and balance dysfunction ii. Average age of onset is 18-24 years iii. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 b. Other CNS tumours i. Meningioma 1. Life-time risk of 80% 2. Most are intracranial, however can also occur in the spine 3. May compress the optic nerve and cause visual loss if occur in the orbit ii. Schwannoma – other locations 1. Other cranial nerve schawnnomas 2. Spinal tumours a. 2/3 of individuals with NF-2 develop spinal tumours which are difficult to manage b. Most common are schawnnomas iii. Glioma iv. Neurofibroma v. Other – ependymomas, astrocytomas c. Eye i. Posterior subcapsular lenticular opacities 1. Rarely progress to a visually significant cataract 2. May be the first sign of NF-2 3. 1/3 of individuals have decreased visual acuity in one or both eyes ii. Retinal hamartomas 1. Retinal hamartoma and epiretinal membrane seen in 1/3 of individuals d. Other i. Mono or polyneuropathy 1. Mononeuropathy that occurs in childhood is an increasingly recognized finding – frequently presents as a persistent facial palsy, a squint, or hand/foot drop Neurological • 90% bilateral vestibular schwannoma (benign) before 30yo • 25-50% schwannomas of other cranial nerves • 45-75% intracranial meningiomas – present in childhood • 65-90% spinal tumours • 60% peripheral neuropathy Eye • 60-80% cataracts • 15-40% epiretinal membranes • 5-25% retinal haemorrhages Skin • 60-70% Cutaneous tumours • 50% skin plagues • 50% subcut tumours

Answer 162

Relies on vestibular schwannomas a. Clinical criteria = 1 of the following i. Bilateral vestibular schwannomas ii. First degree relative with NF 2, AND 1. Unilateral vestibular schwannoma 2. Any two of = meningioma, schwannoma, glioma, neurofibroma posterior subcapsular lenticular opacities iii. Unilateral vestibular schwannoma AND any two of = meningioma, schwannoma, glioma, neurofibroma posterior subcapsular lenticular opacities iv. Multiple meningiomas AND 1. Unilateral vestibular schwannoma, OR 2. Any two of = schwannoma, glioma, neurofibroma, cataract (posterior subcapsular lenticular opacities) b. Molecular testing = also possible

Answer 163

5. Treatment a. Surveillance i. Annual MRI beginning at age 10-12 years and continuing until at least age 40 ii. Hearing evaluation iii. Opthal examination b. Treatment of manifestations i. Vestibular schwannomas require surgical excision ii. Appropriate treatment of hearing loss iii. Avastin (bevacizumab) – shrinks vestibular schawnnomas 6. Prognosis a. Average age at death 36 years b. Average time from first symptom to death 15 years c. Spinal tumours in 2/3 – can cause major morbidity

Answer 164

Definite: - NF1 - NF2 (less common than NF1) - McCune Albright - Ring chromosome syndromes - Watson syndrome Questionable: - Bloom syndrome - Ataxia telangiectasia - Tuberous sclerosis - LEOPARD syndrome - Russel-Silver syndrome

Answer 165

Mental retardation Seizures Adenoma sebaceum / angiofibroma

Answer 166

Epidemiology a. Incidence 1/5000 2. Genetics + pathogenesis a. AD with variable expression b. 2/3 de novo mutations (1/3 family history) c. 2 genes = tumour suppressors i. TSC1 = hamartin (9q34) ii. TSC2 = tuberin (16p13.3) iii. NO homology between the two iv. Appear to function in the same pathway d. Can identify mutation in 70% of patients with TS clinical diagnosis i. 50% mutation in TSC2 ii. 20% mutation in TSC1 e. Highly variable expression – broad phenotypic proteins f. Genes encode for tuberin and hamartin proteins g. Abnormal cell signaling + gene expression  hamartomas

Answer 167

i. Hypomelanotic lesion 1. >90% have the typical hypomelanotic skin lesions – likened to an ash leaf on the trunk and extremities 2. Visualisation enhanced by the Wood UV lamp ii. Facial angiofibromas (= angiofibromata = adenoma sebaceum/ fibroadenoma) 1. Develop between 4-6 years of age 2. Appear as tiny red nodules over the nose + cheeks; sometimes confused with acne 3. Later they enlarge and assume a fleshy appearance 4. Present in butterfly/malar distribution 5. Present in >75% iii. Shagreen patch 1. Roughened, raised lesion with an orange-peel consistency located primarily in the lumbosacral region 2. Present in 60% iv. Forehead plaque 1. Distinctive brown fibrous plaque on forehead 2. Present in 25% v. Small fibromas or nodules 1. Around fingernails or toes in 15-20% of patients; usually in adolescence

Answer 168

b. Eyes i. Retinal lesions = hamartomas (elevated mulberry lesions or plaque like lesions) and white de-pigmented patches (phakoma) c. Brain i. Cortical dysplasia = including tubers and cerebral white matter migration lines ii. Sub ependymal nodules (SEN) 1. Found along wall of the lateral ventricles 2. Undergo calcification and project into the ventricular cavity 3. In 5-10% of cases can grow into sub-ependymal giant cell astrocytomas (SEGAs) iii. Sub-ependymal astrocytomas (SEGAs) 1. Can grow and block the circulation of the CSF -> hydrocephalus iv. Epilepsy 1. TSC may present during infancy with infantile spasms and hypsarrhythmic EEG pattern a. 20% of infants with infantile spasms have TS 2. Seizures may be difficult to control and may develop into myoclonic epilepsy 3. Vigabatrin is first line therapy for infantile spasms caused by TSC 4. ACTH can be used if treatment with vigabatrin fails 5. Can be highly refractory v. Cognitive impairment/ ID 1. Mild to severe 2. 30% profound vi. Behaviour 1. Autism spectrum disorders

Answer 169

d. Renal i. Renal angiomyolipoma 1. 75-85% of patients 2. Begin in childhood, but may not become problematic until adulthood 3. By the third decade of life may cause lumbar pain and haematuria from slow bleeding, and rarely they may result in sudden retroperitoneal bleeding ii. Single or multiple renal cysts 1. Benign iii. Renal cell carcinoma 1. Occur in 3% e. Other organ involvement i. Cardiac rhabdomyoma 1. 50% of children have cardiac rhabdomyoma 2. Diagnosed in the fetus by an echocardiogram 3. May be numerous or located at the apex of the left ventricle 4. Can cause congestive heart failure and arrythmias in a minority of patients 5. Usually slowly resolve spontaneously ii. Lymphangioleiomyomatosis = classic pulmonary lesion 1. Only affects women after the age of 20 2. Dilated lymphatics and interstitial proliferation 3. Resultant obstruction and cystic lung disease 4. Presentation – pneumothorax/dyspnea 5. F >> M 6. Poor prognosis

Answer 170

``` CNS Cortical tuber 90-100% Subependymal nodule 90-100% White matter hamartoma 90-100% Subependymal giant cell astrocytoma 6-16% ``` ``` Skin Facial angiofibroma (adenoma sebaceum) 80-90% Hypomelanotic macule (ash leaf) 80-90% Shagreen patch 20-40% Forehead plaque 20-30% Peri and subungual fibroma 20-30% ``` Eyes Retinal hamartoma 50% Retinal giant cell astrocytoma 20-30% Hypopigmented iris spot 10-20% GI Microhamartomatous rectal polyp 70-80% Liver hamartoma 40-50% Other Angiomyolipoma (kidney) 50% Cardiac rhabdomyoma 50%

Answer 171

a. Clinical i. Definite = 2 major OR 1 major + 2 minor ii. Probable = 1 major + 1 minor iii. Possible TS = 1 major or 2 minor b. Genetic i. TSC1 or TCS2 pathogenic mutation Major Cutaneous • Hypomelanotic macules (>=3, >=5mm in diameter) • Angiofibromas [= adenoma sebaceum] (>=3) or fibrous cephalic plaque [= forehead plaque] • Ungal (nail) fibromas (>=2) • Shagreen patch Brain • Cortical dysplasia – including tubers and cerebral white matter migration lines • Subpendymal giant cell astrocytoma (SEGA) • Subependymal nodules (SENs) Other • Eyes = multiple retinal nodular hamartomas • Heart = Cardiac rhabdomyoma (>=1) • Lymphangioleiomyomatosis (LAM) • Renal Angiomyolipoma (>=2) ``` Minor • ‘Confetti’ skin lesions (numerous 1-3mm hypopigmented macules scattered over regions of the body such as the arms and legs) • Dental enamel pits (>3) • Intraoral fibromas (>=2) • Multiple renal cysts • Non-renal hamartomas • Retinal achromic patch ```

Answer 172

ASHLEAF ``` A = ashleaf spots S = Shagreen patch H = heart rhabdomyosarcoma L = lung hamartoma E = epilepsy from cortical tumours A = angiomyolipoma in kidney F = facial angiofibroma ```

Answer 173

a. Surveillance i. Brain 1. MRI = every 1-3 years in asymptomatic individuals <25 years a. For detection of SEGAS b. More frequent if large asymptomatic SEGA to develop hydrocephalus 2. Baseline EEG = follow-up if abnormal ii. Renal 1. Imaging = every 1-3 years (US, CT or MRI) 2. BP and renal function = annually iii. Cardiac 1. Echo every 1-3 years due to risk of rhabdomyoma 2. ECG every 3-5 years iv. Respiratory 1. Clinical screening for LAM (ie. exertional dyspnoea) 2. HRCT every 5-10 years v. Neurodevelopmental testing while in school vi. Annual dermatological examination vii. Dental examination every 6 months viii. Annual opthal examination b. Treatment of manifestations i. mTOR inhibitors = sirolimus, everolimus 1. mTOR = mammalian target of rapamycin 2. mTOR activated by mutations in TSC1 and 2 3. Sirolimus used for 12 months has been shown to reduce size of angiomyolipomas and improve PFTs in some with LAM 4. Everolimus reduced the size of SEGAs and seizure frequency 5. Indications a. Enlarging SEGAs b. Angiomyolipomas or cardiac rhabdomyomas c. LA d. Facial angiofibromas (topical) ii. If unsuccessful surgery of the above lesions iii. Renal angiomyolipomas = embolisation followed by corticosteroids 1. Embolisation usually done when >4cm 2. Nephrectomy should be avoided iv. Seizures = vigabatrin and other anti-epileptic drugs; sometimes require surgery c. Prevention of secondary complications i. For those on vigabatrin therapy – visual field testing at the onset of therapy, 3 monthly intervals for the first 18 months then every 6 months onwards

Answer 174

a. Sporadic vascular disorder; NOT inherited b. Somatic mutation – occurs AFTER conception i. As the cell carrying the mutation continues to divide the cells derived from it are involved in the clinical phenotype; therefore individuals are mosaic c. Single nucleotide variant in GNAQ gene – mutation has been confirmed in most individuals with SWS d. The Gαq protein is part of a group of proteins (complex) that regulates signaling pathways to help control the development and function of blood vessels e. Anomalous development of the embryonic vascular bed in the early stages of facial and cerebral development

Answer 175

a. Sporadic vascular disorder; NOT inherited b. Somatic mutation – occurs AFTER conception i. As the cell carrying the mutation continues to divide the cells derived from it are involved in the clinical phenotype; therefore individuals are mosaic c. Single nucleotide variant in GNAQ gene – mutation has been confirmed in most individuals with SWS d. The Gαq protein is part of a group of proteins (complex) that regulates signaling pathways to help control the development and function of blood vessels e. Anomalous development of the embryonic vascular bed in the early stages of facial and cerebral development

Answer 176

a. Key features i. Facial capillary malformation (port-wine stain) 1. Present at birth, tends to be unilateral, and always involves the upper part of face and eyelid 2. Distribution consistent with the ophthalmic division of the trigeminal nerve 3. May also be evidence over the lower face, trunk, in the mucosa of the mouth and pharynx 4. NOTE: note all children with facial port wine stain have SWS (approximately 8-33%) ii. Abnormal blood vessels of brain (leptomeningeal angiomas) iii. Abnormal blood vessels of the eye = leading to glaucoma 1. Also have buphthalmos b. Clinical consequence i. Seizures/Epilepsy = present in 75-90% of patients 1. Develop in most patients in first year of life 2. Seizures beginning in infancy are not always associated with poor neurological outcome 3. Typically focal tonic-clonic and contralateral to the side of the facial capillary malformation 4. Often refractory to anticonvulsants 5. Associated with slowly progressive hemiparesis ii. Stroke-like episodes + hemiparesis 1. Often persist for several days and unrelated to seizure activity – common and probably due to thrombosis of cortical veins in the affected region iii. Headaches iv. Developmental delay 1. Neurodevelopment appears to be normal in first year 2. Intellectual disability and severe learning disabilities present in at least 50% later in childhood 3. Probably the result of intractable epilepsy + increasing cerebral atrophy

Answer 177

a. Sporadic vascular disorder; NOT inherited b. Somatic mutation – occurs AFTER conception i. As the cell carrying the mutation continues to divide the cells derived from it are involved in the clinical phenotype; therefore individuals are mosaic c. Single nucleotide variant in GNAQ gene – mutation has been confirmed in most individuals with SWS d. The Gαq protein is part of a group of proteins (complex) that regulates signaling pathways to help control the development and function of blood vessels e. Anomalous development of the embryonic vascular bed in the early stages of facial and cerebral development

Answer 178

a. Key features i. Facial capillary malformation (port-wine stain) 1. Present at birth, tends to be unilateral, and always involves the upper part of face and eyelid 2. Distribution consistent with the ophthalmic division of the trigeminal nerve 3. May also be evidence over the lower face, trunk, in the mucosa of the mouth and pharynx 4. NOTE: note all children with facial port wine stain have SWS (approximately 8-33%) ii. Abnormal blood vessels of brain (leptomeningeal angiomas) iii. Abnormal blood vessels of the eye = leading to glaucoma 1. Also have buphthalmos b. Clinical consequence i. Seizures/Epilepsy = present in 75-90% of patients 1. Develop in most patients in first year of life 2. Seizures beginning in infancy are not always associated with poor neurological outcome 3. Typically focal tonic-clonic and contralateral to the side of the facial capillary malformation 4. Often refractory to anticonvulsants 5. Associated with slowly progressive hemiparesis ii. Stroke-like episodes + hemiparesis 1. Often persist for several days and unrelated to seizure activity – common and probably due to thrombosis of cortical veins in the affected region iii. Headaches iv. Developmental delay 1. Neurodevelopment appears to be normal in first year 2. Intellectual disability and severe learning disabilities present in at least 50% later in childhood 3. Probably the result of intractable epilepsy + increasing cerebral atrophy

Answer 179

3. Diagnosis a. MRI brain with contrast = demonstrate the leptomeningeal angiomas i. Often atrophy is noted ipsilateral to the leptomeningeal angiomatosis ii. Calcifications are best seen with head CT b. Opthal examination for glaucoma c. Genetic testing available d. Classification i. Type I = facial and leptomeningeal angiomas; may have glaucoma ii. Type II = facial angiomas alone (no CNS involvement), may have glaucoma iii. Type III = isolated leptomeningeal angiomas; usually have no glaucoma 4. Management a. Seizure control i. Anticonvulsants ii. If refractory, especially in infancy, ad arise primarily from 1 hemisphere: hemispherectomy b. Treatment of headaches c. Prevention of stroke like episodes d. Monitoring and treatment of glaucoma e. Cosmetic = laser therapy can help clear port-wine stain

Answer 180

1. Genetics a. Autosomal dominant mutation in VHL gene b. 80% of individuals have an affected parent, 20% de novo mutation c. Tumour suppressor gene d. Single gene testing of VHL available - detects mutation in almost 100% of probands 2. Clinical criteria a. Should be suspected in individuals with or without family history and: i. Retinal angioma, especially in a young patient ii. Spinal or cerebellar hemangioblastoma iii. Adrenal or extra-adrenal phaeochromocytoma iv. Renal cell carcinoma – if the patient is under age 47 years or has a personal or family history of any other tumor typical of VHL v. Multiple renal and pancreatic cysts vi. Neuroendocrine tumors of the pancreas vii. Endolymphatic sac tumors viii. Less commonly, multiple papillary cystadenomas of the epididymis or broad ligament

Answer 181

a. Major neurological features = cerebellar haemangioblastomas and retinal angiomas b. Spinal or cerebellar haemangioblastoma i. Patients with cerebellar haemangioblastoma present early in adult life with symptoms and signs of increased ICP ii. Small number have haemangioblastoma of spinal cord  abnormalities of proprioception and disturbances in gait or bladder dysfunction c. Retinal angiomas i. 25% of patients with cerebellar haemangioblastoma have retinal angiomas ii. Retinal angiomas are characterised by small masses of thin walled capillaries that are fed by large and tortuous arterioles and venules iii. Usually locate in the peripheral vision so do not affect vision iv. Exudation in the region of the angiomas may lead to retinal detachment and visual loss d. Cystic lesions of the kidneys, pancreas, liver and epididymis and phaeochromocytoma – frequent i. Renal cell carcinoma most common cause of death

Answer 182

a. Treatment of manifestations i. CNS lesions = surgical removal ii. Renal cell carcinoma = nephron-sparing or partial nephrectomy when possible 1. Dialysis +/- renal transplantation = required if bilateral nephrectomy iii. Phaeochromocytoma, neuroendocrine tumours = surgical removal iv. Cystadenomas of the epididymis or broad ligament = treatment if threatens fertility v. Retinal angiomas are treated with photocoagulation and cryocoagulation b. Prevention of secondary complications i. Early detection and removal of tumours to prevent/minimise secondary deficits (eg. hearing loss, vision impairment, neurological symptoms, renal replacement therapy) c. Surveillance i. Starting at 1 year of age = annual evaluation for neurological symptoms, vision problems, hearing disturbance, BP and opthal examination ii. Starting at 5 years of age = annual blood or urinary fractionated metanephrines, audiology assessment every 2 years, MRI with contrast of the interval auditory canal in those with repeat ear infections iii. Starting at 16 years of age = annual abdominal USS, MRI of the abdomen, brain and spine every 2 years

Answer 183

1. Key points a. Sporadic condition characterised by a LARGE facial nevus and neurodevelopmental abnormalities 2. Genetics a. NOT inherited b. All reported cases sporadic 3. Features a. Nevus is located on the forehead and nose and tends to be midline i. May be faint during infancy but later becomes hyperkeratotic, with yellow-brown appearance b. 2/3 have associated neurological findings  cortical dysplasia, glial hamartoma, low-grade glioma i. Cerebral and cranial anomalies (hemimegalencephaly + enlargement of lateral ventricle) = 70% c. Consequences i. Epilepsy as high as 75% ii. Intellectual disability as high as 60% iii. Focal neurological signs including hemiparesis and homonymous hemianopia may be seen

Answer 184

Aetiology unknown -> ?association not syndrome Posterior fossa malformation, haemangioma of the face, arterial nomalies, cardiac anomalies, eye abnormalities (+/- sternal clefting and supraumbilical raphe) a. Features i. Posterior fossa malformation 1. Include: hypoplasia or agenesis of the cerebellum, cerebellar vermis, corpus callosum, cerebrum and septum pellucidum 2. CVA anomalies can result in acquired, progressive vessel stenosis with acute ischaemia ii. Haemangiomas of the face (large or complex) 1. May be associated with a Dandy-Walker malformation 2. Typically ipsilateral to the aortic arch iii. Arterial anomalies iv. Cardiac anomalies 1. Include: coarctation of aorta, aplasia or hypoplastic carotid arteries, aneurysmal carotid dilatation, aberrant left subclavian artery v. Eye abnormalities 1. Include: Glaucoma, cataracts, microphthalmia, optic nerve hypoplasia b. Also referred to as PHACES syndrome – when ventral developmental defects present: i. Sternal clefting ii. Supraumbilical raphe c. Other features i. 44% language delay ii. 35% gross motor delay iii. 8% fine motor delay iv. 50% abnormal neurological exam

Answer 185

1. Key points a. Disorder that affects the skin, hair, teeth, nails, eyes and CNS b. Primarily occurs in females 2. Genetics a. Produced by functional mosaicism b. Random X-inactivation of X-lined dominant gene that is lethal in males – IKBKG 3. Clinical manifestations a. Skin lesions = evolve through four stages i. Blistering = birth to 4 months 1. Can be confused for herpes ii. Wart like rash = for several months iii. Swirling macular hyperpigmentation (age 6 months to adulthood) iv. Linear hypopigmentation (hairless) b. Other features = present in 80% i. Alopecia = 40% ii. Dental anomalies = 80% 1. Hypodontia 2. Abnormal tooth shape iii. CNS manifestations = 30% 1. Seizures 2. Hemiplegia 3. Hemiparesis 4. Spasticity 5. Microcephaly 6. Cerebellar ataxia iv. Dystrophic nails v. Ocular = >30% (however 90% have normal vision) 1. Neovascularization of the retina  detachment 2. Microphthlmaos 3. Strabismus 4. Optic nerve atrophy c. Clinical consequences i. Seizures ii. Intellectual disability iii. Developmental delays 4. Diagnosis a. 1 major criterion (skin lesion) in a female i. Wood’s lamp examination can be helpful to identify pigmentary abnormalities b. Molecular testing available i. In males pathogenic mutation can confirm diagnosis if clinical features inconclusive (UNCOMMON) 5. Treatment a. Treatment of manifestations i. Standard management of blisters and skin infections ii. Dental care +/- implants iii. Cryotherapy and laser photocoagulation to reduce risk of retinal detachment iv. Standard management of seizures b. Prevention of secondary complications i. Standard measures to reduce risk of skin infection ii. Evaluate for retinal detachment if vision decreases, strabismus appears, or head trauma c. Surveillance i. Eye examination = very regular eye examination; reduce to annually after 3 years ii. Neurological functional assessment

Answer 186

Neuroaxis • Upper motor neuron = innervate lower motor neurons • Lower motor neurons = innervate skeletal muscles and cranial nuclei o Anterior horn cell o Peripheral nerve – lined with axon from Schwann cell o NMJ o Muscle • Lesions at ANY level of the neuraxis can cause hypotonia/weakness Lower Motor Neurons • Ventral horn spinal cord (for control of body) • Motor nuclei of cranial nerves in brainstem (for movement of the eyes, moth and face) • If destroyed then the muscle becomes totally paralysed and cannot be activated by the upper motor neurons OR by reflex inputs • Also exert trophic influence and without them, muscles atrophy Upper Motor Neurons • From motor region of cortex or brain stem with descending projections (mediate voluntary activation of the lower motor neurons) o Lesions results in spasticity, muscle weakness, exaggerated reflexes and a flaring of toes and extensor plantar response known as the Babinski sign o Note that lower motor neurons can still be activated by reflex inputs even though voluntary control is lost • Comparable cortical projections innervate cranial nerve motor nuclei (for the control of skilled movements of the face and mouth

Answer 187

Neuromuscular Junction • Action potential moves down the nerve and reaches the synapse • Release of acetylcholine into the synapse • Acts on membrane receptor on muscle membrane • Results in influx of calcium + contraction Muscle • Muscle made up of fascicles • Within each fascicle lots of muscles fibres • Within myofibrils containing myofilaments • Myofilaments contain actin and myosin to form sarcomere – contractile apparatus Two actins move across myosin resulting in contraction

Answer 188

1. Myopathies (congenital myopathies) and dystrophies a. Usually PROXIMAL b. Myopathies tend to have static dysfunction, dystrophies are progressive c. Myopathies can be associated with pain, whereas dystrophies do not get pain d. Tendon stretch reflex preserved 2. Neuropathies a. Usually DISTAL b. Tendon stretch reflexes are LOST c. Fasciculation suggests denervation 3. NMJ a. Characterised by fatigability

Answer 189

1. Classification a. Central b. Peripheral 2. Floppy weak vs floppy strong a. Floppy weak – neuromuscular -> no or reduced antigravity movements b. Floppy strong – central -> can move against gravity (may have mild weakness) 3. Examination a. Muscle tone i. Resistance to passive movement ii. Phasic tone = appendicular tone = tone in the extremities iii. Postural tone = axial tone = Tone in the axial muscles (neck, trunk) iv. Note 1. Central causes – may see reduced axial tone but increased appendicular tone 2. LMN causes – reduced axial and appendicular tone, plus weakness 3. Spasticity may not be evident in the first few months of life b. Reflexes i. If reflexes are truly absent (best to tap with fingers) 1. Neuromuscular disorder probable 2. Reflexes are usually absent in a. Neuropathies b. Anterior horn cell disorders (eg. SMA) ii. Reflexes may be present (normal or reduced) in 1. Muscular disorders 2. NMJ disorder c. Summary i. Posture at rest = frog leg posture ii. Activity at rest = spontaneous and antigravity iii. Posture with specific manoeuvres 1. Ventral suspension, traction response iv. Activity with specific manoeuvres 1. Traction response to flexor muscle of arm and leg 2. Maintain posture d. ALWAYS EXAMINE MOTHER i. Floppy baby that you think has a peripheral cause  evaluate mother for myotonia ii. Congenital myotonic dystrophy – assess for myotonia (ask them to squeeze hands and then release) 4. Note a. Weakness and areflexia are probably the two best discriminators of ‘central’ hypotonia and neuromuscular disease i. Weak + areflexic = neuromuscular eg. SMA, congenital myopathy (floppy weak) ii. Cerebral malformation = centrally hypotonic, not particularly weak (floppy strong) b. Although encephalopathy and seizures point to a ‘central cause’, a congenital neuromuscular disorder may predispose to perinatal hypoxia c. Central cause most common – particularly HIE and sepsis d. If you have a neuromuscular condition from birth at higher risk of HIE

Answer 190

``` Causes: HIE (most common) Infection Endocrine Genetic/syndromal: t21, Fragile X, PWS Cerebral malformations Demyelination Metabolic eg. Zellweger syndrome Spinal cord disorder Benign congenital hypotonia (dx of exclusion) ``` ``` Features (general): Dysmorphic features Malformations of other organs Reduced alertness Seizures Macro or microcephaly Global delay (vs isolated motor delay) Hx of difficult delivery Normal or brisk tendon reflexes Fisting of hands, scissoring on vertical suspension ```

Answer 191

``` Causes: Anterior horn cell • SMA and SMA plus syndromes • SMA mimics eg. mitochondrial disease Neuropathies • Demyelinating and axonal infantile neuropathies Neuromuscular junction • Transient autoimmune neonatal myasthenia • Congenital myasthenia syndromes Muscle • Congenital muscular dystrophies • Congenital myopathies • Metabolic myopathies eg. Pompe • Congenital myotonic dystrophy ``` ``` Features: Weak + Areflexic = KEY Reduced in utero movements Failure of movement on postural reflexes Myopathic facies Fasciculations – check tongue (at rest) ** severe denervation Muscle atrophy Ptosis Impaired extra-ocular movements Contractures, DDH, orthopaedic abnormalities Family history of neuromuscular disorder ```

Answer 192

1. History a. Acquired vs congenital b. Family history 2. Examination a. Dysmorphic – myopathic, or other anatomical change b. Distribution of weakness c. Distribution of sensory change – anaesthesia, paraesthesia vs other d. Specific maneuvers i. Gait – waddling gait (proximal) ii. Gower’s iii. Myotonia iv. Going up and down 1 foot per step = demonstrates good proximal strength v. Hopping + heel-toe walking = demonstrates good distal strength (can be impaired in neuropathy) 3. DDx a. Muscle b. Nerve c. NMJ 4. Investigations a. Lab testing b. Genetic testing c. Electrical studies d. Biopsy

Answer 193

i. Lower motor neuron – spinal cord or brainstem  muscle ii. Axon – which forms peripheral nerve iii. Neuromuscular junction iv. Muscle fibre

Answer 194

``` Serum enzymes: CK (MM skeletal muscle, MB cardiac, BB brain) Molecular genetic markers - copy number variant (CMT1A) - dystrophin gene - microarray - sequencing for point mutations Nerve conduction studies - conduction = velocity = myelin - amplitude = number of nerves/muscle fibres = axonal loss (note also if muscle is weak, size of response will be reduced despite normal neuron) EMG Imaging Muscle biopsy - traditionally most important and specific diagnostic study of most neuromuscular disorders - immunohistochemistry e.g. dystrophin Nerve biopsy Cardiac evaluation ```

Answer 195

i. Any condition where muscle fibres fragile results in elevated CK ii. CK most clinically relevant – 3 isoenzymes 1. MM skeletal muscle, MB for cardiac muscle, BB for brain iii. Characteristically elevated in muscular dystrophy eg. Duchenne muscular dystrophy iv. DDX = inflammatory, myopathy, muscular dystrophy, metabolic, drug toxicity, endocrine (hypothyroid, hypoparathyroid), idiopathic, denervation, infectious v. DMD – usually in 10’s of thousands vi. Very elevated = rhabdomyolysis vii. Low CK 1. Decreased muscle mass = myosin loss in late stage dystrophy 2. Corticosteroid treatment 3. Late dermatomyositis 4. Multi-organ failure 5. Hyperparathyroidism 6. Rheumatic disease = active inflammation, rheumatoid arthritis, SLE, spondyloarthropathies, fasciitis, perimyositis Marked elevation consistent with congenital muscular dystrophies (DMD, BMD, FSH MD, limb girdle MD)

Answer 196

i. Nerve conduction velocity increases with age 1. Also affected by temperature + limb length 2. Used standardised reference values ii. Motor and sensory nerve conduction velocity can be measured by EPS using surface electrodes 1. Motor = measure Compound Muscle Action Potentials (CMAPs) a. Axonal = lower amplitudes but normal velocity b. Demyelinating = latency and slower conduction velocity 2. Sensory = measure Sensory Nerve Action Potential (SNAPs) iii. Decrement = useful for diagnosis of NMJ problems iv. Increment = classically seen in postsynaptic NMJ problem eg. botulism v. CONDUCTION 1. Conduction velocity depend mostly on the integrity of the myelin sheath eg. CMT type 1 2. Demyelinating process a. Conduction velocity <50% normal b. Sensory fibres affected first c. In advanced demyelination sensory may be lost completely vi. APMPLITDE 1. Any pathology which decreases the number of nerve fibres or muscle fibres responding will reduce the amplitude eg. CMT type 2 (axonal neuropathy) 2. Axonal loss a. Sensory fibres affected first decreasing amplitude b. As the lesion becomes more severe, motor amplitudes will be decreased c. Velocity will also be slowed due to dropout of the fast conducting fibres

Answer 197

• Myopathies = FUNCTIONAL o In general, genetic disorders of the contractile apparatus cause myopathies o Myopathies are usually more static disorders of muscle contraction with characteristic pathological changes that do not change greatly over time o Normal CK (or mildly elevated) • Dystrophies = DESTRUCTIVE o Genetic disorders of the supporting structures – sarcolemmal proteins and proteins which anchor the contractile apparatus in place – cause muscular dystrophies o Dystrophies are progressive disorders in which muscle pathology is characterised by degeneration and regeneration of muscle fibers o Elevated CK • Types of abnormal muscle activity o Fasciculation = spontaneous, random twitching of a group of muscle fibres o Fibrillation = spontaneous contraction of a single muscle fibre, NOT visible through skin o Myokymia = repetitive fasciculations causing a quivering or undulating twitch o Myotonia = disturbance in muscle relaxation following voluntary contraction or percussion o Neuromyotonia = continuous muscle activity characterised by muscle rippling, muscle stiffness and myotonia

Answer 198

Fascioscapulohumeral muscular dystrophy | Myotonic dystrophy

Answer 199

Fascioscapulohumeral muscular dystrophy | Limb girdle muscular dystrophy

Answer 200

Oropharyngeal dystrophy Mitochondrial myopathies (CPEO) NMJ disorders

Answer 201

Fascioscapulohumeral muscular dystrophy | Limb girdle muscular dystrophy

Answer 202

1. Key points a. Heterogenous group of primary muscle disorders that are present from birth – expression may be delayed until infancy or childhood b. Rare disease c. Most of these disorders have sub-cellular abnormalities that can be demonstrated only by muscle biopsy + Immunohistochemical and electron microscopy d. Genetic basis for many of the congenital myopathies e. Many congenital myopathies are non-progressive conditions – but some patients show slow clinical deterioration accompanied by additional changes in muscle biopsy f. In some congenital myopathies (eg. Nemaline myopathy) – clinical expression can be severe and life threatening due to dysphagia and respiratory and/or cardiac failure g. CK usually normal 2. Classification – most common a. Nemaline myopathy b. Central core disease c. Centronuclear/ myotubular myopathy d. Congenital fiber type disproportion 3. Clinical manifestations a. Highly variable b. Affected individuals usually present at birth or in infancy c. Most common manifestations i. Hypotonia, weakness, hypoactive deep tendon reflexes – ‘floppy infant’ / floppy weak 1. Prominent facial weakness common 2. Dysmorphic features – dolichocephaly (long, narrow face), high arched palate 3. Usually generalised weakness more prominent in proximal and limb girdle weakness ii. Delayed motor milestones if later presentation – frequent falls, weakness iii. Normal intelligence d. Weakness tends to be stable or slowly progressive over time e. Most severe presentation – floppy infant with frog-leg posture and respiratory and bulbar weakness f. Less common i. Dysmorphic features ii. Eye movement abnormalities iii. Cardiac involvement

Answer 203

One of the more common congenital myopathies (second to nemaline) 1. Key points a. First congenital myopathy described b. Inherited autosomal dominant – variable expression 2. Genetics a. Autosomal dominant – variable penetrance c. Related to ryanodine (RYR1) mutations i. >80% have RYR1 mutations 3. Clinical manifestations a. Typical facial and proximal weakness i. Most patients walk 3-4 years ii. Weakness often slowly progressive iii. Occasional atypical presentations b. Orthopaedic problems relatively common i. CDH, kyphoscoliosis 4. NOTE: a. Tendency to malignant hyperthermia (Nelsons says ALL patients get malignant hyperthermia) b. ANY PATIENTS with muscle condition should NOT have volatile anaesthetics

Answer 204

1. Key points a. Most common congenital myopathy b. Various clinical forms i. Severe congenital (most common) ii. Intermediate congenital iii. Classical (or typical congenital) iv. Childhood-onset, adult-onset (rare) c. NOTE: key difference: Centronuclear – eye movements involved 2. Genetics a. Autosomal dominant, autosomal recessive and X-linked dominant form in girls all reported b. At least 9 genetic mutations identified – ACTA1 most common c. All encode muscle thin filament or intermediate proteins

Answer 205

Extraocular muscles spared, no cardiac involvement a. Neonatal form i. Decreased fetal movements ii. Neonates suffer from hypoxia and dysphagia iii. Severe and usually fatal due to respiratory failure from birth iv. Respiratory insufficiency, feed intolerance b. Infantile form i. Generalised hypotonia and proximal weakness (can include bulbar-innervate and respiratory muscles), and a very thin muscle mass are characteristic ii. Head is doliochecephalic (long skull) and the palate is high arched or even cleft iii. Muscles of the jaw may be too weak to hold it closed iv. Arthrogryposis may be present v. Motor delay c. NOTE i. Infants with severe neonatal and infantile nemaline myopathy have facies and phenotype that are initially indistinguishable from those of neonatal myotonic dystrophy, but their mothers have normal facies ii. Juvenile form is the mildest and NOT associated with respiratory failure iii. Extra-ocular muscles are spared iv. NO cardiac involvement

Answer 206

4. Investigations a. CK = normal or mildly elevated b. Muscle biopsy = diagnostic -> Nemaline rods (also shows CMFTD or at least type I fibre predominance) c. Genetics i. Heterogenous ii. ACTA1 most common iii. All encode muscle thin filaments or intermediate proteins 5. Treatment a. Therapy is supportive b. Survivors confined to wheelchair and usually unable to overcome gravity c. Proximal and distal muscles are involved d. Congenital arthrogryposis can occur and predicts a poor prognosis e. Gastrostomy is needed for dysphagia f. In the juvenile form, patients are ambulatory and able to form ADL g. Weakness is usually NOT progressive but some patients have more difficulty over time h. Cardiomyopathy is uncommon i. Death is usually from respiratory insufficiency +/- LRTI

Answer 207

1. Pathogenesis a. Loss of myotubularin protein, leading to structural and functional abnormalities in the organisation of T tubules and sarcoplasmic reticulum, and defective excitation-contraction coupling 2. Genetics b. X-linked recessive inheritance most common 3. Clinical manifestations a. Fetal movements can decrease late in gestation b. Polyhydramnios common due to pharyngeal weakness of the fetus and inability to swallow amniotic fluid c. At birth – affected infants have at thin muscle mass involving axial, limb girdle and distal muscles; severe generalised hypotonia, and diffuse weakness d. Respiratory effort may be ineffective, requiring ventilatory support e. Gavage feeding may be required because of weakness of the muscles of sucking and deglutition f. Testes often undescended g. Facial muscles may be weak; do NOT have characteristic facies of myotonic dystrophy h. Ptosis and ophthalmoplegia may be present i. NOT associated with cardiomyopathy 4. Investigations a. CK/EMG/nerve conduction/ECG/CXR = normal f. Genetic tests = can be performed in prenatal period; in most cases however diagnosed at birth g. Muscle biopsy = diagnostic i. >90% of muscle fibres small and have large centrally placed, vesicular nuclei ii. Histochemical stains for oxidative enzymatic activity and glycogen reveal a central distribution as in fetal myotubes 5. Treatment a. Supportive only b. Progressive scoliosis -> long posterior fusion 6. Prognosis a. 75% of severely affected neonates with the X-linked disease die in the first few weeks or months of life b. Survivors do not experience a progressive course but have major physical handicaps, rarely walk, and remain severely disabled c. Late onset and especially autosomal dominant forms have a much better prognosis with milder weakness

Answer 208

1. Key points a. Occurs as an isolated congenital myopathy but also develops in association with unrelated disorders that include nemaline rod disease, Krabbe disease early in the course before expression of the neuropathy, cerebellar hypoplasia and other brain malformations b. Should be regarded as a syndrome unless specific genetic mutation confirmed c. Non-progressive disorder 4. Clinical manifestations a. If isolated without other diseases – non-progressive disorder present at birth b. Generalised hypotonia and weakness c. Usually no respiratory distress or dysphagia d. Contractures are present at birth in 25% of patients e. Poor head control and gross motor developmental delay – not walking until 18-24 months f. Subluxation of the hips can occur due to hypotonia g. Muscle bulk is reduced h. Cardiomyopathy is a rare i. Facies of children with CMFTD often raise suspicion – head is dolichocephalic and facial weakness present, palate high arched, thin muscles of trunk and extremities 5. Investigations a. CK, ECG, EMG, NCS – all normal b. Muscle biopsy – shows disproportion in size and elative ratios of histochemical fiber types – type I fires are uniformly small and type II are hypertrophic; type I fibers are more numerous than type II 6. Treatment a. No treatment available

Answer 209

(Nelsons) Episodic, reversible weakness or paralysis, known as periodic paralysis, is associated with transient alterations in serum potassium levels, usually hypokalemia but occasionally hyperkalemia. All familial forms of periodic paralysis are caused by mutations in genes encoding voltage-gated ion channels in muscle: sodium, calcium, and potassium. Nonhereditary causes of periodic paralysis are caused by a diverse group of disorders that affect potassium balance. During attacks of hypokalemic paralysis, myofibers are electrically unexcitable, although the contractile apparatus can respond normally to calcium. The genetic disorder is inherited as an autosomal dominant trait. It is precipitated in some patients by a heavy carbohydrate meal, insulin, epinephrine including that induced by emotional stress, hyperaldosteronism or hyperthyroidism, administration of amphotericin B, or ingestion of licorice. Attacks of hypokalemic paralysis often begin in infancy, particularly in the hyperkalemic form, and the disease is nearly always symptomatic by 10 yr of age, affecting both sexes equally. Periodic paralysis is an episodic event; patients are unable to move after awakening and gradually recover muscle strength during the next few minutes or hours. All four extremities are involved. Muscles that remain active in sleep, such as the diaphragm, extraocular muscles (rapid eye movements), and cardiac muscle, are not affected. Patients are normal between attacks, but in adult life the attacks become more frequent, and the disorder causes progressive myopathy with permanent weakness even between attacks. The usual frequency of attacks in childhood is once a week. Paralytic attacks of hypokalemic periodic paralysis are best treated by the oral administration of potassium or even fruit juices that contain potassium. A low sodium intake and the administration of carbonic anhydrase inhibitor (acetazolamide) are effective.

Answer 210

1. Key points a. Generally progressive muscle disorders b. Characterised by muscle weakness and hypertrophy c. Respiratory and cardiac involvement d. CNS relatively more common – for congenital muscular dystrophies e. Pathology = changes within cytoskeleton rather than contractile apparatus f. Excludes neurogenic diseases such as SMA, non-hereditary myopathies such as dermatomyositis, non-progressive and non-necrotizing congenital myopathies such as CMFTP, and non-progressive inherited metabolic myopathies 2. Muscular dystrophy must meet four criteria a. Primary myopathy b. Genetic basis c. Progressive course d. Degeneration and death of muscle fibers occur 3. Classification a. Age of onset, pattern of weakness i. Congenital 1. Brain involvement – Fukuyama, Muscle-Eye-Brain, Walker-Warburg 2. Merosin (lamininalpha2) positive/negative 3. Specific clinical features – eg. brain/eye involvement, rigid spine etc ii. Later onset 1. Limb girdle – LGMD 1/2, DMD/BMD 2. Fascioscapulohumeral – FSH, EDMD b. Inheritance i. AD – myotonic dystrophy, FSHD, LGMD type 1 ii. AR – congenital muscular dystrophies, LGMD, type 2 iii. X-linked – DMD/BMD, EDMD

Answer 211

1. Key points a. Dystrinopathies result from pathogenic variants of DMD which encodes the protein dystrophin i. Range from mild (asymptomatic increase in CK and muscle cramps) to severe (DMD/BMD) b. Dystrophinopathies i. DMD ii. BMD iii. Familial cramps + myalgia iv. Other – X-linked dilated cardiomyopathy, isolated elevated CK, manifesting carrier females, isolated quadriceps myopathy 4. Epidemiology a. DMD = 1/5000 b. BMD = 1/35,000 2. Genetics a. Gene i. DMD is the only gene in which pathogenic variants cause dystrinopathies 1. Second largest gene known = 1% of X-chromosome, 0.1% of the entire genome iv. BMD vs DMD 1. DMD = disruptions of the reading frame (= frame-shift) results in loss of dystrophin 2. BMD = maintain reading frame (= in frame mutations) -> abnormal but largely functional b. Inheritance i. X-linked manner – carrier females have a 50% chance of transmitting DMD pathogenic variant in each pregnancy 1. Sons who inherit  muscular dystrophy 2. Daughters who inherit  cardiomyopathy; can have milder phenotype of muscular dystrophy ii. NOTE: 1. 2/3 of DMD inherited, 1/3 new mutation 3. Pathogenesis a. Dystrophin links the internal cytoskeleton to the extra-cellular matrix b. The N (amino) terminus of dystrophin binds to F-actin and the carboxyl (C) terminus to the dystrophin-associated protein complex (DAPC) at the sarcolemma c. The DAPC links the actin cytoskeleton to the extracellular matrix – stabilises sarcolemma during cycles of contraction and relaxation, transmits force generated in the muscle sarcomeres to the extracellular matrix d. DAPC is also involved in cell signaling e. Loss of dystrophin causes loss of DAPC at the sarcolemma  fragility of sarcolemma during repeated cycles of muscle contraction and relaxation  calcium influx, apoptosis +necrosis  inflammation + fibrosis f. Disrupted muscle architecture, signaling defects, secondary loss of other proteins

Answer 212

1. Clinical manifestations a. Delayed motor milestones – mean age walking 18 months (normal <18 months) b. Gait difficulties i. Broad-based, waddling gait, proximal weakness ii. Trouble climbing steps, Gower’s manoeuvre iii. Persistent toe-walking, flat feet c. Fatigability, frequent falls i. Inability to run or to keep up with peers d. Calf/thigh cramps, hypertrophy e. Speech delay, learning problems i. IQ shifted 15-20 points to left ii. Increased ADHD/autism spectrum f. Cardiomyopathy 4. Examination (facial and extra ocular muscles spared) a. Enlarge, rubbery muscles i. Caused by hypertrophy of some muscle fibres, infiltration of muscle by fat, and proliferation of collagen ii. Calves +/- quads, gluteal, deltoid iii. Early hypertrophy, late pseudohypertrophy b. Tongue and forearm hypertrophy c. Gower’s = roll from supine to prone; wide-based, walk up legs d. Trendelenberg gait e. Deep tendon reflexes – preserved until terminal stages f. Weak neck flexors g. Lumbar lordosis 5. Diagnosis a. CK very level high = 10-20x normal (often 50-200x normal) b. AST and ALT also raised c. TFT should be checked = hypothyroidism can mimic DMD d. Genetic testing e. Muscle biopsy = only done if high suspicion of DMD but genetic tests negative i. Immunohistochemistry – DMD absent dystrophin, BMD decreased/abnormal dystrophin

Answer 213

2. Natural history a. <5 years = presentation  delayed milestone b. 3-6 years = honeymoon phase c. 8 years = difficulty climbing stairs, walking i. Loss of function may not correlate with measured strength ii. Progressive contractures of Achilles, ITBs, hips d. 12 years = non-ambulatory e. 13 years = wheelchair dependent by age 13 f. Respiratory or cardiac failure late teens early 20s i. Respiratory – weak and ineffective cough g. Pharyngeal weakness can occur resulting in dysphagia h. Few survive after 3rd decade – respiratory complications and cardiomyopathy cause of death i. Death average is 21 years – usually respiratory, cardiac (10%) ii. Good physiotherapy and respiratory/cardiac care – aim to live to mid-30s 3. Complications a. Contractures = most commonly involve ankles, knees, hips and elbows b. Scoliosis = common i. Thoracic deformity further compromises pulmonary capacity and compresses the heart ii. Progresses more rapidly than in ambulant individuals c. Cardiomyopathy = including persistent tachycardia and myocardial failure i. Seen in 50-80% of patients with this disease ii. Severity does NOT correlate with the degree of skeletal muscular weakness d. Intellectual impairment = occurs in all patients, although 20-30% have IQ <70 i. Majority have learning disabilities

Answer 214

a. Key principles i. Genetic counselling ii. Maintaining ambulation (maintains independence, reduces risk of scoliosis and contractures) 1. Steroids prolong ambulation by 2 years iii. Prevention and treatment of contractures iv. Anticipatory monitoring for DMD complications v. Medical therapy of DMD vi. Palliative care c. Orthopaedic/muscular i. Prevent and treat contractures, physio, stretching, night splints, surgical release ii. Scoliosis 1. Surgery less often required 2. Average age at surgery 14 years d. Respiratory i. Restrictive deficit resulting from weak intercostal and associated muscles ii. VC in early years increases with age and growth, plateaus in early teens then declines steadily iv. Respiratory failure typically occurs in late teens or early 20s – nocturnal hypoventilation and hypoxia v. Nocturnal assisted ventilation provides symptomatic relief vi. Respiratory status ultimately worsens and is typically associate with demise e. Cardiac i. Cardiomyopathy 1. Decreased LV contractility - commonly asymptomatic/ subclinical 2. 1/3 teenagers, 1/2 by 18 years, all by >18 years 3. Symptoms of heart failure often minimal until late owing to musculoskeletal limitation ii. Manifestations = sinus tachycardia, ectopic rhythms – 90% abnormal ECG iii. Myocardial fibrosis, occasional CCF iv. DCM > hypertrophic > conduction defects v. Cardiac death in 10% of cases vi. Cardiomyopathy more common in BMD vii. Increasing prevention of Duchenne cardiomyopathy – early treatment with ACE-I and beta blockers f. Non-pharmacological i. Physiotherapy ii. Good nutritional state is important g. Pharmacological i. Glucocorticoids 1. The only medical treatment shown to be effective in DMD (myogenesis, increase muscle mass, stabilise muscle fibre) 3. Steroids improve strength rapidly in DMD a. Usually offered at time of decline and frequent falls (4-6 years), continue until ambulation lost b. Would be offered earlier if side-effects were less of an issue c. Effect measurable at 10 days, maximal at 3 months 4. Prolongs independent ambulation by 2-3 years 5. Preserve respiratory muscle function 6. Delays onset of cardiomyopathy and scoliosis 7. Prolongs survival 8. Strength usually improves initially, but the long-term complications of steroids particularly weight gain and osteoporosis, offset this advantage or can result in greater weakness i. Surveillance i. School functioning ii. Orthopaedic/muscular = contractures, scoliosis iii. Cardiology 1. Annual or biannual examination by cardiologist from age 10 years 2. NOTE: female heterozygous require cardiac evaluation iv. Respiratory = baseline pulmonary function testing

Answer 215

Clinical manifestations • Later onset skeletal muscle weakness (>5 years); some individuals ambulatory until their 20s • Progressive symmetrical muscle weakness and atrophy (proximal > distal) often with calf hypertrophy o Weakness of quadriceps may be the only sign • Activity-induced cramping (in some individuals) • Flexion contracture of elbows (if present, late in the course) • Heart failure from DCM more common – characterised by left ventricular dilatation o Note females heterozygous for DMD pathogenic variant are at an increased risk of DCM • Wheelchair dependency (If present, after age 16) • Mean age of death is mid 40’s • Preservation of neck flexor muscles (differentiates BMD from DMD)

Answer 216

1. Key points a. Generally progressive muscular disorders – mainly affect hip and shoulder girdles i. Distal muscles also eventually become atrophic and week b. Onset 2nd-6th decade, M=F c. Rarely appear before middle or late childhood, often delayed until early adulthood d. CK elevation more marked in AR than AD LGMDs e. Pathology = cytoskeletal rather than contractile f. Remember – not all limb girdle weakness is LGMD – remember SMA3 and 4 g. Hypertrophy of the calves and ankle contractures develop in some forms – causing potential confusion with BMD 3. Clinical manifestations a. Musculoskeletal i. Present with muscle weakness and hypertrophy 1. Usually pelvic girdle first 2. Early facial, distal and extra-ocular weakness NOT seen 3. Weakness of neck flexor and extensor 4. Average 10-15 years until other girdle is affected ii. Variable CNS involvement iii. Also c/o low back pain iv. Confinement to a wheelchair around 30 years of age v. Rate of progression varies significantly b. Cardiac i. Many subtypes have cardiac involvement ii. Cardiomyopathy c. Respiratory i. Respiratory failure 4. Treatment = supportive

Answer 217

1. Key points a. Autosomal dominant condition b. Presents in later adolescence and adulthood – can occasionally have onset <10 years of age (infantile) c. Affects face and scapula muscles and humeral muscles (upper arm) – can also affect proximal hip flexors and tibialis anterior muscles and lower abdominal muscles 2. Genetics a. Chromosome 4 b. Due to deletion of triplet repeat – D4Z4 – well methylated, silent area; usually 11-100 c. In FSHD <10 – results in protein production – DUX4 – toxic, resulting in muscle inflammation and degradation d. Majority FSHD1, small number FSHD2 (gene on chromosome 2, SMCHD1) 3. Clinical manifestations a. Earliest and most severe weakness in facial and shoulder girdle i. Trapezius first muscle affected ii. Scapular winging is prominent – may be asymmetrical b. The mouth is rounded and appears puckered because the lips protrude i. Cannot smile, whistle, drink through a straw, mask like face c. Inability to close the eyes during sleep is common – some patients also have extra-ocular muscle weakness although ophthalmoplegia is rarely complete d. Unable to do sit-up i. Beevor sign when lift head up the umbilicus is pulled upwards – lower abdominal muscles do not contract, upper abdominal muscles pull umbilicus upwards e. Pharyngeal and tongue weakness usually absent f. Muscles of the hip girdle and thigs eventually lose strength and undergo atrophy 4. Investigations a. CK varies from normal to elevated b. EMG non-specific c. Molecular genetic diagnosis – most specific 5. Treatment a. Nil b. Steroids do not work

Answer 218

AKA scapuloperoneal or scapulohumeral dystrophy 1. Genetics a. Rare X-linked recessive dystrophy b. Different mutations associated with condition 2. Clinical manifestations a. Begins between 5—15 years of age b. Many patients survive to adult life c. Note, rare severe infantile presentation d. Muscles do NOT exhibit pseudohypertrophy as in DMD/BMD e. Contractures of elbows and ankles develop early f. Muscle becomes wasted in scapulohumeroperoneal distribution g. Facial weakness does NOT occur  distinguished from autosomal dominant form of scapulohumeral and scapuoperoneal syndrome h. Myotonia absent i. Intellectual function normal j. DCM – severe and often cause of death, usually due to arrythmia k. Stroke – secondary to arrythmia 3. Investigations a. CK – mild to moderately elevated b. Muscle biopsy – necrosis c. Genetic testing of specific genes available 4. Treatment = supportive

Answer 219

1. Key points a. Clinically and genetically heterogenous disorders b. Two major forms – DM1, DM2 i. DM1 = classified into congenital, childhood, classic and mild phenotypes ii. DM2 = rarely expressed in infancy or early childhood c. Both similar multisystem disorders i. Skeletal muscle weakness and myotonia (ie. abnormally slow or delayed muscle relaxation following normal muscle contraction) ii. Cardiac conduction abnormalities iii. Cataracts iv. Other abnormalities = endocrine, gastrointestinal d. Most common muscular dystrophy among adults of European ancestry 2. Epidemiology a. Most prevalent inherited neuromuscular disease in adults b. Male: female = 1:1 c. Variable penetrance 4. Pathophysiology a. In both the repeat expansion is transcribed into RNA but remains untranslated b. RNA toxicity from the expanded repeat

Answer 220

3. Genetics a. AD – usually inherited via mother b. Variable penetrance c. DM1 i. Expansion of cytosine-thymine-guanine (CTG) trinucleotide repeat in the 3’-untranslated region of the dystrophia myotonica protein kinase gene (DMPK gene) 19q13.3 ii. Expansion is associated with an earlier age of onset and more severe clinical phenotype 1. Normal alleles = 5-35 repeats 2. Pre-mutation = 35-49 repeats (asymptomatic, offspring at risk) 3. Full penetrance alleles = >50 CTG repeats  symptoms d. DM2 i. Expansion of cytosine-cytosine-thymine-guanine (CCTG) tetranucleotide repeat expansion located in ZNF9 gene ii. No definite correlation between repeat length and disease severity 5. Phenotypes a. Congenital i. Most severe ii. Respiratory failure and early death common b. Classic DM1 i. Most common ii. Presents in adolescence or adulthood with proximal muscle weakness c. Adult DM1 i. Cataract and mild myotonia in adulthood

Answer 221

Numerous and multisystem. Common feature is weakness and myotonia (abnormal relaxation after normal contraction). Weakness is predominantly facial and distal (forearms, hands, ankles) - exception to general dystrophy rule of proximal>distal. a. Cranial i. Face = temporalis muscle atrophy ii. Ptosis iii. Palate +/- tongue – indistinct speech (later) b. Proximal muscles i. Quadriceps, diaphragm and intercostals, later in disease ii. Distal muscle involved (NB. usually spared in other myopathies) 1. Wrist and finger extension, grip ankle > toe dorsiflexors c. Myotonia i. Delayed relaxation of muscle after voluntary or involuntary contraction ii. Evoked by percussion or muscle contraction iii. Onset 5-25 years – not in neonates iv. Rarely causes disability or too many symptoms - can be uncomfortable v. Useful for diagnosis – not seen in affected neonates but will be often present in affected parent (usually mother) d. CNS i. Personality – avoidant personality, apathy, depression ii. Hypersomnia – excessive daytime sleepiness iii. Mental retardation (10%-25%) e. Eyes i. Cataracts – posterior subcapsular, multiple, punctate ii. Ptosis f. Endocrine i. Hypogonadism – testicular atrophy and primary tubular degeneration ii. Insulin resistance – diabetes mellitus iii. Pregnancy – frequent fetal loss and major complications g. Respiratory i. Reduced response to hypoxia, hypercapnia -> hypoventilation – Pickwickian syndrome iii. Aspiration pneumonia secondary to esophageal dysfunction iv. Anaesthetic complications h. Cardiac i. Conduction defects – ectopic beats; SCD ii. Tachyarrythmias + cardiomyopathy – usually late in course iv. Occasional involvement in patients <18 years – risk low <15-18 years i. Gastrointestinal i. Dysphagia (pharyngeal or esophageal) ii. Megacolon iii. Cholelithiasis iv. Constipation, faecal incontinence

Answer 222

7. Investigations a. Genetic testing diagnostic b. CK may be mildly elevated 8. Prognosis – summary a. Adult onset – mean age at death 60 years i. Minor correlation between CTG repeat length and younger age at death b. 50% of patients wheel-chair bound before death c. Cause of death i. Pneumonia and respiratory insufficiency (>30%) ii. Cardiac arrythmia (sudden death) (30%); heart block; ventricular tachyarrythmias

Answer 223

a. No specific management b. Treatment of manifestations i. AFOs, wheelchairs, assistive devices ii. Treatment of hyperthyroidism iii. Cardiac management of arrythmia 1. Arrythmias are the major issue throughout life v. Removal of cataracts vi. Hormone replacement for males with hypogonadism c. Surveillance i. Annual ECG or holter monitor ii. Fasting serum glucose iii. Eye exam every 2 years iv. Attention to nutritional status d. Anaesthetic i. Pre-operative 1. Awareness of diagnosis and avoidance of unnecessary procedures 2. Careful pre-op assessment of cardiac and respiratory status 3. ECG – specific attention to defects of rhythm and conduction defect 4. PFT 5. Minimal opiates ii. Post-operative 1. Ensure respiration is established with early physiotherapy 2. Monitor for arrythmias 3. Small dose of opiates

Answer 224

Premutation - Signs: None - CTG repeats: 38 to 49 - Age of onset/death: N/A Mild - Adult DM1 - Signs: Cataracts, mild myotonic - CTG repeats: 50 to 150 - Age of onset: 20 to 70 - Age of death: Normal life span Classical - Most common - Present in adolescence or early adulthood - Signs: Muscle weakness with respiratory failure, myotonia, cataracts, cardiac arrhythmias, excessive daytime sleepiness - CTG repeats: 50-1000 - Age of onset: 10-30 - Age of death: 48-60 Childhood onset - Signs: Psychosocial problems, low IQ, incontinence - CTG repeats: >800 - Age of onset: 1-10 - Age of death: N/A Congenital - Signs: infantile hypotonia, respiratory failure, learning disability, feeding difficulty, arthrogryposis (congenital contractures) - Antenatally: polyhydramnios, talipes, reduced FM - CTG repeats >1000 - Age of onset: birth - Age of death: 45 (neonatal deaths excluded)

Answer 225

isleading name as all muscular dystrophies are genetically determined • Used to encompass several distinct diseases that have the common characteristics of involvement at birth, but often follow a more benign clinical course than the early onset would suggest o Present with muscle weakness and hypotonia at birth or in infancy • Distinguishing feature = high association with brain malformations o Particularly disorders of cortical development such as lissencephaly/ pachygyria and polymicrogyria o Often complicated by severe epilepsy o AR inheritance is the rule • Diagnosis based on o Early onset of weakness o Markedly elevated CKD o Dystrophic process on muscle biopsy • Various subtypes o Isolated skeletal muscle o Abnormalities of CNS, muscle + eye

Answer 226

Risk of decompensation of weakness (atelectasis, resp infection, fluid shifts, medications) Risk of hypersensitivity (myotonic dystrophy) Risk of AEs (malignant hyperthermia, anaesthesia-induced rhabdomyolysis, acute hyperkalaemia)

Answer 227

1. Congenital = congenital myasthenic syndromes a. Usually present early in life with ‘floppy baby’ syndrome b. Can sometimes present later in childhood c. Genetic disorder of receptors on the post-synaptic membrane d. There is a rare familial myasthenia gravis is an autosomal recessive trait – associated with increased plasma anti-ACh antibodies e. One familial form is deficiency of motor end plate acetylcholinesterase (ACHe) f. Most congenital (familial) forms are post-synaptic defects 2. Acquired a. Usually present later in life b. Most common = myasthenia gravis c. Acquired autoimmune disorder d. Associated with antibodies against acetylcholine receptor (AChR) in most cases e. Other - Toxin-induced myasthenia (eg. botulism)

Answer 228

1. Key points a. Autoimmune disease resulting in neuromuscular blockade  characterised by rapid fatigability of striated muscle, particularly extra-ocular and palpebral muscles and those of swallowing i. Juvenile form affects children b. Antibodies to most-synaptic ACh receptors c. More common in Asians than Caucasians, females > males d. Can be associated with other autoimmune diseases – thyroid, IDM, JRA i. Always check TFTs e. Rarely associated with thymoma 2. Pathogenesis a. Acetylcholine receptor antibodies (AChR-Ab) block receptor activity at the post-synaptic motor endplate b. Results in decreased number of receptors + structural changes

Answer 229

3. Clinical manifestations (fatiguability, worse at end of day) a. Rapid fatigue of muscles = most characteristic feature b. Acquired weakness – may affect just extra-ocular muscles -> ocular myasthenia gravis i. Ptosis, ophthalmoplegia ii. Diplopia c. May cause generalised weakness i. Dysphagia, dysarthria, facial weakness, proximal limbs, respiratory muscles ii. Worse at end of day d. Other symptoms/signs i. Dysphagia and facial weakness = infants (difficulty feeding), older children (fatigue chewing) ii. Airway obstruction – in severe cases, can result in aspiration iii. Poor head control due to weakness of neck flexors iv. Involvement of appendicular muscles, distal hand muscles 4. Examination a. Earliest and most consistent signs i. Unilateral or bilateral but usually asymmetrical ptosis ii. Extra-ocular muscle weakness = progressive; NO defect in acuity itself, PEARL b. Summary of signs i. Ptosis increases progressively as patients asked to sustain up-gaze ii. Holding head off from surface is difficult + gravity cannot be overcome for >few seconds iii. Repetitive opening and closing of the fists produces rapid fatigue of hand muscles an iv. Patients cannot elevate arms for more than 1-2 minutes c. NOT present in myasthenia gravis = fasciculations, myalgias, sensory symptoms d. Tendon stretch reflexes – may be diminished but rarely are lost 5. Natural history a. 50% of ocular MG generalised within 2 years – 75% within 4 years b. Maximal disease severity is within 2 years of onset c. Spontaneous remission – more common among young patients (up to 30% of cases within 15 years of disease onset in one study) d. Symptoms worsen by undercurrent illness and some treatments (NMJ blockers, aminoglycosides) e. If untreated usually progressive and can become life-threatening due to respiratory muscle involvement and the risk of aspiration (particularly while child is unwell eg URTI/LRTI) f. Myasthenic crisis = acute or subacute severe increase in weakness in patients with MG

Answer 230

Myasthenic crisis = acute or subacute severe increase in weakness in patients with MG i. Precipitated by intercurrent infection, surgery, or emotional distress ii. May require IV cholinesterase, IVIG, plasma exchange, gavage feeding, and transient ventilatory support iii. DDx cholinergic crisis – due to overdose with anticholinesterase medications 1. Muscarinic effects include abdo cramps, diarrhoea, sweating, salivation, bradycardia, increased weakness and miosis 2. Cholinergic crisis requires only supportive care and with-holding further doses and it passes within a few hours

Answer 231

a. Serology i. Anti-AChR = 30% of affected adolescents have elevated titre 2. Seroconversion within 12 months of onset is 15% - repeat testing sometimes of value ii. Anti-MusK (anti-muscle-specific tyrosine kinase) 1. Up to 40% of seronegative adults +ve for anti-MuSK 2. MuSK localised on the NMJ and appears essential to development of this junction b. Nerve conduction studies = decremental response to repetitive nerve stimulation; muscle potentials diminish rapidly in amplitude until the muscle becomes refractory (electro decremental response) i. Motor nerve conduction velocity remains normal ii. NOT present in muscles not involved clinically c. CXR = may show enlarged thymus but NOT thymoma d. Muscle biopsy = NOT usually required – cytochemical localisation of AChR e. Clinical test = administration of short acting cholinesterase inhibitor (edrophonium) i. Ptosis and ophthalmoplegia improve in a few seconds ii. Fatiguability of other muscles decreases iii. Children <2 = neostigmine iv. Children >2 = edrophonium (note AE = arrythmia)

Answer 232

7. Treatment a. If mild – sometimes no treatment required b. Immunotherapy required to treat condition c. First line = anti-cholinesterase medications i. Examples = neostigmine, pyridostigmine ii. Note overdoses of cholinesterase inhibitors produce cholinergic crises iv. Does not influence the autoimmunity or control all symptoms v. Response may diminish with time vi. AE = abdominal pain, N+V, diarrhoea, sweating, cholinergic crisis (worsening weakness) d. Immunotherapy i. Short term = plasma exchange or IVIG 1. Plasma exchange removes Ab – results in improvement within days, lasts 4-10 weeks ii. Long term 2. Steroid therapy - usually mainstay 3. Azathioprine a. Metabolises to cytotoxic 6PM inhibiting DNA and RNA synthesis interfering with T cell b. Used as steroid sparing agent in refractory MG e. Surgical = thymectomy i. Considered in patients with high titres of anti-ACh receptor antibodies in the plasma and who have been symptomatic for 2 years Good remission rates, need to complete excise and more effective within 12 months of onset Ineffective in congenital or familial forms

Answer 233

8. Complications a. Do not tolerate neuromuscular blockade drugs (eg. succinylcholine, pancrurnium) b. Some antibiotics can potentiate MG (eg. gentamicin) 9. Prognosis a. Variable prognosis – some patients experience spontaneous remission after a period of months or years, others have permanent disease extending into adult life b. Immunosuppression, thymectomy, and treatment of hypothyroidism may provide cure c. Genetically determined congenital Myasthenic syndromes may show initial worsening in infancy but then remain static into adulthood

Answer 234

• Neonates born to myasthenic mothers have a transient myasthenic syndrome due to placental transferred antibodies • Clinical manifestations o Respiratory insufficiency o Inability to suck or swallow o Generalised hypotonia and weakness • May show little spontaneous motor activity for days to weeks; some require ventilatory support • After abnormal Ab disappear from blood and muscle tissue  regain normal function • NOT at increased risk of developing MG later in childhood • Minority develop fetal akinesia sequence with multiple joint contractures (arthrogryposis) – develops from lack of fetal movements • Cholinesterase inhibitor may be required for a few days/weeks to allow feeding (neostigmine) • No other treatment required

Answer 235

1. Key points a. Heterogenous group of genetic diseases of the neuromuscular junction b. Aetiology and pathogenesis unrelated to neonatal transient myasthenic syndrome/autoimmune myasthenia gravis c. Nearly always permanent static disorders WITHOUT remission d. Most do NOT experience myasthenic crisis e. Rarely exhibit elevation of antiACh antibodies 2. Classification a. Pre-synaptic defects i. Paucity of synaptic vesicles and decreased quantal release (synthesis) – CHAT defect * most common b. Synaptic effects = end plate acetylcholinesterase deficiency c. Post-synaptic defects - some (DOK7 and SCCMS) worsen with pyridostigmine 3. Genetics Variable b. Most autosomal recessive d. Downstream-of-kinase 7 (DOK7) is demonstrated in 85% of cases

Answer 236

4. Clinical manifestations a. Onset at birth or early infancy b. Prenatal i. Decreased fetal movements c. Neonatal i. Poor cry, suck, choking spells, stridor, apnoea, droopy eyelids ii. Hypotonia iii. Symptoms worsened by crying or activity iv. Joint contractures d. Late childhood i. Delayed motor milestones; seldom learn to run, cannot climb stairs well ii. Abnormal fatiguability on exertion iii. Cannot keep up with peers in sports iv. Ptosis, limited eye movements v. Spinal deformities, small muscles vi. Sometimes have respiratory insufficiency or failure, often precipitated by concomitant infections 5. Treatment a. Cholinesterase inhibitors (pyridostigmine) – in some cases this worsens symptoms i. Rare familial myasthenia gravis caused by absence of end plate AChE cholinesterase inhibitors are not useful; Rx ephedrine or diaminopyridicne which increase ACh release from terminal axons b. Steroids – not as helpful c. Vary based on underlying mutation

Answer 237

• MG is occasionally associated with hypothyroidism (particularly Hashimoto’s) and other collagen vascular disease • Thymoma – noted in some adults – rarely coexist with MG in children • Eaton-Lambert syndrome – seen in adults with carcinoma of the lung o Rare in children, but has been reported with lymphoproliferative disorders and neuroblastoma • Post-infectious MG in children is transitory and usually follows VZV infection by 2-5 weeks 1. Organophosphate chemicals = commonly insecticides 2. Botulism = from ingestion of food containing C. botulinum (Gram positive spore bearing bacillus) 3. Tick paralysis = disorder of ACh release from axonal terminals due to neurotoxin that blocks depolarisation

Answer 238

1. Key features a. Degenerative disease of motor neurons b. Muscle weakness and atrophy results from progressive denervation and loss of anterior horn cells in spinal cord (ie. lower motor neurons) and the brainstem nuclei c. Onset ranges from before birth to adolescence or young adulthood d. Weakness is symmetrical; proximal > distal and progressive e. Heart is not involved f. Intelligence is normal 2. Genetics + pathogenesis a. AR – SMN1 gene b. Usually homozygous deletion (rarely point mutation) c. Carrier 1/50 d. SMA is caused by mutations of the telomeric copy of the survival motor neuron gene (SMN1) i. Two very similar copies on chr 5q13 – telomeric SMN1 and centromeric SMN2 ii. Both SMN1 and SMN2 cause production of SMN protein iii. SMN1 is lost in SMA – all patients retain the centromeric copy (SMN2) 1. SMN1 usually produces most full-length SMN 2. 90% of SMN2 product lacks exon 7 – SMNΔ7 is unstable and cannot compensate for loss of SMN1 ii. SMN2 protein can partially compensate for loss of SMN1 protein iii. Severity of SMA correlates inversely with SMN2 gene copy – 3 or more SMN2 associated with milder phenotypes 3. Pathogenesis a. Progressive denervation of muscle is compensated for by re-innervation from an adjacent motor unit, but giant motor units are thus created with subsequent atrophy of muscle fibers when the reinnervating motor neuron eventually becomes involved 4. Disease involvement a. Preserved motor units i. Motor neurons of CNIII, IV and VI to extraocular muscles ii. Sacral spinal cord innervating striated muscle of anal and urethral sphincters iii. UMN b. Sympathetic and parasympathetic are NOT spared – usually do not show clinical manifestations until late stage c. Autonomic deficits may involve the detrusor muscle of the urinary bladder or smooth urethral and anal sphincters

Answer 239

a. Prior to the advent of molecular diagnosis, SMA was classified into phenotypic subtypes b. Classification i. Type 1 = Werdnig-Hoffman disease (most common) ii. Type 2, 3 = childhood onset iii. Type 4 = adult c. ALSO: i. Non-5q SMA’s rare, but many forms ``` SMA-0 = severe fetal form, prenatal onset, no motor milestones, death <6mo, hypotonia/weakness/resp failure SMA-1 = most common, infantile, onset <6mo, never sit independently, death <2yrs (changing with new therapies), normal/minimal facial weakness SMA-2 = late infantile, onset 6-18mo, sits but never walks independently, live to 3rd decade SMA-3 = onset >2 years, walk independently, normal lifespan SMA-4 = adult onset ```

Answer 240

a. History i. History of motor difficulties, especially loss of skills b. Examination i. Diffuse, symmetrical muscle weakness (Proximal > distal) 1. More severe in LL than UL ii. Areflexia/hyporeflexia iii. Hypotonia iv. Fasciculations (often tongue) = nonspecific sign of muscle denervation 1. In infants seen in deltoid and biceps, occasionally quadriceps 2. Best observed in the tongue – more difficult to see when the tongue is relaxed 3. Outstretched hand often shows tremor due to fasciculations v. Respiratory insufficiency (restrictive) Type I • Marked proximal weakness – frog leg positioning • Decreased spontaneous movement • Bell-shaped chest = paradoxical respiratory (breathe in, stomach bulges out) • Mobile, expressive face – no facial weakness at onset • Normal intelligence • Tongue fasciculations • Bulbar weakness – swallowing difficulties • Sparing of extra-ocular muscles and sphincters • Absent reflexes • Muscle bulk may seem normal (or may have thin muscle mass) • Contractures uncommon • Diaphragmatic involvement is LATE • 65% die by age 2 years Type II • Infants are usually able to suck and swallow • Respiration adequate in early infancy • Show progressive weakness, but many survive in to school years of beyond • Mobilise in wheelchair • Nasal speech and problems with deglutition develop later • Scoliosis becomes a major problem • Gastroesophageal reflux may lead to malnutrition or aspiration Type III • Can appear normal in infancy • Progressive weakness in proximal distribution – particularly affecting shoulder girdle muscles • Usually able to walk • Slower progression than type II • Symptoms of bulbar weakness are rare • 25% of patients have hypertrophy rather than atrophy (confused with muscular dystrophy) • Longevity can extend well into adult life

Answer 241

Gene testing a. If you diagnose clinically go straight to gene testing b. CK = normal or mildly elevated c. CXR = thin ribs early in disease d. Nerve conduction studies i. Almost never actually done e. EMG = active denervation of muscle i. Fibrillations (neurophysiological finding on EMG), fasciculations (esp infants) ii. Residual motor units have high amplitude f. Repetitive nerve simulation = normal g. Molecular genetic test of SMA gene = diagnostic h. Muscle biopsy = only if equivocal diagnosis

Answer 242

a. Novel therapies becoming available (nusinersen, gene therapy) b. Nutrition – NG/PEG i. Bulbar difficulties and respiratory distress c. Respiratory surveillance and support i. Vigilance for aspiration ii. Early treatment of respiratory infections iii. Chest physiotherapy, cough assist (particularly type II and III) iv. RSV prophylaxis (and routine immunisations) v. Non-invasive ventilation eg. nocturnal CPAP for SMA2 and SMA3 vi. Invasive ventilation – controversial for SMA1 d. Scoliosis and contracture management e. Therapies in research/novel i. Increase SMN2 protein levels eg. NUSINERSEN (Spinraza), valproate, HADC inhibitors 1. Nusinersen approved by FDA for all forms of SMA 2. Intrathecally administered anti-sense oligonucleotide 3. Binds to SMN pre-mRNA to direct alternative splicing and increase inclusion of exon 7 in SM2 4. Approved by TGA, but not funded ii. Gene therapy (one off dose but ~$3mil)

Answer 243

Distinguished by: respiratory involvement EARLY, and DISTAL involvement over proximal a. IGHMB2 mutation (recessive) c. Early onset respiratory distress i. First few months of life ii. Due to diaphragmatic paralysis iii. Eventration of diaphragm on CXR iv. Respiratory failure occurs before severe skeletal muscles (c/f SMA1) v. Weak cry, inspiratory stridor d. Distal muscles affected first contrasting proximal in SMA1 e. Prognosis very poor due to progressive respiratory failure

Answer 244

``` SMA (covered separately) Non-5q SMAs Poliomyelitis (used to be the other major cause of chronic disability however now rare) Enterovirus infections (polio-like) Hopkins syndrome ALS ```

Answer 245

Hereditary motor sensory / Charcot Marie Tooth Toxic Autonomic Guillain Barre • Peripheral nerves o Motor = anterior horn of spinal cord o Sensory = dorsal root ganglion • Peripheral neuropathies divided into two types o Disorders with loss of myelin = demyelinating neuropathy – SLOW nerve conduction o Disorders with injury to axon = axonal neuropathy – NORMAL (or slightly reduced) nerve conduction with reduced CMPA • Myelination o Production of insulating material for peripheral nerve axons (fibres) o Starts before birth o Complete by 2-3 years of age o Incomplete myelin formation or loss of myelin damages nerve fibres o Nerve fibre damage causes weakness and loss of muscle bulk (atrophy)

Answer 246

1. Key points a. Most common genetically determined neuropathy b. Group of disorders characterised by chronic motor and sensory polyneuropathy c. KEY FEATURES i. Length-dependent muscle wasting and weakness = distal > proximal + LL > UL ii. Reduced reflexes – particularly distally (eg. present knee jerk, absent ankle jerk) iii. Variable foot deformity – reflection of chronicity iv. Impaired distal sensation – vibration affected EARLIER than pin-prick v. Motor and sensory neuropathy on NCS vi. Wide variation in age of onset and severity 3. Genetics a. CMT hereditary neuropathy syndrome can be inherited in an autosomal dominant, autosomal recessive, OR X-linked recessive manner b. Need to establish method of transmission in each family through genetic testing 4. Investigations a. Nerve conduction studies = motor and sensory velocities are greatly reduced b. EMG + muscle biopsy = usually not required for diagnosis c. CK = normal d. Sural nerve biopsy = diagnostic: large and medium size myelinated fibres are reduced in formation, collagen is increased and characteristic onion bulb formations of proliferated Schwann cell cytoplasm surrounds axons e. Genetic diagnosis

Answer 247

a. Pathophysiology = demyelinating vs. axonal i. Demyelinating (NCV <38 m/s) 1. CMT1, CMT3, CMT4 2. Most common (60-70%) = CMT1A (PMP22) --- duplication of PMP22; detected on microarray ii. Axonal (NCV > 38m/s) 1. CMT2 2. Most common (20-30%) = CMT2 (MFN2) iii. Intermediate (NCV 25-45m/s) 1. CMTX, DICMT b. Mode of inheritance i. AD: CMT1, CMT2, CMT3 ii. AR: CMT4 iii. XL: CMTX types 1-6 c. Causative gene/chromosomal locus i. Mutations in genes whose protein products are expressed in myelin and/or axonal structures within peripheral nerves ii. Phenotypes often genetically heterogenous iii. Many genes cause multiple phenotypes

Answer 248

a. Age of onset i. Most are asymptomatic until late childhood or early adolescence – can be delayed until 5th decade ii. Young children sometimes manifest gait disturbance as early as 2nd decade of life b. Features in childhood i. Slowly progressive throughout life; occasional rapid decline ii. Motor 1. The peroneal and tibial nerves are earliest and most severely affected 2. Results in difficulty walking or running, clumsy, ankle sprain + ankle instability 3. Toe-walking 4. Clumsy hands, handwriting difficult, tremor 5. Atrophy of muscles of hands and forearm usually not as severe; can result in finger wasting a. Particularly thenar eminence 6. Distal muscle weakness and atrophy iii. Foot deformities 1. Pes canus 2. Pes planus – more common in younger iv. Sensory 1. Relatively mild in childhood 2. Mainly affects large demyelinated nerves that convey proprioception and vibration 3. Threshold for pain and temperature can also increase v. Autonomic 1. Poor vasomotor control with blotching or pallor of the skin and the feet, and inappropriately cold feet c. Resultant functional problems i. Motor difficulties 1. Falls, weakness 2. Clumsy hands, tremor, poor writing ii. Consequences of sensory loss = injuries, ulceration, self-mutilation iii. Pain 1. Foot and leg pain/cramps common 2. From postural and orthopaedic problems iv. Ortho abnormalities = foot and ankle deformities, scoliosis, hip dysplasia (10% of patients) d. Examination i. Muscles of anterior compartment of lower legs  atrophic = stork like contour ii. Progressive weakness of dorsiflexion and eventual foot drop iii. Usually bilateral, but can be slightly asymmetrical iv. Pes cavus deformities result from denervation of intrinsic foot muscles v. Wasting of hand and forearm muscles

Answer 249

a. Treatment of manifestations i. Stabilisation of ankles – AFOs ii. Surgical fusion sometimes considered b. Prevention of secondary complications i. Physiotherapy ii. Prevention from injury c. No medical treatment available to slow progression d. Ascorbic acid and CMT1 - promising results in mice, clinical trials in humans have conclusively shown no difference

Answer 250

1. Key features a. Characterised by peripheral nerve demyelination 2. Genetics a. AD inheritance b. Duplication of PMP22 gene = 70-80% of cases 3. Clinical manifestations a. Present in first or early second decade b. Distal muscle weakness – difficulty running or keeping up with peers c. Sensory loss – gradually progress (initially proprioception + vibration); contributes to clumsiness d. Late change – intrinsic loss of hand and foot muscles e. Palpable enlargement of peripheral nerves f. Kyphosis or scoliosis may occur g. Complete loss of ambulation uncommon h. Normal life expectancy

Answer 251

1. Key features a. Axonal damage 2. Genetics a. AD inheritance b. Heterogenous mutations 3. Clinical manifestations a. Presents in second on third decade of life b. Distal weakness = atrophy c. Sensory loss d. Reduced DT reflexes e. Variable foot deformity

Answer 252

1. Key features a. Onset <2 years b. Delayed motor development c. Extremely slowed motor nerve conduction (<12 m/sec) 2. Investigations a. Nerve biopsy = marked reduction in myelinated fibre density, thin myelin sheaths and onion bulb formation b. CSF protein often elevated c. Genetic = De novo mutations in MPZ, PMP22, EGR2 3. Clinical features a. Delayed motor development b. Hypotonia c. Areflexia d. Distal, and often proximal muscle weakness e. Foot deformity common

Answer 253

• Many chemicals (organophosphates), toxins, and drugs can cause peripheral neuropathy • Lead poisoning, particularly if chronic, causes mainly a motor neuropathy selectively involving large nerves such as common peroneal, radial and median nerves (ie. Mononeuritis multiplex) • The most frequent cause of toxic neuropathies in children is prescribed medications o Vincristine, cisplatin and paclitaxel

Answer 254

2. Background a. Acute inflammatory polyneuropathy b. Commonly characterised by rapidly progressive, essentially symmetric weakness and areflexia i. Usually distally predominant, at least at onset ii. An initially proximal pattern of weakness is seen in 15-20% of children iii. Cranial nerve involvement is common in paediatric GBS iv. Distal paresthesiae are common, and neuropathic pain is prominent in many affected children v. The neurologic deficit of GBS progresses over several days to a month c. Key diagnostic features = cytoalbuminological dissociation (elevated CSF protein without pleocytosis), neurophysiological findings of neuropathy d. In the post-polio era, GBS is the most common cause of acute flaccid paralysis in childhood, with an incidence in Australia of approximately 0.8 per 100 000 children aged less than 15 years of age/year. 3. Aetiology a. 70-80% of paediatric GBS preceeded by infection or vaccination in 3-6 weeks prior b. Infections particularly associated with GBS i. GIT = campylobacter jejuni, H pylori ii. Respiratory = Myocoplasma pneumoniae c. Vaccines particularly associated with GBS i. Rabies vaccine ii. Influenza iii. Oral polio vaccine iv. Conjugated menincoccal C vaccine

Answer 255

4. Clinical features (NELSON’s + Lecture) a. Onset is gradual and progresses over days to weeks; plateaus in 1-28 days b. Maximal severity of weakness is usually reached by weeks c. Weakness i. Usually starts in LL  ascends to involve UL ii. Proximal (20%) iii. Usually symmetrical d. Cranial nerve involvement common i. Facial weakness ii. Bulbar involvement iii. Ophthalmoplegia e. Pain common = legs, buttocks, back i. Neuropathic, poorly localised ii. Associated irritability f. Sensory involvement = dyastheasias common (but objective deficit difficult to demonstrate) g. Loss of reflexes h. BEWARE i. Respiratory failure ii. Autonomic instability iii. Bulbar weakness 5. History and examination (RCH GUILDEINE) a. Features required for diagnosis i. Progressive weakness of more than one limb ii. Loss or decrease in deep tendon reflexes within one week of onset b. Features supportive of diagnosis i. Rapid initial progression of weakness, but no progression beyond 4 weeks. ii. Relative symmetry iii. Mild sensory symptoms and/or signs iv. Cranial nerve involvement (present in approximately 50% of patients) v. Autonomic dysfunction, such as BP instability, abnormal sweating, or cardiac arrhythmias (present in 30%) vi. Absence of fever at the onset of neurological symptoms c. Features casting doubt on diagnosis i. Persistent asymmetry of weakness ii. Identifiable sensory level iii. Prominent bladder or bowel dysfunction iv. >50 mononuclear cells/mm3 in CSF v. Internal ophthalmoplegia (abnormal pupillary responses) 6. Summary of examination findings a. Symmetrical weakness; may have distal > proximal [BUT can have proximal predominant] b. Cranial nerve involvement c. Loss of tendon reflexes – areflexia is common but hyporeflexia may also be seen d. Signs of autonomic dysfunction – lability of BP, cardiac rate, postural hypotension, profound bradycardia/tachycardia/asystole

Answer 256

a. Spinal cord lesions = acute transverse myelitis, epidural abscess, tumours, polio, enterovirus etc. b. Peripheral neuropathies = toxic (vincristine), infections (HIV, diphtheria), inborn errors of metabolism, vasculitis syndromes c. Neuromuscular junction disorders = tick paralysis, myasthenia gravis, botulism, hypercalcaemia d. Myopathies = periodic paralyses, dermatomyositis, critical illness myopathy/ polyneuropathy

Answer 257

a. CSF i. WCC <10 cells/mm3 and protein >0.45 g/L (cytoalbuminologic dissociation) ii. Protein may be normal in first 48 hours iii. WCC >50 cells VERY atypical b. Nerve conduction studies i. Demyelinating vs. axonal (subtype) ii. Usually abnormal within the first week iii. Can also help distinguish the type of GBS iv. Features consistent with GBS 1. Slowing of motor and sensory nerve conduction (>80% of lower limit of normal values for age). c. MRI i. Required urgently if spinal lesion suspected due to sensory level or prominent sphincter dysfunction ii. Nerve root enhancement in 90% of children with GBS (note enhancement may follow LP so MRI should be done first) iii. Consider testing for GQ1b and GM1 antibodies if there is evidence of cranial nerve involvement and/or significant ataxia d. Stool MCS i. 2 samples 24 hours apart – to exclude polio ii. MCS for campylobacter iii. Notify VIRDL of acute flaccid paralysis e. Blood tests i. Antiganglioside A 1. Anti-GM1  campylobacter associated GBS 2. Anti-GQ1b  Miller Fisher syndrome f. Other tests (rule out differentials) i. Blood culture if febrile. ii. ACE level, Ca++. iii. Heavy metals and toxins (lead, mercury, arsenic, organophosphates). iv. Urinary porphyrins. v. Botulinum toxin identification (stool, serum). vi. Drug toxicology screen. vii. Consider IV edronphonium or PO pyridostigmine trial if considering MG

Answer 258

10. Management a. Supportive i. Vigilant monitoring for respiratory and autonomic complications of this disorder 1. 15-20% require respiratory support ii. Neuropathic pain management – NSAIDs, gabapentin, corticosteroids iii. NOTE: even if C jejuni infection is documented in stool culture or serology, treatment of infection is not necessary as it is self-limited, and does not change outcome b. IVIG = 2g/kg over 2 days i. Children with mild GBS who are able to ambulate are not usually treated with IVIG ii. Those with rapid clinical progression, loss of the ability to walk, or significant bulbar or respiratory compromise should receive 2g/kg of intravenous immunoglobulin (IVIg) over 2 days iii. Plasma exchange may be effective but IVIG easier iv. No evidence for IVIG+plasma exchange together j. IVIG therapy is helpful at speeding recovery, but probably does not alter the final outcome of GBS k. Corticosteroids may be effective in alleviating pain, they do not otherwise ameliorate the course of GBS 11. Outcome a. Children with GBS recover better than adults (can take many months) b. 90% of children fully recover – small number have mild weakness c. Relapses uncommon d. Very small percentage later develop CIDP h. Features predictive of poor outcome i. Cranial nerve involvement ii. Intubation iii. Maximum disability at time of presentation

Answer 259

• Subtypes of GBS include acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy – distinguished by nerve conduction studies, geography, and pattern of anti-ganglioside antibodies • Chronic inflammatory demyelinating polyradiculopathy (CIDP) o Chronic varieties of GBS that recur intermittently or do not improve, or progress slowly [confusing in Nelsons] o A chronic, demyelinating polyneuropathy o 2 types  Relapsing remitting course  Slowly progressive course  NB. course over more than 8 weeks, c/f GBS nadir within 3-4 weeks and does not recur o Features  Weakness – proximal and distal  Sensory involvement – distal, less prominent than motor involvement  CN and bulbar involvement in minority  Absent r decreased reflexes  Dx confirmed by NCS o Treatment  IVIG (or plasma exchange)  Steroids  Steroid sparing agents • Congenital GBS o Rare condition o Manifests as generalised hypotonia, weakness and areflexia in affected neonate o Fulfil CSF and EMG criteria o Treatment may to be required o Gradual improvement over the first few months of life, and then no evidence of residual disease y 1 year of age

Answer 260

1. Key points a. Seizures are generalised or focal, but we might not be able to say which without EEG – do not label seizures ‘generalised tonic clonic’ or ‘absence’ unless has been diagnosed on EEG b. Epilepsy is having unprovoked seizures c. The causes of epilepsy are genetic, structural, infectious, metabolic or unknown/idiopathic d. Epileptic syndromes are conditions with well-defined clinical features, investigation findings and outcome 2. Definitions a. Seizure = transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain b. Epilepsy = disorders of the brain characterised by an enduring predisposition to generate epileptic seizures and the neurobiological, cognitive, psychological and social consequences of these conditions 3. General information a. ¾ of people with seizures have onset <15 years b. Prevalence of seizures in childhood 2-5% c. Prevalence of epilepsy in childhood 0.5% d. Incidence of seizures and epilepsy is greatest in infancy e. 25-30% of children with epilepsy have uncontrolled seizures

Answer 261

a. Generalised onset seizure = generalised seizure i. Originating at some point within, and rapidly engaging, bilaterally distributed networks ii. Bilateral networks can include cortical and subcortical structures, but not necessarily the entire cortex iii. Individual seizure onsets can appear localised, but the localisation and lateralised are not consistent from one seizure to another iv. Can be asymmetric v. Examples 1. Generalised tonic-clonic a. Initial tonic phase (brief flexion of axial muscles, then longer tonic extension), followed by clonic phase (alternating contraction + atonia) b. May be associated with autonomic features c. Can have decorticate  decerebrate  clonic movements (decorticate + decerebrate is the tonic component) d. Febrile convulsions are classically generalised clonic seizure – no tonic phase 2. Tonic a. Sudden stiffening b. May be subtle with only eyelid opening + eye deviation c. Axial tonic seizure: rigidity of posterior neck, paraspinal + abdominal muscles d. Average length ~ 10 seconds e. Characteristic of Lennox-Gastaut syndrome 3. Myoclonic a. Sudden involuntary shock like contraction b. May be single/repetitive c. Can be generalised, focal, symmetrical or asymmetrical d. Can also have negative myoclonus from muscular inhibitions e. EEG correlate – high amplitude, polyspike slow wave discharges 4. Typical absence a. Impaired consciousness b. May have mild clonic / tonic/ atonic or automatisms c. Brief episodes lasting 5-45 seconds d. Activated by hyperventilation e. EEG shows 3Hz spike-wave in CAE, >4Hz in JAE 5. Atonic a. Sudden loss of muscle tone without falling b. EEG: generalized fast activity OR poly spike slow wave c. Seen in both symptomatic + idiopathic generalized epilepsies b. Focal onset seizure = focal seizure i. Originating within networks limited to one hemisphere ii. May be discretely localised or more widely distributed iii. May originate in subcortical structures iv. For each seizure type, ictal onset is consistent from one seizure to another v. Preferential propagation patterns that can involve the ipsilateral and/or contralateral hemisphere vi. Can be described by their semiology (features) vii. Semiology reflects the regional networks involved in the seizure origin or propagation viii. If an aura is present must be focal ix. If a child ‘calls out’ at onset eg. During sleep – classic for focal epilepsy eg. Benign epilepsy of childhood x. Examples 1. Focal clonic 2. Focal impaired awareness seizure 3. Focal sensory 4. Focal hyperkinetic 5. Focal to bilateral tonic-clonic

Answer 262

Structural, genetic, infectious, metabolic, immune, unknown a. Structural abnormalities i. Focal epileptogenic lesions 1. Mesial temporal sclerosis 2. Focal cortical dysplasia 3. Hypothalamic hamartoma ii. Major cerebral malformations 1. Surge-Weber syndrome 2. Tuberous sclerosis 3. Double cortex subcortical banding 4. Hemimegalencephaly b. Epilepsy genetics i. Chromosomal anomalies ii. Copy number variants (deletions, duplications) iii. Single-gene defects iv. Complex inheritance (polygenetic) v. Somatic mutations c. Metabolic conditions i. Eg. pyridoxine dependent seizures d. Infectious i. Neurocysticercosis – single most common cause of epilepsy worldwide (pork tapeworm parasite) e. Immune i. Limbic encephalitis – can lead to chronic epilepsy ii. ADEM f. Unknown i. FIRES – febrile infection-related epilepsy syndrome ? infectious ? immune ? genetic

Answer 263

Territory - Often complex partial (impaired awareness) - Fear or rising epigastric sensation - Deja vu, jamais vu* - Autonomic, olfactory, auditory - Behavioural arrest, staring, unresponsive - Oromotor automatisms: lip smacking, walking - Contralateral dystonic posturing Associated pathology - Hippocampal sclerosis - CNS infection - Trauma - Hamartoma - Glial tumour

Answer 264

Territory - Short duration < 30s - Nocturnal/during sleep - Hyperkinetic seizures: axial movements, vocalisation, bilateral automatisms, motor jerking - Bicycling automatisms - Pelvic thrusting, sexual automatisms - Head and eye movements - Hemiclonic activity (focal or marching)  to contralateral side Pathology - Trauma - Neoplasia - Vascular - Encephalitis - Cortical dysplasia

Answer 265

Territory - Flash of light - Complex visual hallucinations - Visual distortion - Loss of vision - Eye movements Pathology - Tumours - Vascular malformations

Answer 266

Uncommon and poorly characterised Territory - Numbness, paraesthesia - Sensory: simple visual hallucinations, complex visual phenomenon, olfactory, gustatory, auditory

Answer 267

a. Normal phenomenon i. Jitteriness ii. Sleep jerks iii. Daydreaming iv. Startle reflex b. Parasomnias/sleep disorders i. Night terrors ii. Sleep walking iii. Narcolepsy/cataplexy c. Syncope i. Neurocardiogenic (vasovagal) ii. Reflex anoxic iii. Orthostatic iv. Congenital Heart Disease (AS, tetralogy) v. Arrythmia d. Breath-holding (forms of syncope) i. Cyanotic = hyperventilation + vasovagal syncope ii. Pallid = reflex anoxic syncope (also vasovagal) e. Cerebrovascular disorders i. Ischaemic stroke ii. ICH f. Migraine with aura g. Migraine variants i. Benign paroxysmal torticollis of infancy ii. Benign paroxysmal vertigo/vertebrobasilar migraine iii. Confusional migraine h. Metabolic i. Movement disorders i. Tic ii. Tremor iii. Stereotypy iv. Paroxysmal dyskinesis (dystonia, choreoathetosis) v. Myoclonus vi. Benign myoclonus of infancy vii. Hyperkeplexia j. Iatrogenic and PICU non-epileptic events i. Anaesthetic emergence phenomenon ii. PICU HR and pupillary changes iii. PICU sedation and emergence movements iv. Post cardiac bypass myoclonus v. NICU Brainz and other CFM artefacts vi. Coning (decorticate, decerebrate, hiccoughs)

Answer 268

``` SYNCOPE Precipitating event: 50% Falls: Flaccid or stiff Convulsions: 80%, Usually <30s, Arrythmic, multi-focal and/or generalised Eyes: Open, Transient upward or lateral deviation Hallucinations: Late in the attack Tongue bite: Rare Postictal: <30s ``` ``` GTCS Precipitating: None Fall: Stiff Convulsions: Always, 1-2 min, Rhythmic, Generalised Eyes: Open, Often sustained deviation Hallucinations: May precede seizure in focal epilepsy Tongue bite: Common Postictal: 2-20 min ``` Post ictal is the biggest distinguisher - I ask parents if the child could speak and what was said: if they can speak unlikely to be GTC seizure

Answer 269

1. Key point a. Most EEG patterns can be caused by a wide variety of diseases b. Many diseases cause more than 1 type of EEG pattern c. Intermittent EEG patterns may NOT be present at the time of EEG (esp for temporal lobe epilepsy, frontal lobe epilepsy, idiopathic generalised epilepsy) 2. Role of EEG in patients with seizures a. Support clinical diagnosis of epileptic seizures b. Distinguish partial vs generalized epilepsies c. Identify specific epilepsy syndromes d. Localization of seizure foci in intractable epilepsy e. Rarely, monitor anti-epileptic therapy f. Assessment of sleep, coma and encephalopathy’s 3. Indications for EEG a. First afebrile seizure b. And in some children with established epilepsy if: i. Previously normal or discordant EEG ii. Appearance of new seizure type ie Rolandic vs ESCS iii. Increase in seizure frequency iv. New developmental or neurological concerns 1. Eg. Landau-Kleffner – infrequent seizures but active sleep EEG, loss of language v. Considering withdrawing therapy 1. If EEG shows ongoing epileptiform activity – may not be appropriate to cease AED c. NOT indicated in febrile seizures or behavioural or developmental disorders without seizures 4. Practical value a. Clarify the nature of seizures with convulsing, falling, staring b. Help determine need for brain imaging i. Focal seizure – require imaging unless benign focal epilepsy c. Assist in decision to treat and choice of medication d. Aid determination of prognosis e. Not sort out whether seizures or not!

Answer 270

1. Principles of EEG b. Relies on i. Neuronal synchronization (thalamocortical connections) ii. Neuronal alignment (cortical layering and folding) c. EEG rhythm generation in normal neurons i. EXTRACELLULAR recording of changing scalp potential over time overlying large area of normal cortex compared to epileptic cortex ii. INTRACELLULAR recording of changing membrane potential over time in one normal neuron compared to one of many epileptic neurons 6. EEG techniques a. Technique i. 10-20 electrode placement iv. Recordings based on DIFFERENCES between two electrodes v. Letters correspond to regions, even numbers = R odd numbers = L b. Types i. Routine awake EEG ii. Sleep EEG – nap sedation, sleep deprivation, overnight iii. Provocation procedures – hyperventilation, photic stimulation, precipitant 1. Hyperventilation – stimulates absence seizures 2. Photic stimulation – idiopathic generalised epilepsy iv. Postictal EEG v. Video EEG monitoring

Answer 271

Absence seizure/epilepsy

Answer 272

Infantile spasms No normal background activity

Answer 273

Normal in preterm neonate

Answer 274

Lennox Gastaut Syndrome

Answer 275

1. Indications and role of neuroimaging a. Non idiopathic epilepsies ie epilepsies with a potential underlying structural, metabolic or inflammatory cause -> not typical CAE, BECTS, JME, FS etc on history + EEG iii. Associated neurological or developmental problems b. Deteriorating seizure control condition (seizure, syndrome) c. Epilepsy surgery d. Summary i. Diagnose underlying condition (lesion, syndrome) ii. Determine prognosis iii. Plan appropriate treatment 2. What might we find a. Structural i. Malformative vs acquired ii. Focal vs multifocal vs diffuse b. Findings c/w a metabolic or genetic disorder c. Nonspecific findings d. Nothing 3. Epileptogenic lesions a. Focal lesions i. Hippocampal sclerosis ii. Developmental tumours and hamartomas 1. Eg. hypothalamic hamartoma – gelastic epilepsy, mirthless laughter iii. Focal cortical dysplasia iv. Cavernous and other vascular malformations v. Focal traumatic, infection or ischemic lesions vi. Other – dysembroblastic NET, ganglioglioma, encephalomalacia b. Bilateral, multifocal and diffuse lesions i. Tuberous sclerosis ii. Major cerebral malformations 1. Hemimegalencephaly 2. Polymicrogyria – too many and too small gyri 3. Schizencephaly 4. Hemidysplasia 5. Meningeal angiomatosis – Sturge-weber syndrome 6. Diffuse heterotopia 7. Agyria/ pachygyria iii. Extensive traumatic, infective or ischaemic lesions 4. Importance of lesion detection on MRI in epilepsy a. Generally predicts medical intractability b. Accelerates referral for epilepsy surgery c. Increases likelihood of selection for epilepsy surgery d. Associated with significantly better seizure outcomes following surgery e. Especially for DNTs, FCD-II, HS and cavernomas

Answer 276

1. Overview a. Causing acute symptomatic seizures i. Hypoglycemia ii. Electrolyte disturbance iii. Metabolic acidosis iv. Toxins, drugs b. Causing epilepsy i. Inborn errors of metabolism 2. The easy metabolic diagnosis a. Detected on routine plasma biochemistry i. Hypoglycaemia, acidosis ii. Hyperammonaemia iii. Hypocalcaemia, hypomagnesaemia b. Detected on urine metabolic screen i. Ketones, protein, blood, glucose ii. Amino acids iii. Total glycosaminoglycans iv. Organic acids – ONLY if requested/indicated 3. The difficult metabolic diagnosis a. Routine biochemistry normal b. Routine metabolic screen normal/non-specific c. Specific diagnostic test required d. All very rare conditions 5. Don't miss diagnosis a. Vitamin responsive epilepsies b. Glut-1 deficiency – respond somewhat to ketogenic diet

Answer 277

1. Chromosomal abnormalities associated with epilepsy a. Trisomy 21 c. Ring chromosome 14 and 20 d. Copy number variants (CNVs) at 15q13.3, 16p13.11, 15q11.2 2. Chromosomal testing a. Chromosomal microarray i. Copy number variants in 5-10% of cohorts of patients with: 1. Epileptic encephalopathies 2. Refractory epilepsy 3. Idiopathic epilepsies ii. 9% of IGE + ID had microdeletions at one 15q13.3m 16p13.11 and 15q11.2 1. These CNVs also seen in ‘normals’ and some with other neurodevelopmental disorders (eg ID, autism, schizophrenia) likely susceptibility loci as incompletely penetrant b. Banded karyotype i. Ring chromosome 20 3. Single gene causes a. >300 known genes b. Neuronal function i. Ion channel function ii. Synaptic transmission iii. Intracellular transport and signaling iv. Transcriptional regulation c. Patterns of inheritance d. Mosaic mutations 4. Testing for single gene disorders a. Test one gene – sanger sequencing b. Test multiple i. Gene panels ii. Whole exome sequencing iii. Other

Answer 278

b. Distinctive disorders identifiable on the basis of a typical age onset, specific EEG characteristics, seizure types, and often other features which, when taken together, permit a specific diagnosis ``` Neonatal • Benign neonatal seizures • Benign familial neonatal seizures • Early myoclonic encephalopathy • Ohtahara syndrome ``` ``` Infancy (onset <2 years) • Migrating focal seizures of infancy • West syndrome • Myoclonic epilepsy in infancy • Benign familial infantile seizures • Dravet syndrome ``` Childhood • Febrile seizures plus • Early onset benign childhood occipital epilepsy • Epilepsy with myoclonic-atonic seizures • Benign epilepsy with centrotemporal spikes • ADNFLE • Late onset childhood occipital epilepsy • Epilepsy with myoclonic absences • Lennox-Gastaut syndrome • CSWS/ Landau Kleffner syndrome • Childhood absence epilepsy ``` Adolescent-Adult • Juvenile absence epilepsy • Juvenile myoclonic epilepsy • Epilepsy with generalised TCS alone • Progressive myoclonus epilepsies • ADPEAF • Other familial temporal lobe epilepsies ```

Answer 279

1. Key points a. Good prognosis b. Also called ‘fifth day fits’ – peak day of onset 2. Clinical manifestations a. Seizures within first 7 days of life – 90% between day 4 and 6 b. Resolve within 2 weeks c. Occur in term or later preterm infants in those with uneventful pregnancy, labour and delivery d. NO family history of seizures e. NORMAL neurological examination f. Most common seizure type is unifocal clonic, associated with apnoea 3. EEG a. Ictal EEG = not distinctive b. Inter-ictal EEG = normal or abnormal 4. Diagnostic criteria a. Apgar score greater than seven at one minute b. Typical interval between birth and seizure onset (four to six days) c. Normal neurologic examination before seizure onset and during the interictal periods d. Normal laboratory and imaging findings (eg metabolic studies, neuroimaging, and cerebrospinal fluid analysis) e. No family history of neonatal seizures or post neonatal epilepsy 5. Treatment + prognosis a. Thorough investigation + work-up for symptomatic cause of seizures b. Anti-seizure drugs acutely administered c. Uniformly good prognosis

Answer 280

1. Genetics a. Channelopathy b. Most cases caused by mutation in voltage-gated K+ channels – KCNQ2 and KCNQ3 c. Autosomal dominant – penetrance 85% 2. Clinical manifestations a. Focal or multifocal clonic or tonic seizures b. Family history of neonatal seizures but NO other neurological abnormalities c. Usually occur within a few days to 1 week of life d. Resolve spontaneously in early infancy 3. Treatment a. Thorough investigation + work-up for symptomatic cause of seizures b. Anti-seizure drugs acutely administered c. Uniformly good prognosis

Answer 281

* Most often associated with inborn errors of metabolism * Neonates are encephalopathic at presentation, with erratic myoclonus and multiple seizure types that typically begin within the first hours of life * EEG shows burst suppression pattern – most noticeable during sleep Poor prognosis - progressive impairmenet, neonatal death, vegetative state

Answer 282

AKA Ohtahara syndrome * Rare disorder typically associated with structural brain abnormalities +/- genetic syndromes (cerebral dysgenesis, anoxia, genetic) * Infants usually present within first 2-3 months with developmental delay, spasticity, and seizures, including tonic spasms and focal motor seizures * Inter-ictal EEG shows a burst suppression * Treatment is often unsuccessful * Half of patients die in infancy, survivors have severe neurological impairment

Answer 283

The triad of spasms, arrest of psychomotor development, and hypsarrhythmia is known as West syndrome

Answer 284

1. Key points a. Estimated incidence of 0.25-0.60 per 1000 live births b. 65% of patients have an identifiable cause c. Single most common and important cause is focal cortical dysplasia -> can be treated d. Classification i. Symptomatic = cause identified ii. Cryptogenic = probably symptomatic iii. Idiopathic = no cause identified e. Age of onset i. Peak onset 3-7 months, >95% have onset before 2 years 2. Aetiology a. CNS malformations i. Cortical dysplasia = most common ii. Cerebral dysgenesis = Aicardi syndrome iii. Lissencephaly = Miller-Dieker syndrome iv. Holoprosencephaly v. Hemimegalencephaly b. Tuberous sclerosis c. Other neurocutaneous disorders d. Genetic i. Chromosomal disorders – T21 ii. Oher genetic mutations e. Inborn errors of metabolism f. Congenital infections g. Perinatal causes h. Postnatal insults

Answer 285

3. Clinical manifestations a. Triad of (West syndrome) i. Epileptic spasms (seizures type) ii. Hypsarrythmia (EEG) iii. Arrest of psychomotor development/regression (clinical) b. Spasms i. Spasms can be flexor (salaam) extensor (cruciate) or mixed ii. Can be asymmetric or have focal features iii. Typically occur in clusters 5-30 seconds apart iv. Frequently occur just after waking v. Can be associated with other seizure types 4. Natural history a. Initial stage – infrequent, isolated, mild; abrupt developmental regression may occur b. Most severe stage – spasms increase in frequency and appear in a series of clusters; in peak hundreds of spasms can occur in a 24 hour period; developmental regression/arrest is most pronounced c. Final stage – characterised by a progressive and sustained decrease in frequency and severity of spasms 6. EEG a. EEG demonstrates hypsarrythmia (meaning high amplitude abnormal rhythms) b. ‘Electrical chaos’ 7. Investigations a. MRI brain – identify structural brain abnormalities b. Metabolic work-up 8. Treatment a. ACTH b. Corticosteroids – high dose c. Vigabatrin – first line in those with TS

Answer 286

``` Non-epileptic • Colic • GERD • Excessive startle • Exaggerated Moro reflexes • Repetitive body arching • Spasticity ``` ``` Neurological • Benign myoclonus of early infancy • Benign neonatal sleep myoclonus • Tonic reflex seizures of early infancy • Benign and severe neonatal epilepsies ```

Answer 287

1. Key points a. Also known as = severe myoclonic epilepsy of childhood b. Characterised by refractory epilepsy and neurodevelopmental problems beginning in infancy 2. Epidemiology a. Rare b. M = F 3. Genetics a. >90% SCN1A mutation b. >700 mutations described – truncating mutation most common 4. Clinical manifestations a. Birth to 1 year of age i. Seizure onset in first year of life – usually between 5-8 months ii. Typical initial seizure is febrile tonic-clonic seizure – unilateral (hemiclonic) or bilateral iii. Triggered by fever/illness, immunisations, bathing or no precipitants iv. Can be prolonged and sometimes evolve into status b. 1 to 5 years of age i. Seizures 1. Appearance of afebrile focal, hemiclonic, myoclonic and generalised tonic-clonic seizures 2. Stimuli = fever/hyperthermia (environmental temperature sensitivity), emotional stress or excitement, flashing lights, contrasting lights and visual patterns ii. Development 1. Developmental plateau or regression between 1-4 years 2. Neurological signs include a. Hypotonia – detectable by 1 year of age in most patients b. Ataxia and incoordination – usually noted on walking c. Pyramidal signs (spasticity, hyperreflexia) iii. Behavioural = ADHD, autistic traits, irritability, aggressiveness, opposition c. 5 years of age to adulthood i. Lifelong persistent seizures 1. Tend to occur mainly during sleep 2. Fever sensitivity in 50% of patients – photic and pattern sensitivity no longer present ii. Moderate to severe cognitive impairment iii. Motor system dysfunction – ‘crouched gait’ pattern with hip and knee flexion with ankle dorsiflexion throughout the stance phase of gate with minimal or no associated spasticity iv. Premature mortality – most common causes of death SUDEP and status epilepticus

Answer 288

AKA severe myoclonic epilepsy of childhood 5. Investigations a. EEG i. Initially normal ii. Appearance of multifocal and/or generalised spike-wave activity and photosensitivity in the second year b. MRI = usually normal c. Genetic testing 6. Diagnostic criteria a. Family history of epilepsy or febrile convulsions b. Normal development before onset of seizures c. Seizures beginning before one year of age d. Pleomorphic epilepsy (myoclonic, focal clonic, absence, and generalized seizures) e. EEG with generalized spike waves and polyspike waves f. Early photosensitivity or focal abnormalities g. Psychomotor retardation after two years of age h. Appearance of subsequent ataxia, pyramidal signs, or interictal myoclonus after the onset of psychomotor slowing i. Exacerbation of seizures by hyperthermia

Answer 289

AKA severe myoclonic epilepsy of childhood a. Goal of treatment i. Reduce length and number of seizures ii. Prevent status epilepticus iii. Limit adverse effects iv. Improve neurocognitive development b. Lifestyle = avoidance of triggers i. Hyperthermia – avoid hot baths, excessive physical activity on warm days 1. No evidence to support anti-pyretics or BDZ as prophylactic therapy ii. Minimise photic and pattern stimulation iii. Prophylactic anti-pyretics with vaccinations c. Pharmacological i. Initial therapy 1. Valproate 2. Adjunctive clobazam iii. Drugs to avoid = Na+ blockers including carbamazepine d. Other i. Ketogenic diet ii. Cannabinoids iii. Surgical therapy 1. Vagal nerve stimulation 2. DBS

Answer 290

* Autosomal dominant epilepsy characterised by afebrile seizures in an otherwise normal infant * Begin at 6 months of age * Seizures typically cease by 2 years of age * Normal development

Answer 291

• Many benign focal epilepsies – familial and sporadic – have been described • Includes: o Benign infantile convulsions (see neonates section) o Benign infantile convulsions associated with mild gastroenteritis o Benign infantile focal epilepsy with midline spikes and waves during sleep • Half of patients have a family history of infantile seizures • Inter-ictal EEG normal • Seizures remit in 90% of patients within 4 months and all patients within 2 years • Normal neurological development

Answer 292

* Group of genetic epilepsy syndromes in which there is a family pedigree of seizures with heterogenous semiology (the study of symptoms, somatic signs and laboratory signs, history taking and physical examination) that often begin during the first year of life * Characterised by multiple febrile seizures, generalised tonic-clonic seizures, and other seizure types including absences, myoclonic seizures and focal seizures

Answer 293

• Myoclonic seizures may occur in the first year of life o Myoclonus = brief synchronous jerk of one or more limbs with and without involvement of bulbar musculature o May be focal, multifocal, generalised and are more likely flexor than extensor • Myoclonus termed epileptic when it occurs in association with synchronous cortical epileptiform discharge • May be accompanied by other types of seizures

Answer 294

Benign childhood epilepsy with centrotemporal spikes Benign occipital epilepsy of childhood - early onset Benign occipital epilepsy of childhood - late onset

Answer 295

AKA BECTS 1. Key points a. THE most common epilepsy in childhood b. Age of onset = peak age of onset 7-9 years (<13 years) 2. Clinical manifestations a. Sleep-related seizures – 75% occur at night or on waking b. Focal sensorimotor seizures of the tongue and mouth/face i. Most commonly have no impairment of consciousness ii. Ictal symptoms correspond to origin of seizure in the rolandic or perisylvian sensorimotor complex (represents face and oropharynx) – facial numbness or twitching, guttural vocalisations, hypersalivation, drooling, dysphasia, speech arrest c. Motor activity in the upper (NOT lower) extremity is common d. Secondary generalised tonic clonic seizure during sleep – often presenting symptom i. 50% of children have at least one secondary generalised seizure 3. EEG = unilateral or independent bilateral centrotemporal spikes (CTS), activated by sleep a. Note that this EEG pattern can be seen in other neurodevelopmental conditions 4. Treatment a. AED often not recommended – particularly if focal seizures without impaired awareness b. Treatment = valproate i. Carbamazepine, phenobarbital and lamotrigine CONTRA-INDICATED 5. Prognosis a. Universal seizure remission, usually by puberty b. Normal developmental in general, but increased rate of cognitive and attentional difficulties

Answer 296

AKA PANAYIOTOPOULOS 1. Key points a. Age of onset = peak onset between 3-5 years (range 1-14 years) b. Unique seizure type with prominent autonomic features c. Often treated for encephalitis 2. Clinical manifestations a. Results in infrequent episodes of status epilepticus with autonomic symptoms b. Prominent autonomic symptoms (vomiting, pallor, cyanosis, mydriasis, apnoea, HR changes) i. Vomiting most characteristic feature c. Usually nocturnal seizures d. Last for >5 minutes e. Impaired awareness, head and eye version, hemiclonic f. Infrequent seizures but status epilepticus is typical (last >30 minutes) g. 25% have only a single seizure, 50% have <6 seizures 3. EEG = occipital or multifocal discharges (may be normal) 4. Prognosis a. Benign clinical course – infrequent seizures and half of patients have a single seizure b. Spontaneous remission occurs within 2-3 years from onset c. If treated – carbamazepine first line

Answer 297

AKA Gastaut 1. Key points a. Age of onset = peak onset between 8-9 years 2. Clinical manifestations a. Elementary visual hallucination and ictal blindness b. Tonic deviation of eyes, nystagmus, eyelid fluttering c. Ictal vomiting uncommon (cf. Panayiotopoulos) d. Consciousness preserved unless seizure spreads e. Seizures more frequent but short duration (cf. Panayiotopoulos) f. Diurnal (daytime) seizures (cf. Panayiotopoulos) 3. EEG = similar to Panayiotopoulos; epileptiform activity more predominantly occipital, occurs in long bursts of spike-wave complexes, and is markedly activated by eye closure 4. Treatment a. More often treated than other benign focal epilepsies b. Any medication used in focal epilepsies likely to be effective c. Carbamazepine most commonly prescribed 5. Prognosis a. Remission less likely (50-60% of patients)

Answer 298

1. Key points a. 2-8% of patients with epilepsy b. 20% of children have positive family history of epilepsy c. Age of onset = frequent absence seizures between ages 2-12 years, peak at 5-6 years 2. Clinical manifestations a. Absences are typically induced by hyperventilation b. Sudden, profound impairment of consciousness without loss of body tone c. A minority (30%) have GTCS during adolescence d. Often have automatisms e. Can have many daily 3. Investigations a. EEG shows generalised 3 Hz spike wave – absence seizure occurs at the same time as EEG abnormality; normal background activity i. Induced by hyperventilation 4. Treatment a. First line = ethosuxamide, sodium valproate i. Ethosuxamide – blocks T type calcium channels; AE – GI symptoms, hiccups, rash, joint pain b. Second line = lamotrigine c. Medications to avoid – aggravate seizures i. Carbamazepine ii. Vigabatrin iii. Gabapentin iv. Tigabine d. Phenytoin and phenobarbital are ineffective 5. Prognosis a. Seizures remit in 80% with treatment b. Some patients actually prove to have JME c. If continues into adolescence – consider another diagnosis

Answer 299

1. Key points a. 2-3% of all childhood epilepsies b. M > F 1.5: 1 c. Associated with severe seizures in childhood d. Age of onset i. Peak age of onset 3-5 years (<8 years) ii. May involve into LGS from WS and other infantile epilepsies 1. BUT 25-30% are previously normal children 2. Clinical manifestations a. Multiple seizure types = generalised seizures: tonic, atonic, atypical absence, myoclonic i. Periods of non-convulsive status epilepticus ii. Usually have seizures everyday – wear helmet (other group is myotonic astatic epilepsy) b. Cognitive dysfunction (mental retardation) c. Behavioural problems d. Psychotic symptoms common e. Neurodevelopment often normal before first seizure 3. EEG = interictal EEG pattern of slow spike-and-wave (<2.5Hz) 4. Treatment a. No drug highly effective b. Valproic acid, lamotrigine, topiramate, rufinamide, felbamate, and clobazam may be helpful c. Ketogenic diet + vagal nerve stimulation sometimes helpful

Answer 300

AKA Doose syndrome 1. Key points a. Age of onset = 1-8 years in previously normal children b. ‘Bad genetic generalised epilepsy’ 2. Clinical manifestations a. Often wear helmets b. Myoclonic and myoclonic-atonic seizures c. Other seizures: tonic-clonic > absence > myoclonic status 3. EEG = Paroxysmal 4 Hz theta bursts, fast generalised spike and polyspike-wave, photosensitivity 4. Treatment a. Ketogenic diet is specifically effective i. May have GLUT transporter defect associated – but ketogenic diet often works regardless 5. Prognosis a. Variable prognosis (50% do well)

Answer 301

1. Key points a. Syndrome associated with continuous or near-continuous spike-and-wave activity during sleep = electrical status epilepticus during sleep (ESES) or epileptic encephalopathy with continuous spike and waves during sleep (CSWS) b. Landau-Kleffner = epileptic encephalopathy associated with predominant language regression 2. Clinical manifestations a. Develop normally until 3-6 years of age – loose language function (LATER than autism) i. Begins with verbal agnosia – children behave as if they are deaf ii. Ultimately have difficulty with expressive language b. Personality disorders c. Hyperkinetic behaviour d. Do NOT have decline of overall cognitive function e. Seizures = 75% have clinical seizures but rarely severe 3. EEG a. Bilateral centrotemporal spikes and sharp waves with fields that spread widely throughout both hemispheres b. When the child falls asleep epileptiform activity becomes continuous – ESES 4. Treatment = nil effective

Answer 302

1. Key points a. Complex or Mendelian inheritance, family history of epilepsy is common b. Age of onset = onset at 8-25 years; peak 12-15 years 2. Clinical manifestations a. Myoclonic jerks – most frequent in the morning, within the first hour after awakening i. Seen as isolated jerks preferentially involving one but usually both arms b. Absence seizures – ‘typical’ petit mal seizures that often precede the other seizures and begin toward the end of the first decade c. Generalised tonic-clonic seizures – tendency to occur upon awakening i. Often index event leading to diagnosis ii. If you see a teenager with GTCS need to check for a history of myoclonus – has significant implications on prognosis of condition d. Increased risk of comorbid psychiatric illness and personality disorder e. Triggers i. Sleep deprivation ii. Alcohol iii. Photic stimulation 3. EEG a. Interictal EEG abnormal in 75% b. Generalised fast spike-wave discharges, polyspike discharges c. 35% have photosensitivity 4. Treatment a. 1st line = valproate i. Best established efficacy ii. Controls all seizure types b. Drugs to avoid = carbamazepine, phenytoin, oxcarbazepine (aggravate absence seizures and myoclonic jerks) 5. Prognosis a. LOW remission rate b. Requires lifelong treatment

Answer 303

Rare form of seizure Typically involves sudden burst of energy, usually laughing or crying Typically caused by hypothalamic hamartoma (benign mass of glial tissue near hypothalamus)

Answer 304

1. Key points a. Seizures most important and common indicator of significant neurologic dysfunction in the neonatal period 2. Types of seizures a. Subtle b. Clonic c. Tonic d. Spasms e. Myoclonic 3. Aetiology a. Acute i. Hypoxic-ischaemic encephalopathy ii. Ischaemic stroke – arterial, venous iii. Intracranial haemorrhage – intraparenchymal, intraventricular, subarachnoid, subdural iv. CNS infection – meningitis, encephalitis, intrauterine infection v. Metabolic disturbance – hypoglycaemia, hypocalcemia, hypoMg b. Chronic i. Isolated cerebral dysgenesis (eg. lissencephaly) ii. Cerebral dysgenesis associated with inborn errors of metabolism iii. Chronic infection iv. Neurocutaneous syndromes 1. Incontinentia pigmenti 2. Hypomalansosi of Ito 3. Sturge-Weber 4. Tuberous sclerosis 5. Linear sebaceous nevus v. Specific early onset epilepsy 1. Benign neonatal seizures 2. Benign familial neonatal seizures 3. Early myoclonic encephalopathy 4. Early infantile epileptic encephalopathy 5. Genetic epilepsies - KCNQ2 encephalopathy, SCN2A encephalopathy 4. Treatment a. Treatment is directed at the cause of neonatal seizures b. Examples i. CNS infection – treat infection ii. Hypoglycaemia – 10% dextrose 2 ml/kg iii. Hypocalcaemia – 10% calcium gluconate 100 mg/kg or 1 ml/kg IV iv. HypoMg – 50% Mg sulfate given IM v. Pyridoxine or PLP responsive seizures vi. Biotinidase deficiency – biotin supplementation c. Anti-epileptic agents i. 1st line = phenobarbital

Answer 305

* GLUT-1 deficiency * Pyridoxine dependent * Folinic acid responsive * Biotinidase deficiency Vitamin deficient epilepsies (pyridoxine, biotinidase, molybdenum cofactor) are rare but treatable causes of refractory neonatal seizures.

Answer 306

a. AR disorder, prevalence 1/400,000-700,000 b. Early onset epileptic encephalopathy c. Aetiology = defect in alpha-aminoadipic semialdehyder (AASA) dehydrogenase due to gene mutation in antiguitin gene ALDH7A1 d. Clinical features i. Seizures soon after birth (can be later) ii. EEG: multifocal abnormalities -> burst suppression iii. Consider in preterm infants with HIE / idiopathic refractory seizures e. Investigations i. Elevated AASA and pipecolic (nonspecific) in urine, plasma and CSF f. Management i. Pyridoxine therapy improves outcomes with early treatment ii. Allows early weaning iii. Intrauterine treatment can prevent seizures! iv. Pyridoxine 1. Pyridoxine 100 mg/kg IV or orally, followed by 30 mg/kg for 3 days (max 200-300 mg/day ) 2. If ineffective, can increase dose to 30-50 mg/kg/ day in three divided doses for three days 3. If ineffective, add on folinic acid 3.5 mg/kg/day

Answer 307

a. Mutations in biotinidase gene can result in medically refractory neonatal seizures responsive to oral biotin supplementation

Answer 308

a. Molybdenum cofactor deficiency is an AR disorder that results from one of several genetic defects in biosynthetic pathway of molybdenum cofactor b. Most patients present in first few days of life with exaggerated startle, lethargy, intractable seizure and autonomic dysfunction (resemble HIE)

Answer 309

1. Key points a. GLUT 1: expressed in luminal + abluminal membranes of brain capillaries, BBB and other neural cells b. Is also the predominant glucose transporter in erythrocytes 2. Aetiology – defect in GLUT1, either AD/de novo mutation 3. Clinical features a. Seizures onset 1-4 months b. Episodic/paroxysmal non epileptic events c. Often related to fatigue and hunger before meals d. Features: abnormal eye movements, intermittent ataxia, dystonia, alternating hemiparesis, sleep disturbance, dysarthria 4. Diagnosis a. Paired CSF/serum glucose ratio: lower than normal 0.19-0.46 (normal 0.6) with normal cell count/protein/ blood glucose b. Absolute CSF glucose < 2.2 c. Lactate is low-low normal d. Genetic tests – SLC2A1 gene

Answer 310

1. Mutations can cause a. Ion channelopathies b. IEM c. Cortical malformations d. Abnormalities of cerebral microstructure/function 2. Monogenetic epilepsies a. Voltage gated ion channel i. GEFS+, Dravet, infantile seizures – SCN1A, 1B, 2A ii. Neonatal seizures, absence epilepsy – KCNQ2, KCNQ3 iii. Absence epilepsies – CACNA b. Ligand gated ion channel subunits i. Frontal lobe epilepsy – CHRNA, CHRNB ii. GEFS+, absence epilepsy, JME – GABRA1, GABRG2 c. Non ion channel genes i. Idiopathic generalized epilepsies 1. Early onset absence epilepsy – GLUT1 2. Myoclonic astatic epilepsy – GLUT1 d. Focal epilepsies i. Benign familial convulsions – PRRT2 ii. Lateral temporal lobe epilepsy LFI1 e. Epileptic encephalopathies i. Ohtahara syndrome – STXBP1 ii. Infantile spasms- ARX, CDKL5 iii. Epilepsy limited to females with mental retardation – PCDH1 3. Chromosomopathies associated with epilepsy a. Trisomy 21

Answer 311

1. Goals of AED therapy a. No seizures or at least no ‘major’ seizures b. No AED side effects c. No exacerbation (possibly improvement) in comorbidities d. Reduce mortality and morbidity e. Improved quality of life (patient/family, home/school) f. Maximise normal development (cognitive, physical, social) g. Reduced health costs 2. General principles a. Treat the patients seizures not their EEG b. Start low go slow (especially LTG, TPM, CBZ, VPA, BZP) – drowsiness, rash, behavioural tolerability all less if slowly increased c. Aim for monotherapy d. Push AEDs to clinical effect, toxicity or high level eg. CBZ 1. Treatment of underlying cause eg. hypoglycaemia, cerebral tumour, metabolic problem 2. Counselling patients and family eg. factual information, emergency management 3. Avoid precipitating factors eg. sleep deprivation (particularly IGE in teenagers), flashing lights, viral infections (often in toddlers) 4. Lifestyle constraints = bathing, swimming, heights, alcohol (particularly withdrawal from alcohol; mainly teenagers with IGE), driving, vocational 5. Management of comorbidities = educational, psychological, psychiatric, behavioral 6. Anti-epileptic drug therapy if indicated = which drug, how long, side effects, goals of therapy a. Not treating the underlying condition – giving anti-seizure medications b. Dying from a seizure is less common in children c. Children are more likely to grow out of seizures 7. Special treatments for refractory epilepsy = surgery, ketogenic diet, VNS * Drugs which have multiple mechanisms of actions tend to have broad efficacy (eg. phenytoin, valproate) * Keppra is ineffective for absence epilepsy * Carbamazepine WORSENS absence epilepsy * Wary about using carbamazepine in patients with generalised epilepsy * For most childhood epilepsies – valproate would be the treatment of choice -> good for all seizure types including absence seizures * Phenobarbital is the treatment of choice for neonatal seizures * Focal epilepsy (lesional, not idiopathic) – carbamazepine * Benign rolandic and benign occipital – carbamazepine can sometimes worsen these seizures, only use in low doses * Idiopathic generalised epilepsy – valproate (appetite stimulation, weight gain, teratogenicity), keppra can also be used but not as good (however better side effect profile) * Keppra can be used for everything (focal symptomatic or focal idiopathic, and generalised) but NOT absence or spasms * Carbamazepine worsens idiopathic seizures AED levels are rarely necessary (phenytoin only mentioned in lecture) iii. Problems with drug level monitoring 1. Drug-level response relationship poor for most drugs 2. Reliable therapeutic ranges not available for most drugs 3. Wide variability in effects of different levels 4. Issue with unmeasured (neuroactive) free compound iv. No evidence to support routine AED levels with the aim of optimisation of treatment in patients with newly diagnosed epilepsy with AED monotherapy v. Which drugs are monitored? 1. CBZ = when at high doses (CYP autoinduction) 2. Barbiturates = often, especially in infants/disabled 3. Phenytoin = often, especially in infants/disabled

Answer 312

1. Treatment of underlying cause eg. hypoglycaemia, cerebral tumour, metabolic problem 2. Counselling patients and family eg. factual information, emergency management 3. Avoid precipitating factors eg. sleep deprivation (particularly IGE in teenagers), flashing lights, viral infections (often in toddlers) 4. Lifestyle constraints = bathing, swimming, heights, alcohol (particularly withdrawal from alcohol; mainly teenagers with IGE), driving, vocational 5. Management of comorbidities = educational, psychological, psychiatric, behavioral 6. Anti-epileptic drug therapy if indicated = which drug, how long, side effects, goals of therapy a. Not treating the underlying condition – giving anti-seizure medications b. Dying from a seizure is less common in children c. Children are more likely to grow out of seizures 7. Special treatments for refractory epilepsy = surgery, ketogenic diet, VNS

Answer 313

Predisposes to risk of SJS/TEN with carbamazepine. a. HLA-B*15:02 allele i. HLA-B*15:02 allele frequency varies widely by ethnicity 1. Common in Han Chinese (10-15%) 2. Also common in Filipinos, Malays, South Indians, Thais (>5%) 3. Uncommon in Caucasians, Latin Americans, Africans, Japanese, Koreans (<1%) ii. Risk 1. CBZ = risk of SJS/TEN a. Significantly more common with this allele; estimated to be 5% b. Odds ratio for SJS/TEN was 2500, 80-100% CBZ-SJS/TEN cases +ve in SE Asian study 2. PHT, OXC = risk of rash (but SJS also reported) 3. No increased risk of rash or HSS (DRESS) iii. Pharmacogenomics testing for prior to CZ prescription 1. Recommendation screen in any Asian with epilepsy 2. Even if not intending to prescribe initially 3. Potentially not if IGE iv. Clinical practice 1. Send plasma/serum 2. Prescribe keppra or valproate in interim if AED prescription is necessary 3. If positive do NOT prescribe CBZ or PHT, and best avoid OXC and LTG

Answer 314

a. General i. CNS side effects common to all drugs, especially during introduction and toxicity 1. Examples = drowsiness, ataxia, tremor, diplopia, vomiting, headache 2. Especially for Na+ channel blockers (PHT, CBZ, VPA, TPM, LTG, LCM) ii. Adverse behaviour effects relatively specific 1. Eg. hyperactivity, aggression, irritability, mood disturbance especially GABAergic drugs (PB, BZP, VGB, VPA), LEV, PER iii. Cognitive effects of AED in children are difficult to distangle from the effects of seizures, epileptic EEG abnormalities and the underlying brain a. HLA-B*15:02 allele -> SJS/TEN with carbamazepine. b. Weight gain i. Major issue with medication for many patients (40% of patients gain >5kg) ii. Common cause of non-compliance iii. Significant effect on psychological wellbeing iv. Classification 1. Weight gain = carbamazepine, oxcarbazepine, gabapentin, pregabalin, valproate, vigabatrin, clobazam 2. Weight neutral = lamotrigine, keppra, phenytoin 3. Weight loss = felbamat, topiramate, zonisdamide, rufinamide c. Fractures and bone mineral density i. Epilepsy and AED therapy are associated with increased fracture risk and reduced bone mineral density ii. Fracture risk greater than attributable to reduced BMD, presumably related to trauma iii. Particularly – valproate, phenytoin, topiramate a. Teratogenesis -> do not prescribe VPA in women of childbearing age i. Increased risk of most types of birth defects with all AEDs ii. Greatest risk with VPA 10% and polytherapy iii. Small risk increase with epilepsy and no AEDs (1%)

Answer 315

= increased clearance -> decreased steady state of other drugs Phenobarbitone Phenytoin Topiramate Carbamazepine - metabolised by CYP3A4 -> induces, increases metabolism of itself and other drugs - inhibition of CBZ metabolism can occur with macrolide antis, metronidazole, certain antidepressants, verapamil, diltiazem -> increase CBZ levels

Answer 316

= decreased clearance -> increased steady state of other drugs Valproate

Answer 317

1. VPA + LTG +/- CLB | 2. VPA + ESM +/- CLB

Answer 318

i. Hepatic = almost ALL | ii. Renal = GBP, VGB, TPM, LEV, ZNS

Answer 319

a. Rapid titration (oral/IV load) = increases risk of rash i. BDZ (load) ii. Phenytoin (load) iii. Phenobarbitone (load) iv. Keppra (days) v. Valproate (weeks) vi. Lacosamide (weeks) b. Slow titration (oral) i. Carbamazepine (weeks) ii. Oxcarbazapine (weeks) iii. Lamotrigine (months) – best tolerated drug for absence seizures iv. Toprimate (months)

Answer 320

a. Predictors of seizure recurrence i. Symptomatic aetiology, intellectual disability, abnormal neurological examination ii. Seizure onset in second decade iii. Myoclonus, especially JME iv. Strong family history v. Abnormal EEG before or during withdrawal vi. Recurrence after previous attempts to withdrawal b. Recommendations i. Recognize favourable syndromes (BRE, BOA, CAE) and unfavourable syndromes (TLE, FLE, JME) for withdrawal ii. Consider after 2 years seizure free therapy in unspecified epilepsy syndrome iii. Best if patient/parent initiated decision iv. Easier decision if AED side effects are present v. Everyone understands risks vi. Modify lifestyle (esp driving) vii. Withdrawal one drug at a time, slowly (particularly slow for BDZ) viii. Monitor for mood, behavior disturbance and migraine (some drugs have positive effects on other aspects)

Answer 321

1. Na+ channel blockers a. Phenytoin (also enhances GABA) b. Carbamazepine c. Oxcarbazepine d. Valproate (also enhances and inc GABA) e. Topiramate (also enhances GABA, diminishes glutamate + inhibits carbonic anhydrase) f. Lamotrigine (also decreases glutamate) g. Zonidamide ( also blocks Ca channels + inhibits carbonic anhydrase 2. GABAergic a. Phenobarbitone b. Benzodiazepines c. Vigabatrin (increase levels) d. Valproate (mixed) e. Tigabine (increases levels) 3. Blocks Ca2+ channels 4. Novel – keppra, gabapentin, Pregabalin

Answer 322

a. Features i. Medically supervised and strictly regulated diet with restricted fluid, high fat, minimum protein and very low CHO intake ii. Classical 4 fat : 1 protein + CHOO, MCT or modified MCT forms iii. Body burns fat for energy rather than CHO and protein -> produces ketones to mimic starvation and illness iv. Brain can extract beta-hydroxybutyrate and acetoacetate and metabolise them separately to glucose v. KD raises seizure threshold but mechanism is unknown b. Outcome i. 1/3 marked improvement, 1/3 mild improvement, 1/3 no improvement ii. Medications usually able to be reduced iii. Side effects usually transient or reversible iv. Effects on cognition and behaviour have not been studied ? improved seizure control ? decrease medication ? real v. Caution with VPA because of risk of mitochondrial dysfunction vi. Duration and long term AE unknown vii. No evidence that alters the natural history c. Indications i. Some refractory childhood epilepsies ii. Pyruvate dehydrogenase deficiency iii. Glucose transporter defect – need to get energy INTO brain d. Contraindicated or caution in metabolic diseases with fat oxidation deficits and/or lactic acidosis i. Pyruvate carboxylase deficiency ii. Carnitine deficiency iii. Mitochondrial disorders iv. Organic acidurias

Answer 323

a. NOT targeted therapy b. Consider in children with epilepsy who i. Failed appropriate AED ii. Are not candidates for respective surgery iii. Are being considered for callosotomy iv. May benefit from seizure termination v. Tonic drop attacks, recurrent status c. Realistic expectations i. 50% have >=50% seizure reduction ii. <10% chance of seizure freedom iii. Stay on drugs iv. Battery replacement after 5 years Lennox Gastaut mentioned in lecture as a good option for VNS

Answer 324

a. Surgical remediable syndromes i. Focal lesional epilepsies 1. Mesial TLE with hippocampal sclerosis 2. Neocortical epilepsies secondary to tumours, cortical dysplasias/malformations, vascular malformations 3. Gelastic epilepsy and hypothalamic hamartoma ii. Hemispheric lesional epilepsies 1. Unilateral SWS, PMG, HMG, schizencephaly 2. Unilateral MCA territory infarct 3. Chronic encephalitis (Rasmussen’s) iii. Multilesional, unifocal epilepsy 1. Tuberous sclerosis 2. Posttraumatic/infective iv. Some non-lesional epilepsies 1. Neocortical partial epilepsies 2. Lennox-Gestaut syndrome 3. Landua Kleffner syndrome b. Operations for uncontrolled epilepsy i. Cortical resection – lesionectoy, corticectomy, lobectomy ii. Multilobar resection iii. Corpus callosotomy iv. Multiple subpial transection v. Stereotactic radiosurgery c. Presurgical evaluation i. Neurological assessment ii. VEEG +/- ictal SPECT iii. High res seizure focused MRI iv. Neuropsychological assessment v. Other functional imaging (eg. PET, fMRI) 1. Characterise and localise seizure 2. Determine underlying etiology (lesion) 3. Assess impact of seizures and likely prognosis 4. Outline treatment (surgical) options

Answer 325

1. Uncontrolled epilepsy a. Epilepsies in which seizures are not adequately controlled by anti-epileptic medications, or seizure control is possible only with intolerable side effects b. 20% of children have uncontrolled seizures 2. Uncontrolled epilepsies of childhood a. Some lesional partial epilepsies of childhood – examples: mTLE/HS, neocortical epilepsy secondary to focal cortical dysplasia/ TS, tumours, gelastic/HH b. Some generalised epilepsies of childhood – Lennox-Gastaut syndrome, SMEI, various myoclonic epilepsies c. ‘Catastrophic’ infantile spasms – infantile spasms, Sturge-Weber, hemimegalencephaly, TS d. Epileptic aphasia syndromes – Landua Kleffner syndrome, CSWS/ESES e. Progressive neurological conditions – Rasmussen syndrome, progressive myoclonic epilepsies f. Uncommonly, some idiopathic epilepsies – absence epilepsy, JME, atypical BFEC 3. Key points in management a. Review diagnosis (? Non-epileptic, ? correct syndrome) b. Remove triggers and modify lifestyle c. Check patient compliance (drug levels) d. Use best AED for specific seizure type and syndrome e. Remove AEDs potentially aggravating seizures f. Use maximum tolerated doses +/- levels g. Use ‘rational’ AED combinations eg. VPA + LTG h. Use new AEds with greater efficacy, multiple actions or novel action i. Consider older mechanisms eg. PHT, PB, PRM j. Change from preventative treatment to acute treatment of seizures or seizure clusters 4. Treatments a. New antiepileptic drugs b. Epilepsy surgery c. Vagal nerve stimulation (VNS) d. Ketogenic diet e. Deep brain stimulation f. Immunotherapies g. Stereotactic radiotherapy h. Behavioral therapies i. Alternative treatment

Answer 326

a. Currently available i. Corticosteorids – ACTH, hydrocortisone, prednisolone, methylpred ii. Immunoglobulins iii. Interferons iv. Monoclonal Ab v. Plasma exchange b. Indications i. Epileptic encephalopathies 1. West syndrome 2. Lennox Gastaut syndrome 3. Epileptic-aphasia syndromes (Landau-Kleffner, electrical status epilepticus during slow-wave sleep, EOS) ii. Inflammatory epilepsies 1. Rasmussen encephalitis 2. Encephalitis/post-encephalitis eg. HSV, mycoplasma 3. Seizures with ADEM iii. Refractory idiopathic epilepsy 1. Refractory myoclonic or absence epilepsy 2. Atypical benign focal epilepsy iv. Status epilepticus of unknown etiology in PICU c. Infantile spasm/ West syndrome i. Steroids are BETTER than vigabatrin – reduction in steroids and improvement in neurodevelopmental outcomes ii. Prednisolone (except TS or treatable condition) 1. 10 mg QID 2 weeks then wean by 10 mg dose every 5 days 2. Increase to 20 mg TDS if spasms continue after 1 week 3. Refer to HITH for BD electrolytes, glucose and BP iii. Vigabatrin in TS, and if prednisolone fails after 2-4 weeks 1. 50 mg/kg/day increasing to 150 mg/kg/day over 1 week if spasms do not cease after each dosage step 2. Treat for 3 months, increasing the dose with increases in weight iv. Follow-up EEG when seizure free 1. Aim for EEG normalization 2. EEG abnormalities may not be treated if child seizure free

Answer 327

a. >80 active compounds in cannabis with varying psychoactive properties b. Natural extracts and synthetic compounds tested in epilepsy models and marked worldwide for pain (cancer), spasticity (MS) and seizures c. Potential long-term effects in children/adolescents unknown i. Concern about mental health, dependence e. Open-label trial of Epidiolex i. RCTs of epidiolex (CBD) in Dravet (n=120) and Lennox Gastaut syndrome ii. Significant reduction in children seizures iii. Side effects 1. Somnolence, fatigue, lethargy 20-30% 2. Diarrhoea, LOA, vomiting, weight loss in 20-30% 3. Elevated LFTs in 20% (also on valproate) iv. CYP2C19 inhibition increases level of N-desmethylclobazam (active clobazam metabolite)

Answer 328

50% or greater reduction in seizures

Answer 329

1. Background a. Convulsions, in a child between 6 months and 6 years of age, in the setting of an acute febrile illness, without previous afebrile seizures, significant prior neurological abnormality, and no CNS infection. i. Occur in 3% of health children ii. Are normally associated with simple viral infection iii. Are benign 2. Risk factors a. Major i. Age <1 year ii. Duration of fever <24 hours iii. Fever 38-39 degrees b. Minor i. Family history of febrile seizures ii. Family history of epilepsy iii. Complex febrile seizures iv. Daycare v. Male gender vi. Low sodium at the time of presentation c. Risk of recurrence i. No risk factors = 12% ii. 1 risk factor = 25-50% iii. 2 risk factors = 50-60% iv. 3+ risk factors = 75-100% 3. Classification a. Simple = generalised, tonic-clonic seizure lasting <15 minutes that do not recur within the same illness b. Complex = have one or more of the following features i. Focal features at onset or during seizure ii. Duration of >15 minutes iii. Recurrence within the same febrile illness iv. Incomplete recovery in an hour c. Febrile status epilepticus = febrile convulsion lasting >30 minutes d. Note: ‘afebrile febrile convulsion’ = presentation of convulsions with an acute infection (eg. gastroenteritis) WITHOUT documented fever – same management as classic febrile convulsions

Answer 330

4. Acute management a. Treat as per usual convulsion guideline 5. Assessment a. In a simple febrile convulsion once the convulsion has terminated, the aim of the assessment is to determine the cause of the fever. b. Usual history and examination of febrile child c. In addition, look for the following risk factors which make simple febrile convulsion unlikely: i. previous afebrile seizures ii. progressive neurological conditions iii. signs of CNS infection d. Investigations i. In a simple febrile convulsion, where the focus of infection can be identified, blood tests and invasive investigations are often NOT indicated ii. In a child less than 6 months of age reconsider your diagnosis, especially the possibility of CNS infection iii. Consider LP if child <12 months and not fully immunised, are unwell, or already on oral antibiotics that may mask meningitis 6. Long-term a. Recurrence rate depends on the age of the child; the younger the child at the time of the initial convulsion, the greater the risk a further febrile convulsion (1 year old 50%; 2 years old 30%) b. Risk of future afebrile convulsions (epilepsy) is increased by i. Family history of epilepsy ii. Any neurodevelopmental problem iii. Atypical febrile convulsions (prolonged or focal) c. Based on number of risk factors i. No risk factors: risk of subsequent epilepsy approx. 1% (similar to population risk). ii. 1 risk factor: 2%. iii. More than 1 risk factor: 10%. d. Long term anticonvulsants are not indicated except in rare situations with frequent recurrences. e. It may be appropriate to offer a review appointment with a general paediatrician, especially in the case of complex febrile convulsions

Answer 331

1. Key points a. Risk of sudden unexpected death in those with epilepsy (sudden unexpected death in epilepsy = SUDEP) b. Formal definition = sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death in patients with epilepsy with or without evidence of a seizure, and excluding documented status epilepticus ≥30m in duration, in which post mortem examination does not reveal other cause for death 2. Cause a. Unknown b. Likely heterogenous 3. Epidemiology a. Causes 2-18% of all deaths in patients with epilepsy b. Proportion likely higher in children with epilepsy 4. Risk factors a. Seizure type and frequency i. Uncontrolled or frequent seizures ii. Generalised tonic clonic seizures 1. Presence and frequency of generalised tonic-clonic seizures = most important risk factor 2. Patients with GTCS have a 10-fold higher risk of SUDEP b. Age i. Most reported cases are in adults 18-40 years of age ii. Children <1 year can also be affected c. Genetic factors d. Many other factors i. Seizures that begin at a young age/ Long duration of epilepsy ii. Male gender iii. Young adulthood iv. Frequent changes of dose and type of AED v. Poor compliance vi. Epileptic syndromes 5. Management a. Inform epilepsy patients and when appropriate, family members b. Counselling about the probability of having and not having SUDEP c. No strategies to reduce risk of SUDEP – maximal seizure control recommended d. Nocturnal supervision has been studied prospectively and has been associated with reduced risk of SUDEP

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