PARANEOPLASTIC

NEUROLOGICAL SYNDROMES
Professor Dr.B.P.Shelley
MMBS,MD,DM,FRCP Edin

AIM .
Introduction
Pathophysiology
General Diagnostic Approach
Classification of Paraneoplastic Neurological Syndromes
Specific Paraneoplastic Neurological Syndromes

Paraneoplastic syndromes
Paraneoplastic Neurological syndromes (<0.1% of patients
with cancer)
Paraneoplastic Endocrine-Metabolic syndromesNeuroendocrine tumours- Na, K, Ca (SIADH; Cushings)
Paraneoplastic Rheumatological syndromes-Hypertrophic
osteoarthropathy; Carcinomatous polyarthritis; Amyloid
arthritis, Secondary gout

Paraneoplastic Vascular Syndromes-vasculitis ,vasculopathy

(migratory thrombophlebitis, leukocytoclastic vasculitis,
paraneoplastic ANCA-associated vasculitis, erythromelalgia )
Paraneoplastic Dermatological/Cutaneous syndromesDermatomyositis
Paraneoplastic Hematological syndromes- RBC aplasia,
anemia, leukocytosis (leukemoid reaction),erythrocytosis,
thrombocytosis, eosinophilia, basophilia, DIC,
thrombocytopenic purpura, Coombs'-positive hemolytic
anemia

Paraneoplastic Neurological
Syndromes
Heterogenous group of disorders caused by cancers not located
in the nervous system.
May affect any part of nervous system
Difficult to diagnose & treat
May occur before the presence of systemic cancer is known,
making the diagnosis more difficult
Onset : usually acute / subacute
followed by stabilization within a few weeks

Limitations-Paraneoplastic Ab
Heterogeneity: A given clinical syndrome may be associated with
several antibodies.
A given antibody may be associated with several syndromes.
Antibodies may be present without neurologic manifestations.
Some patients with antibodies may not develop a tumor.
Negative antibody assay does not rule out PND.

Pathophysiology
Different from that of metastases or that of other complications
of cancer ( metabolic / nutritional deficits / infections /
coagulopathy / side effects of cancer chemotherapy )
Incompletely understood
Increasing evidence to say it is IMMUNE MEDIATED
Current concept
Expression of neuronal proteins by a tumor provokes immune
response against both the tumor & nervous system

Immune mediated Hypothesis

Supported by frequent detection of antibodies in serum & csf
reacting with antigens expressed by tumor & nervous system
( onconeuronal antigens )

Most antibodies associated PNSs affecting CNS are highly

specific for presence of cancer

WELL CHARACTERIZED PARANEOPLASTIC

ANTIBODIES
ANTIBODY

SYNDROME

ASSOCIATED CANCER

Anti Hu

Focal Encephalitis , PEM, PCD,

PSN, Autonomic dysfunction

Small Cell Lung Cancer

(SCLC)

Anti Yo

PCD

Gynecological , Breast

Anti Ri

PCD,
Opsoclonus Myoclonus

Breast, Gynecological , SCLC

Anti Tr

PCD

Hodgkins Lymphoma

Anti
CV2/CRMP5

PEM, PCD, Chorea, Uveitis,

Peripheral Neuropathy

SCLC, Others

Anti Ma proteins

Limbic, Diencephalic, Brainstem Germ cell Tumors of Testes,

Encephalitis, PCD
Other solid tumors

Anti NMDAR

Limbic Encephalitis, Seizures,

Psychiatric symptoms

Teratoma

Anti amphiphysin

Stiff person syndrome,

encephalomyelitis

SCLC

Anti Recoverin

Cancer associated retinopathy

SCLC

PARTIALLY CHARACTERIZED PARANEOPLASTIC

ANTIBODIES

ANTIBODY

SYNDROME

ASSOCIATED CANCER

Anti - Zic 4

Cerebellar Degeneration

SCLC

mGluR1

Cerebellar Degeneration

Hodgkins Lymphoma

ANNA-3

Sensory Neuronopathy,
Encephalomyelitis

SCLC

PCA -2

Encephalomyelitis,
Cerebellar Degeneration

SCLC

Anti-bipolar cells
of retina

Melanoma associated
retinopathy

Melanoma

ANTIBODIES WITH / WITHOUT CANCER

ASSOCIATION

ANTIBODY

SYNDROME

ASSOCIATED CANCER

Anti VGCC

LEMS, Cerebellar Degeneration

SCLC

Anti AChR

Myasthenia Gravis

Thymoma

Anti-VGKC

Neuromyotonia,
Limbic Encephalitis,
Cerebellar Dysfunction

Thymoma
Others

nAChR

Subacute Pandysautonomia

SCLC

In Contrast.
Antibodies associated with some PNSs are not cancer specific .
They occur in nonparaneoplastic settings
They might have direct pathogenic effect
Eg : LEMS Antibodies to P/Q VGCC
MG Antibodies to AchR
Neuromytonia Antibodies to VGKC

Cell mediated Immunity Hypothesis

Cytotoxic T-cell responses important in pathogenesis of PNS
Presence of prominent infiltrates of CD8+ & CD4+T cells in
nervous tissues
Invitro studies have shown cytotoxic effect of lymphocytes on
cells expressing onconeuronal antigens
Albert et al 1998

Pathogenic effect of antibodies invitro ( anti Hu, amphiphysin )

has been shown in some PNSs.
De Giorgio et al 2003

Nonimmunological
Mechanisms
Metabolic abnormalities due to tumoral secretion of hormones
and cytokines
Hyponatremia due to SIADH
Hypercalcemia due to PTHrP

Competition between the tumor and nervous system for the

substance
Carcinoid tumor and Tryptophan

Synthesis by tumor of Immunoglobulins that react with

peripheral nervous system and antibodies against
myelin associated glycoprotein (MAG)
Distal, symmetric & slowly progressive sensorimotor p.neuropathy
in Waldenstroms macroglobulinemia

Incidence
Varies with the neurological syndrome and type of tumor
Common syndromes : LEMS, Myasthenia gravis
LEMS 3% pts with Small cell lung cancer
Myasthenia gravis 15% pts with Thymoma
Paraneoplastic peripheral neuropathies affect 5 15% of
patients with plasma cell dyscrasias
More than 50 % pts with Osteosclerotic myeloma develop a
predominantly motor paraneoplastic peripheral neuropathy

General Diagnostic
Approach

Specificity of paraneoplastic antineuronal antibodies for PNSs

make them useful diagnostic tools
In 60 % of patients with PNS, the neurological symptoms
preceed the tumor diagnosis
Most of paraneoplastic antineuronal antibodies are detectable
in low titers, in sera of variable proportion of pts with cancer
but without PNS.
Consider testing for paraneoplastic antineuronal antibodies
only when the patient is suspected to have a PNS

Consider other causes for neurological dysfunction if the

isolated antibody is usually not associated with the syndrome
If the detected cancer is not the histological type typically
found in association with antibody , a second neoplasm should
be suspected
Clinical experience so far suggests that finding high titers of
paraneoplastic antibodies in CSF is confirmatory evidence of a
PNS of CNS
Diagnostic Criteria : Definite & Possible Categories

Definite Syndrome
A Classical syndrome and cancer that develops within 5 yrs of
diagnosis of neurological disorder
Non classical syndrome with paraneoplastic antibodies and cancer
that develops within 5 yrs of diagnosis of neurological disorder
A Non classical syndrome that resolves or significantly improves
after cancer treatment without concominant immunotherapy,
provided that syndrome is not suseptible to spontaneous remission
A Neurological syndrome ( classical or not ) with well characterized
paraneoplastic antibodies and no cancer
Eg : anti Hu, CV2, Ri, Ma2, Amphiphysin

Possible Syndrome
A Classical syndrome as defined above, no paraneoplastic
antibodies, no cancer but at high risk to have an underlying
tumor
A neurologic syndrome ( classic or not ) with partially
characterized paraneoplastic antibodies and no cancer
A Non classical syndrome, no paraneoplastic antibodies and
cancer present within 2 yrs of diagnosis.

Antibody Screening
To be done in patients when paraneoplastic neurological syndrome is
suspected
Rarely antibodies may be present in CSF and absent in Serum
Antibodies such as P/Q VGCC antibodies or AChR antibodies associate
with specific disorders, they do not differentiate b/w paraneoplastic and
non paraneoplastic cases
Different antibodies can be associated with same paraneoplastic syndrome
One antibody can be associated with several PNSs.
Several paraneoplastic antibodies can co-occur in same patient Eg: SCLC

Identify Coexisting PNSs-Dual

PNS
Testing for paraneoplastic antibodies can facilitate recognition
of simultaneous occurrence of 2/more PNSs in one patient.
In Small Cell Lung Cancer patient can have LEMS.
An association is development of LEMS in about 6% of
patients with anti Hu associated paraneoplastic
encephalomyelitis

Other Diagnostic Tests

Absence of paraneoplastic antibodies does not exclude a
paraneoplastic syndrome
In absence of characteristic antibodies in serum , specific
diagnostic tests need to be done to diagnose PNSs
CSF STUDY
MRI
PET
ELECTROPHYSIOLOGICAL STUDIES : NCV/ EMG / RNS

Classification

 SYNDROMES AFFECTING CNS

Cerebellar Degeneration
Paraneoplastic Limbic, Brainstem, Striatal
Encephalitis ; Paraneoplastic movement
disorders = cerebellar syndrome,
opsoclonus myoclonus, basal ganglia
disorders (chorea,parkinsonism,
dystonia) ,stiff person syndrome, and
neuromyotonia
Encephalomyelitis
Opsoclonus Myoclonus
Stiff person syndrome
Necrotizing Myelopathy
Motor Neuron Disease

SYNDROMES AFFECTING

PNS

Sensory Neuronopathy
Vasculitis of Nerve & Muscle
Subacute / Chronic Sensorimotor
peripheral neuropathy
Sensorimotor neuropathies
associated with plasma cell
dyscrasia & B cell Lymphoma
Autonomic Neuropathy
Brachial Neuritis

ALS

Gullian Barre Syndrome

Subacute motor neuronopathy

Peripheral Nerve
Hyperexcitability

 SYNDROMES AFFECTING
NEUROMUSCULAR
JUNCTION & MUSCLE
Lambert Eaton Myasthenic
Syndrome
Myasthenia gravis
Neuromyotonia
Dermatomyositis
Acute necrotizing myopathy
Carcinoid myopathy
Cachectic myopathy

SYNDROMES AFFECTING
VISUAL SYSTEM
Retinopathy
Optic Neuritis
Uveitis ( in association with
encephalomyelitis )

Specific Paraneoplastic
Syndromes

Encephalomyelitis
Develop clinical features of dysfunction depending on involvement
of different levels of neuraxis
Limbic Encephalitis : confusion, depression, agitation, anxiety,
memory deficits, dementia, complex-partial seizures
Cerebellar Dysfunction : gait ataxia ( 15 % PEM pts )
Brainstem Encephalitis : oscillopsia, diplopia, dysarhria, dysphagia,
gaze abnormalities, subacute hearing loss, facial numbness
Myelitis : Sensory neuronopathy ( dorsal root ganglia involvement )
Autonomic Dysfunction : postural hypotension, gastroparesis,
intestinal dysmotility, impotence

Most patients have Anti-Hu antibodies ( ANNA-1) directed

against neuron specific RNA-binding nuclear proteins
Associated with
Encephalomyelitis
Paraneoplastic Sensory Neuronopathy

Limbic Encephalitis
Cancer Lung usually SCLC
Seminoma , Other testicular tumors
Thymoma
Breast Carcinoma
Hodgkins Lymphoma
2/3rd pts with LE develop multifocal involvement of NS
( encephalomyelitis )
Neurological symptoms preceed discovery of tumor by weeks
or months

Limbic Encephalitis
MRI areas of hyperintensity and / or contrast enhancement in
medial temporal lobes
PET hypermetabolism in medial temporal lobes
Autoantibody varies with type of tumor associated
SCLC : Anti-Hu or CV2/CRMP5 antibodies in serum / csf

PARANEOPLASTIC BRAINSTEM ENCEPHALITIS-ANTI Hu& ANTI-Ri

Ab POSITIVE
(A) Coronal T2 weighted image revealing an extensive, high signal
intensity lesion, diffusely infiltrating the brainstem and thalamus. (B)
Axial FLAIR images showing infiltration of the pons, the
mesencephalon, the hippocampus and the thalamus.

Limbic Encephalitis
Treatment
Syndrome usually improves with
Tumor treatment
Immunomodulation with Corticosteroids and IVIg

LIMBIC ENCEPHALITIS

Paraneoplastic Antigens
Intraneuronal antigens : Anti Hu ; Anti Ma2 ; Anti CRMP
5 (CV2) ; Anti amphiphysin
Cell membrane antigens : VGKC ; NMDA ; GABA B
receptor; AMPA receptor ; Anti VGCC ; Novel cell
membrane Ags

Ma2 associated Encephalitis

Clinical presentation differs from that of limbic
encephalopathy
Isolated or combined limbic, diencephalic, brain stem
encephalopathy
Excessive day time sleepiness
Eye movement abnormalites : Vertical gaze paresis
Total external ophthalmoplegia
Atypical parkinsonism

Ma2 associated Encephalitis

Associated with Testicular Germ cell tumors
Treatment : more responsive to oncogenic treatment
and immunological treatment

NMDA Receptor associated Limbic

Encephalitis
Clinical Presentation : Prodromal Headache, Fever and followed in
few days by multistage progression of symptoms
Prominent Psychiatric : anxiety, agitation, bizarre behaviour,
hallucinations, delusions, insomnia
Language dysfn : mutism , decreased word output, echolalia
Memory deficits
Seizures
Decreased level of consciousness, stupor with catatonia
Dyskinesias : orofacial, choreoathetoid movements, dystonia
Dysautonomia

NMDA Receptor associated Limbic

Encephalitis
Differential diagnosis : Viral encephalitis
Primary Psychiatric Disorders
Neuroleptic Malignant Syndrome
CSF : lymphocytic pleocytosis / oligoclonal bands
MRI : Often normal / transient FLAIR / Contrast enhancing
abnormalities in cortical and subcortical areas
Diagnosis is confirmed by detection of antibodies to NR1/NR2
heteromers of NMDAR in serum or csf

NMDA Receptor associated Limbic

Encephalitis
Associated with Teratoma
Also SCLC, Hodgkins Lymphoma, Neuroblastoma
Treatment : Resection of Tumor
Glucocorticoids
IVIg
Rituximab / Cyclophosphamide

Encephalitis & VGKC

antibodies
Clinical presentation : features of encephalitis and
accompanying dysautonomia , neuromyotonia, REM sleep abn
Possible in nonparaneoplastic conditions
Look for SCLC & Thymoma
MRI : signal abnormalities in mediotemporal lobes
CSF : VGKC antibodies
Treatment : Glucocorticoids/Plasmapheresis/IVIg
70 80 % pts respond

Brainstem Encephalitis
Clinical presentation : symptoms localized to pons and / or
medulla
Associted with
SCLC : Anti-Hu antibodies
Testicular Cancer : Anti Ma2 antibodies
Breast Carcinoma : Anti-Hu antibodies
Hypernephroma : Anti-Hu antibodies
Prostate Adenocarcinoma : Anti-Hu antibodies

Cerebellar Degeneration
Clinical features :
Rapid development of severe pancerebellar dysfunction
Dizziness, nausea & vomiting followed by a few days later
Truncal and Appendicular Ataxia
Dysarthria
Downbeat Nystagmus
Subacute onset of PCD differentiates it from chronic
degenerative diseases of cerebellum

Cerebellar Degeneration
Associated Tumor
SCLC
Breast Carcinoma
Ovarian Carcinoma
Hodgkins Lymphoma

For unclear reasons, cerebellum is a frequent target of paraneoplastic

autoimmunity
All paraneoplastic antibodies have been reported in association with
PCD

Autoantibodies
2 autoantibodies predominantly associated with cerebellar
dysfunction : Anti-Yo & Anti-Tr antibodies
Anti-Yo antibodies : Breast Cancer, Ovarian / Endometrial /
Fallopian Tube Cancers ; Men Adenocarcinoma
Anti-Tr antibodies : Hodgkins Lymphoma
Anti-Hu antibodies : SCLC
Anti CV2 antibodies : SCLC, Thymoma, Uterine Sarcoma
Anti-Zic4 antibodies : SCLC

Treatment
PCD associated with Anti-Hu & Anti-Yo antibodies usually do not improve with Immunosuppression &
Antitumor treatment
Combination of IVIg, Cyclophosphamide, Methylprednisolone
Rituximab : Anti-Yo antibody associated disease

Opsoclonus Myoclonus
Spontaneous, arrhythmic, large amplitude conjugate saccades occuring in
all directions of gaze that are associated with myoclonus of head, trunk,
limbs
In children, it has a subacute onset with staggering & falling leading to
misdiagnosis of acute cerebellitis
Initial symptoms are followed by body jerks, drooling, refusal to walk or
sit, opsoclonus, hypotonia, irritability & sleep disturbances
In adults, symptoms range from opsoclonus with mild truncal ataxia to a
more severe syndrome characterized by opsoclonus, myoclonus, ataxia,
encephalopathy stupor & death

Opsoclonus Myoclonus
In children Neuroblastoma
Neurological symptoms precede the tumor diagnosis in 50% of
patients
Neuroblastoma with Opsoclonus better prognosis
In adults Several underlying tumors are associated
most common : SCLC ; Breast Cancer

Opsoclonus - Myoclonus
Anti Ri antibodies : Breast & Gynecological Cancers

Anti-Hu antibodies : SCLC , 5 % children with Neuroblastoma

Many children & adults with Neuroblastoma do not have

paraneoplastic antibodies

Opsoclonus Myoclonus Treatment

Neuroblastoma induced OM : responds to
treatment of tumor ( chemotherapy ) + Prednisone + IVIg or
Rituximab
Sleep disturbances : Trazadone
Paraneoplastic OM in adults : respond partially to
Immunosuppression & IVIg
Patients with prompt tumor treatment have a better outcome
Adults : Depletion of serum IgG using Protein A columns,
Clonazepam, Piracetam, Valproic acid, Thiamine

Stiff Person Syndrome

Fluctuating rigidity of axial musculature with superimposed
spasms
Muscle stiffness primarily affects lower trunk & legs
Muscle stiffness can extend to arms, shoulders & neck
Precipitating factors of muscle spasms : Emotional upset
Auditory stimuli
Somesthetic stimuli
Rigidity disappears during sleep and after local / general
anesthesia

Stiff Person Syndrome

Associated with Breast Cancer
Lung Cancer
Hodgkins Lymphoma
Main autoantigen associated is AMPHIPHYSIN
Antibodies to amphiphysin may occur in pts with other paraneoplastic
syndromes such as Encephalitis
80% pts with stiff person syndrome develops as a non paraneoplastic
phenomenon in association with Diabetes Mellitus Type 1 &
Polyendocrinopathy
They often have anti GAD antibodies to Glutamic acid decarboxylase

Stiff Person Syndrome

Treatment
Corticosteroids may improve paraneoplastic stiff person
syndrome
IVIg is useful in Non paraneoplastic stiff person syndrome
GABA enhancing agents : Benzodiazepines
Gabapentin
Baclofen
for symptomatic relief

Paraneoplastic Sensory
Neuronopathy
Subacute onset
Progressive sensory loss that may involve limbs, trunk, face
Sensorineural hearing loss
Symmetric / Asymmetric reduction / loss of DTR
Painful dysesthesias
At onset, symptoms usually asymmetrical
(confused with radiculopathy or polyneuropathy)
All modalaties of sensation are eventually affected
With progression sensory deficits result in Ataxia, Gait difficulty,
Pseudoathetoid movements

Paraneoplastic Sensory
Neuronopathy
PSN may develop alone or more commonly in association with
PEM
Neurological dysfunction precedes cancer diagnosis in 2/3rd pts
NCV : reduced / absent sensory potentials with normal or
borderline motor nerve conduction velocities
CSF : increased protein level with pleocytosis
oligoclonal bands
intrathecal synthesis of IgG

Paraneoplastic Sensory
Neuronopathy
70% pts with PSN have SCLC
Breast, Prostate, Colon Cancers
Lymphoma
Uterine Sarcoma

Differential Diagnosis :
Toxic side effects of Chemotherapeutic drugs
Cisplatin, Paclitaxel, Docetaxel, Vinca Alkaloids

Paraneoplastic Sensory
Neuronopathy
Anti-Hu antibodies found in serum of pts with PSN and SCLC
Anti-Hu antibodies are rarely found in PSN associated with other
tumors
A few pts with PSN are positive for
antibodies against amphiphysin and CV2/CRMP5
Treatment :
Usually does not respond to treatment
IVIg, Cyclophosphamide, Rituximab : uncertain
Some improved when tumour completely responds to therapy

Myelitis
Occurs in association with involvement of other areas of
nervous system
Like Encephalitis / Sensory Neuronopathy / Chorea / Optic
Neuropathy
Antibodies : Anti-Hu, Anti-CRMP5/CV2, Anti amphiphysin
Usually associated Cancer : SCLC

Necrotizing Myelopathy
Associated with Several Carcinomas & Lymphoma
Usually involve Thoracic portion of spinal cord
Ascending Sensory Deficits
Sphincter Dysfunction
Flaccid / Spastic Paraplegia Tetraplegia
MRI Contrast Enhancement
Difficult to make an antemortem diagnosis

Motor Neuron Disease

Subacute Motor Neuronopathy :
Associated with Hodgkins & Non Hodgkins Lymphoma
Subacute, progressive, painless, asymmetric LMN weakness
Primary Lateral Sclerosis
Associated with Breast Cancer
Amyotrophic Lateral Sclerosis
Associated with Breast Cancer

Vasculitis Of Nerve & Muscle

Occur in Older men
Painful symmetrical / asymmetrical, subacute, sensorimotor
polyneuropathy
Mononeuritis multiplex
NCV : Axonal degeneration involving motor & sensory nerve
ESR : Elevated
CSF : protein concentration elevated
Diagnosis is confirmed by Biopsy

Vasculitis Of Nerve & Muscle

Associated Tumor : Small Cell Lung Cancer
Lymphoma
Cancer of Colon, Kidney, Bile duct, Stomach
Prostate Carcinoma
Serological markers of Paraneoplasia are not usually associated
with this vasculitis
ANCA identifiable in pts with Mononeuritis multiplex and HCC
and Carcinoma Colon

Vasculitis Of Nerve & Muscle

Treatment : Responds to Steroids, Cyclophosphamide or both
Treatment of tumor may also improve the neurological disorder

Chronic Sensorimotor
Neuropathy
Common in cancer patients
Cause : multifactorial
metabolic
nutritional deficiency
toxicity from chemotherapy
Paraneoplastic sensorimotor neuropathy may develop before or after
diagnosis of cancer
Onset is acute / subacute
Course is progressive

Chronic Sensorimotor
Neuropathy
Tumor associated are SCLC
Breast Cancer
Thymoma
Serum antineuronal antibodies are usually not present
Some pts with lung cancer and thymoma may harbour
Anti-CV2/CRMP5 antibodies
Treatment : Respond poorly to treatment
May respond to Steroids / IVIg

Peripheral Neuropathy associated with

Plasma cell dyscrasias & B cell
Lymphoma
10 % of pts with chronic sensorimotor neuropathy of unknown
origin have
MGUS
Primary Amyloidosis
Multiple Myeloma
Waldenstroms Macroglobulinemia
POEMS syndrome

Neuropathy also occurs in Osteosclerotic myeloma

B cell Lymphoma

Syndromes of plasma cell

dyscrasias
Osteolytic myeloma without amyloidosis
< 10 % pts
Plasma exchange has no consistent effect on neuropathy
Amyloid Neuropathy
autonomic dysfunction
lancinating and burning dysesthesias
treatment of underlying plasma cell dyscrasias produce little benefit
stem cell transplantation may be more beneficial

Syndromes of Plasma cell

Dyscrasias
Osteosclerotic myeloma / POEMS syndrome
distal symmetrical sensorimotor neuropathy with predominant motor
symptoms
neuropathy improves with irradiation of bone lesions or with
prednisone alone or in combination with melphalan
plasmapheresis / IVIg are rarely useful
Waldenstroms Macroglobulinemia
demyelinating sensorimotor neuropathy
IgM paraprotein has reactivity against MAG
plasma exchange, IVIg, treatment of primary disease , Rituximab

Acute Sensorimotor Neuropathy

(GBS)
Associated with Hodgkins Lymphoma
In some pts GBS may be the 1st manifestation of tumor recurrence
Treatment is same as for the non cancer related form of syndrome
Plasmapheresis / IVIg
Also seen in Non SCLC, CLL, Metastatic disease of unknown
primary, RCC, Esophageal Cancer, Vocal cord Cancer

Paraneoplastic Autonomic
Neuropathy
Frequently accompanies other paraneoplastic syndromes
Can occur singly
Hypothermia, Hypoventilation, Sleep apnea, Gastroparesis, Intestinal
pseudo obstruction, Cardiac arrhythmias
d/t true paraneoplastic phenomenon or local infiltration of
sympathetic nerves by tumor
Tumor associated : SCLC Anti Hu antibodies
Ca Pancreas, Thyroid, Rectum, Hodgkins Lymphoma
Treatment : Antitumor treatment , Immune therapy ( Prednisone /
Mycophenolate mofetil )

Peripheral Nerve
Hyperexcitability
Neuromyotonia / Undulating Myokymia / Issacs Syndrome
Symptoms : muscle twitches, cramps, weakness, increased
salivation, sweating, pseudomytotonia , dtr normal
Can occur without associated cancer
If paraneoplastic Thymoma, Lung cancer
Antibodies to VGKC
Thymoma / MG : anti AChR antibodies
Treatment : Plasma Exchange
Anti convulsant blocking Na+ channels

Lambert Eaton Myasthenic

Syndrome
Clinical Features :
Neurological symptoms develop before tumor diagnosis
Gradually progressive over weeks or month
Onset is acute
c/o fatigue, muscle weakness, myalgia, paraesthesias
Cholinergic dysautonomia : dry mouth, erectile dysfunction,
blurry vision
Transitory cranial nerve dysfunction : diplopia, ptosis, dysphagia

On examination
Proximal muscle weakness ( lower limbs > upper limbs )
Absent or depressed DTRs , which may potentiate after a brief
muscle contraction
Strength may improve after brief exercise but continued
exercise increases weakness
NCV : small amplitude compound muscle action potentials
At slow RNS ( 2 5 Hz ) : Decremental response > 10%
At fast RNS ( > 20 Hz ) : Incremental response of atleast 100%

LEMS can develop in association with PCD, PEM

Recurrence of LEMS after remission often heralds tumor
recurrence
60% of pts with LEMS have underlying neoplasm
Usually SCLC
Rarely Lymphoma
Nonparaneoplastic cases have slower course and are associated
with autoimmune disorders like THYROIDITIS & IDDM

Serum antibodies against P/Q type VGCC

Interfere with quantal release of ACh at presynaptic NMJ
These antibodies are seen in SCLC + PCD + LEMS
PEM + LEMS : Anti-Hu antibodies

Treament of LEMS
Most patients with cancer improve neurologically with combined
treatment of their cancer and therapy for LEMS
Medications to increase release of ACh and Immunomodulation
3,4 Diaminopyridine
Combination of Pyridostigmine & Guanidine
Plasmapheresis
IVIg
Immunosuppression : Prednisone & Azathioprine

Myasthenia Gravis
A post synaptic disorder of neuromuscular transmission
Clinical features :
Weakness and Fatiguability of skeletal muscles that improve
with rest and worsen with activity
Ptosis , Diplopia
DTRs, Sensation are Normal
Respiratory muscle weakness

Thymoma / Thymic hyperplasia : 10 % pts with MG

1/3rd of pts with Thymoma develop MG
Associated with
Thyroid Cancer
SCLC
Breast Cancer
Lymphoma

Antibodies to Ach R occur

80-90 % of pts with generalized MG
70% of pts with ocular MG
Thymoma related MG is invariably associated with
AChR antibodies but not MuSK antibodies

Treatment Of MG
First : Treat the underlying tumor : Thymectomy
Symptomatic Treatment
Anticholinesterase medications
Immunomodulation ( Plasmapheresis / IVIg )
Immunosuppression ( Corticosteroids, Azathioprine )

Dermatomyositis &
Polymyositis
Immune mediated Inflammatory diseases of muscle
Definite association with DM
Association with malignancy and PM is unclear
Symptoms of paraneoplastic and non paraneoplastic DM are same
Heliotrope rash with edema & erythematous lesions over knuckles
Necrotic skin ulcerations and pruritis : signifies underlying cancer

Subacute onset
Proximal muscle weakness
Weakness of neck flexors
Weakness of pharyngeal muscles
Weakness of respiratory muscles
DTRs and Sensation are Normal
S.CK : elevated ; may be normal

Diagnosis
EMG
Muscle Biopsy : Inflammatory infiltrates
Muscle necrosis
Perifasicular atrophy

Paraneoplastic Visual
Syndromes
Affects retina, uvea, optic nerves
Paraneoplastic retinopathy : photosensitivity
progressive loss of vision
loss of color perception
central or ring scotomas
night blindness
Fundus : May be normal
Non specific optic disc pallor
arteriolar narrowing

 Melanoma associated retinopathy :

Metastatic cutaneous lymphoma
Acute onset night blindness
Acute onset photopsia
Progress to complete visual loss
Paraneoplastic Optic Neuritis
Uncommon
Associated with PEM
Subacute onset painless loss of bilateral vision + /- papilledema

Associated with small cell lung cancer

Also melanoma
Serum antibodies against retinal proteins are detectable in some
pts
Cancer associated retinopathy : Antibodies to Recoverin
Antibodies identified against : tubby like protein 1
enolase
MAR : Antibodies against bipolar cells of retina
PEM + Uveitis : Anti CV2/CRMP 5

Treatment :
Rarely improve with treatment
May respond to steroids, plasma exchange, IVIg

TAKE HOME POINTS-PEARLS

Thank You