Sensory Neuronopathies

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SENSORY NEURONOPATHIES

Immune
Idiopathic
- Pan-sensory
- Small fiber
Drugs
- Pyridoxine intoxication
  - Acute; High dose (100 - 200 g)
  - Chronic (0.2 - 10 g/day) produces reversible distal axonopathy
- cis-platinum
- Doxorubicin (animals only, no human cases described)
Hereditary
Localized: Herpes zoster

Also see

Paraneoplastic Sensory Neuronopathy with Anti-Hu Antibodies ^¹

Anti-Hu Antibodies

Staining of neuronal nuclei
(Cerebellar granule &
Purkinje cells)

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%)
  - Occasional sensory-motor involvement (25%): May be subclinical
  - Weakness may be 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 syndromes (40% to 70%)
  - Limbic Encephalitis ± Seizures (10%)
  - Epilepsia partialis continua
  - Cerebellar: Ataxia; Nystagmus
  - Autonomic (30%)
    - Blood pressure: Lability; Hypotension (20%)
    - Constipation (10%)
    - Intestinal obstruction (10%)
    - Urinary (10%)
      Limbic Encephalitis
      MRI
      
      from A Kornberg
  - LEMS
  - Myelitis: Patchy weakness; Arms > Legs
  - Brainstem encephalitis
    - Vestibular disorders
    - Oculomotor paresis
    - Bulbar palsy
    - Hearing loss
  - Gastrointestinal
    - Gastroparesis
    - Pseudo-obstruction
    - Esophageal achalasia
  - Inappropriate ADH
- Associated neoplasms (88%): Often small & slow growing
  - Small-cell lung cancer³
    - Strongest neoplasm association
    - External link: Telescan
      - 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
  - Others (rare)
    - Breast; Ovary; Renal; Esophagus; Testis;
      Prostate; Melanoma; Thymoma; Hodgkins
    - May coexist with small-cell lung cancer
  - Hu antibody associated neoplasm cells often express MHC type I
Laboratory features
- Electrodiagnostic
  - Sensory nerve action potentials (SNAPs)
    - Absent or Reduced diffusely
    - May be variable among nerves
  - Motor studies: Variable involvement
    - Often normal
    - Occasional axonal loss: 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 and paraneoplastic syndrome
  - Antibody location: Serum & CSF
  - Antibody type
    - 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 ; HuC; Hel-N1; Hel-N2; ple21
  - Indications for testing
- Other antibodies: CV-2 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
- Pathology
  - Dorsal root ganglion inflammation & neuronal loss: Patchy
  - ~ 50% with inflammation elsewhere in spinal cord or brain
  - 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

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) or La (SS-B)
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: Sensory¹⁰
    - 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
        
        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
    - Laboratory
      - Nerve conduction velocities: Often normal
      - Nerve pathology: Axonal loss
      - Skin: Epidermal nerve fiber with reduced density or abnormal morphology
  - 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
  - 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 multiplex⁹
    - 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 weeks⁷
- 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
- Myopathy⁶
  - 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
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
    - Axonal loss
  - Lymphocytic (CD4+) infiltration of exocrine glands
  - 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
Treatment
- Mostly symptomatic
- ? D-penicillamine, Corticosteroids, Hydroxychloroquine
- ? Infliximab: Neuropathy

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 IVIg⁴

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

Limbic encephalitis

from A Kornberg

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References
1. Neurology 1998;50:652-657, Brain 2002;125:166-175, Brain 2003;126:1409-1418
2. Clin Rheumatol 1999;18:299-303, Best Pract Res Clin Rheumatol 2004;18:313-329
3. JNNP 1999;67:353-357
4. Neurology 2000;54:1008
5. Arthritis & Rheumatism 2000;43:1647-1654
6. J Rheumatol 2002;29:717-725
7. Neurology 2002;59:1113-1114
8. J Rheumatol 2003;30:1552-1557
9. Mod Rheumatol 2003;13:160-167
10. Muscle Nerve 2006;33:672�676, Neurology 2005;65:925-927
11. JNNP 2007 Oct 2

10/12/2007

SENSORY NEURONOPATHIES

Paraneoplastic Sensory Neuronopathy with Anti-Hu Antibodies1

Sjögren's syndrome2

Idiopathic Sensory Neuronopathy: Pan-sensory

Sensory Neuronopathy: Small fiber 11

Paraneoplastic Sensory Neuronopathy with Anti-Hu Antibodies ^¹

Sjögren's syndrome^²

Sensory Neuronopathy: Small fiber ¹¹