Paraneoplastic syndromes2013

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PARANEOPLASTIC SYNDROMES

Prof. Ashraf AbdouNeuropsychiatry department

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Objectives

• Definition• Pathogenesis• Incidence• Diagnosis• Common paraneolastic

syndromes

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DEFINITION

All neurological abnormalities Not Caused By: Invasion by the tumor or its

metastases Infections Ischemia, metabolic or nutritional

deficits Surgery or other treatment

modalities• “Remote effects of cancer on the nervous

system”

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PARANEOPLASTIC SYNDROMES

• Neurological symptoms of paraneoplastic syndromes usually precede the identification of the cancer

• Usually when the paraneoplastic-related cancer is identified, it is small, nonmetastatic, and indolently growing

• Neurological disability caused by paraneoplastic syndromes is often profound in the absence of any other cancer symptoms

• Paraneoplastic syndromes are generally, but not always, irreversible

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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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Importance of Paraneoplastic Syndromes

Although rare, recognition by the physician is important: Neurological symptoms precede and

prompt the diagnosis of systemic cancer in about 50% of patients

Some syndromes direct search to particular organs

In many cases the syndrome’s onset is while the cancer is small and curable

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Frequency of Paraneoplastic Syndromes

• “Clinically significant paraneoplastic syndromes probably occur in fewer than 1% of patients with cancer”

• 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%

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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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Autoimmunity

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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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Pathogenesis

• Pathologically: loss of neurons + inflammatory infiltrates

• CSF: pleocytosis – intrathecal synthesis of IgG – oligoclonal band

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Antibody Target Tumor Syndrome

Hu Pan-neuronal nuclei

SCLC PEM/PSN, PCD

Yo Purkinje cytoplasm

Ovary, breast

PCD

Ri As Hu but not PNS

Breast POM

Tr As with Yo but M layer

Hodgkin’s PCD

GluR1 mGluR1 receptor

Hodgikin’s PCD

CV2 Oligo cytoplasm

SCLC, uterine sarcoma

LEMS, PCD, LE

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Diagnosis

• PNS is the differential diagnosis of unexplained neurological syndromes

• NOT A WAIST BASKET FOR UNEXPLAINED CASES

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Relation of the PND to tumor

• 70% of cases PND proceed the diagnosis of cancer

• 70% of cases identification of the tumor in the 1st screening

• Screening:CT chest, abdomen and pelvisFDG-PET whole body

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Paraneoplastic syndromes

Classic Non-classic

Brain, cranial n, retina •Cerebellar deg•Limbic encephalitis•Encephalomyelitis•Ospoclonus-myoclonus

•Brainstem encephalitis•Optic neuritis•Cancer-related retinopathy•Melanoma-associated retinopathy

Spinal cord •Stiff-person syndrome•Myelitis•Necrotizing myelopathy•Motor-neuro syndromes

NMJ Lambert-Eaton myasthenic synd

Myasthenia gravis

Peripheral nerves or muscle

•Sensory neuronopathy•Dermatomyositis•Intestinal pseudo-obstruction

•Sensorimotor neuropathy•Acquired neuromyotonia•Autonomic neuropathy•Polymyositis•Acute necrotising myopathy

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Diagnosis

Paraneoplastic syndromes occur in patients:not known to have cancer

(most common)with active cancerin remission after treatment

exclude other cancer-associated process

Diagnostic criteria of PND

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Suspected PND

Know cancer

Abs -ve

Rule out otherNeuro

complications Of cancer

Abs +ve

No cancer diag

Abs -ve Ab +ve

Search of tumor

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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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Diagnosis

Suggestive clinical features:Subacute onset, progress over

weeks to monthsSevere neurological disabilityOne portion of nervous system

more than widespread involvement

Some syndromes present stereotypically

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DiagnosisAutoantibodies

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

neurological disability• Immunosuppression ineffective in

most, except LEMS• ? rapid onset without diagnosis

or treatment before irreversible neuronal damage has occurred

• Treatment of underlying tumor; stabilization of the condition

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“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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“Classic Paraneoplastic Syndromes”Specific Syndromes

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Paraneoplastic Cerebellar Degeneration

• Most common• Best characterized• Rare disorder

300 cases report by 1995• A group of related disorders

that differ in clinical features, prognosis, and types of malignancies

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• 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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• Neurological symptoms prompt patient to see doctor before cancer is symptomatic

• Cancer is usually found months to 2-4 years after onset of neurological symptoms

• Sometimes only at autopsy

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Clinical features:slight incoordination in

walkingrapidly evolving over weeks

to months with progressive gait ataxia

incoordination in arms, legs and trunk

dysarthrianystagmus with oscillopsia

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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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• Neurological 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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Investigations diffuse cerebellar atrophy months to

years after onset on head imaging CSF (early)

increased lymphocytesslightly elevated protein and IgG concentrations

Pleocytosis resolves with timeOligoclonal band

Ovarian carcinoma

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Autoantibodies in serum and CSFfound in a subset of patients

number is unknownreact with Purkinje cells of

cerebellum & tumorwell characterized

anti-Yo, anti-Hu, anti-Ri, anti-Tr, anti-CV2, anti-Ma proteins

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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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Pathology CNS may be normal at autopsy usually the cerebellum is atrophic

with abnormally widened sulci and small gyri

microscopicextensive/complete loss of Purkinje cells of the cerebellar cortex

pathologic changes sometimes involving other parts of nervous system

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Diagnosis recognize characteristic clinical syndrome exclude other causes of late-onset

cerebellopathyLeptomeningeal metastasisinfectionstoxicity of chemotherapiesviral brainstem encephalitisdemyelinating diseaseCreutzfeld-Jakob diseaseinfarction, hypothyroidismalcoholic and hereditary cerebellar degenerations

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• 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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Classical paraneoplastic syndromes

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More “Classic” SyndromesSensory Neuronopathy (SN)

• <20% paraneoplastic• Also occurs in patients with autoimmune

disorders, Sjogren’s syndrome• 2/3 of paraneoplastic SN have small-cell lung

cancer• Neurological syndrome usually precedes

diagnosis of cancerdysesthetic pain and numbness of distal

extremitiessevere sensory ataxiaall sensory modalities affected, loss of

DTRsmotor nerve action potentials are

normal

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• Onset Painful paresthesias & dysesthesias Asymmetric; Distal or Proximal No tumor at initial workup: 50%

• Sensory loss (95%) All modalities involved

Proprioceptive loss: Prominent Ataxia: Sensory Pseudoathetosis

Distribution Proximal & Distal Asymmetric (35%) or Symmetric Upper limb only (25%) Lower limb only (45%)

• Discomfort: Pain (80%); Paresthesias • Motor

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Motor• Normal (75%)

Occasional sensory-motor involvement (25%): May be subclinical

Weakness may be proximal or distal Rare (5%): Amyotrophy; Fasciculations Course

Progression Over days to 6 months Distribution: To diffuse sensory loss Then plateau with little improvement

• Occasional improvement with treatment-induced remission of neoplasm

• Less common outcomes Mild course Acute (< 24 hrs; 3%) Chronic (> 6 mo; 15% to 40%)

• Survival: Mean 28 months; Range 6 to 96 months

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Subacute Motor Neuronopathy

(Spinal Muscular Atrophy)

• Rare complication of Hodgkin’s and other lymphomas

• 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

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Encephalomyelitis• Cancer patients with clinical signs of damage to more than one

area of the nervous system

• Limbic encephalitisrare complication of small-cell lung cancer

personality/mood changes develop over days or weeks

severe impairment of recent memorysometimes 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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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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• >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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• Unlike most paraneoplastic syndromes LEMS usually responds to:plasmapheresiscorticosteroidsazathioprineintravenous immunoglobin

• Long-term treatment often needed

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Summary• 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 [Onconeural Ab]

• Disability persists despite treatment of underlying tumor

Education

Paraneoplastic syndromes2013