Nervous System & Special Senses

Peripheral neuropathy: diabetic and non-diabetic workup

Clinical Overview and When to Suspect Peripheral Neuropathy

— Diabetes is the #1 cause in the US (~50% of long-standing diabetics develop distal symmetric polyneuropathy, DSP).

— Other top causes: alcohol use disorder, chemotherapy (platinum, taxanes, vincristine, bortezomib), CKD, B12 deficiency, hypothyroidism, HIV, monoclonal gammopathy, hereditary (CMT).

— ~25–30% remain idiopathic after thorough workup.

— Distal, symmetric, "stocking-glove" numbness, tingling, burning pain, often nocturnal.

— Unsteady gait, frequent falls in elderly diabetic/alcoholic patients.

— Painless foot ulcer or Charcot joint discovered incidentally — implies advanced sensory loss.

— Burning feet + weight loss + macrocytic anemia → suspect B12 deficiency.

— Asymmetric/multifocal weakness → think vasculitis or mononeuritis multiplex, not DSP.

— By fiber type: large-fiber (vibration, proprioception, reflexes) vs small-fiber (pain, temperature, autonomic).

— By distribution: symmetric polyneuropathy, mononeuropathy, mononeuritis multiplex, polyradiculopathy, plexopathy.

— By tempo: acute (<4 wk, e.g., GBS, toxic), subacute (4–8 wk), chronic (>8 wk, e.g., diabetic, CIDP, hereditary).

— Drives outpatient management decisions: glycemic control, fall prevention, foot care referral, neuropathic pain pharmacotherapy.

— Misdiagnosis (e.g., calling CIDP "diabetic neuropathy") delays disease-modifying therapy.

Board pearl: A diabetic with asymmetric, rapidly progressive, or predominantly motor symptoms does not have simple DSP — pursue CIDP, vasculitic neuropathy, or compressive lesion workup before attributing to diabetes.

Definition: Disorder of peripheral nerves producing sensory, motor, or autonomic dysfunction; may be axonal (most metabolic/toxic) or demyelinating (immune-mediated, hereditary).

Epidemiology:

When to suspect on Step 3:

Classification framework (high-yield):

Why it matters for Step 3:

Presentation Patterns and Key History

— Gradual onset, length-dependent: toes → feet → mid-calf before fingertips involved ("stocking before glove").

— Positive symptoms: burning, tingling, electric/lancinating pain, allodynia (sock pressure painful).

— Negative symptoms: numbness, imbalance, painless injury.

— Worse at night, improved with walking (vs restless legs, which improves with movement during rest).

— Diabetic amyotrophy (lumbosacral radiculoplexopathy): asymmetric thigh pain, quadriceps wasting, weight loss in older type 2 diabetic.

— GBS: ascending weakness + areflexia, post-infectious (Campylobacter, CMV, Zika).

— Diabetes duration, A1c trajectory, prior DKA.

— Alcohol quantity/duration; nutritional status.

— Medications: isoniazid, metronidazole, nitrofurantoin, amiodarone, statins (rare), phenytoin, colchicine, linezolid, chemo, antiretrovirals (ddI, d4T).

— Occupational/toxin: lead, arsenic, mercury, n-hexane (glue sniffing), organophosphates.

— Family history (high-arched feet, hammer toes → CMT).

— B symptoms, rash, sicca, joint pain → connective tissue/vasculitis.

— HIV risk, recent diarrheal/respiratory illness (GBS trigger).

Step 3 management: In any new neuropathy patient, always reconcile the med list — discontinuing a culprit drug (e.g., metronidazole, B6 megadose, linezolid) is the cheapest, fastest intervention and is a frequent stem twist.

Distal symmetric polyneuropathy (DSP) — classic diabetic pattern:

Small-fiber neuropathy: Burning pain + autonomic symptoms (orthostasis, gastroparesis, sweating changes, ED) with preserved reflexes and vibration — common early diabetic presentation.

Mononeuropathy: Median (CTS), ulnar (cubital tunnel), peroneal (foot drop after leg crossing/weight loss), lateral femoral cutaneous (meralgia paresthetica in obese/pregnant).

Mononeuritis multiplex: Stepwise involvement of named nerves over days–weeks → vasculitis (PAN, EGPA), DM, HIV, cryoglobulinemia, leprosy worldwide.

Polyradiculopathy/plexopathy:

Key history elements (must elicit):

Physical Exam Findings and Bedside Assessment

— Large fiber: vibration (128 Hz tuning fork at hallux MTP), proprioception (toe up/down), 10-g Semmes-Weinstein monofilament at 4 plantar sites — loss = high ulcer risk.

— Small fiber: pinprick, temperature (cold tuning fork).

— Map distal-to-proximal sensory level; document the "sock line."

— Inspect for intrinsic foot/hand atrophy, hammer toes, pes cavus (CMT clue).

— Test toe extension/flexion, ankle dorsiflexion (peroneal/L5), plantarflexion (S1).

— Wasted thenar eminence with preserved hypothenar → median (CTS).

— Generalized weakness with areflexia + ascending pattern → GBS.

— Orthostatic vitals (drop ≥20 systolic or ≥10 diastolic without compensatory HR rise = autonomic).

— Resting tachycardia, pupillary asymmetry, anhidrotic feet with compensatory upper-body sweating.

— Calluses, fissures, ulcers (especially plantar over MTPs), Charcot deformity (rocker-bottom foot, warm/erythematous, often painless).

— Pulses (DP, PT) — neuropathy + ischemia worsens ulcer prognosis.

Board pearl: A painless warm, swollen, deformed foot in a diabetic = Charcot neuroarthropathy until proven otherwise — offload immediately with total contact cast; X-ray often shows midfoot collapse. Misdiagnosing as cellulitis or DVT delays care.

Sensory exam (test all modalities — they map to fiber type):

Motor exam:

Reflexes: Ankle jerk lost early in DSP; diffuse areflexia suggests GBS/CIDP; hyperreflexia + neuropathy + macrocytosis → B12 deficiency with subacute combined degeneration.

Gait/coordination: Romberg positive in large-fiber loss; high-steppage gait in foot drop; sensory ataxia with positive Romberg + lost proprioception → dorsal column or large-fiber neuropathy.

Autonomic assessment:

Foot inspection (mandatory in diabetics):

Provocative tests: Tinel and Phalen for CTS; Tinel at cubital tunnel for ulnar; straight-leg raise for radiculopathy.

Diagnostic Workup — Initial Labs and Screening

— Fasting glucose + HbA1c; if normal, 2-hour OGTT (impaired glucose tolerance alone causes small-fiber neuropathy).

— CBC (macrocytosis → B12; cytopenias → malignancy/myelodysplasia).

— CMP (renal, hepatic).

— TSH (hypothyroidism causes mixed sensorimotor neuropathy + CTS).

— Vitamin B12 with methylmalonic acid (MMA) and homocysteine if B12 is 200–400 (borderline) — elevated MMA confirms tissue deficiency.

— SPEP with immunofixation + serum free light chains — screens for monoclonal gammopathy (MGUS neuropathy, amyloidosis, POEMS, myeloma).

— ESR/CRP if vasculitis suspected.

— HIV, hepatitis B/C, RPR if risk factors.

— ANA, RF, anti-Ro/La, ANCA → connective tissue/vasculitic neuropathy.

— Heavy metals (lead, arsenic, mercury) if exposure.

— B1 (thiamine), B6, vitamin E, copper — alcoholism, bariatric surgery, zinc overuse (denture cream → copper deficiency myeloneuropathy).

— Lyme serology in endemic areas with cranial neuropathy or radiculitis.

— A1c is NOT enough to rule out dysglycemia-related neuropathy — OGTT catches IGT.

— Long-standing diabetic with classic length-dependent DSP, normal initial Tier 1 → no further testing required.

— All others: at minimum the Tier 1 panel.

— Routine MRI not indicated for symmetric polyneuropathy.

— MRI lumbosacral spine if radiculopathy/cauda equina suspected.

— Nerve/plexus MRI for asymmetric plexopathy, suspected tumor infiltration.

Step 3 management: In ambulatory practice, the cost-effective first-pass panel = A1c, CBC, CMP, TSH, B12+MMA, SPEP/IFE/SFLC. Ordering everything upfront (paraneoplastic panel, ganglioside antibodies) without indication is low-value care and a common wrong answer.

Tier 1 labs for every new polyneuropathy (AAN-endorsed, high-yield panel):

Conditional/second-tier labs (based on history):

When to skip extensive workup:

Imaging:

Diagnostic Workup — Advanced and Confirmatory Studies

— Confirms presence, distribution, chronicity, and axonal vs demyelinating pattern.

— Axonal: reduced amplitudes, preserved velocities → diabetes, alcohol, toxic, B12, uremia, most hereditary axonal.

— Demyelinating: slowed conduction velocities, prolonged distal latencies, conduction block, temporal dispersion → GBS, CIDP, CMT1, MMN, paraprotein-associated.

— Order when: asymmetric, predominantly motor, rapidly progressive, atypical exam, or considering immune-mediated disease (treatable!).

— Not needed for textbook diabetic DSP if exam and labs are classic.

— Gold standard for small-fiber neuropathy when NCS is normal but symptoms suggest small-fiber involvement.

— Punch biopsy at distal leg; reduced fiber density confirms diagnosis.

— Albuminocytologic dissociation (high protein, normal cell count) → GBS, CIDP.

— Pleocytosis → infectious (Lyme, HIV, CMV polyradiculitis), lymphomatous infiltration.

— Reserved for suspected vasculitis, amyloid, sarcoid, leprosy, atypical tumors — when diagnosis remains unclear and findings would change management.

— Permanent sensory deficit risk; not routine.

— Anti-MAG → IgM paraproteinemic demyelinating neuropathy.

— GM1 → multifocal motor neuropathy (MMN).

— Anti-GQ1b → Miller-Fisher.

— Anti-Hu, CRMP5 → paraneoplastic sensory neuronopathy (often small cell lung cancer).

Key distinction: NCS distinguishes axonal from demyelinating — this single result reroutes management from glycemic optimization (axonal/DM) to IVIG/steroids (demyelinating/CIDP). Missing this is a classic Step 3 trap.

Electrodiagnostic studies (NCS/EMG) — the cornerstone confirmatory test:

Skin biopsy with intraepidermal nerve fiber density (IENFD):

Autonomic testing: QSART, tilt table, heart rate variability — diabetic autonomic neuropathy, amyloid, Sjögren-related ganglionopathy.

Lumbar puncture:

Nerve biopsy (sural usually):

Genetic testing: PMP22 duplication for CMT1A; targeted panel if family history, pes cavus, very slow conduction velocities.

Targeted antibodies:

Risk Stratification and First-Line Management Logic

— Diabetes: intensive glycemic control (target A1c individualized, typically <7%) prevents and slows DSP in type 1; effect in type 2 is more modest but still recommended. Tight control does not reverse established neuropathy.

— Alcohol use disorder: abstinence + thiamine, folate, multivitamin repletion.

— B12 deficiency: IM cyanocobalamin 1000 mcg daily × 1 wk → weekly × 4 → monthly, or high-dose oral 1000–2000 mcg daily.

— Hypothyroidism: levothyroxine replacement.

— Drug-induced: discontinue offender (chemo dose-reduce or switch; stop isoniazid/metronidazole/B6 megadoses).

— CIDP: IVIG, corticosteroids, or plasmapheresis — disease-modifying!

— GBS: IVIG or plasmapheresis within 4 weeks of onset; steroids do NOT work in GBS.

— Vasculitic neuropathy: high-dose steroids ± cyclophosphamide/rituximab.

— Diabetic foot care education, annual comprehensive foot exam, podiatry referral if loss of protective sensation.

— Fall prevention: PT for balance, home safety eval, vision/hearing optimization.

— Driving safety if foot pedal proprioception impaired.

— Risk 0: intact sensation → annual exam.

— Risk 1: sensory loss → annual exam + footwear assessment.

— Risk 2: sensory loss + deformity/PAD → podiatry q3–6 mo, custom shoes.

— Risk 3: prior ulcer/amputation → podiatry q1–3 mo, multidisciplinary team.

CCS pearl: In a CCS case of new neuropathy, order A1c, B12, TSH, SPEP, CBC, CMP before reaching for gabapentin — the grader credits cause-finding orders, and disease-modifying treatment scores higher than symptomatic-only management.

Step 1 — Identify and treat the underlying cause (disease-modifying takes priority over symptom control):

Step 2 — Symptomatic neuropathic pain control (when underlying treatment is insufficient or not curative).

Step 3 — Prevent complications:

Risk stratification for diabetic foot ulcer/amputation:

Pharmacotherapy — First-Line Neuropathic Pain Regimen

— Gabapentinoids:

— Gabapentin 300 mg qhs, titrate to 900–3600 mg/day divided TID. Renal dose-adjust.

— Pregabalin 75 mg BID, max 600 mg/day. Faster titration; Schedule V. FDA-approved for diabetic neuropathy.

— AEs: sedation, dizziness, peripheral edema, weight gain, dose-dependent CNS depression with opioids (FDA boxed warning).

— SNRIs:

— Duloxetine 30 mg daily × 1 wk → 60 mg daily (max 120 mg). FDA-approved for diabetic neuropathy.

— Venlafaxine 75–225 mg ER (off-label).

— AEs: nausea, hyponatremia (SIADH), BP elevation (venlafaxine), discontinuation syndrome.

— Best choice if comorbid depression or anxiety.

— TCAs:

— Amitriptyline, nortriptyline, desipramine 10–25 mg qhs, titrate to 75–150 mg.

— Nortriptyline/desipramine preferred (fewer anticholinergic effects).

— Avoid in elderly (Beers), urinary retention, narrow-angle glaucoma, recent MI, conduction disease — check ECG (QTc, conduction) before starting in older patients.

— Topical agents (small-fiber, focal pain):

— Capsaicin 8% patch (clinic-applied), lidocaine 5% patch — useful adjuncts, low systemic AEs.

— Depression/anxiety → duloxetine.

— Insomnia, no cardiac disease → nortriptyline.

— Renal impairment → avoid gabapentinoids at high doses; favor duloxetine (avoid if CrCl <30) or TCA.

— Older adult fall risk → start low, avoid TCAs.

Board pearl: Pregabalin, duloxetine, and the capsaicin 8% patch are the only FDA-approved agents for painful diabetic peripheral neuropathy; gabapentin and TCAs are guideline-supported but off-label.

AAN/ADA-endorsed first-line agents (any of four classes is acceptable):

Choosing the agent (Step 3 logic):

Second-line/adjuncts: tramadol (caution — opioid risks, serotonergic), tapentadol.

Avoid as first-line: chronic opioids — no long-term benefit, addiction/overdose risk. Carbamazepine/oxcarbazepine = first-line for trigeminal neuralgia, not DSP.

Expanded Pharmacology and Immune-Mediated Treatment

— First-line: IVIG 2 g/kg loading, then maintenance, OR corticosteroids (prednisone 60 mg/day with taper, or pulsed dexamethasone), OR plasmapheresis.

— Steroid AEs limit chronic use → switch to IVIG or SC Ig for maintenance.

— Refractory: rituximab, cyclophosphamide, mycophenolate.

— IVIG 0.4 g/kg/day × 5 days OR plasma exchange × 5 sessions — equally effective; do NOT combine.

— No role for steroids — actually shown to be ineffective.

— Supportive: VC monitoring q4–6h (intubate if VC <20 mL/kg, NIF less negative than −30, or MIP/MEP failing — "20/30/40 rule"), DVT prophylaxis, autonomic monitoring (BP/HR swings, arrhythmia).

— IVIG is first-line; steroids and plasmapheresis worsen MMN — high-yield distinction.

— Induction: high-dose corticosteroids + cyclophosphamide or rituximab.

— Maintenance: azathioprine, methotrexate, or rituximab.

— MGUS-IgM with anti-MAG: rituximab if disabling.

— AL amyloidosis: refer hematology for chemo/autologous SCT.

— Hereditary ATTR amyloidosis: tafamidis, patisiran, inotersen — disease-modifying.

— No proven preventive agent (cryotherapy, compression gloves emerging).

— Duloxetine is the only agent with positive RCT data for established painful CIPN.

— Dose reduction or agent switch most impactful.

— Orthostasis: fluid/salt, compression stockings, midodrine, fludrocortisone, droxidopa.

— Gastroparesis: small meals, metoclopramide (short course — tardive dyskinesia risk), erythromycin.

Key distinction: Steroids help CIDP but harm MMN and don't help GBS — three demyelinating neuropathies, three different answers.

CIDP (chronic inflammatory demyelinating polyradiculoneuropathy):

GBS (acute, <4 wk):

Multifocal motor neuropathy (MMN):

Vasculitic neuropathy (PAN, EGPA, microscopic polyangiitis, isolated):

Paraproteinemic/amyloid neuropathy:

Chemotherapy-induced peripheral neuropathy (CIPN):

Diabetic autonomic neuropathy:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher prevalence of polyneuropathy (~25% >65 yo), often multifactorial.

— Fall risk amplified by sensory loss + polypharmacy + orthostasis — leading cause of morbidity.

— Beers Criteria flag for neuropathy meds:

— Avoid TCAs (anticholinergic, orthostasis, confusion, falls).

— Gabapentinoids: start at lowest dose, titrate slowly; combined with opioids → fatal respiratory depression risk.

— Avoid skeletal muscle relaxants (cyclobenzaprine, carisoprodol).

— Preferred first-line: duloxetine (mind hyponatremia/SIADH risk) or low-dose gabapentin with renal adjustment.

— Vision and proprioception optimization (cataract surgery, AFO bracing).

— Uremic neuropathy: axonal, sensorimotor, length-dependent — improves with dialysis adequacy and resolves after kidney transplant.

— Restless legs frequently coexists — treat iron deficiency first (ferritin >75–100), then dopamine agonist or gabapentinoid.

— Gabapentin dosing by CrCl:

— CrCl 30–59: max 1400 mg/day.

— CrCl 15–29: max 700 mg/day.

— CrCl <15: 100–300 mg/day.

— HD: supplemental dose post-dialysis.

— Pregabalin: similarly dose-reduced; supplemental post-HD.

— Duloxetine: avoid if CrCl <30.

— Duloxetine: avoid in chronic liver disease/heavy alcohol use — hepatotoxicity.

— TCAs: reduce dose; monitor for sedation.

— Gabapentinoids preferred (renally cleared, no hepatic metabolism).

— Each new psychotropic-class neuropathic agent should trigger med reconciliation; check for serotonergic load (duloxetine + tramadol + SSRI → serotonin syndrome).

Step 3 management: In an 80-year-old diabetic with CKD stage 4 and painful neuropathy, avoid amitriptyline (Beers), avoid duloxetine (CrCl <30), use low-dose gabapentin (start 100 mg qhs) — this stem pattern recurs.

Elderly considerations:

Chronic kidney disease (CKD):

Hepatic impairment:

Polypharmacy review:

Special Populations — Pregnancy, Pediatrics, and Other Subgroups

— Carpal tunnel syndrome is the most common pregnancy-related neuropathy (3rd trimester fluid retention) — usually resolves postpartum; treat with night splints, avoid steroid injection if possible.

— Meralgia paresthetica: lateral femoral cutaneous nerve compression — reassurance, weight management postpartum.

— Bell palsy risk increased 3× in pregnancy/postpartum — prednisone within 72 h is acceptable; valacyclovir added if severe.

— Pharmacology:

— Gabapentin/pregabalin: limited safety data; use only if benefit outweighs risk.

— Duloxetine category C — caution; SSRI/SNRI use late pregnancy → neonatal adaptation syndrome.

— TCAs (nortriptyline) historically considered relatively safe but use lowest effective dose.

— Avoid topiramate (cleft palate), valproate (NTDs).

— Lactation: amitriptyline, nortriptyline, gabapentin generally compatible.

— Most pediatric polyneuropathy is hereditary (CMT) or post-infectious GBS.

— Type 1 diabetes — DSP rare in childhood, screen annually after 5 years of disease duration and age ≥10.

— Toxic exposures: lead (in older homes), accidental medication ingestion.

— Genetic testing pivotal; family pedigree mandatory.

— Two patterns: distal sensory polyneuropathy (chronic HIV or ART neurotoxicity from older NRTIs) and inflammatory demyelinating (early HIV).

— Modern ART regimens (TAF, integrase inhibitors) minimize neurotoxic risk.

— CIPN — counsel before chemo, document baseline exam; dose-reduce on grade ≥2 symptoms.

— Paraneoplastic sensory neuronopathy (anti-Hu, SCLC) — asymmetric sensory loss, ataxia; treat underlying malignancy.

Board pearl: New paresthesias in 3rd-trimester pregnancy with nocturnal hand numbness = CTS → night wrist splints first, not surgery.

Pregnancy:

Pediatrics:

HIV-associated:

Cancer patients:

Veterans/military: Agent Orange-associated early-onset peripheral neuropathy is a presumptive service-connected condition — disability benefit eligibility.

Bariatric surgery patients: Screen B1, B12, copper, vitamin E annually — deficiencies cause neuropathy years post-op.

Complications and Adverse Outcomes

— Lifetime risk of foot ulcer in diabetics ~19–34%; ulcer precedes ~85% of amputations.

— Triad: neuropathy + deformity + minor trauma → ulcer; add PAD → poor healing.

— Plantar location over MTP heads; painless → patient walks on it.

— Initial care: offloading (total contact cast, removable boot), debridement, infection control, vascular assessment (ABI, toe pressures), imaging (X-ray for osteomyelitis, MRI if equivocal, probe-to-bone test highly specific).

— Acute stage: warm, swollen, erythematous foot, often painless or mildly painful — frequently misdiagnosed as cellulitis or DVT.

— Imaging: bony fragmentation, dislocation, midfoot collapse (rocker-bottom).

— Total contact casting × months; failure to offload → permanent deformity, ulceration, amputation.

— Silent MI (impaired anginal perception) — diabetics with autonomic neuropathy.

— Gastroparesis, postprandial hypoglycemia (impaired counterregulation).

— Hypoglycemia unawareness — major hazard; loosen A1c target.

— Neurogenic bladder, recurrent UTIs.

— Erectile dysfunction.

— Resting tachycardia, QT prolongation, sudden cardiac death.

— Opioid use disorder from chronic pain prescribing.

— Gabapentinoid misuse — rising; potentiates opioid OD.

— Falls from sedating regimens.

— Hyponatremia from duloxetine/venlafaxine (especially elderly).

CCS pearl: A diabetic with a "red, swollen, warm foot, no pain, no fever, normal WBC" → order foot X-ray + offload + non-weight-bearing; Charcot is the answer, not cellulitis. Empirically treating with antibiotics alone misses the diagnosis.

Diabetic foot ulcer and amputation:

Charcot neuroarthropathy:

Falls and fractures: Sensory ataxia, proprioceptive loss, autonomic orthostasis → recurrent falls; hip fracture mortality high.

Autonomic complications:

Neuropathic pain chronicity: Sleep disruption, depression, opioid misuse.

Iatrogenic:

Critical illness: GBS respiratory failure, autonomic dysautonomia (BP/HR lability, arrhythmia).

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Suspected GBS — admit ALL patients, even ambulatory ones, for respiratory and autonomic monitoring.

— Acute, rapidly progressive weakness (hours–days).

— Bulbar symptoms (dysphagia, dysarthria) — aspiration risk.

— Autonomic instability — BP swings, arrhythmia.

— Severe infected diabetic foot ulcer / wet gangrene / sepsis.

— Suspected acute vasculitic mononeuritis multiplex with systemic involvement.

— Forced vital capacity <20 mL/kg, NIF less negative than −30 cm H₂O, MEP <40 cm H₂O ("20/30/40 rule") → impending respiratory failure → intubate electively before crash.

— Rapid progression (<7 days from onset to peak), severe weakness (cannot lift head/arms), bulbar dysfunction → ICU for monitoring even if respiratory function adequate.

— Autonomic dysfunction with hemodynamic instability.

— Neurology: any atypical, asymmetric, rapidly progressive, motor-predominant, or demyelinating-pattern neuropathy; need for NCS/EMG, LP, immunotherapy.

— Endocrinology: poorly controlled diabetes, refractory glycemic targets.

— Podiatry: loss of protective sensation, callus, deformity, prior ulcer.

— Vascular surgery: ABI <0.9, non-healing ulcer, rest pain.

— Infectious disease: osteomyelitis, deep space infection.

— Hematology/Oncology: monoclonal gammopathy, amyloid, paraneoplastic.

— Rheumatology: suspected vasculitic neuropathy.

— PM&R/PT: balance training, AFO fitting, fall prevention.

— Foot drop developing over days/weeks.

— Bilateral hand weakness, dysarthria, ptosis (think MG, Miller-Fisher, botulism).

— Saddle anesthesia, bowel/bladder incontinence — cauda equina, emergency MRI + neurosurgery.

Step 3 management: Suspected GBS in clinic = call EMS, transport to ED, admit for serial spirometry q4–6h, neurology consult, prepare for IVIG or PLEX — never send home for outpatient follow-up.

Inpatient admission criteria:

ICU criteria (GBS-focused):

Consultations:

Outpatient red flags requiring urgent referral:

Key Differentials — Same-Category (Neuropathy) Causes

— Both axonal, length-dependent, painful — overlap common.

— Alcoholic: nutritional (thiamine), often with macrocytosis, LFT elevation, history of heavy use.

— Treatment: abstinence + thiamine 100 mg IV/PO + multivitamin.

— Mixed peripheral + dorsal column (subacute combined degeneration) → paresthesias + hyperreflexia + Romberg positive + cognitive changes.

— Macrocytic anemia, hypersegmented neutrophils, elevated MMA/homocysteine.

— Causes: pernicious anemia, vegan diet, metformin, PPIs, terminal ileal disease, bariatric surgery.

— CIDP: proximal + distal weakness, areflexia, symmetric, chronic >8 wk, demyelinating on NCS, high CSF protein.

— Treatable with IVIG/steroids/PLEX — must not miss.

— Acute (<4 wk), ascending weakness, areflexia, post-infectious.

— Variants: Miller-Fisher (ophthalmoplegia + ataxia + areflexia, anti-GQ1b), AMAN (motor axonal, Campylobacter).

— Asymmetric distal upper-limb weakness, no sensory involvement, conduction block on NCS, anti-GM1 antibodies.

— Treat with IVIG; avoid steroids.

— Family history, pes cavus, hammer toes, "inverted champagne bottle" legs, very slow NCV (CMT1A: PMP22 duplication).

— Stepwise painful asymmetric deficits; PAN, EGPA, RA, SLE, cryoglobulinemia.

Key distinction: Length-dependent stocking-glove = metabolic/toxic (diabetes, alcohol, drugs). Non-length-dependent or asymmetric = immune, vasculitic, paraneoplastic, hereditary — pursue different workup.

Diabetic DSP vs alcoholic neuropathy:

B12 deficiency neuropathy:

CIDP vs diabetic DSP:

GBS / AIDP:

Multifocal motor neuropathy (MMN):

Hereditary (Charcot-Marie-Tooth):

Vasculitic mononeuritis multiplex:

Paraproteinemic neuropathy: MGUS, multiple myeloma, Waldenström, POEMS, AL amyloid — SPEP/IFE/SFLC screen catches.

Paraneoplastic sensory neuronopathy: Asymmetric, non-length-dependent sensory loss, ataxia; anti-Hu antibodies; SCLC workup with CT chest.

Toxic/drug-induced: isoniazid (give B6 prophylaxis), chemo, amiodarone, metronidazole, nitrofurantoin, linezolid, statins (rare).

Key Differentials — Other-Category Mimics

— Bilateral leg pain/paresthesias worse with walking and standing, better with flexion (sitting, leaning forward, walking uphill).

— Pulses preserved; differentiates from vascular claudication (which improves with rest in any position).

— MRI lumbar spine; conservative → epidural steroids → decompression.

— Calf pain on exertion, relieved by rest alone (not posture), diminished pulses, ABI <0.9.

— Coexists with diabetic neuropathy — assess both.

— Dermatomal pain/sensory loss, myotomal weakness, positive straight-leg raise for L5/S1.

— MRI confirms; epidural injection, PT; surgery for progressive deficit.

— Urge to move legs at rest, evening/night, relieved by movement — opposite of neuropathy.

— Check ferritin; iron repletion if <75–100; dopamine agonists or gabapentinoids.

— Focal, mechanical, exam-localized — not stocking-glove distribution.

— Diffuse pain, tender points, sleep disturbance, normal neuro exam and NCS; small-fiber neuropathy increasingly recognized as overlap.

— Proximal weakness, elevated CK, normal sensation, normal reflexes.

Board pearl: Bilateral leg pain that improves leaning on a shopping cart = neurogenic claudication (lumbar stenosis), not diabetic neuropathy — MRI spine, not gabapentin first.

Lumbar spinal stenosis (neurogenic claudication):

Vascular claudication (PAD):

Radiculopathy (cervical/lumbar disc):

Myelopathy: Cervical spondylotic myelopathy — hand clumsiness, hyperreflexia, Babinski, spastic gait, sensory level — UMN signs distinguish from neuropathy.

Restless legs syndrome:

Plantar fasciitis / Morton neuroma:

Fibromyalgia:

Myopathy (statins, hypothyroid, polymyositis):

Multiple sclerosis: UMN signs, optic neuritis, MRI brain/cord with demyelinating lesions.

ALS: Mixed UMN + LMN signs, no sensory involvement, fasciculations.

Conversion disorder / functional: Inconsistent exam, give-way weakness, non-anatomic distribution.

Acute limb ischemia: "6 Ps" — pain, pallor, pulselessness, paresthesia, poikilothermia, paralysis → vascular emergency.

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Individualized A1c target — typically <7%; <8% if elderly, hypoglycemia unawareness, advanced complications.

— Tight control prevents neuropathy in type 1, slows progression in both.

— Avoid recurrent hypoglycemia (worsens autonomic dysfunction).

— Statin for primary prevention if age 40–75 with diabetes (USPSTF/ACC).

— ACE inhibitor or ARB if hypertensive, albuminuria, or established ASCVD.

— Aspirin 81 mg for secondary prevention only (or selected primary prevention).

— SGLT2 inhibitor or GLP-1 RA for diabetics with ASCVD/HF/CKD per ADA.

— Smoking cessation — worsens both PAD and neuropathy.

— Daily self-inspection (use mirror); never walk barefoot.

— Properly fitted footwear; Medicare covers therapeutic shoes for at-risk diabetics.

— Annual comprehensive foot exam by PCP; podiatry as risk-stratified.

— Toenail care by podiatry if sensation impaired.

— Abstinence with brief intervention, AA referral, naltrexone or acamprosate; B-complex supplementation.

Step 3 management: Diabetic neuropathy patients need the full ABCs of diabetes care at every visit: A1c, BP, Cholesterol (statin), Diet/Drugs, Eyes (annual ophtho), Feet (exam), Glycemic agent optimization (SGLT2/GLP-1), Hypoglycemia review.

Glycemic control (diabetic neuropathy):

Cardiovascular risk reduction (diabetes-related neuropathy patients):

Foot care plan (discharge bundle):

Alcohol use disorder:

B12 deficiency: Lifelong replacement if pernicious anemia, bariatric, ileal resection.

Medication reconciliation: Re-evaluate culprit drugs at each visit (chemo, isoniazid, B6, linezolid).

Vaccinations: Annual flu, COVID, pneumococcal, shingles (>50 yo) — neuropathic pain catastrophe if PHN superimposed.

Mental health: Depression screening (PHQ-9) — high comorbidity with chronic neuropathic pain.

Driving safety: Counsel and document; consider OT driving evaluation if proprioception/foot pedal sensation impaired.

Disability accommodations: AFO bracing, cane/walker, home modifications.

Follow-Up, Monitoring Parameters, and Rehab/Counseling

— Diabetic neuropathy (stable): every 3–6 months; A1c q3 mo if not at goal, q6 mo if stable.

— Annual comprehensive foot exam with monofilament + vibration + pulses + skin/deformity inspection.

— Annual urine ACR + eGFR, dilated eye exam, lipid panel.

— Diabetic autonomic neuropathy screen with orthostatic vitals annually.

— Reassess efficacy at 2–4 weeks after dose change; titrate to effect or maximum tolerated.

— Duloxetine: check Na within 1–2 wk in elderly; LFTs if symptomatic.

— Gabapentinoids: monitor sedation, edema, weight; avoid concurrent opioids when possible.

— TCAs: baseline + follow-up ECG (QTc) in older patients or doses >100 mg; monitor anticholinergic effects.

— Use a validated pain scale (DN4, neuropathic pain scale) at each visit.

— Neurology q3 mo; periodic NCS to assess treatment response.

— Functional outcome measures (INCAT, ONLS).

— PT: balance, gait, AFO fitting for foot drop.

— OT: ADL adaptation, splinting (CTS), driving evaluation.

— Pain psychology / CBT for chronic pain — strong evidence for combined approach.

— Tai chi, supervised exercise — improve balance and reduce falls.

— Burn prevention (test bathwater with elbow, no heating pads on feet).

— Fall-proof home (lighting, rugs, grab bars).

— Sexual dysfunction (PDE5 inhibitors after cardiac risk assessment).

— Set realistic expectations: pain meds typically reduce pain by ~30–50%, do not abolish.

Board pearl: In painful diabetic neuropathy, success = 30–50% pain reduction + functional improvement (sleep, mobility), not complete relief — counsel upfront to prevent unrealistic expectations and opioid escalation.

Routine follow-up cadence:

Neuropathic pain medication monitoring:

CIDP/GBS follow-up:

Foot ulcer follow-up: weekly until healed; offloading compliance, debridement, vascular reassessment.

Rehabilitation referrals:

Counseling topics:

Ethical, Legal, and Patient Safety Considerations

— Use written opioid treatment agreements with single prescriber/pharmacy, random urine drug screens, PDMP checks before each prescription.

— Discuss alternatives (gabapentinoids, duloxetine, topical, non-pharmacologic) and document shared decision-making.

— CDC guidance: avoid initiating opioids for chronic non-cancer neuropathic pain; if used, lowest effective dose, reassess every 3 months.

— Co-prescribe naloxone if MME >50/day or concurrent benzodiazepines.

— Patients with severe sensory loss, autonomic syncope, or hypoglycemia unawareness may be impaired drivers.

— State laws vary — some mandate physician reporting (e.g., California, Pennsylvania for lapses of consciousness); others permissive.

— Document counseling and capacity to drive in the chart.

— High readmission rate; ensure wound care follow-up within 7 days of discharge, clear written offloading instructions, home health if needed.

— Failure to coordinate is a leading source of preventable amputation and litigation.

— Document exposure history, OSHA reporting where applicable (heavy metals, n-hexane).

— Carpal tunnel from repetitive work may be compensable.

— Patients with cognitive impairment + severe neuropathy may lack capacity for safe insulin self-administration or wound care → involve family, home health, or LTC.

— Reasonable accommodations for sit-stand work, footwear, breaks.

— Inform anesthesia of pre-existing neuropathy — risk of new/worsened deficit from positioning, regional blocks.

— Document baseline exam preoperatively.

Step 3 management: Before refilling gabapentin for a diabetic on chronic opioids, check the state PDMP, screen for opioid use disorder, and consider naloxone co-prescription — gabapentinoid + opioid combination has a black-box overdose warning.

Informed consent for chronic opioid therapy:

Driving safety and reporting:

Diabetic foot ulcer — transitions of care risk:

Workers' compensation and occupational neuropathy:

Capacity for self-care:

Disability and accommodations (ADA):

Surgery and anesthesia:

End-of-life: In amyloid, paraneoplastic, or end-stage CIDP with refractory pain/disability, integrate palliative care early; clarify goals.

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: Bilateral carpal tunnel syndrome in an older adult with cardiac symptoms → screen for transthyretin (ATTR) amyloidosis; tafamidis can be disease-modifying.

Diabetes → distal symmetric polyneuropathy (most common), autonomic, mononeuropathies (CN III pupil-sparing, median), diabetic amyotrophy.

Alcohol → axonal sensorimotor + thiamine deficiency; check folate, B1, B12.

B12 deficiency → peripheral neuropathy + dorsal column + cognitive ("subacute combined degeneration"); metformin lowers B12 — check after years of use.

B6 (pyridoxine) → deficiency AND megadose toxicity (>200 mg/day) both cause neuropathy.

Isoniazid → B6 depletion → neuropathy; co-prescribe pyridoxine 25–50 mg/day.

Lead → motor-predominant neuropathy (wrist drop), basophilic stippling.

Arsenic → painful sensorimotor + Mees lines on nails, GI symptoms.

GBS triggers → Campylobacter jejuni (AMAN), CMV, EBV, Mycoplasma, Zika, recent vaccination (rare), recent surgery.

Miller-Fisher → ophthalmoplegia + ataxia + areflexia, anti-GQ1b.

POEMS syndrome → Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes.

Amyloidosis (AL or hereditary ATTR) → small-fiber + autonomic + carpal tunnel (bilateral CTS) + cardiomyopathy.

Leprosy → globally #1 infectious cause; thickened nerves, hypopigmented anesthetic patches.

HIV → distal sensory polyneuropathy or inflammatory demyelinating.

Lyme → cranial neuropathy (CN VII, often bilateral), radiculitis (Bannwarth).

Sjögren → sensory neuronopathy/ganglionopathy, asymmetric.

Paraneoplastic → anti-Hu (SCLC), CV2/CRMP5 (SCLC, thymoma).

Hereditary → CMT1A (PMP22 duplication, most common), HNPP (PMP22 deletion — recurrent pressure palsies).

Bariatric/copper deficiency → myeloneuropathy mimicking B12 deficiency.

Chemo → vincristine (axonal, painful), platinum (sensory ataxia, "coasting" weeks after stopping), taxanes, bortezomib (small-fiber, painful).

Pregnancy → CTS, meralgia paresthetica, Bell palsy.

Hypothyroidism → CTS + sensorimotor polyneuropathy + delayed-relaxation reflex.

Board Question Stem Patterns

Key distinction: "Classic diabetic" stems → treat; "diabetic with atypical features" stems → workup before treating.

Stem 1 (classic diabetic DSP): 58-yo with T2DM × 12 yrs, A1c 9.2%, burning feet worse at night, decreased monofilament sensation, absent ankle jerks. Best initial step: intensify glycemic control + start duloxetine or pregabalin. Don't order MRI/NCS — exam is classic.

Stem 2 (CIDP masquerade): 60-yo diabetic with progressive proximal + distal weakness over 3 months, diffuse areflexia, NCS shows demyelination with conduction block, CSF protein 120. Diagnosis: CIDP. Treatment: IVIG (or steroids/PLEX) — not just gabapentin.

Stem 3 (GBS): 30-yo with ascending weakness 1 week after diarrheal illness, areflexic, VC 18 mL/kg. Next step: intubate + ICU; treat with IVIG or plasmapheresis; steroids contraindicated.

Stem 4 (B12): Vegan with paresthesias, hyperreflexia + Romberg positive, macrocytic anemia. Order: B12, MMA, homocysteine. Treat with B12 replacement.

Stem 5 (metformin + B12): Diabetic on metformin × 8 years with new neuropathy. Check B12 before assuming diabetic neuropathy.

Stem 6 (Charcot foot): Diabetic with warm, swollen, deformed foot, no pain, no fever, normal WBC. Diagnosis: Charcot neuroarthropathy → offload with total contact cast, X-ray, podiatry referral. Not cellulitis.

Stem 7 (foot drop after leg crossing): Thin patient with new foot drop, sensory loss on dorsum of foot → peroneal neuropathy at fibular head; counsel positioning, observe.

Stem 8 (bilateral CTS + heart failure): Older man with bilateral CTS, HFpEF, LV thickening on echo → ATTR amyloidosis; technetium-PYP scan, tafamidis.

Stem 9 (chemo CIPN): Breast cancer patient on paclitaxel with painful neuropathy → duloxetine (only evidence-based agent for established painful CIPN); consider dose reduction.

Stem 10 (isoniazid neuropathy): Patient on INH × 3 mo with new paresthesias → add pyridoxine 50 mg/day.

Stem 11 (mononeuritis multiplex): Stepwise wrist drop + foot drop + asymmetric sensory loss with weight loss/rash → vasculitic neuropathy → ESR, ANCA, nerve biopsy, high-dose steroids + cyclophosphamide.

One-Line Recap

Peripheral neuropathy management hinges on three steps: classify the pattern (length-dependent vs not, axonal vs demyelinating, symmetric vs asymmetric), identify and treat the underlying cause with a targeted workup (A1c/OGTT, B12+MMA, TSH, SPEP/IFE/SFLC, CBC/CMP — and NCS/EMG when atypical), then layer evidence-based symptomatic therapy (duloxetine, pregabalin, gabapentin, or TCA) with prevention of complications.

Board pearl: "Stocking-glove + diabetic + classic exam" = treat. "Anything atypical" = workup first. Missing CIDP or GBS for "diabetic neuropathy" is the highest-yield trap on Step 3 in this topic.

Workup essentials: Every new polyneuropathy gets A1c (+ OGTT if normal), CBC, CMP, TSH, B12 with MMA/homocysteine, SPEP/IFE/SFLC. Add NCS/EMG when asymmetric, motor-predominant, rapidly progressive, or demyelinating suspected.

Treatable mimics you cannot miss: CIDP (IVIG/steroids/PLEX), GBS (IVIG or PLEX, never steroids), MMN (IVIG only, steroids harm), B12 deficiency (replacement), vasculitic neuropathy (steroids + cyclophosphamide/rituximab), drug-induced (stop the culprit), hereditary ATTR amyloidosis (tafamidis/patisiran).

Symptomatic pharmacotherapy: First-line = duloxetine, pregabalin, gabapentin, or TCA (nortriptyline). Pick based on comorbidities: depression → duloxetine; renal disease → avoid duloxetine if CrCl <30, dose-adjust gabapentin; elderly → avoid TCAs (Beers); chronic pain + opioids → naloxone co-prescription, PDMP, taper opioids.

Diabetic foot bundle: annual comprehensive foot exam, risk-stratified podiatry follow-up, daily self-inspection, proper footwear, Charcot = offload immediately, statin + ACEi + SGLT2/GLP-1 for cardiovascular risk, smoking cessation, shingles vaccine.