Peripheral Neuropathy
The pattern is the diagnosis: symmetric stocking-glove disease has a short evidence-based lab list, while asymmetric, acute, or motor-predominant disease is a different problem with a different clock. Three labs find most treatable causes, EMG answers a specific question rather than "everything," and the pain drugs work on the pain, not the nerve. Mononeuritis multiplex is vasculitis until proven otherwise.
🔍 Overview
The Pattern Is the Diagnosis
- Distal symmetric polyneuropathy (DSP) -the overwhelming majority. Length-dependent, so the longest axons fail first: numbness and burning start in the toes, ascend, and reach the hands around the time symptoms reach the knees ("stocking-glove"). Diabetes, alcohol, and idiopathic disease dominate.
- Mononeuropathy -one nerve: median (carpal tunnel), ulnar (elbow), peroneal (fibular head foot drop). Compression at known sites; a different workup entirely.
- Mononeuritis multiplex -multiple discrete nerves failing stepwise (wrist drop today, foot drop next month). This is nerve infarction: vasculitis until proven otherwise, and an urgent workup (ANCA, cryoglobulins, hepatitis serologies) because untreated vasculitic neuropathy accumulates permanent deficits.
- Polyradiculoneuropathy -proximal and distal weakness with areflexia: GBS when acute (days to 4 weeks; respiratory monitoring, covered in its own topic), CIDP when relapsing or progressive beyond 8 weeks (treatable with IVIG/steroids -a diagnosis not to miss because it responds).
- Small fiber neuropathy -burning pain and allodynia with normal strength, normal reflexes, and a NORMAL EMG, because EMG only tests large fibers. Autonomic features (dry eyes and mouth, orthostasis, sweating changes) travel with it. Diagnosis is clinical ± skin biopsy for intraepidermal nerve fiber density.
Large Fiber vs Small Fiber (the bedside split)
- Large fiber: vibration and proprioception loss, sensory ataxia (worse in the dark, positive Romberg), diminished reflexes. Falls are the danger.
- Small fiber: pain and temperature loss, burning, electric shocks, allodynia. Ulcers and Charcot joints are the danger, because painless injury goes unnoticed.
- Most DSP is mixed; documenting which predominates guides both testing (EMG useful only for large fiber) and counseling.
Red Flags That Change the Clock
- Acute onset over days to weeks -GBS: check vital capacity and bulbar function, not just reflexes.
- Asymmetric, multifocal, or stepwise -vasculitis workup now.
- Motor-predominant or proximal weakness, prominent autonomic failure, or rapid progression -EMG and neurology referral promptly; these are not "diabetic neuropathy, follow up in a year."
- Prominent ataxia with a demyelinating EMG -think paraproteinemic neuropathy and CIDP variants.
🧪 Workup
The Evidence-Based First Tier (AAN)
- Three tests find the most treatable causes of DSP: (1) fasting glucose or A1c -and if normal, a 2-hour glucose tolerance test, because impaired glucose tolerance causes painful small-fiber neuropathy before diabetes is diagnosable; (2) B12 with methylmalonic acid, since low-normal B12 with high MMA is deficiency and is treatable; (3) SPEP with immunofixation ± free light chains, because paraproteinemic neuropathy changes the entire pathway (MGUS, myeloma, amyloid, POEMS).
- Reasonable additions by context: TSH, CMP (renal and hepatic disease), CBC, ESR, HIV and hepatitis serologies, Lyme where endemic, celiac serologies with GI features.
- Take the exposure history yourself: alcohol quantified, chemotherapy (platinums, taxanes, vincristine, bortezomib), isoniazid without pyridoxine, and pyridoxine excess -B6 causes neuropathy in overdose as well as deficiency, and patients take gram doses from supplement stores without mentioning it.
- Family history and feet: high arches, hammertoes, and "clumsy since childhood" point to hereditary neuropathy (CMT) -common, underdiagnosed, and workup-sparing once recognized.
When (and Why) to Order EMG/NCS
- Not required for a classic, mild, length-dependent DSP with an obvious cause (a well-controlled diabetic with slowly progressive stocking numbness) -the test will confirm what you know.
- Order it for: atypical features (asymmetry, motor predominance, rapid course), unclear cause, or when the axonal vs demyelinating distinction will change management -demyelinating physiology reframes the case toward CIDP, paraprotein-associated disease, and hereditary neuropathy, all with different treatments.
- A normal EMG does not exclude neuropathy: small fiber disease is invisible to it. Skin biopsy for intraepidermal nerve fiber density (or referral) makes that diagnosis.
- MRI of the spine is not a neuropathy test -order it for radiculopathy or myelopathy suspicion (dermatomal pattern, hyperreflexia, sphincter involvement), not for stocking-glove numbness.
🚨 Management
Treat the Cause (where the disease can actually be modified)
- Diabetes: glycemic control convincingly slows neuropathy in type 1; the effect in type 2 is more modest, which is why prevention and foot protection carry the weight there. Enrol the feet: annual monofilament and inspection, daily self-checks, and early podiatry -the neuropathy itself is why diabetic foot infections happen (see that topic).
- Alcohol: cessation plus thiamine and nutrition -partially reversible if caught early.
- B12 deficiency: replete (oral high-dose is effective if absorption is intact; parenteral if not) and find the reason -pernicious anemia, metformin, PPIs, gastric surgery.
- Drug-induced: stop or swap the offender where the oncology or ID calculus allows; chemotherapy neuropathy often stabilizes or partially improves after completion.
- Paraprotein found: this is no longer a neuropathy clinic problem -hematology referral (myeloma, amyloid, POEMS, anti-MAG disease each have specific treatment).
- Idiopathic (a third of cases after full workup): name it honestly, protect the feet, treat the pain, and re-examine yearly -new features reopen the workup.
Treating the Pain (expectations first)
- Set the goal out loud: a 30-50% reduction in pain is a successful outcome. Patients expecting zero pain will call every effective drug a failure.
- First-line options are equivalent enough that comorbidity picks the drug: duloxetine (co-existing depression), gabapentinoids (co-existing sleep disruption; renal dosing), TCAs (cost, once-nightly dosing; avoid in cardiac disease and the elderly).
- Trial each drug at an adequate dose for several weeks, then switch or combine -partial responders often do best with two mechanisms at moderate doses rather than one maximized.
- Topicals (lidocaine, high-concentration capsaicin patch) for focal or medication-intolerant patients.
- Opioids are not recommended for chronic neuropathic pain -poor long-term efficacy, and this population accumulates them. Tramadol adds serotonergic and seizure risk on top.
- Non-drug measures earn their place: exercise has direct evidence in diabetic neuropathy, and PT for balance training addresses the fall risk the sensory loss creates.
💊 Medications
Medications
| Drug | Dose | Why choose it / Watch for |
|---|---|---|
| Duloxetine (Cymbalta) FIRST-LINE | 30 mg → 60 mg daily | Treats the neuropathic pain AND comorbid depression/anxiety with one drug. Nausea early; avoid in hepatic disease and heavy alcohol use. |
| Pregabalin (Lyrica) | 75 mg BID → 150-300 mg BID | Faster, more predictable titration than gabapentin. Sedation, edema, weight gain; renal dosing required; modest misuse potential. |
| Gabapentin (Neurontin) | 300 mg qHS → 900-3,600 mg/day divided TID | Cheap and familiar; absorption saturates so high doses give diminishing returns. Same sedation/edema/renal caveats; taper rather than stop. |
| Nortriptyline | 10-25 mg qHS → 75 mg | Preferred TCA: less anticholinergic and orthostatic burden than amitriptyline, same efficacy, once nightly, pennies. Avoid in cardiac conduction disease; caution in the elderly; ECG at higher doses. |
| Amitriptyline | 10-25 mg qHS → 75 mg | Effective but the most anticholinergic option -dry mouth, urinary retention, confusion in the elderly. Nortriptyline usually the better version of the same idea. |
| Lidocaine 5% patch | Up to 12 h on / 12 h off | Focal pain, minimal systemic effect -useful in the frail and the polypharmacy-burdened. |
| Capsaicin 8% patch | Single 30-60 min application per 3 months (clinic-administered) | TRPV1 defunctionalization; burning during application is expected. For patients failing or intolerant of orals. |
| Vitamin B12 | 1,000 mcg IM or 1,000-2,000 mcg PO daily | For proven deficiency (check MMA when B12 is low-normal). High-dose oral works even in pernicious anemia (mass-action absorption). |
Two B6 traps in one vitamin: pyridoxine deficiency causes neuropathy (classically with isoniazid, which is why INH is co-prescribed with B6), and pyridoxine excess causes a sensory neuronopathy -patients taking gram-level supplement doses present with ataxia and numbness that improves only if you ask about the supplement and stop it. Both directions of the same vitamin are on the differential.
🏥 Rounds
Pimp Questions
❓ Why is mononeuritis multiplex an urgent diagnosis rather than a routine neuropathy referral?
Because the mechanism is nerve infarction from vasculitis of the vasa nervorum -each "event" (a wrist drop, then a foot drop weeks later) is an infarct, and every untreated week accumulates permanent axonal loss. The workup (ANCA, cryoglobulins, hepatitis B and C serologies, ESR, complements) and treatment (immunosuppression) run on a rheumatologic timescale of days, not the months a routine neuropathy referral takes. Stepwise, asymmetric, painful multifocal deficits are the tell.
❓ A patient has classic burning feet, allodynia, and orthostatic dizziness, but the EMG is normal. Does that exclude neuropathy?
No -it localizes it. EMG/NCS measures only large myelinated fibers; small unmyelinated and thinly myelinated fibers (pain, temperature, autonomic) are invisible to it. Burning pain with preserved strength, reflexes and a normal EMG is small fiber neuropathy, confirmed if needed by skin biopsy for intraepidermal nerve fiber density. It also explains the autonomic features. Notably, impaired glucose tolerance -before overt diabetes -is a leading cause, which is why a normal A1c earns a 2-hour glucose tolerance test.
❓ Why check methylmalonic acid when the B12 level is "normal"?
Because the serum B12 assay is poorly sensitive at the low-normal range: a meaningful fraction of patients with values of 200-400 pg/mL are functionally deficient at the tissue level. MMA accumulates when B12-dependent methylmalonyl-CoA mutase fails, so an elevated MMA unmasks the deficiency the serum level missed. This matters because B12 neuropathy is treatable and progresses (with possible subacute combined degeneration) if missed. Ask about metformin, PPIs and gastric surgery -the common depletion mechanisms.
❓ Why does the workup of a demyelinating neuropathy differ from an axonal one?
Axonal physiology is the common final pathway of metabolic and toxic causes (diabetes, alcohol, drugs) and mostly confirms the usual suspects. Demyelinating physiology is a different disease list: CIDP (treatable with IVIG or steroids -the diagnosis you cannot afford to miss), paraprotein-associated neuropathy (anti-MAG, POEMS), and hereditary disease (CMT1, with uniform slowing vs the patchy conduction block of acquired disease). Demyelination on the EMG is therefore the branch point that sends you toward SPEP, referral, and potentially immunotherapy.
❓ Why is nortriptyline preferred over amitriptyline for neuropathic pain in older patients?
Same tricyclic mechanism and comparable analgesia, but nortriptyline (a secondary amine) carries substantially less anticholinergic, antihistaminic and alpha-blocking burden than amitriptyline (its tertiary-amine parent) -so less dry mouth, urinary retention, orthostatic hypotension, sedation and confusion, the exact toxicities that hurt older patients. Both still warrant caution in cardiac conduction disease (TCAs are class IA-like in overdose) and an ECG at higher doses.
Sample Presentation
Mr. Osei is a 61-year-old man with 2 years of slowly progressive burning and numbness in both feet, now to mid-shin, worse at night, with occasional electric shocks. Exam: diminished pinprick and vibration to the ankles, absent ankle jerks, normal strength, negative Romberg. He has prediabetes (A1c 6.2), drinks 3-4 beers nightly, and takes metformin 1,000 mg BID for 6 years plus an over-the-counter "nerve support" supplement containing 100 mg pyridoxine. B12 is 260 with MMA elevated. SPEP negative.
Key Points: (1) Classic length-dependent DSP with multiple contributors, none of which required an EMG to find: impaired glucose metabolism, alcohol, metformin-associated B12 deficiency proven by the MMA despite a "normal" B12, and a B6-containing supplement worth stopping on principle. (2) The plan is cause-directed: replete B12 and recheck MMA, cut the alcohol, tighten glucose, stop the supplement, and enroll the feet in surveillance. (3) For the pain: he sleeps poorly, so pregabalin at night is a rational first pick (or duloxetine if mood symptoms surface), with the 30-50% improvement expectation stated up front and a several-week adequate trial before any verdict.
Clinic Checklist
- Pattern documented: symmetric vs not, length-dependent vs not, large vs small fiber, motor involvement -the pattern is the differential.
- First-tier labs sent: A1c (then GTT if normal), B12 with MMA, SPEP with immunofixation.
- Exposures asked: alcohol quantified, chemo history, INH, and supplements including B6 by name.
- Red flags screened: acute course, asymmetry, motor predominance, autonomic failure -any one accelerates the referral.
- EMG ordered for a question, not a reflex -and small fiber disease remembered when it comes back normal.
- Feet examined and enrolled: monofilament, inspection, footwear advice, podiatry in diabetics.
- Pain goal set at 30-50% reduction, drug chosen by comorbidity, renal dosing checked for gabapentinoids.
- Falls addressed -balance PT and home safety for large-fiber loss; the sensory deficit is a falls diagnosis.
📋 Summary
Summary
Read the Pattern Before Ordering Anything
Symmetric stocking-glove = DSP, the common pathway of diabetes, alcohol and idiopathic disease. One nerve = compression. Multiple discrete nerves stepwise = mononeuritis multiplex = vasculitis until proven otherwise, urgently. Proximal + distal weakness with areflexia = GBS (acute) or CIDP (chronic, treatable). The pattern does the diagnostic work the lab panel cannot.
Three Labs Do Most of the Work
A1c (then a 2-hour GTT if normal -impaired glucose tolerance causes painful neuropathy before diabetes exists), B12 WITH methylmalonic acid, and SPEP with immunofixation. That is the evidence-based first tier for symmetric disease. Context adds TSH, renal/hepatic panels, HIV and hepatitis serologies. A paraprotein reroutes the whole case to hematology.
The Exposure History Is a Lab Test
Alcohol quantified, chemotherapy agents named, isoniazid, and supplements asked about by ingredient -pyridoxine causes neuropathy in both deficiency and excess, and gram-dose B6 sits in "nerve support" products patients take for the very symptoms it causes. Metformin and PPIs quietly deplete B12 over years.
EMG Answers Questions, Not Reflexes
Skip it for classic mild DSP with an obvious cause; order it for atypia or when axonal-vs-demyelinating changes management -demyelination reframes toward CIDP, paraprotein disease and CMT. A normal EMG never excludes small fiber neuropathy (burning pain, normal strength and reflexes, autonomic features): that diagnosis is clinical, with skin biopsy as the confirmer.
Treat the Cause Where One Exists
Glycemic control clearly slows type 1 diabetic neuropathy (more modest in type 2), alcohol cessation partially reverses, B12 repletion treats -and each found cause needs its reason found (why was the B12 low?). A third of cases end idiopathic after honest workup: name it, protect the feet, treat the pain, re-examine yearly.
Say the Pain Goal Out Loud
A 30-50% reduction is success, and patients told otherwise will abandon effective drugs. Comorbidity picks the agent: duloxetine with depression, gabapentinoids with sleep disruption (renally dosed), nortriptyline over amitriptyline when a TCA fits. Adequate dose, several weeks, then switch or combine mechanisms. Opioids are not recommended for chronic neuropathic pain.
The Feet Are the Complication
Small-fiber loss means painless injury: ulcers, infection and Charcot arthropathy follow unnoticed trauma. Annual monofilament testing, daily self-inspection, footwear review and early podiatry are the interventions that prevent the amputation pathway -the diabetic foot infection topic is this page's downstream sequel.
Falls Are the Other Complication
Large-fiber loss produces sensory ataxia -worse in the dark, positive Romberg -and the fall risk is additive with age, sedating pain drugs, and orthostasis from autonomic involvement. Balance-focused PT, lighting, and a deliberate look at the med list belong in the plan alongside the analgesic, because the fracture is preventable and the numbness is not.
