Peripheral neuropathy, also known as peripheral polyneuropathy, is a general term for a broad range of disorders that cause damage and dysfunction of the nerves of the peripheral nervous system in several different patterns. Electrodiagnostic (EDX) testing can not only identify whether or not a peripheral neuropathy may be present, but can help give the clinician information to determine the etiology, the severity, and the prognosis of the disorder. Thorough history taking, physical examination, and electrodiagnostic testing are all integral to the evaluation and treatment of patients presenting with symptoms of peripheral neuropathy. Although peripheral polyneuropathies are commonly found in patients with diabetes mellitus or excessive alcohol use, many medical conditions have associations with peripheral neuropathies. Peripheral polyneuropathies can be acquired, such as in diabetes mellitus, amyloidosis, HIV, or cis-platinum chemotherapy, while some may be inherited, as in Charcot-Marie-Tooth.
Common symptoms to most peripheral polyneuropathies involve paresthesias, numbness, or pain in the distal extremities, such as in the feet or hands. Some can present acutely, while many have a more insidious onset. A patient may describe difficulty with buttoning their clothes or tripping over their feet, which may be signs of worsening weakness and progression of the disease. Inherited polyneuropathies may present with ataxia and muscle cramping while acquired polyneuropathies typically present as burning or paraesthesias.
Electrodiagnostic testing can be a useful tool in finding an etiology and thus guiding treatment. Therefore, it is critical to obtain a detailed history, including medications, diet, social/occupational history, and family history. Exposure to heavy metal toxins or certain medications, such as vincristine and amiodarone or a medical history significant for hypothyroidism or vitamin b12 deficiency, indicate a risk for developing peripheral polyneuropathies. Patients with a family history of hereditary motor and sensory neuropathies (HMSN) such as Charcot-Marie-Tooth Type 1 disease (HMSN I) or Refsum’s disease (HMSN IV) might point the clinician toward a hereditary cause for the neuropathy. Infectious diseases such as Lyme’s disease and HIV and autoimmune-mediated diseases such as acute inflammatory demyelinating polyneuropathy(AIDP) or chronic inflammatory demyelinating polyneuropathy (CIDP) can also present with symptoms of peripheral neuropathy.
The physical examination may also assist in identifying the etiology and characteristics of peripheral neuropathy. Patients with diabetic peripheral neuropathy often describe a “stocking-glove” distribution of numbness in the hands and feet. Deafness, cataracts, or musculoskeletal deformities point toward a hereditary cause. A predominant sensory neuropathy may have decreased sensation to light touch or vibration while distal muscle weakness and decreased Deep Tendon Reflexes (DTR) may indicate a motor predominant neuropathy. For example, a patient on dapsone therapy may present with weakness and abnormal DTRs and has electrodiagnostic findings of primarily axonal motor neuropathy. A patient who had high dose cis-platinum therapy may have preserved deep tendon reflexes and muscle strength, but complain of abnormal sensation, as well as other drug side effects such as ototoxicity and GI upset. In cis-platinum peripheral neuropathy, electrodiagnostic testing often yields the presence of a primarily axonal sensory neuropathy.
The pathophysiology behind the common peripheral neuropathies is dependent on their specific disease etiology. For example, ETOH-related peripheral neuropathy may be caused by direct nerve injury or by malnutrition. Multifocal motor neuropathy (MMN) is an immune-mediated disorder causing asymmetric inflammatory demyelination and remyelination.
HIV-related neuropathies have several distinct categories with variable presentations based on the nerves affected. For example, mononeuropathy multiplex presents at all stages of HIV infection due to varying etiologies. It is often caused by thrombosis of the vasa nervorum, which leads to multiple lesions in various nerves causing primarily axonal loss with relative myelin sparing. Autonomic neuropathy may also occur in the HIV patient when there is damage to the nerves responsible for functions that regulate autonomic activities such as blood pressure, heart rate, or bowel and bladder emptying.
It is important to note that electrodiagnostic testing can only test Type I fibers and cannot detect small fiber neuropathies. Nonetheless, electrodiagnostic testing can help guide the clinician toward this diagnosis if the patient has typical peripheral neuropathy symptoms with normal electrodiagnostic testing. A skin biopsy or autonomic reflex testing may be needed for confirmation. Common disorders that produce small fiber neuropathies are diabetes, amyloidosis, and HIV.
When a patient describes symptoms such as paresthesias, pain, or weakness in more than one extremity, which cannot be explained by a focal mononeuropathy, such as a nerve entrapment neuropathy, the clinician may turn to electrodiagnostic (EDX) testing to identify whether a peripheral neuropathy may be present. A thorough history and physical examination will typically reveal a specific risk factor for peripheral nerve damage, such as toxic, metabolic, hereditary, microangiopathic, or autoimmune exposures or disorders. The electrodiagnostic testing may also help narrow the differential diagnosis based on the disease’s common electrodiagnostic features.
There are few absolute contraindications to performing nerve conduction studies (NCS) and electromyography (EMG) needle testing. Physicians sometimes defer important electrodiagnostic testing in patients with implanted cardiac pacemakers and defibrillators because of fear about potential negative effects on the device. Multiple studies have indicated that in pacemakers with bipolar sensing, there is no evidence of electromagnetic interference activity. In two studies that looked at unipolar pacemaker sensing and repetitive nerve stimulation studies, some evidence of interference activity was noted. Most modern pacemakers have bipolar sensing, and repetitive nerve stimulation studies are not routinely used in most nerve conduction studies for peripheral neuropathy.
It is generally accepted that NCS does not routinely cause risk to modern bipolar implantable pacemakers. Nevertheless, it is recommended that stimulation directly over or near the device should be avoided. It is essential to follow device manufacturers’ guidelines and obtain the patient's cardiologist’s advice regarding implanted defibrillators and pacemakers with unipolar sensing. Performing the electrodiagnostic study after device deactivation and monitoring of patients via telemetry is also a possibility. NCS should be avoided in patients with external cardiac pacemakers as these wires could be more electrically sensitive. Stimulating over a central line should also be avoided as it could generate a stimulus to the heart.
Needle EMG should be avoided in those with severe bleeding disorders, but may still be considered in patients on anticoagulation with careful monitoring to ensure proper control of bleeding. Holding anticoagulant or antiplatelet medications is not routinely necessary. Clinicians should use caution when patients have low platelet counts or a high INR outside of the therapeutic range. Needles should never be inserted into areas of active soft tissue infection.
The following is a general guide of equipment needed, but does not represent an exhaustive list:
A physiatrist or neurologist with subspecialization in neurodiagnostic studies is consulted for electrodiagnostic testing. A specially trained technician is sometimes used to collect the nerve conduction studies and electromyographic results, which can be read and interpreted by the specialist after the examination; however, this is not recommended as the physician may need to change and adapt the examination in real-time based on the patient’s individual presentation or particular test findings.
Patients should be given information on the components of the testing before the examination day. They should be instructed to take their medications and eat as they normally would on the examination day. Patients should bathe or cleanse skin before the examination and avoid applying any lotions or creams to the extremities.
On the day of the examination, the patient may dress in loose clothing or be asked to change into a gown to allow for better access to the proximal musculature. Attention to the room temperature and the temperature of the limbs are important as cool limbs can cause waveform changes that may lead to an incorrect diagnosis. A decrease in temperature can temporarily affect the protein configuration of the sodium channels on the nerve, causing a delay in the opening and closing of the channels. This can artificially increase the amplitude and decrease conduction velocity. Focal cooling of the extremities can cause delayed latency, decreased conduction velocity, and abnormally high amplitude, while a generalized cooling of limbs may cause prolonged latency and decreased conduction velocity with a normal amplitude. When this occurs, the clinician should adjust the room thermostat, warm the extremities with heat packs for several minutes, and repeat the examination.
The electrodiagnostic study’s goal is to confirm the presence of peripheral neuropathy and assess its pattern and severity. Electrodiagnostic (EDX) testing involves nerve conduction studies (NCS) and electromyography (EMG) testing. Planning an electrodiagnostic study is based on careful history taking and physical examination. The patient’s unique presentation should guide the study design rather than utilizing a cookbook approach to performing the study. For example, in some vasculitic neuropathies, chronic inflammatory demyelinating polyradiculopathy, and sometimes in diabetes mellitus, the upper limbs may demonstrate abnormalities first, and the clinician may choose to design their test accordingly. Both sensory and motor nerve conduction studies and needle EMG testing in proximal and distal muscles should be performed and should include at least one upper and lower extremity, but in practice, most test at least three limbs. In general, most nerve conduction studies and EMG should progress from distal to proximal so that the longer nerves, which are usually affected first, are assessed before the shorter nerves.
Nerve conduction studies generally begin with motor conduction in one lower extremity and include routine Peroneal and Tibial motor studies and their F-wave responses. If motor responses are absent while recording over the usual distal muscles such as the Extensor Digitorum Brevis (EDB) muscles, peroneal motor studies may be performed using the Tibialis Anterior. Tibial motor studies may be performed more proximally at the Soleus if necessary. The contralateral limb should be tested for symmetry. Amplitude differences of more than 50% when comparing side by side would be seen as abnormal. The soleus H reflex can be performed; however, it is often absent in polyneuropathies where the ankle reflex is absent and often does not add to the study. After motor studies are completed in the lower extremities, the clinician should obtain a lower extremity sensory response, such as the Sural or Superficial Peroneal nerves. It is common for amplitude responses to be very small in polyneuropathies; therefore, averaging may be required.
After the lower extremity studies, an upper extremity test is conducted. The Ulnar motor and sensory nerve conduction study in the non-dominant hand may be chosen. It is less likely to be affected in a concurrent entrapment neuropathy at the wrist. One may also choose to use the radial sensory response, as it is much less commonly involved in entrapment neuropathy. In severe polyneuropathies, sensory responses distally may be absent in the lower extremities, but may still be present in the upper extremities; therefore, the clinician may choose to test bilateral upper extremities to assess symmetry in the absence of sensory responses in the lower extremities.
The EMG study is performed, assessing first for abnormal spontaneous muscle fiber activity when the muscle is at rest. Secondly, it can assess Motor Unit Action Potentials (MUAP) during voluntary muscle activity. The strategy for EMG testing in polyneuropathy is similar in that distal and proximal muscles of at least one upper and lower extremity should be sampled. Muscle sampling is continued until a negative proximal muscle is found. The anterior tibialis muscle is useful as it is usually mildly affected, but not usually atrophic. Though often affected, the intrinsic foot muscles are avoided in the EMG evaluation as they are often painful and activation of these muscles is usually difficult, making an assessment of MUAP difficult. Some degree of atrophy, especially in the EDB muscle, is common in some healthy older adults.
The risk of complications in both nerve conduction study and EMG needle examinations are rarely severe. Electrical stimulation does not usually cause any permanent or even temporary damage to the nerves tested. As with any needle stick procedures, there is a risk of infection or bleeding with needle insertion during the EMG; however, with proper antiseptic and pressure techniques, the risk is minimal.
Most patients find the electrical stimulation NCS studies uncomfortable, but tolerable. At times a patient may be unable to tolerate the examination due to the unpleasant “shock” sensation, needle exam, or, very rarely, a vasovagal episode. The patient may choose to take breaks during the exam or reschedule the exam for another date. Usually, preparing patients ahead of time regarding what to expect and instructing them to eat and drink before the exam can help avoid these complications.
Electrodiagnostic (EDX) testing can be performed to understand the etiology, severity, prognosis, and possible treatment options for peripheral neuropathy. It can identify the primary characteristics of the neuropathy as axonal, demyelinating, sensory, motor, multifocal, or diffuse; however, there is often overlap.
Classic nerve conduction study (NCS) findings for demyelinating injury include prolonged distal latency, slowed conduction velocity, and a prolonged F-wave latency. Demyelination generally occurs at many sites along a nerve, causing variation in nerve action potential propagation such as a slowed conduction velocity or a conduction block. Slowed conduction velocity in a non-uniform pattern causes abnormal dispersion of arrival times of nerve action potentials at the recording site, referred to as abnormal temporal dispersion. Conduction block refers to a blockage of many axons over a short segment of nerve and is most frequently encountered at sites of entrapment in mononeuropathies such as in carpal tunnel syndrome or peroneal neuropathy at the knee. In peripheral neuropathies, focal conduction block can be evident in a site unaffected by entrapment and may represent focal demyelination. It is also important to note that slowed conduction may occur from reversible metabolic causes with no myelin damage.
The presence of conduction block and abnormal temporal dispersion may be consistent with demyelinating injury; however, it is more likely present in acquired versus hereditary demyelinating peripheral neuropathy. In Charcot-Marie-Tooth type 1, the compound muscle action potential (CMAP) amplitude does not markedly decrease between distal and proximal stimulation sites because it is a slowly occurring neuropathy with uniform changes to myelin along nerve fibers. Thus, there is a diffuse slowing of conduction velocity without abnormal temporal dispersion.
In acute inflammatory demyelinating polyneuropathy (AIDP), with one common variant known as Guillain-Barre syndrome (GBS), weakness may occur within one month of an upper respiratory or gastrointestinal illness or vaccination, likely due to a viral attack on the myelin and Schwann cells. If performed early, the electrodiagnostic testing may be relatively normal, though the F-wave may be abnormal. Later on, electrodiagnostic testing may show a motor more than sensory demyelinating neuropathy with evidence of temporal dispersion and conduction block. Identifying this disorder can help guide treatment, such as starting IV immunoglobulins promptly. It is important to note that other GBS variants have different electrodiagnostic presentations, including axonal motor and sensorimotor variants.
NCS findings in axonal injury show reduced sensory nerve action potential/compound muscle action potential (SNAP/CMAP) amplitude with near-normal distal latency and near-normal conduction velocity. It is also important to note that, as a primarily demyelinating peripheral neuropathy progresses, mild axonal damage may occur. Primarily axonal polyneuropathies can be motor or sensory predominant, although a mixed pattern is also possible. In Acute Intermittent Porphyria, electrodiagnostic testing often reveals axonal degeneration with secondary demyelination in motor nerves more than sensory nerves. Friedreich’s Ataxia is classically associated with a sensory predominant axonal neuropathy.
Needle electromyography (EMG) is used in defining the chronicity of an axon loss lesion. EMG testing should assess for spontaneous activity at rest and the motor unit action potential (MUAP) activity during voluntary activity. The presence of positive sharp waves and fibrillations indicates denervation from axonal loss, which would not be present in a demyelinating-type polyneuropathy.
Abnormal spontaneous activity with very low amplitude (less than 50µV) indicates a chronic, slowly progressive denervation. Assessment of recruitment and MUAP amplitude and complexity can also help determine the time course. At low levels of activation, the needle electrode records from around 3 to 5 MUAPs, which can help better assess the recruitment pattern of MUAPs. Observation of several MUAPs discharging at frequency rates greater than 20 Hz support motor unit loss. MUAP waveforms can be inspected for increased amplitude as well. In slowly progressive neuropathies, usually of the hereditary type, there will be markedly reduced recruitment, very high amplitude (around 5 to 10 times normal), and minimal complexity. In axonal peripheral neuropathies with ongoing denervation, one would find moderately reduced recruitment and moderately increased MUAP amplitude and complexity. Increased MUAP complexity can be found in up to 10% of normal individuals’ motor units; therefore, the clinician should not use its presence solely for diagnosis.
Another important classification system is based on whether there is electrodiagnostic evidence of diffuse (uniform) versus a multifocal (segmental) disease pattern. A patient with diffuse polyneuropathy presents with peripheral neuropathy that involves most nerves in a length-dependent fashion, while a multifocal-type peripheral neuropathy involves one or more nerves in an asymmetric patchy distribution. Heavy metal toxins or drugs like alcohol typically present as a diffuse axonal mixed sensorimotor polyneuropathy, while vasculitis and porphyria are more typically multifocal axonal neuropathies. Charcot-Marie-Tooth Type I (HMSN-I) presents as a diffuse demyelinating mixed sensorimotor polyneuropathy, while Guillain-Barre syndrome presents as a multifocal demyelinating motor greater than sensory neuropathy. Diabetic neuropathy is a prevalent and widespread cause of polyneuropathy. Typically patients present with disabling dysesthesias and numbness in the lower extremities with physical findings demonstrating reduced two-point discrimination and vibratory sensation symmetrically in the lower extremities. It starts distally, gradually moving proximally as it progresses. The electrodiagnostic findings typically involve a uniform mixed axonal and demyelinating sensorimotor polyneuropathy. In patients with chronic renal failure and in all patients requiring dialysis, similar electrodiagnostic findings are observed.
Peripheral polyneuropathies can be encountered in many clinical settings regardless of specialty and cause significant morbidity to patients due to the accompanying pain, weakness, and deformity associated with them. In some estimates, its prevalence in the general population is 1 to 3% and increases to 7% in patients older than 50. Internists, pediatricians, physiatrists, and neurologists must recognize the symptoms and risk factors associated with peripheral neuropathies and understand that further evaluation with electrodiagnostic testing may assist with the diagnosis and treatment plan.
Ideally, a thorough history by the primary care or referring physician should be performed, including past medical history, surgeries, medications used, diet, recreational drug or alcohol use, occupational exposures, and family history. The referring physician may choose to start a diagnostic workup with blood work based on the working differential diagnosis to assist the electrodiagnostician.
An interprofessional approach to patient care should be pursued, which would involve an open dialogue between the referring physician and the physician performing the electrodiagnostic testing. Ideally, a discussion about any relevant history, physical, or lab findings before the EDX testing can help narrow down the differential and assist in planning the NCV and EMG studies. The electrodiagnostic results can help the referring physician decide whether to pursue additional studies such as CSF analysis or nerve biopsy to assist with the diagnosis and treatment plan.
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