Immunostaining with Anti-Tr antibody

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 Paraneoplastic Neurological
Syndromes

A Review.

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 Objectives

• To understand when in the course of

malignancy the syndromes occur

• To know the antineural antibodies associated

with the syndromes

• To differentiate efficacy of symptomatic

treatment vs. treatment of underlying disease
in the different syndromes
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 Outline for the Session

• Introduction
• History and Evolution of knowledge
• Pathogenesis – Concept of ―Onconeural‖ Antigen
• Definition – Terminology
• Criteria for Diagnosis
• Individual Syndromes
• Summary
 Outline for the Session

• Introduction
• History and Evolution of knowledge
• Pathogenesis – Concept of ―Onconeural‖ Antigen
• Definition – Terminology
• Criteria for Diagnosis
• Individual Syndromes
• Summary
 Background

• Heterogeneous group of disorders

– Associated with systemic cancers
– Mechanisms other than…
• Metastases
• Metabolic and nutritional deficits
• Infections
• Coagulopathy
• Side effects of treatment

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 DEFINITION

• ―All neurologic abnormalities not caused by the

cancer’s spread to the nervous system are
paraneoplastic‖
• Seminars Neurol 2004
• ―Remote effects of cancer on the nervous system‖
• NEJM 2004
• ―Distal, non metastatic menifestations of a tumor‖
• OTO 2005

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• Most symptomatic paraneoplastic syndromes
are rare, affecting perhaps 0.01 percent of
patients with cancer
• Rudnicki SA, Dalmau J. Paraneoplastic syndromes of
the spinal cord, nerve, and muscle. Muscle Nerve
2000;23:1800-18

• Exceptions…..

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• Lambert–Eaton myasthenic syndrome, which affects
about 3 percent of patients with small-cell lung cancer
• Sculier J-P, Feld R, Evans WK, et al. Neurologic disorders in
patients with small cell lung cancer. Cancer 1987;60:2275-83
• Myasthenia gravis, which affects about 15 percent of
patients with thymoma
• Levy Y, Afek A, Sherer Y, et al. Malignant thymoma associated
with autoimmune diseases: a retrospective study and review of the
literature. Semin Arthritis Rheum 1998;28:73-9.
• Demyelinating peripheral neuropathy, which affects
about 50 percent of patients with the rare osteosclerotic
form of plasmacytoma
• Latov N. Pathogenesis and therapy of neuropathies associated with
monoclonal gammopathies. Ann Neurol 1995;37:Suppl 1:S32-S42

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PARANEOPLASTIC SYNDROMES

• Neurologic symptoms of paraneoplastic

syndromes usually precede the identification
of the cancer
– Antoine JC, Cinotti L, Tilikete C, et al.
[18F]fluorodeoxyglucose positron emission tomography in the
diagnosis of cancer in patients with paraneoplastic neurological
syndrome and anti-Hu antibodies. Ann Neurol 2000;48:105-8

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PARANEOPLASTIC SYNDROMES

• Usually when the paraneoplastic-related cancer

is identified, it is small, nonmetastatic, and
indolently growing
– Graus F, Dalmou J, Reñé R, et al. Anti- Hu antibodies in
patients with small-cell lung cancer: association with complete
response to therapy and improved survival. J Clin Oncol
1997;15:2866-72

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PARANEOPLASTIC SYNDROMES

• Paraneoplastic syndromes are generally, but

not always, irreversible

• Neurologic disability caused by paraneoplastic

syndromes is often profound in the absence of
any other cancer symptoms
– Graus F, Keime-Guibert F, Reñe R, et al. Anti-Hu-associated
paraneoplastic encephalomyelitis: analysis of 200 patients.
Brain 2001;124:1138-48

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 Paraneoplastic Syndromes May
Affect Any Portion of the Nervous
System
• Cerebral cortex
• Brainstem
• Spinal cord
• Peripheral nerves
• Neuromuscular junction
• Muscle

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 Background

• Occur in < 1% of pts with systemic cancer

• Heralds diagnosis of cancer in up to 60%
• Highly specific antineuronal antibodies
• Most common (presence overlaps)
– Paraneoplastic cerebellar degeneration (PCD)
– Paraneoplastic encephalomyelitis /
sensory neuronopathy (PEM/PSN)
– Paraneoplastic opsoclonus myoclonus (POM)
– Lambert-Eaton myasthenic syndrome (LEMS)
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 Diagnosis

• Paraneoplastic syndromes occur in patients:

– not known to have cancer (most common)
– with active cancer
– in remission after treatment
• exclude other cancer-associated process

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 Diagnosis with Known Cancer

• Search for metastases

– MRI of involved site
– CSF cytology
• Search for nonmetastatic disorders
– Vascular, infectious, metabolic disorders,
chemotherapy, radiation therapy
• Serum/CSF for autoantibodies

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 Diagnosis without Known Cancer

• Exclude other causes of nervous system dysfunction

• Search for Cancer
– CXR, pelvic examination,
– mammograms, examine lymph nodes, serum cancer
markers (CEA)
– CSF for cells, IgG, OCB, cytology examination
– Serum/CSF for autoantibodies
– If CSF or autoantibodies positive then follow and search
again

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 Outline for the Session

• Introduction
• History and Evolution of knowledge
• Pathogenesis – Concept of ―Onconeural‖ Antigen
• Definition – Terminology
• Criteria for Diagnosis
• Individual Syndromes
• Summary
• The concept of immune surveillance of cancer was first
formally put forward by Thomas and Burnet in the mid-
1950s
– Burnet, F. M. Cancer: a biological approach. Brit. Med. J. 1, 841-847 (1957).
• they proposed that immune mechanisms could act as a
natural defence against tumour cells
– Thomas, L. Cellular and humoral aspects of the hypersensitivity states.
in Discussion to P. B. Medawar's paper. (ed. Lawrence, H. S.) 529-534
(Harper, New York, 1959).

• link between the neurological degeneration and cancer in

PND is an immunological one
– Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer
immunoediting: from immunosurveillance to tumor escape. Nature
Immunol. 3, 991-998 (2002)

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• Symptoms usually develop rapidly in days or a
few weeks and then stabilize, leaving the patient
severely disabled.
• Exceptions do occur, and some patients develop
insidious forms of PND that can be misdiagnosed
as chronic degenerative disorders
– Graus F, Bonaventura I, Uchuya M, et al. Indolent anti-Hu-
associated paraneoplastic sensory neuropathy. Neurology
1994;44:2258-2261
– Bataller L, Graus F, Saiz A, Vilchez JJ. Clinical outcome in adult
onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain
2001;124:437-443

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• Spontaneous neurological improvement,
although reported in some syndromes, is rare
and should lead to the consideration of a
nonparaneoplastic etiology.
– Voltz, R. D., Posner, J. B., Dalmau, J. & Graus, F.
Paraneoplastic encephalomyelitis: an update of the effects of
the anti-Hu immune response on the nervous system and
tumour. J. Neurol. Neurosurg. Psychiatr. 63, 133-136 (1997)

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 Immune Mediated ANTIGEN !!!!!

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 Outline for the Session

• Introduction
• History and Evolution of knowledge
• Pathogenesis – Concept of ―Onconeural‖ Antigen
• Definition – Terminology
• Criteria for Diagnosis
• Individual Syndromes
• Summary
 Pathogenesis

• Onconeuronal Immunity
• ―Tumor expression of proteins that normally
are restricted to the nervous system triggers an
immune response against the tumor that also
affects the nervous system‖
• Only a small amount of tumor may trigger
response

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 Pathogenesis continued

• Tests for antibodies against the cancer-

expressed neuronal proteins
• Some disorders caused by antibodies
– Myasthenia gravis
– LEMS
• Other disorders most likely caused by B
and T cell mechanisms of neuronal injury

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• Darnell, R. B. & Posner, J. B. Observing the
invisible: successful tumor immunity in humans. Nat
Immunol. 4, 201 (2003).
• Darnell, R. B. & Posner, J. B. Paraneoplastic
syndromes of the nervous system. N. Engl. J.
Med. 349, 1543-1554 (2003)

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 Discovery of MHC

Role of MHC as APC…

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 Target Cell - DC

The Problem, However…

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 Are PNS only based on Humoral
Immunity ?

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 Outline for the Session

• Introduction
• History and Evolution of knowledge
• Pathogenesis – Concept of ―Onconeural‖ Antigen
• Definition – Terminology
• Criteria for Diagnosis
• Individual Syndromes
• Summary
 “Classic Paraneoplastic
Syndromes”

• A group of disorders, when present, strongly

suggests an underlying cancer
– Lambert-Eaton myasthenic syndrome (LEMS)
– Opsoclonus/myoclonus found in children
– Subacute cerebellar degeneration
– Encephalomyelitis
– Subacute motor neuronopathy
– Sensory neuronopathy

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 “Non-classic” Paraneoplastic
Syndromes

• Second group of clinical syndromes

―sometimes‖ associated with cancer
• More often appearing in the absence of a
neoplasm
– Polymyositis
– Amyotrophic lateral sclerosis
– Sensorimotor polyneuropathy
• Extensive search for a neoplasm is
generally unwarranted

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 Outline for the Session

• Introduction
• History and Evolution of knowledge
• Pathogenesis – Concept of ―Onconeural‖ Antigen
• Definition – Terminology
• Criteria for Diagnosis
• Individual Syndromes
• Summary
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 Outline for the Session

• Introduction
• History and Evolution of knowledge
• Pathogenesis – Concept of ―Onconeural‖ Antigen
• Definition – Terminology
• Criteria for Diagnosis
• Individual Syndromes
• Summary
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 Some generalizations …

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 Frequency of Paraneoplastic
Syndromes

• ―Clinically significant paraneoplastic syndromes

probably occur in fewer than 0.1% of patients with
cancer‖
– Robert B. Darnell, M.D., Ph.D., and Jerome B. Posner, M.D, N Engl J
Med 2003;349:1543-54.

• If a patient without a known cancer presents with one

of the ―classic‖ paraneoplastic syndromes the
likelihood he/she has cancer is considerable
– i.e., LEMS 60% paraneoplastic
– Subacute cerebellar degeneration 50%
– Robert B. Darnell, M.D., Ph.D., and Jerome B. Posner, M.D, N Engl J
Med 2003;349:1543-54.
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 Diagnosis

• Suggestive clinical features:

– Acute or Subacute onset, may progress over
commonly days, sometimes weeks to months
– Severe neurologic disability
– One portion of nervous system more than
widespread involvement
– Some syndromes present stereotypically

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 Diagnosis
Autoantibodies
• Presence of autoantibodies:
– helps to confirm the clinical diagnosis
– focus the search for an underlying malignancy
– Anti-Hu, Anti-Yo, Anti-Ri, Anti-Tr, Anti-CV2, etc.

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 Treatment

• Unrewarding in general
• Most patient left with severe neurologic disability
• Immunosuppression ineffective in most, except
LEMS and MG

• Exceptions …
• LEMS, MG, Neuropathy with Myeloma
• Adult OMS – may respond

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 “Classic Paraneoplastic
Syndromes”
Specific Syndromes
• Paraneoplastic cerebellar degeneration
• Most common
• Best characterized
• Rare disorder
– 780 cases report by 2005
• A group of related disorders that differ in clinical
features, prognosis, and types of malignancies
– Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic
cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody
positive patients. Neurology 2002; 42:1931-7

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 Paraneoplastic Cerebellar
Degeneration

• Disorders can be separated by characteristic

antibodies to particular tumor-associated
antibodies
• PCD can be associated with any cancer, but
most common:
– lung cancer (small-cell)
– ovarian
– uterine
– lymphomas

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 Paraneoplastic Cerebellar
Degeneration
• Neurologic symptoms prompt patient to see
doctor before cancer is symptomatic
• Cancer is usually found months to 2-4 years
after onset of neurologic symptoms
• Sometimes only at autopsy

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 Paraneoplastic Cerebellar
Degeneration

• Clinical features:
– slight incoordination in walking
– rapidly evolving over weeks to months
with progressive gait ataxia
– incoordination in arms, legs and trunk
– dysarthria
– nystagmus with oscillopsia

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 Paraneoplastic Cerebellar
Degeneration

• Within a few months it reaches its peak

and then stabilizes
– most cannot walk without support
– cannot sit unsupported
– handwriting is impossible
– eating independently difficult
– speech very difficult to understand
– oscillopsia may prevent reading
– diplopia & vertigo

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 Paraneoplastic Cerebellar
Degeneration

• Neurologic signs always bilateral, usually symmetric

• Deficits frequently limited to cerebellar dysfunction
• Other neurologic deficits (mild)
– sensorineural hearing loss
– dysphagia
– hyperreflexia
– extrapyramidal signs
– peripheral neuropathy
– dementia

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 Paraneoplastic Cerebellar
Degeneration
• Laboratory evaluation
– diffuse cerebellar atrophy
months to years after onset on
head imaging
– CSF (early)
• increased lymphocytes
• slightly elevated protein and
IgG concentrations
• Pleocytosis resolves with time

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 Paraneoplastic Cerebellar
Degeneration

• Autoantibodies in serum
and CSF
– found in a subset of patients
• number is unknown
– react with Purkinje cells of
cerebellum & tumor
– well characterized
• anti-Yo, anti-Hu, anti-Ri,
anti-Tr, anti-CV2, anti-Ma
proteins,

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 Paraneoplastic Cerebellar
Degeneration

• Autoantibodies in serum and

CSF/cancer
– anti-Yo ovary, breast
– anti-Hu SCLC
– anti-Ri Breast, SCLC,
– anti-Tr Hodgkin’s lymphoma
– anti-CV2 SCLC
– anti-Ma proteins Testicular

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 Paraneoplastic Cerebellar
Degeneration

• Pathology
– CNS may be normal at autopsy
– usually the cerebellum is atrophic with
abnormally widened sulci and small gyri
– microscopic
• extensive/complete loss of Purkinje cells of the
cerebellar cortex
– pathologic changes sometimes involving other
parts of nervous system

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 Paraneoplastic Cerebellar
Degeneration
• Diagnosis
– recognize characteristic clinical syndrome
– exclude other causes of late-onset cerebellopathy
• Leptomeningeal metastasis
• infections
• toxicity of chemotherapies
• viral brainstem encephalitis
• demyelinating disease
• Creutzfeld-Jakob disease
• infarction, hypothyroidism
• alcoholic and hereditary cerebellar degenerations

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 Paraneoplastic Cerebellar
Degeneration
• Once the disease peaks it doesn’t usually
change
• Treatment or cure of underlying cancer usually
doesn’t help
• Immune suppression (steroids) or
plasmapheresis is not effective
• ? clonazepam for ataxia

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 More “Classic” Syndromes
Sensory Neuronopathy (SN)
• <20% paraneoplastic
• Also occurs in patients with autoimmune disorders,
Sjogren’s syndrome
• 2/3 of paraneoplastic SN have small-cell lung cancer
• Neurologic syndrome usually precedes diagnosis of
cancer
• dysesthetic pain and numbness of face, trunk, extremities
• severe sensory ataxia
• all sensory modalities affected, loss of DTRs
• motor nerve action potentials are normal

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 Subacute Motor Neuronopathy
(Spinal Muscular Atrophy, ALS like diseases)

• Rare complication of Hodgkin’s and other lymphomas

• <3% of cases are paraneoplastic
• Subacute, progressive, painless, patchy lower motor neuron
weakness
• Affects legs more than arms
• Profound weakness
• Degeneration of neurons in the anterior horns of the spinal cord

• Sometimes can have associated UMN signs

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 Encephalomyelitis

• Cancer patients with clinical signs of damage to

more than one area of the nervous system
• Limbic encephalitis
• rare complication of small-cell lung cancer
• personality/mood changes develop over days or weeks
• severe impairment of recent memory
• sometimes with agitation, confusion, hallucinations, &
seizures
• brain MRI: normal or signal changes in the medial temporal
lobe(s)

• may improve with treatment of underlying tumor

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 Opsoclonus/Myoclonus Found in
Children

• Opsoclonus
– involuntary, arrhythmic, multidirectional, high-
amplitude conjugate saccades
– associated with myoclonus
– may have cerebellar signs
• 50% of children harbor a neuroblastoma
• Neurologic signs precede discovery of tumor in
50%
• Anti-Ri antibody associated with opsoclonus

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 POM

• In adults, most commonly associated with…

– Small cell lung cancer
– Breast cancer
• Develops prior to diagnosis of cancer
• Manifestations
– Rapidly progressive cerebellar ataxia
– Opsoclonus
– Myoclonus
• Treatment of cancer > immunosuppressive tx
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 Photoreceptor Degeneration

• Cancer-associated retinopathy (CAR)

• Rare syndrome
• Small-cell lung cancer, melanoma, gynecologic
tumors
• Episodic visual obscurations, night blindness,
light-induced glare, photosensitivity, impaired
color vision progressing to painless vision loss
• Typically precedes diagnosis of cancer
• ? prednisone

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 Lambert-Eaton Myasthenic
Syndrome (LEMS)

• Presynaptic disorder of neuromuscular

transmission
• Proximal weakness, areflexia or hyporeflexia,
autonomic dysfunction
• 45% to 60% associated with SCLC, reported
also with renal cell carcinoma, lymphoma and
breast
• Syndrome precedes tumor diagnosis by several
months to years

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 Lambert-Eaton Myasthenic
Syndrome (LEMS)

• Onset with proximal lower extremity weakness

• Later proximal upper extremity weakness
• Respiratory and craniobulbar involvement uncommon
• Autonomic dysfunction prominent
– dry mouth, dry eyes, impotence, orthostatic hypotension,
hyperhidrosis
• Facilitation with sustained contraction
• >100% CMAP increase with repetitive stimulation

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 Lambert-Eaton Myasthenic
Syndrome (LEMS)

• >92% with antibodies against P/Q-type voltage-gated

calcium channels (presynaptic)
• Impaired influx of calcium into nerve terminal with
reduced neuromuscular junction transmission
• A LEMS diagnosis warrants a thorough investigation
for underlying carcinoma, SCLC
• Careful observation and serial evaluations until tumor
found

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 Lambert-Eaton Myasthenic
Syndrome (LEMS)

• Unlike most paraneoplastic

syndromes LEMS usually
responds to:
– plasmapheresis
– corticosteroids
– azathioprine
– intravenous immunoglobin
• Long-term treatment often needed

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 Are PNS’s because of abberencies
within the immune system ??

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• “Specifically, an immune response to neuronal
proteins that are expressed by the tumour cells
(termed onconeural antigens) recognize and
suppress the growth of the malignancy”
» Darnell, R. B. & Posner, J. B. Observing the invisible:
successful tumor immunity in humans. Nat Immunol. 4,
201 (2003).
» Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes of
the nervous system. N. Engl. J. Med. 349, 1543-1554
(2003)

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• The tumor is often occult, and the neurologic disorder
typically precedes the diagnosis of the tumor.8,22
• patients with the Hu paraneoplastic syndrome typically
harbor small-cell lung cancers that are limited to single
nodules (53 of 55 patients in one study)
– Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu–associated
paraneoplastic encephalomyelitis/sensory neuropathy: a clinical study of
71 patients. Medicine (Baltimore) 1992;71:59-72.
• This was despite the fact that most small-cell lung
cancers (over 60 percent) are widely metastatic at
diagnosis.

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• The histologic features of tumors in
paraneoplastic neurologic disorders do not differ
from those of other tumors, except that the tumors
may be heavily infiltrated with inflammatory
cells.
» Cooper R, Khakoo Y, Matthay KK, et al. Opsoclonus-
myoclonus-ataxia syndrome in neuroblastoma:
histopathologic features — a report from the Children’s
Cancer Group. Med Pediatr Oncol 2001;36:623-9.
» Rosenblum MK. Paraneoplasia and autoimmunologic
» injury of the nervous system: the anti-Hu syndrome. Brain
Pathol 1993;3:199-212.

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• Many reports suggest that patients with
paraneoplastic neurologic disorders have a better
prognosis than patients with histologically
identical tumors that are not associated with
paraneoplastic neurologic disorders.
» Altman AJ, Baehner RL. Favorable prognosis for survival in
children with coincident opso-myoclonus and neuroblastoma.
Cancer 1976;37:846-52.
» Maddison P, Newsom-Davis J, Mills KR, Souhami RL.
Favourable prognosis in Lambert- Eaton myasthenic
syndrome and smallcell lung carcinoma. Lancet
1999;353:117- 8.

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 Treatment

• two treatment approaches

• removal of the source of the antigen by treatment of the
underlying tumor, and,
• suppression of the immune response

• Overall results disappointing in majority.

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 Immunotherapy

• Predominantly Ab mediated – Plasma

exchange, IvIg, Corticosteroids
• Example – MG, LEMS

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 Immunotherapy

• Predominantly T cell mediated

• drugs such as tacrolimus or mycophenolate Mofetil
» Albert ML, Austin LM, Darnell RB. Detection and treatment of
activated T cells in the cerebrospinal fluid of patients with
paraneoplastic cerebellar degeneration. Ann Neurol 2000;47:9-17
» Schneider C, Gold R, Reiners K, Toyka KV. Mycophenolate mofetil
in the therapy of severe myasthenia gravis. Eur Neurol 2001; 46:79-
82.

• Examples - paraneoplastic cerebellar degeneration with

anti-Yo antibodies or encephalomyelitis with anti-Hu
antibodies

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 Recommended Regime

• IVIG @ 0.5 gm/kg/day x 5 days

• IV methylprednisolone @ 1 gm/day x 3days,
• IV cyclophosphamide @ 600 mg/m-2 BSA X 1 day
• Keime-Guibert F, Graus F, Fleury A, et al. Treatment of
paraneoplastic neurological syndromes with antineuronal
antibodies (Anti-Hu, Anti-Yo) with a combination of
immunoglobulins, cyclophosphamide, and
methylprednisolone. J Neurol Neurosurg Psychiatry
2000;68:479-82.

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• If there is evidence of improvement or stability, the
treatment can be repeated three times at three-week
intervals.
• If the patient improves after the third treatment,
maintenance treatment with
– IVIG @ 0.5 gm/kg/day x 5 days
– IV methylprednisolone @ 1 gm/day x 3days,
– IV cyclophosphamide @ 600 mg/m-2 BSA X 1 day
• Keime-Guibert F, Graus F, Fleury A, et al. Treatment of
paraneoplastic neurological syndromes with antineuronal
antibodies (Anti-Hu, Anti-Yo) with a combination of
immunoglobulins, cyclophosphamide, and methylprednisolone.
J Neurol Neurosurg Psychiatry 2000;68:479-82.

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• Tacrolimus @ 0.15 mg/kg/per day for 14 days,
followed by 0.3 mg/kg/day for 7 days.
• This regimen decreased the number of
activated T cells in the spinal fluid but had no
substantial effect on the clinical course.
» Albert ML, Austin LM, Darnell RB. Detection and
treatment of activated T cells in the cerebrospinal fluid of
patients with paraneoplastic cerebellar degeneration. Ann
Neurol 2000;47:9-17.

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• Most of the syndromes may have both arms,
therefore preferable to block both.

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 Outline for the Session

• Introduction
• History and Evolution of knowledge
• Pathogenesis – Concept of ―Onconeural‖ Antigen
• Definition – Terminology
• Criteria for Diagnosis
• Individual Syndromes
• Summary
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 Summary, take home points

• Paraneoplastic syndromes are rare

• Often precede the diagnosis of cancer
• Thought to result from cross-reactivity of
antibodies to a common antigen within tumor
and nervous tumor
• Disability persists despite treatment of
underlying tumor

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