PARANEOPLASTIC

DISORDERS OF CENTRAL
NERVOUS SYSTEM
CHAIRPERSON: DR POONAM KHAMBRA
MODERATOR: DR GAURAV SINGHLA
PRESENTED BY: DR RITURAJ
 OVERVIEW
• Introduction
• Pathogenesis and antibodies
• Diagnosis of PNDs
• Individual disorders in brief
• The differential diagnosis of important disorders
• Treatment
 INTRODUCTION
• Paraneoplastic neurologic syndromes are a heterogeneous group
of neurologic disorders associated with systemic cancer and
caused by mechanisms other than metastases, metabolic and
nutritional deficits, infections, coagulopathy, or side effects of
cancer treatment.

• These syndromes may affect any part of the nervous system from
cerebral cortex to neuromuscular junction and muscle.
PATHOGENESIS
• Most PNDs are mediated by immune responses triggered by neuronal proteins

expressed by tumors (onconeural antigens).

• These are shared antigens that are ectopically expressed by the tumor, but otherwise

exclusively expressed by the nervous system. 

• Both humoral (antibodies) and cell mediated immunity (CD4 & CD8) may be activated.

• Subsequently microglial activation leads to gliosis and neuronal loss.

 Hu
Antibodies in (also
PNDsknown
have as
been
typedivided in two nuclear
1 antineuronal categories depending
antibody [ANNA- on
1]),of the antigen --
the location
Ri (also known as type 2 antineuronal nuclear antibody [ANNA-
• Antibodies against intracellular neuronal proteins, whose detection
2]),
almost 
always indicates
Yo (also known asthe presence
Purkinje of an underlying
cell cytoplasmic antibodytumor.
type 1
[PCA-1]),
amphiphysin, Ma2,
Tr (also known as delta/notch-like epidermal growth factor-
related receptor [DNER]),
Collapsin response-mediator protein-5 (CRMP-5), and Recoverin
• These antigens are not readily accessible by the antibodies, and hence

the antibodies are unlikely to be pathogenic.

• The antibodies are therefore considered epiphenomena, and a cytotoxic

T-cell mediated immune response against neurons is more likely.

• Response to immunotherapy is poor.

Antibodies directed against neuronal cell surface or synaptic proteins:
N-methyl-D-aspartate (NMDA) receptor,
Leucine ­rich glioma ­inactivated protein 1 (LGI1)
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptor,
Gamma-aminobutyric acid type A (GABA-A) and type B (GABA-B)
receptors, and
Contactin-associated protein-like 2 (Caspr2)
• They have direct pathogenic effects on the target antigens. (surface target
antigens are disrupted by the antibodies)

• This has been studied most extensively in anti-NMDAR encephalitis:

antibodies bind directly to the NMDAR and cause the receptor to move
away from the synapse and to get internalized, disrupting inhibitory
neurotransmission.

• These antibodies may occur with or without a tumor association.

• Immunotherapy is usually effective.

Recognition of the paraneoplastic antibodies
Cell Location Antibody Disorder Associated Tumour

Anti-Hu/ANNA-1 Sensory neuronopathy, SCLC

encephalomyelitis
Anti-Ri/ANNA-2 Opsoclonus/myoclonus Neuroblastoma,
Neuronal Breast, Gynecologic
Anti-CV2/CRMP- Sensory neuronopathy,
5? encephalomyelitis, limbic SCLC
encephalitis, cerebellar
degeneration,

Anti-Yo/PCA-1 Cerebellar degeneration Breast, Gynecologic

Cytoplasmic Amphiphysin Stiff-person syndrome,

encephalomyelitis, Breast, SCLC
opsoclonus-myoclonus

Plasma N- & P/Q-type LEMS SCLC

Membrane VGCC
Acetylcholine Myasthenia Gravis Thymoma
Receptor
 DIAGNOSIS

Complete panel of
Assays for autoantibodies may
laboratory studies of
CLINICA confirm the paraneoplastic
blood, urine, and L
FEATURE origin of a patient’s condition.
cerebrospinal fluid (CSF). S

DIAGNOSIS

IMAGING
ANTIBODY (CT/MRI
SCREENING AND FDG-
PET)
Example of a patient who presented with
paraneoplastic cerebellar degeneration
• Extensive investigations had failed to reveal
the site of a tumor.
• The scan reveals a single hot spot under the
left jaw which was biopsied and shown to
be Hodgkin’s disease.
Whole body FDG-PET scan in a 69 year old
man with cerebellar degeneration of unknown
cause.
 Recognition of the Neurological Syndrome
Area Involved Classical Syndromes Nonclassical Syndromes
Central nervous Encephalomyelitis Brain stem encephalitis
system Limbic encephalitis Stiff person syndrome
Cerebellar degeneration Necrotizing myelopathy
Opsoclonus-myoclonus Motor neuron disease
Dorsal root ganglia Subacute sensory neuronopathy Acute sensorimotor neuropathy
or peripheral nerves Gastrointestinal paresis or pseudo- (Guillain-Barre´ syndrome, plexitis)
obstruction Subacute and chronic
sensorimotor neuropathies
Neuropathy of plasma cell
dyscrasias and lymphoma
Classic PNDs is most likely associated with cancer. Vasculitis of the nerve and muscle
Acquired neuromyotonia
Non classical PNDs is not frequently occur with cancer. Pure autonomic neuropathy
NMJ Lambert-Eaton myasthenic syndrome Myasthenia gravis
Eye and retina Cancer-associated retinopathy Optic neuritis
Melanoma-associated retinopathy
 DIAGNOSTIC CRITERIA
Definite PND:

1. A classical syndrome and cancer that develops within five years of

the diagnosis of the neurological disorder.

2. A non-classical syndrome that resolves or significantly improves after

cancer treatment without concomitant immunotherapy, provided that the
syndrome is not susceptible to spontaneous remission.
3. A non-classical syndrome with onconeural antibodies (well
characterized or not) and cancer that develops within five years of the
diagnosis of the neurological disorder.

4. A neurological syndrome (classical or not) with well characterized

onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin),
and no cancer.
Possible PND

1. A classical syndrome, no onconeural antibodies, no cancer but at high

risk to have an underlying tumour.

2. A neurological syndrome (classical or not) with partially

characterized onconeural antibodies and no cancer.

3. A non-classical syndrome, no onconeural antibodies, and cancer

present within two years of diagnosis.
Diagnostic criteria for PND
Neurological syndrome

Classical Non-Classical

Tm +ve Tm -ve Tm +ve Tm -ve

±ve -ve +ve -ve

onconeural onconeural onconeural onconeural
Ab Ab Ab Ab
Improvement
after cancer
therapy or
High risk Well Partially +ve
cancer characterized characterized onconeural
Ab Ab Ab

Definite Possible Definite Possible Possible Definite

 PARANEOPLASTIC ENCEPHALOMYELITIS (PEM)

• Encephalomyelitis is an inflammatory process with multifocal involvement of

the nervous system.

PEM presents as involving :

• The limbic system (severe amnesia, confusion, seizures, personality changes)

• Brainstem/cerebellum (vertigo, ataxia, eye movement abnormalities, jaw

spasms)
• Spinal cord (myelopathy),

• Dorsal root ganglia (loss of joint position and vibration sense), and

• Autonomic system (orthostatic hypotension, gastric paresis and

intestinal pseudo obstruction)

In many patients, symptoms begin with, and may

remain restricted to, the dorsal root ganglia, causing a
subacute sensory neuronopathy. 
• Pathologic examination usually reveals perivascular and interstitial
inflammatory infiltrates of T lymphocytes, gliosis, neuronophagic
nodules and loss of neurons.

• B cells and plasma cell infiltrates may also be seen in perivascular

areas.

• The findings are typically more extensive than symptoms would

suggest.
• Virtually all cancer types have been associated with paraneoplastic
encephalomyelitis or its variants (limbic encephalitis, brainstem
encephalitis, myelitis).

• However, the underlying tumor is small cell lung carcinoma (SCLC) in

about 75 % of patients.

• The tumor is frequently undiagnosed when neurologic syndrome

develops and may be difficult to demonstrate because of its small size.
Three types on the basis of type of antibody
Anti Hu Anti Ma2 Anti CRMP5

These antibodies are directed Antigen produced by PMNA2 Antibodies against paired helical
against neuron-specific RNA- gene. Against nucleoli of neuron filaments in cytoplasm of
binding nuclear proteins. neurons

SCLC is found in most patients Testicular germ cell tumors are The most common associated
the most common associated cancers are SCLC and thymoma
neoplasms

Limbic involvement Brainstem and cerebellar Chorea and peripheral

involvement neuropathy
• Encephalitis associated with anti-NMDAR antibodies is one of the most
commonly identified autoimmune encephalitis and can occur as a
paraneoplastic disorder. 

• About 50% of them are young women (18-45 years) having ovarian
teratoma.

• In contrast, most children (<12 years) male or female, do not have a tumor.

• Removal of the tumor and/or immunotherapy result in improvement or full

neurological recovery.
• Evaluation of the cerebrospinal fluid
(CSF) often shows abnormalities such
as pleocytosis, increased protein
concentration, oligoclonal bands,
and elevated immunoglobulin G
(IgG) index, suggesting an
inflammatory process.
 PARANEOPLASTIC LIMBIC
ENCEPHALITIS
• PLE is an inflammatory process localized to structures of the
limbic system (eg, hippocampus, amygdala, hypothalamus,
cingulate gyrus, limbic cortex)
• It is characterized by acute or subacute mood and behavioral
changes, short-term memory problems, focal seizures with
impaired awareness (complex partial seizures), and cognitive
dysfunction 
• The pathologic, clinical, and radiologic findings are often not
confined to these areas.

• Symptoms identical to paraneoplastic limbic encephalitis may occur

without cancer as autoimmune limbic encephalitis

• These patients often have antibodies to LGI1.

MRI: sensitive
but not specific
for limbic
encephalitis.
• Electroencephalographic (EEG) : focal or generalized
slowing and/or epileptiform activity, which is maximal in the temporal
regions.

• Positron emission tomography (PET) intitially hypermetabolism in the

medial temporal lobes; later in the course of disease,
hypometabolism may be present.
 PARANEOPLASTIC BRAINSTEM
ENCEPHALITIS
• PBE often occurs during the course of other paraneoplastic syndromes,

such as limbic encephalitis, cerebellar degeneration, or

encephalomyelitis.

• In some patients, however, the neurologic symptoms and pathologic

findings (such as perivascular and interstitial inflammatory infiltrates,

gliosis, and loss of neurons) appear restricted to the brainstem.

• Clinically heterogeneous and characterized by a combination of cranial

nerve palsies, long tract signs, and cerebellar ataxia.

• Less common features include movement disorders, such as

parkinsonism, chorea, jaw opening dystonia, and myoclonus.

• Investigations are rarely helpful—high signal change may be seen

within the brainstem and basal ganglia and the CSF may be

inflammatory with oligoclonal bands.

• Anti-Hu antibodies are more often associated with lower brainstem

involvement

• Anti-Ma2 antibodies commonly associate with upper brainstem findings.

• Anti-Hu brainstem encephalitis has also been described in association with

breast cancer, renal cell carcinoma, prostate adenocarcinoma, and, rarely, in
patients who appear cancer free.

• These disorders are usually life threatening and rarely respond to treatment.
 SUBACUTE SENSORY NEURONOPATHY
• The sensory deficits typically begin with loss of vibratory sensation and
joint position sense followed by impairment in pain and temperature
sensation.

• By the time the patient is first examined, usually all sensory modalities
are involved

• Patients may complain of the sensation of "pins and needles" or "electric

shocks."
• The symptoms may initially affect one extremity but, in a few weeks or
months, usually progress to involve other extremities, the face, the
abdomen, or the trunk.

• Nerve conduction studies show low sensory nerve action potentials but
normal motor studies.

• The CSF is typically inflammatory, particularly if the neuronopathy is

associated with encephalomyelitis. 
HISTOLOGY
• Lymphocytes infiltrate dorsal root ganglia, surrounding individual ganglion
cells and sometimes appearing to invade their degenerating or necrotic
perikarya.

• They are replaced, in tombstone-like fashion, by nests of reactive

satellite cells known as nodules of Nageotte.

• The end-stage is a ‘burnt-out’ ganglion devoid of neuronal elements, but

deceptively free of inflammatory infiltrates.
The consequences of advanced
ganglion cell extinction may be
appreciable at autopsy as an
atrophy of the posterior spinal
roots and pallor of the dorsal
columns of the spinal cord
changes that reflect secondary
degeneration of peripherally and
centrally directed sensory axons.
 MYELITIS
• Paraneoplastic myelitis usually occurs in association with involvement of
other areas of the nervous system; examples include encephalitis, sensory
neuronopathy, chorea, and optic neuropathy.

• Associated antibodies most frequently detected are anti-Hu, anti-

CRMP5/CV2, and anti-amphiphysin antibodies.

• The usual culprit is small cell lung cancer (SCLC).

 A case series described 31 patients with an
isolated progressive paraneoplastic myelopathy
• The most common coexisting cancers were lung and breast

• kidney, thyroid, gynecologic cancers, and melanomas were also present in a few patients.

• Antibodies to amphiphysin and CRMP5 were the most commonly identified paraneoplastic

biomarker, respectively.

• MRI findings included signal abnormality that extended over more than three vertebral segments

and was often associated with contrast enhancement.

• Cerebrospinal fluid (CSF) analysis often showed elevated protein levels and/or pleocytosis.

• Most patients did not improve, even after oncologic and/or immunosuppressive therapy.

PARANEOPLASTIC AUTONOMIC
NEUROPATHY
• It frequently accompanies other paraneoplastic symptoms, including
encephalomyelitis and sensory neuronopathy.

• But it can be the only manifestation of an underlying malignancy.

• Autonomic dysfunction is associated with a variety of symptoms,

including: orthostatic hypotension, dry mouth, erectile dysfunction,
sphincter incontinence, gastroparesis, intestinal pseudo-obstruction,
and cardiac arrhythmias that can lead to sudden death.
• Signs of sympathetic hyperactivity (excessive spontaneous sweating),
may occur as a true paraneoplastic phenomenon or from local
infiltration of sympathetic nerves by the tumor.

• The tumor most frequently involved is SCLC

• These patients usually have anti-Hu antibodies and, less frequently,

anti-CRMP5 antibodies.
• Other tumors include: carcinoma of the pancreas, thyroid, and rectum; Hodgkin
lymphoma; and carcinoid tumors of the lung.

• Some of these patients have antibodies against ganglionic acetylcholine

receptors (AChR), which can also occur in patients without cancer.

• The treatment should focus on antitumor treatment

• Immune therapy is more effective in patients with ganglionic AChR antibodies

than in patients with classic paraneoplastic antibodies (anti-Hu) or no antibodies.
 PARANEOPLASTIC STIFF-PERSON
SYNDROME
• This disorder is characterized by antibodies to proteins involved in
function of inhibitory synapses like GABA and Glycine.

• Electrophysiological studies show continuous motor activity ,which

improve during sleep or general anesthesia.

• There is progressive muscle rigidity and painful spasms, which may lead
to limb deformities and fracture.

• Triggered by auditory, sensory and emotional stimuli

• 70% of SPS have non-paraneoplastic etiology

• They have glutamic acid decarboxylase (GAD) antibodies and

rarely have cancer

• Usually associated with type 1 DM.

• PSPS usually have anti amphiphysin antibodies.

• Malignancies associated with PSPS include breast and lung

cancer and Hodgkin lymphoma.
PARANEOPLASTIC CEREBELLAR
DEGENERATION
• PCD is characterized by sub-acutely progressing ataxia of both upper and lower limbs,
dysarthria, dysphagia, diplopia and nystagmus.

• Most patients are women with underlying adenocarcinomas of müllerian (usually

ovarian) or mammary origin.

• High serum and CSF titers of anti-Yo antibodies.

• Signs of cerebellar degeneration typically precede tumor detection and progress to

incapacitating disability despite treatment of the underlying neoplasm and
plasmapheresis.
• Anti-Yo antibodies
characteristically yield
bands of 34 and 62 k Da
on Western blotting
against purified Purkinje
cell proteins.
Immunohistochemical
preparations demonstrate
perikaryal distribution of the
protein in Purkinje cells
• The hallmark is Purkinje cell loss that occurs throughout the cerebellar cortex
• MRI reveals cerebellar
atrophy.

• The associated tumors are

SCLC (anti VGCC), Ca breast,
Ca ovary (anti Yo), Hodgkins
lymphoma (anti Tr ).
PARANEOPLASTIC
OPSOCLONUS/MYOCLONUS
• Opsoclonus, an eye movement disorder characterized by involuntary,
arrhythmic and multidirectional ocular saccades

• May occur as part of a PNS, although more commonly caused by viral

infection of the brain stem or toxic/metabolic and degenerative etiologies.

• Paraneoplastic opsoclonus is often accompanied by myoclonus and, in the

adult population, usually occurs with manifestations of encephalopathy,
cerebellar degeneration and bulbar dysfunction.
• The most frequently implicated neoplasm is SCLC, usually unassociated
with anti-Hu or other neuronal autoantibodies.

• A distinctive variant is encountered in post-menopausal women who

develop acute-onset opsoclonus (often associated with cerebellar ataxia
and rigidity) and exhibit high-titres of anti-Ri antibodies.
• Opsoclonus/myoclonus of childhood onset is caused by peripheral
neuroblastomas when paraneoplastic

• Neurological complaints often presaging tumor diagnosis.

• It is considered an autoimmune response to neural antigens, but a

specific marker antibody has not been demonstrated.
• Neuroblastomas associated with paraneoplastic phenomena are:
More likely discovered at early and curable stages of disease,
Rarely manifest N-myc amplification,
Show prognostically favourable histological features by International
Neuroblastoma Pathology Classification (Shimada) criteria
Regularly have diffuse and extensive lymphocytic infiltration with
germinal centre formation
 NECROTIZING MYELOPATHY
• A rare disorder that occurs in association with several carcinomas and
lymphomas.

• At presentation, symptoms usually involve the thoracic portion of the spinal

cord, including ascending sensory deficits, sphincter dysfunction, and flaccid or
spastic paraplegia, which may evolve to tetraplegia.

• Back and/or radicular pain are infrequent.

• Symptoms progress over days or weeks and often terminate in respiratory

failure and death.
• Cerebrospinal fluid (CSF) examination: an elevated protein
concentration, usually without pleocytosis.

• There are no biologic markers or antibodies associated with this

disorder; as a result, a definitive diagnosis cannot be made
premortem.

• MRI may show contrast enhancement within the spinal cord.

The differential diagnosis includes

• leptomeningeal, epidural, and intramedullary metastasis.

• It can also result from viral infections (particularly of the herpes

group), septic infarcts, and toxic effects of intrathecal chemotherapy
and radiation therapy.
 Additional Considerations in Patients Differential Diagnosis Paraneoplastic Disorder
Known to Have Cancer
Cerebellar metastasis Alcohol-related Cerebellar degeneration
Chemotherapy toxicity (5-fluoruracil, Ara-C) Vitamin deficiency (thiamine, vitamin E)
Toxins (anticonvulsants, other)
Infectious or postinfectious cerebellitis
GAD- associated cerebellar ataxia
Idiopathic

Brain metastasis Viral encephalitis (HSV) Limbic encephalitis

Herpesvirus 6 limbic encephalitis (in particular Temporal lobe tumor
after bone marrow transplantation) Stroke
Idiopathic

Chemotherapy toxicity (cisplatin, paclitaxel, Sjögren’s syndrome Sensory neuronopathy

docetaxel, vincristine) Toxins (pyridoxine)
Idiopathic
Brain metastasis Infectious, postinfectious encephalitis Opsoclonus-myoclonus
Toxins
Metabolic encephalopathy
Idiopathic
 LAMBERT-EATON MYASTHENIC
SYNDROME
• The Lambert-Eaton myasthenic syndrome (LEMS) is also an autoimmune
disorder of the neuromuscular junction caused by antibodies directed
against the voltage-gated calcium channels (VGCC).

• Approximately 50% of patients with LEMS have cancer, almost always an

SCLC.

• The presence of antibodies against SOX1 in patients with LEMS predicts

the presence of a SCLC.
• The clinical presentation of LEMS usually involves the gradual onset
of hip girdle weakness

• The motor weakness tends to progress in a caudo-cranial direction

and to be associated with decreased or absent reflexes

• In general, effective antitumor treatment usually results in neurologic

improvement.
ACUTE SENSORIMOTOR
RADICULONEUROPATHY
• A disorder clinically identical to Guillain-Barre syndrome (GBS),

• Associated with Hodgkin and non-Hodgkin lymphomas

• Patients develop acute-onset rapidly progressive sensorimotor or pure motor

neuropathy and the CSF shows elevated protein.

• The neuropathy may develop at any stage of the cancer and can herald cancer
recurrence.

• Treatment is the same as for GBS

• Studies suggest that patients with cancer have worse neurologic outcomes. 
 CANCER-ASSOCIATED
RETINOPATHY 
• It is the most common of the paraneoplastic visual syndromes.

• Patients with CAR develop symptoms related to dysfunction of both cones

(photosensitivity, abnormal visual acuity, color vision abnormalities, central
scotomata) and rods (night blindness, prolonged dark adaptation,
peripheral scotomata).

• Patients typically describe photopsias along with bilateral visual dimming.

• Symptoms may initially be unilateral but progress to both eyes within weeks.
• Histopathology: Diffuse loss of inner and outer segments of the
photoreceptors and loss of the outer nuclear layer with preservation of the
inner nuclear layer.

• Inflammation is variably observed.

• The most commonly associated tumors are small cell lung cancer (SCLC),
breast cancer, gynecologic cancers, and hematologic malignancies.

• CAR precedes cancer diagnosis in 50% patients.

• Recoverin antibodies almost always associate with SCLC.

 PARANEOPLASTIC OPTIC
NEUROPATHY
• PON is usually seen in association with other paraneoplastic
neurologic syndromes, in particular encephalomyelitis or retinitis.

• Many of these patients harbor antibodies to CRMP-5, but these are

not sensitive markers.

• Patients typically present with painless visual loss and optic disc
edema.

• MRI reveals a swollen optic nerve that may mildly enhance. 

• Fluorescein angiography can show optic disc hyperfluorescence and
leakage.

• CSF may reveal a mild lymphocytic pleocytosis and/or a mildly

elevated protein.
• Neuropathological findings: perivascular lymphocytic infiltration and
demyelination of the optic nerve

• PON usually occurs in the setting of known cancer, but occasionally is its first
manifestation.

• SCLC is the most commonly associated cancer

• Can be seen with non-small cell lung cancer, breast cancer, thymoma, renal
cancer, and thyroid cancer.

• Vision may improve with antitumor treatment.

 TREATMENT
IMMUNOTHERAPY
(IV Ig,
Steroids, rituximab,
Cyclophosphamide,
PLEX)

SYMTOMATIC REMOVAL OF TUMOR

TREATMENT
Thank you!!!!!!