Approach to Neuropathies

Educational Objectives

The goal of this program is to improve management of neuropathies. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize classic presentations of neuropathy.
2. Implement recommended neurologic evaluation strategies.
3. Optimize management of Guillain-Barré Syndrome.
4. Conduct focused neurologic examinations.
5. Select evidence-based medications for neuropathic pain.

Summary

Acuity: the evaluation of a patient begins with obtaining history; whether acute, subacute, or chronic, it affects the approach and differential diagnostic consideration; Guillain-Barré syndrome (GBS) is a classic presentation of acute form (particularly immune-mediated); other subacute or chronic manifestations of immune-mediated neuropathy are also there; the most common form of neuropathies is chronic axonal neuropathies with a length-dependent distribution; hereditary neuropathies are expected to have a more chronic course

Pattern: distal symmetric polyneuropathy (PN) — most neuropathies typically fit this pattern; can be distal symmetric sensory predominant or sensorimotor PN; symptoms reflect the longest nerve involvement; nerve symptoms typically manifest in feet as the nerves are much longer than in arms; if involvement occurs in the hands before the feet, it is atypical and non-length-dependent; distal predominance — some forms of neuropathy target the distal nerve terminal, affecting the hands or legs, eg, anti-myelin-associated glycoprotein (MAG) neuropathy; the converse of these features reflect atypical forms of neuropathy, which include asymmetry, non-length dependence, or proximal involvement

Positive vs negative sensory symptoms: positive symptoms are more common in acquired neuropathies, eg, painful diabetic neuropathy (DN), which manifests as paresthesia, lancinating or burning pain, and allodynia; negative sensory symptoms, eg, numbness (can be nonspecific; numbness in isolation without any positive sensory symptoms may suggest chronicity or a hereditary form of neuropathy); positive symptoms are not typical for Charcot-Marie-Tooth (CMT) disease or hereditary forms of neuropathy and are often elicited on examination rather than reported by the patient; weakness or gait disturbances are the main evaluations in CMT

Imbalance: assess patients for balance and whether they require assistive devices for walking; most typical neuropathies, including DN (eg, chronic idiopathic axonal polyneuropathy [CIAP]), do not involve severe imbalance; severe sensory ataxia with reliance on assistive device to walk is atypical, especially early in the course

Weakness: evaluate the pattern of weakness in neuropathy; prominent weakness on an examination suggests a more atypical manifestation, eg, significant foot drop would not occur with DN, chronic axonal PN (APN), idiopathic PN; however, toe strength is affected in many neuropathies

Associated features: autonomic features — can be a part of specific forms of neuropathy and a significant source of morbidity and decreased quality of life; include heat and cold intolerance, abnormal sweating, and orthostasis; urinary symptoms and bowel symptoms can also occur; weight loss — with acuity, this is an atypical feature; some variants of DN (eg, diabetic amyotrophy, diabetic cachectic neuropathy) can cause significant weight loss and autonomic features; amyloidosis can cause significant weight loss

Medication history: chemotherapy is a well-established cause; immune checkpoint inhibitors can cause atypical forms of neuropathy; history of chemotherapy is important; toxic exposure — heavy metals and alcohol use (the most common) can cause neuropathy; lead neuropathy typically manifests with wrist drop bilaterally; arsenic exposure can manifest as GBS; alcohol use can cause insidious sensory symptoms primarily affecting the feet; hand symptoms should not develop until numbness extends to the knees, suggesting a degree of non-length dependence

Medical history: diabetes mellitus (DM) is the most common cause of neuropathy; end-stage renal disease (uremic neuropathy) can also be a cause (often in patients on hemodialysis); history of cardiovascular issues and older medications, eg, azidothymidine, are other causes; family history of hereditary forms of neuropathy, eg, CMT disease

Examination: physical examination is important; multisystem involvement can occur with neuropathies, particularly cardiac (amyloidosis) and autonomic involvement; orthostatic vital signs are helpful

Focused Neurologic Examinations

Motor examination: significant weakness in a diffuse way is atypical for neuropathies, which are typically length-dependent and affect toes, toe extensions, toe flexions, and intrinsic foot muscles; extensor digitorum brevis is a useful test; early neuropathy can cause atrophy, indicating involvement of large motor fibers; chronic neuropathies can cause weakness in toe extension (particularly great toe extension), suggesting motor involvement; significant foot drop (ankle dorsiflexion weakness) is atypical for most common neuropathies, eg, typical DN and CIAP

Sensory examinations: divided into large fiber modalities and small fiber modalities; vibration and joint position sense are important large fiber modalities; vibration is more affected in neuropathies than in spinal cord issues; joint position sense affected out of proportion to vibration may suggest a spinal cord issue (a dorsal column issue), myelopathy, or myeloneuropathy; Romberg testing — often associated with gait and coordination; a sensory examination that can indicate cerebellar ataxia (with or without closing eyes); pinprick testing is useful for small fiber modality; heat and cold sensation is also useful

Reflexes: the Achilles reflex is affected first, which can be a physiologic finding in patients with advanced age; diffuse hyporeflexia or areflexia may suggest demyelinating neuropathy; a reliable finding in chronic inflammatory demyelinating polyneuropathy (CIDP), GBS and other demyelinating neuropathies because of temporal dispersion; reflexes rely on synchrony of nerve transmission; demyelination causes a difference in nerve activity, leading to dispersion and dyssynchrony in conduction causing loss of reflexes (before weakness); a focused neurologic examination can determine the type of fiber involvement; most neuropathies affect these fibers to some degree, though not in a diffuse manner; some neuropathies have small fiber preferences, eg, amyloidosis; motor fibers may be preferentially affected without much sensory involvement, eg, amyotrophic lateral sclerosis; some acquired forms of neuropathy that are immune-mediated can have motor predominance, eg, CIDP, multifocal motor neuropathy; significant motor involvement outside the distribution of intrinsic foot muscles is atypical for length-dependent neuropathies; autonomic fibers can also be affected, causing sweat sensation

Investigations of neuropathies: thyrotropin is recommended; vitamin B₁₂, glucose tolerance tests, and screening for gammopathy are recommended by the American Academy of Neurology as the first-tier tests; get a methylmalonic acid with vitamin B₁₂ (high methylmalonic acid indicates vitamin B₁₂ deficiency); a glucose tolerance test, especially hemoglobin A_1C, can help diagnose neuropathy (one of the most common causes of neuropathy); screening for gammopathy — serum protein electrophoresis with a reflex to immunofixation and serum free light chains (FLC; important in diagnosing hematologic malignancy and light chain amyloidosis risks); other laboratory tests are indicated for more atypical variants; electromyography (EMG) and nerve conduction studies (NCS) can also help

Red flags: include acute onset, asymmetry (increases suspicion for mononeuropathy multiplex), significant sensory ataxia (often in chronic APN), motor predominance, and significant autonomic symptoms

Referring patients to the emergency room: GBS is an emergency, which typically presents with an ascending pattern of paresthesia and can impair walking (usually ≤2 wk); GBS vs acute inflammatory demyelinating polyneuropathy (AIDP) — AIDP is the most common form of GBS in North America, including axonal forms (more common in Asia), which are associated with specific autoantibodies, eg, immunoglobulin (Ig) G and anti-GM1 antibodies, and Campylobacter jejuni infection; cross-reactivity of epitopes has been found as a mechanism for developing GBS; consider antecedent events, eg, vaccination, infection (infection is a stronger trigger than vaccination); intravenous Ig (IVIg) or plasma exchange (PLEX) is the treatment of choice; studies found it most effective ≤2 wk of symptom onset in ambulatory patients; corticosteroids are not indicated in GBS (can precipitate worsening); IVIg and PLEX combination is not proven to be effective

Electrodiagnosis: order EMG/NCS in classic DN or chemotherapy-induced neuropathy (standard test with low risk); the main complication with EMG/NCS is the EMG component, which is often bruising and painful; helps demonstrate whether the neuropathy is axonal or demyelinating

Demyelinating neuropathies: treatable (immune-mediated neuropathies); can show length-dependent sensorimotor APN with etiologies that include vitamin B₁₂ deficiency, DN, and CIAP; primary demyelinating neuropathies can support CMT1 (an autosomal dominant form of hereditary neuropathy)

Sensory neuronopathy or ganglionopathy: important to distinguish from length-dependent neuropathy; has a non-length-dependent reduction or absence of sensory snap amplitude; affects the dorsal root ganglia

Mononeuropathy multiplex: has other causes besides vasculitis; classic manifestation of vasculitis is a stepwise involvement of different nerves; the sciatic nerve is mostly affected; foot drop is a classic manifestation of vasculitis; other nerves, eg, the ulnar nerve, become involved sequentially

Bilateral carpal tunnel syndrome (BCTS): detection on EMG/NCS may indicate amyloidosis, hypothyroidism, or acromegaly; DN is the most common cause; consider other neuropathy forms, especially in older patients with BCTS, excluding amyloidosis

Brachial and lumbosacral plexopathy: sensory responses are important in distinguishing these from radiculopathy; classic examples include radiation plexopathy and neoplastic-associated plexopathy; diabetic amyotrophy and lumbosacral radiculoplexus neuropathy are forms of lumbosacral plexopathy; neuralgic amyotrophy is a form of brachial plexopathy

Axonal vs demyelinating processes: the median nerve measuring from the thumb; conduction block is a hallmark of acquired demyelinating neuropathies; in temporal dispersion, individual axons are affected by demyelination that transmits the signal at different rates; axon loss is characterized by decreased amplitudes (reduced response when stimulating at the distal site, not proximally)

Acquired vs hereditary forms: GBS or CIDP causes conduction block or abnormal temporal dispersion, but CMT1A causes uniform slowing of conduction velocity

Considerations: sural responses (recorded at the ankle) are one of the earliest findings; ratio of the sural to the radial can be more sensitive; a more sensitive response, distal to the sural, can be absent in patients ≥55 yr of age and drops every decade after 30 yr of age; can be an early sign of neuropathy if it is absent; chronic denervation changes occur by wear and tear on the feet, causing muscles to be denervated and reinnervated; active denervation (fibrillations, sharp positive waves) can be the first sign of sensorimotor PN; sensorimotor APN is sensory-predominant, but electrodiagnosis shows motor nerve terminals can be affected to the distal-most part of the nerve

Autonomic reflex testing: evaluates the sympathetic and parasympathetic nervous systems; the pseudomotor index (a part of the sympathetic nervous system) measures the sweat response; the adrenergic index measures blood pressure changes and sympathetic response; the cardiovascular heart rate index is a measure of the parasympathetic nervous system and heart rate variability to deep breathing

Common forms of neuropathy: diabetic PN — common; monoclonal gammopathy of undetermined significance (MGUS) has been conclusively demonstrated for forms of gammopathy; IgM paraproteins (with anti-MAG antibodies) mimic CIDP with significant sensory ataxia; lambda restricted paraproteins indicate the possibility for POEMS syndrome; amyloidosis has been proven to have pathogenicity; IgA and IgG MGUS may also be pathogenic; vitamin B₁₂ deficiency — often causes myelopathy and subacute combined degeneration (test for other vitamin deficiencies); copper deficiency can cause myeloneuropathy; CIAP — prominent ataxia, weakness, or acuity are red flags

Diabetic PN: some studies suggest higher risks with type 2 DM (T2D) than type 1 DM (T1D); neuropathy contributes to infection, ulceration, and amputation; glycemic control is more effective in T1D than T2D; weigh the risks and benefits of tight glycemic control with increased risk for hypoglycemic events

Vitamin B₁₂ deficiency-related neuropathy: oral repletion is found to be equivalent to intramuscular repletion, even in patients with impaired absorption; patients need a very high dose (2,000 μg/day) and require monitoring metabolites like methylmalonic acid; counsel patients that some symptoms may not be reversible, especially if motor involvement or significant ataxia from spinal cord involvement has progressed; FLCs, laboratory testing, and investigation for gammopathy are important (monitor patients if identifying gammopathy); FLCs can help identify the risk for development of multiple myeloma or other blood dyscrasia

Chronic idiopathic APN: has no proven disease-modifying therapy; advancing age is a major risk factor; low prevalence in the general population; has a benign course; a multifactorial disorder with cumulative and potentially heritable risk factors

Alcoholic PN: cessation is the mainstay of treatment; important to supplement thiamine empirically; prognosis is generally favorable, but residual deficits may occur

Chemotherapy-induced neuropathy: no proven treatment; research focuses on prevention (prescribing agents with chemotherapeutic agents to prevent neuropathy); cessation of chemotherapy may lead to worsening or development of neuropathy; a low threshold to refer for neurology or neuromuscular consultation; can either precipitate, worsen, or unmask the neuropathy in patients with CMT

Autonomic neuropathy (AN): diabetic AN is common; can be quantified and characterized through autonomic reflex tests; cardiac AN increases the risk for silent myocardial ischemia and death; amyloidosis is important; there are immune-mediated forms of AN and panels available, eg, ganglionic acetylcholine receptor antibodies; postural orthostatic tachycardia syndrome is a form of dysautonomia that can be diagnosed using autonomic reflex testing

Medications: pregabalin (Lyrica) has the highest level of evidence and is a Schedule V drug; gabapentin has a better adverse effect (AE) profile than pregabalin and has more sedation capacity; pregabalin and gabapentin are reasonable first-line options; serotonin-norepinephrine reuptake inhibitors have level B evidence; duloxetine has been studied more (especially in diabetic painful neuropathy); valproate, opioids, capsaicin, dextromethorphan (DXM), and percutaneous electrical nerve stimulation have level B evidence; some modalities may not improve nerve function or numbness but may help with pain and symptoms; lidocaine patch has level C evidence; oxcarbazepine, lamotrigine, lacosamide, mexiletine, pentoxifylline, and clonidine are probably not effective; topiramate and α-lipoic acid have less evidence

Proposed algorithm: ≤3 lidocaine patches on feet (≤12 hr per day), followed by pregabalin or gabapentin titrated as tolerated and effective; monitoring for AEs is important; serotonin and norepinephrine reuptake inhibitors can be added; duloxetine is preferred (dosages >60 mg have less evidence); because of their AE profile, amitriptyline and tricyclic antidepressants should be prescribed with caution; tramadol can be added for neuropathic pain; limit opioid use; DXM may promote sleep and minimize opioid exposure

Neuromuscular conditions requiring referral: include vasculitic neuropathy, CIDP, hereditary amyloid neuropathies, sensory ganglionopathy, and paraneoplastic neuropathy; sensory ganglionopathy — caused by mega-doses of vitamin B₆, chemotherapy with cisplatin or platinum-based agents; others include Sjӧgren syndrome and paraneoplastic causes; a hereditary form of neuropathy, a late-onset ataxia, recently has been genetically characterized; vasculitic neuropathy — first-tier tests include antineutrophil cytoplasmic antibodies and erythrocyte sedimentation rate (>100 mm/hr indicate systemic vasculitis); urinalysis for proteinuria and cryoglobulinemia and complement levels

Amyloidosis: amyloid light chain (AL) amyloidosis — an aggressive disease with multisystem involvement; can have cardiac, renal, liver, and spleen involvement; the neuropathy tends to have small fiber and autonomic predominance; treatable but has a poorer prognosis; hereditary transthyretin — variable penetrance and age of onset (mostly develop symptoms in 60s); can progress into aggressive neuropathy and has significant autonomic dysfunction, with regression >10 yr; treatable; AL amyloidosis is an oncologic and hematologic disorder, while hereditary transthyretin amyloidosis is a genetic disorder; wild-type transthyretin amyloidosis — a common cause of cardiomyopathy; accumulates in the heart and can also accumulate in carpal tunnels (consider in older patients with BCTS); biopsy specimens can be performed during carpal tunnel surgery; however, cardiomyopathy often manifests after carpal tunnel syndrome; monitoring is less aggressive than AL amyloidosis

Readings

Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-65. doi: 10.1212/WNL.0b013e3182166ebe; Carolus AE, Becker M, Cuny J, et al. The interdisciplinary management of foot drop. Dtsch Arztebl Int. 2019;116(20):347–354. doi: 10.3238/arztebl.2019.0347; England JD, Gronseth GS, Franklin G, et al. Practice parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review): report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72(2):185-192. https://doi.org/10.1212/01.wnl.0000336370.51010.a1; Eussen SJPM, Groot LCPGM, Clarke R, et al. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005;165(10):1167-72. doi: 10.1001/archinte.165.10.1167; Kim S, Takeuchi A, Kawasumi Y, et al. A Guillain-Barré syndrome-like neuropathy associated with arsenic exposure. J Occup Health. 2012;54(4):344-7. doi: 10.1539/joh.12-0023-cs; Leonhard SE, Mandarakas MR, Gondim FAA, et al. Diagnosis and management of Guillain–Barré syndrome in ten steps. Nature Reviews Neurology. 2019;15:671–683. https://doi.org/10.1038/s41582-019-0250-9; Mascaro RS, Sobrino TG, Hernandez AH, et al. Clinical practice guidelines for the diagnosis and management of Charcot-Marie-Tooth disease. Neurología. 2024. https://doi.org/10.1016/j.nrleng.2024.02.008; Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot–Marie–Tooth disease. The Lancet Neurology. 2009;8(7):654-667; Serin HM, Yılmaz S, Kanmaz S, et al. A rare cause of brachial plexopathy: hereditary neuralgic amyotrophy. Turk Pediatri Ars. 2019;54(3):189–191. doi: 10.5152/TurkPediatriArs.2018.5837; Shastri A, Aiyan AA, Kishore U, et al. Immune-mediated neuropathies: pathophysiology and management. Int J Mol Sci. 2023;24(8):7288. https://doi.org/10.3390/ijms24087288; Vidal-Alaball J, Butler C, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005;(3):CD004655. doi: 10.1002/14651858.CD004655.pub2.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Wilks was recorded at the 56th Annual Primary Care Review, held February 10-14, 2025, in Portland, OR, and presented by the Oregon Health & Science University. For information on upcoming programs from this presenter, please visit https://www.ohsu.edu/school-of-medicine/cpd. Audio Digest thanks Dr. Wilks and Oregon Health & Science University for their cooperation in the production of this program.

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