Clinical/Scientific Notes Paraneoplastic encephalomyelitis

Clinical/Scientific Notes
Paraneoplastic encephalomyelitis
associated with pancreatic tumor and
anti-GAD antibodies
L. Hernández-Echebarrı́a, MD; A. Saiz, MD; A. Arés, MD;
J. Tejada, MD; L. Garcı́a-Tuñón, MD; C. Nieves, MD;
and F. Graus, MD
Glutamic acid decarboxylase (GAD), the enzyme that catalyzes
the conversion of glutamate to ␥-aminobutyric acid (GABA), is
expressed in GABA-secreting neurons and pancreatic ␤ cells.1
Anti-GAD antibodies (GAD Abs) have been described in patients
with type 1 diabetes mellitus and patients with two CNS disorders, stiff-person syndrome and cerebellar ataxia associated with
polyendocrine autoimmunity.2 We report a patient with paraneoplastic encephalomyelitis associated with a pancreatic tumor and
GAD Abs.
Case report. A 67-year-old man presented paresthesias and
numbness in hands, feet, and perioral region. Over the next 2
weeks, he developed gait instability that required bilateral support for walking. The general examination was unremarkable.
The neurologic examination showed gaze-evoked downbeat nystagmus. Deep tendon reflexes were absent in the legs. There was
hypoesthesia in glove and stocking distribution, with decreased
vibration and joint position sense in the fingers and toes. He
showed truncal and gait ataxia and moderate limb dysmetria.
Routine hematologic and biochemical analysis were normal. CSF
analysis revealed a protein level of 314 mg/dL, 11 lymphocytes/
mm3, and negative oligoclonal IgG bands. Serum and CSF serologies and cultures ruled out an infectious etiology. Antineuronal
antibodies (Hu, Yo, Ri, Ma 1 and 2, CV2, and amphiphysin antibodies) were negative, but GAD Abs, detected by immunohistochemistry and RIA,2 were present in serum (1/80,000) and CSF
(1/800). No other autoantibodies were detected either by immunohistochemistry or immunoblot of neuronal extracts. Nerve conduction studies demonstrated absent sensory nerve action potential
in the legs with normal motor nerve and F-wave studies. Brain
MRI was normal. A CT scan of the abdomen demonstrated a mass
(5.5 ⫻ 3 ⫻ 5 cm) in the body of the pancreas without evidence of
metastasis. The patient underwent a resection of the corpus and
cauda of the pancreas combined with splenectomy. A histopathologic examination revealed a neoplasm of the pancreatic body,
which showed an intense infiltration of inflammatory cells (figure)
and a positive immunostaining for synaptophysin and chromogranin A. The tumor was classified as a well-differentiated, nonfunctioning pancreatic endocrine neoplasm. Symptoms worsened
over the ensuing months. He also developed painful spasms in the
left leg with fixed dorsiflexion posture of the foot. A new electromyogram demonstrated persistent motor activity in the left leg.
Symptoms did not improve after several courses of IV immunoglobulins; he developed confusion and agitation and died from
aspiration bronchopneumonia.
The expression of GAD antigen by the patient’s tumor was
demonstrated by the characteristic immunoreactivity of the tumor
cells after incubation with GAD-6 monoclonal antibody (Hybrioma
Bank, Iowa City, IA) (see figure) or biotinylated IgG of a patient
with high titers of GAD Abs. Specificity of staining for GAD antigen was confirmed by competition experiments in which binding
of the GAD-6 monoclonal antibody was blocked by preincubation
of tumor sections with a human serum with high titers of GAD
Abs (see figure) but not with serum from a normal individual (not
shown).
At brain autopsy, the CNS appeared grossly normal. Microscopically, there was an extensive loss of Purkinje cells in the
cerebellum and proliferation of Bergmann astrocytes. A vacuolization in the posterior columns of the spinal cord was also noticeable. Inflammatory infiltrates were not detected in the cerebellum
or other areas of the nervous system.
Discussion. The current study shows that GAD Ab response
can be associated with tumors other than thymoma.3 This finding
is important because the presence of GAD Abs is usually associated with the nonparaneoplastic form of the stiff-person syndrome
and in the cerebellar ataxia associated with polyendocrine autoimmunity, which are unrelated to malignancies with the exception of
thymoma.1,2,4,5 The detection of high titers of GAD Abs in a patient
with a neurologic syndrome usually indicates that the probable
cause is nonparaneoplastic autoimmunity, and the search for an
underlying cancer is unnecessary. Although this statement is
probably correct when the patient has a stiff-person or cerebellar
syndrome,1,2 in the clinical setting of a possible encephalomyelitis,
a possible paraneoplastic origin should be considered even if the
patient has GAD Abs.6
The pathogenic role of GAD Abs in the two characteristic neurologic disorders, stiff-person and cerebellar ataxia, has been
questioned because GAD is a cytoplasmic antigen.7 In our patient,
the massive infiltration of the tumor by T lymphocytes suggests
that the GAD expression by the tumor could induce a complex
(humoral and cellular) immune response, initially driven to control the tumor growth and later misdirected to the nervous system. The final mechanisms of neuronal damage are unclear, but it
was probably caused by a T cell–mediated immune attack against
GAD-positive neurons.6
From the Neurology (L.H.-E., A.A., J.T., L.G.-T.) and Pathology (C.N.) Services, Hospital de León, and Neurology Service (A.S., F.G.), Institut
d’Investigació Biomédica August Pi i Sunyer, Hospital Clı́nic, University of
Barcelona, Spain.
Disclosure: The authors report no conflicts of interest.
Received April 18, 2005. Accepted in final form October 21, 2005.
Address correspondence and reprint requests to Dr. L. HernándezEchebarrı́a, Neurology Service, Hospital de León, Altos de Nava s/n, 24071
León, Spain; e-mail: lhernandez@ya.com
Copyright © 2006 by AAN Enterprises, Inc.
References
1. Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to
GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome.
N Engl J Med 1990; 322: 1555–1560.
2. Saiz A, Arpa J, Sagasta A, et al. Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulindependent diabetes mellitus, and polyendocrine autoimmunity.
Neurology 1997;49:1026–1030.
3. Vernino S, Lennon VA. Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res 2004; 10: 7270–7275.
4. Meinck H-M, Faber L, Morgenthaler N, et al. Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases. J Neurol
Neurosurg Psychiatry 2001;71:100–103.
Figure. (A) Tumor section immunostained with a monoclonal antibody
against CD3 antigen (T lymphocytes)
shows a massive infiltration of T lymphocytes around tumor cells. (B) Incubation of the section with glutamic acid
decarboxylase-6 monoclonal antibody
demonstrates positive staining of tumor
cells. (C) Glutamic acid decarboxylase-6 immunoreactivity is abolished by preincubation with the patient’s serum. Counterstained with hematoxylin and eosin; ⫻100 (A); ⫻200 (B, C).
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5. Barker RA, Revesz T, Thom M, Marsden CD, Brown P. Review of 23
patients affected by the stiff man syndrome: clinical subdivision into stiff
trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998;65:633–
640.
6. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous
system. N Engl J Med 2003;349:1543–1554.
7. Dalakas MC, Li M, Fujii M, Jacobowitz DM. Stiff person syndrome:
quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57:780–784.
Lower motor neuron weakness after
diving-related decompression
Our patient’s hand weakness is explained by infarction involving the anterior horn cells in the spinal cord due to diving-related
decompression. Spinal cord damage following diving is
recognized,1-5 but our case is unusual because of the cervical cord
involvement with lower motor neuron weakness of the upper limb,
in contrast to the more typical thoracic spinal cord involvement
with upper motor neuron weakness of the lower limbs and sensory
loss.1-3 In our case, this presentation had led to the initial diagnosis by a neurologist of ALS.
Spinal cord infarction is usually reported with type II decompression sickness1 but can occur in the absence of clinical signs of
decompression sickness.5 In a study of goats with different diving
exposures, the presence of spinal cord lesions did not correlate
with the typical features of decompression sickness.5 Spinal cord
involvement may occur following dives conducted in accordance
with US Navy decompression tables.1,4 Rapid ascent has been associated with spinal cord involvement.1,5
The most likely mechanism responsible for decompressionrelated myelopathy is spinal cord ischemia due to congestion of
the epidural vertebral venous system by nitrogen gas bubbles. The
epidural vertebral venous system (Batson plexus) can be obstructed by gas bubbles that collect, coalesce, and grow, when
other major veins do not become obstructed, because the system
functions as a valveless relatively stagnant venous lake in which
the direction of flow changes frequently, in contrast to the unidirectional conduit function of other veins.6 In addition to mechanically obstructing venous outflow, gas bubbles in the venous bed
may accelerate coagulation, leading to more complete venous
obstruction.6
Robert D. Henderson, FRACP; and Michael P. Pender, MD
Myelopathy is a recognized complication of diving and usually
presents with upper motor neuron weakness and sensory loss of
the lower limbs due to thoracic spinal cord damage.1,2 Here we
present a case of lower motor neuron upper limb weakness due to
infarction of the anterior horn cells of the spinal cord following
diving. To our knowledge, this is the first report of an isolated
lower motor neuron syndrome following diving-related
decompression.
A 46-year-old woman was referred for electromyography
(EMG) with a clinical diagnosis of ALS. Two months earlier,
she had noted weakness in her right hand without sensory
symptoms. The patient was a recreational scuba diver and recalled diving to 90 ft, 1 week prior to the onset of weakness. She
ascended quickly but not in violation of her diving table and 20
hours later took an international flight. There was no significant past medical history.
On examination, there was wasting of the small muscles of the
right hand and a prominent inability to extend the right middle
finger. Scattered fasciculations were seen in the small muscles of
the right hand. There was mild weakness of right elbow extension,
forearm pronation, wrist extension and thumb abduction, and
moderate weakness of finger extension and abduction. Left finger
abduction was mildly weak, but power was otherwise normal in
the left upper limb. The biceps, supinator, and triceps jerks were
normal bilaterally. The upper limb sensation, cranial nerves, and
lower limb examination were normal.
Nerve conduction studies showed low amplitude right ulnar
and median compound muscle action potentials (CMAPs) with
normal conduction velocities, F waves, and corresponding sensory studies. No conduction block was present. The right radial
CMAP recording over the extensor digitorum was normal. The
EMG showed fibrillations and fasciculations in the right first
dorsal interosseous and opponens pollicis muscles with reduced
recruitment of complex large motor units. There was increased
size of motor units in the right deltoid, triceps, pronator teres,
and lower cervical paraspinal muscles. Large motor units were
also present in the left first dorsal interosseous and opponens
pollicis muscles.
MRI of the cervical spine at the time of the clinical examination showed increased signal in the spinal cord from C3 to C7
vertebral bodies on sagittal T2 imaging. On T2 axial cuts, the
increased signal was predominantly in the right anterior horn,
with hypointensity on T1 imaging (figure). T2 hyperintensity was
also present to a lesser extent in the left anterior horn. No enhancement occurred following the injection of gadolinium. The
MRI was consistent with focal infarction of the cervical spinal
cord. On follow-up, 4 months after the onset of weakness, her
neurologic condition was unchanged.
From the Department of Neurology, Royal Brisbane and Women’s Hospital,
School of Medicine, University of Queensland, Australia.
Disclosure: The authors report no conflicts of interest.
Received August 25, 2005. Accepted in final form October 25, 2005.
Address correspondence and reprint requests to Dr. R.D. Henderson, Department of Neurology, Royal Brisbane and Women’s Hospital, Butterfield St.,
Herston, 4029, Queensland, Australia; e-mail: Robert_Henderson@
health.qld.gov.au
Copyright © 2006 by AAN Enterprises, Inc.
References
1. Kimbro T, Tom T, Neuman T. A case of spinal cord decompression
sickness presenting as partial Brown–Sequard syndrome. Neurology
1997;48:1454–1456.
2. Hierholzer J, Tempka A, Stroszczynski C, et al. MRI in decompression
illness. Neuroradiology 2000;42:368–370.
3. Manabe Y, Sakai K, Kashihara K, Shohmori T. Presumed venous infarction in spinal decompression sickness. AJNR Am J Neuroradiol 1998;19:
1578–1580.
4. Aharon-Peretz J, Adir Y, Gordon CR, Kol S, Gal N, Melamed Y. Spinal
cord decompression sickness in sport diving. Arch Neurol 1993;50:753–
756.
Figure. (A) Axial T2 MRI of the spine
at C3 to C4 level with hyperintensity of
the right anterior horn and to a lesser
extent of the left anterior horn. (B) Corresponding T1 scan showing hypointensity of the right anterior horn consistent
with infarction.
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5. Blogg SL, Loveman GA, Seddon FM, et al. Magnetic resonance imaging
and neuropathology findings in the goat nervous system following hyperbaric exposures. Eur Neurol 2004;52:18–28.
6. Hallenbeck JM, Bove AA, Elliott DH. Mechanisms underlying
spinal cord damage in decompression sickness. Neurology
1975;25:308–316.
Cortical liquefaction in severe human
herpesvirus 6 encephalopathy
and 5, resulting in laminar necrosis.2,3 It is histologically defined
as pan-necrosis, that is, the death of neurons, glia, and blood
vessels with resultant denatured proteins, reactive gliosis, and
deposition of fat-laden macrophages.3 On MRI, cortical laminar
necrosis is seen as high intensity both on T1-weighted and FLAIR
images.2,4 Though the exact mechanism of T1 shortening in laminar necrosis is still uncertain, it is postulated to reflect the presence of denatured protein and fat-laden macrophages.2,4 Cortical
lesions were not reported to manifest low signal intensity at any
stage of cortical laminar necrosis on either T1-weighted and
FLAIR images.4 Therefore, the appearance of the cortical lesions
in this case is distinct from cortical laminar necrosis as reported
in the literature.
What is the mechanism by which the cortex liquefied in this
patient? Histopathologic studies in patients with severe perinatal
asphyxia have revealed that cortical injuries generally involve all
layers of the cerebral cortex and are only occasionally laminar.5 In
addition, intracortical fibers do not seem to be myelinated in neonates or young infants, as staining with Luzon fast blue (for evaluation of myelination) does not appear until after 12 months.6 The
absence of myelin might make the cortex more likely to liquefy, as
myelin gives stability to the axons and also nourishes them.7
Thus, one explanation might be that liquefaction results from the
different pattern of cortical involvement and the absence of intracortical myelin in this 9-month-old infant. However, the fact that
cortex does not liquefy after arterial infarction at this age makes
this explanation unlikely. Another possibility is that HHV6 might
directly affect neurons, astrocytes, and macrophages.1 By the effects on astrocytes and macrophages, the virus might reduce reactive gliosis and the deposition of fat-laden macrophages that cause
T1 shortening in cortical laminar necrosis. In any case, further
study and further cases will be needed to determine the clinical
significance of this severe liquefactive change and the factors
causing it.
J. Takanashi, MD; A.J. Barkovich, MD; H. Tada, MD;
N. Takada, MD; K. Fujii, MD; and Y. Kohno, MD
Human herpesvirus 6 (HHV6) is the causative agent of the common childhood infectious disease exanthema subitum. Primary
infection of CNS by HHV6 can cause seizures and encephalitis/
encephalopathy.1 We report a 9-month-old girl with severe HHV6
encephalopathy, in whom a subacute MRI showed an unusual
appearance of the cerebral cortex suggesting cortical liquefaction.
Case report. A previously healthy 9-month-old Japanese girl
was admitted because of status epilepticus for 1 hour following a
1-day prodromal illness consisting of fever (around 38.5 °C for 3
days) and vomiting. After her seizure was controlled, she was in a
comatose state and required intubation. Laboratory examination
revealed elevated serum liver enzyme activities. CSF showed normal cell count (1/mm3), protein level (18 mg/dL), and glucose level
(122 mg/dL). EEG showed polyspikes in bilateral centroparietal
regions. HHV6 was later isolated from her throat swab and serum, and a diagnosis of HHV6 encephalopathy was established.
Clinical symptoms or laboratory data suggesting hemorrhagic
shock and encephalopathy syndrome (shock, diarrhea, disseminated intravascular coagulation or renal dysfunction) were not
observed. A faint skin rash appeared on her body on the 5th day.
She was treated with methylprednisolone (30 mg/kg/day for 3
days) and acyclovir. Her liver function gradually normalized
within a month. Her consciousness level gradually improved, but
she was discovered to have severe psychomotor retardation and
tetraplegia.
MRI on the 40th day demonstrated marked T2 prolongation of
the frontal and occipital cortex overlying the abnormally high
intensity white matter (figure, A). The abnormal cortex was of
homogenously low signal intensity in its deeper layers with its
more superficial layers demonstrating isointensity to the remainder of the cortex on T1-weighted and fluid-attenuated inversion
recovery (FLAIR) (figure, B) images. T1 shortening and T2 prolongation in the corpus striatum and cerebral atrophy were seen.
Discussion. Markedly high signal intensity on T2-weighted
images and low signal intensity on T1-weighted and FLAIR images would imply liquefactive changes within the cortex. A search
of the literature has revealed no report of apparent cortical liquefaction in patients with encephalopathy or infarction.
Histologic and animal studies have demonstrated much more
vulnerability of gray matter than white matter to hypoxic–
ischemic insults. Of the six cortical layers, layers 3 and 5 are the
most vulnerable; layers 2 and 4 are more resistant. Therefore,
neuronal damage has a tendency to occur especially in layers 3
Acknowledgment
The authors thank Dr. Masaharu Hayashi (Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan) for
comments.
From the Department of Pediatrics (J.T., H.T., N.T., K.F., Y.K.), Graduate
School of Medicine, Chiba University, and Department of Pediatrics (J.T.),
Kameda Medical Center, Kamogawa, Japan; and Neuroradiology Section
(A.J.B.), Department of Radiology, University of California San Francisco.
Disclosure: The authors report no conflicts of interest.
Received June 7, 2005. Accepted in final form October 25, 2005.
Address correspondence and reprint requests to Dr. J.-I. Takanashi, Department of Pediatrics, Kameda Medical Center, 929 Higashi-cho, Kamogawashi, Chiba 296-8602, Japan; e-mail: jtaka@kameda.jp
Figure. (A) T2-weighted image (4,000/
100 milliseconds repetition/echo time)
on 40th day demonstrated marked T2
prolongation of the frontal and medial
parietal and occipital cortex (arrows).
(B) Sagittal fluid-attenuated inversion
recovery images (10,000/110 milliseconds, 2,200 inversion time) show low
intensity of the deeper layers of the
frontal cortex (arrow) but normal intensity of the most superficial portions of
the cortex.
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NEUROLOGY 66
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Copyright © 2006 by AAN Enterprises, Inc.
References
1. Yoshikawa T, Asano Y. Central nervous system complications in human
herpesvirus-6 infection. Brain Dev 2000;22:307–314.
2. Siskas N, Lefkopoulos A, Ioannidis I, Charitandi A, Dimitriadis AS.
Cortical laminar necrosis in brain infarcts: serial MRI. Neuroradiology
2003;45:283–288.
3. Boyko OB, Burger PC, Shelburne JD, Ingram P. Non heme mechanism
for T1 shortening: pathologic, CT, MR elucidation. AJNR Am J Neuroradiol 1992;13:1439–1445.
4. Komiyama M, Nakajima H, Nishikawa M, Yasui T. Serial MR observation of cortical laminar necrosis caused by brain infarction. Neuroradiology 1998;40:771–777.
5. Hopkins IJ, Farkas-Bargeton E, Larroche JC. Neonatal neuronal necrosis: its relationship to the distribution and maturation of oxidative enzymes of newborn cerebral and cerebellar cortex. Early Hum Dev 1980;
4:51–60.
6. Iai M, Yamamura T, Takashima S. Early expression of proteolipid protein in human fetal and infantile cerebri. Pediatr Neurol 1997;17:235–
239.
7. Barkovich AJ. Magnetic resonance techniques in the assessment of myelin and myelination. J Inherit Metab Dis 2005;28:311–343.
Glomeruloid hemangiomas: A marker
for POEMS
Tracy Weimer, MD; Amy Norton, MD; and Ludwig Gutmann, MD
Polyneuropathy, organomegaly, endocrinopathy, M protein, and
skin changes (POEMS) is a multisystem syndrome that may accompany plasma cell dyscrasias.1,2 Polyneuropathy and a monoclonal plasmaproliferative disorder must be present along with one
other minor criterion, including sclerotic bone lesions, Castleman’s disease, organomegaly, edema, endocrinopathy, skin
changes, or papilledema. Other associated findings may include
ascites, pleural effusions, and thrombocytosis.
We describe a patient with glomeruloid hemangiomas, a skin
abnormality seen exclusively in POEMS.3,4 This has been reported
only rarely in the neurologic literature and is a useful diagnostic
criterion.5
Case report. A 58-year-old woman presented with weakness,
distal sensory loss, pain, and edema in the lower extremities. The
symptoms had progressed over 3 years. She was using a walker to
ambulate. Neurologic examination 3 years earlier, at the time of
an episode of low back pain, was normal.
She was an obese woman with extensive edema of the extremities and thickening of the skin in the legs and forearms. Muscle
strength was 4-/5 in the arms and legs except distally in the legs
where no motor function was present. Vibration was moderately
decreased in the hands and absent in the feet. Position sense, pin,
and temperature were moderately decreased in the feet. All reflexes were absent. Bulbar strength was normal.
Laboratory studies revealed an elevated TSH of 8.45. Serum
protein electrophoresis was consistent with a monoclonal gammopathy and immunofixation revealed monoclonal IgA lambda
M-protein. Initial skeletal survey was negative. CT of the chest/
abdomen/pelvis showed scattered lymph nodes, which failed to
meet size criteria for lymphadenopathy. Bone marrow biopsy
showed 5% plasma cells and normoblastic maturation.
Nerve conduction/EMG studies on both median and ulnar
nerves showed prolonged distal motor latencies ranging from 6.9
to 9.5 m/sec (normal 4.2) and slowed velocities ranging from 17.8
to 23.1 m/sec (normal greater than 45 m/sec). All sensory nerve
action potentials were absent. Many fibrillations were seen in
distal and proximal muscles of the legs and distally in the arms.
Motor unit potentials were decreased or absent in legs. The patient was treated with five courses of IV immunoglobulin (IVIg)
with some mild subjective improvement of the distal extremity
pain.
Despite treatment with IVIg, she was dramatically worse 4
months later. Weakness was severe distally in the legs and moderate in the arms. Reflexes remained absent. At this follow-up
visit, erythematous papules were noted across the abdominal skin.
Skin biopsy was performed on these lesions and revealed a glomeruloid hemangioma (figure). A repeat skeletal survey revealed
a previously unseen area of sclerosis in the right fourth rib. The
sclerotic lesion was biopsied and revealed a small area of plasma
cell proliferation.
Discussion. The cardinal features of POEMS include a polyneuropathy, organomegaly, endocrinopathy, M protein, and skin
changes. The sensorimotor polyneuropathy is generally the presenting complaint in POEMS syndrome. It usually has both demyelinating and axonal features and is slowly progressive and
debilitating in most cases.
The monoclonal (M) protein abnormality consists of IgA or IgG
Figure. Microscopic section showing glomeruloid hemangioma stained with hematoxylin and eosin. Insert shows
hemangioma on abdominal wall.
heavy chains with lambda light chains. Anti-myelin-associated
glycoprotein antibodies are not present in POEMS as it is in many
IgM paraproteinemias. Bone lesions, when present, are usually
sclerotic. In cases of POEMS associated with solitary osteosclerotic lesions, improvement of all symptoms is seen after irradiation or surgical excision of the lesion.
The skin changes may consist of hyperpigmentation, hypertrichosis, hyperhidrosis, skin thickening, and hemangiomas. Endocrinopathies includes diabetes, impotence, gynecomastia, and
hypothyroidism. Organomegaly may be hepatosplenomegaly or
lymph node enlargement. Approximately 60% of biopsies of enlarged lymph nodes show histopathology similar to that seen in
Castleman’s disease (angiofollicular lymph node hyperplasia, vascular proliferation, sinusoidal histiocytes, and sheets of plasma
cells).6
The patient described in this report fulfills the criteria for a
diagnosis of POEMS. Her polyneuropathy showed evidence of demyelination and axonal degeneration. She had an osteosclerotic
myeloma and an IgA lambda M-protein. Hypothyroidism and
marked peripheral edema were present. Skin changes included
marked thickening and glomeruloid hemangiomas.
Glomeruloid hemangiomas are a unique skin abnormality in
POEMS, present in as many as 24 to 44% of patients.7 These
appear as multiple red-purple lesions occurring on the trunk and
proximal limbs and have not been reported in patients without
POEMS. The formation of glomeruloid hemangiomas is most
likely mediated by angiogenic factors. Deposition of immunoglobulins in endothelial cells has also been proposed as a possible triggering mechanism for these lesions. PAS-positive material is
found in the cytoplasm of endothelial cells and may represent
immunoglobulins derived from the circulation. These hemangiomas may be specific markers for POEMS and their identification
may facilitate a more rapid diagnosis.
From the Departments of Neurology (T.W., L.G.) and Medicine (A.N.),
Robert C. Byrd Health Sciences Center, Morgantown, WV.
Disclosure: The authors report no conflicts of interest.
February (1 of 2) 2006
NEUROLOGY 66
453
Received September 5, 2005. Accepted in final form October 26, 2005.
Address correspondence and reprint requests to Dr. Tracy Weimer, Department of Neurology, Robert C. Byrd Health Sciences Center, Morgantown,
WV 26506-9180.
Copyright © 2006 by AAN Enterprises, Inc.
References
1. Crow RS. Peripheral neuritis in myelomatosis. BMJ 1956;2:802–804.
2. Fukase M, Kakimatsu T, Nishitani H, et al. Report of a case of solitary
plasmacytoma in the abdomen presenting with polyneuropathy and endocrinological disorders. Clin Neurol 1969;9:657.
Acute trismus associated with
Foix–Marie–Chavany syndrome
Jennifer A. Frontera, MD; and David Palestrant, MD
Foix–Marie–Chavany syndrome is a clinical disorder characterized by faciopharyngoglossomasticatory weakness and loss of
voluntary control of facial movements with preserved automatic
and emotional motility. It is classically associated with bilateral anterior opercular lesions. Trismus is defined as tonic contraction of the muscles of mastication and can be caused by
neuroleptic-induced dystonia, tetanus, basal ganglia disorders,
acute infection, idiopathic dystonia, neoplasm, or as a complication of radiation therapy. Though hand dystonia associated
with bilateral opercular lesions has been reported,1 trismus
associated with Foix–Marie–Chavany syndrome is atypical.
We report a patient with trismus and automatic-voluntary
dissociation of facial movements after bilateral opercular
infarcts.
Case report. A 41-year-old right-handed woman, with a history of tobacco use, past cocaine use (⬎10 years ago), and elevated cholesterol, experienced sudden onset dysarthria and left
arm and leg numbness and weakness. Her medical history was
notable for cryptogenic strokes in the left insula, left temporalparietal, and right frontal territories 5 years prior to admission.
Her evaluation at that time included a normal transesophageal
echocardiogram (TEE), angiography negative for intracranial
stenosis, normal telemetry monitoring, and negative hypercoagulable and vasculitis laboratory studies. The patient was
treated initially with warfarin and a statin, but was noncompliant with her medications. She did not receive any neuroleptics
prior to or during her hospital stay.
Physical examination. Blood pressure was 121/71 mm Hg.
Pulse was 62 and intermittently irregular. Respirations were
stenorous. The rest of the general examination was
unremarkable.
Neurologic examination. The patient’s mental status deteriorated within 6 hours of symptom onset from oriented, conversant,
and dysarthric to somnolent and intermittently agitated. She
demonstrated evidence of left neglect. Cranial nerve examination
revealed normal pupils, right gaze preference, and left homonymous hemianopia. The masseter muscles were tonically contracted. She exhibited dysphagia, pooling of secretions, and
bifacial weakness with inability to tightly close her eyes or puff
her cheeks during spontaneous and emotive facial movement. Assessment of hypoglossal function was impossible given the patient’s trismus. Motor examination revealed left arm and leg
plegia with lead pipe rigidity suggestive of dystonia with normal
muscle strength on the right. Sensation was decreased to pain on
the left face, arm, and leg. Deep tendon reflexes were brisk
bilaterally.
Because of her trismus and poor mental status, the patient
underwent nasal intubation and later tracheostomy. Over the subsequent month the patient improved and was able to move her
lips and frontalis muscles both spontaneously and as an emotional
response to stimuli. She was able to blink and close her eyes when
sleeping, but when instructed to close her eyes, or move her forehead or lips, she was unable to do so. Her masseter muscles
remained tonically contracted and the patient was unable to open
her mouth either involuntarily or to command. She could communicate by writing and pantomime and had no evidence of aphasia.
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3. Chan JK, Fletcher CD, Hicklin GA, et al. Glomeruloid hemangioma. A
distinctive cutaneous lesion of multicentric Castleman’s disease associated with POEMS syndrome. Am J Surg Pathol 1990;14:1036–1046.
4. Tsai CY, Lai CH, Chan HL, Kuo TT. Glomeruloid hemangioma-a specific
cutaneous marker of POEMS syndrome. Int J Derm 2001;40:401–414.
5. Vital C, Vital A, Ferrer X, et al. Crow-Fukase (POEMS) syndrome: a
study of peripheral nerve biopsy in five new cases. J Periph Nerv Sys
2003;8:136–144.
6. Shahidi O, Myers J, Kvale P. Castleman’s disease. Mayo Clin Proc 1995;
70:969–977.
7. Takatsuki K, Sanada I. Plasma cell dyscrasia with polyneuropathy, organomegaly, and endocrine disorder: clinical and laboratory features of 109
cases. Jpn J Clin Oncol 1983;13:543–556.
She required a gastric feeding tube, had copious secretions, and
had recurrent aspiration pneumonias.
Diagnostic studies. Telemetry revealed evidence of paroxysmal atrial fibrillation. TEE did not reveal a thrombus or patent
foramen ovale.
Imaging studies. MR diffusion-weighted imaging and apparent diffusion coefficient sequences on day 1 post-stroke revealed patchy acute infarcts in the right insula, opercula, and
high parietal and frontal lobes in the MCA territory. T2weighted sequences revealed left opercular, parietal, and right
frontal encephalomalacia. There were no basal ganglia, internal
capsule, thalamic, or brainstem lesions. Cerebral angiography
demonstrated multiple acute branch occlusions of the right rolandic and callosomarginal arteries. The patient was started on
warfarin and refused masseter botulinum toxin injection.
Figure. Axial MR diffusion-weighted imaging (A) and
fluid-attenuated inversion recovery sequences (B) 1 day
poststroke and axial CT sections (C, D) 1 week poststroke
demonstrate acute patchy right MCA territory infarcts involving the operculum and pre- and postcentral gyrus. Old
infarcts of the left anterior operculum and left parietal
lobe were present.
Discussion. The clinical presentation of facial and pharyngeal weakness accompanied by dissociated automatic and voluntary facial movements with radiographic evidence of anterior
opercular lesions is typical of Foix–Marie–Chavany syndrome.2
Supranuclear control of the jaw is largely bilateral, with motor
fibers originating in the frontal-opercular area. Our patient
was unique in that she developed trismus of acute onset associated with this syndrome. While trismus after stroke has been
described with lesions of the basal ganglia, bilateral internal
capsules, and brainstem,3,4 it is unusual with bilateral opercular lesions or any of the lesions seen on this patient’s MRI.
Additionally, poststroke trismus typically develops subacutely
along with spasticity. Our patient developed trismus within 6
hours of symptom onset. Trismus has been successfully treated
with botulinum toxin injection into the masseter, temporalis,
medial, and lateral pterygoid muscles (figure).3,5
From the Department of Neurology, Division of Stroke and Neurocritical Care,
Columbia University College of Physicians and Surgeons, New York, NY.
Disclosure: The authors report no conflicts of interest.
Received June 16, 2005. Accepted in final form October 27, 2005.
Address correspondence and reprint requests to Dr. David Palestrant, Columbia Presbyterian Hospital, 710 W 168th Street, 8th floor, New York, NY
10032; e-mail: dpalestrant@neuro.columbia.edu
Copyright © 2006 by AAN Enterprises, Inc.
References
1. Puertas I, Garcia-Soldevilla MA, Jimenez-Jimenez FJ, Cabrera-Valdivia
F, Jabbour T, Garcia-Albea E. [Bilateral hand dystonia secondary to a
bilateral opercular syndrome or Foix-Chavany-Marie syndrome.] Rev
Neurol 2002;35:430–433.
2. Foix CCJ, Marie J. Diplegie facio-linguo-masticartrice d’origine souscorticale sans paralys des membres (contribution a l’etude de la localisation des centres de la face du membre superieur). Rev Neurol 1926;33:
214–219.
3. Spillane KS, Shelton JE, Hasty MF. Stroke-induced trismus in a pediatric patient: long-term resolution with botulinum toxin A. Am J Phys Med
Rehabil 2003;82:485–488.
4. Lai MM, Howard RS. Pseudobulbar palsy associated with trismus. Postgrad Med J 1994;70:823–824.
5. Kadyan V, Clairmont AC, Engle M, Colachis SC. Severe trismus as a
complication of cerebrovascular accident: a case report. Arch Phys Med
Rehabil 2005;86:594–595.
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