Peripheral Neuropathies & Nerve Injury Classification

Patterns of Neuropathy

Axonal vs demyelinating. Most acquired neuropathies are axonal: the axon degenerates from its distal end, so nerve conduction studies show reduced amplitudes with near-normal velocities, and EMG shows denervation. Demyelinating neuropathies damage myelin or Schwann cells, so impulses slow or fail to cross the injured segment.

Length dependence and fiber size. The longest axons fail first, so symptoms begin in the toes, climb toward the knees, and reach the fingertips at about the time leg symptoms reach knee level. Small fibers (Aδ and C) carry pain, temperature, and autonomic function; their loss causes burning pain, allodynia, and autonomic symptoms. Large fibers carry vibration, proprioception, and motor output; their loss causes numbness, sensory ataxia with a positive Romberg sign, and weakness.

Anatomic patterns. A mononeuropathy involves one nerve, usually by compression or entrapment (median nerve at the carpal tunnel, peroneal nerve at the fibular head). Mononeuritis multiplex is painful, stepwise, asymmetric damage to separate named nerves from infarction of their blood supply, caused by vasculitis (polyarteritis nodosa, often hepatitis B-associated; EGPA), diabetes, sarcoidosis, or leprosy; many overlapping lesions can merge and mimic a symmetric pattern. Polyneuropathy is diffuse, symmetric, and usually distal.

Diabetic Neuropathy

Distal symmetric polyneuropathy. Diabetes is the leading cause of polyneuropathy in developed countries. It is length-dependent and axonal: burning feet and allodynia (small fibers) with lost vibration, monofilament sensation, and ankle reflexes (large fibers). Contributing mechanisms include sorbitol accumulation through aldose reductase, advanced glycation end products, oxidative stress, and microvascular ischemia of the vasa nervorum. Insensate feet develop painless ulcers and Charcot neuropathic joints, so foot examination with a monofilament is routine. Neuropathic pain responds to duloxetine, pregabalin, gabapentin, or tricyclic antidepressants.

Autonomic neuropathy. Gastroparesis (early satiety, vomiting, erratic glucose), orthostatic hypotension, fixed resting tachycardia, erectile dysfunction, neurogenic bladder, and hypoglycemia unawareness.

Focal neuropathies. Diabetic CN III palsy spares the pupil because ischemia damages the core of the nerve while the parasympathetic pupillary fibers run on its surface; a compressive aneurysm dilates the pupil. Diabetic amyotrophy (lumbosacral radiculoplexus neuropathy) presents with acute, asymmetric thigh pain, proximal leg weakness, and weight loss. Entrapment neuropathies such as carpal tunnel syndrome are also more common.

Acquired Causes

Nutritional and metabolic. Thiamine (B1) deficiency, often from alcohol use, causes dry beriberi (symmetric sensorimotor axonal neuropathy) and, with high-output heart failure, wet beriberi. B12 deficiency pairs a neuropathy with dorsal column and corticospinal damage. Pyridoxine (B6) deficiency, classically from isoniazid, causes a sensory neuropathy prevented by B6 supplements; paradoxically, B6 megadoses cause a sensory neuronopathy with ataxia. Alcohol adds direct toxicity, producing a painful axonal neuropathy. Uremia causes a distal axonal sensorimotor neuropathy, often with restless legs, that improves with dialysis or transplantation. Hypothyroidism causes a mild polyneuropathy and carpal tunnel syndrome from myxedematous tissue; other carpal tunnel associations are pregnancy, diabetes, rheumatoid arthritis, acromegaly, and amyloidosis (including dialysis-related β2-microglobulin amyloid).

Infections. Mycobacterium leprae, the leading infectious cause worldwide, prefers cool tissues and invades Schwann cells, producing thickened, palpable nerves with anesthetic hypopigmented patches (tuberculoid) or widespread symmetric sensory loss (lepromatous). HIV causes a painful distal symmetric sensory neuropathy, worsened by older nucleoside analogs such as stavudine. Lyme disease causes facial palsy, often bilateral, and painful radiculoneuritis.

Paraproteins and amyloid. IgM MGUS with anti-MAG antibodies causes a distal demyelinating, sensory-ataxic neuropathy. AL amyloidosis causes a painful small-fiber and autonomic neuropathy with carpal tunnel syndrome, and hereditary transthyretin amyloidosis produces a similar picture. POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M protein, Skin changes) arises from a lambda plasma cell clone with sclerotic bone lesions and high VEGF; its demyelinating neuropathy is often mistaken for CIDP.

Immune and Hereditary Neuropathies

CIDP. Chronic inflammatory demyelinating polyneuropathy is the chronic counterpart of Guillain-Barré syndrome: it progresses or relapses for more than 8 weeks, whereas GBS peaks within 4 weeks. Symmetric proximal and distal weakness, sensory loss, and areflexia are accompanied by demyelinating conduction, albuminocytologic dissociation in CSF, and onion bulbs on biopsy. Unlike GBS, CIDP responds to corticosteroids; IVIG and plasma exchange also work.

Charcot-Marie-Tooth disease. The most common inherited neuropathy. CMT1A, the most frequent type, is an autosomal dominant duplication of PMP22, a myelin protein gene on chromosome 17p, giving uniform demyelinating slowing. Beginning in childhood or adolescence, patients develop distal atrophy (stork legs), pes cavus, hammer toes, foot drop with a steppage gait, areflexia, and mild sensory loss; repeated demyelination and remyelination form onion bulbs. CMT2 is an axonal form. Deletion of PMP22 causes hereditary neuropathy with liability to pressure palsies, with recurrent palsies after minor compression.

Nerve Injury and Regeneration

Wallerian degeneration. When an axon is cut, the distal segment and its myelin break down and are cleared by macrophages and Schwann cells, while the neuronal cell body undergoes chromatolysis. Schwann cells then align into bands of Büngner that guide sprouts from the proximal stump.

Tracking recovery. An advancing Tinel sign marks the regenerating front, and the distance to the target muscle predicts when function should return. Sprouts that cannot find the distal tube form a painful neuroma.

If an injured nerve shows denervation on EMG, the injury is not a pure neurapraxia; if no recovery occurs by the time regrowth should have arrived, suspect neurotmesis and consider surgical exploration.