A Practical Approach to Diagnosing Peripheral Neuropathies

Abstract

Polyneuropathies are common, with the incidence increasing with older age. The causes of polyneuropathies are diverse and numerous, and it can be challenging for clinicians to determine the etiology of a particular patient's neuropathy. In this article, we systematically detail a practical approach to polyneuropathies, beginning with the most important aspects of the workup, the history and physical. We then discuss the limited diagnostic approach required for patients who present with a distal symmetric polyneuropathy and the more comprehensive approach for patients who present with other neuropathy subtypes.

Keywords

Peripheral neuropathy - Polyneuropathy - Electrodiagnostic studies

Peripheral neuropathy is one of the most common neurological conditions in the United States and is a common reason for neurological consultation. Peripheral neuropathy refers to any disorder that affects the peripheral nervous system; this article will focus on the approach for patients who present with suspected polyneuropathy. The global prevalence of polyneuropathy ranges from 1 to 4%, as high as 7% in those greater than 65 years of age, and 13.2% in those greater than 80 years of age.[1] [2]

The approach to a patient with suspected polyneuropathy has similarities to other neurological complaints. As always, the clinician first needs to localize the symptoms and then develop a differential diagnosis based on that localization. A clinical presentation of numbness in bilateral feet can localize to the spinal cord, lumbosacral nerve roots, or bilateral lumbosacral plexus in addition to peripheral nerve. The history and exam are instrumental in differentiating between these possibilities. For example, the localization for a patient who has lower motor neuron weakness and numbness in bilateral legs proximal to the knee without any symptoms in the upper extremities is more likely to be in the plexus or nerve root rather than the nerve. If a localization of peripheral nerve is suspected, the clinician then must determine the cause of the polyneuropathy. This can be challenging, however, as determining which of the greater than one hundred causes of polyneuropathy can be overwhelming.[1]

To navigate through some of the complexities inherent to a polyneuropathy diagnosis, a framework to localize and subtype neuropathies can be helpful. Neuropathies have been classically categorized based on (1) acuity: acute, subacute, or chronic; (2) anatomical distribution: distal symmetric, nonlength-dependent, multifocal, or focal nerve involvement; (3) fiber type: motor, sensory, or sensorimotor, and large or small fiber; and (4) pathophysiology: axonal or demyelinating. Classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), for example, can be categorized as subacute to chronic, nonlength-dependent, sensorimotor, and demyelinating.

While it is valuable to think of each of these categories when obtaining a history and physical exam of a patient, an easier approach when assessing a patient for the first time is to first determine whether the patient presents with a distal symmetric polyneuropathy (DSP), the most common type of neuropathy, or an alternative, less common neuropathy subtype. This can be done by looking for any red flags ([Table 1]) during the history and physical exam. If the patient has a classic DSP, a small but essential number of tests are recommended. If red flags are present, which include asymmetry, acute or subacute onset, motor predominance, severe sensory symptoms, and length-independent symptoms and signs, then the clinician should proceed with a more comprehensive workup, starting with electrodiagnostic testing (EDX; [Fig. 1]). In the rest of this article, we will walk through an initial encounter with a patient who presents with a possible polyneuropathy, starting with a history and physical exam.

Table 1 Red flags on history and physical exam and corresponding diagnoses to consider

Red flag	Diagnoses to consider
Acute or subacute onset	Acute nutritional neuropathy due to thiamine deficiency Guillain–Barre syndrome (GBS) Infectious neuropathies Toxic neuropathies Vasculitic neuropathy
Asymmetry	Multifocal-acquired demyelinating sensory and motor neuropathy (MADSAM) Multifocal motor neuropathy (MMN) Plexopathies Sjogren's disease Superimposed entrapment neuropathy or radiculopathy Vasculitic neuropathy
Motor predominance	Charcot–Marie–Tooth Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) GBS Lead poisoning MMN Porphyria
Nonlength-dependent	CIDP GBS Paraproteinemic neuropathies Rheumatologic neuropathies Vasculitic neuropathies
Severe sensory symptoms with sensory ataxia	Celiac disease Paraneoplastic neuropathies Sjogren's disease Vitamin B6 toxicity

Fig. 1 Diagnostic approach for a patient who presents with a polyneuropathy. If there are no red flags on history and physical exam, the patient has a chronic DSP. If red flags (acute or subacute onset, asymmetry, motor predominance, nonlength dependence, and severe sensory symptoms with sensory ataxia) are present, then electrodiagnostic testing should always be performed. The results of the electrodiagnostic testing, when considered with the history and physical exam, help narrow the differential diagnosis by determining the neuropathy subtype. AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AMAN, acute motor axonal neuropathy; anti-MAG, anti-myelin-associated-glycoprotein; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; DSP, distal symmetric polyneuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; MMN, multifocal motor neuropathy; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes; SLE, systemic lupus erythematosus.

Taking a History

During an initial encounter with a peripheral neuropathy patient, we systematically explore each element of the history, highlighting aspects that are particularly important to isolate the specific region of nerve damage, determine the type of neuropathy, and provide clues to the underlying cause.

When taking the primary history of illness, the physician should inquire as to the presence of both positive and negative symptoms. “Positive” symptoms can be described as paresthesias, or abnormal sensations (including a sense of “swelling” in large-fiber neuropathies), and dysesthesias, or painful sensations. In a neuropathy, usually the small-fiber type, patients frequently describe feeling “sharp,” “electrical,” “squeezing,” “pins and needles,” and “burning” sensations in their feet, or in a stocking distribution.[3] These patients may also suffer from hyperalgesia (increased sensitivity to painful stimuli) or allodynia (painful sensation to non-noxious stimuli).[4] In addition, patients with neuropathy typically experience “negative” symptoms, such as numbness and loss of balance, in the same anatomical distribution. At times, patients will describe the paradoxical situation of experiencing both numbness and burning simultaneously. In patients with a DSP, these abnormal sensations originate in the distal toes and feet and then slowly ascend proximally. Once the sensations reach the knees, they begin to involve the hands. As proprioception is frequently spared compared with other sensory modalities in mild–moderate neuropathies, gait and balance issues are not typically predominant. Only later in the neuropathy course do patients complain about falling in the dark or walking “more carefully.” The exceptions to this rule are patients suffering from posterior column diseases, such as B12 deficiency, or sensory ganglionopathies, such as Sjogren's disease.[5]

In addition, while sensation is most frequently affected in most neuropathies, the physician should also ask about nonsensory symptoms. One should inquire as to weakness, muscle fasciculations, muscle atrophy, and inability to perform both fine and gross motor tasks, including handwriting, buttoning, and using silverware. Early involvement of the motor system is highly unusual in sensory or sensorimotor neuropathies and points to either pure motor neuropathies, motor neuronopathies, or polyradiculoneuropathies. Etiologies include sarcoidosis, amyloidosis, vasculitis, inflammatory/autoimmune, infectious, or paraneoplastic causes.

In the history-taking, the physician should specifically inquire for the presence of dysautonomia by asking about vasovagal phenomena (light-headedness, palpitations, and leg swelling), cutaneous manifestations (abnormal skin color, especially in temperature extremes), abnormal sweating (hyperhidrosis or anhidrosis), genitourinary (erectile dysfunction, urinary urgency/frequency, and incontinence), and gastrointestinal (constipation/diarrhea, abdominal bloating, and fecal incontinence) symptoms.[4] It is advisable to administer specific autonomic questionnaires, such as the Composite Autonomic Symptom Score (COMPASS).[6] Neuropathies with significant autonomic involvement include amyloidosis, diabetes, HIV, and Guillain–Barre syndrome (GBS; [Table 2]).

Table 2 Diagnoses to consider if autonomic symptoms are present

Amyloidosis: hereditary and sporadic

Diabetes mellitus

Guillain–Barre syndrome

Infectious neuropathies: Chagas disease, HIV, leprosy

Inherited neuropathies: Allgrove syndrome, HSAN, Fabry disease, Tangier disease

Paraneoplastic neuropathies

Toxic neuropathies: amiodarone, ciguatera, cisplatin, heavy metals, vincristine

Abbreviation: HSAN, hereditary sensory and autonomic neuropathy.

The distribution of symptoms is critical in history-taking and is key to making a diagnosis. A symmetric and length-dependent distribution does not provide a clue to the etiology, although diabetes is the most common cause.[7] However, evoking length-independent and asymmetric symptoms, whether multifocal or proximal in distribution, allows the clinician to focus on rarer neuropathies, such as multifocal-acquired demyelinating sensory and motor neuropathy (MADSAM) or a vasculitic neuropathy.

A crucial element of the history is the duration of symptoms. Is the course acute (<4 weeks), subacute (3–12 weeks), or chronic (>12 weeks)? As the vast majority of neuropathies are chronic, acute cases significantly alter the differential diagnosis and may signify a toxic exposure, such as chemotherapeutic agents, or immune-mediated disease, including GBS. Acute nutritional neuropathy due to thiamine deficiency should also be considered, as it can present as a GBS mimic.[8]

Besides the symptoms in the history of illness, there are other elements useful in diagnosing causes of neuropathy. Family history is a key component, particularly in younger patients. The clinician should ask about the patient's ethnicity, consanguinity, and specific details about parents and siblings, including high-arched feet, “clawed hands,” and lower leg muscle atrophy (or “inverted champagne bottle legs”). In addition, a family history of bilateral carpal tunnel syndrome and autonomic dysfunction may suggest hereditary amyloidosis, an important diagnosis to consider, given the FDA-approved treatments available.[9]

Other key elements of the history include social factors, such as use of illicit drugs (heroin, cocaine) and alcohol, both of which have been implicated in the development of sensory neuropathies. Along these lines, a patient's toxic exposures, including heavy metals (as in a factory worker), can be risk factors for peripheral sensory neuropathy.

Certain medications (including over-the-counter and supplements) predispose to developing a predominantly sensory neuropathy, rarely with motor weakness ([Table 3]). Common classes of medications include chemotherapies (paclitaxel, vincristine, thalidomide) and antibiotics (isoniazid and linezolid). Usually, stopping the offending medication leads to the cessation of symptoms, although there can be a “coasting” phenomenon, where even after ending the medication, symptoms may persist for months before resolving spontaneously.[10]

Table 3 Medications that can cause neuropathy

Axonal sensory	Axonal motor	Axonal mixed	Demyelinating	Axonal and demyelinating
Bortezomib	Botulism	Acrylamide	Chloroquine	Amiodarone
Cisplatin	B-Bungarotoxin	Alcohol	Diphtheria toxin	Ethylene glycol
Cyclosporine	Lead	Arsenic	Tacrolimus	Hexacarbons
Doxorubicin	Mercury	Cadmium	TNF-α-antagonists
Ethambutol	Misoprostol	Colchicine	Gold
Etoposide	Tetanus	Dapsone		n-Hexane
Isoniazid		Disulfiram
Leflunomide		Heroin
Linezolid		Lithium
Metronidazole		Polychlorinated biphenyls
Nitrous oxide		Taxol
Nucleosides		Thallium
Pyridoxine		Vinca alkaloids
Thalidomide

The presence of other medical issues is critical for understanding causes of neuropathy. Diabetes is the most common cause of distal sensory polyneuropathy, as 50% of type 1 and 2 patients have distal symmetric sensory neuropathies.[11] Other diseases commonly associated with peripheral neuropathy include systemic infections (HIV, syphilis, and leprosy), rheumatologic (sarcoidosis, vasculitis), and dysproteinemic disorders.

Physical Examination

On the general exam, the neurologist should look for certain skeletal and joint abnormalities, including a “Charcot” joint (loss of the foot arch), pes cavus (high-arched feet; [Fig. 2]), hammertoes, “clawed hands,” and contractures, mainly in chronic neuropathies. There may be distal muscle atrophy in the hands and feet. Palpation of peripheral nerves can demonstrate nerve enlargement, seen in focal compressive neuropathies and in specific diffuse neuropathies, such as leprosy. In addition, neuropathy patients frequently possess skin changes, including ulcers, peripheral hair loss, and xerosis or dry skin.[12] [13] Neuropathy patients can develop calluses on their soles, due to uneven distribution of force during ambulation, and shoe “scuffing” is common since patients can't clear the ground when they walk.

Fig. 2 Example of pes cavus and hammertoes noted in the right foot of a patient with hereditary motor neuropathy type 5A.

Ideally, the examiner should test all sensory modalities, engaging with the different types of sensory nerves. While some neurologists utilize a 10-g Semmes–Weinstein monofilament in sensory testing, this is not ideal and can miss small-fiber nerve dysfunction, including 25 to 50% of those with diabetic neuropathy.[14] Vibration testing for large-fiber myelinated 1a nerves with a 128 Hz tuning fork is more sensitive than proprioception for most large-fiber neuropathies (with the exception of B12 deficiency and tabes dorsalis).[15] This modality is tested beginning with the distal phalanx of the toes, and if absent, then progressively tested more proximally at the malleolus, tibia, and patella. Vibratory sensation should last at least 10 seconds, although it decreases with age.[15] [16] Proprioceptive testing involves minimal movement of the same distal phalanxes in the foot and hand, with absent responses necessitating the testing of more proximal joints. Patients with significant sensory loss may exhibit “pseudoathetosis” or “piano-playing” movements of extended fingers.[17]

In terms of testing small-fiber nerve damage, the examiner applies a pin against the distal leg with constant pressure from point to point, to be as reproducible as possible. The examiner tests pinprick moving from the distal foot (or hand) proximally, until reaching normal sensation.

The exception to the symmetric loss of sensation is mononeuritis multiplex, where multiple specific nerves are dysfunctional, so there can be asymmetric loss of sensation and/or focal weakness. For example, a patient may have left foot drop and right wrist drop or numbness in the right foot and left hand, as this neuropathy presents in a multifocal and nonlocalizable manner. This presentation is pathognomonic for this specific diagnosis, which has a narrow differential ([Fig. 1]).

Strength testing and elicitation of reflexes also help in anatomical localization and neuropathy diagnoses. The vast majority of patients with peripheral neuropathies either have full strength or only minimal ankle/toe weakness. The extensor hallucis longus muscle is affected first, as it is farthest from the motor neuron. Areflexia/hyporeflexia is the most sensitive sign of large-fiber neuropathy,[18] and the ankle reflexes are lost first.

Gait testing is essential to making a diagnosis in peripheral neuropathy patients. First, the examiner should assess whether a patient can rise from a seated position without using their arms. If they cannot, this may suggest proximal weakness, even if the patient has full strength of proximal muscles on confrontation testing. For ambulation, patients with proprioceptive loss possess a wide-based “sensory ataxic” gait. There can be a “Romberg's” sign for those with severe proprioceptive loss. On the other hand, those with distal weakness may engage in a “steppage” gait due to bilateral foot drop and will be unable to walk on their heels. Subjects unable to tandem walk may be affected by cerebellar dysfunction, but those with sensory neuropathies can also have difficulty with this test.

Determining a Neuropathy Subtype to Help Narrow the Differential Diagnosis

Once the history and physical exam are completed, there is a decision point to determine whether the patient has a chronic DSP or whether red flags are present that may suggest an alternative neuropathy subtype. In many patients who present with a chronic DSP subtype, the likely etiology can be determined by the history. The most common cause is diabetes, responsible for 18 to 49%, followed by alcohol use disorder.[1] [18] [19] Twenty to thirty percent of cases are classified as idiopathic. New diagnostic criteria for idiopathic DSP, which were created primarily for research purposes, were recently published.[20] If red flags, such as asymmetry, acute or subacute onset, motor predominance, severe sensory symptoms such as loss of joint position sense or ataxia, or nonlength dependence are present, EDX testing should be done. A neuropathy subtype can then be determined based on the results of EDX testing, the history, and the physical exam. Subtypes include acute axonal sensorimotor neuropathy, axonal motor neuropathy, sensory neuronopathies, demyelinating neuropathies, and mononeuritis multiplex ([Fig. 1]). Within many of these subtypes, the differential diagnosis depends on whether the neuropathy is acute/subacute or chronic.

Diagnostic Workup

Laboratory Testing

If a patient presents with a chronic DSP, it is reasonable and value-conscious[21] to perform a limited laboratory diagnostic workup. The 2009 practice parameter copublished by the American Academy of Neurology (AAN), the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), and the American Academy of Physical Medicine and Rehabilitation (AAPM&R) found that the laboratory tests with the highest yield for DSP are fasting glucose, serum protein electrophoresis with immunofixation, and vitamin B12 with methylmalonic acid ± homocysteine.[22] To increase the sensitivity for detecting diabetes mellitus and impaired glucose tolerance, the addition of a 2-hour glucose tolerance test is recommended if routine blood glucose testing is normal, especially if pain is present.[23] These tests, in addition to a complete blood cell count and comprehensive metabolic panel, should be sent in all patients who present with a peripheral neuropathy. Thyroid function tests and rheumatologic studies, commonly ordered as part of a DSP workup, do not add significant value if tested indiscriminately.[24] Other laboratories should be considered for patients with a DSP without atypical features if risk factors are present, including but not limited to a rheumatologic screen, infectious diseases including HIV, Lyme, and hepatitis, and Vitamin B1 and B6 levels.

Patients who do not have a chronic DSP phenotype require further laboratory testing, with specific tests dependent on the subtype of the neuropathy ([Fig. 1]). Acute neuropathies can be either demyelinating (acute inflammatory demyelinating [AIDP]) or axonal. If axonal, they can present as multifocal/mononeuritis multiplex (vasculitis, infectious such as hepatitis and Lyme, infiltrative), predominantly motor (acute motor axonal neuropathy, West Nile Virus [WNV], porphyria) or sensorimotor (toxic neuropathies such as arsenic, acute nutritional neuropathies, and infections such as HIV). Patients who have a multifocal/mononeuritis multiplex neuropathy need an extensive laboratory evaluation. Tests should include rheumatologic studies such as antinuclear antibody, erythrocyte sedimentation rate, C-reactive protein, antineutrophilic cytoplasmic antibody, rheumatoid factor, SSA/B, dsDNA, angiotensin-converting enzyme and cryoglobulins, and infections including a hepatitis panel, HIV screen, and Lyme testing.[25]

Chronic neuropathies that do not fit a DSP pattern can be subtyped as sensory neuronopathies, demyelinating, or motor (of which most are hereditary). For sensory neuronopathies, testing for Sjogren's, systemic lupus erythematosus, celiac disease, and paraneoplastic antibodies, particularly anti-Hu and anti-CV2/contactin response mediator protein 5, should be done.[26] [27] For demyelinating neuropathies, in addition to serum protein electrophoresis/immunofixation (SPEP/IFE), other laboratories include anti-GM1 to assess for multifocal motor neuropathy, anti-myelin-associated-glycoprotein, and vascular endothelial growth factor to assess for POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes) syndrome. If a hereditary neuropathy is suspected, genetic testing is recommended. This can be done prior to EDX testing. If EDX testing is normal and a small-fiber neuropathy is suspected, additional tests may be warranted if there are risk factors or atypical features present. For an in-depth discussion of small-fiber neuropathies, see Giuseppe et al.[28]

Electrodiagnostic Testing

All patients who present with red flags should get EDX testing consisting of a nerve conduction study (NCS) and electromyography. Whether to perform EDX on all patients who present with a DSP is controversial. One study found that EDX rarely (<1%) led to changes in diagnosis and management,[29] suggesting that EDX should only be utilized in patients with DSP if atypical features are present.[21] Another study found that EDX changed the diagnosis or uncovered an additional diagnosis in 43% of patients and changed management in 41% with DSP.[30] This was especially the case in those with distal weakness and retained Achilles reflexes, although there was still a change in diagnosis in nearly 30% of typical DSP patients. The most common alternative diagnosis in the study was lumbar radiculopathy. The drastically different findings between the two studies highlight that there is still uncertainty regarding the role of EDX testing in patients with DSP. A 2018 position statement by the AANEM has provided some general guidelines including clinical scenarios in which EDX testing is and is not advised ([Table 4]).[31]

Table 4 When to perform electrodiagnostic testing in patients who present with a distal symmetric polyneuropathy

When to consider EDX testing	When EDX testing is likely not necessary
Atypical presentation	Mild symptoms/signs
Lack of a diagnosis based on history, exam, or initial laboratory testing	Symmetric, distal, and predominantly mild sensory symptoms
Moderate or severe symptoms/signs	There is a known cause, such as diabetes mellitus
Presence of symptoms or signs indicating another disorder	There is little suspicion of a coexisting nerve disorder
Rapid progression of symptoms

Abbreviation: EDX, electrodiagnostic testing.

NCS only assesses large, myelinated fibers. Therefore, a normal study suggests that the localization is either the small nerve fibers (myelinated Aδ, B and unmyelinated C fibers), sensory nerve roots, or the central nervous system. A normal study can help the clinician to arrive at a diagnosis. For example, in a patient who presents with sensory ataxia, reduced reflexes, and normal EDX testing, chronic immune sensory polyradiculopathy should be high on the differential.[32] In the correct clinical context, a normal test may also suggest a small-fiber neuropathy. EDX can provide information on the pattern and type of nerve involvement: symmetric or asymmetric, length-dependent or length-independent, and whether motor, sensory, or sensorimotor fibers are affected. One study showed that a greater than 50% amplitude difference between at least two bilateral nerves, in either the upper or lower extremity, showed good discriminatory threshold for detecting vasculitic neuropathies.[33] As most polyneuropathies are sensorimotor, the presence of a pure motor or pure sensory neuropathy is helpful in narrowing a differential to a short list of possible etiologies. EDX can also determine whether the neuropathy is primarily axonal, primarily demyelinating, or a mixture of the two. Similar to findings of a pure motor or a pure sensory neuropathy, a demyelinating polyneuropathy on EDX greatly narrows the differential ([Fig. 1]).

Demyelination on NCS can be seen with both motor and sensory nerves, although may be less evident in sensory nerves if the demyelination is severe as the responses are smaller. Demyelination is associated with marked slowing of conduction velocity (CV) (slower than 75% of the lower limit of normal [LLN]) and marked prolongation of distal latencies (larger than 130% of the upper limit of normal).[34] Both a compound motor action potential (CMAP) and sensory nerve action potential (SNAP) are summations of many individual motor and sensory fibers, respectively. The individual fibers travel at different speeds, with some fibers travelling slower than the normal cutoff, although all fibers travel faster than 75% of the LLN. Therefore, axonal lesions can cause reduced CVs, although never lower than 75% of the LLN.

Acquired demyelination, as seen with AIDP and CIDP, is associated with conduction block and abnormal temporal dispersion during motor studies. Suppose there is a site of demyelination between a distal and proximal stimulation site, such as the wrist and forearm of the median nerve. This results in a conduction block in the forearm, where some or all fibers within the nerve are blocked, resulting in a significant decrease in CMAP amplitude without a corresponding increase in CMAP duration. Alternatively, that lesion in the forearm could slow the individual nerve fibers without completely blocking them. As the motor fibers naturally travel at different speeds, when significantly slowed by demyelination, those differences will become more pronounced. As a result, the CMAP will become abnormally temporally dispersed, leading to a reduction in CMAP amplitude with a corresponding increase in CMAP duration. This is termed abnormal temporal dispersion ([Fig. 3]). Practically, conduction block and abnormal temporal dispersion have the same significance, indicating patchy demyelination seen in an acquired demyelinating disorder. In contrast, demyelination is uniform in genetic demyelinating neuropathies; therefore, conduction block and abnormal temporal dispersion are not seen. If the demyelinating polyneuropathy is severe, it can be challenging to find demyelination as responses may be absent. In these cases, it is helpful to look for demyelination in the arms or to look for abnormal blink reflexes. As most axonal neuropathies are length-dependent, blink reflexes should be normal, even if the neuropathy is very severe.[35] The European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) has developed guidelines on the diagnosis and treatment of CIDP, which details findings strongly supportive of demyelination of motor and sensory nerves ([Table 5]).[36]

Fig. 3 Examples of abnormal temporal dispersion of the right peroneal nerve recorded from the extensor digitorum brevis and the right tibial nerve recorded from the abductor hallucis. In both nerves, there is a greater than 30% decrease of proximal relative to distal negative peak CMAP amplitude. In the peroneal nerve, there is a greater than 30% increase of proximal relative to distal negative CMAP duration, while in the tibial nerve, the change in CMAP duration increases by greater than 100%. CMAP, compound motor action potential.

Table 5 Demyelinating criteria according to the European Academy of Neurology/Peripheral Nerve Society[36]

Demyelinating criteria according to EAN/PNS
Motor nerve conduction criteria
At least 1 of the following:
Distal latency prolongation ≥ 50% above ULN in 2 nerves excluding median at the wrist
Reduction in motor CV ≥ 30% below LLN in 2 nerves
Prolonged F-wave latency > 20% above ULN in 2 nerves (threshold raised to ≥ 50% if CMAP amplitude < 80% LLN)
Absent F waves in 2 nerves (if CMAP ≥ 20% LLN) AND 1 other demyelinating feature in ≥ 1 other nerve
Motor conduction block ≥ 30% decrease of proximal relative to distal negative peak CMAP amplitude, excluding tibial nerve, and distal negative peak CMAP amplitude ≥20% of LLN in 2 nerves, or in 1 nerve + ≥ 1 more demyelinating parameter, except the absence of F-waves
Abnormal temporal dispersion in ≥ 2 nerves (>30% duration increase between proximal and distal negative peak CMAP (at least 100% in Tibial nerve)
Distal CMAP duration (interval between onset of first negative peak and return to baseline of last negative) prolongation AND 1 other demyelinating parameter
LFF 2 Hz: Median > 8.4 ms, ulnar > 9.6 ms, peroneal 8.ms, tibial 9.2 ms    LFF 5 Hz: median > 8.0ms, ulnar > 8.6 ms, peroneal > 8.5 ms, tibial 8.3 ms
LFF 10 Hz: median 7.8 ms, ulnar 8.5 ms, peroneal 8.3 ms, tibial 8.2 s
LFF 20 Hz: median 7.4 ms, ulnar 7.8 ms, peroneal 8.1 ms, tibial 8.0 ms
Notes:
Test median, ulnar, peroneal, and tibial nerve; if not fulfilled check other side and/or at axilla/Erbs point. Between Erbs point and wrist 50% CMAP amplitude reduction is required
For ulnar motor conduction block in the forearm, Martin-Gruber anastomosis should be ruled out with median stimulation at elbow recorded over abductor digiti minimi
For median motor conduction block in the forearm, costimulation of the ulnar nerve at the wrist must be ruled out
If distal CMAP severely reduced <1 mV, may record over proximal muscles of peroneal, median ulnar, radial nerve
Skin temperatures of at least 33°C at palm and 30°C at external malleolus
Sensory nerve conduction criteria
Sensory conduction abnormalities (prolonged distal latency, or reduced SNAP, or slowed conduction velocity outside normative values) in 2 nerves
Possible CIDP is the above with normal motor studies and 1 or 2 below:
CV < 80% LLN for SNAP amplitude > 80% LLN, but CV threshold is 70% if SNAP amplitude < 80% LLN in at least 2 nerves (median, ulnar, radial, sural)
Sural sparing pattern (abnormal median or radial SNAP amplitude with normal sural SNAP amplitude if carpal tunnel syndrome is excluded)
Other relevant details:
Since these criteria do not permit to identify normal reference values compatible with sensory nerve demyelination, sensory CIDP is not more than possible diagnosis
Temperature of 33°C at palm and 30°C at external malleolus
Decline in sural nerve SNAP amplitude occurs with age, use of age-dependent reference value recommended after age 60 is advised

Abbreviations: CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CMAP, compound muscle action potential; CV, conduction velocity; EAN/PNS, European Academy of Neurology/Peripheral Nerve Society; LFF, low frequency filter; LLN, lower limit of normal; MG, Martin-Gruber; SNAP, sensory nerve action potential; ULN, upper limit of normal.

Cerebrospinal Fluid Testing

Cerebrospinal fluid (CSF) testing is indicated in certain clinical scenarios, particularly to look for cytoalbuminologic dissociation when considering an acute demyelinating neuropathy. CSF analysis is not necessary to diagnose CIDP if diagnostic criteria are already met, and CSF protein elevation should be interpreted with caution to diagnose CIDP, especially in patients with diabetes and those over 50 years old, as normative values increase with age.[36] [37] If a diagnosis of CIDP is uncertain, CSF analysis can be helpful to support the diagnosis and rule out other causes.[36] Findings of CSF pleocytosis point to an infectious neuropathy such as Lyme disease or HIV, or a neoplastic disorder such as neurolymphomatosis or leptomeningeal carcinomatosis.

Peripheral Nerve Imaging

Neuromuscular ultrasound and magnetic resonance imaging (MRI) can both help determine the etiology of a neuropathy. Neuromuscular ultrasound, the topic of Miller et al,[38] is best used as a complementary test to EDX studies. While EDX studies can localize and provide information about the function of a nerve, ultrasound can provide visualization of the anatomy and potentially lead to a specific etiology as to the cause of dysfunction. Ultrasound is particularly helpful in diagnosing entrapment and traumatic neuropathies, although it has been used in many other types of neuropathies. MRI can be helpful in the evaluation of pathology of deeper anatomical structures, including plexopathies, polyradiculopathies, and radiculoplexus neuropathies.[21] A new classification and grading system of peripheral neuropathies utilizing MRI has been recently published that separates pathologies based on classes, including severity of injury, neoplasia, entrapment, diffuse neuropathy, and postintervention status.[39] The development of this grading system may facilitate the more routine use of MRI in the evaluation of neuropathies. While there are advances in the capability of MRI imaging of peripheral nerves, MRI of the brain and spine should not be routinely done in the evaluation of DSPs. This point has been highlighted by the AANEM after it was found that these MRIs were frequently ordered for peripheral neuropathy patients.[40]

Skin Biopsy

Skin biopsy, which measures intraepidermal nerve fiber density, and neurophysiological testing, including quantitative sensory testing and quantitative sudomotor axon reflex testing, is helpful in diagnosing small-fiber neuropathies. The sensitivity and specificity of skin biopsies are high, 82.8 and 90%, respectively.[41] The procedure has been standardized in the lower extremity 10 cm proximal to the lateral malleolus.[42] The clinician needs to be aware of the possibility of technical artifacts, that if not recognized by the pathologist, can lead to erroneous results. Artifacts can occur from specimens being crushed by forceps during the procedure or from specimens freezing during transport to the pathology laboratory.

Nerve Biopsy

Nerve biopsy continues to play an important role in the diagnosis of some neuropathies, although it is less frequently needed than in the past due to advances in molecular diagnostics, peripheral nerve imaging, and skin biopsies. Clinical presentations that may warrant a nerve biopsy are cryptogenic acute and subacute onset neuropathies that are asymmetric or multifocal. Diagnoses in which nerve biopsies continue to be of high importance include vasculitic neuropathies, neurolymphomatosis, pure neuritic leprosy, amyloidosis, sarcoidosis, and nerve sheath tumors.[43]

Conclusion

It is critical to approach patients who present with symptoms of a polyneuropathy using a systematic approach. The history and physical exam are the most important aspects. The first step during an evaluation is to determine whether a patient is presenting with a chronic DSP or if there are any atypical features that suggest a rarer neuropathy subtype. In patients with a chronic DSP, there is a limited workup as recommended by the AAN.[22] In patients with atypical features, EDX studies can help determine the neuropathy subtype and guide further diagnostic studies.

Conflict of Interest

N.J. has received consulting honoraria from Argenx.

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Artikel online veröffentlicht:
21. Oktober 2024