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PARANEOPLASTIC SYNDROMES ¹

GENERAL PRINCIPLES

Anatomy Diagnostic principles Neoplasm   Associations   Incidence   Malignancy Temporal Types   Endocrine   Immune     Antigen is tumor protein       Intracellular       Membrane     Neoplasm produces antibody     Unknown immune mechanism

Polyneuropathy & Cancer: First associations

• Anatomical relation with neoplasm: None
  • Diseased tissue is "remote" from neoplasm
  • Syndrome is not a direct effect of mass of 1° tumor or metastases
• Temporal relation of syndrome with neoplasm: Variable
  • Onset: Before or after identification of neoplasm
  • Length of time between identification of syndrome & neoplasm
    • Usually weeks to months
    • Occasionally years apart
• Types of syndromes: Often identifiable and "specific"
  • Presence indicates high likelihood of associated neoplasm
• Malignancy of associated neoplasm: Varies from
  • Life threatening: Treatment of neoplasm determines survival
  • Minimal: Undetected until careful search, or autopsy
    • Paraneoplastic signs more disabling than neoplasm
    • Paraneoplastic syndromes indicate evaluation for neoplasm
• Associations: Several paraneoplastic syndromes may be related to one type of neoplasm
  
  

  NEOPLASM-ASSOCIATED SYNDROMES
  Thymoma	Small cell lung cancer
  NEUROLOGIC SYNDROMES Myasthenia gravis Isaac's syndrome (Neuromyotonia) Rippling muscle syndrome GI pseudo-obstruction Autonomic neuropathy Stiffman syndrome Cerebellar: CV2 syndrome Encephalopathy CRMP-5 SYSTEMIC SYNDROMES Acquired hypogammaglobulinemia Cushing syndrome Pure red cell aplasia Alopecia Hypercalcemia Pemphigus	NEUROLOGIC SYNDROMES Lambert-Eaton MG Autonomic neuropathy Sensory neuronopathy Myelopathy Cerebellar Opsoclonus-Myoclonus Limbic encephalitis SYSTEMIC SYNDROMES Endocrine   Hypercortisolism (ACTH)   Carcinoid (Serotonin)   ↑ Ca++ (Parathyroid)   Hyperthyroid (TSH)   Hyperpigmentation (MSH)   SIADH; ↓ Na+ (ADH)   Erythrocythemia (Erythropoetin)   Gynecomastia (Gonadotropin)   Hypoglycemia (Insulin)   Diabetes (Glucagon) Retinopathy

  
  
• Incidence
  • Mild disorders of nerve + muscle: Common
    • >15% weight loss, or Late disease: Nearly 100%
    • Polyneuropathy: Distal, Symmetric, Sensory > Motor; Axonal
    • Myopathy: Proximal 2° Type II muscle fiber atrophy
    • Weakness: Proximal & Distal sparing intermediate muscles
  • Disabling "specific" syndromes: Less common
    • Signs due to cell death (e.g. anti-Hu): Rare (0.3%)
    • Signs due to cellular dysfunction: Not infrequent
      • e.g. Myasthenia gravis + thymoma association: Up to 10% to 20%
• Categories: By underlying etiology
  • Immune
    • Immune reactivity to tumor + tissue antigen
    • Neoplasm produces antibody
    • No specific immune process identified
  • Metabolic Disorders
    • Electrolyte abnormalities
    • Endocrine dysfunction
  • Vascular: Clotting disorder; Hyperviscosity
  • Infectious: ↑ susceptibility 2° ↓ immune response
• Immune paraneoplastic syndromes: Types
  • Tumor protein is antigenic target
    • Location of disease
      • Regional, Not diffuse
      • May be in CNS, PNS or both
    • Stereotypic clinical syndromes
      • Examples: Sensory neuronopathy (Hu); LEMS; Isaac's
      • Not: "Maybe, its paraneoplastic"
    • Disease Course: Subacute onset ® Plateau
    • Cancer-association
      • Frequency: Common, but not invariable
      • Common neoplasms: Small cell lung; Thymoma; Lymphoma
    • Antibodies
      • Polyclonal IgG
      • Bind to antigen common to Neural tissue & Neoplasm
    • Antigen types
      • Membrane protein is antigen: Usually membrane ion channel
        • Disease location: Usually Nerve or Muscle; Rarely CNS
        • Antigen
          • Neurotransmitter receptor, or Voltage-gated ion channel
          • Location: In target tissue & probably in neoplasm
        • Antibodies
          • Location: Serum; Usually not CSF
          • Probably pathogenic
            • Passive transfer of antibodies induces disease features
            • Reduction of antibody titers is often therapeutic
        • Frequency of neoplasm when antibody present
          • Common, Not invariable
          • 10% to 70%
        • Disease pathology
          • Membrane dysfunction
          • Focal damage to nerve or muscle cell
        • Treatment
          • Diseases often improve with immunomodulation
          • Effective types: Many; May include Plasma exchange; Corticosteroids...
        • Examples

          Channel	Syndrome	Neoplasm
          Ca++, P-type (α1A)	Lambert-Eaton MG	Small cell lung
          AChR, subunit α3	Autonomic neuropathy	Small cell lung
          K+	Isaac's neuromyotonia	Thymoma
          AChR, Nicotinic	Myasthenia gravis	Thymoma

      • Intracellular protein is antigen
        • Disease location: Usually CNS; Occasionally PNS
        • Tissue locations of antigen
          • Neoplasm
          • Neural cells: Nucleus (Hu); Cytoplasm (Yo)
        • Antibodies
          • Type: Polyclonal IgG
          • Location: Serum + CSF
          • ? Pathogenic: No disease with passive transfer
        • Frequency of neoplasm when antibody present
          • Nearly always: 80% to 95%
        • Neoplasm
          • May be smaller & slower growing than similar neoplasm without paraneoplastic syndrome
          • Examples: Small cell lung; Gynecologic; Testicular
        • Disease pathology: Neural cell loss
        • Treatment: Disease rarely improves with immunomodulation
        • Examples: Hu; Yo
  • Neoplasm produces antibody
    • Location of disease: Usually nerve or muscle
    • Antibodies
      • Monoclonal
      • IgM antibody
        • Neural target antigen common
        • Epitope is often carbohydrate on protein or membrane lipid
      • IgG & IgA antibody: Identified antigenic target rare
      • Location: Serum; Not CSF
    • Stereotypic clinical syndromes
      • Age of onset: More common > 50 years
      • Disease course: Slowly progressive
      • Especially with IgM antibody (M-protein)
        • Clinical: May involve selective functional change
          • Motor: IgM vs GM1 ganglioside
          • Sensory: IgM vs GD1b ganglioside
        • Nerve pathology: May involve specific tissue
          • Myelin: GM1; MAG; Sulfatide; GALOP
          • Axons: Motor (GM1) or Sensory (GD1b)
      • Syndromes with IgG or IgA M-protein
        • POEMS Syndrome
        • Scleromyxedema: Skin papules; Myopathy; Raynaud's; ? Neuropathy
        • Polyneuropathy: Sensory > Motor; Axonal
        • Chronic Immune Demyelinating Polyneuropathy (CIDP)
        • Other: Amyloid; Cryoglobulinemia
    • Neoplasm
      • Benign Monoclonal gammopathy (MGUS): Common
      • Malignant neoplasm: Occasional; Requires chronic surveillance
    • Disease mechanisms
      • Immune reaction vs. antigen: Cellular dysfunction or Damage
      • Cryoglobulin: Vasculopathy
      • Amyloid
    • Treatment: ↓ Antibody titer for > 6 months or more
      • Effective: Chemotherapy (Cyclophosphamide) + PE
      • Occasionally effective: IVIg; Plasma Exchange
      • Rarely effective: T-cell drugs (Prednisone; Azathioprine; Cyclosporine)
  • No currently identified antibody or target antigen
    • Motor Neuropathy: Subacute; Lymphoma-associated
    • Necrotizing myopathy: Subacute
    • Dermatomyositis
    • Rippling muscle syndrome
    • Necrotizing myelopathy
• Diagnosis
  • Presence of recognized clinical paraneoplastic syndrome
  • Exclusion of other cancer-related disorders
  • Confirmatory laboratory studies

SPECIFIC SYNDROMES ⁵

• Regional Ischemic Immune Myopathy (RIIM)
  • Neoplasms: Lung; Gastrointestinal; Breast
• Necrotizing myopathy with pipestem capillaries
  • Neoplasm: Bladder transitional cell
• Dermatomyositis + Vascular Pathology (DM-VP)
  • Neoplasms: Ovarian; GI; Non-Hodgkin lymphoma
• Polymyositis: Mild increased risk
  • Neoplasms: Non Hodgkin lymphoma; Lung; Bladder
• Type 2 Muscle Fiber Atrophy (Cachectic myopathy)
  • Especially with weight loss > 15%
  • Wasting > weakness
  • Neoplasms: Multiple types
• Anti-Decorin (BJ) myopathy
  • Clinical
    • > 50 years of age
    • Weakness: Proximal; symmetric
    • CK: Mildly elevated
  • Neoplasm: Waldenström's macroglobulinemia
• Rippling Muscle Syndrome
  • Neoplasm: Thymoma
• Scleromyxedema
  • Skin papules; Myopathy; Raynaud's
  • Neoplasm: IgG or IgA λ M-protein
• Amyloid myopathy
• Metabolic/Hormonal
  • Corticosteroid myopathy
    • Ectopic ACTH production
  • Carcinoid syndrome
  • Hypercalcemia 2° hormone producing tumors

• Myasthenia Gravis
  • Clinical: Patients > 25 years of age
  • Neoplasm: Thymoma
  • Antibodies
    • Anti-acetylcholine receptor
    • Anti-striational (Skeletal muscle)
• Lambert-Eaton myasthenic syndrome
  • Neoplasm: Small cell lung
  • Antibody: Voltage-gated Ca⁺⁺ channel

• Sensory neuronopathy
  • Antibody: Anti-Hu
  • Neoplasm: Small cell lung
• Subacute motor neuronopathy
  • Clinical
    • Weakness: Subacute; Arms > Legs
  • Neoplasm: Lymphoma

• Sensory-Motor Neuromyopathy
  • Neoplasm: Many
  • Frequency
    • ~ 5% of patients with cancer
    • 100% with weight loss > 15%
• Autonomic neuropathies
  • Sensory neuronopathy: IgG vs Hu; Small cell lung cancer
  • Dysautonomia: IgG vs α3 subunit of acetylcholine receptor
  • Enteric neuropathy: IgG vs Hu; CV-2; Amphiphysin
  • LEMS: IgG vs Voltage Gated Ca⁺⁺ Channels; Small cell lung cancer
  • Amyloid: M-protein
• M-protein associated neuropathies & myopathies
  • Neoplasms
    • IgM Monoclonal gammopathies: Benign; Especially IgM; Specific target antigens
      • Decorin (BJ): Myopathy
      • GALOP antigen: Gait disorder & polyneuropathy
      • GD1b ganglioside (without GM1 binding): Ataxic sensory neuropathy
      • GM1 ganglioside: Motor neuropathy
      • Myelin-associated glycoprotein: Sensory ± motor neuropathy
      • Sulfatide: Sensory ± motor neuropathy
      • Tubulin: CIDP variant
    • Waldenström's macroglobulinemia (IgM)
    • Multiple myeloma
    • Osteosclerotic myeloma & POEMS
    • Other IgG & IgA M-proteins: Cryoglobulins; Sensory > Motor neuropathy
  • CIDP
    • Increased incidence of IgA & IgG M-proteins
    • IgM M-protein vs β-tubulin
      • Antigenic epitope: Tubulin amino acids 301-314
• CV-2 syndrome
• Isaac's Syndrome (Neuromyotonia)
  • Antibody: K⁺ channels
  • Neoplasm: Thymoma

• Stiffman Syndrome
  • Neoplasm: Breast
    • Antibody: Amphiphysin; Other antibodies with non-neoplastic syndromes
  • Other neoplasms: Lung & Thymoma
  
  
• ? Primary Lateral Sclerosis
  • Neoplasm (unusual): Breast
  • Onset: 45 to 80 years
  • 50% eventually develop LMN signs
  • Progression: Years
  
  
• Myelopathies
  • Necrotizing myelopathy, Paraneoplastic ¹¹
    • Neoplasms: Lymphoma; Leukemia; Lung; Thyroid; Breast; Renal
    • Clinical
      • Onset
        • Time: Before or after neoplasm
        • Symptoms: Pain in back or Radiating to legs
      • Weakness: Flaccid paraplegia
      • Sensory loss: All modalities
      • Sphincter paralysis
      • Reflexes: Tendon reduced; ± Extensor plantar
      • Course
        • Progressive: Ascending paralysis
        • Poor prognosis: Prolonged paralysis; Death 2° neoplasm
    • Laboratory
      • Antibodies: Variable
        • Amphiphysin
        • CRMP-5 IgG
        • Hu
        • Yo
        • Not AQP4
      • CSF: Inflammatory
      • MRI
        • Normal (50%) or Cord enhancement & enlargement
        • Symmetric
        • Longitudinally extensive tract
        • Gray matter–specific: Some
      • Pathology
        • Necrotic
        • ? White matter predominance; Gray also involved
        • Location: Especially thoracic cord
        • Hodgkins lymphoma: Vasculitis of cord described
    • Treatment: None clearly effective; ? Intrathecal corticosteroids
  • Myelitis: Anti-Hu-associated
    • Motor
      • Patchy weakness: Arms > Legs
      • May progress to neck & respiratory failure
      • Fasciculations
    • Sensory: Associated ganglionopathy
    • Neoplasm: Small cell lung
  
  
• Cerebellar & Multisystem syndromes
  
  

  Ataxia +   General features   Antibodies     Ca++ channel Ab     CARP 8     CV2     Hu     Ma     Ma2 (Ta)     mGluR1     Tr     Yo     PCA-2 Opsoclonus/Myoclonus   Definition   Adult   Child   Ri

  Anti-Yo antibody Stains: Cerebellar Purkinje cells

  
  
  • Paraneoplastic Ataxia: General Features
    • Onset
      • Before neoplasm
      • Gait disorder
    • Clinical
      • Pancerebellar syndrome: Symmetric; Vertigo & Nausea; Ocular dysmetria
      • Evolution: Rapid over weeks to months, then stabilization
    • Associated neoplasms: Most common
      • Lung: Small cell; Hu or Ca⁺⁺ channel antibody
      • Ovarian: Epithelial; Yo antibody
      • Breast: Yo or Ri antibody
      • Lymphoma: Hodgkins
    • Laboratory
      • MRI: Cerebellar atrophy late in course
      • CSF
        • Protein high
        • Cells: Pleocytosis common
        • IgG: Moderately high; Some oligoclonal bands
      • Pathology: Loss of Purkinje cells
    
    

    Yo antibody syndrome Epidemiology: Most common in Sex Female (> 95%) Male: 3 patients reported, 2 with gynecomastia Associations: Gynecologic neoplasms Yo antibody General features Location: Serum & CSF; Intrathecal synthesis Type: IgG Subclass: IgG1 Titers: May decrease after tumor resection Antigens Cell targets Ribosomes, membrane bound & free Golgi complex in Purkinje cell cytoplasm (Golgi) Gynecological tumor cells associated with PCD & Yo antibodies cdr1 : 34kDa (CDR-34) cdr2 : 62 kDa (CDR-62; PCD17) Leucine zipper DNA-binding protein Other possible antigens CDR3 : Leucine zipper 58 kDa (CZF1; ZNF470) : Zinc finger Clinical features Onset Age: Mean 58 years; Range 26 to 85 years Progression: Subacute, Weeks Neoplasm: Temporal association of cerebellar syndrome Before cancer: 63% After starting tumor treatment: 30% May begin with tumor relapse: 20% Ataxia: Trunk & Limb Severe Pancerebellar Trunk & Limb Dysarthria Oculomotor Nystagmus (100%) Rotary or Vertical in 50% Downbeating in some Oscillopsia & Diplopia Diplopia Vertigo Peripheral neuropathy (50%) Progression & Course Weeks to Months: Mean 2 to 3 months Eventually non-ambulatory: 70% to 94% Not affected by treatment of neoplasm Survival Reduced Mean: 2 to 11 years Death from neoplasm 50% Dependent on tumor type Breast: 100 months Gynecological: 22 months Causes of death Progression of neoplasm 55% Neurologic 36% Neoplasms Types Ovary (50%): Lymphoepithelial; Müllerian adenocarcinoma, Breast (25%): Adenocarcenoma; HER2+ (96%); Estrogen receptor + (17%) Male patients: Gastric, parotid, esophageal adenocarcinoma Other gynecologic: Endometrial, Fallopian tube, Mesovarium Metastases: Invasion of regional lymph nodes common (83%) No neoplasm found: 9% Work-up Mammography Pelvic exam & imaging Serum: CEA & CA 125 antigen CSF Protein: Mildly elevated Cells: Mild mononuclear pleocytosis (70%) Anti-Yo antibody present CSF IgG: High Oligoclonal bands May be normal Pathology Cerebellum: Loss of Purkinje cells; Late atrophy Neoplasm: May have HER2/neu over expression Treatment Therapy for neoplasm: Only rare improvement in ataxia ? Cyclophosphamide

    Anti-Yo antibody Staining of cerebellar Purkinje cell cytoplasm Yo staining Cerebellar Purkinje cell

    
    
  • Tr syndrome ⁷
    • Antibody
      • Antigen
        • Delta & notch-like epidermal growth factor-related receptor (DNER)
      • Tissue staining
        • Cerebellum
          • Purkinje cell cytoplasm & dendrites
          • Dotted pattern in molecular cerebellar molecular layer
        • Neoplasm: Only rarely stained
      • Tr cell localization: Cytosol & Outer surface of Endoplasmic reticulum
      • Location: Usually present in serum & CSF; May be only in CSF
      • Isotypes: IgG1 & IgG3
      • Course
        • No neoplasm: Spontaneously disappears
        • Treatment (successful): Disappears
    • Clinical
      • Sex: Male > Female 3:1
      • Age: Median 61 years; Range 14 to 75 years
      • Onset
        • Time: Before (71%) or after cancer; During remission
        • Course: Subacute
      • Ataxia
        • Severity: Moderate to Severe
        • Usually irreversible
        • Remissions (15%): More common younger than 40 years of age
      • Variant syndromes
        • Limbic encephalitis (7%): Reversible
        • Optic neuritis
      • Survival
        • Mean > 9 years
        • Longer than Hu or Yo syndromes
    • Neoplasm
      • Hodgkins lymphoma (89%): Especially nodular sclerosis
      • No neoplasm (11%)
    • Cerebellar pathology
      • Loss of Purkinje cells
      • No inflammation
    
    
  • Hu syndrome
    • Clinical
      • Sex: Female > Male
      • Onset: Before cancer
      • Ataxia: Associated with other CNS & PNS syndromes
    • Neoplasm: Small cell lung
    
    
  • LEMS-associated
    • Antibodies: ± Voltage-gated Ca⁺⁺ channels
    • Neoplasm: Lung (Small cell)
    • Increased incidence in Hu syndromes
    
    
  • CRMP-5 (CV2; DPYSL5) syndromes ⁶
    • CRMP-5 antigen
      • Collapsin response-mediator protein (CRMP) family
      • Molecular weight: 62 kD
      • Neural specific: Antigen located in
        • Oligodendrocytes: Cytoplasm
        • Cerebellum, Brainstem, Spinal cord & Optic chiasm
      • Cellular distribution
        • Synapse-rich regions of brain & Gut
        • Small DRG neurons
        • Small cell neoplasms
      • Paraneoplastic syndromes associated with antibody staining of oligodendrocytes
      • Co-associated with amphiphysin
    • Clinical syndromes: Varied clinical features
      • Peripheral nervous system: Often associated with CNS disorder
        • Neoplasm & other associations: Especially chest
          • Small cell lung (70% to 80%)
          • Thymoma (5%)
          • Other: Uterine sarcoma
          • Smoking 88%
        • Sensory or Sensory-Motor disorders (47%)
          • Clinical
            • Onset: Subacute
            • Legs > Arms
            • Asymmetric (84%)
            • Weakness (54%)
            • Sensory
              • Pain (65% to 79%)
              • Pure sensory (18%)
            • Autonomic dysfunction (31%): GI paresis
            • CNS: Some patients with Optic neuritis or Myelopathy
            • Treatment: Corticosteroids may reduce pain
            • Associated neoplasm (69%): Neuropathy often predates neoplasm
            • Less severe than Hu syndromes
              • Death in 5 years (33%) vs 68% with Hu
              • Less neuronopathy
          • Nerve Pathology
            • Axon loss: Multifocal
            • Epineurial arteriole inflammation
          • CSF: Cells (50% to 90%)
        • Autonomic dysfunction (31%)
          • Especially: Isolated GI: Pseudo-obstruction
          • Also: Multiple systems
        • Polyradiculopathy (3%)
        • Pathology
          • Axon loss
          • Inflammation (50%)
      • Neuromuscular junction (12%): Thymoma-associated
        • LEMS
        • Myasthenia gravis
      • Cerebellar (26% to 50%)
        • Ataxia
        • Nystagmus
        • Dysarthria
      • Encephalopathy (30%): Limbic & Diffuse encephalitis
        • Dementia
        • Mental status & Mood changes
        • Seizures
      • Cranial nerve disorders (17%)
        • Optic neuropathy
        • Abnormal Olfaction/Taste
      • Myelopathy (16%)
      • Movement disorders
        • Basal ganglia (14%): Chorea
        • Opsoclonus/Myoclonus (5%)
      • Uveo-retinal syndromes
      • Course
        • Longer survival than Hu syndromes
      • Treatment: ? Tumor removal
    • Laboratory
      • CSF: Pleocytosis (Lymphocytes); High Protein
      • Anti-CRMP-5 antibodies (IgG): Present in Serum & CSF
      • Concurrent Hu antibodies in occasional patients
    
    
  • Ataxia with antibodies to metabotropic glutamate receptor R1 (mGluR1) ²
    • Clinical
      • Onset: Months to years after neoplasm (80%)
      • Ataxia: Truncal; Gait
      • Intention tremor
      • Mental status: Normal
      • Course: Persistent or Monophasic
    • Antibodies
      • Target: Metabotropic glutamate receptor (mGluR1; GRM1)
        • Hereditary disorder: Congenital ataxia
      • Tissue staining
        • Cerebellum: Purkinje cell bodies (punctate) & spines
        • Glomeruli of olfactory bulb: Neurons & neuropil
        • Cerebral cortex: Superficial layer
        • Other: Hippocampus (CA3); Thalamus; Superior colliculus; Spinal trigeminal nucleus
      • Location: Serum + CSF
    • Other laboratory
      • CSF: High IgG & IgG index
      • MRI: Normal
    • Neoplasm: Hodgkin's lymphoma; During remission
    • Treatment: ? Plasma exchange
    
    
  • Ataxia with antibodies to CARP 8 ¹⁰
    • Epidemiology: 1 patient; 77 year old female
    • Clinical: Pure cerebellar syndrome
      • Onset: 3 years after neoplasm
      • Ataxia: Limb; Truncal; Gait; Dysarthria
      • Ocular: Horizontal nystagmus
      • Mental status: Normal
      • Course: Progressive ataxia
    • Antibodies
      • Target: Carbonic ahnydrase-related protein 8 (CARP 8)
      • Tissue staining
        • Cerebellum: Purkinje cell cytoplasm & dendrites
        • Weaker staining
          • Lateral nuclei of thalamus
          • Bronchial epithelial cells
          • Melanomas: 1 of 7 tested
      • Location: Serum + CSF
    • Other laboratory
      • CSF: Lymphocytosis; Oligoclonal bands
    • Neoplasm: Melanoma, treated without evidence of recurrence
    • Treatment: None
    
    
  • Opsoclonus/Myoclonus: Children
    • Opsoclonus: Conjugate saccades
      • Involuntary
      • Multidirectional
      • Arrhythmic
      • Nearly continuous
      • High Amplitude
      • Persist: Eyes closed & During sleep
      • Associated with: Blinking; Myoclonus
      • Increases with: Visual pursuit; Voluntary refixation
    • Clinical Syndrome
      • Age: 18 months
      • Sex: Female > Male
      • Onset: Before or after cancer
      • Treatment: Corticosteroids
      • Residua: CNS signs frequent
    • Neoplasm: Neuroblastoma with single copy of N-myc oncogene
    • Antibodies: Neurofilaments & other CNS antigens
    • Other associations: Post-viral syndrome
    • Differential diagnosis
      • Toxic: Thallium; Lithium; Amitriptyline
      • Diabetic hyperosmolar coma
      • Encephalitis: Viral; Post-infectious
      • Intracranial lesions: Tumor; hydrocephalus; Thalamic hemorrhage
      • Hereditary: KCTD7 mutations
    
    
  • Opsoclonus/Myoclonus: Adults
    • Clinical
      • Associated features: Encephalopathy; Seizures; SIADH
      • Remissions: May occur spontaneously
      • Treatment: Thiamine; Clonazepam; Immunosuppression (HIG; Prednisone)
    • Neoplasm: Lung (Small cell) + Gynecologic
    • Other associations: Post-viral syndrome
    
    
  • Opsoclonus/Myoclonus: Ri (ANNA-2) syndrome ⁸
    • Epidemiology
      • Male: Female = 1:2
    • Clinical
      • Onset age: 35 to 82 years
      • Movement disorder
        • Opsoclonus (30%): Triggered by visual fixation
        • Myoclonus
      • Cerebellar: Ataxia
        • Most common feature of Ri syndrome (50%)
        • Truncal ataxia & Gait disorder
        • Dysarthria: Rare
        • Nystagmus: 33%
      • Other associated disorders in some patients
        • Myelopathy (18%)
        • Peripheral neuropathy (25%)
          • Onset: Often subacute
          • Distribution: Sensory-motor; Polyradiculopathy
          • Often associated alternative causes
        • Cranial neuropathy: VI; VIII (Deafness or Tinnitus)
        • Movement disorder (25%)
          • Laryngospasm
          • Dystonia: Jaw opening or Neck
        • Encephalopathy: Confusion; Seizures
        • Lambert-Eaton syndrome
        • Visual blurring
        • Incontinence
      • Course
        • Waxing & waning
        • 30% wheelchair-bound 1 month after neurological symptom onset
        • Less long term disability than Yo or Hu syndromes
        • Longer survival than Yo or Hu syndromes
      • Treatment
        • Most with neurological improvement after immunomodulatory or tumor-directed therapy
        • Treatment types: Corticosteroids; IVIg
    • Neoplasm association
      • Frequency: 86%
      • Types: Breast; Lung (SCLC & NSCLC)
      • Neoplasm discovered before neurological disorder: 15%
      • Distant metastases: 12%
    • Antibodies
      • Antigens
        • 55 kDa (Nova-1 & 2 : CNS proteins; RNA binding
        • 80 kDa: CNS proteins
      • Immunohistochemistry: Antibodies bind to CNS but not PNS neurons
      • Other associated antibodies (73%): Hu, ANNA-3, CRMP-5-IgG, P/Q-type & N-type Ca⁺⁺ channel, AChR
    • Laboratory
      • CSF: High protein (37%); Pleocytosis (42%)
      • CNS imaging: Normal in 66%; Occasional changes in cortex, brainstem or cauda equina
    
    
  • Ma syndromes: Brainstem & Cerebellar disorders
    • Age: 58 to 63 years
    • Clinical: Not uniform
      • Cerebellar: trunk & extremities
      • Brainstem: EOM limitation; Dysphagia
      • Other: Sensory loss; Myokymia
    • Prognosis: Death in 50%
    • Antigen
      • Ma1 protein
        • 37 and 40 kDa neuronal & testicular germ cell proteins
        • Homology to Ma2
      • Ma2 protein
    • Tumors: Not uniform
      • Parotid; Breast; Lung (Large cell); Colon
      • Timing: Neoplasms concurrent to 1 year after syndrome
    • Pathology: Gliosis of Brainstem & Cerebellar nuclei; Inflammation
  
  
• Encephalopathies
  • Hu syndrome: Limbic encephalitis
    • Clinical
      • Male = Female
      • Progressive over days-weeks
      • Memory loss; Seizures
      • May be associated with neuronopathy
      • CSF: Inflammatory (lymphocytes)
    • Antibody: Hu
    • Neoplasm: Small cell lung
    • Treatment: Not responsive to immunomodulation
    
    
  • Ma2 (Ta) : Limbic ± Brainstem encephalitis
    • Age: 22 to 45 years; Younger than Hu syndrome
    • Clinical
      • Limbic: Halllucinations; Lethargy; Seizures; Memory loss
      • Brainstem: Dysarthria; Ataxia; EOM changes
      • Onset: 3 years before to 1 year after tumor
      • Prognosis: Death to mild improvement after treatment
    • Antibody
      • Anti-Ma2 antibody
        • Location: Serum & CSF
        • Not cross-reactive with Ma1
      • Tissue targets: Granular structures in neuronal cytoplasm; Nuclei
    • Ma2 (Ta) Antigens
      • 40 kD & 50 kD protein
      • Homology to Ma1
      • Location: Hippocampus, Amygdala, Diencephalic, Tegmental & Dentate nuclei
    • Tumor associations
      • Testicular germ-cell or seminoma: May be occult
      • Breast: Occasional
    • CSF: Abnormal
    • MRI: Temporal lobe ± Hypothalamic change
    
    
  • Morvan's syndrome (Fibrillary Chorea) ¹²
    • Clinical
      • Prodrome: Fever common
      • Onset age: Mean 4th decade; Range 2 years to 7th decade
      • Muscle
        • Neuromyotonia
        • Myokymia
        • Twitching
      • Autonomic
        • Hyperhidrosis
        • Hypersalivation
        • Orthostatic hypotension: Few patients
      • Polyneuropathy
        • Pain
        • Paresthesias
      • CNS dysfunction: Limbic encephalitis
        • Sleep disorders
          • Insomnia
          • Deep sleep: Absent
          • REM behavior disorder
          • Periodic leg movements
        • Cortical function
          • Hallucinations
          • Memory loss
          • Disorientation
        • Seizures
      • Other CNS
        • Tendon reflexes: Brisk
        • Tremor
      • Neoplasm association: Thymoma in some patients
      • Course
        • Encephalopathy: Improvement
          • May improve spontaneously
          • Common with immunosuppression
        • Persistent pain or seizures reported
      • Treatment
        • Plasma exchange
        • Corticosteroids
        • Immunosuppression
    • Laboratory
      • Serum antibodies
        • vs K⁺ channel-related molecules
          • CASPR-2
          • Lgi-1
        • Bind to: Hippocampal dentate gyrus, Molecular layer
      • EMG
        • Neuromyotonia
        • Myokymia
        • Fasciculations
        • Positive sharp waves
      • Autonomic function: Varied disorders
    • Differential diagnosis: Creutzfeld-Jakob
    
    
  • Anti-K⁺ channel antibodies ⁹
    • Frequency: 25% of limbic encephalitis
    • Neoplasm
      • Frequency: 50%
      • Type
        • Lung, small cell
        • Also: Adenomas, Thymoma, Hematologic malignancies
    • Clinical
      • Onset: Subacute
      • Multifocal
      • Encephlopathy
        • Short-term memory loss
        • Confusion
        • Seizures: Generalized or Psycho-motor
        • Dyssomnia
      • Dysautonomia
      • Polyneuropathy
      • Movement
        • Myoclonus
        • Extrapyramidal dysfunction
      • Brainstem/cranial nerve dysfunction
      • Other autoimmune: Thyroiditis, Type 1 diabetes mellitus
      • Treatments
        • Improvement after corticosteroids in some patients
        • Other: Plasmapheresis, IVIg
        • Less benefit in patients with associated neoplasm
      • Survival: 10 to 60 months; Longer than anti-Hu syndrome
    • Other antibodies: SOX1
    • Laboratory: Hyponatremia
    • Pathology: ? Less neuronal loss than anti-Hu syndromes

VISUAL LOSS SYNDROMES: Paraneoplastic

• Cancer-associated retinopathy (CAR)
  • Clinical
    • Visual loss
      • Onset: Unilateral; Often before detection of tumor
      • Course: Fluctuating; Rapidly progressive
      • Scotomas: Peripheral & ring; Later central
    • CSF: Normal
    • Electrophysiology: ERG abnormal; VER normal
  • Neoplasms: Small cell lung; Melanoma; Gynecologic
  • Antibodies
    • Recoverin (21 kDa calcium-binding protein)
    • Nuclear steroid receptor in outer nucdlear layer of retina ⁴
    • Other protein bands
• Melanoma-associated retinopathy
  • Visual loss
  • Antibody: Bipolar retinal neurons

Paraneoplastic Sensory-Motor Neuromyopathy

• Neoplasm: Many
• Frequency
  • Clinical
    • ~ 5% of patients with cancer: More common later in disease course than at onset
    • 100% with weight loss > 15%
  • Electrophysiological change: 30% to 40%
• Clinical
  • Distribution: Distal; Legs > Arms; Symmetric
  • Sensory: Panmodal sensory loss; Paresthesias
  • Weakness: Distal & Proximal with sparing of intermediate muscles
    • Mild distal weakness 2° axonal neuropathy: Less prominent than sensory change
    • Proximal weakness 2° type II muscle fiber atrophy
• Progression
  • Slow
  • Occurs later in course of disease: Rare at neoplasm onset
  • Severity: Neuropathy not disabling
• Associated disorder: Proximal weakness 2° Type II muscle fiber atrophy
• Lab
  • Nerve conduction: Axonal loss
  • CSF: Normal
  • Pathology: Distal axonal degeneration
• Pathogenesis
  • ? via Cytokines
    • Types: TNF-α; IL-1; IL-6; Interferon-γ;
      Leukemia inhibitory factor (LIF); Ciliary neurotrophic factor (CNTF)
  • Other cachexia related molecules: Uncoupling proteins 2 & 3
  • Origins: Cancer; Immune system in response to cancer
  • Mechanisms: Mimic leptin; Alter body weight regulation
• Differential diagnosis
  • Early in disease: Search for immune neuropathy, or specific paraneoplastic syndrome
  • Late in disease: Tumor infiltration
    • Especially with asymmetry, lymphoma
  • Sensory neuronopathy: Anti-Hu antibodies

OTHER CANCER-ASSOCIATED ANTIBODIES

• Antigen
  • MAP1B
  • Location (IgG binding)
    • Neuron-specific
    • Purkinje cell cytoplasm in soma & dendrites
    • Other: Dentate neurons; Enteric ganglia & nerves; Renal sympathetic axons; Hippocampal pyramidal cell dendrites
• Antibody
  • Serum ± Low titers in CSF
  • IgG
• Associations
  • Frequency: 0.024% of paraneoplastic serum tests
  • Smokers (82%)
  • Neoplasm: Most (80%) lung cancer, especially small cell
  • Other antibodies
    • Hu (13%)
    • CRMP-5 (26%)
    • MAP1A (17%)
    • Ca⁺⁺ channels (P/Q & N) (22%)
    • AChR (Neuronal & Muscle)
• Clinical features
  • Sex: Females 47%
  • Ages: Median 68 years; Range 22 to 89 years
  • Varied syndromes
    • General
      • Similar to varied associations of other SCLC-related antibodies
      • May be multifocal & combinations of syndromes
    • Polyneuropathy (45%): Sensory-Motor
      • Most common: Paresthesias & Pain
    • Encephalopathy (27%): Some with seizures
    • Cerebellar ataxia: 38%
    • Lambert-Eaton myasthenic syndrome: 20%
    • Autonomic neuropathy (15%): GI dysmotility
    • Motor syndrome: 10%
    • Eye: Optic nerve or Retina
    • Spinal cord
    • No neurologic syndrome: 10%
• Laboratory
  • Brain MRI: Spinal cord lesions; Cerebral atrophy
  • CSF: Cells (Median 20/HPF); Protein mildly high (Median 60)