Peripheral Neuropathy

Primary Axonal Degeneration (Axonopathy)

• Axonal degeneration begins distally and progresses proximally in a "dying-back" pattern, resulting in a characteristic length-dependent distribution affecting longest fibers first
• The pathophysiologic basis involves disruption of axonal transport (both anterograde and retrograde), leading to depletion of essential proteins, neurotransmitters, and metabolic substrates at the distal axon
• Axonopathies are typically metabolic in origin: hyperglycemia in diabetes impairs axonal glycolysis and increases oxidative stress via the polyol pathway and advanced glycation end-products (AGEs); mitochondrial dysfunction reduces ATP availability for ion pumps and transport proteins
• Toxic axonopathies (chemotherapy, heavy metals, alcohol) accumulate their metabolites preferentially in distal axons, exceeding the capacity of axonal repair mechanisms and leading to progressive degeneration
• Electrophysiologically, axonopathies show reduced compound muscle action potential (CMAP) amplitudes with relatively preserved conduction velocities and normal distal latencies (reflecting intact remaining axons)
• Morphologically, axonal loss predominates with relative preservation of myelin structure, though secondary demyelination may occur as a consequence of axonal loss

Primary Demyelination (Myelinopathy)

• Demyelinating neuropathies result from autoimmune attack on myelin-producing cells (Schwann cells) or myelin antigens themselves, or from genetic defects in myelin proteins
• The molecular basis in acquired demyelination involves complement-mediated destruction of myelin and antibodies against nodal proteins (contactin-associated protein, neurofascin) or paranodal domains, disrupting the ordered structure of nodes of Ranvier
• Loss of myelin segments increases membrane capacitance and reduces conduction velocity disproportionately; conduction block (complete failure of action potential propagation) may occur at demyelinated segments, causing rapid and severe weakness despite preserved axonal integrity
• In genetic demyelinating neuropathies (e.g., Charcot-Marie-Tooth disease type 1 caused by PMP22 mutations), abnormal myelin formation during development and adulthood results in onion-bulb formations (concentric layers of Schwann cell processes) on electron microscopy
• Electrophysiologically, demyelinating neuropathies show disproportionately slowed conduction velocities (<80% of lower limit of normal), prolonged distal latencies, and conduction blocks; CMAP amplitudes may be relatively preserved early
• Demyelinating neuropathies often have proximal predilection and may show proximal-distal dissociation of slowing in conditions like CIDP (chronic inflammatory demyelinating polyradiculoneuropathy)

Neuronopathy (Cell Body Involvement)

• Neuronopathies result from primary pathology in the neuronal cell body (dorsal root ganglion neurons for sensory neuropathies; anterior horn cells for motor neuropathies), causing degeneration of both axons simultaneously rather than distally first
• The mechanism involves either direct cellular infiltration (paraneoplastic ganglionitis), toxic accumulation within neuronal perikarya, or infectious destruction
• Pathophysiologically, this leads to "sensory neuronopathy" (selective dorsal root ganglion involvement) or "motor neuronopathy," affecting all fiber calibers relatively uniformly rather than showing length-dependence
• Affected neurons show characteristic central chromatolysis with loss of Nissl substance on histology
• Clinically and electrophysiologically, neuronopathies cause greater proximal than distal involvement and relatively early loss of sensory nerve action potentials (SNAPs) with preserved motor conduction velocities initially

Common Pathophysiologic Mechanisms Across Neuropathy Types

• Oxidative Stress and Inflammation: Increased reactive oxygen species (ROS) from hyperglycemia, mitochondrial dysfunction, or toxic exposure activates nuclear factor-kappa B (NF-κB) and other inflammatory cascades, promoting neuroinflammation and nerve damage
• Mitochondrial Dysfunction: Impaired oxidative phosphorylation reduces ATP synthesis, impairing Na+/K+ ATPase function and axonal transport; this is particularly relevant in toxic and metabolic neuropathies
• Disruption of Ion Channel Function: In acquired neuropathies, antibodies may target voltage-gated potassium or calcium channels; in genetic neuropathies, mutations in SCN9A (sodium channel), TRPV1 (pain receptor), or other ion channels cause sensory or motor dysfunction
• Impaired Axonal Regeneration: Schwann cell dysfunction, deficient neurotrophic factors (NGF, GDNF), or intrinsic axonal limitations prevent adequate nerve regeneration, leading to chronic deficits

Metabolic and Systemic Diseases

• Diabetes Mellitus (most common cause in developed nations): Both hyperglycemia-induced metabolic stress (polyol pathway accumulation, AGE formation, oxidative stress) and microvascular ischemia of the vasa nervorum contribute to predominantly distal, symmetric, length-dependent, sensorimotor axonal neuropathy; risk increases with duration and glycemic control, though tight glycemic control in DCCT showed only modest reduction in neuropathy progression
• Uremia/Chronic Kidney Disease: Accumulation of uremic toxins (particularly middle molecular weight substances) causes axonal neuropathy; severity correlates with degree of renal insufficiency and improves with dialysis
• Hypothyroidism: Causes a predominantly demyelinating neuropathy, sometimes with carpal tunnel syndrome and myxedema coma complications; thyroid hormone replacement reverses the neuropathy
• Hypoglycemia: Acute severe hypoglycemia may cause transient neuropathic symptoms; chronic mild hypoglycemia is not established as a cause

Nutritional and Vitamin Deficiencies

• Vitamin B12 Deficiency (cobalamin): Causes subacute combined degeneration affecting dorsal and lateral spinal cord columns as well as peripheral nerves; neuropathy may be irreversible if prolonged, and neurologic manifestations may precede hematologic findings; pernicious anemia from intrinsic factor antibodies is most common cause in developed countries
• Thiamine (Vitamin B1) Deficiency: Causes acute Wernicke encephalopathy (ophthalmoplegia, ataxia, confusion) and chronic Korsakoff syndrome, with associated peripheral neuropathy; alcohol use disorder is the primary risk factor in developed nations
• Vitamin E Deficiency: Causes ataxia with prominent posterior column involvement and spinocerebellar degeneration; associated with fat malabsorption syndromes (cystic fibrosis, celiac disease, abetalipoproteinemia)
• Pyridoxine (B6) Deficiency and Toxicity: Deficiency (rare in developed nations) causes sensorimotor neuropathy; excessive supplementation (>2 g/day) causes large-fiber sensory neuropathy with ataxia and dorsal root ganglion destruction
• Pantothenic Acid, Niacin, and Folate Deficiencies: Less common but documented causes in malnourished populations

Infectious Causes

• HIV-Associated Neuropathy: Multiple mechanisms include distal sensory polyneuropathy (most common, painful, small-fiber predominant) from direct HIV neurotoxicity and antiretroviral toxicity (didanosine, stavudine), inflammatory demyelinating polyradiculoneuropathy, mononeuropathy multiplex, and opportunistic infections (CMV polyradiculopathy, herpes zoster)
• Leprosy (Mycobacterium leprae): Causes infectious mononeuropathy multiplex with characteristic asymmetric nerve thickening; still endemic in parts of Africa and Southeast Asia; damage results from both direct bacterial invasion and immune-mediated inflammation
• Lyme Disease (Borrelia burgdorferi): Causes Lyme neuroborreliosis with painful radiculopathies, mononeuropathy multiplex, or cranial nerve palsies (particularly CN VII); common in endemic areas (northeastern US, Northern Europe)
• Hepatitis C Virus (HCV): Associated with mixed cryoglobulinemia, causing vasculitic neuropathy with painful mononeuropathy multiplex; also direct HCV-related axonal neuropathy
• CMV Polyradiculopathy: Occurs in severely immunocompromised hosts (CD4 <50), causing lumbosacral polyradiculomyelitis with lower extremity weakness and urinary retention; requires urgent IV ganciclovir

Inflammatory and Autoimmune Neuropathies

• Guillain-Barré Syndrome (GBS) / Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP): Fulminant ascending paralysis with areflexia developing over days; electrodiagnostic findings show demyelination with conduction blocks; commonly preceded by infection (Campylobacter jejuni, other respiratory/GI pathogens); diagnosis requires clinical recognition as CSF and EMG findings lag behind symptoms; ~5% progress to respiratory failure
• CIDP (Chronic Inflammatory Demyelinating Polyradiculoneuropathy): Progressive or relapsing-remitting demyelinating neuropathy with proximal predilection; diagnosis requires ≥2 months of symptoms with supportive electrodiagnostic criteria (prolonged distal latencies, slowed conduction velocities, conduction blocks, prolonged F-wave latencies) or CSF protein elevation; responsive to immunotherapy (IVIG, plasma exchange, corticosteroids)
• Vasculitic Neuropathy: Systemic vasculitis (polyarteritis nodosa, microscopic polyangiitis, Churg-Strauss syndrome, ANCA-associated) causes painful mononeuropathy multiplex from ischemic nerve infarction; diagnosis requires nerve/muscle biopsy showing vasculitis of epineural vessels; requires urgent immunosuppressive therapy to prevent progressive disability

Malignancy-Related Neuropathy (Paraneoplastic and Infiltrative)

• Paraneoplastic Sensory Neuronopathy: Selective dorsal root ganglion destruction associated with small cell lung cancer, breast cancer, and other malignancies; mediated by antibodies (anti-Hu/ANNA-1, anti-CV2/CRMP5) targeting neuronal antigens; presents with prominent proprioceptive loss and ataxia; often precedes cancer diagnosis
• Paraneoplastic Lambert-Eaton Myasthenic Syndrome (LEMS): Associated with small cell lung cancer in 50% of cases; caused by autoantibodies against presynaptic P/Q-type calcium channels; presents with proximal weakness, autonomic dysfunction, and decreased reflexes that augment with sustained contraction
• Leptomeningeal Infiltration: Direct neoplastic invasion of nerves (e.g., lymphoma, breast cancer) causes polyradiculopathy or plexopathy; requires MRI and CSF cytology
• Chemotherapy-Induced Peripheral Neuropathy (CIPN): Platinum agents (cisplatin, oxaliplatin), taxanes (paclitaxel), vinca alkaloids, bortezomib, and proteasome inhibitors cause dose-dependent axonal neuropathy; often irreversible; cumulative dose-limiting toxicity

Toxic/Medication-Related Neuropathies

• Alcohol: Chronic ethanol causes toxic axonal neuropathy via direct neurotoxicity, thiamine deficiency, and liver disease; typically presents as distal, symmetric, sensorimotor polyneuropathy with painful paresthesias
• Platinum Chemotherapy: Cisplatin and oxaliplatin cause dose-dependent axonal neuropathy via accumulation in dorsal root ganglia; oxaliplatin uniquely causes acute temperature-sensitive neuropathy
• Antiretrovirals: Reverse transcriptase inhibitors (didanosine, stavudine) cause dose-limiting distal sensory neuropathy; modern regimens have lower incidence
• Metronidazole and Fluoroquinolones: Can cause sensory neuropathy with prolonged use
• Thalidomide and Lenalidomide: Immunomodulatory agents causing dose-dependent axonal neuropathy in multiple myeloma patients
• Heavy Metal Exposure (lead, arsenic, mercury, thallium): Cause predominantly motor axonal neuropathies with characteristic findings (lead: motor neuropathy with radial/ulnar nerve predilection and encephalopathy; thallium: alopecia and severe pain)
• Organophosphates and Pesticides: Cause cholinergic crisis acutely and delayed neuropathy chronically

Genetic/Inherited Neuropathies

• Charcot-Marie-Tooth Disease (CMT): Most common hereditary neuropathy (prevalence 1:2500); heterogeneous group subdivided into demyelinating (CMT1, AD, slow conduction velocities) and axonal forms (CMT2, variable inheritance); over 100 genes identified; CMT1A (PMP22 duplication) accounts for 50% of cases; presents in childhood/adolescence with distal weakness, pes cavus, and tremor; CMT2 typically has later onset and faster conduction velocities
• Hereditary Sensory and Autonomic Neuropathy (HSAN): Rare autosomal recessive or dominant disorders causing progressive loss of pain and temperature sensation with prominent autonomic dysfunction and skin ulceration; HSAN1 (AD) causes neuropathic ulcers on feet; HSAN5 and HSAN9 mutations in NGF receptor genes cause loss of pain/temperature with preserved vibration sense
• Familial Amyloid Polyneuropathy (FAP): Autosomal dominant inheritance of transthyretin (TTR) mutations causes progressive axonal neuropathy with autonomic involvement (orthostatic hypotension, GI dysmotility), carpal tunnel syndrome, and cardiac arrhythmias; endemic in Portugal, Japan, and Sweden; recently targetable with tafamidis (TTR kinetic stabilizer)
• Fabry Disease: X-linked lysosomal storage disorder with α-galactosidase deficiency causing accumulation of globotriaosylceramide; presents with small-fiber neuropathy causing acral pain ("Fabry crises"), angiokeratomas, cardiac involvement, and renal failure; treatable with enzyme replacement therapy (imiglucerase, agalsidase)
• Krabbe Disease and Other Leukodystrophies: Dysmyelinating disorders affecting central and peripheral nervous systems; infantile form presents with neuropathy and developmental regression

Metabolic Neuropathies (Non-Diabetic)

• Porphyria: Acute intermittent porphyria causes episodic autonomic instability, psychiatric symptoms, and motor neuropathy triggered by certain medications, fasting, or stress; urgent management with IV heme
• Hypophosphatasia: Alkaline phosphatase deficiency causing rickets and bone disease with associated neuropathy in severe forms

Compression/Entrapment Neuropathies

• Carpal Tunnel Syndrome: Most common entrapment neuropathy; median nerve compression at wrist causing paresthesias in thumb, index

The classic length-dependent pattern

• Stocking-glove sensory loss: numbness and tingling begin in the toes and ascend; hands typically become involved once leg symptoms ascend to about the knee, when arm fiber length matches the affected leg fiber length. The stem is usually a patient with long-standing type 2 diabetes, a patient with alcohol use disorder, or one on chemotherapy.
• Small-fiber symptoms first in metabolic/toxic axonopathy: burning, lancinating, or allodynic pain and loss of pinprick and temperature, with preserved reflexes and vibration early — small unmyelinated C and thinly myelinated A-delta fibers are the most metabolically vulnerable and are affected earliest.
• Large-fiber signs: loss of vibration at the great toe (128-Hz tuning fork), impaired proprioception, sensory ataxia with a positive Romberg sign, and loss of ankle jerks — the ankle reflex arc is the longest and dies first.
• Motor findings: distal weakness with toe extensor and intrinsic foot muscle wasting, pes cavus and hammertoes in chronic/hereditary disease, foot drop with a steppage gait, and atrophy producing an inverted champagne bottle leg in Charcot-Marie-Tooth.

Patterns that point away from a simple axonopathy

• Demyelinating polyradiculoneuropathy: ascending weakness over days with early global areflexia and only mild sensory loss; proximal and distal weakness together (conduction block, not axon loss). Often follows Campylobacter gastroenteritis or a viral illness.
• Mononeuropathy multiplex: stepwise, painful, asymmetric deficits in named nerves (e.g., wrist drop then foot drop) from nerve infarction — think vasculitis, diabetes, leprosy, or HCV cryoglobulinemia.
• Sensory neuronopathy: non–length-dependent numbness involving face, trunk, and arms with profound proprioceptive loss and pseudoathetosis; classically paraneoplastic with small cell lung cancer.
• Autonomic features: orthostatic hypotension without compensatory tachycardia, gastroparesis, erectile dysfunction, anhidrosis — prominent in diabetes, amyloid, and porphyria.

• Axonal: reduced CMAP and SNAP amplitudes, near-normal conduction velocities and distal latencies; EMG shows fibrillations and large polyphasic reinnervation potentials in distal muscles.
• Demyelinating: conduction velocity slowing well below the lower limit of normal (roughly <70–80%), prolonged distal and F-wave latencies, temporal dispersion, and conduction block. Uniform slowing suggests hereditary CMT1; multifocal, non-uniform slowing suggests acquired CIDP.
• Small-fiber neuropathy has normal NCS — confirm with punch skin biopsy showing reduced intraepidermal nerve fiber density, or with quantitative sudomotor/autonomic testing.

Step 4 — condition-specific confirmation

• Guillain-Barré: CSF shows albuminocytologic dissociation (elevated protein with few cells; the Brighton criteria require <50 cells/µL), though protein may be normal in the first week — do not let a normal LP delay treatment.
• CIDP: ≥8 weeks of progression plus demyelinating electrophysiology per the EAN/PNS diagnostic criteria.
• Nerve biopsy (sural) is reserved for suspected vasculitis, amyloidosis, or leprosy; genetic testing (PMP22 duplication first) for hereditary phenotypes.

Disease-modifying therapy

• Guillain-Barré: IVIG or plasma exchange — equally effective, not combined. Corticosteroids are ineffective in GBS and should not be given; this is a favorite distractor.
• CIDP: per EAN/PNS, first-line options are IVIG, corticosteroids (prednisone), or plasma exchange; steroid-sparing immunosuppressants are used for refractory disease. The steroid responsiveness of CIDP is the therapeutic contrast with GBS.
• Vasculitic neuropathy: urgent high-dose glucocorticoids plus cyclophosphamide or rituximab to prevent irreversible nerve infarction.
• Reversible causes: B12 repletion (parenteral if malabsorptive), thiamine, levothyroxine, removal of the offending drug or toxin, and glycemic optimization — the ADA Standards of Care emphasize that glucose control prevents neuropathy in type 1 diabetes but has only modest effect in type 2.
• Hereditary transthyretin amyloid neuropathy: TTR stabilizers and gene-silencing agents (e.g., patisiran) are disease-modifying.

Symptomatic neuropathic pain (AAN 2022 painful diabetic neuropathy guideline)

• Gabapentinoids: pregabalin, gabapentin — bind the α2δ calcium-channel subunit; renally dosed, cause sedation and edema.
• SNRIs: duloxetine, venlafaxine — augment descending inhibition.
• TCAs: amitriptyline, nortriptyline — effective but anticholinergic and QT-prolonging; avoid in the elderly and in cardiac conduction disease.
• Topical agents: lidocaine patch, high-concentration capsaicin.
• Opioids are recommended against for chronic neuropathic pain by the AAN because of poor long-term benefit and addiction risk.

Emergencies

• Neuromuscular respiratory failure (GBS, porphyric neuropathy): diaphragm and intercostal weakness produce a falling vital capacity, paradoxical abdominal breathing, and inability to complete a sentence. A normal or rising PaCO2 in a tachypneic patient signals imminent collapse — intubate rather than await blood gas deterioration.
• Autonomic instability in GBS: demyelination of autonomic fibers causes labile hypertension alternating with hypotension, sinus arrest, and bradyarrhythmias; this is a leading cause of death and requires continuous telemetry. Avoid rapid-acting vasoactive drugs, to which these patients are hypersensitive.
• Diabetic foot ulcer with osteomyelitis or sepsis: loss of protective sensation plus autonomic anhidrosis and dry, fissured skin allows painless wounds; the ADA emphasizes annual foot examination and daily self-inspection precisely because the ulcer is painless.

Chronic disease complications

• Charcot neuroarthropathy: repetitive unperceived trauma with autonomic hyperemia causes bone resorption; the foot is warm, swollen, and erythematous with a rocker-bottom deformity, mimicking cellulitis. Misdiagnosis leads to amputation.
• Falls and fracture: sensory ataxia plus distal weakness; a positive Romberg and inability to tandem walk are the signals.
• Painless injury and mutilating acral ulcers: hallmark of hereditary sensory and autonomic neuropathy and of leprosy.
• Orthostatic syncope, gastroparesis, neurogenic bladder from autonomic fiber loss; supine hypertension often coexists.
• Residual disability: axonal loss regenerates at roughly a millimeter per day at best, so axonal neuropathies recover slowly and often incompletely; demyelinating disease with preserved axons recovers faster.

Treatment complications

• IVIG: thrombosis from hyperviscosity, aseptic meningitis, acute kidney injury, and anaphylaxis in IgA-deficient patients — screen when feasible.
• Plasma exchange: citrate-induced hypocalcemia (perioral paresthesias, Chvostek sign), hypotension, and central line infection.
• Gabapentinoids: sedation and falls, especially with renal impairment. TCAs: anticholinergic delirium, urinary retention, QT prolongation. Prolonged corticosteroids: hyperglycemia that worsens the underlying diabetic neuropathy, osteoporosis, and infection.

• Axonal vs demyelinating is decided by NCS amplitude vs velocity: low amplitudes with preserved velocity = axonal (metabolic, toxic, diabetic); markedly slowed velocities with prolonged distal/F-wave latencies and conduction block = demyelinating (GBS, CIDP, CMT1). This single dichotomy drives most of the differential.
• Ascending weakness with early areflexia after diarrheal illness = Guillain-Barré after Campylobacter jejuni. The single best next step is bedside spirometry (FVC/NIF), not lumbar puncture or MRI — airway first.
• Albuminocytologic dissociation (high CSF protein, few cells) is the classic GBS finding, but it is often absent in the first week; a normal LP never excludes GBS.
• The most tested treatment fact: IVIG or plasma exchange for GBS, and steroids do not work in GBS — yet steroids are first-line in CIDP. Examiners exploit this contrast.
• Painful, asymmetric, stepwise wrist drop then foot drop = mononeuritis multiplex → think systemic vasculitis (or diabetes, HCV cryoglobulinemia, leprosy); the pain of acute nerve infarction is the discriminator from a painless compressive mononeuropathy. Nerve/muscle biopsy confirms, and treatment is urgent immunosuppression.
• Multifocal deficits that are painless point instead toward leprosy or compressive/hereditary causes such as hereditary neuropathy with liability to pressure palsies (HNPP).
• B12 deficiency: check methylmalonic acid and homocysteine when B12 is low-normal; neurologic deficits can precede macrocytic anemia, and giving folate alone corrects the anemia while the myeloneuropathy progresses. Look for the vegan, post–gastric bypass, chronic metformin, or nitrous oxide abuse stem.
• Pyridoxine is a trap in both directions: deficiency (isoniazid) and megadose supplementation both cause neuropathy — excess B6 produces a large-fiber sensory ataxia from dorsal root ganglion damage.
• Non–length-dependent sensory loss with pseudoathetosis and areflexia in a smoker = paraneoplastic sensory neuronopathy, anti-Hu, small cell lung cancer; image the chest.
• Common distractor: normal nerve conduction studies do not exclude neuropathy — small-fiber neuropathy requires skin biopsy for intraepidermal nerve fiber density.