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Sensory Neuronopathies ¹⁴

Immune Paraneoplastic with anti-Hu antibodies Sjögren's syndrome Acute: Sensory neuronopathy IgG vs FGFR3 IgG vs Amphiphysin IgM vs TS-HDS Small fiber neuropathy: Non-length dependent Idiopathic Pan-sensory Small fiber Drugs Pyridoxine intoxication Acute High dose (100 - 200 g) Neuronopathy Chronic Moderate dose (0.2 - 10 g/day) Distal axonopathy, Reversible cis-platinum Doxorubicin Animals only: No human cases described Hereditary HSN CANVAS: RFC1 Mitochondrial COX20 POLG HADHA Friedreich Ataxia: Frataxin SCO2 SNAX1 SCA4 SCA25 AVED: ATTP Localized Herpes zoster Also see Sensory Ataxia Dorsal root ganglia Peripheral axons

Sensory Ataxic Disorders with Neuropathy ¹⁵

General Earlier terminology Tabes dorsalis Locomotor ataxia Anatomy: Lesions Dorsal root ganglia Spinal cord: Posterior columns Physical Examination: Features Romberg sign Sensory loss Vibration Joint position Tendon reflexes: Usually absent Also see: Sensory Neuronopathy Causes Immune Paraneoplastic + Anti-Hu antibodies Sjögren's syndrome IgM M-protein MAG antibody Disialosyl moiety: CANOMAD CISP Acute Sensory neuronopathy Miller Fisher Syndrome Nutritional Vitamin deficiencies: B1; B12; E Copper deficiency Toxins Drugs: Pyridoxine; Platin drugs Arsenic Infection Syphilis Diphtheria Hereditary HSN CANVAS SNAX1 Friedreich Ataxia SCA4 CMT 4F AVED ABL Mitochondrial SANDO NARP

Romberg Test

Paraneoplastic Sensory Neuronopathy with Anti-Hu Antibodies ¹

Clinical Features Epidemiology Female: 80% (US study); 15% (European study) White: 98% Age of onset: Mean 60's; Range 39 to 83 Tobacco smoking: > 95% 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 Normal (75%) Sensory-motor involvement (25%): May be subclinical Weakness: Proximal or Distal Rare (5%): Amyotrophy; Fasciculations Course Initial localized pain or sensory loss 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 Associated neurologic syndromes (40% to 70%) Limbic Encephalitis ± Seizures (10%) Epilepsia partialis continua Cerebellar: Ataxia; Nystagmus Autonomic (30%) Blood pressure: Lability; Hypotension (20%) Gastrointestinal Gastroparesis Pseudo-obstruction Esophageal achalasia Urinary (10%) LEMS Myelitis: Patchy weakness; Arms > Legs Brainstem encephalitis Vestibular disorders Oculomotor paresis Bulbar palsy Hearing loss Inappropriate ADH Associated neoplasms (88%) General Often small & slow growing Neoplasm cells: Often express MHC type I Sensory neuronopathy: Often precedes neoplasm diagnosis (3 to 8 months) Small-cell lung cancer 3 Strongest neoplasm association Frequency: 81% of Hu positive serums Prevalence: 17% of SCLC May only be detected by additional or follow-up testing (30%) MRI [18F]fluorodeoxyglucose positron emission tomography Surgical testing Bronchoscopy Mediastinoscopy Thoracotomy Tumor malignancy in Hu antibody+ patients Survival (Variable data) Similar to, or better than, Hu- patients ? More frequent complete response to therapy Limited disease at time of diagnosis Initial metastases tend to spare nervous system Lung adenocarcinoma (6%) Prostate small-cell carcinoma (2.5%) Gynecological cancer (Breast, Ovary, Uterus) (2.5%) Others (rare) Renal; Esophagus; Testis; Melanoma; Thymoma; Hodgkins May coexist with small-cell lung cancer Laboratory features Electrodiagnostic Sensory nerve action potentials (SNAPs) Absent or Reduced diffusely May be variable among nerves Motor studies: Variable involvement Often normal Axon loss: Occasional; May occur without associated weakness Autoantibodies: IgG vs Hu (ANNA 1) Cell targets: Selectively stain nuclei Neurons (PNS & CNS); Adenohypophesis; Adrenal cortex; Retina Clinical correlations Titers Low titers of IgG vs Hu associated with: Neoplasm with no neurologic signs High titers of IgG vs Hu associated with: Neoplasm + Paraneoplastic syndrome Neoplasm association Specificity for neoplasm: Up to 99% Sensitivity for neoplasm: 80% Antibody location: Serum & CSF Antibody type Type: IgG IgG Subtypes: All, but predominantly IgG1 Hu antigens: RNA binding proteins Hu is a family of 35 to 40 kDA neuronal nuclear proteins Proteins: HuD (ELAVL4) ; HuC; Hel-N1; Hel-N2; ple21 Indications for testing Other antibodies: CV-2/CRMP-5 in 15% Serum M-Protein: Never CSF Cells: Mononuclear; High in 50%; 2 to 26/mm3 Protein: High in 70%; 22 to 189 Oligoclonal bands (60%) Pathology Dorsal root ganglion inflammation & neuronal loss: Patchy Inflammation elsewhere in spinal cord or brain: ~ 50% Spinal cord: Loss of axons in posterior columns Intralesional lymphocytes: CD45RO memory cells. Differential diagnosis Toxin: cis-platinum; Pyridoxine Sjögren's Treatment Therapy for neoplasm Neurologic syndrome: None Physical therapy for sensory ataxia Anti-Hu antibodies: Usually persist with reduced titer after tumor treatment

Anti-Hu Antibodies Staining of neuronal nuclei (Cerebellar granule & Purkinje cells) Limbic Encephalitis MRI from A Kornberg

Sjögren's Syndrome 2 Henrik Sjögren

Diagnostic Criteria for Sjögren's Syndrome Criteria Definitions Ocular symptoms Dry eyes every day for more than 3 months Recurrent sensation of sand or gravel in the eyes, or Use of tear substitutes more than three times a day Oral symptoms Dry mouth, daily for more than 3 months Recurrent or persistently swollen salivary glands, or Use of liquids to aid in swallowing dry food Ocular signs Positive Schirmer's test (<5 mm in 5 min), or Rose Bengal score of ≥4 (van Bijsterveld system) Histopathology Minor salivary gland (lip) biopsy: Focus score ≥ 1 Salivary gland involvement Positive: Salivary scintigraphy     Parotid sialography, or     Salivary flow (≤1.5 mL in 15 min) Autoantibodies Antibodies: Ro (SS-A); La (SS-B)   Also see: IgG vs FGFR3 Probable Sjögren's syndrome: 3 criteria present Definite Sjögren's syndrome: 4 or more criteria present.

• General
  • Inflammatory exocrinopathy
    • Affects salivary & lachrymal glands
  • Classification
    • Primary: No associated disorders
    • Secondary: Associated rheumatoid arthritis, lupus or progressive systemic sclerosis
  • Clinical features, Systemic
    • Xerostomia
    • Dry eyes
  • Course: Chronic, slowly progressive
  • Pathogenesis: Autoimmune disease
  • Pathology: Lymphocytic infiltration of exocrine glands
  • Diagnostic exclusions:
    • Past head and neck radiation treatment
    • Hepatitis C infection
    • AIDS
    • Pre-existing lymphoma
    • Sarcoidosis
    • Graft versus host disease
    • Anticholinergic drugs
• Epidemiology
  • Female > Male (9:1)
  • Incidence: 2 in 10,000
  • Prevalence: (0.5 to 1.0%)
  • Onset
    • Peak ~ 50 years
    • Range = Childhood to Late adult
• Clinical Features
  • PNS
    • General features
      • Frequency: 10% to 20% of patients with Sjögren's syndrome
      • May be initial symptom of Sjögren's syndrome
      • No relation to extraneural or serological features
    • Polyneuropathy: Sensory ¹⁰
      • General: Small fiber neuropathy syndromes
      • Frequency
        • Common
        • PNS syndrome present in: 8% to 30% of 1° Sjögren's patients
      • Epidemiology
        • Older patients (> 50 years)
        • Independent of disease duration
      • Clinical
        • Sensory loss
          • Distribution: Symmetric; Distal
          • Modalities
            • Small fiber loss: Pain & Temperature
            • Vibration: Relatively preserved
          • Severity: Mild
        • Paresthesias: Frequency 59%
          • Painful
          • Distal or Non-length dependent
          • Legs > Arms
        • Other clinical features
          • Sweating: Abnormal in 40%
          • Motor: Usually normal
          • Tendon reflexes: Not affected
          • ± Carpal tunnel syndrome
        • Disease course: Non-progressive
      • Laboratory
        • Nerve conduction velocities: Often normal
        • Nerve pathology: Axonal loss
        • Skin: Epidermal nerve fibers
          • Reduced density or Abnormal morphology
          • Non-length dependent pattern of loss
    • Ganglionopathy (Pure sensory neuropathy) ⁸
      • Frequency: Rare
      • Especially females
      • Sensory loss
        • Modalities: All
        • Proximal & Distal
        • Trigeminal involvement (40%)
      • Ataxia: Sensory
      • Pain
      • Adie's pupil (25%)
      • Progression
        • Usual: Slow, insidious
        • Occasional: Rapid progression at onset or after few years
        • Symptoms often stable over many years
      • Nerve biopsy: Loss of myelinated axons
      • Differential diagnosis: CANVAS
    • Autonomic neuropathy
      • Adie's pupil
      • Blood pressure changes
      • Anhidrosis: Associated with small fiber neuropathy
      • Constipation
      • Bladder dysfunction
      • May contribute to Sjögren's features: Dry eyes & mouth
      • ? Associated with IgG binding to M₃-muscarinic AChRs
    • Mononeuritis multiplex ⁹
      • General
        • Frequency: 1% to 2% of Sjögren's patients
        • All described patients female
        • Most with primary Sjögren's
      • Neuropathy
        • Weakness: Asymmetric; Distal; Arms or Legs
        • Sensory: Distal loss; Paresthesias & Pain
        • Nerves: Major nerve involvement (Mediaqn, Ulnar, Peroneal)
      • Systemic disorders
        • Systemic features of Sjögren's
        • Skin: Vasculopathy; Livedo reticularis
      • Pathology: Vasculitis
        • Involvement of epineurial arterioloes & small vessels
        • T-cell inflammation
      • Treatment
        • Corticosteroids & other immunomodulation: Partial response reported in many
    • Treatment
      • Poor response to most immunotherapy
      • ? Infliximab (anti-TNFα) 3 to 5 mg/kg at 0, 2, 6 & q12 weeks ⁷
  • Pain syndromes (44%)
    • Myalgias: 20% to 33%; Back, Hips, Shoulders & Legs
    • Fibromyalgia syndrome: 30%; Diffuse muscle pain, Fatigue, Stiffness
  • Cranial nerve disorders
    • Trigeminal sensory neuropathy
    • Occasional III & VIII
  • CNS (8%)
    • Younger patients: < 50 years
    • Encephalopathy: Fatigue; Memory loss; Depression; Psychosis
    • Transverse myelitis
    • ± Focal or multifocal CNS signs: Ataxia; Hemiparesis
    • MRI: Hyperlucent lesions, especially in white matter, on T2
  • Myopathy ⁶
    • Usually subclinical
    • Not related to muscle pain
    • Weakness (10%): Proximal; Arms > Legs
    • Serum CK: Usually normal
    • Muscle pathology
      • Inflammation in muscle (70%): Perivascular
      • Inflammatory myopathy (50%)
      • Vacuolar changes: Noted in some patients; Atypical morphology; Older patients
      • Immunocytochemistry
        • MHC class I (50%)
        • MHC class II (44%)
        • MAC (C_5b-9) deposition (75%)
          • Location: Capillaries
          • More frequent with sicca symptoms & other SS associated conditions
  • Systemic features
    • Sicca syndrome
      • Xerophthalmia: Dry reddened eyes; Deficient tear production
      • Xerostomia: Dry mouth; Increased dental caries
      • Vaginal dryness
    • Skin
      • Hypergammaglobulinemic purpura
        • Multiple; Symmetric; Lower extremity; Non-palpable
        • With type II mixed cryoglobulinemia
        • Vaginal dryness
        • Raynaud's (35%)
        • Candidiasis
      • Palpable purpura: With vasculitis, cutaneous or systemic
    • Thymus hyperplasia
    • Vasculopathies, other: Raynaud's (30%)
    • Parotid swelling: Especially younger patients
    • Discomfort: Myalgias; Arthralgias (60%); Fatigue
    • Respiratory: Bronchitis; Thick secretions; Lymphoma; Interstitial pneumonitis
    • GI: Atrophic gastritis; Dysphagia; Liver disease
    • Lymphadenopathy
    • Endocrine
      • Hypothyroidism; Thyroiditis
      • Adrenal insufficiency
    • GU
      • Renal dysfunction: Often subclinical
      • Interstitial cystitis
      • Membranous glomerulonephritis: Often in the Sjögren’s/SLE overlap group
    • Pediatrics
      • Children: Recurrent parotitis
      • Neonates: Pregnant with anti-Ro & anti-La antibodies have 1:20 risk of delivering a baby with heart block
  • Disease associations
    • Rheumatoid arthritis
    • Systemic lupus erythematosis
    • Progressive systemic sclerosis
    • Vasculitis
    • Chronic active hepatitis
    • Lymphoma: Non-Hodgkins
      • Frequency: 40x increased risk; 5%
      • Type: IgMκ B-cell
      • Low grade
      • Disease association: Later in course
    • HTLV-1
  • Treatment
    • Mostly symptomatic
    • ? D-penicillamine, Corticosteroids, Hydroxychloroquine
    • ? Infliximab: Neuropathy
• Laboratory
  • Electrodiagnostic
    • Absent sensory potentials
    • Normal motor studies
  • Serum autoantibodies
    • ANA (Hep-2 cells): Homogeneous or Fine speckled; > 1:320
    • IgG (IgG1) vs SS-A or SS-B: Associated with
      • Earlier disease onset
      • Longer disease duration
      • Salivary gland enlargement
      • Severity of lymphocytic infiltration of minor salivary glands
      • Extraglandular manifestations: Lymphadenopathy, Purpura, Vasculitis
    • Antibodies to α-fodrin
    • Rheumatoid factor: High > 1:320
    • B-cell hyperreactivity: Polyclonal elevation of serum Ig
    • IgG vs M₃-muscarinic AChRs ⁵: Occur in both 1° & 2° Sjögren's; 70%
    • Disease target antigen location: ? Epithelial cells of exocrine glands: Antibody
    • Cryoglobulins: Worse prognosis
  • Leukopenia: Mild
  • HLA associations
    • HLA-B8, -DR3 & -DRw52
    • Class II genes: HLA DQA1*0501 allele
  • Pathology
    • Nerve
      • Inflammation: Dorsal root ganglia; Perivascular
      • Axon loss
    • Small fiber sensory neuropathy: Skin biopsy
      • Axon loss: Non-length dependent pattern
    • Lymphocytes
      • CD4+ infiltration of exocrine glands
      • Ectopic lymphoid structures
    • Diagnosis: Minor salivary gland biopsy
      • Biopsy clinically normal (lip) mucosa
      • Focal sialidenitis: Clusters of > 50 mononuclear cells/mm²
  • Ocular dryness: Schirmer < 8mm wetting in 5 min; + Rose bengal test
  • Parotid salivary flow: Reduced

Sensory Neuropathy/Neuronopathy with serum IgG vs FGFR-3 ¹³

• Target antigen: Fibroblast Growth Factor-3, Intracellular domain
• Antibody type: IgG
• Epidemiology
  • Female:Male = 5:3
• Clinical syndrome
  • Onset
    • Age: 18 to 73 years
    • Course: Progressive or Acute
  • Sensory
    • Loss (95%)
      • Modalities: Large & Small fiber
      • Limbs ± Face
    • Pain (45%)
    • Ataxia (60%)
  • Associated disorders
    • Immune (59%): Sjögren, Lupus
• Laboratory
  • NCV: Neuropathy (90%), Often non-length dependent
  • Nerve pathology: Axon loss without regeneration
  • Small fiber neuropathies (Skin biopsy): Non-length dependent axon loss

Idiopathic Sensory Neuronopathy: Pan-sensory

• Epidemiology
  • Female > Male
  • Ages: 40's to 60's
• Clinical
  • Sensory loss
    • Distribution
      • Extremities, Face & Trunk
      • Asymmetric
    • Large > Small fiber
    • Sensory ataxia: + Romberg
  • Discomfort: Hyperalgesia
  • Autonomic
    • Occasional: Usually subclinical
    • Types: Adie's pupils; Loss of sinus arrhythmia; Reduced Valsalva ratio
  • Tendon reflexes: Absent
  • Motor: Normal strength
  • Progression: Slow
• Laboratory
  • CSF: Protein & Cells usually normal
  • Electrophysiology
    • SNAPs: Absent or Reduced amplitudes
    • CMAPs: Occasional reduced amplitudes
• Treatment: Occasional response to IVIg ⁴

Sensory Neuronopathy: Small fiber ¹¹

• Onset
  • Age: 18 to 64 years
  • Pain & Dysesthesias
  • Hands or Face in 40%
  • Course: Days to Years
• Clinical
  • Strength: Normal
  • Sensory
    • Loss distribution
      • Not length dependent
      • Hands, Face, Scalp, Tongue, Trunk & Feet
    • Modalities affected
      • Pain: Most common
      • Vibration: Some patients
      • Joint position: Normal
    • Pain
    • Paresthesias
  • Tendon reflexes: Normal
  • Course
    • Progressive
    • Persistent pain
• Laboratory
  • Skin biopsy: Non length dependent loss of small axons
  • Abnormal glucose tolerance: 23%
  • Nerve conduction studies
    • Usually normal
    • Reduced SNAP amplitude in some patients
• Treatment: Pain control

Cerebellar Ataxia, Neuronopathy, Vestibular Areflexia Syndrome (CANVAS) ¹²

• Epidemiology
  • > 200 patients
  • CANVAS clinical syndrome: > 50%
  • Common cause of HSAN with Cough & Ataxia
  • North America: 1.6% to 3% of undiagnosed ataxia
  • Late onset Ataxia
    • Frequency: 22%
    • Ataxia + Sensory Neuronopathy: 62% of patients
  • Male = Female
• Genetics
  • Common Mutation: Biallelic expansion of intronic repeat in Alu element
    • Normal allele: (AAAAG)₁₁
    • Disease
      • Expansion sizes: 400 to 2,000; Most ~ 1,000
      • Expnsion Patterns
        • AAGGG(n)
        • (AAAGG)10-25(AAGGG)n
        • (AAAGG)10-25(AAGGG)n(AAAGG)4-6
      • Some repeat units replaced by AAGGG
      • Repeat size: Stable within families
      • Size of smaller repeat: Larger → ↓ Onset age & ↑ Disease severity
    • Allelic carrier frequency of AAGGG repeat: 0.7%
    • Nucleotide change
      • From AAAAG to AAGGG or AAAGG
      • May represent ancestral founder event
      • Expanded AAAAG repeats: Not pathogenic
      • GAAGG: Uncertain significance
    • Disease features: Severity & Onset ¹⁹
      • Associated with repeat length: Especially shorter allele
  • Other mutations: Truncating (Nonsense)
  • Allelic disorders
    • Ataxia, Late onset (20%)
    • Multiple System Atrophy
    • HSAN ± Cough or Ataxia ¹⁷
    • Ataxia ± Cough ¹⁸
    • ALS-like syndromes: Possible association with RFC1 expansion ²¹
  • Other expansions in Alu elements
    • Friedreich ataxia
    • SCA37
    • Benign adult familial myoclonic epilepsy (FAME1)
• RFC1 protein: DNA repair
  • Loads proliferating cell nuclear antigen onto DNA
  • Activates DNA polymerases &delta & ε
  • Promotes coordinated synthesis of both DNA strands
    • During replication
    • After damage
• Clinical
  • Onset
    • Age: Mean 53 to 60 years; Range 15 to 71 years
    • Gait imbalance
    • Cough
  • Cerebellar & Vestibular
    • Eye movements
      • Saccadic smooth pursuit
      • Visually enhanced vestibulo-ocular reflex (VVOR): Abnormal
      • Saccadic eye movements with slow head turn while eyes visually fixed on target
      • Combined loss of
        • Smooth pursuit (Cerebellar)
        • Vestibulo-ocular reflex (VOR; Vestibular)
    • Ataxia: Appendicular; Dysarthria
    • Nystagmus: Gaze-evoked; Horizontal or Down beat
  • Polyneuropathy/Neuronopathy: Sensory (100%)
    • Gait disorder: Sensory ataxia; Imbalance; Often worse in dark
    • Sensory loss
      • Pan-modal
      • Anatomic patterns: Diffuse or Distal Dominant
    • Romberg sign
    • Tendon reflexes
      • Varied: Ankles absent, Normal or Brisk
      • Distinctive pattern
        • Brisk DTRs & present H-reflex with
        • Absent SNAPs or reduced SNAP amplitudes
  • Autonomic (25%)
    • Lightheadedness
    • Dry mouth/eyes
    • Cold feet
    • Hypohidrosis: Feet
    • Constipation
    • Erectile dysfunction
    • Urinary leakage
  • Cough ²⁰: Some patients
    • Early in disease course
      • May occur as isolated symptom
      • Asymptomatic SNAP abnormalities common
    • Features
      • Bursts
      • Non-productive
    • Environmental triggers: Dry foods
  • Pyramidal (29%): Spasticity; Tendon reflexes brisk
  • Lower motor neuron (18%)
    • Cramps
    • Fasciculations
    • Weakness: Distal
  • Extrapyramidal (10%)
  • Hearing: Normal
  • Strength: Normal
  • Course
    • Progressive: Slow; Over decades
    • Some require wheelchair
  • Differential diagnosis
    • Multiple system atrophy (MSA)
    • SCA27B
• Laboratory
  • Brain MRI
    • Cerebellar atrophy
      • Anterior & Dorsal vermis & Hemispheric crus I
      • Symmetric
    • Basal ganglia: Atrophy
    • Brainstem: Small
    • White matter: Corpus callosum & Deep tracts
  • NCV: Suggest sensory ganglionopathy
    • SNAPs: Absent (91%)
    • Motor: Normal
  • Vestibular testing
    • Bilateral vestibulopathy
    • Abnormal smooth-pursuit eye movements
    • Vestibulo-ocular reflex (VOR): Abnormal
    • Visual acuity on vertical head shaking: Reduced
  • Autonomic testing
    • Postural hypotension
    • Sympathetic
      • Postural systolic blood pressure decline
      • Diastolic blood pressure response to sustained handgrip reduced
    • Parasympathetic
      • Heart rate response to deep breathing or standing reduced
      • Valsalva ratio low
  • Pathology
    • Cerebellum
      • Purkinje cell loss
      • Vermal atrophy
      • No RNA foci
    • Sensory ganglia: Loss of neurons
      • Vestibular
      • Trigeminal
      • Facial
      • Dorsal root
    • Spinal cord: DRG atrophy; Posterior column axon loss
    • Nerve pathology
      • Axon loss
      • Vessels abnormal
    • Muscle: Chronic denervation with reinnervation
• RFC1 variant: Multiple system atrophy (MSA) ¹⁶
  • Epidemiology: Pentanucleotide repeat expansion in 1% of Chinese MSA patients
  • Genetics
    • Inheritance: Recessive
    • Mutation: Biallelic (AAGGG)exp or heterozygous with (AAAGG)exp
  • Clinical
    • Onset age: 34 to 60 years
    • Gait ataxia
    • Bradykinesia
    • Autonomic: Urinary; Hypotension; Constipation
  • Laboratory
    • Brain imaging: Cerebellar atrophy
    • Vestibular hypofunction

Limbic encephalitis from A Kornberg