Neurology & Internal Medicine & Family Medicine
Peripheral neuropathy
Peripheral neuropathy refers to a group of conditions affecting the nerves of the peripheral nervous system—namely the cranial nerves (with the exception of the optic nerve), the spinal roots, the plexuses, and the peripheral nerves of the limbs—which transmit sensory (touch, pain, temperature, proprioception), motor (muscle contraction), and autonomic (heart rate, blood pressure, digestion, sweating) signals between the central nervous system and the rest of the body. It encompasses a wide variety of clinical presentations—from tingling in the feet to the paralyzing Guillain-Barré syndrome, from silent diabetic neuropathy to debilitating burning neuropathic pain—and an equally broad range of causes: diabetes is by far the most common cause in industrialized countries (diabetic polyneuropathy is present in 50 to 60% of people with diabetes after 25 years of disease progression), followed by chronic alcoholism, vitamin deficiencies (B12, B1), drug-induced neuropathies (chemotherapy, metronidazole, isoniazid), and hereditary neuropathies (Charcot-Marie-Tooth disease). From a pathophysiological perspective, peripheral neuropathies can affect the axon (axonal neuropathies—the most common, often metabolic or toxic), the myelin sheath (demyelinating neuropathies—often inflammatory or hereditary), or both components simultaneously (mixed neuropathies). Distinguishing between these types, performed via electromyography (EMG) with assessment of nerve conduction velocities, is fundamental as it guides the determination of etiology, prognosis, and treatment. Management combines treatment of the underlying cause when it is identifiable and modifiable, and symptomatic treatment of neuropathic pain—one of the most difficult chronic pains to treat—based on tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoid anticonvulsants.
Anatomical and electrophysiological classification
- Polyneuropathy Diffuse and symmetrical involvement of all peripheral nerves, with length-dependent distribution (longest fibers affected first) → symptoms starting in the feet and gradually ascending to the knees and then the hands (sock-and-glove distribution) → most common causes of neuropathy in general → diabetes, alcoholism, deficiencies, medications
- Mononeuropathy single peripheral nerve involvement → symptoms limited to the nerve's distribution area + causes: mechanical compression (carpal tunnel syndrome—median nerve + ulnar nerve palsy at the elbow + fibular nerve palsy at the knee) + trauma + ischemia (diabetic mononeuropathy) + Lyme disease + sarcoidosis
- Multiple mononeuropathy (mononeuritis multiplex): successive or simultaneous involvement of several distinct nerves in non-contiguous territories → asymmetric presentation + suggestive of nerve vasculitis (polyarteritis nodosa + cryoglobulinemia + SLE + Churg-Strauss syndrome) + diabetes + sarcoidosis + Lyme disease
- Axonal neuropathy (EMG: reduced potential amplitude - normal or slightly decreased conduction velocities): axonal degeneration itself + metabolic causes (diabetes + alcohol + uremia) + toxic causes (chemotherapy + heavy metals) + deficiency causes (B12 + B1 + B6) + hereditary causes (CMT type 2) + slow and incomplete recovery
- Demyelinating neuropathy (EMG: very reduced conduction velocities — prolonged distal latencies — conduction blocks): destruction of the myelin sheath + inflammatory causes: Guillain-Barré syndrome (GBS) + chronic inflammatory demyelinating polyneuropathy (CIDP) + paraproteinemic neuropathy + hereditary causes: Charcot-Marie-Tooth disease type 1 (CMT1) + potentially better recovery if cause is treated (CIDP)
- Small fiber neuropathy Selective involvement of unmyelinated sensory fibers (C fibers) and thinly myelinated fibers (A-delta fibers) responsible for pain and thermoalgesia + normal standard EMG (measures only myelinated fibers) + diagnosis by skin biopsy (reduced epidermal nerve fiber density) + or quantitative sensory testing (QST) + causes: diabetes + Sjögren's syndrome + amyloidosis + HIV + hypothyroidism + idiopathic (frequent)
Main etiologies
| Etiology | Mechanism and clinical features | Distinctive diagnostic features |
|---|---|---|
| Diabetic polyneuropathy | Most common cause in Quebec and industrialized countries + mechanisms: chronic hyperglycemia → oxidative stress + glycation of nerve proteins + ischemia of vasa nervorum → early axonal damage of small fibers then large fibers + sock-and-glove distribution + insidious and progressive + burning nocturnal pain + paresthesias + distal hypoesthesia + ulceroneuropathic foot at risk | High HbA1c + fasting blood glucose + duration of diabetes + foot exam (10g monofilament + 128 Hz tuning fork + pinprick) + EMG confirms distal axonopathy + annual screening recommended for all diabetics |
| Alcoholic neuropathy | Second leading cause of chronic polyneuropathy in Western countries + mixed mechanism: direct toxicity of alcohol on axons + vitamin B1 (thiamine) deficiency often associated + distal sensory and motor involvement + intense burning pain + cramps + sensory ataxia + possible Wernicke's encephalopathy if severe B1 deficiency | Documented chronic alcohol consumption + elevated GGT and MCV + B1, B6, B12, folate levels + distal axonopathy EMG + partial improvement with alcohol withdrawal + vitamin supplementation |
| Vitamin B12 deficiency | Subacute combined degeneration of the spinal cord (posterior columns + pyramidal tracts) AND peripheral nerves (subacute combined degeneration) + symmetrical distal paresthesias + proprioceptive ataxia + Lhermitte's sign (electric shock on neck flexion) + causes: atrophic gastritis + pernicious anemia + bariatric surgery + strict vegetarianism + long-term metformin | Low serum vitamin B12 (< 150 pmol/L) + macrocytosis + megaloblastic anemia + high methylmalonic acid (more sensitive functional marker) + anti-intrinsic factor + axonal-demyelinating EMG + rapid correction with IM B12 supplementation before irreversible lesions |
| Guillain-Barré Syndrome (GBS) | Post-infectious acute inflammatory demyelinating polyradiculoneuritis (AIDP) (Campylobacter jejuni + CMV + EBV + SARS-CoV-2) + rapid onset of flaccid paralysis (days to 4 weeks) + areflexia + albumin-cell dissociation in CSF + may affect respiration (20–30% require mechanical ventilation) + neurological emergency | CSF: elevated protein + normal cells (albuminocytologic dissociation) + EMG: conduction blocks + reduced velocities (AIDP form) or pure axonopathy (AMAN form) + IVIG or plasmapheresis for treatment + monitoring of vital capacity (intubation if VC < 15-20 mL/kg) |
| Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) | Chronic Guillain-Barré: progressive or relapsing course over more than 8 weeks + symmetric proximal and distal limb weakness + areflexia + sensory disturbances + autoimmune + may be associated with myeloma + MGUS + diabetes | LCR: elevated proteins + demyelinating EMG + sural nerve biopsy in atypical forms + treatment: IVIG + corticosteroids + plasma exchange + rituximab in refractory forms |
| Drug-induced and toxic neuropathies | Chemotherapy (paclitaxel + oxaliplatin + vincristine + cisplatin) → dose-dependent sensorimotor neuropathy + metronidazole + isoniazid (B6 deficiency) + statins (rare) + heavy metals (lead + arsenic + mercury) + organic solvents (hexane) | Detailed medical and occupational history + heavy metal testing if exposure is suspected + B6 dosage if isoniazid + improvement upon drug discontinuation (partial for chemotherapy) + sensorimotor axonopathy EMG |
| Charcot-Marie-Tooth disease (CMT) | Group of hereditary neuropathies (prevalence 1/2,500) + CMT1 (demyelinating - PMP22 mutation) + CMT2 (axonal) + onset in childhood or adolescence + pes cavus foot deformities (high arches + hammer toes) + leg atrophy (stork legs) + progressive distal weakness + areflexia + little to no neuropathic pain | Family history (often unknown) + symmetric demyelinating EMG + very reduced conduction velocities (CMT1: CV < 38 m/s) + genetic analysis (17p11.2 duplication — PMP22 for CMT1A) + no curative treatment + physiotherapy + orthotics |
Etiological assessment
In the face of any polyneuropathy, a minimal first-line assessment helps identify the most common and modifiable causes:
- First-line blood test: Fasting blood glucose + HbA1c (diabetes) + Complete blood count + Mean corpuscular volume (macrocytosis → B12 deficiency + alcoholism) + Serum vitamin B12 + Folates + TSH (hypothyroidism) + Creatinine + Glomerular filtration rate (uremia) + Complete liver function tests + GGT (alcoholism) + Serum protein electrophoresis (MGUS + myeloma) + ESR + CRP (inflammatory or infectious process)
- Second-line assessment based on clinical context Lyme serology (Borrelia burgdorferi) + HIV + Hepatitis B and C (cryoglobulinemia) + ANA + ANCA + anti-ganglioside antibodies (GQ1b + GM1 + GD1b) + immunofixation (paraprotein) + methylmalonic acid and homocysteine levels (functional B12 deficiency) + TSH + parathyroid hormone + vitamins B1 + B6 + urine toxicology + blood heavy metals if occupational exposure
- Electromyography (EMG) with nerve conduction studies (NCS): baseline test to confirm neuropathy + characterize the type (axonal vs. demyelinating vs. mixed) + specify the distribution (polyneuropathy + mononeuropathy + mononeuritis multiplex) + assess severity + guide etiological investigation + EMG does not replace clinical assessment — a normal EMG does not rule out small fiber neuropathy
- Skin biopsy (density of intraepidermal nerve fibers — IENF): 3 mm cutaneous punch biopsy + anti-PGP 9.5 immunohistochemical staining + intraepidermal nerve fiber count + reference method for small fiber neuropathy + available at select university neurology centers in Quebec
- Sural nerve biopsy rarely necessary in routine practice + indicated if cause is uncertain after complete workup + or if vasculitis of the nerves is suspected + or granulomatous neuropathy (sarcoidosis) + or amyloidosis
Neuropathic pain treatment
| Drug | Dosage and protocol | Efficacy and side effects |
|---|---|---|
| Amitriptyline or nortriptyline (ATC) – first line | Amitriptyline: 10 to 25 mg at bedtime + increase of 10 to 25 mg every 1 to 2 weeks + target dose 25 to 75 mg/night (higher doses than for depression) + nortriptyline: better tolerated in the elderly (less anticholinergic) 10 to 75 mg/night | NNT (Number Needed to Treat) of 2 to 3 for a 50% reduction in pain (%) + also effective for associated insomnia and anxiety + side effects: dry mouth + constipation + urinary retention + drowsiness + risk of falls in the elderly + QT prolongation (ECG required beforehand if heart disease is present) |
| Duloxetine (Cymbalta®) — first-line | 30 mg/morning × 1 week then 60 mg/morning + maximum dose 120 mg/day + SNRI inhibiting serotonin and norepinephrine reuptake + approved by Health Canada for diabetic peripheral neuropathic pain | NNT of 4 to 5 + fewer anticholinergic effects than TCAs + adverse effects: nausea (frequent at first + subsides) + insomnia + slight increase in blood pressure + increased risk of bleeding if NSAIDs are combined + contraindicated in severe liver failure |
| Gabapentin (Neurontin®) - First-line | Start 300 mg/night + gradual increase of 300 mg every 3 to 7 days + target dose 900 to 3,600 mg/day in three divided doses + slow titration to limit initial somnolence + reduce dose if GFR < 60 mL/min | NNT from 4 to 6 for paresthesias, burning sensations, and allodynia. Side effects: somnolence, dizziness, lower limb edema, weight gain, memory problems, risk of dependence (controlled substance in some provinces). |
| Pregabalin (Lyrica®) — first-line | 75 mg twice daily + increase to 150 mg twice daily after 1 week + maximum dose 300 mg twice daily + more predictable pharmacokinetic profile than gabapentin + dose reduction for renal impairment | NNT similar to gabapentin + proven efficacy in diabetic neuropathy + postherpetic neuralgia + fibromyalgia + similar adverse effects to gabapentin + controlled substance + documented dependence at high doses |
| Tramadol — second or third line | 50 to 100 mg every 4 to 6 hours (max 400 mg/day) + LP (long-acting release): 100 to 300 mg/day + weak opioid agonist + serotonin-norepinephrine reuptake inhibitor | Effective in second-line therapy if first-line therapy is insufficient + risk of dependence and abuse + serotonergic interactions (serotonergic agents + SNRIs + SSRIs + triptans) + convulsions at high doses + contraindicated in severe hepatic or renal insufficiency |
| Topical capsaicin (0.075% cream or 8% patch — Qutenza®) | 0.075% cream (%): apply 3 to 4 times daily to the painful area + 8-patch (%) (Qutenza®): single 60-minute application administered by a healthcare professional + repeatable every 12 weeks + TRPV1 receptor agonist → desensitization of cutaneous nociceptors | 0.075% cream %: modest efficacy + initial local burning sensation (subsides after 2 to 4 weeks) + 8% patch %: superior efficacy + duration of action 12 weeks + ideal for localized pain or if systemic medications are contraindicated + no systemic effects |
ℹ️
Diabetic neuropathy of the feet is the leading cause of non-traumatic lower limb ulcers and amputations in Quebec and Canada. Every diabetic patient should undergo a foot examination at every medical visit—10-g monofilament (pressure sensitivity) + 128 Hz tuning fork (vibration sensitivity) + prick test + skin inspection + foot and posterior tibial pulses. Early detection of peripheral neuropathy allows for the implementation of preventive measures (appropriate footwear + regular podiatric care + therapeutic education) that reduce the risk of ulceration by 50 to 60%.
Situations requiring urgent medical assessment
Call 911 or go to the emergency room immediately if progressive muscle weakness of the limbs appears rapidly (over a few days to weeks), especially if it rises from the feet to the thighs and then the trunk. This presentation suggests Guillain-Barré syndrome, a neurological emergency, where involvement of the respiratory muscles may require intubation and mechanical ventilation. Dysphagia, dysphonia, difficulty raising the arms, or decreased respiratory effort are additional warning signs that warrant immediate hospitalization.
Prompt medical consultation (within the following days) is recommended for numbness or burning pain in the feet in a known diabetic patient, asymmetrical loss of sensation in the limbs, or symptoms of dysautonomia (orthostatic hypotension + digestive problems + genitourinary problems) — these manifestations may indicate progressive neuropathy requiring a complete workup and modification of risk factor treatment.
For the evaluation of peripheral neuropathy, prescribing etiological workup, requesting EMG, and referral to neurology, Clinique Omicron offers medical consultations at its service points in Quebec and through telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's physicians and nurse practitioners (NPs) assess patients presenting with symptoms of peripheral neuropathy (numbness + burning pain + distal weakness + balance disorders), prescribe initial etiological workup, order EMG with nerve conduction studies, initiate neuropathic pain treatment (amitriptyline + duloxetine + gabapentin), and refer to neurology for complex or severe cases requiring nerve biopsy or immunomodulatory treatment. Consultations are available at several service points in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute medical or neurological advice. Any rapidly progressing muscle weakness associated with sensory disturbances requires urgent medical evaluation to rule out Guillain-Barré syndrome or another neurological emergency.
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