Glenn A. Mackin, MD, FAAN, FACP
DESCRIPTION
Acquired or hereditary disorder of multiple peripheral nerves. Injury to sensory and/or motor axons/neurons, myelin, and/or autonomic fibers.
EPIDEMIOLOGY
Incidence
- Sparse population-based, cause-specific data
- Age: Occurs at all ages
Prevalence
- Overall: 2,400/100,000 (2.4%)
- Elderly: 8,000/100,000 (8%)
- Neuropathy Association (US) estimates 5–10% of US population (30 million) affected
RISK FACTORS
- Genetic mutations: Listed elsewhere
- Habits: Alcohol, poor diet, smoking, HIV risks
- Toxic medications: Amiodarone, bortezomib, chloramphenicol, chloroquine, cisplatin, dapsone, colchicine, cytarabine, disulfiram, docetaxel, ergots, ethambutol, gold, hydralazine, imipramine, indomethacin, isonicotinylhydrazine, linezolid, metronidazole, misonidazole, nitrofurantoin, nucleoside, oxaliplatin, paclitaxel, phenytoin, perhexiline, penicillamine, procainamide, pyridoxine, procarbazine, statins, sulfa, suramin, tacrolimus, thalidomide, vincristine
- Occupational: Acrylamide, allyl chloride, arsenic, biphenyls, cadmium, carbon disulfide, ethylene oxide, dichlorodiphenyltrichloroethane, hexacarbons, lead, mercury, methyl bromide, nitrous oxide, organophosphates, thallium, trichloroethylene, triorthocresyl phosphate, vacor
- Environmental: Cold, vibration, electric injury
Genetics
- HMSN (hereditary motor sensory neuropathy; Charcot–Marie–Tooth disease), many types
- Autosomal dominant > recessive, X-linked
- Demyelinating (HMSN-I), axonal (HMSN-II)
- HNPP (hereditary neuropathy with liability to pressure palsies). Entrapment vulnerability
- Hereditary sensory neuropathies (HSN)
- Hereditary sensory autonomic neuropathies
- Familial amyloid polyneuropathy (FAP)
- Leukodystrophies (metachromatic, globoid cell/Krabbe’s), lipoprotein disorders (HDL deficiency/Tangier’s, abetalipoproteinemia), lysosomal enzyme deficiency (Fabry’s)
- Peroxisomal: Adrenomyeloneuropathy
- Porphyrias (acute intermittent, variegate)
- Miscellaneous: Refsum's disease (phytanic acid accumulation), giant axonal neuropathy
- Multisystem: Myotonic dystrophy, Friedrich's ataxia, spinocerebellar degenerations
GENERAL PREVENTION
- Balanced, nutritious diet; blood sugar control
- Avoid excess alcohol, excess B6, above risks
PATHOPHYSIOLOGY
- Axon loss with secondary demyelination
- Primary demyelination, secondary axon loss
- Multifocal neuropathy (immune, compressive)
ETIOLOGY
- Genetic: Multiple identified gene mutations
- Acquired: Commonest acquired neuropathy in Western world is diabetes; worldwide is leprosy
COMMONLY ASSOCIATED CONDITIONS
- Immune-mediated
- Primary demyelinating diseases
- Acute inflammatory demyelinating polyneuropathy [AIDP; Guillain–Barré (GBS)]
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
- Multifocal motor neuropathy (MMN)
- Collagen vascular diseases (Behçet’s, mixed connective tissue, relapsing polychondritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus)
- Gastrointestinal (celiac, inflammatory bowel)
- Granulomatosis (sarcoidosis, Wegener’s)
- Vasculitis (connective tissue syndromes, hypersensitivity, systemic necrotizing vasculitis, polyarteritis nodosa, Churg–Strauss, others)
- Infection (HIV, Lyme, leprosy, syphilis)
- Metabolic [diabetes, dyslipidemia, thyroid, malabsorption, malnutrition, porphyria, vitamin deficiencies (B1, B6, B12, E), acromegaly]
- Malignancy (lymphoma, myeloma, infiltrating)
- Paraneoplastic (sensory neuropathy or neuronopathy, sensory motor neuropathy)
- Multi-organ failure (critical-illness neuropathy)
- Paraproteins [monoclonal gammopathy of undetermined significance (MGUS), myeloma, Castleman’s, cryoglobulinemia, POEMS, primary systemic amyloidosis, Waldenstrom's macroglobulinemia]
- Cryptogenic: Incidence approx 50% in elderly
HISTORY
- Numbness (lost pinprick, vibration, position)
- Dysesthesias (tingling, burning, lancinating)
- Hypersensitivity (heat, cold, touch intolerance)
- Gait ataxia, pseudoathetosis (large fiber loss)
- Muscle weakness, atrophy, and fatigability
- Muscle cramps, fasciculations
- Autonomic dysfunction (hyperhidrosis or anhidrosis; dry skin; dry eyes and mouth; orthostasis; bowel, bladder, sexual dysfunction)
- Cranial nerves (facial numbness, tingling, weakness; diplopia, rarely dysarthria/dysphagia)
PHYSICAL EXAM
- Hyporeflexia, ranging ankles only to areflexia.
- Most acquired polyneuropathies involve slow “dying-back” of axons, resulting in a “fiber-length-dependent” pattern of symmetrical sensory before motor loss starting in the feet. As tingling reaches mid-calves, fingertips start tingling, and so forth.
- Asymmetric or non-length-dependent acquired neuropathies (hands involved before or with feet).
- Primary demyelinating (e.g., AIDP, CIDP). Diffuse reflex loss, motor predominant signs
- Mononeuropathies multiplex: Random sensory motor deficits of “named” nerves
- HMSN: Many genotypes, similar phenotypes, variable severity. Pes cavus, hammertoes, foot drop. Diffuse hyporeflexia to areflexia (HMSN-I) vs. relatively preserved reflexes (HMSN-II).
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
- Rational lab testing requires knowing whether neuropathy acute or subacute/chronic, symmetric or multifocal, primarily axonal or demyelinating, and fiber-type specific or mixed sensory motor.
- Among identifiable neuropathies, most likely cause usually is a known or clinically identifiable disease, mutant gene, metabolic (diabetes and prediabetes are the commonest acquired causes), medication toxicity, vitamin deficiency, alcoholism, IV drug abuse, occupational or environmental exposure.
- Primary tests (everyone, if not recently done):
- EMG and nerve conductions (NCS) – essential
- Blood tests: CBC,CMP, FBS, HgbAIc, TSH, B12, ESR, ANA, SSA, SSB, RF, SPEP/UPEP
- Secondary tests (often, specific suspicion or abnormality above): 2-hour glucose tolerance (most important of all), antiendomysial IgA and t-TG (small fiber), methylmalonic acid, B1, B6, SIFE, UIFE, hepatitis B and C, T4, dsDNA, C3, C4, CH50, Lyme, HIV, RPR; CXR (atypical sensory).
- Tertiary tests (uncommon, specific suspicion and/or abnormal lab): ANCA, ACE, cryoglobulins, porphyrins (motor), Vitamin E, lead and mercury (motor), arsenic and thallium (sensory), copper.
- Quaternary (rare, specific diseases, genetics):
- GM1 ganglioside Ab: Seen in 60% of MMN. Most helpful if no NCS conduction block
- Anti-MAG antibody: Seen in 50% of CIDP with IgM MGUS; refractory to immunotherapy
- Anti-Hu (ANNA-1): Paraneoplastic sensory neuropathy, usually in SCC lung; CXR, CT
- GQ1B ganglioside: Miller-Fisher variant AIDP
- Antisulfatide antibody: Sensory neuropathies
- HMSN panels: HMSN types, CMT-X, HNPP
- Transthyretin: Amyloid (autosomal dominant, small-fiber sensory–autonomic; organs)
Imaging
Initial Approach
- Suspected “pseudo-neuropathic” symptoms from CNS: MRI brain, lumbosacral/cervical spine
- Atypical sensory neuropathy, suspected to be paraneoplastic: CXR, CT chest/abdomen/pelvis
Follow-Up & Special Considerations
- Possible polyradiculoneuropathy (CIDP, infection, cancer): Contrast MRI of spine, CSF
- Plexopathy (inflammatory, infectious, cancer, hypertrophic): MRI brachial/lumbosacral plexus
- Paraprotein: Skeletal survey (plasmacytoma)
Diagnostic Procedures/Other
- EMG/NCS: Indispensable test to characterize axonal vs. demyelinating, acuteness and severity.
- Cutaneous punch biopsy: Verify small-fiber dying-back polyneuropathy. Can stain for amyloid.
- Nerve biopsy [uncommon, mostly sural nerve; sometimes superficial peroneal sensory fascicle when suspect diagnostic material inside nerve (e.g., vasculitis; amyloidosis; tumor, rarely CIDP)].
- CSF: Albuminocytologic dissociation in demyelinating polyneuropathies (few or no WBC, elevated protein in AIDP and CIDP; HIV-related AIDP >50 WBC). CIDP often very high protein (>125–150 mg/dL). Abnormal Lyme PCR, VDRL.
- Quantitative sensory testing: Sensory thresholds for small and large axonal functions.
- Autonomic testing: Quantitative sudomotor axon reflex test, thermoregulatory sweat test, EKG R-R interval, tilt table, Schirmer’s.
- Other biopsies: Minor salivary gland (Sjögren’s), rectal mucosa or fat pad (amyloid).
DIFFERENTIAL DIAGNOSIS
- Ask whether polyneuropathy is truly present. “Pseudo-neuropathic” referred from CNS.
- Consider time course (acute over days, AIDP, some toxic neuropathies; subacute over months, some inflammatory and vasculitic; or chronic over years, mostly axonal).
- Note associated diseases (diabetes, uremia), family history (HMSN, FAP), habits and occupational exposures (e.g., painters and lead; smelters and arsenic, plastics, and acrylamide; farmers and organophosphates).
- Consider the anatomic distribution.
- Symmetric “length–dependent,” stocking-glove, legs > arms, distal > proximal: Over
of neuropathies, most axon loss (Mimics: CIDP, mononeuropathy multiplex). - Proximal ≥ to distal signs, symmetric (e.g., AIDP/GBS, occasionally CIDP).
- Asymmetric, multifocal pattern. Uncommon. Mononeuropathies multiplex (random lesions affecting “named” nerves, usually vasculitic infarcts, diabetic), inflammatory or infiltrative processes, MMN, HNPP.
- Ascertain whether paresthesias are present. “Positive” sensory symptoms (e.g., tingling, burning) often indicate acquired neuropathy. HSN can be dysesthetic, HMSN usually not.
- Note if symptoms are predominantly sensory or motor. Most acquired neuropathies are pure sensory or sensory > motor. AIDP, CIDP, HMSN-I, HMSN-II are mainly motor.
- Painful (alcohol, amyloid, arsenic, diabetes, uremia, cancer, vasculitis, small fiber).
- Note diffuse hyporeflexia (demyelinating polyneuropathies, AIDP, CIDP, HMSN-I).
- Consider other informative physical findings.
- Palpably large peripheral nerves (HMSN-I, amyloid, leprosy, occasionally CIDP).
- Autonomic (AIDP, porphyria, amyloid, renal).
- Determine if there is selective but uncommon fiber-type involvement, narrowing differential.
- Large sensory neurons/axons (ataxic): Paraneoplastic (SCLC), Sjögren’s, toxic (B6), cis-platinum, docetaxel, vincristine, vitamin deficiency (B12 or E), idiopathic.
- Small sensory neurons/axons (often painful): Elderly cryptogenic sensory neuropathy, diabetes, vasculitis, amyloid, arsenic, HIV.
- Motor neurons/axons: Motor neuron diseases, HMSN-II, demyelinating (MMN, AIDP, CIDP), porphyria, lead, dapsone.
- Autonomic: Diabetes, amyloid, AIDP, HIV, vincristine, paclitaxel, amiodarone, porphyria, HSAN, idiopathic and paraneoplastic pandysautonomias.
- Obtain NCS to determine whether primary process is axonal loss or demyelination.
MEDICATION
First Line
- AIDP/GBS: Plasma exchange (PLEX) = IVIg
- CIDP: Steroids, azathioprine, mycophenolate mofetil, cyclosporine; IVIg or PLEX if severe
- Connective tissue: Treat primary condition
- Deficiency states: Appropriate supplement
- Familial amyloid neuropathy: Liver transplant
- MMN: IVIg, cyclophosphamide, rituximab
- Osteosclerotic myeloma: XRT and/or surgery
- MGUS: If mild, monitor; if severe, PLEX, IVIg, immunosuppression (IgM and MAG are refractory)
- Vasculitis: Corticosteroids, cytotoxic agents
- Generic Rx: α-Lipoic acid, acetyl-L-carnitine
ADDITIONAL TREATMENT
General Measures
- Rational, pattern-recognition, cost-effective testing approach. If unusual progression presents or emerges, re-evaluate, consider nerve biopsy.
- Low threshold for consulting neuromuscular diseases specialized neurologist for unexplained neuropathy, especially <age 50, no family history.
- Treatment of cause – if known – may halt or improve neuropathy (e.g., tight diabetes control).
- Immunotherapy for autoimmune neuropathies.
- Effectively treat neuropathic, nociceptive pain.
- Monitor cognition and function on analgesics.
- Limit complications of immunosuppressants.
- Steroids: Calcium, bisphosphonates, DEXA
- Immunosuppressants: Monitor LFTs, CBC
- Encourage exercise and well-balanced diet.
- Review “alternative” meds for possible toxins.
- Limit vitamin B6 to <50 mg/day (RDA is 2 mg).
- Frequently inspect insensate feet for trauma.
- Excellent foot and nail care (e.g., diabetics).
- Lubricants to avoid cracking, drying, infection.
- Effective arch supports, customized shoewear.
- AFOs (footdrop) or boots (ankle instability).
- Ambulation aids, visual guidance for ataxia.
- Car hand controls (severe proprioceptive loss).
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Symptomatic treatment
- Neuropathic pain: Antiepileptics (gabapentin, pregabalin (1)[A], carbamazepine (2)[B]; others), antidepressants (tricyclic, duloxetine (3)[A]), topical agents (lidocaine, capsaicin [B]), mexiletine, clonidine, opioids (off label)
- Nociceptive pain: Nonsteroidals, tramadol
- Autonomic: Tears, midodrine, elastic hose
- Adjunctive treatment
- Depression: Exercise, medication, counseling
- PT: Flexibility, endurance, range of motion
- OT: Adaptive aids, splints, home safety
- Durable goods: AFO, cane, walker, scooter, wheelchair, ramps, grab bars, shower seats
SURGERY/OTHER PROCEDURES
- Nerve biopsy: Biopsy site pain may persist.
- Other biopsies: Skin, minor salivary gland, abdominal fat pad, rectal mucosa, bone marrow.
IN-PATIENT CONSIDERATIONS
Admission Criteria
- AIDP: ICU or high-level monitor, FVC q shift
- Severe: PLEX, IVIg, IV immunosuppression
FOLLOW-UP RECOMMENDATIONS
Variable, depends on rate of progression.
DIET
Balanced diet. Standard multivitamin.
PATIENT EDUCATION
- Charcot-Marie-Tooth Association, PO Box 105, Glenolden, PA 19036. Phone: 800-606-2682 (US) or 610-499-9264. Website: www.cmtausa.org
- The Neuropathy Association, 60 East 42nd Street, Suite 942, New York, NY 10165. Phone: 212-692-0662. Website: www.neuropathy.org
PROGNOSIS
Quite variable, depending on specific cause
