Clinical/Scientific Notes
Successive yet distinct episodes of isolated
ophthalmoplegia associated with
anti-GQ1b antibody
Doris Cardenas, MD; Shri K. Mishra, MD;
Arbi G. Ohanian, MD; and Bruce Ovbiagele, MD
Recurrent episodes of the Miller Fisher syndrome (MFS) are uncommon.1 Furthermore, isolated internal ophthalmoplegia is rare
in MFS.2,3 We report a patient who presented first with internal/
external ophthalmoplegia, then 7 years later with an isolated
internal ophthalmoplegia associated with elevated anti-GQ1b IgG
antibodies and confirmed Campylobacter jejuni enteritis.
Case report. A 20-year-old Latino man first presented to an
outside neurology group with double vision, photophobia, and
ataxia following a bout of diarrhea 2 days prior to symptom onset.
On examination there were limited extraocular movements, dilated, non-reactive pupils, impaired vibratory sense of the distal
extremities, and normal reflexes. After unremarkable brain imaging and spinal fluid results, the patient was diagnosed with atypical MFS. No treatment was initiated and symptoms resolved over
the course of 3 months.
At age 27 years he presented again with the gradual onset of
double vision, photophobia, and paresthesias of the distal extremities 2 days after another bout of diarrhea. On examination, 4
days after the onset of visual symptoms, the patient was alert
with normal cognition. His pupils were dilated at 7 mm, nonreactive to light or accommodation. Ocular motility was normal. His
corrected visual acuity was 20/30 in the right eye and 20/25 in the
left. Instillation of pilocarpine 1% induced bilateral miosis. The
remainder of his cranial nerves were normal as was his motor and
sensory examination. There were no signs of cerebellar dysfunction and his deep tendon reflexes were normal.
MRI of the brain and orbits with contrast was unremarkable.
Lumbar puncture on day 5 after onset of symptoms demonstrated
no white blood cells and a protein level of 21 mg/dL. A lumbar
puncture repeated 10 days after symptom onset remained unremarkable. There were no oligoclonal bands detected in the CSF.
Detailed nerve conduction studies and EMG were unremarkable.
The Venereal Disease Research Laboratory test, Lyme serologies,
and HIV screening tests were negative. The erythrocyte sedimentation rate, leukocyte count, and angiotensin converting enzyme
studies were normal. An ELISA (Focus Diagnostics) showed an
elevated serum anti-GQ1b IgG antibody titer of 1:400 (normal
⬍1:100). An ELISA titer sent to Focus Diagnostics for serum C
jejuni antibody was also elevated at 3.5 (normal ⬍ 2). On day 18
after symptom onset a 3-day course of IVIg was initiated. Examination on day 19 demonstrated minimal reactivity to light of the
right pupil.
Discussion. Our patient is at least the fifth report of isolated
internal ophthalmoplegia associated with a positive anti-GQ1b
antibody. Although a previous report described a patient with two
episodes of MFS followed by an episode of Bickerstaff’s brainstem
encephalitis,4 as far as we know, this is the first report detailing
the recurrence of an atypical Miller Fisher syndrome associated
with elevated titers of anti-GQ1b IgG antibody and serologic evidence of C jejuni enteritis.
This patient had double vision at his second presentation, but
did not have objective external ophthalmoplegia; the subjective

Vascular dysplasia in neurofibromatosis type 2
Aisling M. Ryan, MRCPI, PhD;
Michael Hurley, MRCPI, FFR (RCSI);
Paul Brennan, MRCPI, FFR (RCSI); and
Joan T. Moroney, MD, MRCPI
Neurofibromatosis type 1 (NF1) and 2 (NF2) are autosomal dominant disorders characterized by dysplasia in tissues of mesodermal and neuro-ectodermal origin. NF1 is associated with
pigmented cutaneous lesions, neurofibromas, and other systemic

complaint of double vision may reflect pupillary abnormalities, as
noted in other patients with isolated internal ophthalmoplegia.2,4
GQ1b is a tetrasialoganglioside cell surface molecule found within
human central and peripheral nervous systems. Serum IgG antibody against GQ1b is very closely associated with MFS, Guillain
Barré syndrome with ophthalmoplegia, acute ophthalmoparesis
without ataxia,5 and also found among those with isolated pupillary areflexia with limited or no external ophthalmoplegia.2,3 Over
90% of patients with MFS and GBS with ophthalmoplegia have an
elevated serum anti-GQ1b antibody (with a broad range of positive titers) and this test has high specificity for the two diseases.5
Murine monoclonal anti-GQ1b antibody strongly stains the paranodal regions of the extramedullary portion of human oculomotor,
trochlear, and abducens nerves and weakly stains the deep cerebellar nuclei.5 It has been hypothesized that there is also an enrichment of the GQ1b ganglioside in the ciliary ganglion leading
to presentations of pupillary areflexia.2
C jejuni enteritis is a frequent antecedent pathogen in both
GBS/MFS with a recent study demonstrating 18% of patients with
MFS having seropositivity for C jejuni.6 Anti-GQ1b antibody
cross-reacts with the lipopolysaccharide epitope on C jejuni.7 This
has led to the hypothesis that the anti-GQ1b antibody exerts its
immunopathologic effect through molecular mimicry between C
jejuni and specific neural tissue, and may involve direct inhibition
of neuromuscular transmission, antibody dependent complement
activation, or inflammatory demyelination.
From the Department of Neurology (Drs. Cardenas, Ohanian, and
Ovbiagele), UCLA Medical Center; Department of Neurology (Drs. Mishra
and Ovbiagele), Olive View-UCLA Medical Center; and Department of Neurology (Dr. Mishra), Keck School of Medicine, University of Southern California, Los Angeles.
Received January 5, 2005. Accepted in final form March 7, 2005.
Address correspondence and reprint requests to Dr. Doris Cardenas, Department of Neurology, University of California at Los Angeles, 710 Westwood
Plaza, Los Angeles, CA 90095; e-mail: dcardenas@mednet.ucla.edu
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Chida K, Nomura H, Konno H, Takase S, Itoyama Y. Recurrent Miller
Fisher syndrome: clinical and laboratory features and HLA antigens. J
Neurol Sci 1999;165:139–143.
2. Radziwill AJ, Steck AJ, Borruat F-X, Bogousslavsky J. Isolated internal
ophthalmoplegia associated with IgG anti-GQ1b antibody. Neurology
1998;50:307.
3. Yuki N, Koga M, Hirata K. Isolated internal ophthalmoplegia associated
with immunoglobulin G anti-GQ1b antibody. Neurology 1998;51:1515–
1516.
4. Hamaguchi T, Yamaguchi K, Komai K, et al. Recurrent anti-GQ1b IgG
antibody syndrome showing different phenotypes in different periods.
JNNP 2003;74:1350.
5. Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I. Serum antiGQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher
syndrome and Guillain-Barré syndrome: clinical and immunohistochemical studies. Neurology 1993;43:1911–1917.
6. Koga M, Yuki N, Takahashi K, Saito K, Hirata K. Close association of
IgA anti-ganglioside antibodies with antecedent Campylobacter jejuni
infection in Guillain-Barré and Fisher’s syndromes. J Neuroimmunol
1998;81:138–143.
7. Yuki N, Taki T, Takahashi M, et al. Molecular mimicry between GQ1b
ganglioside and lipopolysaccharides of Campylobacter jejuni isolated
from patients with Fisher’s syndrome. Ann Neurol 1994;36:791–793.

features including pheochromocytoma, scoliosis, and epilepsy.1 An
important cause of morbidity and mortality is an associated vasculopathy causing stenosis, occlusion, aneurysm, or arteriovenous
fistula formation.2 Patients with NF2 have few cutaneous lesions
but a strong propensity to develop multiple tumors of the CNS,
particularly bilateral vestibular schwannomas (VS).3 Systemic features are rare and vasculopathy is not known to be a manifestation of NF2. We report a case of intracerebral vascular dysplasia
leading to left middle cerebral artery (MCA) infarction in a patient
with molecularly confirmed NF2.
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Case report. An 18-year-old right-handed woman was diagnosed clinically with NF2 in another institution. On presentation
at age 11, she had a right trigeminal neuropathy, right eye proptosis, bilateral papilledema, and partial right third nerve palsy.
There were no motor or sensory deficits in the extremities. MRI
brain and spinal cord revealed bilateral VS, multiple intracranial
meningiomas, posterior meningioma at T1, and multiple schwannomas along lumbar nerve roots. The patient’s mother had clinical
NF2 (unconfirmed molecularly) and died at age 35 following spinal surgery. At the time of death, she had bilateral VS, three
other brain tumors, and two spinal tumors. There was no family
history of another affected relative.
Our patient underwent surgical excision of a cribriform plate
and right orbital meningioma with subsequent insertion of a ventriculoperitoneal shunt. A postoperative brain CT shows bilateral
VS, calcified right sphenoid wing meningioma, falcine meningioma, and postoperative frontal gliotic change (figure, A).
In August 2003, she presented with stuttering onset of expressive dysphasia and right hemiparesis. There were no known vascular risk factors. She was in sinus rhythm, was normotensive,
and had a normal cardiovascular examination. She had a global
aphasia, right homonymous hemianopia, right facial weakness,
and a dense right hemiparesis. Diffusion-weighted MRI revealed
acute infarction in the left MCA territory (figure, B). MR angiography (MRA) of head and neck showed asymmetry with narrowing
and irregularity of the left MCA (figure, C). Four-vessel angiogram revealed a diffusely dysplastic left MCA extending from
close to the origin of the M1 segment and involving several insular
branches, one of which was markedly stenosed (figure, D). There
was no other evidence of intracranial stenosis or vascular abnormality. A complete thrombophilia and vasculitic screen, transthoracic echocardiogram, and Holter monitor were normal. She was
treated with warfarin, low dose aspirin, and statin therapy. Clinically there was moderate recovery of right upper and lower limb
function, but a moderately severe aphasia persisted. Follow-up
MRA at 1 year showed persistent left MCA stenosis.
A previously described splice site mutation, 600-2A⬎G,4 was
identified in exon 7 of the NF2 gene confirming the diagnosis of
NF2.
Discussion. Vascular dysplasia has not been reported in association with NF2 although some vascular abnormalities have been
described in patients with NF25 and retinal hamartomas are a
recognized feature. The true incidence of vascular dysplasia in
NF1 is not known and many patients may be asymptomatic. As
the incidence of NF2 is approximately one tenth that of NF1
(1:33,000 to 1:3,000),1,3 the association may not have been appreciated because of its rarity.
Genotype-phenotype correlations have been described for NF2associated intracranial meningiomas, spinal, and peripheral nerve
tumors.6 Missense and splice-site mutations (as in our patient)
have been associated with fewer tumors than nonsense or frameshift mutations but this may depend on the location of the splicesite mutation within the gene, 3= mutations causing less severe
disease than 5=.
Although the vasculopathy of NF1 is incompletely understood,
it may be due to failure to regulate intimal proliferation. This is
suggested pathologically by intimal proliferation and hyperplasia
resulting in luminal stenosis.2 This case now raises the question of
a link between the vasculopathy of NF1 and NF2. NF2 is caused
by a mutation in the merlin protein located on chromosome
22q12.2. Merlin functions as a tumor suppressor gene and regulates cell growth and proliferation.7 Similar to NF1, failure of
merlin to control intimal proliferation in the vascular tree may
lead to hyperplasia and vessel occlusion.
From the Departments of Neurology (Drs. Ryan and Moroney) and Neuroradiology (M. Hurley and P. Brennan), Royal College of Surgeons Ireland,
Beaumont Hospital, Dublin, Ireland.

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Figure. (A) Axial brain CT showing bilateral vestibular
schwannomas (arrows), calcified right sphenoid wing meningioma (arrowhead), falcine meningioma (curved arrow), and postoperative frontal gliotic change. (B) Axial,
diffusion-weighted image showing diffuse high signal in
the left middle cerebral artery (MCA) territory consistent
with acute infarction. (C) Asymmetry with focal narrowing
of the left MCA (arrows) on MRA. (D) Left carotid angiogram showing focal stenoses (arrows) and interstenotic
dilatation (arrowheads) of left MCA.

Received January 12, 2005. Accepted in final form March 7, 2005.
Address correspondence and reprint requests to Dr. J.T. Moroney, Department of Neurology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland;
e-mail: joantm@gofree.indigo.ie
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Arun D, Gutmann DH. Recent advances in neurofibromatosis type 1.
Curr Opin Neurol 2004;17:101–105.
2. Hamilton SJ, Friedman JM. Insights into the pathogenesis of neurofibromatosis 1 vasculopathy. Clin Genet 2000;58:341–344.
3. Baser ME, Evans DG, Gutmann DH. Neurofibromatosis 2. Curr Opin
Neurol 2003;16:27–33.
4. Evans DG, Trueman L, Wallace A, Collins S, Strachan T. Genotype/
phenotype correlations in type 2 neurofibromatosis (NF2): evidence for
more severe disease associated with truncating mutations. J Med Genet
1998;35:450–455.
5. Lesley WS, Thomas MR, Abdulrauf SI. N-butylcyanoacrylate embolization of a middle meningeal artery aneurysm in a patient with neurofibromatosis type 2. Am J Neuroradiol 2004;25:1414–1416.
6. Baser ME, Kuramoto L, Joe H, et al. Genotype-phenotype correlations
for nervous system tumors in neurofibromatosis 2: a population-based
study. Am J Hum Genet 2004;75:231–239.
7. Ramesh V. Merlin and the ERM proteins in Schwann cells, neurons and
growth cones. Nat Rev Neurosci 2004;5:462–470.

Encephalopathy in a patient with previous
malignancy but normal brain imaging
C . McGuigan, MRCP; S. Bigham, MRCP;
D. Johnston, MRCP, FRCR; and P.E. Hart PhD, MRCP
A 61-year-old man presented following two generalized tonic
clonic seizures. For 2 weeks prior to admission he had had occipital headaches. The patient’s family had noticed a change in his
personality with confusion, memory impairment, and unsteadiness when walking.
The patient had a history of non-small cell lung cancer (stage
IV) diagnosed 2 years previously. He had completed three courses
of chemotherapy with regimes of gemcitabine and carboplatin,
docetaxel, and carboplatin with a clinical trial drug TZT1027. His
most recent course was with oral gefitinib (Iressa). This was discontinued 6 months previously because of a persistent urticarial
rash. He had no other significant past medical history.
On admission the patient was oriented in time and place. Hs
speech was normal. He was afebrile. No focal neurologic deficits were
noted. At the admitting hospital routine hematologic and biochemical investigations were normal. Liver transaminases were slightly
elevated. A noncontrast enhanced CT scan of brain was reported as
showing small vessel ischemic change. Lumbar puncture examination was normal. An initial diagnosis of viral encephalitis was considered and the patient was commenced on acyclovir and valproic acid.
Over a period of 2 days the patient’s condition gradually deteriorated. He became disorientated and drowsy. On examination he
had broken saccadic eye movements and exhibited perseveration.
No focal neurologic deficits were found on limb examination; plantar responses were flexor. He had a right pleural effusion. A
contrast enhanced MRI scan was reported as showing a few areas
of high signal intensity on T2-weighted images consistent with
small vessel ischemic change. FLAIR and gradient echo sequences
were not performed. An EEG record showed diffuse slow wave
activity. Multiple CSF examinations were performed and were
negative for cytology, viral PCR, tuberculosis PCR, and ammonium. Autoimmune and vasculitic screens were negative.
As a result of continued clinical deterioration a repeat MRI
scan was performed 2 weeks after the initial scan. This revealed
innumerable small high signal foci in the brain parenchyma on
T2-weighted axial images. There was no mass effect or generalized edema (figure). Axial T1-weighted images with gadolinium
contrast showed only vague enhancement within a few lesions.
Coronal gradient echo images showed focal signal change in two
lesions indicating hemorrhagic change.
A diagnosis of carcinomatous encephalitis was made based on
the clinical picture and MRI appearances. The differential diagnosis of these lesions would have included miliary infections such as
tuberculosis but there was no clinical or laboratory evidence of
infection. The patient’s condition continued to deteriorate and he
was transferred to a hospice for palliative care. The patient died 1
month after initial presentation.
Discussion. The term carcinomatous encephalitis (miliary
metastases) was used first by Madow and Alpers in 19511 to
describe the appearance of numerous tiny perivascular nodules
consisting of tumor cells originating from a distant primary neoplasm, usually lung. The original patients presented had a combination of an organic mental syndrome and hemiparesis.1
Subsequent reports have recognized seizures,2 speech difficulties,3
and gait abnormalities4 to be early presenting features of the
condition.
It is estimated that between 20 and 30% of all patients with a
systemic carcinoma have brain metastases at time of death.5 The
usual appearance of cerebral metastases is of single or multiple
intra-axial masses at or near the gray white matter junction with
surrounding edema. The lesions of carcinomatous encephalitis
typically occur in perivascular spaces and do not cause surrounding edema or mass effect.3,4
Previous reports on carcinomatous encephalitis have been

Figure. (A, B) Axial T2-weighted images showing multiple
high signal foci in the brain parenchyma of the supra and
infratentorial compartments including the brainstem. Note
the lack of mass effect or edema.

scant in the medical literature and those containing MR imaging
have been inconsistent, suggesting the lesions are contrast enhancing,3,6 non-contrast enhancing,2 calcified,7 or possibly hemorrhagic.4 The prognosis for carcinomatous encephalitis is
considered to be poor with published figures from diagnosis to
death ranging from 14 days5 to 7 months.2 However, the poor
prognosis may be in part due to the prolonged delay in diagnosis
because of over-reliance on currently available imaging techniques. In this case metastatic brain disease was always the most
likely clinical diagnosis despite the unremarkable initial MRI scan
although the first scan was incomplete, not including FLAIR and
gradient echo sequences. There are currently no published data on
how often imaging should be repeated to identify carcinomatous
encephalitis in the presence of strong clinical suspicion.
Previously published individual trials of brain irradiation did
not affect outcome3 but this may be due to delivery of the treatment late in the clinical course. Further studies are required to
establish whether irradiation therapy administered based on
strong clinical suspicion alone, even in the presence of unremarkable imaging, may prolong patient survival.
From the Departments of Neurology (Drs. McGuigan, Bigham, and Hart)
and Neuroradiology (Dr. Johnston), Atkinson Morley Wing, St. George’s
Hospital, Blackshaw Road, London, UK.
Received December 8, 2004. Accepted in final form March 8, 2005.
Address correspondence and reprint requests to Dr. Christopher McGuigan,
Department of Neurology, Atkinson Morley Wing, St. George’s Hospital, Blackshaw Road, London, UK SW17 0QT; e-mail: cmcguigan@doctors.org.uk
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Madow L, Alpers BJ. Encephalitic form of metastatic carcinoma. ArchNeurol 1951;65:161–173.
2. Nemzek W, Poirier V, Salamat MS, Yu T. Carcinomatous encephalitis
(miliary metastases): lack of contrast enhancement. AJNR Am J Neuroradiol 1993;14:540–542.
3. Olsen WL, Winkler ML, Ross DA. Carcinomatous encephalitis: CT and
MR findings. AJNR Am J Neuroradiol 1987;8:553–554.
4. Bhushan C. “Miliary” metastatic tumours in the brain. J Neurosurg
1997;86:564–566.
5. Posner JB. Neurologic complications of cancer. F.A. Davies, Philadelphia, 1995.
6. Shirai H, Imai S, Kajihara Y, et al. MRI in carcinomatous encephalitis.
Neuroradiology 1997;39:437–440.
7. Ara Cazillo JR, Gimenez-Mas JA, Lacasa J. Calcified brain metastases from acinarcell carcinoma of the pancreas. Neuroradiology 1989;
31:200.

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Acute multifocal CNS demyelination as first
presentation of systemic malignancy
Nicole Gonzales, MD; Elke Jarboe, MD;
B.K. Kleinschmidt-DeMasters, MD; and Patrick Bosque, MD
We present a patient with adenocarcinoma of the lung, without
CNS metastases, who developed progressive quadreparesis like
that seen in the paraneoplastic syndrome acute necrotic myelopathy.1 Pathologic examination revealed only areas of brainstem and
spinal cord demyelination resembling the acute lesions of multiple
sclerosis (MS).
Case report. A 66-year-old man was hospitalized after 4
weeks of persistent cough and 10 days of weakness and paresthesias of the legs. Over the next 5 days, his weakness progressed to
paralysis of all extremities, dysphagia, and respiratory failure. He
developed bilateral Babinski signs. Cognition and vision were unaffected and the sensory examination remained normal despite
paresthesias. Chest CT scan revealed a hilar mass and abnormal
masses in the liver and an adrenal gland, but biopsies of the hilar
mass and the liver nodule were nondiagnostic. MRI of the brain
and cervical spinal cord showed increased T2 signal in the medulla, extending into the upper cervical cord and a separate focus
of T2 hyperintensity in the spinal cord at the level of the third
thoracic vertebra, without abnormal enhancement (figure, A).
CSF had 10 leukocytes/␮L (99% mononuclear), 8 erythrocytes/␮L,
protein 42 mg/dL, glucose 78 mg/dL, no oligoclonal bands, negative cytology, and negative PCR testing for herpes simplex and
varicella zoster viruses. An IgG index was not determined. Assays
for the following serum antibodies associated with paraneoplastic
syndromes were negative: Anti-Hu; Anti-Yo; anti-neuronal type 1,
2, and 3; Purkinje cell cytoplasmic type 1, 2, and Tr; antiamphiphysin; anti-CRMP-5 IgG; striational antibody; anticalcium channel P/Q type and N-type; and anti-acetylcholine
receptor.
Methylprednisolone 500 mg daily for 8 days failed to improve
the patient’s condition. He died on the 11th hospital day after
ventilatory support was withdrawn at his request.
Autopsy revealed an adenocarcinoma arising from the right
mainstem bronchial mucosa, with spread to hilar nodes and to the
right adrenal. The tumor showed no features of neuroendocrine
differentiation by light microscopy nor did it stain for neural cell
adhesion molecule (CD-56) or chromogranin. Neuropathologic examination disclosed three separate well-circumscribed lesions in
the cord and brainstem with the largest, 1.2 ⫻ 1.0 cm, encompassing the floor of the medulla and extending into the basis pontis
(figure, B). Thoracic and lumbar cord demyelinative plaques were
wedge-shaped, adjacent to pial surface, abutted the central canal,
and showed symmetry across the ventral sulcus, patterns identical to those classically seen in MS. These sharply demarcated,
noncavitated, non-necrotic lesions demonstrated sheets of CD68⫹
macrophages containing Luxol fast blue positive debris, indicating
acute myelin breakdown. Swollen axons and perivascular CD3⫹ T
cell lymphocytic cuffing were also frequent. Stains for herpes simplex virus, cytomegalovirus, and Epstein Barr virus were negative. Metastatic tumor, neuronal degeneration, small perivenular
demyelinative lesions, optic chiasm demyelination, or remote MS
plaques were not identified in the CNS.
Discussion. Our patient developed multiple acute demyelinating lesions in the brainstem and spinal cord as a presenting sign
of adenocarcinoma of the lung. The pathologic findings, including
subependymal and subpial involvement, symmetric demyelinative
lesions crossing the spinal cord ventral sulcus, and perivascular
inflammation, more closely resemble those of an acute episode of
MS than other demyelinating syndromes. The lesions were not as
widespread as is typical for the related condition acute disseminated encephalomyelitis.
Our patient rapidly progressed to quadreparesis, had prominent involvement of the spinal cord, a poor response to corticosteroid therapy, and a carcinoma of the lung. These features are
similar to the rare but well-documented paraneoplastic syndrome,
acute necrotic myelopathy.1 However, the pathologic examination
revealed no evidence of necrosis in the CNS. A related condition,
neuromyelitis optica, was further excluded by the absence of optic
nerve lesions.
Single focal tumor-like areas of cerebral demyelination have been
described as a paraneoplastic manifestation of seminoma (two cases),
CML (one case), and non-Hodgkin lymphoma (one case).2-4 A similar
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Figure. (A) T2-weighted gradient echo MR image (repetition time 500, echo time 19, flip angle 20°) demonstrating
two of the patient’s three distinct, hyperintense lesions involving the lower brainstem and upper thoracic cord (arrows). (B) Whole mount section from the medulla stained
for myelin showing a subependymal sharply demarcated
demyelinative plaque involving the floor of the fourth ventricle. Luxol fast blue, 3x.
focal tumor-like area of demyelination may be a “sentinel lesion” for
primary CNS B-cell lymphoma.5 Other cases with demyelination in
association with systemic neoplasms have also displayed significant
neuronal degeneration and were most consistent with the syndrome
of anti-Hu mediated limbic encephalitis.6
Although we conducted an extensive search for antibodies associated with paraneoplastic neurologic syndromes, we found
none. No antibody is known to be associated with single focal
acute demyelinating lesions or paraneoplastic necrotizing myelopathy, but anti-CRMP-5 antibodies have been found in a paraneoplastic syndrome resembling neuromyelitis optica.7 We cannot
establish a direct cause-and-effect relationship between the acute
MS-like syndrome and the systemic cancer in our single patient,
but the temporal link was striking.
From the Departments of Neurology (Drs. Bosque and KleinschmidtDeMasters), Pathology (Drs. Kleinschmidt-DeMasters and Jarboe), and Neurosurgery (Dr. Kleinschmidt-DeMasters), University of Colorado Health
Sciences Center, Denver; the Division of Neurology (Dr. Bosque), Denver
Health Medical Center, CO; and the Department of Neurology (Dr. Gonzales), University of Texas Health Science Center, Houston.
Received September 6, 2004. Accepted in final form March 18, 2005.
Address correspondence and reprint requests to Dr. Patrick Bosque, Division
of Neurology, Denver Health Medical Center, 777 Bannock Street, Denver,
CO 80204-4507; e-mail: patrick.bosque@dhha.org
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Mancall EL, Rosales RK. Necrotizing myelopathy associated with visceral carcinoma. Brain 1964;87:639–656.
2. Wong K, Poon P, Berry K. et al. Paraneoplastic demyelinating disorder
in the brain of a patient with seminoma. J Comput Assist Tomogr 1998;
22:136–138.
3. Jaster JH, Bertorini TE, Dohan FC. et al. Solitary focal demyelination in
the brain as a paraneoplastic disorder. Med Pediatr Oncol 1996;26:111–115.
4. Kepes JJ. Large focal tumor-like demyelinating lesions of the brain:
intermediate entity between multiple sclerosis and acute disseminated
encephalomyelitis? A study of 31 patients. Ann Neurol 1993;33:18–27.
5. Brecher K, Hochberg FH, Louis DN. et al. Case report of unusual leukoencephalopathy preceding primary CNS lymphoma. J Neurol Neurosurg Psychiatry 1998;65:917–920.
6. Pillay N, Gilbert JJ, Ebers GC. et al. Internuclear ophthalmoplegia and
“optic neuritis”: paraneoplastic effects of bronchial carcinoma. Neurology. 1984;34:788–791.
7. Cross SA, Salomao DR, Parisi JE. et al. Paraneoplastic autoimmune
optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol 2003;
54:38–50.

Systemic autoantibodies against discrete
inner ear compartments in bilateral
vestibular loss
Charlotte Ågrup, PhD; Geoffrey Keir, PhD, FRCPath;
Edward J. Thompson, DSc, FRCP; and
Adolfo M. Bronstein, PhD, FRCP
Thirty to 50% of cases of bilateral vestibular failure are idiopathic.1 However, an autoimmune cause has been suggested in some
cases with bilateral idiopathic vestibular failure (BIVF).2-4 The
pathogenesis in autoimmune inner ear disease (AIED) is poorly
understood, and no specific diagnostic test is available. The western blot technique is useful in diagnosing AIED, although the
antigen used is often heat shock protein-70 (hsp-70) from bovine
kidney tissue and therefore lacks ear specificity.
Case reports. Two patients were admitted for investigations.
This project was approved by the Ethics Committee of the Institute of Neurology and the National Hospital for Neurology and
Neurosurgery (Queen Square, London, UK).Patient A was a 57year-old man who had a 3-year history of recurrent episodes of
severe vertigo and progressive unsteadiness. Examination revealed an unsteady ataxic gait and a bilateral positive head-thrust
test. No nystagmus could be elicited during caloric irrigation (30
and 44 °C) or with rotational steps of 60°/s. CSF analysis showed
a protein concentration of 0.43 g/L and oligoclonal bands in the
CSF with few matched bands in the serum (figure). Patient B was
a 51-year-old woman who presented with a history of a single
acute episode of vertigo and sickness. In this patient, the vertigo
gradually resolved, but a severe imbalance remained. Clinical examination showed an unsteady gait and a bilateral positive headthrust test. There was total absence of nystagmic response to
rotational steps of 80°/s. In both patients, antineuronal antibodies
were negative and brain MRI and pure tone audiogram were
normal (for additional information see table E-1 on the Neurology
Web site at www.neurology.org).
Antibodies in sera were studied by using the western blot
technique. Discrete compartments of inner ear tissue from guinea
pigs were used as antigen (organ of Corti, stria vascularis, three
semicircular canals with the ampullary tissue, utricle, and endolymphatic sac).5 Renal medulla and brain were used as control
tissues. Extracted antigens were separated by sodium dodecyl
sulfate–polyacrylamide gel electrophoresis. The same amounts of
protein from the various tissues were loaded on each gel to enable
semiquantitative evaluation. The filters were incubated overnight
with sera (diluted 1:1,000) followed by incubation with antihuman IgG secondary antibody. Detection was performed with
enhanced chemiluminescent substrate.
Results. Both patients had ear-specific antibodies against
proteins migrating at 188, 49, and 17 kd (see the figure). In addition, both patients had antibodies against a 68-kd kidney protein
with a weak corresponding band in the whole-ear tissue preparation. This band may represent hsp-70.6,7 Serum from two subjects
(one with congenital profound sensorineural hearing loss with
bilateral vestibular hypofunction and one with noise-induced sensorineural hearing loss) served as controls and had no ear-specific
antibodies. The oligoclonal bands in CSF present in Patient A
prompted us to investigate the presence of ear-specific antibodies
in CSF. Interestingly, when incubated with CSF (diluted 1:1,000),
some weak bands corresponding to those found in serum were
found.
Discussion. In the current study, we used discrete inner ear
tissues as antigens to investigate patients with BIVF. The bands
in Patient A were present only in parts containing secretory epithelia. It is therefore tempting to conclude that the antibodies are
directed against proteins present only in secretory epithelia, leading to loss of function in this particular cell type. In Patient B, the
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Contents for the July 12 issue to find the title link for this article.

Figure. Isoelectric focusing used to detect oligoclonal
bands of IgG in serum and CSF from Patient A. Double
arrow ⫽ matched bands; single arrow ⫽ unmatched band.
reaction is not only present in the parts containing secretory epithelia but also in the purely sensory epithelial tissue preparation
(i.e., the organ of Corti) (see the figure). The absence of cochlear
symptoms in this patient could be explained if the identified protein were, under normal conditions, not easily reached by the
immune system.
Our findings are in agreement with a previous immunofluorescent study in which sera in 8 of 12 patients with BIVF were shown
to have antibodies mainly against the ampullary tissue and the
semicircular canals.2 Interestingly, using the western blot technique, the same group of researchers has also shown reaction with
a CNS-related 45-kd rat protein in serum from a patient with
suggested sympathetic vestibulopathy.3
In the current study, the two patients with BIVF were shown
to have three ear-specific autoantibodies in common. This may
indicate similar pathoetiology despite different clinical presentation. The presence of autoantibodies does not prove that they are
the underlying cause of vestibular loss. However, the antigens
found in this study may be more specific for BIVF than kidney
hsp-70, which is the antigen often used to support the diagnosis of
AIED.
As the western blot technique provides the possibility of identifying the specific protein responsible for autoantibody production, it may be a useful diagnostic tool for BIVF.
From the Department of Neuro-Otology (Dr. Ågrup), National Hospital for
Neurology and Neurosurgery, Department of Neuro-Immunology (Drs.
Ågrup, Keir, and Thompson), Institute of Neurology, and Academic Department of Neuro-Otology (Dr. Bronstein), Division of Neuroscience and Psychological Medicine, Imperial College, Charing Cross Hospital, London, UK.
Supported by the Swedish Society for Medical Research (Curth Nilssons
Fund) and the Swedish Society of Medicine (Frenckner Fund).
Received August 31, 2004. Accepted in final form March3, 2005.
Address correspondence and reprint requests to Dr. C. Agrup, Department of
Neuro-Immunology, Institute of Neurology, Queen Square, London, WC1N
3BG, UK; e-mail: C.Agrup@ion.ucl.ac.uk
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Rinne T, Bronstein AM, Rudge P, Gresty MA, Luxon LM. Bilateral loss
of vestibular function: clinical findings in 53 patients. J Neurol 1998;245:
314–21.
2. Arbusow V, Strupp M, Dieterich M, et al. Serum antibodies against
membranous labyrinth in patients with “idiopathic” bilateral vestibulopathy. J Neurol 1998;245:132–136.
3. Schulz P, Arbusow V, Strupp M, Dieterich M, Sautier W, Brandt T.
Sympathetic contralateral vestibulopathy after unilateral zoster oticus. J
Neurol Neurosurg Psychiatry 1999;66:672–676.
4. Schüler O, Strupp M, Arbusow V, Brandt T. A case of possible autoimmune bilateral vestibulopathy treated with steroids. J Neurol Neurosurg
Psychiatry 2003;74:825.
5. Ågrup, C, Bagger-Sjöbäck D, Fryckstedt J. Presence of plasma
membrane-bound Ca2⫹-ATPase in the secretory epithelia of the inner
ear. Acta Otolaryngol 1999;119:437–445.
6. Billings PB, Keithley EM, Harris JP. Evidence linking the 68 kilodalton
antigen identified in progressive sensorineural hearing loss patient sera
with heat shock protein 70. Ann Otol Rhinol Laryngol 1995;104:181–188.
7. Bloch DB, San Martin JE, Rauch SD, Moscicki RA, Bloch KJ. Serum
antibodies to heat shock protein 70 in sensorineural hearing loss. Arch
Otolaryngol Head Neck Surg 1995;121:1167–1171.

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Infarction of the central cerebellar arbor vitae
and transient loss of spatial orientation
O. Sedlaczek, MD; E. Grips, MD; H. Bäzner, MD; A. Claus, MD;
J. Wöhrle, MD, PhD; and M. Hennerici, MD, PhD
Case report. A 45-year-old man traveling by train had acute severe pain in the right shoulder after lifting a heavy suitcase,
followed by 15 seconds of non-motion-directed vertigo. He sat
down and felt well, except for minor persisting pain in the shoulder. After a symptom-free interval of 4 hours, he reported a sudden transient loss of spatial orientation and a feeling of being
shaken in an airplane during severe turbulence. Apparently he
had involuntarily moved on his seat, prompting startled looks
from fellow passengers. During this episode, he had no diplopia,
nausea, or visual disturbances. After a few minutes, he recovered
completely apart from persisting pain in the right shoulder and
neck. Orthopedic consultation and neurologic examination 5 hours
after onset of symptoms were normal, at which time the pain was
subsiding. Electronystagmography was normal except for a minimally decreased downward optokinetic nystagmus.
Extracranial Doppler/duplex sonography and MR angiography
confirmed a dissection of the right vertebral artery as suspected
from the acute pain syndrome. Diffusion-weighted MRI, the
apparent diffusion coefficient, and fluid-attenuated inversion recovery studies revealed a small acute infarction of 2 mm in diameter in the center of the cerebellar vermis. T2-weighted images
demonstrated a hematoma of the wall and missing flow void in the
V5 segment of the right vertebral artery. By means of perfusionweighted MRI, the vascular territory affected by the dissection
could be identified: Time-to-peak maps demonstrated a late
arrival of the contrast medium in the complete right posterior
inferior cerebellar artery (PICA) territory1(figure, A). Ischemia
was considered of arterioarterial embolic origin from the dissected
vertebral artery into the most distal PICA territory of the vermiform branches, where emboli were trapped in an area of very low
perfusion.

Discussion. The fastigial nuclei close to the medullary center
of the vermis integrate afferences from the vermiform cortices, the
vestibular nuclei, and the accessory olives and have efferences via
the lower cerebellar peduncles back to the vestibular nuclei. They
are the major cerebellar relay mediating inhibition on the vestibular system. The acute ischemic lesion observed in this patient fits
both the fastigial nucleus and its afferent tracts2,3 from the vermiform cortex (VII) (see figure, B).
A history of sudden-onset vertigo associated with a loss of
spatial orientation, though transient and nondirected, is indicative of acute cerebellar stroke. By clinical presentation, cerebellar
signs may already have improved. Although the lesion site may
vary, the syndrome is underestimated owing to often scant history
taking in emergency room settings. If vertigo is combined with
characteristic pain, dissection of the vertebral artery is highly
suggestive, and MRI should include isotropic diffusion weighting
with particular attention to midline structures, which might be
misinterpreted as artifacts. Spatial orientation seems to be integrated in the center of the arbor vitae.
From the Department of Neurology and Orthopedic Surgery, Universitätsklinikum Mannheim, University of Heidelberg, Germany.
Received October 13, 2004. Accepted in final form March 10, 2005.
Address correspondence and reprint requests to Dr. O. Sedlaczek, Department of Neurology, Universitätsklinikum Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany; e-mail:
oliver.sedlaczek@neuro.ma.uni-heidelberg.de
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Tatu L, Moulin T, Bogousslavsky J, Duvernoy H. Arterial territories of
human brain: brainstem and cerebellum. Neurology 1996;47:1125–1135.
2. Scudder CA. Role of the fastigial nucleus in controlling horizontal saccades during adaptation. Ann NY Acad Sci 2002;978:63–78.
3. Wearne S, Raphan T, Cohen B. Control of spatial orientation of the
angular vestibuloocular reflex by the nodulus and uvula. J Neurophysiol
1998;79:2690–2715.

Figure. (A) Infarction in the center of the cerebellar vermis (diffusion-weighted imaging, 6 hours after initial symptoms).
(Inset) Perfusion-weighted imaging indicating delayed bolus arrival in the right posterior inferior cerebellar artery territory due to a dissection of the right vertebral artery. (B) Diffusion-weighted MRI of the lesion in the center of the cerebellar vermis (sagittal projection) vs schematics2 (rhesus monkey) of the fastigial nucleus (FN) integration and the critical
cerebellar projection area (VII). The corresponding area of the infarction is shown in the schematic drawing (inset). Further components2: nucleus reticularis tegmenti pontis (NRTP), saccadic burst generator.
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Isolated oculomotor palsy following minor
head trauma
Richard L. Levy, MD; Craig E. Geist, MD; and
Neil R. Miller, MD
Case report. A 54-year-old woman with an unremarkable medical history was in a minor motor vehicle collision resulting in
airbag deployment. She reported loss of consciousness lasting a
few seconds. She had no bruises or lacerations, but she immediately noted drooping of her left eyelid and double vision when she
elevated the lid. She was taken to a local hospital, where she had an
isolated, complete left oculomotor nerve palsy with a nonreactive
pupil (figure). CT, MRI, and MR angiography were all normal (see
figure E-1 on the Neurology Web site; go to www.neurology.org).
Over the next 6 weeks, the patient experienced mild improvement in ptosis, pupillary function, and ocular motility, but because of persistent diplopia and ptosis, she presented to the
Wilmer Eye Clinic. On examination, the patient had normal visual sensory function, except for reduced accommodation on the
left. The pupils were equal in size, but the left pupil was less
reactive than the right pupil to both light and near stimulation.
There was a moderate left ptosis that improved on attempted downgaze and right-gaze. The right eye moved fully. The left eye had
moderately reduced adduction, elevation, and depression. There was
intorsion of the left eye on attempted down-gaze to the left. In primary position, the patient had a 45-prism-diopter exotropia and a
small left hypotropia. Corneal and facial sensation were equal and
normal bilaterally. There was no proptosis or enophthalmos.
Because of the history of relatively mild trauma, we were concerned about an underlying vascular lesion. Accordingly, the patient underwent a four-vessel digital subtraction angiogram. The
study showed no intracranial arterial or venous abnormalities. No
further testing was performed.
At the last follow-up visit, 5 months after the accident, the
patient reported only intermittent diplopia. She had a mild left
ptosis that improved on down-gaze and left-gaze. The left pupil
now reacted well to light and near stimulation but slightly less so
than the right pupil, and on slit-lamp examination, there was a
relative hypokinesis of the superior aspect of the pupillary margin. The left eye could now adduct, and both elevation and depression were markedly improved although still limited. There was
now an 18-prism-diopter exotropia in primary gaze.
Discussion. Third nerve palsies following blunt head trauma
are common. The trauma required to damage the oculomotor
nerve usually is extensive and associated with loss of consciousness, basilar skull fracture, or subarachnoid hemorrhage. Thus,
traumatic third nerve palsies usually occur in association with
other neurologic deficits.1 In rare cases, blunt trauma can cause
an isolated third nerve palsy, but even in this setting, the trauma
is generally severe. For this reason, a third nerve palsy that occurs after mild trauma should raise concern that there is an
underlying lesion that is compressing, stretching, or infiltrating
the oculomotor nerve, predisposing it to dysfunction following an
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Contents for the July 12 issue to find the title link for this article.

otherwise inconsequential injury. In some patients, a third
nerve palsy after minor head trauma is the presenting sign of a
posterior circulation aneurysm2-4 or a basal intracranial tumor.5
In such cases, the trauma is insufficient to cause fracture or
loss of consciousness. Although our patient reported a transient
loss of consciousness, we still consider her trauma minor, given
the mechanism of injury and the lack of fracture or associated
neurologic deficits.
True traumatic third nerve palsies may be caused by damage
to the nerve at any point along its path, from the brainstem to the
orbit.6 In one report, a 39-year-old woman developed a left partial,
pupil-involving third nerve palsy immediately following a car accident in which she experienced a brief loss of consciousness.7 MRI
revealed no abnormalities except on gradient echo T2-weighted
images that showed a signal hypointensity consistent with hemorrhage at the midbrain exit site of the oculomotor nerve. The authors concluded that gradient echo MR sequences may be more
sensitive than other sequences in detecting this phenomenon. Our
patient underwent MRI that included gradient echo images, but
no abnormalities of the third nerve were identified.
Because our patient developed a complete third nerve palsy
with involvement of the pupil after relatively minor trauma, followed by partial recovery and secondary aberrant regeneration,
she underwent not only noninvasive imaging studies (CT, MRI,
MR angiography) but a subsequent catheter angiogram. The lack
of findings on these studies indicates that it is possible to have a
severe oculomotor nerve palsy following relatively minor trauma
without associated morbidity. As this is a rare event, an underlying vascular or other abnormality should still be investigated. In
addition, as not all noninvasive studies provide optimal images,
noninvasive imaging that is suboptimal should be repeated before
catheter angiography is performed.
From the Wilmer Eye Institute (Drs. Levy and Miller), Johns Hopkins Hospital, Baltimore, MD; and Department of Ophthalmology (Dr. Geist), George
Washington University, Washington, DC.
Received December 21, 2004. Accepted in final form March 14, 2005.
Address correspondence and reprint requests to Dr. R.L. Levy, 600 N. Wolfe
St., Maumenee B-109, Baltimore, MD 21287; email: rlevy12@jhmi.edu
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Solomons NB, Solomon DJ, de Villiers JC. Direct traumatic third nerve
palsy. S Afr Med J 1980;58:109–111.
2. Newman SA. Aneurysms. In: Miller NR, Newman NJ, Biousse V, Kerrison JB, eds. Walsh and Hoyt’s clinical neuro-ophthalmology. 6th ed.
Baltimore: Lippincott Williams & Wilkins, 2005:2173–2174.
3. Walter KA, Newman NJ, Lessell S. Oculomotor palsy from minor head
trauma: initial sign of intracranial aneurysm. Neurology 1994;44:148–150.
4. Park-Matsumoto YC, Tazawa T. Internal carotid–posterior communicating artery aneurysm manifesting as an unusual ocular motor paresis
after minor head trauma— case report. Neurol Med Chir (Tokyo) 1997;
37:181.
5. Eyster EF, Hoyt WF, Wilson CB. Oculomotor palsy from minor head
trauma. An initial sign of basal intracranial tumor. JAMA 1972 ;220:
1083–1086.
6. Heinz J. Cranial nerve avulsion and other neural injuries. Med J Aust
1969;2:1246–1249.
7. Balcer LJ, Galetta SL, Bagley LJ, Pakola SJ. Localization of traumatic
oculomotor nerve palsy to the midbrain exit site by magnetic resonance
imaging. Am J Ophthalmol 1996;122:437–439.

Figure. Appearance of patient on initial
presentation. Note complete third nerve
palsy with pupil involvement.

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Delayed oculomotor nerve palsy after
bilateral cervical zoster in an
immunocompetent patient
Yuval Karmon, MD; and Natan Gadoth, PhD
Case report. A 54-year-old Israeli-Arab man noticed drooping of
the left eyelid, which evolved over 4 days prior to his admission
(PTA) to the Department of Neurology at the Meir General Hospital. Left retro-orbital pain appeared 2 days later; on the day of
admission, vertical diplopia was noticed.
Three weeks PTA, he experienced excruciating neck pain more
on the left side and also over the right occipital scalp. A few days
later, he noticed right posterior cervical skin eruption in the form
of small clear blisters, for which he was given antibiotics. The
eruption resolved in 2 weeks, yet neck pain persisted.
On admission, he was afebrile with few hyperpigmented tender
scars present mainly over the right and, to a lesser extent, over
the left posterior aspect of the neck, which was supple. The neurologic examination revealed isolated left oculomotor nerve palsy
with pupillary sparing. However, on the following morning, left
pupillary dilatation with sluggish reaction to light was noticed.
Brain CT, computed cranial angiography, and gadoliniumenhanced MRI were all normal. The clear and sterile CSF was
under normal opening pressure and contained 150 mononuclear
cells/mL3, which were classified as T lymphocytes by immunophenotyping. No malignant cells were detected. The protein was elevated (66 mg%), and the glucose level was normal. Complete blood
counts, blood chemistry, protein and immunoelectrophoresis, serologic tests for antinuclear antibodies, complement, perinuclear antineutrophil cytoplasmic antibodies (ANCA), cytoplasmic-ANCA,
lupus anticoagulant, anticardiolipin, angiotensin-converting enzyme, and antibodies to acetylcholine receptor were normal or
negative. Serologic tests for various infectious agents including
HIV were negative. Chest radiographs, abdominal sonography,
isotope bone scan, and tumor markers were all negative. PCR on
CSF was positive for varicella zoster virus (VZV) and negative for
herpes simplex virus1 and 2. IV Acyclovir was given for 21 days;
pain and diplopia resolved completely over 2 weeks, and ptosis
resolved completely 1 month later.
Discussion. There are two outstanding clinical features in our
patient. The first is the bilateral distribution of herpes zoster
(HZ), which is unusually encountered in immunocompetent subjects,1 and the second is the fact that delayed oculomotor palsy is a
known complication of ophthalmic zoster only.
CNS lesions including cranial neuropathies that are remote
from the site of the HZ eruption were considered to be caused by a

Life-threatening acute pancreatitis associated
with interferon beta-1a treatment in
multiple sclerosis
Rune Midgard, MD, PhD; Kåre Ertresvåg, MD;
Erik Trondsen, MD, PhD; and Olav Spigset, MD, PhD
The treatment goal in patients with relapsing–remitting multiple
sclerosis (RR-MS) is to reduce the frequency and severity of relapses and to prevent or postpone the development of disability.
Large trials have demonstrated that interferon beta-1a (IFN␤-1a),
IFN␤-1b, and glatiramer acetate partially meet this purpose.1 The
approved drugs are well tolerated with largely transient adverse
effects. Pancreatitis is not mentioned as an adverse effect in the
current Summaries of Product Characteristics for IFN␤-1a. However, acute pancreatitis has been associated with IFN␣-2b treatment.2 We report a case in which a life-threatening acute
pancreatitis developed 8 weeks after the initiation of treatment
with IFN␤-1a for RR-MS.
Case report. A healthy 53-year-old man on no concurrent
medication was diagnosed with MS. He started with IFN␤-1a
(Rebif) 22 ␮g subcutaneously three times weekly 8 weeks after
diagnosis. Initially, he experienced minor injection site reactions
and flu-like symptoms. However, 8 weeks later, he developed
symptoms of an acute pancreatitis. The serum amylase concentration was ⬎3,000 U/L (reference interval 70 to 300 U/L). MR
cholangiopancreatography and ultrasonography showed no signs
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July (1 of 2) 2005

vascular–ischemic mechanism.2 The blood supply of all cranial
nerves stems from the carotid system through small branches that
supply groups of two or three cranial nerves.3 It was postulated
that there are anatomic pathways by which VZV could spread
from trigeminal skin afferents to the walls of pial and dural blood
vessels of the carotid system.4 The presence of such pathways was
demonstrated in the cat model.5 Those observations sufficiently
explain oculomotor neuropathy following ophthalmic zoster but
cannot account for oculomotor palsy following cervical zoster,
which has never been reported so far.
The occurrence of brainstem strokes following ophthalmic,
maxillary, and cervical HZ suggests the presence of an anatomic
network connecting the trigeminal and cervical ganglionic neurons with the vertebrobasilar system.6,7 Indeed, bilateral removal
of the C1 to C3 dorsal root ganglia in cats results in reduced
concentration of substance P in the vertebrobasilar system, which
is prevented by prior removal of both trigeminal ganglia.4
Thus, it can be stated that the cranial neuropathy in our patient is additional clinical evidence of the presence of these anatomic neurovascular connections.
From the Department of Neurology, Meir General Hospital, Kfar Saba,
Israel.
Received December 22, 2004. Accepted in final form March 17, 2005.
Address correspondence and reprint requests to Dr. N. Gadoth, Department
of Neurology, Meir General Hospital, Kfar Saba 44281, Israel; e-mail:
gadoth@post.tau.ac.il
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Vu AQ, Radonich MA, Heald PW. Herpes zoster in seven disparate
dermatomes (zoster multiplex): report of a case and review of the literature. J Am Acad Dermatol 1999;40:868–869.
2. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R,
Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster
virus. N Engl J Med 2000;342:635–645.
3. Lapresle J, Lasjaunias P. Cranial nerve ischaemic arterial syndromes: a
review. Brain 1986;109:207–216.
4. Saito K, Moskowitz MA. Contributions from the upper cervical dorsal
roots and trigeminal ganglia to the feline circle of Willis. Stroke 1989;20:
524–526.
5. Mayberg MR, Zervas NT, Moskowitz MA. Trigeminal projections to supratentorial pial and dural blood vessels in cats demonstrated by horseradish peroxidase histochemistry. J Comp Neurol 1984;223:46–56.
6. Ross MH, Abend WK, Schwartz RB, Samuels MA. A case of C2 herpes
zoster with delayed bilateral pontine infarction. Neurology 1991;41:
1685–1686.
7. Snow BJ, Simcock JP. Brainstem infarction following cervical herpes
zoster. Neurology 1988;38:1331.

of gallstones. The common bile duct and the main pancreatic duct
appeared normal. There were no signs of infections, hyperlipidemia, hypercalcemia, trauma, ischemic disease, or tumors. He had
no history of alcohol abuse. Prior to IFN␤-1a therapy, a hematologic and biochemical workup including ␥-glutamyl transferase
(13 U/L), alanine aminotransferase (14 U/L), and aspartate aminotransferase (23 U/L) were normal. He scored 3 of a maximum of
40 points in an Alcohol Use Disorders Identification Test (AUDIT)3 questionnaire interview.
Two days after hospitalization, he was transferred to intensive
care. Abdominal and thoracic CT scans showed pancreatic necrosis and peripancreatic fluid collection. The IFN␤-1a therapy was
stopped after 4 days in hospital. After 3 weeks, changes in the
clinical and biochemical variables indicated an infected pancreatic
necrosis. Drainage was performed, using pigtail catheters percutaneously for 3 weeks. An exploratory laparotomy was done, comprising partial resection of the pancreas, splenectomy, and
abdominal abscess drainage. Following this intervention, his condition gradually improved. He was transferred to rehabilitation
after 12 weeks of hospitalization. Two weeks thereafter, he was
readmitted with increasing pain in the upper abdomen. A new
pancreatic abscess was identified and drained. Subsequently, a
pancreatic fistula developed. Finally, the main pancreatic duct
was stented, and his condition improved. The stent was later
removed.
A neurologic follow-up 4 months later showed a stable situation without new clinical MS-related disease activity. He was go-

ing back to work and was not prepared to start any new kind of
immunomodulatory treatment. A rechallenge with IFN␤-1a was
considered inappropriate for ethical reasons.
Discussion. The underlying causes of acute pancreatitis include
obstruction of the pancreatic duct outlet, abdominal trauma, metabolic abnormalities comprising hyperlipidemia and hypercalcemia, inherited conditions, infections, vascular abnormalities,
iatrogenic conditions, and toxins. The most common causes are
gallstone disease and ethanol abuse.4 The drugs most often implicated are azathioprine, mercaptopurine, valproic acid, didanosin,
estrogens, metronidazole, tetracyclines, and rifampicin.5
The general disease history of our patient and his family did
not include any specific risk factors for pancreatitis. His alcohol
consumption was low, his AUDIT score putting him well below the
validated cut-off of 8 that indicates a likelihood of hazardous or
harmful alcohol consumption in men.3 He did not use any concomitant medication, and no signs of gallstone disease or other possible causes were detected.
Epidemiologic studies in Norway indicate an MS incidence rate
of 5 per 100,000 per year,6 whereas the rate for acute pancreatitis4
is 30 to 40 per 100,000 per year. Thus, we cannot rule out that the
appearance of a severe acute pancreatitis and the start of IFN␤-1a
therapy in a patient with MS can be a coincidence.
Up until February 18, 2005, the World Health Organization
database of adverse drug reactions7 held a total of 45 reports on
pancreatitis for IFN␤-1a and 34 for IFN␤-1b. The severity of these
adverse effects is not reported. In total, this database contains
about 3 million reported cases of suspected adverse drug reactions
from ⬎70 countries. However, as these reports in many cases
represent only a suspicion of a relationship and might be based on
a coincidence, no proof of causality can be made on the basis of
these data.
As we were able to exclude other potential causes of acute
pancreatitis, our case report strengthens the suspicion of a causal
relationship between the administration of IFN␤-1a and the de-

Progressive cervical myelopathy
secondary to chronic
ventriculoperitoneal CSF overshunting
D.M. Wingerchuk, MD, FRCPC; N.P. Patel, MD; A.C. Patel, MD;
D.W. Dodick, MD, FRCPC; and K.D. Nelson, MD
CSF hypovolemia typically causes orthostatic headache with or
without nonlocalizing symptoms such as neck pain, nausea, aural
fullness, and dizziness.1 Focal complications are rare and are usually secondary to subdural hematoma. We report findings from a
patient with progressive cervical myelopathy associated with cord
distortion due to dural thickening and tortuous venous dilation.
Chronic CSF hypotension caused by excessive ventriculoperitoneal shunting seemed to be the primary etiology.
Case report. A 72-year-old woman presented for evaluation of
an undiagnosed gait disorder. Twenty-seven years earlier she underwent right suboccipital craniectomy and ventriculoperitoneal
shunt placement for a posterior fossa meningioma. There was no
tumor recurrence or shunt malfunction. Four years earlier, she
noted the insidious onset of right lower extremity spastic monoparesis. During the year prior to presentation, she developed bilateral leg and right arm weakness, left upper extremity numbness,
and urinary urge incontinence. She denied headache, neck and
shoulder pain, and orthostatic symptoms.
Examination revealed a moderately severe, right-predominant,
asymmetric spastic quadriparesis with generalized hyperreflexia,
bilateral extensor plantar responses, and mild vibratory and proprioceptive difficulties. There were neither segmental motor findings nor a sensory level. Her shunt valve depressed but filled
extremely slowly.
Brain MRI (figure, A) demonstrated the shunt tip in the left
frontal horn and postoperative changes involving the right cerebellum. The lateral ventricles were slit-like and there were bilateral subdural fluid collections and diffuse dural thickening and
gadolinium enhancement consistent with intracranial hypotension
secondary to CSF hypovolemia. These features were unchanged
from an MRI performed 18 months earlier. There was no evidence
of superficial siderosis. Lumbar puncture confirmed low opening

velopment of pancreatitis. However, the occurrence is obviously
rare.
From the Department of Neurology (Dr. Midgard), Molde Hospital, Department of Surgery (Dr. Ertresvåg), Diakonhjemmet Hospital, and Surgical
Division (Dr. Trondsen), Department of Gastrointestinal Surgery, Ullevål
University Hospital, Oslo, and Department of Clinical Pharmacology (Dr.
Spigset), St. Olav University Hospital, Trondheim, Norway.
Dr. Midgard has received personal compensation from Serono Nordic AB
(2005/090662).
Received January 18, 2005. Accepted in final form March 21, 2005.
Address correspondence and reprint requests to Dr. R. Midgard, Department
of Neurology, Molde Hospital, Parkvn 84, Molde, Norway, 6407; e-mail:
rmidgard@online.no
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis. Report of the Therapeutics and Technology
Assessment Subcommittee of the American Academy of Neurology and
the MS Council for Clinical Practice Guidelines. Neurology 2002;58:169–
178.
2. Eland IA, Rasch MC, Sturkenboom MJ, et al. Acute pancreatitis attributed to the use of interferon alfa-2b. Gastroenterology 2000;119:230–233.
3. Saunders JB, Aasland OG, Babor TF, de la Fuente, JR, Grant M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO
Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption–II. Addiction 1993;88:791–804.
4. Gislason H, Horn A, Hoem D, et al. Acute pancreatitis in Bergen, Norway. A study on incidence, etiology and severity. Scand J Surg 2004;93:
29–33.
5. Eigler A, Eigenbrod S, Endres S. Medikamentös induzierte Pankreatitis.
Dtsch Med Wochenschr 2003;128:366–369.
6. Dahl OP, Aarseth JH, Myhr KM, Nyland H, Midgard R. Multiple sclerosis in Nord-Trøndelag County, Norway. A prevalence and incidence
study. Acta Neurol Scand 2004;106:378–384.
7. www.who-umc.org; accessed February 2005.

pressure (30 mm H20). The CSF was xanthochromic but acellular,
total protein level was 189 mg/dL, and immunologic studies were
negative. Serologic testing for medical causes for myelopathy was
unrevealing.
Cervical spine MRI demonstrated cord distortion associated
with dilated and tortuous dorsal vasculature. The spinal pachymeninges were diffusely thickened and enhanced with gadolinium; in
some dorsal regions, the enhancement had a nodular appearance
due to enlarged epidural veins (figure, B). There was no abnormal
T2-weighted signal abnormality or enhancement within the cord.
MR angiography of the cervical and upper thoracic spinal canal
confirmed the presence of dilated epidural veins but did not detect
a dural arteriovenous fistula (figure, C).
The patient was offered surgical intervention (shunt clamping
with intracranial pressure monitoring) but declined. Nineteen
months later, her hand weakness had progressed mildly but imaging abnormalities were unchanged.
Discussion. We hypothesize that the clinical findings are best
explained by cord distortion and compression secondary to diffuse
pachymeningeal thickening and venous dilation as a result of CSF
hypovolemia from chronic overshunting. The protracted duration
of overshunting may have obscured or prevented postural symptoms, which are not always present in cases of CSF hypovolemia
from other causes. The spinal pachymeningeal abnormalities may
represent an extension of the chronic dural sterile inflammation
and thickening present in cranial dural biopsy specimens obtained
in cases of CSF hypovolemia. We excluded the main primary
cause for venous dilation, an occult dural arteriovenous fistula, by
MR angiography; such a lesion would not explain CSF hypovolemia. Other vascular mechanisms, including cord ischemia due to
shunt or steal phenomena, are unlikely since there was no abnormal cord MRI signal.
A similar case of cervical myelopathy after ventriculoperitoneal shunting was reported with MRI evidence of cord deformation associated with a shrunken subarachnoid space surrounded
by dilated venous plexus.2 However, that patient presented much
earlier (15 months) after the shunt procedure and the nodular and
diffuse pachymeningeal thickening and enhancement described in
our case was not noted. Other reports suggest that the most comJuly (1 of 2) 2005

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Figure. (A) Axial FLAIR image of the
brain (left image) demonstrates a
right parietal shunt and decompressed ventricles. Peripheral hyperintensity is due to dural thickening.
Coronal gadolinium-enhanced T1weighted brain MRI (right image)
demonstrates diffuse dural thickening and enhancement and a postoperative defect in the right cerebellum.
(B) Sagittal gadolinium-enhanced
image of the cervical and upper thoracic spine demonstrates dural and
epidural enhancement. The nodular
enhancement ventral and dorsal to
the cord is due to intradural vein
prominence. (C) Coronal magnetic
resonance angiography of the cervicothoracic spine demonstrates tortuous vessels. Evaluation for dural
arteriovenous fistula was negative.

mon explanation for myelopathic symptoms in patients with CSF
hypovolemia is cord compression from an extramedullary fluid
collection; Lhermitte’s symptom3 and radiculomyelopathy4 have
been reported with such lesions in the setting of spontaneous or
shunt-related CSF overdrainage. In most instances, spinal MRI
features such as extradural or subdural fluid collections,5-7 meningeal gadolinium enhancement,5,6 and the presence of dilated epidural veins or venous plexus abnormalities6,7 are detected in
patients with CSF hypovolemic symptoms for fewer than 6
months and no focal neurologic abnormalities.
The presence of cervical meningeal thickening with gadolinium
enhancement or dilated epidural veins should alert one to the
possibility of chronic CSF hypotension in a patient with myelopathy and a history of a CSF diversion procedure, even in the absence of postural headache and other characteristic symptoms of
intracranial hypotension.
From the Department of Neurology, Mayo Clinic, Scottsdale, AZ.
Received February 4, 2005. Accepted in final form April 4, 2005.
Address correspondence and reprint requests to Dr. Dean M. Wingerchuk,
Department of Neurology, Mayo Clinic, Scottsdale, AZ 85255; e-mail:
wingerchuk.dean@mayo.edu

PFO management: Neurologists vs cardiologists
Steven R. Messé, MD; Brett Cucchiara, MD;
Jeanie Luciano, NP; and Scott E. Kasner, MD
Patent foramen ovale (PFO) is associated with stroke, particularly
in younger patients without another identifiable etiology. Therapeutic options available include antiplatelet medications, warfa-

Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Contents for the July 12 issue to find the title link for this article.
172

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July (1 of 2) 2005

Copyright © 2005 by AAN Enterprises, Inc.

References
1. Mokri B. Headaches caused by decreased intracranial pressure: diagnosis and management. CurrOpin Neurol 2003;16:319–326.
2. Miyazaki T, Chiba A, Nishina H, Uesaka Y, Nasake H, Kanazawa I.
Upper cervical myelopathy associated with low CSF pressure: a complication of ventriculoperitoneal shunt. Neurology 1998;50:1864–1866.
3. Rabin BM, Roychowdhury S, Meyer JR, Cohen BA, LaPat KD, Russell
EJ. Spontaneous intracranial hypotension: spinal MR findings. Am
J Neuroradiol 1998;19:1034–1039.
4. Matsumoto K, Ohta M, Takeshita I. Symptomatic spinal extramedullary
mass lesion secondary to chronic overdrainage of ventricular fluid– case
report. Neurol Med Chir (Tokyo) 2002;42:140–142.
5. Moayeri NN, Henson JW, Schaefer PW, Zervas NT. Spinal dural enhancement on magnetic resonance imaging associated with spontaneous
intracranial hypotension. Report of three cases and review of the literature. J Neurosurg 1998;88:912–918.
6. Yousri I, Förderreuther S, Moriggl B, et al. Cervical MR imaging in
postural headache: MR signs and pathophysiological implications. Am
J Neuroradiol 2001;22:1239–1250.
7. Chiapparini L, Farina L, D’Incerti, L, et al. Spinal radiological findings
in nine patients with spontaneous intracranial hypotension. Neuroradiology 2002;44:143–150.

rin, surgical closure, or percutaneous closure, yet there have been
no adequate head-to-head trials to guide management decisions.1
We conducted a survey of cardiologists and neurologists to determine current management strategies for patients with PFO.
Methods. In April 2004, a 17-item questionnaire (see the survey on the Neurology Web site at www.neurology.org) was sent to all
neurologists and cardiologists participating as local principal investigators in the CLOSURE-I PFO closure trial (NMT medical), a study
comparing PFO closure to medical management. The survey addressed practice patterns prior to participation in the trial focusing
on PFO diagnosis, high risk characteristics, treatment choices, and
alternative indications for PFO closure. Results were analyzed in
aggregate and by specialty. Neurologists and cardiologists were compared using t tests or ␹2 tests as appropriate.

Table Diagnostic and treatment strategies for patent foramen
ovale (PFO) by specialty
Neurologists,
n ⫽ 47

Cardiologists,
n ⫽ 46

Transesophageal
echocardiogram

34

37

Transthoracic
echocardiogram

62

63

Transcranial
Doppler

4

0

Antiplatelet
agents

49 ⫾ 33

26 ⫾ 26

0.0003

Warfarin

28 ⫾ 26

17 ⫾ 22

0.04

Surgical closure

2.3 ⫾ 9

0.2 ⫾ 0.8

0.05

Endovascular
closure

20 ⫾ 21

55 ⫾ 34

0.0001

Have recommended
PFO closure
in an
asymptomatic
patient

2

9

0.2

Have recommended
PFO closure for
SCUBA diving

6

24

0.02

Have recommended
PFO closure for
migraines

0

14

0.01

p

Initial study to
rule out
cardioembolic
source

0.25

Distribution of
treatments*

Values are percentages. Responses are reported as mean ⫾ standard deviation.
* Respondents reported the proportion of their patients that received each of the four options; the total was required to add
up to 100%.
Results. A total of 108 neurologists and 129 cardiologists
were surveyed. After two mailings, we received a response from
39% (44% of neurologists, 36% of cardiologists). Of respondents,
56% of cardiologists and 42% of neurologists were practicing in a
community-based as opposed to academically based setting. All
respondents (100%) felt that recurrent stroke risk was increased
in the presence of an atrial septal aneurysm. A total of 62% felt
that a larger shunt was associated with increased risk of recurrence while 47% felt that a larger distance between the septum
primum and secundum was associated with increased risk. A total
of 72% of respondents did not feel that age impacted future risk of
stroke with PFO.
The table describes diagnostic and treatment strategies for
PFO according to specialty.
Discussion. In 1877, Cohnheim first suggested that ischemic
stroke may be caused by paradoxical embolism through a PFO.2
Over a century later, case-control trials have confirmed an association between ischemic stroke and PFO, particularly in younger
patients with cryptogenic stroke.3,4 However, there are no adequate comparative data available to guide treatment decisions.1
Thus, given the confusing state of the literature, we undertook
this survey to help define current management strategies for patients with PFO.
Overall, we found that surgical closure is rarely undertaken

while percutaneous closure is frequently recommended for stroke
prevention. Across all physicians, we found a great deal of variability in the management of patients with PFO as noted by the
large standard deviations for each therapeutic option. We also
observed significant differences in the practice patterns of neurologists and cardiologists. In general, neurologists were more likely
to favor conservative therapy such as antiplatelet medications,
while cardiologists more often chose percutaneous closure for their
patients. In addition, a sizable minority of physicians—predominantly cardiologists— have recommended percutaneous closure for
asymptomatic patients, migraineurs, and SCUBA divers.
This survey included a balanced distribution of neurologists
and cardiologists (the two specialties most likely to encounter
these patients) and a mix of academic and nonacademic clinicians.
Nevertheless, there are several limitations to this study. The practice patterns we report are influenced by the mix of patients that
respondents see in their clinic. This survey did not investigate the
types of patients that physicians encounter. Questionnaires were
sent to neurologists and cardiologists who were already participating in a clinical trial addressing this topic. Therefore, respondents
may not be representative of all practicing physicians as they
have already demonstrated an interest in this subject. In addition,
all cardiologists involved were interventionalists and were presumably actively performing endovascular closure. Thus, they
may be more likely to recommend this procedure than the average
cardiologist. Similarly, patients seen by cardiologists may have
already been referred by a neurologist specifically for percutaneous closure. Finally, the response rate was only moderate, resulting in a potential response bias that may limit generalizability.
There are no published prospective randomized studies proving
that closure is beneficial in preventing recurrent stroke.5,6 The Food
and Drug Administration has issued a humanitarian device exemption (HDE) for the use of PFO closure devices in patients with
stroke.7 However, the HDE restricts use of these devices to patients
who have had recurrent strokes while on anticoagulation. This study
suggests that many patients are receiving closure devices off label.
There are currently three ongoing clinical trials in the United States
comparing PFO closure to medical management for stroke prevention: The CLOSURE-I study (NMT medical), the RESPECT trial
(AGA medical), and the CARDIA trial (CARDIA medical). Despite
existing biases in clinical practice, the evidence for or against each
treatment option is lacking, and whenever possible, physicians
should encourage eligible patients to enroll in these studies.
From the Department of Neurology, University of Pennsylvania Medical
Center, Philadelphia.
Supported by an AHA physician-scientist fellowship award (S.R.M.), an
AHA fellow-to-faculty award (B.C.), the Inverso-Baglivo foundation (J.L.),
and NIH K23-NS02147 award (S.E.K.).
The division of stroke and neurocritical care at the Hospital of the University
of Pennsylvania is participating in the CLOSURE-I PFO Closure trial
(NMT medical). The authors receive compensation for patient enrollment in
this trial.
Received February 17, 2005. Accepted in final form April 5, 2005.
Address correspondence and reprint requests to Dr. Steven R. Messé, Department of Neurology, Comprehensive Stroke Center, University of Pennsylvania Medical Center, 3W Gates Building, 3400 Spruce Street, Philadelphia,
PA 19104; e-mail: messe@mail.med.upenn.edu
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Messe SR, Silverman IE, Kizer JR, et al. Practice parameter: recurrentstroke with patent foramen ovale and atrial septal aneurysm: report of
the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004;62:1042–1050.
2. Cohnheim J. Thrombose und Embolie: Vorlesung uber allgemeine Pathologie. Berlin, Germany: 1877;134.
3. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale
in patients with stroke. N Engl J Med 1988;318:1148–1152.
4. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke:
a meta-analysis of case-control studies. Neurology 2000;55:1172–1179.
5. Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003;139:753–760.
6. Windecker S, Wahl A, Nedeltchev K, et al. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with
cryptogenic stroke. J Am Coll Cardiol 2004;44:750–758.
7. USA Food and Drug Administration. HDE #H990011. 2000.
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Bi-hemispheric anterior cerebral artery with
drop attacks and limb shaking TIAs
Elizabeth Gerstner, MD; Bernardo Liberato, MD; and
Clinton B. Wright, MD, MS
True drop attacks are characterized by a sudden fall without loss
of consciousness. Cardiac disease and epilepsy are widely accepted
causes, but other etiologies have been described, including vestibulopathy, hypothyroidism, third ventricle or posterior fossa
cysts, cervical spine disease, and brainstem ischemia.1-3 We
present a case of drop attacks caused by an anomalous circle of
Willis in the setting of a critical stenosis of the ipsilateral internal
carotid artery (ICA).
Case report. A 73-year-old right-handed man with a history of
hypertension and past smoking, on oral anticoagulation for atrial
fibrillation, presented to an outside institution with several
months of drop attacks. The episodes occurred one to four times
per week and he described his legs giving out, seeing the floor
“coming up,” and then being on the ground. There were no prodromal symptoms such as lightheadedness, palpitations, or residual
weakness after an attack. Witnesses confirmed no alteration in
consciousness. He had a widened QRS by ECG and 24 hour ambulatory monitoring revealed about 10 2-second pauses. An EEG and
brain MRI were normal and an MRA of the neck demonstrated
stenosis of the ICA of 90%. A pacemaker was placed with a subjective decrease in frequency of the attacks, but without complete
resolution. At this point the patient presented to our center.
Upon further questioning, he reported that in addition to the
drop attacks he had shaking of the right arm, leg, or both, that
would occur shortly after exertion. For example, he described
shaking of the right arm lasting seconds, when reaching for a
glass of water after coming in from mowing the lawn. His physical
examination was notable for normal blood pressure in both arms,
without orthostatic hypotension, and a left carotid bruit. The neurologic examination was normal. Doppler studies revealed a left
ICA stenosis of 80 to 99%. Transcranial Doppler was used to
measure cerebral vasodilatory capacity (CVC) as the percent rise
in the ipsilateral middle cerebral artery mean flow velocity per 1
mm Hg PCO2 after inhalation of 5% carbon dioxide in air. The
CVC was impaired on the left (1.9%/mm Hg PCO2) but normal on
the right (6%/mm Hg PCO2). A cerebral angiogram revealed a
stenosis of the left ICA with the left A1 segment of the anterior
cerebral artery (ACA) feeding both medial frontal lobes (figure, A
and B). On right carotid injection there was no evidence of flow in
the right A-1 segment. Pial collaterals from the right middle and
posterior cerebrals to the distal right ACA territory were seen
(figure, C through E). The patient underwent carotid endarterectomy (CEA) resulting in complete resolution of his drop attacks
and limb-shaking TIAs.

Discussion. Our patient was initially diagnosed with cardiogenic drop attacks and had a pacemaker placed. The partial improvement suggests a contribution of the atrial fibrillation or
pauses in triggering the attacks. The left ICA stenosis seemed an
unlikely cause of his bilateral leg weakness. However, both medial
hemispheres were supplied from the left A1 segment of the ACA
with agenesis or hypoplasia of the contralateral A1 segment, explaining the sudden falls. Agenesis has been documented in up to
2%, and hypoplasia in up to 10%, of cases.4 Limb-shaking TIAs
provided an essential clue in this case and are increasingly recognized as due to perfusion failure, often from ICA stenosis. Focal
stenosis of the distal A2 segment of the ACA has also been reported.5,6 Decreased cerebral vasodilatory capacity in response to inhalation of 5% carbon dioxide has been associated with a higher risk
of later ischemic events.7 Evaluation of hypoperfusion due to focal
stenosis should be considered in patients presenting with unexplained drop attacks. A history of limb shaking TIAs may suggest
the underlying cause.
From the Neurological Institute of New York, Department of Neurology,
College of Physicians and Surgeons of Columbia University and Columbia
University Medical Center of New York Presbyterian Hospital, NY.
Received January 12, 2005. Accepted in final form April 6, 2005.
The authors have no financial disclosures or potential conflicts of interest.
Address correspondence and reprint requests to Dr. Clinton Wright, 710
West 168th Street, NI-640, New York, NY 10032; email: cbw7@columbia.edu
Copyright © 2005 by AAN Enterprises, Inc.

References
1. Lee MS, Choi YC, Heo JH, Choi IS. “Drop attacks” with stiffening of the right
leg associated with posteriorfossa arachnoid cyst. Mov Disord 1994;9:377–378.
2. van Norel GJ, Verhagen WI. Drop attacks and instability of the degenerate cervical spine. J Bone Joint Surg Br 1996;78:495–496.
3. Brust JC, Plank CR, Healton EB, Sanchez GF. The pathology of drop
attacks: a case report. Neurology 1979;29:786–790.
4. Maurer J, Maurer E, Perneczky A. Surgically verified variations in the
A1 segment of the anterior cerebral artery. Report of two cases. J Neurosurg 1991;75:950–953.
5. Han SW, Kim SH, Kim JK, Park CH, Yun MJ, Heo JH. Hemodynamic
changes in limb shaking TIA associated with anterior cerebral artery
stenosis. Neurology 2004;63:1519–1521.
6. Tatemichi TK, Young WL, Prohovnik I, Gitelman DR, Correll JW, Mohr
JP. Perfusion insufficiency in limb-shaking transient ischemic attacks.
Stroke 1990;21:341–347.
7. Marshall RS, Rundek T, Sproule DM, Fitzsimmons BF, Schwartz S,
Lazar RM. Monitoring of cerebral vasodilatory capacity with transcranial Doppler carbon dioxide inhalation in patients with severe carotid
artery disease. Stroke 2003;34:945–949.

Figure. Angiogram: (A) Left carotid frontal view showing critical stenosis at the bifurcation. (B) Left carotid injection
frontal view with the left anterior cerebral (ACA) A-1 segment supplying the right A-2 branch (arrow). (C) Right carotid
injection frontal view showing no filling of the right ACA A-1 segment and early pial collaterals to the ACA territory (arrow). (D) Later phase than C showing pial collaterals from the right middle cerebral to the ACA territory (arrows). (E)
Left vertebral injection lateral view showing pial collaterals from the right posterior cerebral to the ACA territory (arrow).
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Serial diffusion and perfusion-weighted MR in
transient hypoglycemia
C. Cordonnier, MD; C. Oppenheim, MD, PhD; C. Lamy, MD;
J.-F. Meder, MD, PhD; and J.-L. Mas, MD
Hypoglycemia may mimic acute stroke. We report a patient with a
stroke-like episode and corresponding transient unilateral MR
changes due to hypoglycemia.
Case report. A 24-year-old woman was admitted for left hemiparesis of sudden onset. She had no vascular risk factors. Three
months before admission, she experienced two episodes of generalized seizures in the context of sleep deprivation. EEGs were
normal. Two months later, she had two episodes of transient right
hemiparesis. She never experienced headaches during or after
these episodes. Head CT scan, cervical Doppler, and transthoracic
echocardiography were normal. Routine blood tests, autoimmune
screening, and lumbar puncture were normal.
She was admitted for a pure left motor deficit of sudden onset.
Two hours after onset, the NIHSS score was 3. FLAIR was normal,
while a right internal capsule hypersignal was seen on DWI with
decreased ADC values (figure 1). First-pass gadolinium perfusion
sequence (PWI) showed a slight increase of relative cerebral blood
volume (20% compared to contralateral hemisphere) restricted to the
lesion seen on DWI, without arterial occlusion on intracranial threedimensional time of flight MR angiography. EKG, body temperature,

and blood pressure were normal. A second MRI, performed 4 hours
after onset because of neurologic worsening (NIHSS score at 7),
showed a clear-cut hypersignal in the right internal capsule on routine DWI, with unchanged PWI finding. Routine blood tests were
normal except for a glucose level of 2.2 mmol/L (normal ⬎ 3.5 mmol/
L). The deficit completely resolved in 6 hours and DWI-PWI MRI
obtained 12 hours after onset returned to normal (figure 1). Cervical
MR angiography, EKG monitoring, and transesophageal echocardiography were normal. An endocrine evaluation was suggestive of
insulinoma. A pancreatic tumor was found and successfully operated
a few days later. Six months after surgery, the patient has remained
asymptomatic.
Discussion. MRI reports of hypoglycemic-induced lesions are
limited,1-3 and mainly concern patients with profound hypoglycemic coma.3-4 Lesions typically involve cerebral cortex, hippocampus, basal ganglia, and also middle cerebellar peduncles,3-5
bilaterally. It has been suggested that DWI changes in hypoglycemic coma portend a poor outcome. There is no consensus regarding the vulnerability of cerebral regions to hypoglycemia. Glucose
deprivation leads to severe brain energy failure and a reduction of
cell membrane ionic pump activity. In experimental hypoglycemia, lesions involve the cortex, hippocampus, and usually respect
the white-matter and the cerebellum while significant ADC reduction in the overall brain has been reported.6
We report a unilateral and transient DWI increased signal with
decreased ADC in a patient with a stroke-like episode due to an
insulinoma. Initially, DWI and ADC were more sensitive than
FLAIR images, which were normal 2 hours after onset. The ADC
values were moderately decreased and similar to ADC values reported in TIAs. Despite initial ADC decrease, the lesion was fully
reversible, similar to a recent case report.2 We also noted a hyperperfusion within the DWI lesion. Even if caution is needed given the
small size of the lesion, experimental and clinical observations indicate that insulin-induced hypoglycemia produces cerebral vasodilatation, presumably resulting from dysfunction of the oxide pathway.7
Thus hypoglycemia not only mimics TIA clinically but radiologically.
From the Departments of Neurology (Drs. Cordonnier, Lamy, and Mas) and
Neuroradiology (Drs. Oppenheim and Meder), Centre Hospitalier SainteAnne, Université Paris V, France.
Received February 4, 2005. Accepted in final form April 6, 2005.
Address correspondence and reprint requests to Dr. Catherine Oppenheim,
Departement d’Imagerie Morphologique et Fonctionnelle, Centre Hospitalier
Sainte-Anne, 1 rue Cabanis, 75674 Paris cedex 14, France; e-mail:
c.oppenheim@ch-sainte-anne.fr
Copyright © 2005 by AAN Enterprises, Inc.

References

Figure. Transient signal changes on serial MRI in hypoglycemia. Two hours after onset, the FLAIR image was
normal while DWI showed a unilateral hypersignal in the
right internal capsule with decreased ADC values (20%
decreased). Four hours after onset, a slight signal increase
was seen on FLAIR images with a clear-cut signal increase on DWI. Twelve hours after onset, the clinical
symptoms had resolved and the MRI returned to normal.

1. Chan R, Erbay S, Oljeski S, Thaler D, Bhadelia R. Casereport: hypoglycemia and diffusion-weighted imaging. J Comput Assist Tomogr 2003;27:
420–423.
2. Böttcher J, Kunze A, Kurrat C, et al. Localized reversible reduction of
apparent diffusion coefficient in transient hypoglycemia-induced hemiparesis. Stroke 2005;36:e20–e22.
3. Finelli PF. Diffusion-weighted MR in hypoglycemic coma. Neurology
2001;57:933–935.
4. Fujioka M, Okuchi K, Hiramatsu KI, Sakaki T, Sakauchi S, Ishii Y.
Specific changes in human brain after hypoglycemic injury. Stroke 1997;
28:584–587.
5. Okamoto K, Tokiguchi S, Furusawa T, et al. MR features of diseases
involving bilateral middle cerebellar peduncles. Am J Neuroradiol 2003;
24:1946–1954.
6. Hasegawa Y, Formato JE, Latour LL, et al. Severe transient hypoglycemia causes reversible change in the apparent diffusion coefficient of
water. Stroke 1996;27:1648–1656.
7. Diéguez G, Fernàndez N, Garcia JL, Garcia-Villalon AL, Monge L, Gomez B. Role of nitric oxide in the effects of hypoglycemia on the cerebral
circulation in awake goats. Eur J Pharmacol 1997;330:185–193.

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Vascular dysplasia in neurofibromatosis type 2
Aisling M. Ryan, Michael Hurley, Paul Brennan, et al.
Neurology 2005;65;163-164
DOI 10.1212/01.wnl.0000167134.04302.17
This information is current as of July 11, 2005
Updated Information &
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References

This article cites 7 articles, 2 of which you can access for free at:
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