Monograph #34: Polyneuropathy: Classification by Nerve Conduction Studies and Electromyography

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MONOGRAPH #34:

POLYNEUROPATHY: CLASSIFICATION BY NERVE CONDUCTION STUDIES AND ELECTROMYOGRAPHY

Peter D. Donofrio, MD James W. Albers, MD, PhD

Approved and reviewed by the AANEM Education committee. Original approval, September 5, 1989. Reviewed and no revisions recommended, September 1994 and October 1998.

Education Committee William J. Litchy, MD, Chair Richard D. Ball, MD, PhD William W. Campbell, Jr., MD James M. Gilchrist, MD John J. Halperin, MD Gerald J. Herbison, MD Susan L. Hubbell, MD John C. Kincaid, MD James J. Rechtien, DO, PhD Lawrence R. Robinson, MD

The ideas and opinions contained in this publication are solely those of the authors and do not necessarily represent those of the AANEM.

AAEM MlNlMONOGRAPH #34 Electrodiagnostic evaluation of patients with suspected polyneuropathy is useful for detecting and documenting peripheral abnormalities, identifying the predominant pathophysiology, and determining the prognosis for certain disorders. The electrodiagnostic classification of polyneuropathy is associated with morphologic correlates and is based upon determining involvement of sensory and motor fibers and distinguishing between predominantly axon loss and demyelinating lesions. Accurate electrodiagnostic classification leads to a more focused and expedient identification of the etiology of polyneuropathy in clinical situations. Key words: polyneuropathy electrodiagnosis nerve conduction studies electromyography MUSCLE & NERVE 13~889-903 1990

AAEM MINIMONOGRAPH #34: POLYNEUROPATHY: CLASSIFICATION BY NERVE CONDUCTION STUDIES AND ELECTROMYOGRAPHY

PETER D. OONOFRIO, MD, and JAMES W. ALBERS, MD, PhD

The electromyographer plays an important role more, the electromyographer can readily identify in the evaluation of patients with established or other primary or superimposed disorders, such as suspected polyneuropathy; no longer is it suffi- polyradiculopathy, that may be clinically indistin- cient to simply confirm the presence or absence of guishable from polyneuropathy . When used as an polyneuropathy. Given the results of conventional extension of the clinical neurologic examination, a electrodiagnostic studies, the electromyographer focused list of specific etiologies consistent with can identify the predominant pathophysiology the combined clinical and electrodiagnostic find- (axonal loss, uniform or segmental demyelina- ings can be developed, useful in directing the sub- tion), establish whether sensory or motor findings sequent laboratory examination. Accuracy in es- predominate, and often determine the temporal tablishing a specific etiology or diagnosis is profile (acute, chronic, old, and/or ongoing) of a related, in part, to appropriate application of elec- peripheral disorder. In addition, the studies pro- trodiagnostic techniques. These include conven- vide a quantitative index of severity that is inde- tional motor and sensory conduction studies, late pendent of the individual patient’s recollection or responses (F response and H reflex), blink re- cooperation. Even in clinically evident polyneuro- flexes, sympathetic skin potentials, and needle pathy, the prognosis often can be established on electromyography . The following summarizes one the basis of electrodiagnostic findings. Further- approach that can be used in examining such patients.

From the Department of Neurology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27103 (Dr. Donof- PERIPHERAL NERVE DISORDERS rio) and the Departments of Neurology and Physical Medicine and Reha- bilitation, University of Michigan Medical Center, Ann Arbor, Michigan Initial classifications of nerve disorders were based 48109. upon anatomic and clinical observations following Acknowledgment: The author gratefully acknowledges that portions of focal nerve damage. Waller demonstrated the pre- the unreferenced clinical information were modified with permission from material prepared by D.D. Duane: Classification of neuropathy, in Neurol- dictable degeneration of nerve fibers in the distal ogy Fellows Handout. Rochester, Minnesota, Mayo Clinic Department of stump of a transected nerve, describing the initial Neurology (unpublished, 1972). discontinuities of axolemma with subsequent dis- Address reprint requests to AAEM. 21 Second Street S.W., Suite 306, Rochester, MN 559 solution of ax on^.**^ “Axonotmesis” was used to describe focal destruction of axons and myelin Accepted for publication December 29, 1989 sheaths without interruption of the nerve stroma. CCC 0148-639)(/90/0100889-015 $04.00 Axonal (wallerian) degeneration occurred distal to 0 1990 Peter D. Donofrio, MD, and James W. Albers. MD, PhD. Pub- lished by John Wiley & Sons, Inc. the lesion, identical to the degeneration associated

AAEM Minimonograph #34: Polyneuropathy MUSCLE & NERVE October 1990 889 with nerve transection. Recovery was prolonged, and motor conduction velocities and distal laten- occurring first in muscles closest to the site of’ cies remain essentially normal with only minimal damage, and related to regeneration of the axon abnormalities at a time when amplitude is substan- via intact endoneurial tubes. “Neurapraxia” was tially diminished. Insertional and rest abnormali- used to define a motor paralysis not associated ties on needle electromyography can be apparent with axonal degeneration; recovery occurred within 7 to 10 days, although may not be evident within hours to months. for up to 3 weeks depending upon the proximity Histopathologic evaluation of experimental of the denervated muscle to the site of nerve sec- nerve compression has increased our understand- tion. Initial abnormality consists of prolonged in- ing of “neurapra~ia.~~~’~~Defects have been dem- sertional activity, followed by the appearance of onstrated under the edges of the compressing sustained positive waves, spontaneous fibrillation tourniquet without extension throughout the com- potentials, and complex repetitive discharges. pressed area. Invagination of one myelin segment With incomplete axon loss lesions, reduced re- into the next has been associated with conduction cruitment is recorded rather than complete ab- block by occluding the node of Ranvier, resulting sence of voluntary MUAPs. MUAPs initially are of in ionic current b10ckade.l’~ normal amplitude, duration, and configuration. A Electrodiagnostic evaluation of polyneuropathy slight increase in the percentage of polyphasic is similar to the evaluation of focal nerve lesions. MUAPs may appear after 10 to 14 days, presum- It is necessary to determine the presence of sen- ably secondary to sprouting or collateral regenera- sory and motor fiber involvement and to accu- tion of surviving motor ax on^.^^^ Within months. rately distinguish between axon loss and demyelin- MUAPs are of increased amplitude and duration ating lesions. Clearly, many polyneuropathies are with an increased percentage of polyphasic poten- neither purely axonal or demyelinating, but tials. rather a combination of both with predominance In contrast, different electrodiagnostic results of one or the other. The results of conventional are obtained following either focal or diffuse electroneuromyography usually can make this demyelination. ’” With a complete focal conduc- distinction. tion block, initial findings are identical to those described for nerve transection. Motor and sensory PHYSIOLOGIC BASIS OF ELECTRODIAQNOSTIC evoked responses cannot be demonstrated with ABNORMALITIES nerve stimulation proximal to the lesion; however, The characteristic electrodiagnostic findings in stimulation distal to the lesion results in normal purely axon loss lesions are best demonstrated fol- responses. Regardless of the duration of the phys- lowing total axonal interruption as in nerve iologic block, all nerve conduction studies distal to transection. Attention to the sequential abnormal- the lesion remain normal. Insertional and resting ities is useful in identifying those components of abnormalities may not develop on needle exami- the electrodiagnostic examination most sensitive to nation. If present, those abnormalities are modest, axonal disorders. Landau demonstrated that mus- commensurate with the mild degree of axon loss cle contraction could be evoked for several days often resulting from insults severe enough to pro- with stimulation of a transected nerve; the reduce conduction block. sponse then diminished with complete loss of ex- The electrodiagnostic abnormalities associated citability after 4 to 5 days.’43 with focal demyelination without conduction block Clinical electrodiagnostic evaluation demon- are similar to those seen in chronic nerve com- strates similar findingsY3 Immediately after pression, ie, substantial reduction of conduction transection, motor and sensory evoked response velocity across the lesion. 159 amplitude, conduction velocity, and distal latency In uniform demyelinating disorders, the remain normal with stimulation distal to the le- marked reduction of conduction velocity is dispro- sion. Needle electromyography demonstrates nor- portionate to the relatively normal evoked re- mal insertional and rest activity, although volun- sponse amplitude with distal ~timulation.~~There tary motor unit action potentials (MUAPs) cannot is relatively homogeneous involvement of all my- be activated. Within days, a progressive decrease elinated fibers. in compound muscle action potential (CMAP) and With multifocal demyelination, conduction ve- sensory nerve action potential (SNAP) amplitude locity may also be reduced disproportionate to the occurs. Evoked responses ultimately disappear af- relatively preserved evoked response amplitude ter 3 to 7 days. Prior to disappearance, sensory with distal tim mu la ti on.^" Proximal stimulation re-

890 AAEM Minimonograph #34: Polyneuropathy MUSCLE & NERVE October 1990 sults in abnormal temporal dispersion of the re- imposed upon a mild polyneuropathy. All individ- sponse, the proximal response being of substan- uals with mononeuropathy should be evaluated tially lower amplitude and lon er duration than for an underlying polyneuropathy. the distal response (Figure 1).'4'@Reducedconduc- A relatively standardized electrodiagnostic tion velocity in some fibers increases temporal dis- evaluation (Table 1) is recommended for the eval- persion by accentuating the differences in conduc- uation of polyneuropathy, although the strategy tion of different fibers within the nerve. Partial may differ depending upon severity. In individu- conduction block can contribute to diminished als with mild symptoms and signs, the electromyo- amplitude. Distal demyelination may be associated grapher is advised to evaluate the most sensitive with prolonged distal latency. or susceptible peripheral nerves. Needle electromyography demonstrates de- For example, in a typical diffuse polyneuropa- creased recruitment (attributable to conduction thy, motor and sensory nerve conduction studies block in some fibers) and MUAPs may show in- of the distal lower extremity are more likely to be creased polyphasia, presumably secondary to dis- abnormal than those in the upper extremity. Sim- tal demyelination. Other characteristic findings as- ilarly, needle electromyography of the intrinsic sociated with denervation are not present on needle electromyography unless superimposed axon loss exists. Table 1. Polyneuropathy protocol

Conduction Studies ELECTRODIAGNOSTIC EVALUATION Test most involved site when mild or moderate, least INSUSPECTEDPOLYNEUROPATHY involved if severe The collective results of nerve conduction studies Peroneal motor (extensor digitorum brevis); stimulate at ankle and knee. Record F response latency following and electromyography are useful in analyzing the distal antidromic stimulation. underlying pathophysiology, and this data, to- If abnormal, tibial motor (abductor hallucis); stimulate at gether with the clinical findings, may suggest a ankle and knee; record F response latency. specific diagnosis in addition to giving an approx- If no responses: imation to the disease duration. Peroneal motor (anterior tibial); stimulate at fibula and knee. Complete electrodiagnostic examination of a Ulnar motor (hypothenar); stimulate at elbow and polyneuropathy requires both motor and sensory wrist. conduction studies, preferably upon multiple Measure F response latency. nerves in upper and lower extremities. Bilateral Median motor (thenar); stimulate at elbow and wrist. Measure F response latency. studies should be performed on several peripheral Sural sensory (ankle): stirnulate 14 cm from recording nerves to demonstrate the characteristic symmetry electrode: perform conduction velocity unless amplitude of abnormality. Since individuals with polyneuro- supernormal. If not clearly normal because of age or pathy are susceptible to focal trauma, it is not technical factors, consider: unusual to find a clinical mononeuropathy super- Needle recording. Averaging. Median sensory (index): stimulate wrist and elbow. If antidromic response is absent or a focal entrapment is suspected, record from the wrist stimulating the palm. Additional peripheral nerves can be evaluated if findings equivocal. Definite abnormalities should result in: Evaluation of opposite extremity. Proceed to evaluation of specific suspected abnormality. If prominent cranial involvement: Facial motor (orbicularis oculi); stimulate at angle of llMV jaw. Blink reflex studies (orbicularis oculi); stimulate 5mS supraorbital nerve. Needle Examination FIGURE 1. Ulnar motor nerve conduction study recording from Examine anterior tibial, medial gastrocnemius, first dorsal the abductor digiti minimi muscle in a patient with chronic inflam- interosseous (hand), and lumbar paraspinal muscles. matory demyelinating polyneuropathy. Marked temporal disper- If normal, intrinsic foot muscles should be examined. sion of the proximal compound motor action potential (CMAP) on Abnormalties should be confirmed by examination of at elbow stimulation (6) is recorded compared with the distal least one contralateral muscle. CMAP on stimulation at the wrist (A).

AAEM Minimonograph #34: Polyneuropathy MUSCLE & NERVE October 1990 891 foot muscles may demonstrate abnormality not Uniform Demyelinatlng, Mixed Sensorimotor Poly. present in upper extremity muscles. Conversely, neuropathy. Hereditary motor sensory neuropa- evoked responses may be absent in the distal lower thy type I (HMSN I) is a dominantly inherited hy- extremities in individuals with moderately severe pertrophic sensorimotor polyneuropathy with symptoms and signs, making it impossible to de- insidious onset in childhood or early adult life. As- termine the presence of a demyelinating compo- sociated features include firm enlarged nerves, nent. Additional studies should be performed us- scoliosis, pescavus, hammer toes, distal weakness ing proximal nerves as well as upper extremity or with little atrophy, abnormal vibratory and posi- facial nerves. tion sensation, and hyp~reflexia.’~There is evi- Needle electromyography is useful in grossly dence of demyelination, remyelination, and onion defining the chronicity of an axon loss lesion, bulb formation on nerve biopsy. based upon the distribution and amplitude of fi- The electrodiagnostic hallmark of HMSN I is brillation potentials and positive waves, as well as reduced maximum conduction velocity, typically MUAP parameters. The distribution of needle ab- less than 85% of the expected lower limit of normality is useful in identifying other disorders Values as slow as 25 m/s are that may be confused with, or superimposed ~ommon.’~*’~Because of the uniform demyelina- upon, an underlying polyneuropathy. For exam- tion of all fibers, temporal dispersion usually is not ple, distal predilection of abnormality, greater in a feature, although phase cancellation may cause the lower than upper extremities, is characteristic abnormal temporal di~persion.’~~Nevertheless, of most axon loss polyneuropathies. Moderately the absence of temporal dispersion is useful in dis- severe, asymmetric involvement of lower extrem- tinguishing hereditary from acquired demyelinat- ity muscles, sparing the intrinsic foot muscles, al- ing polyneuropathies. Motor evoked responses though not completely inconsistent with a diagno- may be reduced, but the predominant abnormal- sis of polyneuropathy, would be more consistent ity remains uniformly reduced conduction veloc- with old poliomyelitis, other motorneuron disor- ity. F responses, when recordable, are prolonged ders, or polyradiculopathy. Similarly, marked ab- as are distal latencies commensurate with slowing normality on examination of paraspinal muscles is in other segments. Sensory evoked responses are unusual in polyneuropathy and suggests a super- usually absent. Needle electromyography demon- imposed polyradiculopathy. strates reduced recruitment; MUAP amplitude and duration may be increased with evidence of mild to moderately severe distal denervation, pro- CLASSIFICATION OF POLYNEUROPATHY BASED portionate to the amount of superimposed axon UPON ELECTRODIAGNOSTIC FINDINGS loss. Although a universally accepted electrodiagnostic Hereditary motor sensory neuropathy type 111 classification is improbable, a useful model can be (Dejerine-Sottas disease) is a rare autosomal re- created using the predominant electrodiagnostic cessive hypertrophic neuropathy with onset in in- abnormalities. In this classification, polyneuropa- fancy; associated features include enlarged nerves, thy is divided into six categories based upon the kyphoscoliosis, pescavus, weakness, ataxia, sensory prevalence of sensory and motor as well as axon loss, and arefle~ia.~’,~~Nerve pathology is similar and myelin involvement. Demyelinating polyneuro- to that of HMSN type I, as are the electrodiag- pathies are subdivided into uniform and segmen- nostic findings exce t for greater reduction of tal disorders. Discussion will be devoted to the conduction ~elocity.~’Listed in Table 2 are other clinical and electrodiagnostic aspects of one or two common polyneuropathies within each category; polyneuropathies with similar electrodiagnostic Table 2. Uniform demyelinating, mixed sensorimotor characteristics are listed in a table under each clas- polyneuropathy . sification. Only polyneuropathies with docu- ~~ ~ mented electrophysiologic abnormalities are listed. Hereditary motor sensory neuropathy types I, Ill, lV45687’ 74 76 Some etiologies are listed under more than one Metachromatic leuk~dystrophy~~87 Krabbe’s globoid le~kodystrophy’~~15’ category as they can manifest several types of dif- Adrenomyel~neuropathy’~~237 fuse and symmetric polyneuropathy. Carcinoma, Congenital hypomyelinating neuropathy”’ lo’lo5 acquired immune deficiency syndrome (AIDS), Tangier diseaseg’ and lupus erythematosus are examples of the lat- Cockayne’s syndromeg8 ter. Cerebrotendinous xanthomatosis” 12’

892 AAEM Minimonograph #34: Polyneuropathy MUSCLE & NERVE October 1990 inherited or congenital diseases with similar elec- mon than slowing in distal or proximal motor trodiagnostic findings. conduction rates. In the case of F responses, the latency was often prolonged out of proportion to Segmental Demyelinating, Motor > Sensory Polyneu. that expected when the distal motor latencies and ropathy. Acute inflammatory demyelinating poly- limb conduction velocities were considered, results neuropathy (AIDP, Guillain- BarrC syndrome) is indicating proximal nerve involvement. of unknown etiology, but is preceded by an infec- Using pooled data, the nadir of abnormality tion in 70% of individuals, raising the hypothesis occurred during the third week for motor conduc- of an immunologic origin. This is supported by tion studies and during the fourth week for sen- the efficacy of therapeutic plasma exchange in sory conduction studies. Motor study abnormali- treating AIDP. ties tended to be homogeneous, while sensory This disorder commonly presents with distal study abnormalities were patchy, revealing defects paresthesias followed by symmetric weakness of of individual nerves and normalcy of other sen- extremity and cranial muscles, usually sparing sory nerves. Most notably, in approximately half extraocular muscles and sphincters. l2 Weakness of patients during the first 4 weeks of disease, predominates and increases for 1 to 4 weeks. Ad- sural studies were normal in the setting of abnor- ditional findings include areflexia and cytoalbu- mal median sensory results, findings atypical in minodissociation after 1 week. An associated auto- any diffuse polyneuropathy. Normal conduction nomic neuropathy may coexist. Pathologic studies studies were unusual: only one patient mani- verify the inflammatory and demyelinating in- fested no abnormality of conduction during the volvement of the peripheral nerve that may be as- first 5 weeks of illness. Using criterion for assess- sociated with severe, secondary axonal and even ing the presence of demyelination, 87% of pa- anterior horn cell degeneration. tients had evidence of a prominent demyelinating Electrodiagnostic findings are variable. In neuropathy in at least one nerve not localizable to 1963, Lambert and Mulder reported electrodiag- a common entrapment site. Two patients were nostic studies for 49 patients evaluated during the classified as having axonal degeneration only; in- first 3 weeks of illness: 14%had no abnormality of determinate results were recorded in 10% of pa- conduction, 6 1 % had conduction velocities less tients. than 70% of the normal mean, and 25% demon- On needle electromyography, abnormal spon- strated prolonged distal latencies with minimal or taneous activity appeared between weeks 2 and 4, no slowing of conduction velocities. 14' Serial eval- while abnormalities of MUAP morphology (in- uation of the latter group demonstrated sequen- creased polyphasia and amplitude) became appar- tial slowing of conduction velocity in some patients ent during weeks 4 to 5. No patient had normal similar to the second group described above. MUAP recruitment at the time of initial examina- The large percentage of patients with normal tion. conduction studies probably reflected the state of Chronic inflammatory demyelinating polyneu- electrodiagnosis at that time when motor conduc- ropathy (CIDP) is a disorder of presumed immu- tion studies were emphasized and sensory conduc- nologic etiology, presenting as a slowly progres- tion studies, H reflexes, and F waves were not in sive, stepwise progressive, or monophasic illness in general use. Variability in reported electrodiag- the majority of patient^.^^ A relapsing and remit- nostic findings can be explained by understanding ting course is seen in approximately one-third of the temporal changes following acute axonal de- patient^.'^ Weakness involves cranial, truncal, and generation and by recognizing this as a multifocal extremity musculature. Pathologically, there is ev- rather than a diffuse disorder. idence for mononuclear cell infiltration, segmental We analyzed sequential electrodiagnostic data demyelination, and hypertrophic changes most of- for 70 consecutive patients with AIDP.4 During ten observed in spinal roots, spinal ganglia, and the first 5 weeks of illness, motor conduction study proximal nerve trunks. Electrodiagnostic findings abnormalities (abnormal CMAP temporal disper- in the individual patient are indistinguishable sion and/or conduction block, reduced amplitude, from AIDP. On occasion, sensory evoked re- slowed conventional or terminal conduction veloc- sponses are spared. Motor conduction velocity ity, and prolonged or absent F responses) were may improve concurrent with clinical remission, more common than sensory conduction abnormal- but disproportionately less than the degree of ities. Early in the disease (weeks 1 to 2), abnormal- clinical improvement would suggest. Neverthe- ities of motor amplitudes were much more com- less, a poor correlation exists between slowing of

AAEM Minimonograph #34: Polyneuropathy MUSCLE & NERVE October 1990 893 motor nerve conduction velocity and the severity Table 3. Segmental demyelinating, motor > sensory of muscle weakness, and conduction velocity often polyneuropathy. remains severely reduced during clinical remis- ~ Acute inflammatory demyelinating p~lyneuropathy~~’”.’~’ ion.^'^ Needle examination usually demonstrates Chronic inflammatory demyelinating polyneur~pathy~~~~~~~~~ distal greater than roximal limb and paraspinal Multifocal demyelinating neuropathy with persistent conduction muscle denervation.Li3 ~~oC~30.149.195,197.212 Several types of polyneuropathy are associated Osteosclerotic myeIoma123,124.125,126 with plasma cell dyscrasias. One type, a severe Waldenstrom’s rnacr~globulinernia’~~~~~~ Monoclonal gamrnopathy of undetermined chronic demyelinating polyneuropathy, has been significance58,66.123,124.225 associated with ostoesclerotic myeloma, Walden- Gamma heavy chain disease123,124,138 strom’s macroglobulinemia, and monoclonal Angiofollicular lymph node hyperpla~ia~~~~”~~’~~~”~’ mopathy of undetermined significance.123,IkEi Hyp~thyroidism~~ ~~~~~~~9.40.164.210.213 Clinical and electrodiagnostic features are similar Diphtheria136 to those of CIDP.“4 Acute arsenic p~lyneuropathy~~ On a global scale, leprosy is the most common Pharmaceuticals cause of peripheral neuropathy. It is best con- Ami~darone~~,’l4 ceived as a mononeuropathy of superficial sensory Perhe~ilene’~,’~~ nerve branches within cutaneous lesions, with sub- High dose Ara-CZ6 sequent involvement of major motor branches. A Lymphoma’ Carcinomazo6 symmetric sensory and motor distal polyneuropa- ~~14.47.62,167.193,205 thy should never be found, although involvement Lyme diseasezz8 may be so widespread as to suggest a diffuse Acromegaly65 pro~ess.~’,~~~The neuropathy of leprosy is classi- Hereditary neuropathy with susceptibility to pressure palsies20,1 65.221 fied under this category because the clinical pre- Systemic lupus erythematosus’68 sentation of multiple mononeuropathies and the Glue sniffing neuropathylZ8 pathologic and electrodiagnostic features of seg- Post portocaval anastomosis238 mental demyelination most mimic a motor greater Neuropathy associated with progressive external than sensory demyelinating polyneuropathy.210 ophthalm~plegia~~~’~~~~~~ Slowed conduction velocity and/or proximal con- Ulcerative colitis3’ Marinesco-Sjogren syndrome6 duction block of motor nerves across focal areas of Cryoglob~linemia’~~ involvement is c~rnrnon.~~’~~Adjacent motor nerves may be normal. Other diseases manifesting electrodiagnosti- in 7 to 10 days and subsequently appear in other cally as segmental demyelinating, motor greater proximal and then distal muscles symmetrically. than sensory polyneuropathy are listed in Table 3. Similar electrodiagnostic findings to porphyria Multifocal demyelinating polyneuropathy with may be observed in lead polyneuropathy, al- persistent conduction block is of particular inter- though there may be greater involvement of up- est to the electromyographer because this poten- per than lower extremities. ’“ tially treatable neuropathy clinically resembles mo- Hereditary motor sensory neuropathy type I1 torneuron disease.20,149J95,197,212 (neuronal Charcot- Marie-Tooth disease) is a dominantly inherited sensorimotor polyneuropa- Axon Loss, Motor > Sensory Polyneuropathy. thy with insidious onset in the third to fourth de- Acute intermittent porphyria is an autosomal cade; associated features include moderate to se- dominant disorder with incomplete penetrance, vere atrophy, yscavus, hammer toes, and mild presentings as a classic triad of psychosis, abdomi- sensory loss.“9 Motor evoked amplitudes are renal pain, and polyneuropathy clinically resembling duced with essentially normal conduction veloci- AIDP. Pathology of peripheral nerve reveals ax- ties. Sensory responses are absent in 50% of pa- onal degeneration with secondary demyelination. tients. Needle electromyography demonstrates Nerve conduction studies demonstrate reduced chronic neurogenic changes, most prominent motor evoked amplitudes, whereas conduction ve- di~tally.’~ locity slowing is spared until substantial reduction Although most pharmaceutically induced poly- of amplitude occur^.^ Sensory evoked amplitudes neuropathies present as a sensory greater than are reduced in approximately 50% of patients. Fi- motor axonopathy, several medications produce, brillation potentials appear in paraspinal muscles as an adverse effect, motor greater than sensory

894 AAEM Minirnonograph #34: Polyneuropathy MUSCLE & NERVE October 1990 involvement. Dapsone neuronopathy is an exam- responses may be of borderline-low am litude ple of such in~olvement.~~"'~~'~~ with slightly reduced conduction ~elocity.~'Mod- Table 4 lists other polyneuropathies with elec- erate slowing of motor conduction velocity is occa- trodiagnostic features similar to porphyria and sionally reported and may be related to selective HMSN type 11. loss of large myelinated fibers.20" Mild, chronic neurogenic changes on needle electromyography Sensory Axon Loss Neuronopathy. Carcinomatous may be evident, most prominently in the distal sensory neuronopathy is the most distinctive of lower extremities. the remote-effect polyneuropathies associated Table 5 lists other diseases with the highly with carcinoma. Its onset is subacute, often pre- characteristic and unique electrodiagnostic find- ceding identification of the neoplasm by several ings recorded in sensory neuronopathy. months. A strong association exists between oat cell carcinoma of the lung and a sensory neuron- Axon Loss, Mixed Sensorimotor Polyneuropathy. opathy. Symptoms and signs include pain, pares- The majority of toxic and metabolic polyneuropa- thesias, dysesthesias, and large, more than small, thies manifest evidence of degeneration of the fiber sensory loss."1 Areflexia, gait ataxia, and distal portion of the axon. In general, these poly- choreoathetoid movements are common, but neuropathies are electrodiagnostically indistin- strength is usually preserved. l1' Neuropathology guishable from one another. Sensory symptoms reveals inflammation and cell loss in dorsal root and signs may initially predominate, and sensory ganglia, and gliosis of the posterior column of the evoked amplitudes may be reduced early in the spinal cord. Nerve conduction studies usually re- course of the disease, when motor studies are nor- veal diminished or absent SNAP amplitudes in the mal. Conduction velocity is normal until there is a setting of normal motor nerve conduction substantial reduction of amplitude, although pre- studies. 11' Motor amplitudes and conduction may dilection for large fibers may reduce the maxi- be slightly reduced in severe cases, perhaps repre- mum conduction velocity slightly. Distal latency senting disuse atrophy, axonal stenosis, or a com- may be slightly prolonged, prior to reduction of bination of both. Needle examination is usually evoked amplitude, perhaps in association with dis- normal except in late, severe disease when sponta- tal axonostenosis. In contradistinction to primary neous activity at rest may be recorded. demyelinating disorders, appreciable temporal Friedreich's ataxia is a recessively inherited dis- dispersion of the proximal, compared with distal, order characterized by ataxia, mild weakness, are- CMAP is not recorded (Figure 2). Fibrillation po- flexia, and dissociated sensory loss involving mo- tentials and positive waves may be seen symmetri- dalities classically interpreted as reflecting posterior column dysfunction (abnormal vibration, two-point discrimination, and joint position sensa- Table 5. Axon loss sensory neuronopathy or neuropathy. tion). Associated signs include scoliosis, pescavus deformity, extensor plantar responses, nystagmus, Hereditary sensory neuropathy types I- IV34~69~'9' and optic atrophy. Sensory responses are usually Friedreich's absent, although responses of markedly reduced Spinocerebellar degenerati~n~~,"~,''~ Abetalipoproteinemia (Bassen- Kornzweig disease)' '2,166,244 amplitude may be re~orded."~~~~~~"'"Motor evoked Primary biliary cirrhosis4' Acute sensory neuronopathyZ2' Cis-platinum toxicity' 70208~209 Carcinomatous sensory neuronopathy' ' 1,234 Table 4. Axon loss, motor > sensory polyneuropathy. Lymphomatous sensory neur~nopathy''~ Chronic idiopathic ataxic ne~ropathy~~ Porphyria5 Sjogren's ~yndrome'~~.~~~,'~~ Axonal Guillian- Barre syndrome7' Fisher variant Guillain-Barre syn~irome'~~'l7 Hereditary motor sensory neuropathy types II and V6' Paraproteinemias66,2'6 Lead neuropathy' '' Pyridoxine toxicity' 94,219 Dapsone neuropathy' loo 239 Idiopathic sensory neuronopathy'22 Vtncristine ne~ropathy~~38 99 Styrene-induced peripheral neuropathy" Remote-effect motor neuronopathy associated with Crohn's disease18' Thalidomide Remote-effect motor neuronopathy associated with Nonsystemic vasculitic neuropathy7O carcinoma248 Chronic gluten enteropathy"' Hypoglycemia/hyperin~ulinemia~~' 75 Vitamin E deficien~y~~,'~~*'l2

AAEM Minimonograph #34: Polyneuropathy MUSCLE & NERVE October 1990 895 1 A Table 6. Axon loss, mixed sensorimotor polyneuropathy.

Amyloidosis22,’26,’27 I Chronic liver disease’ 19,’31 Nutritional diseases Vitamin B12 deficiency8i,’60,’61 A1 MV Folate deficiency28,80 2 ms Whipple’s disease55 Post-gastrectomy syndr~me’~ FIGURE 2. Peroneal motor nerve conduction study recording Gastric restriction surgery for obesity’ from the extensor digitorum brevis muscle in a patient with a Thiamine deficiencyig0 chronic sensorimotor axonal polyneuropathy. The amplitude, AI~oholism’~~~~~~~~~ shape, and duration of the compound motor action potential re- Sar~oidosis~~~’~~~’~~ corded on ankle stimulation (A) does not appreciably change on Connective tissue diseases stimulation at the fibular head (6). Rheumatoid arthriti~~~~’~~,’~~ Periarteritis nodo~a’~ Systemic lupus erythematosus Churg-Strauss va~culitis~~~’~~ cally in distal extremity muscles. These abnormal- Temporal arteriti~~~ ities on needle examination typically precede S~leroderma’~~ clinical evidence of motor involvement. Bechet’s disease’78 A common example is the polyneuropathy as- Hypereosinophilia syndrome’ 71243 Cryoglobulinemia’80 sociated with chronic alcoholism and secondary Toxic neur~pathy“~ nutritional deficiency. The clinical features are Acrylam~de~~,’~~ those of a symmetric and generalized sensorimo- Carbon dis~lfide~~,~~~ tor distal polyneuropathy. Patients complain of Dichlorophenoxyacetic acidg5 paresthesias and dysesthesias of the feet and distal Ethylene ~~ide~~,~~,’~~ Hexa~arbons~,’~~ legs, more so than weakness.223 Physical findings Carbon monoxide227 consist of absent or diminished sensation in a dis- Organophosphorus esters6’ tal to proximal gradient in the lower extremities, Glue ~niffing~,’~~.’~~ absent ankle reflexes, and mild weakness of toe Metal neuropathy and ankle extension. Involvement of the proximal Chronic arsenic intoxication4‘ lower extremity and hands only occurs in severe, Mercury3 progressive alcoholic polyneuropathy. GoJdi20.24’ A detailed list of disorders associated with an Pharmaceuticals axonal sensorimotor polyneuropathy and present- C~lchicine’~~ ing with similar electrodiagnostic findings is found Phenyt~in“~‘~~~* Ethambutol’ 76 in Table 6. Amitriptyline’50 Metr~nidazole~’,49 Mixed Axon Loss and Demyelinating Sensorimotor Misonida~ole’~~ Polyneuropathy. Diabetic polyneuropathy is the Nitrofurantoin’ 10,249 Chlor~quine~~ most common polyneuropathy in North America. Disulfiram10.21.27.235 It also represents a polyneuropathy demonstrat- Gl~tehimide’~~ ing evidence of both axonal degeneration and Nitrous O~ide’~~~’~~~~’~ demyelinati~n.~~’Even though several classifica- Lithi~m~~.”~ tions of diabetic neuropathy exist, this monograph Carcinomatous axonal sensorimotor p~lyneuropathy~’ will discuss only the commonly observed, diffuse, Chronic obstructive pulmonary di~ease~~,’~~ Giant axonal dystrophy’3~’29~’32~204~232 symmetric sensorimotor polyneuropathy. Olivopontocerebellar Patients characteristically manifest paresthe- Neuropathy of chronic illness24,25,252 sias, disabling dysesthesias, or numbness in the di- Acromegaly’ l5 stal lower e~trernities.’~ Examination demon- Hypophosphatemia Lymphomatous axonal sensorimotor polyne~ropathy~~“ strates reduced vibratory sensation and two-point Hypothyroid;sm64,’56,179,201 discrimination in a distal-to-proximal gradient in Myotonic dy~trophy~~.~~,’~~,’72 the lower extremities; proprioception may also be Necrotizing angi~pathy~~~’~~~”~ impaired in severe cases. This apparent dissocia- Lyme di~ease“~,”~~ tive sensory loss relates to predilection of large fi- AIDS, ARC46.62.152.167.193 ber involvement. In more severe disease, small fi- Jamaican ne~ropathy’~,~’ Tangier di~ease’~~~’~’ Gouty neur~pathy~~ Polycythemia veraZ5O Typical multiple myeloma’26 896 AAEM Minimonograph #34: Polyneuropathy bers are involved as evidenced by alteration of neuropathies manifesting electrophysiologically as pain and temperature sensation and dysautono- a mixed axon loss and demyelinating sensorimo- mia. The major pathologic abnormalities are seg- tor polyneuropathy. mental demyelination and remyelination, in addition to axonal degenerati~n.~~’ The electrodiagnostic findings in distal sym- SOURCES OF ERROR metric diabetic polyneuropathy are variable, espe- The primary sources of error in evaluation of pa- cially in early or mild cases. In most patients, tients with suspected polyneuropathy are errors of sensory conduction studies reveal diminished omission, ie, drawing conclusions based upon a evoked amplitude with moderate slowing of con- limited data base. Another common error is over- duction velocity, greater than expected from ax- emphasizing the value of “conduction velocity.” onal degeneration alone. Concurrently or later in This measure is sensitive to demyelination but the course of disease, motor evoked responses may remain normal in the setting of axon degen- demonstrate similar findings with the addition of eration. Similarly, distal latencies, another barom- temporally dispersed proximal responses.224Occa- eter of conduction rate, are markedly prolonged sionally, in patients with asymptomatic or mild only in demyelination, moderately prolonged in polyneuropathy, slowing in motor conduction ve- association with axonal stenosis, and only mildly locity will be the only electrodiagnostic abnor- prolonged in axonal degeneration. ma lit^.^^^ Fibrillation potentials may appear in in- Another pitfall is the failure to exclude from trinsic foot muscles symmetrically prior to clinical interpretation focal slowing of conduction velocity evidence of atrophy or weakness, or reduced due to specific entrapment mononeuropathies be- CMAP amplitudes recorded from foot muscles. fore concluding that a generalized process of re- Polyneuropathy is relatively common in duced conduction exists. Particularly vulnerable to chronic renal failure, and virtually all patients re- entrapment are the ulnar and peroneal nerves at quiring dialysis have evidence of a distal sensori- the elbow and knee, respectively, and the median motor polyneuropathy. In many patients, this nerve at the wrist. manifests as an axon loss, mixed sensorimotor Motor and sensory evoked amplitudes are ex- polyneuropathy with borderline-low motor and tremely sensitive to axonal degeneration despite sensory evoked amplitude^.'^ In other patients, the ,wide range of normal values. Markedly re- nerve conduction studies demonstrate produced motor evoked amplitudes with normal sen- nounced slowing in conduction velocity with pre- sory responses are unusual in polyneuropathy; served proximal CMAPs. These latter findings re- further investigation usually demonstrates a poly- flect the mixed components of segmental radiculopathy, motorneuron disease, or defective demyelination superimposed upon axon loss, veri- neuromuscular transmission (generalized low mo- fied pathologically by Dyck and colleagues.” Fi- tor-normal sensory syndrome).245 brillation potentials are seen in distal extremity Sensitivity of conduction velocity, distal latency, muscles, particularly the intrinsic foot muscles. and evoked response amplitude to change in tem- Unfortunately, determination of motor nerve con- perature requires careful measurement and main- duction velocities alone is probably the most tenance of proper limb temperature (32°C to widely accepted measurement of peripheral nerve 36”C, surface temperature). Warming a limb by function in the evaluation of and serial assessment 5°C may result in as much as a 10-m/s increase in of uremic polyneuropathy. While widely accepted conduction velocity, a 1-ms decrease in distal la- as a measure of adequacy of dialysis, conduction tency, and a 20% decrease in sensory and motor velocity determinations alone are likely inadequate amplitude. and unreliable unless changes are marked.133 Needle electromyography of intrinsic foot For completeness, Table 7 lists the two poly- muscles is a sensitive measure of potential axonal degeneration. Nevertheless, these muscles may also be subject to local trauma and false-positive studies. This situation is most commonly observed in the extensor digitorum brevis and abductor Table 7. Mixed axon loss, demyelinating sensorimotor polyneuropathy. digiti minimi muscles, while the abductor hallucis and first dorsal interosseous muscles are less likely to give aberrant results.8YCareful sampling of individual muscles and documentation of bilaterality

AAEM Minimonograph #34: Polyneuropathy MUSCLE & NERVE October 1990 897 reduces the likelihood of false positive findings ogy in polyneuropathy. In addition, interpretation secondary to local injury. of the results of electrodiagnosis often suggests In summary, a carefully planned and per- a specific diagnosis, particularly when com- formed electrodiagnostic study is useful in quanti- bined with other laboratory and clinical informa- fying and defining the underlying pathophysiol- tion.

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