Clinical manifestations

Presentation and course

The clinical manifestations of neuropathy depend on the type and distribution of affected nerve modalities, the degree of axonal or myelin damage, and the course of the disease. Demyelinating neuropathies primarily affect the myelin sheaths, whereas axonal neuropathies target the peripheral nerve axons. When motor nerves are damaged, weakness and muscle atrophy occur. Damage to sensory nerves can cause loss of sensation, paresthesia, dysesthesia, pain, and sensory ataxia. Involvement of small myelinated and unmyelinated sensory fibers typically results in impaired pin prick and temperature sensation, numbness, and painful burning, cold, or stinging paresthesias. Large diameter sensory fiber involvement manifests as loss of vibration and position sensation, sensory ataxia, and numbness or paresthesias. Autonomic dysfunction can result in postural hypotension, impotence, gastrointestinal and genitourinary dysfunction, abnormal sweating, and hair loss. Deep tendon reflexes are frequently diminished or absent, particularly in the demyelinating neuropathies. Because most nerve trunks have a mixture of fiber types, damage to the peripheral nerves often affects more than one of these modalities.

Peripheral neuropathy can be divided into several categories:

	• Polyneuropathy usually refers to diffuse involvement of the peripheral nerves, and is usually first noted distally in the feet and later in the lower legs and hands.
	• Mononeuropathy or radiculopathy refers to involvement of a single nerve or nerve root, respectively.
	• Mononeuropathy (mononeuritis) multiplex signifies focal involvement of 2 or more nerves. The term “neuritis” is usually restricted to inflammatory conditions, such as vasculitic neuropathy.
	• Neuronopathy refers to primary involvement of the nerve cell body, rather than its axon; ganglioneuritis refers to inflammatory involvement of the nerve cell bodies, usually in the sensory or autonomic ganglia.
	• Plexopathy or plexitis refers to involvement of brachial or lumbosacral plexus.

Neuropathies are classified according to the clinical syndrome, pathological features, associated underlying condition, or other specific etiology. A classification of peripheral neuropathies is shown in the differential diagnosis section (Tables 1 and 2).

Approach to the patient with suspected peripheral neuropathy

History. Not all symptoms of distal numbness, tingling, pain, and weakness are caused by peripheral nerve dysfunction; a central nervous system process or even a somatoform disorder may be responsible. Diagnostic accuracy is facilitated by knowledge of functional neuroanatomy and nerve physiology, which aid in identifying one cause and excluding other reasonable causes. This process begins with a history focused on localization of the problem to the peripheral nervous system, localization within the peripheral nervous system (anterior horn cell, root, plexus, single or multiple nerves, neuromuscular junction, muscle), charting the time course, and identifying the type of nerve fibers involved (sensory, motor, sensory and motor, autonomic). Important historical elements include time course, modalities affected, symmetry of involvement, and distal or proximal predominance. Patients often minimize or neglect to notice “negative” symptoms (loss of function), but frequently complain of “positive” symptoms (altered function) listed in Table 3. Negative symptoms, therefore, should be specifically elicited. Weakness often impairs specific function; proximal or distal weakness can be deduced from changes in daily abilities (eg, climbing stairs). Heaviness, numbness, and balance difficulty--especially in the dark--are common descriptions with large fiber neuropathy. Paresthesia and shooting or stabbing pain are common small fiber symptoms and may be more prominent when walking; comfortable shoes are usually adopted by the patient. Patients may note altered temperature perception, especially differences in water temperature sense with different body areas or misperception of hot for cold. Symptoms tend to be worse at night when other sensory distractions are less. Cold and dry distal extremities are frequently noted.

A significant percentage of neuropathy causes are from underlying conditions or treatments that are already known or easily uncovered, so a thorough general medical history including current and prior illnesses, current and prior medications, and other medical and alternative therapies is vital. Diabetes mellitus is a common cause of polyneuropathy. If questioned, patients may acknowledge a prior “high sugar” or prediabetes but not admit to frank diabetes. Peripheral neuropathy has been reported as the presenting symptom of impaired glucose tolerance (10; 24). Many medications, and especially chemotherapeutic agents, may cause neuropathy (22). A long but partial list of neuropathy causes is presented in Table 1. Other pertinent social, recreational, and occupational exposures are important but are less frequently involved, except for alcohol. A more general review of systems is useful to reveal signs suggestive of underlying conditions, especially systemic signs of malignancy, collagen vascular disease, infection, or vasculitis. Gastrointestinal symptoms could provide clues to inflammatory bowel disease or celiac disease (06). Some hereditary disorders are asymptomatic into adulthood so a thorough family history and age of onset is essential. Inquiring about hereditary neuropathy or Charcot-Marie-Tooth disease often fails to prompt recognition, so more direct questions such as: “does anyone in your family have high arched feet, or hammer/curled up toes?” are more probative. Childhood difficulty with running or other sporting activities may be helpful to establish a hereditary condition. Other questions include: “Do you have difficulty walking on heels or rising from a kneeling position?”, “Is there associated wasting of the hands or feet?”, and “Are there any hand, foot, or spinal deformities?” Patients should be questioned about HIV risk factors, recent travel, nutrition, and alcohol use. Vitamin use should be reviewed in particular, as excess vitamin B6 intake may cause a polyneuropathy (18).

Physical examination. The general examination should include a search for autonomic dysfunction (orthostatic blood pressure measures), a thorough inspection of the skin and orthopedic integrity, palpation of distal pulses, palpation of nerves, and a focused systemic examination that may expose the presence of underlying systemic disease. A fall of greater than 20 mmHg of systolic blood pressure or greater than 10 mmHg of diastolic blood pressure recorded at least 3 minutes after standing following 5 minutes of supine rest is the definition of orthostatic hypotension. A sustained heart rate increase of greater than 40 beats per minute within 10 minutes of standing for individuals aged 12 to 19 years, and a sustained heart rate increase of greater than 30 beats per minute in individuals aged greater than 20, in the absence of orthostatic hypotension, is the definition of postural tachycardia syndrome, or POTS (13). It is important to note that both orthostatic hypotension and POTS may occur in the absence of neuropathy or may be related to a concomitant neuropathy as a dysautonomic feature. Fundoscopic examination may reveal optic pallor, which can be present in some conditions such as hereditary motor and sensory neuropathy and leukodystrophies. Common distal skin changes suggestive of small fiber and autonomic dysfunction include skin thinning and scaling, hair loss, coldness, and dryness.

The sensory examination can be challenging and patient cooperation is important. Both small and large sensory fiber modalities should be tested, most commonly pin sensation for small fiber function and vibration and joint position for large fiber function. Cold and warm sensation may also be tested. Pseudoathetosis may be present with significant large fiber impairment. The pattern of sensory loss should be ascertained; occasionally a sensory level is found that diverts the localization. Elicitation of deep tendon reflexes may require reinforcement methods if initially absent (eg, Jendrassik maneuver—pulling apart interlocked hands). Muscles should be inspected for the presence of atrophy (which typically begins in distal muscles), fasciculations, and myokymia (worm-like movement under the skin). A thorough manual muscle strength testing should be performed. Proximal muscles, especially hip musculature, are large and strong and, therefore, require a strong examiner counter-effort to detect weakness. Functional assessments (such as having patients walk on their toes and heels, or hop on 1 leg at a time) may detect more subtle weakness. Orthopedic signs such as high-arched feet, fallen arches, and hammer toes suggest a long-standing condition.

Prognosis and complications

Prognosis and complications depend on the type and severity of the neuropathy.

Clinical vignette

A 45-year-old female with no significant past medical history presents with progressive paresthesias over the left side of her face and hands more prominently than her feet. The patient denied any changes in vision, gait unsteadiness, focal weakness, urinary or bowel incontinence, or difficulty swallowing or speaking. On neurologic exam she was found to have decreased sensation to pinprick in her left face, hands, interscapular area, thighs, and feet. MRI of the brain was unremarkable. Nerve conduction studies and electromyography were normal. Skin biopsy of the left thigh showed decreased intra-epidermal nerve fiber density. Serum testing revealed elevated antibody levels of tissue transglutaminase IgA, gliadin IgG, and gliadin IgA. There was normal complete blood count, comprehensive metabolic panel, fasting glucose, oral glucose tolerance test, serum Vitamin B12, TSH, gliadin IgA, ANA, anti-dsDNA, SSA, SSB, ESR, and Lyme testing. Duodenal biopsy revealed significant villous atrophy and lymphocytosis. The patient was diagnosed with celiac disease with an associated small fiber neuropathy and was started on a gluten-free diet.

Biological basis

Etiology and pathogenesis

Peripheral neuropathy may be either inherited or acquired. More than 200 specific types of peripheral neuropathy have been identified, each with characteristic--but usually not distinctive--features (16). Acquired peripheral neuropathies are more common and can be grouped into several broad categories: those caused by systemic disease, those caused by trauma from external agents, and those caused by infections or autoimmune disorders affecting nerve tissue (Table 1). Neurologic manifestations of COVID-19, including symptoms involving the peripheral nervous system, have been reported (20; 21; 25). It is not clear to what extent the nervous system involvement is related to a direct involvement of the virus on nervous tissue or to the effect of a robust immune response. New medications are often found to cause neuropathy, such as neuropathy related to immune checkpoint inhibitors (09). Additional causes of neuropathy are also continuously being recognized, such as postsurgical inflammatory neuropathy and ischemic monomelic neuropathy (28; 07). Inherited forms of peripheral neuropathy are caused by inborn errors in the genetic code or by new genetic mutations. The most common inherited neuropathies result from abnormalities in genes responsible for neuron cell development, Schwann cell development, myelin sheath maintenance, or myelin sheath folding. These are collectively referred to as Charcot-Marie-Tooth disease, or hereditary motor and sensory neuropathy (23). A rare but important cause of polyneuropathy includes hereditary transthyretin amyloidosis, a progressive disease with a range of clinical manifestations. Patients typically present with polyneuropathy, and nearly 70% exhibit diffuse motor weakness, sensory loss, and autonomic insufficiency; concurrently, over 60% of patients also develop cardiomyopathy (17; 30). Hereditary transthyretin amyloidosis should be recognized as early as possible as disease-modifying therapies are available. Neuropathies with no known cause are referred to as idiopathic neuropathies.

The peripheral nervous system is made up of anatomically and functionally distinct neurons, which subserve motor, sensory, and autonomic functions. Cell bodies, or perikarya, of motor nerves that innervate skeletal muscle lie in the anterior horn of the spinal cord. Their axons travel through the anterior spinal roots and peripheral nerve trunks, terminating at the neuromuscular junction. Sensory nerves convey impulses from special receptors or bare nerve endings in the skin and internal organs. Their perikarya lie in sensory ganglia adjacent to the spine (dorsal root ganglia), and their processes extend from the receptor organs in the periphery through the dorsal roots into the spinal cord. Autonomic nerves innervate the heart, glands, and smooth muscles; they consist of preganglionic fibers that emanate from the brainstem and spinal cord and postganglionic fibers that emanate either from the sympathetic ganglia on either side of the thoracic spine or from parasympathetic ganglia embedded in or near the target organ. The various elements of the peripheral nerves are interconnected and communicate with the spinal cord and each other through their processes, spanning the body in a manner analogous to a fine electrical network.

The neuronal processes, or axons, travel as bundles within fascicles in peripheral nerves. Individual axons are enveloped by Schwann cell processes, or myelin sheaths, and are embedded in a loose matrix of connective tissue called the endoneurium. Each fascicle is surrounded by a dense band of connective tissue called the perineurium, which functions as a blood-nerve barrier and helps maintain the specialized endoneurial environment necessary for nerve function. Peripheral nerves are ensheathed by a dense collagenous layer called the epineurium through which blood vessels and lymphatic drainage provide nutrients and drainage to the nerve.

Nerve signals are propagated by the axonal membrane, with myelinated axons conducting impulses faster and at higher frequencies than unmyelinated axons. Each myelinating Schwann cell ensheathes an axon segment of 500 to 1500 µm in length called an internode. Adjacent internodes are separated by 1 µm of unmyelinated axonal segments called nodes of Ranvier. The myelinated fibers conduct impulses from node to node, whereas the internodal membranes remain relatively inert. When demyelination occurs, axonal conduction is slowed or blocked as unmyelinated fibers conduct in a continuous rather than salutatory fashion along their entire length (03; 10).

Epidemiology

Peripheral neuropathies are thought to be common, although epidemiologic studies are scarce. Studies that are available suggest that 1% to 7% of the general population may have some form of neuropathy depending on location and age group (14). The most common attributable cause of neuropathy is diabetes, which may account for approximately one third of all neuropathies. The remaining two thirds of neuropathies are split between idiopathic and all other known causes (05).

Prevention

Preventative measures vary according to the type of peripheral neuropathy, such as lifestyle modification and avoidance of offending agents.

Differential diagnosis

When approaching a patient with neuropathy, the differential diagnosis can be broad (Table 1). As discussed earlier, a careful history provides information about the symptoms, distribution, and course of the neuropathy. Medical history, social history, and a review of systems may alert the examiner to a possible systemic, toxic, or nutritional etiology. A thorough family history can uncover a hereditary neuropathy. A detailed neurologic examination is required to confirm the presence of neuropathy and to provide information regarding the distribution, severity, and functional impairment of the disease. As information is gathered and condensed, a narrower differential diagnosis comes into focus, and further testing can help with exact diagnosis (Table 2 and 4). Some etiologies may cause more than 1 type of presentation. Diabetes, for example, may cause of variety of different clinical presentations (27).

Table 1. A Classification of the Peripheral Neuropathies

Etiology	Distal symmetric presentation	Multifocal presentation	Focal presentation	Autonomic involvement
Endocrine, metabolic and renal diseases
Diabetes	X	X	X	X
Uremia	X
Hypothyroid (rare)	X		X
Acromegaly	X		X
Porphyria	X			X
Hypophosphatemia	X
Critical illness polyneuropathy	X
Immune-mediated diseases
Guillain-Barre syndrome or AIDP and variants	X		X	X
Chronic inflammatory demyelinating polyneuropathy (CIDP)	X	X
Multifocal motor neuropathy		X
Antiganglioside antibodies (GM1, GM1 IgM, GM1b, GM1b IgG, GM2 IgG, GD1a, GD1a IgG, GD1b, GD1b IgG, GQ1b IgG, LM1)	X	X	X	X
Celiac disease	X	X		X
Lupus	X	X
Polyarteritis nodosa	X	X
Granulomatosis with polyangiitis	X	X
Eosinophilic granulomatosis with polyangiitis	X	X
Microscopic polyangiitis	X	X
Nonsystemic vasculitis, or microvasculitis	X	X	X
Wartenberg migratory sensory neuropath		X	X
Postsurgical inflammatory neuropathy	X	X	X
Rheumatoid arthritis	X	X
Cryoglobulinemia	X	X
Sjögren syndrome	X	X
Sarcoidosis	X	X	X
Infections
Human Immunodeficiency virus	X	X		X
COVID-19	X	X
Cytomegalovirus		X
Hepatitis C	X	X
Hepatitis B	X
Herpes Zoster		X	X
Leprosy		X	X
Lyme disease	X	X	X
Tuberculosis			X
Diphtheria	X	X
Neoplasms and paraneoplastic syndromes
Anti-Hu antibodies	X	X		X
Anti-CV2 antibodies	X	X		X
Anti-CRMP-5 antibodies	X	X		X
Anti-ganglionic acetylcholine receptor (AchR) antibodies	X	X		X
Anti-Yo Antibodies	X	X
Anti-amphiphysin antibodies	X	X
Anti-glial nuclear antibody	X	X
Anti-MAG IgM kappa	X	X
Caspr2	X	X	X	X
MAP1B-IgG antibodies	X	X		X
Voltage-gated calcium channel antibodies (N-type or P/Q type)	X	X		X
Multiple myeloma	X
Monoclonal gammopathies	X
POEMS syndrome and associated anti-VEGF Ab	X	X		X
Primary amyloidosis	X	X	X	X
Lymphoma	X	X	X	X
Advanced cancer	X	X	X
Entrapment and trauma
Carpal tunnel syndrome			X
Median neuropathy at the elbow			X
Anterior interosseous neuropathy			X
Posterior interosseous neuropathy			X
Radial neuropathy in the upper arm			X
Ulnar neuropathy at the elbow or wrist			X
Sciatic neuropathy			X
Common fibular (peroneal) neuropathy at the knee			X
Lateral cutaneous nerve of the thigh			X
Spinal accessory nerve in the posterior cervical triangle in the neck			X
Nutritional
Thiamine deficiency	X			X
B12 deficiency	X
Pyridoxine (B6) (excess or deficiency)	X
Vitamin E deficiency	X
Gastric restriction surgery for obesity	X	X
Toxic
Alcohol	X
Nitrous oxide	X
Radiation	X
Thallium	X			X
Lead	X
Arsenic	X			X
Glue sniffing (n-Hexane)	X
Acrylamide	X
Organophosphates	X
Mercury	X			X
Carbon monoxide	X
Ethylene oxide	X
Methyl bromide	X
Drugs
Abraxane	X
Ado-trastuzumab emtansine	X
Aldesleukin	X
Alemtuzumab	X	X	X	X
Amiodarone	X
Aprepitant	X
Arsenic trioxide	X
Atezolizumab	X	X
Avelumab	X	X
Bexarotene	X
Bicalutamide	X
Bortezomib	X			X
Brentuximab vedotin	X
Brigatinib	X
Cabazitaxel	X
Cabozantinib-S-malate	X
Capecitabine	X
Carboplatin	X
Carfilzomib	X
Cemiplimab	X	X
Ceritinib	X
Cetuximab	X
Chlorambucil	X
Chloramphenicol	X
Chloroquine		X
Cisplatin	X
Cladribine	X
Colchicine	X
Crizotinib	X
Cytarabine	X	X
Dactinomycin	X
Dapsone	X
Dasatinib	X
Deoxycytidine (ddC)	X
Dexamethasone	X
Disulfiram	X
Didanosine (ddI),	X
Dinutuximab	X	X
Docetaxel (_axotere)	X
Dostarlimab	X
Durvalumab	X	X
Elotuzumab	X
Ethambutol	X		X
Etoposide	X
Encorafenib	X
Entrectinib	X
Eribulin	X			X
Erlotinib	X
Etoposide	X
Exemestane	X
Fludarabine	X
Gefitinib	X
Gilteritinib	X
Gold	X
HMG-CoA reductase antagonists	X
Hydralazine	X
Ibrutinib	X
Interferon alfa-2a	X
Interferon alfa-2b	X
Idarubicin	X
Ifosfamide	X
Imatinib	X
Ipilimumab	X		X	X
Isoniazid	X
Ivosidenib	X		X	X
Ixabepilone	X			X
Ixazomib	X
Ixabepilone	X
Ixazomib	X
Leflunomide	X
Lenalidomide	X			X
Leuprolide	X
Linezolid	X
Lorlatinib	X
Megestrol	X
Metronidazole	X
Misonidazole	X
Mogamulizumab	X
Nab-paclitaxel	X
Nelarabine	X		X	X
Nilotinib	X
Nitrofurantoin	X
Nivolumab	X		X	X
Olaparib	X
Oxaliplatin	X
Perhexiline	X
Paclitaxel (Taxol)	X
Pembrolizumab	X
Pemetrexed	X
Pertuzumab	X
Pexidartinib	X
Phenytoin	X
Platinum	X
Polatuzumab vedotin	X
Pomalidomide	X
Ponatinib	X
Procarbazine	X
Rituximab	X
Sorafenib	X
Stavudine (d4T)	X
Suramin	X
Tacrolimus (FK506)	X
Taxanes	X
Temozolomide	X
Thalidomide	X
Tisagenlecleucel	X
Tocilizumab	X	X
Trabectedin	X
Trastuzumab	X
Vemurafenib	X
Vinorelbine (navelbine)	X
Vincristine	X	X	X	X
Zalcitabine	X			X
TNF-alpha antagonists	X	X
Hereditary
Hereditary neuropathy with predisposition to pressure palsy (HNPP)		X	X
Ehlers Danlos Syndrome		X
Charcot-Marie-Tooth Disease	X
Hereditary transthyretin amyloidosis (hATTR)	X	X	X	X
Neuralgic amyotrophy		X	X
Refsum disease		X	X
Idiopathic	X	X	X	X
(23)

Table 2. Differential Diagnosis of Peripheral Neuropathy Based on Clinical Time Course

Acute onset (days)	Subacute onset (weeks to months)	Chronic or insidious onset (years)	Relapsing remitting course
• Guillain-Barre syndrome (idiopathic and HIV-associated)	• Toxic agents, medications	• Hereditary motor sensory neuropathies	• Guillain-Barre syndrome (idiopathic)
• Critical illness polyneuropathy	• CIDP	• CIDP	• Acute intermittent porphyria
• Infectious (eg, Lyme, diphtheritic neuropathy)	• Metabolic and collagen vascular (diabetes, renal lupus)	• Metabolic and collagen vascular (diabetes, renal lupus)	• Metabolic and collagen vascular (diabetes, renal lupus)
• Toxic agents, medications	• Paraneoplastic	• HIV	• Vasculitis
• Acute intermittent porphyria	• Nutritional and vitamin deficiency	• Nutritional and vitamin deficiency	• CIDP
• Vasculitis	• Infectious (eg, Lyme, CMV)	• MGUS	• Toxic
	• Graft vs. host disease	• Metabolic derangement (diabetes, renal failure)
	• Vasculitis
Abbreviations: CIDP = chronic inflammatory demyelinating polyneuropathy; CMV = cytomegalovirus; HIV = human immunodeficiency virus; MGUS = monoclonal gammopathy of undetermined significance

Table 3. Positive and Negative Symptoms of Peripheral Neuropathy

Type of nerve fiber	Positive symptoms	Negative symptoms
Sensory	• Paresthesia (jabbing, shooting) • Tingling (pins and needles) • Pain (paroxysmal, burning, pricking) • Cutaneous hyperesthesia	• Lack of sensation • Foot ulceration • Loss of balance and gait disturbance (sensory ataxia) • Postural tremor
Motor	• Cramps • Fasciculations • Myokymia	• Weakness • Atrophy • Fatigue • Hypotonia
Autonomic	• Diarrhea • Excessive sweating • Hypertension • Osteoarthropathy • Flushing • Orthostatic hypotension • Postural orthostatic tachycardia syndrome	• Arrhythmia • Impotence • Constipation • Decreased sweating • Urinary retention • Gastroparesis • Dry mouth • Dry eyes • Retrograde ejaculation

Table 4. Partial List of Tests to Consider in Evaluation of Peripheral Neuropathy

Blood tests
	• complete blood count • basic metabolic panel • hepatic function panel • creatine kinase • Lyme • VDRL • hepatitis A, B, C • serum protein electrophoresis • immunofixation • IgG • IgM • IgA • kappa/lambda ratio with kappa light chains and lambda light chains • erythrocyte sedimentation rate • C reactive protein • antinuclear antibody • angiotensin converting enzyme • rheumatoid factor • thyroid stimulating hormone • vitamin B1 • vitamin B12 • homocysteine • methylmalonic acid • folate • vitamin E • 2-hour oral glucose tolerance test • hemoglobin A1C • mercury • copper • myeloperoxidase • proteinase 3 • gliadin IgG antibody • gliadin IgA antibody • transglutaminase antibody • cryoglobulin • thyroid peroxidase antibody • thyroglobulin antibody • double stranded DNA • vascular endothelial growth factor • ganglioside antibodies (GD1A, GD1B, GM1, GQ1B, GT1A) • anti-sulfatide • anti-neuronal nuclear antibodies (includes anti-Hu, Ri) • voltage gated potassium channel antibody • N-type calcium channel antibody • P/Q-type calcium channel antibody • Purkinje cell cytoplasmic antibodies (includes anti-Yo, PCA-2, and Tr) • TS-HDS IgM • FGF-R3 IgG • ganglionic acetylcholine receptor antibody • CRMP-5-IgG • amphiphysin antibody • anti-glial nuclear antibody • paranodal antibodies (includes Caspr, Contactin-1, Neurofascins) • Caspr2 antibody
Hereditary tests
	• neuropathy with liability to pressure palsy (tomaculous neuropathy) • Charcot-Marie-Tooth genetic tests • transthyretin gene • hexosaminidase A, B
Electrodiagnostic studies
	• nerve conduction studies • needle electromyography • somatosensory evoked potentials • autonomic function tests • quantitative sensory testing
Imaging tests
	• Magnetic resonance imaging studies (cervical spine, thoracic spine, lumbosacral spine, or brachial and lumbosacral plexus) • MR neurology • contrast may be used with MRI studies to evaluate for an inflammatory component • skeletal survey • chest x-ray • computed tomography of the chest • peripheral nerve ultrasound
Cerebrospinal fluid analysis
Urine tests
	• urine protein electrophoresis with immunofixation • Bence Jones protein • 24-hour heavy metals (mercury, lead, arsenic) • Porphobilinogen
Biopsy
	• skin epidermal nerve fiber density • sweat gland nerve fiber density • nerve • muscle • bone marrow • duodenal • lacrimal gland • fat pad • rectal • minor salivary gland

Diagnostic workup

A careful history provides information about the symptoms, distribution, and course of the neuropathy. The medical and social history and review of systems may alert the examiner to a possible systemic, toxic, or nutritional etiology. A positive family history is suggestive of hereditary neuropathy. A detailed neurologic examination is required to confirm the presence of neuropathy and to provide information regarding the functional impairment, distribution, and severity of the disease.

Blood and CSF studies can aid in the diagnosis of inflammatory, paraneoplastic, infectious, endocrine, metabolic, toxic, nutritional, or hereditary causes of neuropathies. The most common pattern of polyneuropathy is a length-dependent, distal symmetric sensory greater than motor polyneuropathy. Initial laboratory screening for causes of distal symmetric polyneuropathy usually includes fasting blood glucose, comprehensive metabolic panel, hepatic panel, complete blood count and differential, serum vitamin B12, thyroid stimulating hormone, erythrocyte sedimentation rate, and serum immunofixation electrophoresis (IFE). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (11). See Table 4 for an extensive, but not exhaustive list of tests that may be considered in evaluation of neuropathy. Magnetic resonance imaging (MRI) can aid in identification of structural spinal pathology that can cause neuropathy. MR neurography can be similarly helpful in diagnosing abnormalities of the thoracic outlet, brachial plexus, lumbosacral plexus, and peripheral nerves (33). MRI with contrast of the spine or the lumbosacral or brachial plexus can aid in identification of inflammatory lesions such as chronic inflammatory demyelinating polyneuropathy or meningitis.

High resolution ultrasound is a noninvasive diagnostic tool that can accurately identify focal nerve enlargement seen with focal nerve entrapments (33). It can also identify multifocal or diffuse nerve enlargement to aid in the diagnosis of hereditary and inflammatory neuropathies (31). A prospective multicenter study showed that there is little interobserver variability in nerve ultrasound, even across different hospital sites using different sonographic devices. Therefore, nerve ultrasound is a reproducible tool for diagnostics in routine clinical practice and research (29). Electrodiagnostic studies, including electromyography and nerve conduction studies, may be used to confirm the presence of peripheral neuropathy, reveal whether the underlying process is demyelinating or axonal, determine whether motor, sensory, or a combination of fibers are involved, assess the severity and distribution pattern of neuropathy, and follow the course of the disease. Electromyography and nerve conduction studies are limited as they predominantly evaluate distal neuromuscular segments and may sometimes fail to detect proximal lesions. Additionally, they largely assess the function of large diameter nerve fibers, whereas the majority of axons are small and commonly employed electromyography/nerve conduction studies techniques fail to detect small fiber neuropathy.

Autonomic and small fiber neuropathies may be assessed using epidermal nerve fiber density, sweat gland nerve fiber density, autonomic function testing, or quantitative sensory testing. Proposed diagnostic “gold standards” for small fiber neuropathies include the presence of at least 2 abnormal results in the clinical, quantitative sensory testing, and skin biopsy examinations (08). Epidermal skin punch biopsy is now commonly employed to measure epidermal nerve density using the nerve specific marker PGP 9.5 and is characteristically abnormal when conventional electrodiagnostic studies are normal in small fiber neuropathies (19; 12; 15). It can be used to quantitate sweat gland nerve fiber density and is complementary to epidermal nerve fiber density measurement (02). Quantitative sensory testing is a psychophysical test dependent on factors such as subject cooperation, alertness, site of stimulation, and site of study. It is used extensively in clinical trials but is not widely accepted for routine clinical application. Somatosensory evoked potentials are sometimes helpful when severe peripheral nerve disease is present and nerve conduction studies are inadequate, or when the afferent nerves to be studied present insurmountable technical difficulties (32).

Nerve biopsy is most helpful once adequate clinical, laboratory, and electrodiagnostic evaluation have been performed. It proves most useful in acute/subacute, asymmetric, multifocal, progressive neuropathy (02). Nerve and muscle biopsy can be particularly useful in the diagnosis of autoimmune or vasculitic neuropathies, sarcoidosis, or amyloidosis as other disorders often show nondiagnostic changes in peripheral nerve tissue.

Genetic testing may play an important role in the workup and diagnosis of peripheral neuropathy, and there are multiple commercially available genetic panels. It is becoming increasingly important to identify patients with certain hereditary neuropathies as future gene therapy and molecular-based therapies become available.

Advanced techniques to be considered for further evaluation of peripheral neuropathy include corneal confocal microscopy and laser Doppler image flare. Corneal confocal microscopy images the subbasal nerve plexus of the cornea. Reductions in corneal nerve fiber density and fiber length correspond to polyneuropathy severity. It is noninvasive, repeatable, and particularly useful in the evaluation of length-independent neuropathies due to the proximal location. Limitations include a lack of hardware and personnel for the procedure to be performed.

Laser Doppler image flare evaluates the axon reflex response to heat stimulus with Doppler. The area of vasodilation due to neurogenic flare is measured, and the flare area is reduced in neuropathy or in the setting of local anesthetic. It has also been used to demonstrate early sequelae of diabetes prior to detection of neuropathy with other methods.

Management

Therapy is often directed at the symptoms, or when possible, at the underlying cause of the neuropathy. Symptomatic treatments include medical therapy for the painful paresthesias, physical and occupational therapy to help improve mobility and function, and supportive measures to maintain blood pressure and bladder and bowel function if the autonomic system is involved. Treatment for the causes of neuropathy include antibiotics, antiviral, or other treatments for infectious neuropathies (eg, steroids, intravenous immunoglobulin (IVIg), plasmapheresis), immunomodulating agents for immune-mediated or paraneoplastic neuropathies, improved glycemic control for diabetic neuropathies, vitamin replacement for vitamin deficiency, and surgery for compressive neuropathies, among others (02). Although less common, acquired demyelinating polyneuropathies, such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP), are often treatment responsive. The treatment of neuropathic pain often involves off-label medications. Approaches may include topical agents, anticonvulsants, antidepressants, and if necessary, narcotics. Often, a sequential trial of titration to effective dose, side effects, or nonefficacy is needed. Patient education is also important and may include suggestions for regular foot inspection, orthopedic shoes, podiatric evaluation, as well as fall and injury prevention, such as avoidance of loose rugs and testing water temperature with the hands.

We are in an era of medicine wherein specific genetic and molecular therapies are available for a number of neurologic diseases. For example, in hereditary transthyretin amyloidosis neuropathy, there are FDA-approved TTR gene-modifying therapies available. Both patisiran, a silencing RNA, and inotersen, an antisense oligonucleotide, have been shown to improve multiple clinical manifestations of hereditary transthyretin amyloidosis (01; 04; 26). Therefore, as novel therapies continue to be discovered we expect that more options will become available to treat various neuropathies.