You Shake My Nerves and You Rattle My Brain

“You shake my nerves and
you rattle my brain”
Ai Sakonju, M.D.
David E. Newman-Toker, M.D.
Johns Hopkins University School of Medicine
Feb. 11, 2007
Case Presentation
39 yo man presented due to new falls and
dysphagia.
PMH: Traumatic brain injury to left frontal
area at age 13, with full recovery (last
GTC seizure >2 years prior; no meds)
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ROS (June, 2004):
3 MO: personality change, social
withdrawal, mood irritability, impaired
ADLs, bradykinesia, mutism, dysphagia,
and worsening gait.
1 WK: fever to 102, diarrhea, leg cramps,
socially inappropriate behavior.
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Case Presentation (cont.)
FH: Crohns in sibs and mom
SH:
college MA economics, self employed
consultant, fired from several jobs in 90s and
just prior to symptom onset
marathons, biking throughout the U.S.
travel to China 6 months-1 year prior to
symptom onset
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Physical Exam
Afebrile
Tachycardic (heart rate 108)
Anxious-appearing and functionally mute
Communication by “thumbs up and down”
for yes/no questions
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Physical Exam (cont.)
Sensory and motor exam were normal
His neurologic exam was otherwise
notable for hypophonia, dysarthria,
bradykinesia, and rigidity (without
cogwheeling).
With support, he had retropulsion on
standing and walked with small slow wide
steps.
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Physical Exam (cont.)
Oculomotor examination was remarkable
for frequent intrusive eye movements.
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Eye Movements
Elemental Eye Movement Exam
restriction of upgaze > down, lateral gaze
relative sparing of pursuit, vergence, and
vestibulo-ocular reflex movements
Intrusive Eye Movements
frequent globe intrusions
eyelid fluttering
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10
What are those eye
movements???
Eye Movements
Opsoclonus:
Frequent, brief, irregular bursts of back-toback saccades, multivectorial
Low-amplitude and intermittent saccadic
intrusions, exacerbated by convergence
and upgaze
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Close-up of eye movements
Work up for opsoclonus?
Axial FLAIR
What Next???
Initial tests
LP: gluc 56, prot 60, WBC 2, RBC 520,0
WBC nl, CRP 18.8
B12 435, TSH 1.78, CMP, pyruvate:lactate
ratio nl. Lactate nl. ESR 3. RPR neg.
SPEP/UPEP no monoclonal gammopathy;
Paraneoplastic panel sent to Mayo, ACE,
ANCA, ANA, anti-Ro/La, Anti-DNA all
negative.
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What Next???
Additional Tests
• Pan CT negative
• Whole body PET negative
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Working Diagnosis???
Additional Tests
Possible CNS Whipples
• Apparent response to Ceftriaxone
But…
• Gastroduodenal biopsy negative
Also, brain biopsy negative and unrevealing.
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Now What???
Clinical Course
Initial hospitalization:
finished antibiotic course
Social interactions seemed improved
He returned with progressive symptoms while
being on bactrim
Increased rigidity and falls
Subacute shortness of breath and fever
leading to intubation
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Meanwhile…
his paraneoplastic test resulted
Anti-Ma 2 antibodies positive
Report done 6 months after onset
of sxs
1 ½ months after hospital
discharge
What Test Do You Want
Now???
anti-Ma 2 antibodies
testicular cancers
also with lung cancer but more commonly antiMa1
found in testicular tissue
limbic-brainstem-diencephalic
paraneoplastic syndrome
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Further Testing
Testicular ultrasound
1 cm calcified mass of right testis
MRI Brain without contrast unchanged
Urology consult:
orchiectomy
Tumor markers: AFP 15 (0-10), hCG <2, CEA 5.2 (03), LDH 460 (0-200)
Right orchiectomy (11/9/04)
IV solumedrol x 5 days
IVIg x 5 days
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Testicular biopsy
Diagnosis
Anti-Ma2 limbic-brainstemdiencephalic paraneoplastic
syndrome secondary to embryonal
testicular cancer
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1 year
Au
top
s
y
Ce
llc
ept
Or
IV chie
IG ct
& om
so y
lum
ed
,
6 months
11/2-12/1/04
PE
G
Ga
Bi str
op ic
sie &
s; Bra
Ab in
x
sx
on s
se
t
4 months
6/10-7/9/04
18 mo
11/12/05
31
Dilemmas
Pre-morbid presence of brain pathology (remote
TBI)
Eye movements look similar in anti-Ma2 and
Whipples
Empiric treatment for Whipples seemed to show
improvement
Paraneoplastic panel results were not reported
until readmission three months later
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Testicular
You shake Normal
my nerves
and youPET
rattle my brain
You shake
my nerves
and youa rattle
Too much
love drives
man my
insane
brain
You broke my will
But what a thrill
Conclusion
Testicular ultrasound would have
been the test of choice.
References
Dalmau J., et. al., Clinical Analysis of anti-Ma2-associated encephalitis et.al., Brain (2004), 127,
1831-1844.
Dalmau J., et al., Ma1, a novel neuron-and testis-specific protein, is recognized by the serum of
patients with paraneoplastic neurological disorders, Brain (1999) 122, 27-39.
El-Haddad G et al. Normal variants in [18F]-fluorodeoxyglucose PET imaging. Radiol Clin North
Am (2004) 42: 1063–1081.
Gerard A, Sarrot-Raynaud F, et al., Neurologic Presentation of Whipple Disease: Report of 12
Cases and Review of the Literature, Medicine (2002) 81: 443-57.
Louis ED, Lynch T, Kaufmann P, Fann S, Odel J. Diagnostic guidelines in central nervous
system Whipple’s disease. Ann Neurol (1996) 40: 561-8.
Manzel K, Tranel D, Cooper G, “Cognitive and Behavioral Abnormalities in a Case of Central
Nervous System Whipple Disease”, Arch Neruol, (Mar 2000) 57: 399-403.
Scheld M, Whipple Disease of the Central Nervous System, The Journal of Infectious Diseases
(2003), 188: 797:800.
Schwartz MA, Selhorst JB, Ochs AL, Beck RW, Campbell WW, Harris JK, Waters B, Velasco ME,
“Oculomasticatory myorhythmia: a unique movement disorder occuring in Whipple’s disease.
Ann. Neurol. (1986) 20: 677-83.
Suzer T, et al, “Whipple’s Disease Confined to the Central Nervous System: Case Report and
Review of the Literature” Scand J Infect Dis (1999) 31: 411-14.
Wallace, M., Apstein, M., Whipple’s Disease, UpToDate.com
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The End
Additional Tests
• Brain biopsy unrevealing:
– Dura and deep white matter: histologically
unremarkable
– CORTEX: vascular changes with somewhat
thickened vessels.
– No inflammation.
– Negative Fungi, Bacteria, Acid fast organisms,
Herpes virus, T. whippelii.
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Brain Autopsy Specimens
CNS Whipples disease
10-43% ( 20-40%) have CNS involvement; 5%
with isolated CNS.
CNS diagnostic guidelines
At least 1 of the following:
oculomasticatory myorhythmia (OMM)
Tissue biopsy (GI, brain)
If no biopsy must have supranuclear vertical gaze palsy,
rhythmic myoclonus, dementia, or hypothalamic symptoms
PCR (Blood, csf)
Most common manifestation is cognitive
dysfunction (70% of pts w/ CNS)
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Anti-Ma 2 patient series
– Patients:
• N=38
• mean age 34 (22-70)
• In 12 patients, anti-Ma2 antibody prompted the search for tumor
• 4 never had tumor diagnosis
– 1 had testicular microcalcification with autopsy showing no tumor, 1 had
microcalcification history of cryptorchidism ,1 had PET positive for colon/prostate but
autopsy not done, 1 was lost to follow up
– Findings:
• Neurologic symptoms developed prior tumor diagnosis in 21 patients (62%)
• Median delay to diagnosis = 6 months
• Eye movement abnormalities in 23/25 brainstem patients:
– 5 with isolated brainstem involvement
– severe/total vertical gaze paralysis (12/20)
• Less common clinical features: atypical Parkinson’s, severe hypokinetic
syndrome, ataxia
• 34/38 patients with anti-Ma2 antibodies had the
combination of limbic-diencephalic-brainstem symptoms
• 3 patients had neurologic relapse after treatments
Dalmau et. al (2004)
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Diagnostic Findings and Management
•
Neuroimaging (CT/MRI/SPECT/PET):
– 18/34 with temporal lobe abnnormalities
– 25/34 with limbic/diencephalic symptoms
•
•
LP: WBC 5-113 lymphocytes, normal to increased protein
Treatment:
– Treated 17 with oncologic therapies (chemotherapy, resection)
– 9/17 with immunotherapy (steroids, plasma exchange, IVIg combinations)
– 6 Not treated (did not receive oncologic and/or immunotherapy): all
deteriorated
– 11 improved (f/u time 9mo-6 yrs (median 2 ½ yrs))
– Improvement associated with:
•
•
•
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male < 45 yo
testicular tumor with complete oncological response
limited CNS involvement
negative anti-Ma1 antibodies
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Further workup
Neurocognitive testing:communicates well w/ laptop, hypokinetic dysarthria,
impaired new learning, intact naming, delayed recall. Mini mental = 21.
Wechsler memory scale 14/14. Digits forward 10/16, digits backward 6/14.
Determined to be competent.
Ophtho: no uveitis/vitritis
Whole body PET: r/o occult tumor and sarcoid; negative
Pan CT: negative to r/o occult tumor
EEG: no sz activity; posterior basic rhythm slowing
EMG/nerve conduction study: nl
Repeat MRI on 6/28/05 with contrast: no significant interval change and no
contrast enhancement
ENT evaluation: no vocal fold impairment
GI: Nl gastroduodenal biopsy; negative Whipples
Psychiatry: noted sleep disturbance & feelings of frustration/anger provoked,
not likely psychiatric (not depression/anxiety disorder)
ID consult: agreed w/ antibiotics trial
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