1
Q
A 19-year-old man was admitted to this hospital
in early spring because of
A
- otalgia,
- slurred speech, and
- ataxia.
2
Q
The patient had been well until approximately 1 month before admission, when
A
- fatigue,
- fever,
- pharyngitis, and
- lymphadenopathy developed.
3
Q
Twenty-five days before admission, he went to another medical facility, where a test for streptococcal pharyngitis was
A
negative.
4
Q
Eight days later, a heterophile antibody test was
A
positive
5
Q
the hematocrit, hemoglobin, and blood levels of total protein, albumin, and total and direct bilirubin were
A
normal; other test results are shown in Table 1.
6
Q
A diagnosis of infectious mononucleosis due to
A
Epstein–Barr virus (EBV) infection was made.
7
Q
Two weeks before admission,
A
- dysphagia developed and
- pain and
- decreased hearing occurred in the right ear.
8
Q
On repeat evaluation, a diagnosis of
A
otitis media was made, and prednisone (45 mg daily, for 5 days) and amoxicillin (for 2 days) were administered, followed by azithromycin (for 3 days).
9
Q
Eight days before admission, severe
A
otalgia developed.
10
Q
On examination by an otolaryngologist, there was
A
- perforation of the right tympanic membrane, with 2. bloody purulent material in the external ear canal.
11
Q
for the perforation of the rt. tympanic membrane and bloody purulent material in the external ear canal what med was prescribed?
A
- Oral cefuroxime (500 mg twice daily) and
2. an otic suspension of topical ciprofloxacin and 3. dexamethasone were prescribed.
12
Q
Two days later, increasing
A
unsteadiness developed; the patient fell several times during the next 5 days.
13
Q
The day before admission, he returned to the otolaryngologist; on examination, there was
A
an effusion in the right middle ear.
14
Q
Myringotomy, with fluid aspiration, was performed. After the procedure,
A
- transient unsteadiness occurred, with vomiting;
- ear pain lessened, and
- hearing partially improved.
15
Q
After returning home, the patient noted
A
- slurred speech,
- clumsiness with movements, and
- increasing gait imbalance.
16
Q
Later that night, he went to the emergency department at another hospital.
A
Ceftriaxone (1 g) was administered, and he was transferred to the emergency department at this hospital.
17
Q
The patient reported
A
- fullness and
- decreased hearing in the right ear,
- weight loss of 4.5 kg, and
- persistent fatigue during the previous month, without neck stiffness, headache, photophobia, changes in vision, tinnitus, vertigo, sensory abnormalities, or difficulty with comprehension.
18
Q
He had a history of
A
- acne,
- asthma, and
- otitis media during childhood;
- he had undergone an inguinal herniorrhaphy as an infant.
19
Q
Medications at home included
A
a combination of oxycodone and acetaminophen for otalgia and topical benzoyl peroxide.
20
Q
He had no
A
known allergies. He attended college. He did not smoke, drink alcohol, or use illicit drugs.
21
Q
His paternal grandfather had
A
polymyalgia rheumatica at 75 years of age and a stroke at 80 years of age; there was no other family history of neurologic or rheumatologic diseases.
22
Q
On examination, the patient was
A
- thin,
- alert, and
- oriented, with an appropriate affect.
23
Q
The vital signs and oxygen saturation were normal. The right tympanic membrane was
A
perforated, with dried blood in the external canal.
24
Q
The tonsils were
A
enlarged (3+) and erythematous.
25
His speech was
fluent and mildly dysarthric.
26
Extraocular movements revealed
1. slight saccadic undershoot,
2. normal pursuit, and no nystagmus.
3. Hearing (comprehension of whispered words) was slightly diminished in the right ear.
27
He had
1. dysmetria bilaterally on finger-to-nose testing, with
2. end-point tremor;
3. rapid alternating movements were irregular, and there was
4. overshooting bilaterally when the patient attempted to follow the rapid finger movements of the examiner.
28
Heel-to-shin testing was
intact,
29
but there was marked
truncal ataxia with standing and walking.
30
The remainder of the general and neurologic examinations was
normal, including
1. repetition and naming,
2. strength,
3. deep tendon and
4. plantar reflexes, and
5. sensory examinations.
31
The hematocrit, hemoglobin level, and platelet count were
normal, as were blood levels of electrolytes, glucose, total protein, albumin, lipase, total and indirect bilirubin, phosphorus, calcium, magnesium, vitamin B12, cholesterol, and lipoproteins.
32
Results of renal-function tests were
normal; other test results are shown in Table 1.
33
Dr. Mary E. Cunnane: Computed tomography (CT) of the brain and temporal bones, performed without the administration of contrast material (Fig. 1A and 1B), reveals
1. fluid in the right middle ear and mastoid air cells and
| 2. hemorrhage within the right external auditory canal, findings that are consistent with the recent tympanostomy.
34
There is no associated
1. bony destruction, and
| 2. both the roof of the middle ear and the roof of the mastoid are intact.
35
The brain is normal in
appearance.
36
Magnetic resonance imaging (MRI) of the brain, performed without the administration of gadolinium, reveals
1. opacification of the right mastoid air cells and middle ear, as well as
2. prominent adenoids and cervical lymph nodes.
37
No abnormality is evident in the
brain, and the findings are otherwise normal.
38
Dr. Bogoch: The patient was admitted to the hospital. Results of a lumbar puncture are shown
in Table 1. The oral administration of
cefuroxime (250 mg twice daily) was started by the admitting service.
39
Dr. Cunnane: On the second day, repeat MRI of the brain with the administration of gadolinium was performed. Images from the MRI scan show
unchanged opacification in the right mastoid air cells and middle ear (Fig. 1C and 1D).
40
There is
no extra-axial fluid collection, acute infarction, mass lesion or mass effect, or signal abnormality or enhancement in the brain parenchyma.
41
A magnetic resonance venogram shows
normal flow related enhancement in the dural venous sinuses, without evidence of venous sinus thrombosis or stenosis.
42
A CT scan of the skull base, obtained after the administration of contrast material, shows
opacification of the right middle ear and mastoid air cells, with no destruction of bony mastoid septa.
43
The tegmen tympani and tegmen mastoideum are
intact.
44
Dr. Bogoch: Cefuroxime was
stopped,
45
after cefuroxime was stopped what meds were given to the pt?
1. vancomycin and ceftriaxone were administered intravenously, and
2. antihistamines and metoclopramide were also administered. The patient’s symptoms persisted.
46
On neurologic examination on the fourth hospital day, the patient was
1. awake and cooperative
2, but inattentive, with mild anomia and impaired verbal fluency and
3. verbal working memory.
47
Comprehension was
normal.
48
The ability to perform simple arithmetic was
impaired, and
49
he perseverated when performing the Luria fist-palm-side test of alternating motor sequencing, which is sensitive to
executive dysfunction from lesions of the prefrontal cortex.1
50
Eye movements showed continued
1. hypometric saccades and
| 2. catch-up to both the left and the right sides.
51
Speech was mildly
dysarthric.
52
He had
hypotonia throughout. h his feet together.
53
There was
1. dysdiadochokinesia in both arms and
| 2. dysmetria on finger-to-nose testing.
54
There was proximal overshoot
on heel-to-shin testing.
55
The gait was
wide-based and unsteady, and the patient veered to either side.
56
He was unable to perform
tandem walking and lost his balance when standing with his feet together.
57
The remainder of the examination, which included
Weber and Rinne tests and tests of visual fields, strength, deep-tendon and plantar reflexes, and sensation, was normal.
58
In the early spring, what symptoms were developed in this young man?
1. fever,
2. fatigue,
3. pharyngitis, and
4. lymphadenopathy developed in this young man, followed by
5. purulent otitis media and perforation of the tympanic membrane in the right ear.
59
what symptoms had led to his admission to the neurology service?
1. Progressive unsteadiness,
2. clumsiness,
3. slurred speech, and falls led to his admission to the neurology service.
60
The initial examination revealed
1. cerebellar dysfunction, including
2. hypometric saccades,
3. truncal and appendicular dysmetria, and
4. gait ataxia.
61
Of note, he had no
1. fever,
2. rash,
3. nuchal rigidity,
4. mental-status changes,
5. extraocular movement or other cranial-nerve abnormalities,
62
later, what symptoms developed?
1. sensory loss, or areflexia.
| 2. Later, cognitive impairment developed, predominantly in executive function.
63
This presumably immunocompetent patient had an
upper respiratory tract infection that was complicated by otitis media.
64
The clinical syndrome in this case is that of
1. isolated cerebellar dysfunction involving both the vermis and the intermediate hemispheres symmetrically and,
2. later, the posterior lobe.
65
Otitis media can spread to the
labyrinth, but this usually leads to severe vertigo lateralized to the affected ear and nystagmus, which were absent in this case.
66
The Guillain–Barré syndrome is the most common cause of
postinfectious ataxia, but this syndrome is due to a sensory ataxia manifested by impaired proprioception and the loss of deep-tendon reflexes, findings that were absent in this case.
67
The impairment in executive function raises the possibility of
cerebral involvement, but the associated findings could be explained entirely by a cerebellar lesion (i.e., the cerebellar cognitive affective syndrome).2
68
Therefore, the syndromic diagnosis is
acute cerebellar ataxia after an upper respiratory tract illness.
69
Initially, no sign of hemispheric involvement and no lateralizing signs were present, but because of what led to the imaging study?
the purulent otitis media and worsening mental status, imaging studies were warranted to assess the patient for direct extension of bacterial otitis or encephalitis.
70
MRI is the best neuroimaging technique for
1. identifying a mass,
2. ischemic or hemorrhagic stroke,
3. demyelination, or
4. leptomeningeal inflammation.
71
CT would be more useful for detecting
skull defects, such as erosion from sinusitis.
72
The imaging studies ruled out clinically significant
intracranial lesions.
73
There are many causes of cerebellar ataxia (Table 2). In this case, most of these causes can be ruled out or rendered highly improbable on the basis of
1. the clinical course,
2. physical and neurologic examinations, and
3. laboratory and imaging studies.
74
However, what can NOT be ruled out by the noraml result of imaging?
paraneoplastic cerebellar ataxia mediated by antibodies targeting Purkinje cells (which is most often associated with small-cell lung carcinoma, Hodgkin’s lymphoma, breast and gynecologic carcinomas, and germ-cell tumors of the testis) is not ruled out by the normal results of imaging.3
75
Several autoimmune and inflammatory processes may affect the cerebellum, including
1. acute demyelinating encephalomyelitis,
2. multiple sclerosis,
3. the Miller Fisher syndrome (a variant of the Guillain–Barré syndrome),
4. Bickerstaff’s brainstem encephalitis (which, like the Miller Fisher syndrome, is characterized by the presence of anti-GQ1b IgG antibodies),
5. systemic lupus erythematosus,
6. Sjögren’s syndrome, and
7. gluten sensitivity.
76
However, this patient has
no systemic symptoms or lateralizing signs, and
77
he has
1. normal reflexes,
2. full eye movements,
3. normal results of imaging studies, and
4. normal results of cerebrospinal fluid (CSF) tests.
78
Infectious causes of cerebellar ataxia include
1. encephalitis,
2. meningitis,
3. abscess, and
4. infectious or parainfectious acute cerebellar ataxia.
79
On the basis of CSF testing and MRI, what can be ruled out?
meningitis and abscess can be ruled out.
80
Many infections and vaccinations have been associated with
acute cerebellar ataxia (Table 3).
81
The most common preceding infection is
varicella, which historically occurs most often in younger children.4,5
82
In older children and young adults what is the most commonly identified preceding to acute cerebellar ataxia?,
infectious mononucleosis is the most commonly identified preceding infection.6
83
Acute cerebellar ataxia has also been associated with
1. upper respiratory tract infections and
| 2. gastroenteritis.
84
It may sometimes represent direct infectious encephalitis but is more commonly a
parainfectious and presumably indirect immune process.
85
Cerebellar Ataxia Associated with Epstein–Barr virus
Encephalitis associated with Epstein–Barr virus (EBV) infection may occur with or without clinically evident infectious mononucleosis but is usually accompanied by
headache and fever, which are absent in this case.7,8 It may affect any part of the brain, at one or multiple sites, but the cerebellum is the most common single location.9
86
Images from MRI scans may show T2-weighted
hyperintense foci with or without enhancement, or the images may be normal.
87
A specimen of CSF may reveal a
lymphocytic pleocytosis or a normal profile,
88
and a polymerase-chain-reaction assay of the CSF for EBV and an EBV-antibody test are
positive in many cases.10
89
In contrast, postinfectious or parainfectious EBV-associated acute cerebellar ataxia is preceded by
infectious mononucleosis by 1 to 3 weeks, as in this case.
90
Examination reveals
predominant cerebellar motor symptoms, although cognitive dysfunction is also common.
91
MRI scans are typically normal, but the images may reveal
T2-weighted hyperintense foci. A CSF specimen is usually normal; EBV antibodies are present systemically but are absent in the CSF.
92
This patient’s CSF had relatively
few cells (mostly lymphocytes) and normal levels of protein and glucose.
93
There are few reports on the pathological features of postinfectious encephalitides because of their typically
benign course.
94
The patients reported on in the literature had
no neuronal infection and usually had perivascular lymphocytic infiltration, at times with demyelination.
95
In rare cases, EBV DNA is detected in the CSF or brain tissue, but this most likely represents
either contamination from blood or migration of infected B cells, since the virus has not been detected in neurons.11-13 For these reasons, there is some debate as to whether all cases of EBV-associated encephalitis are autoimmune rather than infectious.
96
In summary, my diagnosis in this case is
acute cerebellar ataxia due to recent infection with EBV (infectious mononucleosis).
97
Dr. Eric S. Rosenberg (Pathology): Dr. Bogoch, would you tell us the thinking of the clinical team at the time?
Dr. Bogoch: When we met this 19-year-old man, we were struck by the fact that he had
1. a positive heterophile antibody test,
2. otitis media, and
3. cerebellar dysfunction.
We wondered whether lymphadenopathy had caused an obstruction of the eustachian tube that resulted in an acute otitis media.
98
Our immediate concern was that the patient might have a
cerebellar abscess. Since that was ruled out by imaging studies, and because the cerebellar signs were bilateral, our preferred diagnosis was postinfectious cerebellitis.
99
Clinical Diagnosis is
Postinfectious cerebellitis.
100
DR. TR ACEY A. CHO’S DIAGNOSIS
1. Infectious mononucleosis,
2. otitis media, and
3. parainfectious acute cerebellar ataxia associated with the Epstein–Barr virus.
101
DISCUSSION OF MANAGEMENT
Dr. Jeremy D. Schmahmann: This patient’s history and examination and the results of laboratory and imaging tests led us to a diagnosis of
infectious mononucleosis due to EBV infection, with postinfectious cerebellitis.
102
Neurologic complications of EBV infection occur in 1 to 18% of cases.14 Postinfectious EBV-associated cerebellitis usually develops
12 to 22 days after the onset of the prodromal illness,4 which is somewhat longer than the latency of cerebellitis due to other causes, such as varicella infection. In this patient, the interval was even longer — at approximately 1 month.
103
MRI scans of the brain in cases of postinfectious cerebellitis are usually normal,
as in this case; however, evidence of cerebellar hyperperfusion15 or hypoperfusion16 may be detected on single-photon-emission CT (SPECT).
104
The patient’s family was astonished at his impairment on tests of
attention, working memory, mental flexibility, and verbal fluency. This constellation of findings is known as the cerebellar cognitive affective syndrome. Motor functions and cognitive and limbic functions have separate anatomical representations in the cerebellum.
105
Damage to the motor cerebellum results in cerebellar motor deficits,29-32 damage to the vestibulocerebellum results in vestibular impairments, and damage to the cognitive cerebellum results in the
cerebellar cognitive affective syndrome.2,28,33,34
106
The cerebellar cognitive affective syndrome is characterized by
1. deficits in executive function,
2. visuospatial impairment,
3. linguistic difficulties, and
4. impairments in emotional modulation (e.g., blunted affect)2,19; this patient had many of these characteristics.
107
In adults who are older than 60 years of age, permanent impairment has been reported6 in association with imaging evidence of
cerebellar atrophy; I have observed prolonged or permanent motor and cognitive disabilities in this patient population.
108
Evidence for an immunologic basis of EBV associated postinfectious cerebellitis comes from
reports of patients who had EBV-associated postinfectious cerebellitis with antibodies directed
against cytoplasmic and nuclear elements of
cerebellar Purkinje cells38 and those with antibodies directed against triosephosphate isomerase in the cerebellar cortex.39
109
These observations suggest that treatment directed at the
immune response may be effective in treating this disorder.
110
I previously reported that plasmapheresis led to improvement within days in two patients with
EBV-associated postinfectious cerebellitis.40 Before seeing this patient, I had treated or consulted on two other patients, who had similar courses of recovery. Treatment with
intravenous immune globulin (IVIG) also resulted in rapid improvement in two reported cases, one in a child without a clear prodrome who had no response to treatment with methylprednisolone16 and the other in a 19-year-old man with EBV-associated postinfectious cerebellitis15; both patients had evidence of altered cerebellar perfusion on SPECT despite normal imaging studies.
111
In summary, our diagnosis in this case was
immune-mediated, EBV-associated postinfectious cerebellitis.
112
The patient had elements of both
1. the cerebellar motor syndrome and
| 2. the cerebellar cognitive affective syndrome.
113
My recommendation, on the basis of the literature and personal experience (and until the results of clinical trials can provide evidence-based approaches to treatment), is to treat patients who have
no improvement by the end of the first week of cerebellitis, who have cognitive or emotional symptoms, or both.
114
The treatment may consist of
1. plasmapheresis or
| 2. IVIG.
115
The use of monoclonal antibodies such as rituximab for immune modulation in such patients is
untested.
116
Glucocorticoids may be effective in some patients, but in others they may simply
delay the initiation of effective treatment.
117
In this case, I recommended either
plasmapheresis or IVIG.
118
After consultation with transfusion medicine, a 5-day course of
IVIG was begun on the fourth hospital day. The patient’s symptoms and signs responded rapidly and completely, and he was discharged on the eighth day.
119
Dr. Rosenberg: This patient had a very dramatic recovery, and he reported that
90% of his function recovered over a 5-day course of therapy.
120
He spent only 1 day in a rehabilitation hospital and regained
100% of his function during the ensuing several weeks, with no residual deficits. He is now in college, travels, is active in sports, and is here with us today. I would like to invite him to comment.
121
A Physician: The onset of cerebellitis in this patient was slower than we have seen
in younger patients.
122
Could the initial treatment with prednisone for lymphadenopathy have influenced the onset of symptoms?
Dr. Schmahmann: The interval to the development of encephalitis is typically longer after EBV infection than after other viral infections. I know of no data that suggest that the administration of glucocorticoids affects the outcome.
123
A Physician: In patients with EBV-associated postinfectious cerebellitis who have residual deficits, is there imaging evidence of atrophy or focal lesions?
Dr. Schmahmann: Yes, all the patients I have seen with persistent symptoms had evidence of cerebellar atrophy on neuroimaging.
124
Final Diagnosis
Acute infectious mononucleosis due to Epstein–Barr virus infection, complicated by acute otitis media and postinfectious cerebellitis.
MLC Unit 3
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