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Sensory Neuronopathies 14


Sensory Ataxic Disorders with Neuropathy 15


General

Causes
   

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
      • 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
  • 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.

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


Idiopathic Sensory Neuronopathy: Pan-sensory


Sensory Neuronopathy: Small fiber 11


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

  Replication factor C subunit 1 (RFC1) ; Chromosome 4p14; Recessive
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
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11. JNNP 2007 Oct 2
12. Ann N Y Acad Sci 2011;1233:139-147, Neurology 2014;82: Online March, Brain 2014; Online July, J Neurol 2018 Apr 25, Nat Genet 2019;51:649-658, J Neurol Neurosurg Psychiatry 2020 Jul 30, Brain 2021 Dec 20
13. JNNP 2015; Online Jan, J Neurol Neurosurg Psychiatry 2019 Nov 5, Muscle Nerve 2019 Oct 25
14. Muscle Nerve 2015 Oct 15
15. J Neurol 2020 Jun 15
16. Ann Neurol 2020 Sep 16
17. Front Neurol 2022;13:986504
18. Neurol Genet 2022;8(5):e200016

10/18/2022