Polyneuropathy

Diseases, ,

Synonyms:

Distal symmetric polyneuropathy

Diagnosis:

This is a clinical diagnosis supported by electrophysiologic (nerve conduction studies and electromyography) testing. The underlying cause may be determined based on blood tests and other testing.

Clinical features:

  • Subtypes: sensory, senosrimotor, autonomic or combination. It may be axonal or demyelinating. Axonal forms are more common.
  • Typical features: Distal symmtric polyneuropathy is usually sensorimotor (affects both sensory and motor nerves), usually affects the distal parts of the extremities first. This may co-exist with small fibre neuropathy and with autonomic neuropathy.
  • The sensory component is usually more prominant than the motor component, but motor predominant types exist.
  • Sensory dysfunction in polyneuropathy:
    • All sensory modalities may be affected in a stocking and glove distribution
    • Prioprioception loss is usually the last modality to be affected
    • Patients may report neuropathic pain, cuts or paresthesias.
    • In hereditary causes the patients rarely report paresthesias
  • Motor dysfunction in polyneuropathy:
    • Tends to affect the distal muscles first
    • Tends to be milder than sensory findings, although motor predominant forms exist
  • Reflexes:
    • These are typically reduced or absent. They are more likely to be absent in demyelinating forms.

Findings on investigations for polyneuropathy in general:

Nerve conduction studies and electromyography NCS/EMG:

  • Protocol should include NCS (sensory +motor +F waves) +/-EMG:
  • Abnormality (>99th or <1st percentile) in two nerves
  • Must include the sural nerve
  • If the patient has normal sural (sensory) and peroneal nerve (sensory/motor) conductions then there is no evidence for polyneuropathy: helps exclude the diagnosis but can not exclude small fibre neuropathy

+Skin biopsy:

  • Immunohistochemistry: polyclonal anti-protein-gene-product 9.5 antibodies (this stains nerve fibres in the skin) to assess Intra-Epidermal nerve fibre density IENF: reduced.
  • If reduced neuropathy is present. If not reduced neuropathy is still possible
  • Helps diagnose co-existent small fibre sensory neuropathy SFSN

Investigations to consider for polyneuropathy in general:

1st line tests:

Nerve conduction studies and electromyography NCS/EMG
If axonal:

  • See patterns below

If demyelinating:

  • See patterns below

1st line blood tests:

  • Fasting blood glucose FBG +/-GTT, B12 level, methylmalonic acid level, Serum protein electrophoresis SPEP and immunoelectrophoresis (immunofixation IFE)
  • FBC, Basic metabolic panel, Creatinine, LFTs, TFTs, ESR
  • LFTs, Phosphate: hypophosphatemia neuropathy

Other tests:

  • Urinalysis: glucose, protein
  • CXR: sarcoidosis
2nd line tests:
  • HIV testing
  • Serum ACE
  • Coeliac disease (gluten neuropathy) antibodies: Antigliadin Ab, antimyelin Ab
  • Syphilis serology, Rheumatoid factor
  • ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • Lyme disease serology, West nile virus serology Hepatitis serology: hepatitis B, hepatitis C
  • Antibodies:
    • Anti-GM1 Ab (multifocal motor neuropathy), anti-MAG Ab (myelin-associated glycoprotein),
    • Anti-GALOP (IgM against central myelin antigen): Gait Disorder, Autoantibody Late-age Onset Polyneuropathy
    • Anti-sulfatide a.k.a. anti-Chondroitin sulfate
    • Anti neuronal antibodies (a.k.a. ANNA-1, anti Hu), anti Yo
  • Cryoglobulins
  • Testing for acromegaly

CSF analysis: IgG index, oligoclonal bands

  • Urine:
    • Bence Jones proteins
    • 24hr urine collection for heavy metal analysis
    • Fresh urine for porphyria

Pathology, biopsies:

  • Lip biopsy: Sjogren syndrome
  • Hair and fingernail clippings for arsenic

Nerve biopsy:

  • Mononeuritis multiplex: vasculitis
  • Sarcoidosis
  • Amyloid neuropathy
  • Leprosy
  • Atypical cases of CIDP
  • Lymphomatous neuropathy (neurolymphomatosis)

Muscle biopsy: see denervation atrophy
Imaging:

  • CT thorax, abdomen, pelvis: small cell carcinoma, ovarian cancer
  • MRI neurography: if NCS/EMG show a localised problem

Genetic testing in polyneuropathy:

  • Demyelinating:
    • AD: PMP22 duplication, PMP22 mutation, (PMP22 is the commonest genetic cause of demyelinating peripheral neuropathy), MPZ mutation
    • X-linked: GJB1 mutation
  • Axonal:
    • AD: MPZ mutation, MFN2 mutation
    • X-linked: GJB1 mutation

 

Classification of distal symmetric polyneuropathy based on clinical and electrodiagnostic pattern:

  • Mixed axonal and demyelinating sensorimotor neuropathy
  • Axonal sensorimotor neuropathy and axonal motor neuropathy
  • Uniform demyelinating neuropathy
  • Acquired Demyelinating neuropathy (sensorimotor) ADN a.k.a. segmental demyelinating neuropathy (sensorimotor)
  • Pure sensory neuropathy (includes sensory ganglioneuronopathy)
  • Small fibre sensory neuropathy SFSN a.k.a. small fibre neuropathy SFN

 

Mixed axonal and demyelinating sensorimotor neuropathy:

NCS:

  • SNAP: reduced amplitude, decreased sensory conducting velocity
  • CMAP: decreased amplitude, decreased motor latency, decreased motor conduction velocity. Mild temporal dispersion may occur.

EMG:

  • Fibrillation and Positive sharp waves PSW in distal muscles.

Investigations to consider:

  • Fasting blood glucose +/-Glucose tolerance test GTT, HbA1c, basic metabolic panel,
  • TFTs, B12, SPEP

 

Axonal sensorimotor neuropathy and axonal motor neuropathy:

NCS:

  • SNAP: reduced amplitude, normal sensory conduction velocity
  • CMAP: reduced amplitude, normal motor latency, normal motor conduction velocity, no temporal dispersion

EMG:

  • Fibrillation and Positive sharp waves PSW in distal muscles.

Investigations to consider:

  • Fasting blood glucose, B1, B12, SPEP, TFT, B6, LFTs (liver disease)
  • Alcohol levels
  • Coeliac disease (gluten neuropathy) antibodies
  • ANA, ANCA, ENA (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere),
  • Lyme serology
  • CXR and ACE level: elevated in sarcoidosis
  • Heavy metal screen: thalium, mercury, gold, lead
  • Paraneoplastic screen
  • CT chest, abdomen, pelvis: underlying neoplasm
  • Nerve biopsy: sarcoidosis,
  • Porphyria testing
  • CSF: increased protein in Axonal Guillain-Barre syndrome
  • CMT Axonal forms

 

Uniform demyelinating neuropathy:

NCS:

  • SNAP: normal amplitude, latency may be increased, conduction velocity may be reduced
  • CMAP: normal amplitude, increased distal latency, reduced conduction velocity
  • No conduction block, no temporal dispersion

EMG:

  • Normal

Investigations to consider:

  • CMT demyelinating subtypes
  • Metachromatic leukodystrophy
  • Krabbe’s disease
  • Adrenomyeloneuropathy
  • Tangier’s disease
  • Cerebrotendinous xanthomatosis

 

Acquired Demyelinating neuropathy (sensorimotor) ADN a.k.a. segmental demyelinating neuropathy (sensorimotor):

*This is an important pattern since many of the causes are treatable
NCS:

  • SNAP: normal or slightly decreased amplitude, decreased sensory conduction velocity
  • CMAP:
    • Conduction block, decreased amplitude may be seen with this
    • Temporal dispersion
    • Increased motor latency, decreased conduction velocity

EMG:

  • Normal

Investigations to consider:

  • CSF: raised protein in CIDP, AIDP
  • SPEP with IFE: osteosclerotic myeloma
  • Tests for CIDP, AIDP
  • Nerve biopsy: Leprosy, CIDP features
  • Arsenic levels: arsenic neuropathy
  • Consider anti-GM1 IgM: multifocal motor neuropathy

 

Pure sensory neuropathy (includes sensory ganglioneuronopathy):

Clinical features:

  • Large fibre involvement:
    • Light touch, vibratory, proprioceptive sensory loss or absent deep tendon reflexes
  • Small fibre:
    • Neuropathic pain; allodynia, hyperalgesia
    • Reduced sensation to pin prick and temperature.
  • Normal motor exam

NCS:

  • SNAP: absent/reduced amplitude, normal sensory conduction velocity
  • CMAP: normal amplitude, normal motor latency, normal motor conduction velocity, no temporal dispersion

EMG:

  • Normal

Investigations to consider:

  • B12
  • B6 levels: high/toxicity
  • Paraneoplastic screen
  • CT chest, abdomen, pelvis: underlying tumor
  • CMT some subtypes
  • Friedrich’s ataxia
  • Spinocerebellar ataxia
  • Abetalipoproteinemia
  • SS-A, SS-B: Sjogren’s syndrome
  • Miller-Fisher variant of Guillain-Barre syndrome
  • SPEP +IFE: paraproteinemia
  • Nerve biopsy: amyloidosis, lymphomatous neuropathy

 

Small fibre sensory neuropathy SFSN a.k.a. small fibre neuropathy SFN:

Clinical features:

  • Small fibre involvement:
  • Neuropathic pain; allodynia, hyperalgesia
  • Reduced sensation to pin prick and temperature.
  • Absence of large fibre involvement: light touch, vibratory, proprioceptive sensory loss or absent deep tendon reflexes
  • Normal motor exam

+Electrodiagnosis NCS (sensory +motor +F waves) +/-EMG:

  • Normal

+Quantitative sensory testing QST:

  • Abnormal

+Skin biopsy:

  • Immunohistochemistry: polyclonal anti-protein-gene-product 9.5 antibodies (this stains nerve fibres in the skin) to assess Intra-Epidermal nerve fibre density IENF: reduced.

Na channel mutations in small fiber neuropathy
Investigations to consider:

  • Fasting blood glucose, HBA1c, TFTs, Lipid profile, ESR, CRP, ANA screen, ENA panel (anti- dsDNA, anti-Sm, anti-RNP, SSA, SSB, anti-Jo-1, antitopoisomerase ‘formerly anti Scl-70’, antinucleolar, anticentromere), ANCA (c-ANCA, p-ANCA), Complement C3, C4 and CH50
  • Infection tests: influenza, HIV
  • Paraneoplastic tests: anti-Hu Antibodies
  • Test for amyloidosis e.g. sural nerve biopsy.
  • Consider:
    • Autonomic neuropathy testing
  • Also see; Tangier disease (high density lipoprotein HDL deficiency), amyloid neuropathy
  • Sensorimotor neuropathy SMN:
    • See under generalised above and under axonal sensorimotor neuropathy and demyelinating sensorimotor neuroapthy

Treatment:

  • Treat the underlying cause
  • Supportive measures and treat complications
  • General measures:
    • Skin care to prevent ulcers
    • Prevention of contractures
    • Protection from minor trauma and burns
  • Monitor respiration function:
    • Forced vital capacity FVC, negative inspiratory force NIF in AIDP
  • Treat orthostatic hypotension if present
  • Treat neuropathic pain if present

 

Causes of polyneuropathy (brief list):

Axonal:

  •  Acute:
    • Porphyria
    • Toxins
    • Axonal form of Guillain Barre syndrome
  •  Subacute:
    • Metabolic and Toxic
  •  Chronic:
    • Metabolic and Toxic
    • Hereditary
    • Diabetic
    • Dysproteinamia

Demyelinating:

Causes of peripheral neuropathy and polyneuropathy (long list):

Immune:

Paraneoplastic:

Endocrine, nutritional and metabolic related:

Toxic:

Infectious:

Hereditary or genetic:

Other causes:

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