Clinical neurophysiology of demyelinating polyneuropathy

Handbook of Clinical Neurology, Vol. 161 (3rd series) Clinical Neurophysiology: Diseases and Disorders K.H. Levin and P. Chauvel, Editors https://doi.org/10.1016/B978-0-444-64142-7.00052-7 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 15

Clinical neurophysiology of demyelinating polyneuropathy MICHAEL P. BOWLEY1 AND DAVID A. CHAD2* Department of Neurology, Massachusetts General Hospital, Boston, MA, United States

1

2

Reliant Medical Group and Saint Vincent Hospital, Worcester, MA, United States

Abstract Demyelinating neuropathies are remarkably varied in their clinical characteristics: In etiology they may be inherited or acquired, in their time course, acute or chronic, and in their distribution, multifocal or generalized. They present with phenotypes that range from an indolent disorder that begins in childhood and progresses slowly over decades (as might be seen in an inherited form) and leads to weakness but preserved ambulation, to a neuropathy with fulminant onset and rapid progression culminating in tetraparesis and respiratory failure (as seen in the Guillain-Barre syndrome). Often demyelinating neuropathies are amenable to treatment that greatly reduces the burden of disease and extent of disability. Thus, electrophysiologic studies are critically important as an investigatory tool in the evaluation of patients with suspected demyelinating neuropathies. In this chapter, we focus our discussion on the manifold electrophysiologic details regarding the demyelinating neuropathies and provide the reader with the clinical context and pathophysiological underpinnings to help appreciate the complex character of these disorders, including the Guillain-Barre syndrome; chronic inflammatory demyelinating polyneuropathy and its variants; the dysimmune demyelinating neuropathies that accompany systemic disease such as paraproteinemia, POEMS syndrome, and multifocal motor neuropathy; diabetic neuropathy; the demyelinating inherited polyneuropathies, and the demyelinating neuropathy from toxic exposures.

INTRODUCTION In this chapter we discuss the electrophysiology of the demyelinating neuropathies. While the concentration of this chapter is on the neurophysiology of these disorders, we also briefly discuss some of their cardinal clinical and pathophysiologic aspects that have been helpful in furthering our understanding of how a variety of specific electrophysiologic features develop into recognizable patterns that advance the diagnostic process. The course of demyelinating polyneuropathies may be acute, subacute, or chronic; their etiology inherited or acquired; and their clinical phenotypes remarkably varied. While clinical findings (such as time course, specific fiber type involvement, pattern of deficits, and nonneurologic systemic features) help in the diagnostic process of assigning a neuropathy to a specific diagnostic category—

either axonal or demyelinating—it is electrodiagnostic testing that plays the determining role in identifying its essential character. In the following sections we focus the discussion on the acquired dysimmune demyelinating neuropathies and Charcot-Marie-Tooth (CMT) disease and also comment on neuropathies caused by diabetes and various toxic neuropathies that may have demyelinating features.

 SYNDROME GUILLAIN-BARRE The Guillain-Barre syndrome (GBS), a predominantly motor disorder that typically begins with fine paresthesia in the toes or fingertips (Ropper, 1992), is the leading cause of acute paralytic illness in Western countries. Its incidence in North America and Europe ranges between

*Correspondence to: David Aaron Chad, M.D., Staff Neurologist, Reliant Medical Group, 123 Summer Street, Suite 230, Worcester, MA, 01608, United States. Tel: +1-508-368-3150, Fax: +1-508-368-3152, E-mail: [email protected]

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0.89 and 1.89 cases (median 1.1) per 100,000 person-years (Yuki and Hartung, 2012). There is a clinical prodrome in two-thirds of patients manifesting as an upper respiratory infection or a diarrheal illness (typically caused by Campylobacter jejuni), 1–4 weeks prior to onset of the neuropathy. The disease is characterized by the acute onset (typically over hours to days) of rapidly progressive proximal and distal weakness along with numbness, paresthesia, and aching pain in the distal limbs. From the time they first emerge, clinical signs and symptoms intensify and advance over days to weeks (most commonly ascending from legs to arms), reaching their point of maximum intensity by 2 weeks in >50% of patients and by the end of 4 weeks in >90% of patients. The diagnosis of GBS requires a supportive history and clinical examination; cerebrospinal fluid (CSF) with albuminocytologic dissociation (Asbury and Cornblath, 1990) and electrophysiologic features of acquired demyelination provide confirmation of the diagnosis. GBS comprises different subtypes—they all share an immune-mediated pathogenesis but differ in their pathophysiologic underpinnings, clinical presentations, and outcomes. In North America and Europe, the most common form is demyelinating, the so-called acute inflammatory demyelinating polyneuropathy (AIDP). The axonal forms are found in only 5% of patients and include acute motor axonal neuropathy (AMAN), causing patients to reach their nadir more quickly than patients with AIDP and to recover at rates comparable to those with AIDP (Yuki et al., 1999); and acute motor and sensory neuropathy (AMSAN), perhaps the most severe of the GBS phenotypes, typically with rapid onset of virtually complete paralysis (Ropper, 1992). In Asia and Central and South America the axonal forms constitute 30%–47% of cases (Hughes and Cornblath, 2005). A small subset of patients with GBS in North America and Europe (5% in large series, but up to 20% of patients in Taiwan and 25% of patients in Japan (Yuki and Hartung, 2012) has a variant of GBS that presents with the triad of acute ophthalmoplegia, ataxia, and areflexia with little weakness, known as the Miller Fisher syndrome (MFS) (Fisher, 1956). Most individuals with this disorder experience a peak in deficit at 1 week after onset, with improvement beginning after 2 weeks and complete recovery by 6 months (Piccione et al., 2014). Electrodiagnostic testing will confirm the presence of a polyneuropathy and permit it to be classified as one of the GBS subtypes or the MFS variant. The other major role of electrodiagnostic testing is to rule out conditions that might mimic GBS, such as various forms of acute myogenic weakness, myasthenia gravis, neuropathic conditions (toxic, vasculitic, porphyric, and infectious), and sensory ganglionopathy.

Because the aberrant electrophysiology that defines each of the subtypes stems from specific abnormalities in peripheral nerve structure and function, it is important to appreciate the immunopathogenesis and pathology that leads to nerve dysfunction; accordingly, we present a brief overview of these aspects of the disease before discussing the electrodiagnostic features.

Axonal Subtypes PATHOPHYSIOLOGY On one end of the spectrum of axonal subtypes lies a mild form of AMAN characterized by binding of IgG antiganglioside antibodies to motor fibers, resulting in a physiologic impairment in conduction that can be rapidly reversed; while on the other end of this spectrum lies a severe form of AMSAN, marked by complement activation and membrane attack complex formation on the nodal and subsequently the internodal axolemma, with consequent macrophage recruitment to the node and the periaxonal space, culminating in degeneration of motor and sensory fibers (Griffin et al., 1996; Yuki and Hartung, 2012).

ELECTRODIAGNOSTIC STUDIES In AMAN and AMSAN, the centerpiece of electrodiagnostic findings is severely reduced amplitude or absent motor responses with relatively preserved conduction velocities (Asbury and Cornblath, 1990). Neurophysiologic criteria for corroborating these diagnoses are marked reduction (<80% of the lower limit of normal [LLN]) in the compound muscle action potential (CMAP) amplitude following distal stimulation in at least two nerves. In AMAN, sensory potentials are normal, while in AMSAN they are markedly reduced or absent (Ho et al., 1995; Hadden et al., 1998). By 3–4 weeks after onset of symptoms, needle electrode examinations of patients with persistently low motor amplitudes are likely to show evidence of widespread active motor axon loss and severe reduction in motor unit potential (MUP) recruitment.

Miller Fisher syndrome PATHOPHYSIOLOGY Almost all patients studied with MFS are found to have elevated antiganglioside antibodies directed against the epitope GQ1B, which is strongly expressed in the oculomotor, trochlear, and abducens nerves as well as muscle spindles in the limbs. Their presence supports a role for anti-GQ1B in the pathogenesis of ophthalmoplegia and ataxia (Yuki and Hartung, 2012).

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY

ELECTRODIAGNOSTIC STUDIES Electrodiagnostic studies disclose profound sensory nerve changes (absent or markedly reduced sensory responses) with minor motor abnormalities (Sauron et al., 1984; Fross and Daube, 1987; Shahrizaila et al., 2014). Unlike AIDP, there is little electrophysiologic evidence of demyelination but rather a pattern that suggests an axonal sensory neuropathy or sensory neuronopathy (Fross and Daube, 1987).

AIDP PATHOPHYSIOLOGY In AIDP, autoantigen-autoantibody interactions activate complement, leading to the formation of the membrane attack complex on the outer surface of Schwann cells that initiates vesicular degeneration of myelin; macrophages subsequently invade the myelin sheath and scavenge myelin debris (Yuki and Hartung, 2012). Inflammatory lesions consist of circumscribed areas of myelin loss in the presence of lymphocytes and macrophages; the most aggressive lesions are populated by polymorphonuclear leukocytes resulting in concomitant axonal injury (Arnason and Soliven, 1993). Therefore nerve involvement (prominence of demyelination with variable degrees of axon loss) occurs along the entire length of peripheral nerves with particular segments of maximal involvement varying from case to case; in general there seems to be preferential damage of the roots, common sites of entrapment, and extreme distal motor nerve twigs (Asbury et al., 1969; Arnason and Soliven, 1993). Because of the multifocal nature of this progressive pathologic process, peripheral nerve involvement by AIDP can range from a form of the disease that might have reached its nadir after a few days and be characterized by a paucity of lesions, mild intensity (affecting the myelin sheath alone), and restricted distribution; to a scenario where the pathologic process may have progressed over weeks, with abundant lesions (damaging to myelin and axons), that are anatomically widespread, causing the disease burden to be high.

ELECTRODIAGNOSTIC STUDIES Nerve conduction abnormalities may be rather mild and nonspecific in patients with benign presentations, especially if tested only a short time after symptom onset; while nerve conduction abnormalities indicative of acquired demyelination may be more readily identified in patients with pronounced clinical features and when tested in the second or third week of the illness. The variety of electrodiagnostic findings reported for patients

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with AIDP likely stems from the physiologic changes that occur in response to cumulative demyelination and axonal degeneration, and the timing of the electrodiagnostic studies as the neuropathic features unfold (Albers and Kelly, 1989). To detect electrophysiologic changes in a patchy and multifocal disease that changes over time, the number of nerves studied also figures into establishing the diagnosis, and serial testing may be necessary (Alam et al., 1998). A published approach includes studying three or more motor nerves, including late responses (F waves and H-reflexes), evaluating proximal nerve segments, and performing precise enough measurements to determine whether partial conduction block and abnormal temporal dispersions exist (Asbury and Cornblath, 1990).

TESTING In AIDP the pattern of abnormalities is heterogeneous. The patchy and multifocal character of the disease creates an electrophysiologic pattern that is often non– length dependent, with changes in sensory and motor amplitudes sometimes as pronounced in the upper as the lower extremities. Findings include prolonged distal motor and peak sensory latencies, absent or prolonged F-wave latencies, absent H-reflexes, slowed conduction velocities, and features of conduction block and abnormal temporal dispersion that accumulate between distal and proximal sites of stimulation (Figs. 15.1 and 15.2). Sensory studies Sensory studies are abnormal in 75% of patients at some time during the course of the illness (Albers et al., 1985; Al-Shekhlee et al., 2007), manifested as reduced amplitudes of sensory responses that may reflect axon loss, conduction block, or phase cancellation. Slowing of conduction velocity is detected less often than other findings because the sensory potential drops out before severe slowing is found. In the first 2 weeks after symptom onset, almost 50% of AIDP patients show a non–length dependent pattern of sensory involvement: the sural response is normal or relatively spared while the median and ulnar sensory responses are absent or attenuated, a finding described as sural sparing, a finding that is not seen in typical length-dependent polyneuropathy (Albers et al., 1985). While a normal sural and a reduced or absent median or ulnar sensory response (Table 15.1) are not diagnostic, the combination of low median/ulnar and spared sural responses should be considered supportive of an acquired demyelinating disorder, especially when seen with an absent H-reflex (Gordon and Wilbourn, 2001). While mimics of AIDP may show

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M.P. BOWLEY AND D.A. CHAD 1 mV 6 ms

W

E

Distance (cm)

Distal latency (ms)

Amplitude (mV)

Area (mV/ms)

Duration (ms)

Wrist (W)

6

13.8

2.0

10.9

13.5

Elbow (E)

23

22.7

1.3

5.3

17.3

Fig. 15.1. Median motor conduction study in a 55-year-old patient with relapsing remitting CIDP (relapsing phase) and disease duration 3 years, illustrating several demyelinating features discussed in the text (one or more of these features could also be seen in the setting of AIDP): The amplitude of the distal motor response (W) is reduced (2.0 mV, normal >4.5 mV); the duration of the distal response is prolonged (13.5 ms, normal <6.6 ms); the distal motor latency is prolonged >300% ULN* (13.8 ms, normal <4.5 ms); there is a drop in amplitude and area following proximal stimulation (E) (partial motor conduction block of 35% [amplitude)]and 48 [area])*; and there is abnormal temporal dispersion (28%). The conduction velocity is 26 m/s (<70% LLN).

200 mV 20 ms

Fig. 15.2. Tibial F-wave study in a patient with CIDP (patient’s full study summarized in Table 15.1) that might also be seen in the setting of AIDP: The minimum F-wave latency is prolonged (>50% ULN) (89.8 ms, normal <58 ms).

prolonged distal motor latencies and abnormal F-wave responses, the sural sparing pattern has a specificity of 96% (Derksen et al., 2014). If the sural response is absent or low in amplitude due to age or peripheral edema,

a comparison between the radial sensory response and the median and ulnar sensory responses can be useful. Patients with AIDP have a sensory ratio (sural + radial sensory amplitudes/median + ulnar sensory amplitudes)

Table 15.1 Nerve conductions in GBS 2 weeks after symptom onset in patient (male) age 19

Sensory/ motor S S S M

M

M

M

Nerve/site Median—Digit II Ulnar—Digit V Sural—Calf Median Wrist Elbow Ulnar Wrist B. Elbow A. Elbow Peroneal Ankle Fib. Head Knee Tibial Ankle Knee

Recording Site

Amplitude (uV,mV)

Normal (uV, mV)

Latency (ms)

Normal (ms)

Conduction velocity (m/s)

Normal (m/s)

Terminal latency Index

F Wave latency (ms)

Normal (ms)

Wrist Wrist Ankle

2.7 4.6 26.4


12.0
10.0
4.0

3 2.5 3.4

3.2 2.8 4.4

57.8 61.1 51.1


49
49
39

— — —

— — —

— — —

APB APB

3.6 3.4


4.0
4.0

5.8 9.9

4.5

0.18

44.4

31.0

58.5


49

ADM ADM ADM

4.0 3.6 3.6


5.0
5.0
5.0

3.7 6.7 8.3

3.5

0.25

NR

33.0

65.6 62.5


49
49

EPB EPB EPB

0.8 0.8 0.7


2.5
2.5
2.5

10.6 15.3 17.3

6.6

0.16

56.0


39
39

—

53.2 50.0

AH AH

2.8 2.7


2.5
2.5

4.8 11.4

6.6

0.42

NR

61.0

49.6


39

The median and ulnar sensory responses are reduced while the sural response is robustly preserved, highlighting the phenomenon of “sural sparing,” an early and specific finding in AIDP. Motor amplitudes are at the lower end of the normal range (tibial), mildly reduced (median and ulnar), or markedly reduced (peroneal), changes that are common by 2 weeks after symptom onset. Conduction block is not seen. Distal motor latencies are normal (tibial), slightly prolonged (ulnar), moderately prolonged (median) and severely prolonged (peroneal), demonstrating the patchy nature of the demyelinating process. The duration of the peroneal nerve distal CMAP is 15 ms (normal <8.5 ms) (not shown), an indicator of abnormal temporal dispersion. Motor conduction velocities are within normal limits at 2 weeks after symptom onset at time when the F-wave latency is prolonged (median) or F waves are absent (ulnar and tibial) and some distal latencies are prolonged, illustrating the predilection of the demyelinating process at week 2 to be expressed along the most distal and most proximal segments of the peripheral nervous system. The TLI 0.25 signals the disproportionate involvement of the distal compared with the intermediate nerve segments (median, ulnar, peroneal).

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>1, unlike a control population whose ratio is ¼ 1 (Al-Shekhlee et al., 2007). The mechanism for this phenomenon (preserved radial response) may stem from random multifocal demyelination with conduction blocks and phase cancellation preferentially affecting the median and ulnar nerves at common entrapment sites that are not present along the radial nerve (Al-Shekhlee et al., 2007). Motor studies. Prominent slowing of motor nerve conduction velocity, often considered the hallmark of AIDP, is uncommon (<25% of patients) in the early phases (first 1–2 weeks after symptom onset) of AIDP; indeed, at a stage in the disease when demyelination is most active, conduction velocity is typically normal or only mildly reduced (Gordon and Wilbourn, 2001) (Table 15.1). Mean motor conduction velocities were found to be relatively well preserved early in the disease, falling to about 70% of normal in the third week, with recovery toward normal after 10 weeks (at a time when motor amplitudes are still relatively depressed) (Albers et al., 1985). It has been observed that, while slowed conduction velocity is thought to be a feature of demyelination, it should more properly be associated with early remyelination (Feasby, 1992). The delayed slowing is a function of the progressive replacement of conduction blocks (where no conduction is occurring) with segmental remyelination, in which each Schwann cell of the “old” internode is replaced by several new cells; in effect, each denuded internode is replaced by several short ones. The “new” incompletely myelinated internodes permit resumption of conduction but at a slower velocity than occurs in a healthy nerve. Motor conduction velocity has long been considered to be an important parameter to consider in the diagnosis of AIDP, but the degree of slowing required to fulfill the “slowing of velocity” criterion has ranged from relatively mild (<95% LLN if motor amplitude >50% LLN in two or more nerves) to more rigorous (<30% LLN in two or more nerves) (Feasby, 1992; Alam et al., 1998) (see the following). Unlike slowing of conduction velocity, conduction block and abnormal temporal dispersion (along with decreased amplitude of motor responses) may be early physiologic changes in AIDP, typically occurring before slowing of conduction velocity and therefore helpful in establishing the presence of a demyelinating neuropathy (Al-Shekhlee et al., 2007). Conduction block in a few fibers is trivial but when it occurs in many fibers, it results in weakness or even total paralysis. It has been suggested that the normal or near-normal maximum conduction velocities in the first 2 weeks of AIDP occur when the fastest conducting motor axons are not those whose impulses are blocked (Brown and Feasby, 1984). Criteria

for partial conduction block in AIDP include greater than 20% drop in negative-peak area of peak-to-peak amplitude between proximal and distal sites in the presence of less than 15% change in CMAP duration between those sites (Brown and Feasby, 1984; Asbury and Cornblath, 1990; Van den Bergh and Pieret, 2004). Another report made two observations: first, that amplitude reductions in excess of 20% have been reported in normal control populations (for example, up to 45% for the median nerve and 50% in the peroneal nerve) (Van den Bergh and Pieret, 2004); and second, that broadening of the range of conduction velocities between stimulation points may lead to negative-peak CMAP area reductions of up to 50% and diminution in amplitude of >50% due to interphase cancellation between overlapping components of opposite polarity that constitute the CMAP (Van den Bergh and Pieret, 2004). More restrictive criteria for conduction block can be formulated as follows: amplitude reduction of >50% and duration increase of <30% of the negative peak of the CMAP in the presence of a distal CMAP amplitude >20% of the LLN values. These criteria for conduction block, if found in two nerves, have been incorporated as a diagnostic parameter in a current set of electrophysiologic criteria for CIDP and by extension AIDP when tested in week 3–4 after symptom onset (Joint Task Force of the EFNS and the PNS, 2010). Conduction blocks are not always a manifestation of an acquired demyelinating polyneuropathy, as they are seen with compressive mononeuropathies. Conduction blocks supportive of AIDP should be located at nonentrapment sites (Piccione et al., 2014). Abnormal temporal dispersion—the phenomenon of both long-duration and reduced CMAP amplitude— can be explained by multifocal and nonhomogeneous demyelination of nerve fibers leading to a spectrum of nerve fiber velocities and conduction failure in a nerve trunk. Abnormal temporal dispersion is found in 58% of patients in at least one nerve in the first week of the illness (Gordon and Wilbourn, 2001). Some criteria use >15% change in duration between proximal and distal sites and >20% drop in negative peak area or peak-topeak amplitude between proximal and distal sites, while other criteria use >30% duration increase between the proximal and distal negative peak CMAP. The latter criteria, when identified in two nerve trunks, are considered a diagnostic parameter for AIDP and CIDP (Van den Bergh and Pieret, 2004; Joint Task Force of the EFNS and the PNS, 2010). With regard to motor response amplitudes, low distal motor amplitude was found to be the most common change in nerves of patients with AIDP tested within 21 days of symptom onset (Clouston et al., 1994). Mean

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY values from distal stimulation were reduced to 50% of normal in the first week, falling further during the second and third weeks to 25%–30% of normal, with a recovery thereafter, so that by 4–6 months the mean values for amplitudes were 66% of normal (AlShekhlee et al., 2007). Low amplitude of the distally evoked CMAP (reduced mean CMAP to <10% LLN) was among the most important predictors of outcome in AIDP (Miller et al., 1988). The reverse outcome predictor for increasing CMAP amplitude over time has also been reported (Al-Shekhlee et al., 2007). Another study determined that a mean distal CMAP amplitude of 0%–20% of the LLN was associated with a marked increased probability of a poor outcome (Cornblath et al., 1988). The predictive value increased after the second electrodiagnostic study, performed on average 5 weeks from onset of symptoms. Very low CMAPs could stem from axon loss or distal demyelination, or some combination of both. It is likely that in patients with the worst outcomes, the underlying pathophysiology is predominantly axon loss. Distal motor latency is at least modestly prolonged in more than 50% of patients when they are first tested within 10 days of symptom onset (Albertí et al., 2011). A smaller percentage of patients shows degrees of slowing that would be deemed unequivocally demyelinating (>150% of the ULN) (Gordon and Wilbourn, 2001). A higher percentage will show a more pronounced degree of prolongation on subsequent studies (Al-Shekhlee et al., 2007). Diagnostic criteria for distal latency prolongation have varied. One study suggested >110% of the upper limit of normal (ULN) with a normal amplitude in two or more nerves (Al-Shekhlee et al., 2007); another suggested >125% of ULN in two or more nerves (Asbury and Cornblath, 1990). Distal CMAP duration is likewise prolonged in approximately 50% of nerves studied within 21 days of symptom onset (Clouston et al., 1994) (Table 15.1). A study of 53 patients with AIDP at a mean of 11.3 days following symptom onset found distal CMAP dispersion (CMAP duration >8.5 ms for any of the motor nerves tested) in at least one motor nerve in 66% of patients with AIDP (compared with 9% of subjects with ALS), emphasizing that distal CMAP dispersion can be a useful criterion in the electrodiagnosis of AIDP by increasing sensitivity and specificity (Cleland et al., 2006). Late responses. In a study of 31 patients with AIDP who underwent testing within 7 days of the onset of motor symptoms, the H-reflex was absent in 97%; in 16% of patients the electrodiagnostic studies were entirely normal with the exception of the absent H waves (Gordon and Wilbourn, 2001). The authors

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concluded that for patients who undergo electrodiagnostic testing within 7 days of the symptom onset, the H-reflex is the most sensitive test for early AIDP. While an absent H-reflex is a common finding in the elderly and may be absent in chronic axonal polyneuropathy and S1 radiculopathy, when accompanied by sural sparing in the appropriate clinical context, there is significant concern for AIDP. The F wave is also often found to be abnormal in AIDP. Some abnormality of the F wave (prolonged F-wave latencies or absent F waves) is considered one of the cardinal demyelinating parameters among the diagnostic criteria for AIDP. Prolongation of the minimum F-wave latency (>120% of ULN if the CMAP amplitude is >80% LLN; and >150% of ULN if the amplitude is <20% LLN) or absence of F waves (if the CMAPs are >20% LLN) in two or more nerves supports the diagnosis of AIDP (Asbury and Cornblath, 1990). Prolonged or absent F waves have been reported in 40% to 80% of patients early in the course of the illness (Table 15.1); in 25% of patients some F-wave abnormality may perhaps be the sole finding in the first week of the illness (Ropper, 1992; Piccione et al., 2014). While F responses are commonly absent early in the course of the illness, the most prolonged latencies are typically recorded during the third to fifth weeks after onset (Al-Shekhlee et al., 2007). Needle examination findings. The results of electromyography in a group of 70 patients with GBS, 87% of whom had AIDP (3% had an axonal subtype and 10% were indeterminate), showed reduced MUP recruitment without abnormalities of configuration or evidence of abnormal spontaneous activity (Albers et al., 1985). MUP recruitment abnormalities were most pronounced distally and no patient had normal MUP recruitment at the time of initial examination. MUP recruitment improved over time; being mildly reduced when studies were performed between 36 and 50 weeks after disease onset when clinical improvement had occurred. Abnormal spontaneous activity (fibrillation potentials) first appeared between the second and fourth weeks following disease onset in distal and proximal muscles simultaneously; the activity was maximal in proximal muscles between 6 and 10 weeks, and in distal muscles between 11 and 15 weeks. The simultaneous appearance of abnormal spontaneous activity suggested that axonal degeneration was occurring randomly along the axon (Albers et al., 1985). Four patients (5%) had transient myokymic discharges recorded from facial (two patients) and limb muscles (two patients) during the first 3 weeks of the illness. The appearance of MUPs changed over time: the earliest abnormality was an increased percentage of polyphasic MUPs during the 4th week, seen in both

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proximal and distal muscles. This increased in degree between the 9th and 35th weeks, and subsequently returned toward normal.

ELECTRODIAGNOSTIC CRITERIA FOR THE DIAGNOSIS OF GBS Over the last few decades, various sets of criteria have been proposed for the AIDP subtype of GBS (Piccione

Table 15.2 Electrophysiologic criteria for AIDP/CIDP, as used by Asbury and Cornblath (1990) and the Ad Hoc Subcommittee for the Diagnosis of CIDP (1991). Definite electrophysiologic diagnosis must have three of the following four features. Parameter

Criterion

Conduction velocity

Reduction in conduction velocity in two or more motor nerves a. < 80% of lower limit of normal (LLN) if amplitude >80% of LLN b. <70% of LLN if amplitude <80% of LLN

Conduction block or Temporal dispersion

One of these parameters in one or more motor nerves (peroneal/median/ulnar) ● Criteria for partial block: o <15% change in duration between proximal and distal sites o >20% decrease in negative-peak area of peak-to-peak amplitude between proximal and distal sites ● Criteria for abnormal temporal dispersion and possible conduction block: o >15% change in duration between proximal and distal sites o >20% drop in negative-peak area of peak-to-peak amplitude between proximal and distal sites

Distal latency

F waves

Prolonged distal latency in two or more nerves ● >125% of ULN if amplitude >80% of LLN ● >150% of ULBN if amplitude <80% of LLN Absent F waves or prolonged minimum F-wave latencies (10–15 trials) in two or more motor nerves. ● >120% of ULN if amplitude >80% of LLN ● >150% of ULBN if amplitude <80% of LLN

et al., 2014). Distal motor latency and the distal CMAP duration reflect the integrity of myelination of the distal segment, conduction velocity and morphology of waveforms show the state of myelination along the intermediate segment of the nerve (elbow to wrist/knee to ankle), and F waves and H-reflexes reflect conduction along the whole course of the peripheral nerve pathway including the proximal segments (plexuses to nerve roots). The criteria vary in specificity and sensitivity. Stringent sets of criteria include those by Asbury and Cornblath (1990) (Table 15.2), and Albers and Kelly (1989), requiring at least three abnormal parameters (with the stipulation that each abnormality be present in two nerves [except for temporal dispersion/conduction block; either in one nerve would suffice]). Less stringent criteria include those by Albers et al. (1985) (Table 15.3), Hadden et al. (1998), and the Dutch GBS study group, requiring one abnormal parameter in two nerves (Albers et al., 1985; Albers and Kelly (1989); Meulstee and van der Meche, 1995; Hadden et al., 1998). The sets of criteria that require three abnormal parameters each in two nerves have excellent

Table 15.3 Electrophysiologic criteria suggestive of acute inflammatory demyelinating polyneuropathy (AIDP) as used by Albers et al. (1985) Parameter

Criterion

Conduction velocity a. <95% of LLN if amplitude >50% of LLN; b. <85% if amplitude <50% of LLN Distal latency

a. >110% of ULN if amplitude normal b. >120% of ULBN if amplitude < LLN

Temporal a. Evidence of unequivocal temporal dispersion or dispersion or conduction block b. Proximal to distal amplitude ratio < 0.7 F Waves Exceptions

>120% of the upper limit of normal ● Exclude isolated ulnar or peroneal nerve abnormalities at the elbow or knee, respectively ● Exclude isolated median nerve abnormality at the wrist ● Exclude the presence of anomalous innervation (e.g., median to ulnar nerve crossover)

Diagnosis requires demonstration of at least one of the criteria in two or more nerves (exceptions noted).

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY

249

Table 15.4 Proposed criteria for electrophysiologic diagnosis of primary demyelination with two levels of confidence (probable, definite) assembled by Van den Bergh and Pieret (2004) Parameter

Criterion

Conduction velocity

Reduction in conduction velocity >30% below the lower limit of normal (LLN) in two or more motor nerves Prolongation of distal motor latency >150% of upper limit of normal (ULN) in two or more nerves Prolongation of F-wave latency in two or more nerves

Distal latency F waves

● >120% of ULN ● > 150% of ULN if amplitude <80% of LLN

Absent F waves in two nerves (if distal amplitude >20% LLN) plus an abnormality in at least one other parameter in one other nerve Abnormal temporal dispersion > 30% negative peak CMAP duration increase in two or more nerves Conduction block (parameter Amplitude reduction of >30% if the distal CMAP amplitude is >20% LLN (median, ulnar or used for “Probable” primary peroneal nerves) in at least two motor nerves OR its presence in one nerve together with one other demyelination) abnormal parameter in at least one other nerve Conduction block (parameter Amplitude reduction of >50% if the distal CMAP amplitude is
20% LLN (median, ulnar, or used for “Definite” primary peroneal nerves) in at least two motor nerves or its presence in one nerve together with one other demyelination) abnormal parameter in at least one other nerve F-wave absence

Diagnosis requires one of the following abnormal parameters.

specificity (>94%) and modest sensitivity (38% for Asbury and Cornblath, 1990; 68% for Albers and Kelly, 1989). Those that require one abnormal parameter have only modest specificity (<50%) but higher sensitivity (89% for Albers et al., 1985) (Alam et al., 1998; Van den Bergh and Pieret, 2004). In an effort to retain a high level of specificity and yet increase sensitivity, a study reanalyzed specificity and sensitivity of 10 sets of criteria and, with some modifications in each of the parameters, created a new set of criteria (Table 15.4) (Van den Bergh and Pieret, 2004). When 53 patients with AIDP, 28 with CIDP, 40 with ALS, and 32 with diabetic polyneuropathy were then placed into either a probable or definite diagnostic category, the diagnosis of AIDP could be made with 100% specificity and a sensitivity of 72% in the probable group and 64% in the definite group. Higher sensitivity was achieved at least in part because patients were studied later in the course of illness (mean interval between onset and testing of 3 weeks, range 1–7 weeks), allowing time for demyelinating features to become more obvious. This study demonstrated that diagnostic sensitivity for AIDP can reach the level achievable for CIDP by 3–4 weeks of illness (Van den Bergh and Pieret, 2004). With minor modifications, these criteria were adopted by the European Federation of Neurological Societies as the standard for the electrodiagnosis of CIDP (Hadden et al., 2006; Van den Bergh et al., 2010) (Table 15.5).

Electrodiagnosis of AIDP in the first 2 weeks following onset of symptoms is difficult. A study attempted to develop new criteria for the early electrodiagnosis of AIDP, using a retrospective review of 66 patients with AIDP compared with 26 patients with critical illness polyneuropathy (Al-Shekhlee et al., 2005). Four categories were defined (Table 15.6): (1) nondiagnostic: abnormalities not specific for GBS, including absent H-reflexes, borderline or low CMAPs, and/or sensory responses, and minimal prolongation of latencies or conduction velocity slowing; (2) suggestive: presence of a sural sparing pattern, or two or more nerves with absent or prolonged minimum F-wave latency (with relatively normal distal CMAP amplitudes) and absent H-reflex; (3) highly suggestive: presence of sural sparing pattern and two or more nerves with absent or prolonged minimum F-wave latency (with relatively normal distal CMAP amplitudes) and absent H-reflex; (4) definite: features of multifocal demyelination as described in the set of criteria of Asbury and Cornblath (1990) (Asbury and Cornblath, 1990). Using these criteria, 64% of patients with AIDP met the highly suggestive and definite criteria, with a specificity of 96%–100%, leaving 26% of patients to be placed in the suggestive category. Of the patients with critical illness polyneuropathy, 80% fell in the nondiagnostic range (specificity 19%), and no patient met definite criteria.

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M.P. BOWLEY AND D.A. CHAD

Table 15.5 Electrodiagnostic criteria for CIDP as proposed by the Joint Task Force of the European Federation of Neurological Societies and Peripheral Nerve Society (2006, 2010) Definite CIDP At least one of the following demyelinating parameters is necessary Parameter

Criterion

Distal motor latency Conduction velocity F-wave latency


50% prolongation above the ULN in two nerves
30% reduction below the LLN in two nerves
20% prolongation of motor distal latency above the ULN in two nerves, or > 50% if the amplitude or the distal negative peak CMAP is <80% of the LLN Absent F waves in two nerves (if distal negative peak CMAP
20% of the LLN), plus at least one other demyelinating parameter in at least one other nerve
50% amplitude reduction of the proximal negative peak CMAP relative to distal, if distal negative peak CMAP is
20% of the LLN, in two nerves, or in one nerve plus at least one other demyelinating parameter in at least one other nerve >30% duration increase between the proximal and distal negative peak CMAP in at least two nerves

F-wave absence Partial motor conduction block Abnormal temporal dispersion Distal CMAP duration

(Interval between onset of the first negative peak and return to baseline of the last negative peak.) Increase in
1 nerve (median
6.6 ms, ulnar
6.7 ms, peroneal
7.6 ms, tibial
8.8 ms) plus
1 other demyelinating parameter in
1 other nerve

Probable CIDP Partial Motor
30% amplitude reduction of the proximal negative peak CMAP relative to distal (excluding the tibial Conduction Block nerve), if distal negative peak CMAP is
20% of the LLN, in two nerves, or in one nerve plus at least one other demyelinating parameter in at least one other nerve Possible CIDP As in Definite CIDP but in only one nerve Table 15.6 Electrodiagnostic criteria for acute inflammatory demyelinating polyneuropathy as proposed by Al-Shekhlee et al. (2005) Diagnostic category Nondiagnostic Suggestive Highly suggestive Definite

Normal nerve conduction studies Nonspecific or nonlocalizing abnormalities including an isolated absent H-reflex, without definite demyelination Sural sparing pattern or 2 or more nerves with absent or prolonged minimum F-wave latency (with relatively normal distal CMAP amplitudes) and absent H reflex Sural sparing pattern and 2 or more nerves with absent or prolonged minimum F-wave latency (with relatively normal distal CMAP amplitudes) and absent H-reflex Both signs of demyelination to be present in 2 motor nerves 1. Focal slowing, temporal dispersion, and/or conduction blocks 2. Absent or prolonged minimum F-wave latency (with relatively normal distal CMAP amplitude) with absent H-reflex

CHRONIC ACQUIRED DEMYELINATING POLYNEUROPATHIES In this section, we consider the chronic acquired demyelinating neuropathies that are seen most frequently in the electrodiagnostic laboratories of neurologists in clinical practice. The most prevalent is chronic inflammatory

demyelinating polyneuropathy (CIDP) and its variants, which include multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy or Lewis-Sumner syndrome, paraproteinemic (IgG, IgA) demyelinating neuropathy (PDN), and distal acquired demyelinating symmetric (DADS) neuropathy. We will also comment on two other acquired demyelinating neuropathies: the

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY syndrome of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS); and multifocal motor neuropathy with conduction block.

Chronic inflammatory demyelinating polyneuropathy Dyck et al. (1975) described “chronic inflammatory polyradiculoneuropathy” and then in 1982 designated the disorder CIDP (Dyck et al., 1975, 1982). To be designated CIDP, the symptoms of motor and sensory polyradiculoneuropathy must progress for 8 or more weeks. CIDP typically has a protracted, often stuttering, course and indolent progression, distinguishing it from AIDP. While both disorders have an immune pathophysiology and similar electrophysiologic profile, the specific antigenic targets and immune effectors as well as the response to treatment appear to be different. The prevalence of the disease in populations from the United Kingdom, Australia, Italy, Japan, and the United States is 0.8–8.9 per 100,000 (Lunn et al., 1999; McLeod et al., 1999; Chiò et al., 2007; Iijima et al., 2008; Laughlin et al., 2009; Rajabally et al., 2009). The neuropathy occurs in individuals of all ages, peaking in the fifth and sixth decades, with an average age of onset of about 50 years; men are more often affected than women in a ratio of 2:1. Most patients have motor and sensory involvement; a small percentage (5%) is purely sensory. The distribution of weakness tends to be proximal and distal and is classically symmetric, though asymmetric onset may occur. The upper and lower limbs are both affected with a preponderance of clinical signs in the legs. Muscle stretch reflexes are attenuated or absent early in the course of the illness. Sensory symptoms and signs include numbness, paresthesias, sensory ataxia, and sometimes pain. Positive sensory experiences are common and help to differentiate individuals with CIDP from forms of hereditary CMT disease. Cranial nerve dysfunction is uncommon but ophthalmoplegia, papilledema, and facial and bulbar weakness have been described. Evaluation in suspected CIDP includes electrophysiologic studies, CSF profile with albuminocytologic dissociation (Barohn et al., 1989), enhanced MRI studies demonstrating hypertrophy and enhancement of cervical and lumbosacral nerve roots, and sural nerve biopsy showing unequivocal evidence of demyelination and/or remyelination by teased fiber analysis or electron microscopy. Clinical and laboratory criteria for the diagnosis of CIDP were developed by a panel of experts from the European Federation of Neurological Societies (EFNS) and the Peripheral Nerve Society (PNS); the electrodiagnostic criteria are presented in Table 15.5 (Hadden et al., 2006; Joint Task Force of the EFNS and the PNS, 2010).

251

PATHOLOGY Bearing some resemblance to AIDP, autopsy studies of remitting cases of CIDP have shown evidence of a multifocal demyelinating disorder (Dyck et al., 1993a) affecting chiefly spinal nerve roots, major plexuses, and/or proximal nerve trunks with lesions extending throughout the peripheral nervous system, including in some cases intramuscular nerves, sympathetic trunks, and terminal autonomic nerves. The chronic proximal demyelinating lesions frequently induce distal axon degeneration with drop out of large myelinated fibers (Vallat et al., 2010).

ELECTRODIAGNOSTIC STUDIES The spectrum of abnormalities in individual cases of CIDP is dependent upon the length of time between symptom onset and the initial study, the severity of pathologic involvement, and the comprehensiveness of the electrophysiologic evaluation. Findings may range from mild nonspecific electrodiagnostic abnormalities in relatively few nerves, to multifaceted abnormalities indicative of acquired demyelination. This may include slowing of motor conduction velocities, prolongation of distal motor latencies, increased duration of the distal motor responses, partial conduction block, temporal dispersion, and prolonged or absent F waves and H-reflexes (Table 15.7, Figs. 15.1 and 15.2). In cases of mild disease, it may be difficult to confirm the diagnosis of CIDP using electrodiagnostic testing and other supportive laboratory studies will be necessary (see earlier); while in cases with marked clinical signs and symptoms, electrodiagnostic testing alone may be diagnostic. The EFNS/PNS electrodiagnostic criteria (2010) for CIDP (Table 15.5) have been widely adopted for diagnostic purposes in clinical practice (Vallat et al., 2010). Electrodiagnostic criteria for CIDP have evolved over the last 30 years. Early electrodiagnostic criteria for CIDP divided the diagnosis into definite, probable, and possible categories (Barohn et al., 1989). Other electrodiagnostic criteria have been published (Albers and Kelly, 1989; “Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP), Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force,” 1991). These criteria were not meant to encompass all cases and rather they were proposed for research purposes with the anticipation that they would be useful in clinical trials. Bromberg (1991) evaluated these three sets (“Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force,” 1991; Albers and Kelly, 1989; Barohn et al., 1989). While specificity was excellent (100%), the published criteria

Table 15.7 Nerve conductions in chronic inflammatory demyelinating polyneuropathy in patient male age 38, disease duration 20 years, mild clinical exacerbation after prolonged remission

Sensory/ motor S S S S M

M

M

M

Nerve/site Median—Digit II Ulnar—Digit V Radial—Forearm Sural—Calf Median Wrist Elbow Ulnar Wrist B. Elbow A. Elbow Peroneal Ankle Fib. Head Knee Tibial Ankle Knee

Recording Site

Amplitude (uV,mV)

Normal (uV, mV)

Latency (ms)

Normal (ms)

Conduction velocity (m/s)

Normal (m/s)

Wrist Wrist Snuff Box Ankle

NR NR 12.1 11.1


12.0
10.0
15.0
4.0

NR NR 3.6 5.2

3.2 2.8 3.5 4.4

NR NR 40.0 35.9


49
49
49
39

APB APB

6.6 4.4


4.0
4.0

7.6 18.9

4.5 23.9


49

ADM ADM ADM

7.0 4.4 4.3


5.0
5.0
5.0

4.9 12.6 17.0

3.5 31.4 22.2


49
49

EPB EPB EPB

2.5 2.2 2.0


2.5
2.5
2.5

7.2 19.5 25.0

6.6 26.5 21.6


39
39

AH AH

1.7 1.2


2.5
2.5

7.7 21.7

6.6 33.5


39

Terminal latency Index

F wave latency (ms)

Normal (ms)

— —

— —

— —

—

—

—

0.33

64.0

31.0

0.39

71.0

33.0

0.47

84.0

56.0

0.39

89.8

61.0

The median and ulnar responses are absent while the sural response is preserved, indicating the often-conspicuous sural sparing and nonlength dependent involvement in CIDP. In this case of longstanding (>20 years) disease, the demyelinating pathology is diffusely distributed with foci of accentuated involvement, as indicated by the following: motor conduction velocities are slowed to <70% of the LLN (median, ulnar, and peroneal), and more modestly slowed 85% LLN (tibial); distal motor latencies are mildly prolonged (tibial and personal), moderately prolonged (ulnar), and more severely prolonged (median); distal CMAP duration is prolonged (10.s ms, normal <8.5 ms) (ulnar); and F-wave latencies are all strikingly prolonged; the TLI is >0.25 in all nerves tested. There is partial conduction block (median, ulnar). Motor amplitudes are normal (median and ulnar), low-normal (peroneal), or mildly reduced (tibial), correlating with a paucity of active denervation in the limbs and clinically well-preserved strength.

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY detected only a modest percentage of patients with CIDP, with sensitivities of 50% (Albers and Kelly, 1989), 46% (“Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force,” 1991) and 43% (Barohn et al., 1989). Bromberg (1991) found that the sensitivities could be increased to 66% by relaxing criteria, requiring only a single abnormality in one nerve rather than two in the criteria of Barohn et al. (1989), and by requiring conduction velocity slowing and distal latency prolongation to be present in only one nerve rather than two in the criteria of Albers and Kelly (1989). Bromberg’s modification of criteria had the effect of capturing a greater number of patients with CIDP while retaining 100% specificity for these criteria, so that no patient with ALS or DPN met any of these criteria (Bromberg, 1991). Following the work of Barohn et al. (1989), the next two decades saw the publication of various sets of criteria for the diagnosis of CIDP (Saperstein et al., 2001; Nicolas et al., 2002), and AIDP (Ho et al., 1995; Meulstee and van der Meche, 1995; Hadden et al., 1998; Hughes et al., 2001 “The prognosis and main prognostic indicators of Guillain-Barre syndrome. A multicentre prospective study of 297 patients. The Italian Guillain-Barre Study Group,” 1996). As noted previously, Van den Bergh and Pieret (2004) tested sensitivity and specificity of 10 published sets of criteria for primary demyelination by reviewing nerve conduction studies from patients with AIDP and CIDP (28 patients who conformed to the Ad Hoc Subcommittee of the AAN mandatory inclusion and clinical criteria for CIDP [1991]), ALS and DPN) (Van den Bergh and Pieret, 2004). They found that sensitivity ranged from 39% to 89% (mean 64.9%) in CIDP; specificity for ALS was 100% in 9/10 sets but was 97% in 1 set. However, 3%–66% of DPN patients fulfilled criteria in 8/10 sets. A set of criteria was assembled (Table 15.4) that “combined stringency for individual parameters with the requirement for one abnormal parameter,” demonstrating 75% sensitivity in their CIDP patient series (for two levels of confidence in the diagnosis, probable and the more restrictive definite categories), and 100% specificity with regard to ALS and DPN. Considering full specificity, these results were superior to those obtained with the 10 previously published sets of criteria. The authors analyzed the 7 CIDP patients who failed to meet proposed criteria and found 4 had at least one unexcitable motor nerve and three others had mild symptoms and signs (patients with either very mild or severe disease did not fulfill criteria). Another study assessed the utility of the distal CMAP (dCMAP) duration as a novel electrodiagnostic criterion for CIDP. Using dCMAP duration of
9 ms for any of four motor nerves yielded a sensitivity of 0.78 for CIDP and specificity

253

of 0.94 vs DPN or ALS; adding this parameter to selected previously published criteria enhanced their sensitivity (by approximately 30%) with little sacrifice in specificity (Thaisetthawatkul et al., 2002). The EFNS/PNS electrodiagnostic guidelines (Table 15.5) are designed to offer criteria to balance more evenly specificity and sensitivity (Hadden et al., 2006). The parameters that comprise the criteria were based on the diagnostic set described by Van den Bergh and Pieret (2004) (Table 15.4) with the addition of the parameter of dCMAP duration described by Thaisetthawatkul et al. (2002). An additional electrodiagnostic subcategory (possible CIDP) was added to include cases with demyelinating features in a single nerve instead of two nerves, increasing the sensitivity of of the criteria (Table 15.5) (Thaisetthawatkul et al., 2002; Van den Bergh and Pieret, 2004). Another group developed two sets of criteria, one including electrodiagnostic criteria and another relying on clinical criteria alone (Table 15.8) (Koski et al., 2009). In a subsequent publication Rajabally et al. (2009) showed that EFNS criteria had an 81.3% sensitivity and 96.2% specificity, the Koski criteria had a 63% sensitivity and 99.3% specificity, and the Ad hoc criteria had a 45.7% sensitivity and 100% specificity (Koski et al., 2009; Rajabally et al., 2009; “Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force,” 1991). Another study confirmed those findings (Breiner and Brannagan, 2014).

Table 15.8 Diagnostic criteria for CIDP (Koski et al., 2009) Proposed rule for the classification of patients with CIDP Patients with a chronic polyneuropathy, progressive for at least 8 weeks, would be classified as having CIDP if: No serum paraprotein and no documented genetic abnormality AND EITHER A. At least 75% of motor nerves tested have recordable response AND one of the following conditions is satisfied: 1. More than 50% of the motor nerves tested have abnormal distal latency, or 2. More than 50% of the motor nerves tested have abnormal conduction velocity, or 3. More than 50% of the motor nerves tested have abnormal F-latency

(All based on the AAN task force criteria [Table 15.2]) OR B. 1. Symmetric onset or symmetric exam, and 2. Weakness in all four limbs, and 3. At least one limb with proximal weakness

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M.P. BOWLEY AND D.A. CHAD

Paraproteinemic (IgG or IgA) Demyelinating Neuropathy CIDP with monoclonal gammopathy (IgG or IgA) of undetermined significance (MGUS) usually has both proximal and distal weakness with motor and sensory impairment indistinguishable clinically and electrophysiologically from typical CIDP (Joint Task Force of the EFNS and the PNS, 2010).

Multifocal Acquired Demyelinating Sensory and Motor Neuropathy Multifocal acquired demyelinating sensory and motor neuropathy (Lewis and Sumner, 1982), sometimes designated by the acronym MADSAM (Saperstein et al., 1999), is probably best categorized as a variant of CIDP. The disorder often initially affects the arms with later spread to distal nerves in the legs, conforming to discrete peripheral nerve distributions. The condition evolves slowly over months to years, and pain and dysesthesia are common, with shock-like radiating pain in the distribution of involved nerves. The hallmark of this neuropathy is its asymmetrical onset, with weakness and sensory loss evolving and accruing over time in the territory of multiple peripheral nerves reminiscent of mononeuropathy multiplex (56). But the frequent findings of raised CSF protein, and primarily demyelinatingremyelinating changes with varying degrees of fiber loss on sural nerve biopsy support an asymmetrical presentation of CIDP (Saperstein et al., 1999). A clinical picture of CIDP evolves within years in about 50% of patients, while the remaining 50% continue to manifest a multifocal distribution of deficits (Viala et al., 2004).

ELECTRODIAGNOSTIC STUDIES As originally described, the key to the diagnosis is the presence of focal conduction blocks (not located at common sites of compression) that are of sufficient degree to account for the clinical findings, persisting for months or years at the same sites. The authors defined the conduction block rigorously as a 50% reduction in the amplitude of the evoked response elicited from proximal as compared with distal sites of stimulation. To reduce the chances that a difference in amplitude might stem from increased dispersion of action potentials, they required that the total area beneath the negative spike of the evoked response on proximal stimulation be less than 60% of the area obtained on distal stimulation. In one study, numerous large “onion-bulbs” surrounding small thinly myelinated axons reflecting chronic demyelination/remyelination were identified on a fascicular biopsy of the plexus, thus highlighting the demyelinating pathology (Puwanant and Herrmann, 2012). Thirteen

patients with Lewis-Sumner syndrome (Verschueren et al., 2005) had from one to four definite or probable conduction blocks as defined by the AAN ad hoc criteria (1991) (Table 15.2) (“Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force,” 1991). The median and ulnar nerves were most frequently affected. In this study motor conduction velocities were normal, distal motor responses were normal in 79% of studied nerves, but sensory responses were always reduced in clinically affected territories. In the initial report of Lewis-Sumner syndrome, the electrodiagnostic demyelinating findings typical of CIDP were not identified (Lewis et al., 1982). However, in another study of 11 patients with Lewis-Sumner syndrome, features of demyelination (using the rigorous AAN criteria [1991]) were found in every case in addition to stringently defined partial conduction block and attenuated or absent sensory responses (Saperstein et al., 1999).

Distal Acquired Demyelinating Symmetric Neuropathy DADS neuropathy is characterized by a lengthdependent, chronic, acquired demyelinating distal sensory or sensorimotor polyneuropathy (Katz et al., 2000). In the initial report, two-thirds of the patients with DADS neuropathy had IgM kappa monoclonal gammopathy (designated DADS-M), and 67% of those had anti-MAG antibodies (Katz et al., 2000). This specific combination predicted a poor response to therapy in contrast to patients with DADS without gammopathy (so called DADS-I [idiopathic]), or patients with CIDP (with or without IgM gammopathy). DADS is distinguished clinically from typical CIDP by distally accentuated sensory predominant symptoms. Weakness of toe and foot dorsiflexors, when present, is usually mild (Allen and Parry, 2015). For most individuals with the peripheral neuropathy associated with IgM monoclonal gammopathy and positive anti-MAG antibodies, the manifestations are predominantly sensory (ataxia in 70% and postural tremor in 30%) with motor involvement involving the distal lower extremities in <50%.

ELECTRODIAGNOSTIC STUDIES DADS neuropathy is electrophysiologically distinguished from typical CIDP by fewer conduction blocks and more prominent distal motor latency prolongation (63) (Table 15.9). One study reported disproportionate prolongation of distal motor latencies in 16/21 (76%) nerves in four patients with anti-MAG or antisulfated glucuronyl paragloboside (SGPG) antibodies and

Table 15.9 Nerve conductions in distal acquired demyelinating symmetric (DADS) neuropathy patient (female) age 55; 3-year history of DADS-I

Sensory/ motor S S S M

M

M

M

Nerve/site Median—Digit II Radial—Forearm Sural—Calf Median Wrist Elbow Ulnar Wrist B. Elbow A. Elbow Peroneal Ankle Fib. Head Knee Tibial Ankle Knee

Recording Site

Amplitude (uV,mV)

Normal (uV, mV)

Latency (ms)

Normal (ms)

Conduction velocity (m/s)

Normal (m/s)

Terminal latency index

Wrist Snuff Box Ankle

NR NR NR


12.0
15.0
4.0

NR NR NR

2.8 3.5 4.4

NR NR NR


49
49
39

— — —

APB APB

2.6 2.3


4.0
4.0

16 21.9

4.5 34.2


49

ADM ADM ADM

2.9 2.6 1.2


5.0
5.0
5.0

15.5 22.2 38.7

3.5 28.4 6.1


49
49

EPB EPB EPB

0.6 0.5 0.5


2.5
2.5
2.5

23.4 30.8 33.4

6.6 33.8 34.0


39
39

AH AH

1.0 0.7


2.5
2.5

12.5 18.5

6.6 47.9


39

0.11

0.14

0.11

0.17

The sensory responses are absent throughout and there is no sural sparing. Motor conduction velocities are either slowed to <70% of the LLN (median, ulnar), to 85% LLN (peroneal), or normal (tibial). Distal motor latencies are severely prolonged throughout with low TLI (<0.25) in all nerves tested, highlighting the predilection for distal segment demyelination, the defining electrophysiologic characteristic of DADS. There is no conduction block.

256

M.P. BOWLEY AND D.A. CHAD

proposed that finding a terminal latency index (TLI) of <0.25 in at least two different motor nerves should be indicative of anti-MAG (and anti-SGPG) polyneuropathy (Kaku et al., 1994). The TLI compares distal nerve segment velocity with intermediate segment velocity and is expressed as a ratio: distal velocity [distal distance/distal motor latency]/intermediate segment velocity [motor conduction velocity]. Isoardo et al. (2005) also showed that the probability of establishing the diagnosis of DADS-M (anti-MAG positive) is significantly increased in the setting of a pure sensory clinical presentation, low (<0.25) median and ulnar TLI, and absence of motor responses in the lower limbs (Isoardo et al., 2005). An EFNS-PNS taskforce summarized the electrophysiologic features of DADS neuropathy: patients with DADS-M may meet definite electrophysiologic criteria as delineated by the EFNS criteria for CIDP, with additional specific features in one or more nerves including: uniform symmetrical reduction of conduction velocities, sensory more than motor involvement, disproportionately prolonged distal motor latencies with TLI <0.25 (Table 15.9), absent sural response, rarity of partial motor conduction block, and marked degrees of temporal dispersion (Van den Bergh et al., 2010).

slowing was more prominent in the intermediate than the distal nerve segment, leading to a higher TLI in POEMS than CIDP (Table 15.10); indeed, a TLI
0.38 in the median nerve demonstrated a sensitivity of 70% and specificity of 77% in discriminating POEMS from CIDP (Mauermann et al., 2012). Compared with CIDP patients, those with POEMS demonstrated greater reduction of motor amplitudes and relatively little temporal dispersion, conduction block, or sural sparing. In POEMS syndrome, lower limb nerves were more severely involved than upper limb nerves (Sung et al., 2002) (Table 15.10). Compared with a CIDP control group, POEMS patients showed a greater number of fibrillation potentials in a length-dependent pattern (Mauermann et al., 2012). The pronounced degree of active denervation correlated with histopathologic studies of POEMS showing sural nerve biopsies with increased rates of active axonal degeneration compared to biopsies from CIDP patients (Piccione et al., 2016). In contrast to CIDP, where the pathology has a predilection for proximal and distal portions of the peripheral nervous system, in POEMS it has been suggested that the electrophysiologic and histopathologic findings are more diffusely distributed and more closely approximate uniform demyelination (Mauermann et al., 2012).

The Polyneuropathy of POEMS POEMS syndrome is a rare multisystem disorder caused by chronic overproduction of proinflammatory and other cytokines, including vascular endothelial growth factor (VEGF). The clinical features include polyneuropathy, organomegaly, endocrinopathy, and M-protein and skin changes (POEMS). Patients with POEMS syndrome present with a polyneuropathy that is similar to CIDP, with chronic and progressive proximal and distal weakness, numbness, tingling, and pain in the lower extremities secondary to a length-dependent polyneuropathy with demyelinating features. Unlike CIDP, POEMS is poorly responsive to traditional immunotherapy, although meaningful improvement has been shown following autologous stem cell transplantation (Karam et al., 2015). POEMS can be difficult to distinguish from CIDP based on clinical and electrophysiologic findings (Piccione et al., 2016).

ELECTRODIAGNOSTIC STUDIES Studies that compared the electrophysiologic findings in POEMS with those found in CIDP detected a number of differences (Mauermann et al., 2012; Sung et al., 2002). While demyelination in CIDP was distributed in a multifocal pattern and involved both the distal and intermediate nerve segments, in POEMS syndrome conduction

Multifocal Motor Neuropathy This disorder is characterized by slowly progressive, asymmetric weakness involving muscles innervated by multiple nerve trunks (Parry and Clarke, 1988; Pestronk et al., 1988). There is often a predilection for upper limb involvement, and sensory symptoms are scant or absent. Muscle cramping, fasciculations, and atrophy commonly occur. In contrast to the clinical findings in motor neuron disease, there is no evidence for upper motor neuron involvement. Multifocal motor neuropathy (MMN) more often affects men than women (2.7:1), usually presenting between the third and sixth decades of life, and it is rare over the age of 70 (Cats et al., 2010; Nowacek and Teener, 2012). Many patients with MMN will have high titers of serum IgG and IgM GM1 or asialo-GM1 ganglioside antibodies (Pestronk et al., 1988), underscoring the suspected immune-mediated nature of this disease. CSF analysis is often normal though a mildly elevated total protein has been observed (Chaudhry et al., 1994). MMN does not respond to immunomodulatory therapy such as prednisone and plasmapheresis; however, most patients respond to intravenous immunoglobulin (IVIg) (Cats et al., 2010), and some to high-dose cyclophosphamide (Pestronk et al., 1988).

Table 15.10 Nerve conductions in the polyneuropathy of POEMS syndrome in a 44-Year-old female; disease duration 3 years Sensory/ motor S S S M

M

M M M M

Nerve/site Median— Digit II Ulnar— Digit V Sural— Calf Median Wrist Elbow Ulnar Wrist B. Elbow A.Elbow Peroneal Fib. Head Peroneal Ankle Tibial Ankle

Recording site

Amplitude (uV,mV)

Normal (uV,mV)

Latency (ms)

Normal (ms)

Conduction velocity (m/s)

Normal (m/s)

Duration (ms)

Normal (ms)

Terminal latency index

Wrist

NR


12.0

NR

3.2

NR


49

—

—

—

Wrist

2.8


10.0

3.7

2.8

43.1


49

—

—

—

Ankle

NR


4.0

NR

4.4

NR


49

—

—

—

APB APB

6.0 6.3


4.0
4.0

5.0 11.4

4.5

6.1 7.0

0.36


49

6.6

33.0

ADM ADM ADM

7.8 4.0 3.5


5.0
5.0
5.0

3.5 9.4 12.0

3.5

5.9 6.8 6.9

0.50


49
49

6.7

34.0 39.2

TA

NR


5.0

NR

6.6

NR


39

NR

—

—

EDB

NR


2.5

NR

6.6

NR


39

NR

—

—

AH

NR


2.5

NR

6.6

NR


39

NR

—

—

There is generalized sensory involvement; sural sparing is not seen. Motor responses are preserved for the median and ulnar nerves; somewhat atypical for POEMS is conduction block (ulnar); and motor responses are absent for the peroneal and tibial nerves, highlighting the predilection for this disease to have elements of length-dependent motor axonopathy. Conduction velocities are reduced to <70% LLN (median, ulnar) while distal motor latencies are normal (ulnar) or mildly prolonged (median) such that the TLI is >0.38 (ulnar) or just slightly below (0.36, median).

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ELECTROPHYSIOLOGIC STUDIES Identification of the demyelinating features of multifocal motor neuropathy is of critical importance, as the clinical presentation of this treatable disease may be indistinguishable from lower motor neuron predominant forms of motor neuron disease (amyotrophic lateral sclerosis). Abnormalities along motor nerves involve a combination of findings, including partial conduction block, prolonged CMAP duration, slowing of motor conduction velocity, prolonged distal motor latencies, and prolonged F-wave latencies. No single electrophysiologic abnormality is seen in all cases of MMN, though the hallmark finding is considered to be partial conduction block. This is defined as a reduction in CMAP amplitude and area across a standard nerve segment (other than an entrapment site), without evidence of abnormal temporal dispersion (see Fig. 15.3). The degree of amplitude loss necessary to define partial conduction block in MMN

5 mV

3 ms

W

E

Distance (cm)

Distal latency (ms)

Amplitude (mV)

Area (mV/ms)

Duration (ms)

Wrist (W)

6

2.7

11.1

29.9

4.3

Elbow (E)

19

6.9

1.5

4.3

4.6

Fig. 15.3. Median motor conduction study in a patient with multifocal motor neuropathy: A median CMAP is recorded from the abductor pollicis brevis muscle following distal stimulation at the wrist (W) and more proximal stimulation at the antecubital fossa (E). The distal CMAP is normal in amplitude (normal >4 mV), area, latency (normal <4.5 ms), and duration (normal <6.5 ms). There is a marked reduction in CMAP amplitude (86.5%) and area (85.6%) with proximal stimulation indicative of partial conduction block due to focal demyelination along this nerve segment. This reduction in amplitude cannot be accounted for by temporal dispersion as the CMAP duration is essentially unchanged.

(and in other acquired demyelinating neuropathies) is a point of contention among electromyographers and across studies (Cornblath et al., 1991; Chaudhry et al., 1994; Cats et al., 2010). Computer models suggest that decrements in CMAP amplitude up to 50% may occur through physiologic phase cancellation of motor unit action potentials over increasing nerve segment length or with loss of the fastest conducting fibers with axonal degeneration (Rhee et al., 1990). Therefore the greatest confidence in the presence of conduction block requires a reduction in CMAP amplitude of more than 50%. This is the definition favored in diagnostic criteria for MMN offered by the EFNS/PNS (Joint Task Force of the EFNS and the PNS, 2010). The earliest descriptions of MMN (Parry and Clarke, 1988; Pestronk et al., 1988) met this level of electrophysiologic rigor with regard to partial conduction block; however, subsequent studies have not found partial conduction block to be a universal phenomenon in MMN in patients who otherwise present with a typical clinical pattern (including response to immunotherapy) and other signs of demyelination on electrophysiologic testing (Chaudhry et al., 1994; Katz et al., 1997). This may be due to several factors. Conduction block may be present in some nerves but only at proximal segments, and thus it is missed on standard electrophysiologic testing (Parry and Clarke, 1988). Transient conduction block triggered by exercise has also been reported, and thus may be missed with traditional testing during rest (Nodera et al., 2006). Most commonly, reductions in CMAP amplitude across nerve segments are between 20% and 50% of the distal CMAP amplitude and are thus termed possible motor conduction block. In case series of patients with MMN, conduction block is observed in at least one nerve in 31%–71% of patients, and possible conduction block (without definite conduction block) in 16%–38% of patients (Katz et al., 1997; Cats et al., 2010). The ulnar and median nerves are most often affected (Chaudhry et al., 1994; Katz et al., 1997; Cats et al., 2010). When possible conduction block is detected, inching studies showing a focal lesion may provide supportive evidence for an acquired demyelinating lesion. Alternatively, combining evidence of possible motor conduction block with other features of demyelination, such as temporal dispersion, prolonged distal motor latency, slowed motor conduction velocities, or prolonged F-wave minimal latencies, reliably provides electrophysiologic support for the diagnosis. Even in the absence of conduction block, other electrophysiologic abnormalities supporting demyelination are typically seen. Slowing of motor conduction velocities (less than 70% of the LLN) and temporal dispersion (with the proximal CMAP duration being more than

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY 130% that of the distal CMAP duration) are the most common findings in approximately 80% and 50% of patients (Chaudhry et al., 1994; Katz et al., 1997). Sensory responses in MMN should be preserved, especially early in the disease course. When there are multifocal reductions in sensory response amplitudes in a patient with a clinical presentation consistent with MMN, the CIDP variant MADSAM should be considered. The clinical and electrophysiologic distinction between MMN and MADSAM is important, as treatment options differ. Several small case series in MMN have shown that patients with longstanding disease may show reductions in sensory response amplitudes, despite a paucity of objective sensory symptoms on examination. Axon loss is also a common feature in MMN (Katz et al., 1997; Cats et al., 2010). In one small study of 16 patients with MMN, 50% of patients had at least one nerve with a pure axonal lesion and 81% had at least one nerve with mixed axonal and demyelinating features (Katz et al., 1997). Findings on needle electromyography will vary depending on the extent of axonal injury in a given case of MMN. Where demyelination predominates, needle EMG may be largely normal or show only reduced recruitment of morphologically normal MUPs on activation of affected muscles. Where axonal degeneration and muscle atrophy have occurred, EMG evidence of chronic and/or active motor axon loss may be observed.

PATHOPHYSIOLOGY The pathogenesis of MMN remains incompletely understood, though the association of MMN with anti-GM1 autoantibodies and the positive response to intravenous immunoglobulin in the clear majority of patients strongly favors an immune-mediated etiology. The GM1 gangliosides have increased expression in the terminal loops of paranodes and the axolemma at nodes of Ranvier and are thought to play a role in stabilizing paranodal junctions and supporting the clustering of ion channels at the nodes. Binding of anti-GM1 autoantibodies is therefore thought to disrupt paranodal architecture and axonal permeability at the nodes of Ranvier, thus altering saltatory conduction and jeopardizing axonal integrity. Anti-GM1 antibodies may also stimulate complement pathways, leading to formation of membrane attack complexes and complement mediated damage to axons (Vlam et al., 2013).

DIABETIC POLYNEUROPATHY Diabetes is the most common cause of length-dependent, symmetric polyneuropathy in the developed world (Dyck et al., 1993b). Risk of polyneuropathy is, in part, correlated with the duration of disease, averaged

259

hemoglobin A1c, and earlier age at diabetes onset (Dyck et al., 2006). The severity of polyneuropathy is associated with higher hemoglobin A1c, presence of microvascular disease (retinopathy and nephropathy), and type of diabetes (Dyck et al., 1999).

Electrophysiologic studies Diabetic polyneuropathy is primarily an axonopathy (Dyck et al., 1986), with nerve fiber degeneration leading to reductions in sensory and motor response amplitudes on electrophysiologic testing. However, electrophysiologic and pathologic features attributed to demyelination are well reported (Lamontagne and Buchthal, 1970; Behse et al., 1977; Herrmann et al., 2002). Slowing of motor conduction velocities in the lower more than the upper extremities, along with reductions in distal lower extremity sensory response amplitudes, can be the earliest electrophysiologic features of polyneuropathy, even in asymptomatic patients (de Souza et al., 2015). The degree of motor conduction slowing is typically 10%– 30% below the LLN, and thus is not in the traditional range seen in acquired inflammatory neuropathies (Table 15.11). With clinical evolution from asymptomatic to symptomatic nerve disease, prolongation in sensory latencies, prolongation in distal motor latencies, slowing in sensory conduction velocities, and attenuation in motor response amplitudes are subsequently seen (de Souza et al., 2015). Nerve conduction abnormalities are dependent on the degree of glycemic control (Kikkawa et al., 2005). Serial studies of diabetic patients immediately prior to, then 4 weeks after, induction of intense insulin therapy have shown reversibility of some abnormal electrophysiologic parameters associated with demyelination, including improved sensory and motor conduction velocities and prolonged sensory latencies. Long-term glycemic control continues this trend with a 1% change in hemoglobin A1c being associated with a 1.3 m/s improvement in motor nerve conduction velocity (Amthor et al., 1994). The cause of the observed electrophysiologic demyelinating features in diabetic polyneuropathy is complex and incompletely understood, likely with both metabolic and ischemic origins. Experimental models in diabetic rats have shown how persistent hyperglycemia leads to a number of ultrastructural changes in myelinated nerve fibers and may cause the conduction velocity slowing observed in diabetic polyneuropathy by “axo-glial dysjunction” (Sima et al., 1986, 1988). It is postulated that the changes in both the axon and Schwann cells at the paranodes disrupt salutatory conduction and lead to the selective conduction slowing in large myelinated fibers seen on nerve conduction studies.

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Table 15.11 Nerve conductions in diabetic polyneuropathy, male, age 57 Sensory/ motor Nerve/site

Recording site

Amplitude (uV,mV)

Normal (uV, mV)

Latency (ms)

Normal (ms)

Conduction Normal velocity (m/s) (m/s)

S S M

Wrist Wrist

2.7 3.6


12.0
10.0

3.5 3.4

3.2 2.8

43.8 40.6


49
49

APB APB

6.3 5.9


4.0
4.0

3.4 8.8

4.5 40.6


49

ADM ADM ADM

8.6 7.5 6.9


5.0
5.0
5.0

2.9 7.9 10.5

3.5 45.5 38.4


49
49

M

Median—Digit II Ulnar—Digit V Median Wrist Elbow Ulnar Wrist B. Elbow A. Elbow

Sensory responses are reduced while motor responses are preserved in amplitude, consistent with the sensory predominant nature of classic diabetic polyneuropathy. Motor conduction velocities, however, reveal a demyelinating component with mild to moderate slowing (80% LLN [median], 85% LLN [ulnar]) that does not meet the EFNS velocity criterion for acquired inflammatory polyneuropathies.

CMT DISEASE CMT disease refers to a diverse group of inherited polyneuropathies. Mutations in more than 80 genes have been shown to cause CMT, with a prevalence for the disease of 1 in 2500 (Fridman and Reilly, 2015). Demyelinating forms (CMT1) predominate as compared to axonal forms (CMT2). In the past decade, genetic testing has become the definitive diagnostic tool for the identification of hereditary polyneuropathies. Four demyelinating subtypes (CMT1A, CMT1X, hereditary neuropathy with liability to pressure palsies, and CMT1B) represent 88% of genetically identifiable hereditary neuropathies (Saporta et al., 2011). CMT1A results from a duplication of the PMP22 gene on chromosome 17 and is the most common identifiable form of CMT in approximately 55% of patients. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominantly transmitted disorder due to deletions in the same PMP22 gene and is observed in 9% of hereditary neuropathy patients. CMT1X is an X chromosome–linked disorder due to mutations in the gap junction beta-1/connexin 32 gene, and CMT1B is caused by mutations in myelin protein zero on chromosome 1, representing 15% and 9% of cases of genetically identifiable CMT, respectively. The remaining discussion will focus on these four subtypes of hereditary demyelinating polyneuropathy.

CMT1A The classic clinical presentation of autosomal dominant CMT1A is one of slowly progressive weakness beginning in childhood or adolescence, though adult-onset cases have been reported. The distal lower extremities are affected early and may be associated with

characteristic morphological features including distal muscle atrophy in the lower legs (inverted “champagne bottle” legs), high arched feet (pes cavus), or fixed flexion of the proximal interphalangeal joints of the toes (hammer toes) (see Fig. 15.4). Motor weakness due to preferential atrophy of peroneal innervated muscles leads to foot drop, a steppage or foot-slapping gait, frequent tripping, and falls; hand intrinsic muscle atrophy and weakness may also occur; proximal muscles are almost always preserved and retained ambulation (often with the aid of ankle-foot orthoses) is seen in the vast majority of cases. Deep tendon reflexes will be reduced or absent in most patients.

CMTX Not surprisingly, the X-linked nature of this hereditary neuropathy results in prominent symptoms in males and variable expression in female carriers. No male-tomale transmission should be seen in the family pedigree. Males typically present with classic features of CMT as described previously, typically in the second decade of life. Symptomatic female carriers will usually develop symptoms later in life and have a variable severity, and may even be asymptomatic (Wang and Yin, 2016).

HNPP This neuropathy does not follow the traditional presentation of CMT. Patients are initially asymptomatic and instead present with recurrent episodes of painless numbness and weakness from a mononeuropathy or multiple mononeuropathies involving nerves commonly prone to entrapment. Median neuropathy at the wrist (carpal tunnel syndrome), ulnar neuropathy at the elbow, radial neuropathy at the spiral groove, common peroneal

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY

A

261

B

Fig. 15.4. Characteristic morphological deformities of the foot in Charcot–Marie–Tooth disease. Hammertoe (A) and high-arched (pes cavus; B) foot deformities are important clinical signs in many patients with hereditary polyneuropathy. The cause of these morphologic changes is not completely understood, though a disparity between agonist and antagonist forces acting across the joints of the ankle and foot over a span of time with plantar-flexion exceeding dorsiflexion is suspected.

neuropathy at the fibular head, and brachial plexus injury from use of a backpack may all occur. Complete recovery can occur, typically over a period of weeks.

CMT1B This autosomal dominant form of CMT is often clinically indistinguishable from that of CMT1A. One exception is the presence of pupillary abnormalities, typically Adie’s tonic pupil in patients with select mutations in the myelin protein zero gene (Hattori, et al., 2003).

Electrophysiologic studies Though genetic testing is the definitive form of diagnosis for CMT, electrophysiologic testing is still an integral tool in the evaluation of patients with suspected hereditary neuropathy. Abnormalities on testing combined with clinical features may help narrow testing to specific genetic targets.

CMT1A CMT1A is most readily defined by the degree of motor conduction velocity slowing in the median or ulnar nerves of less than or equal to 38 m/s (Table 15.12). In one series of 118 patients with CMT1A, the median motor conduction velocity was 21 m/s with a unimodal distribution (Hattori, et al., 2003). The degree of motor conduction velocity slowing develops and reaches its nadir early (in the first 3–5 years of life) and is constant and stable thereafter (Garcia et al., 2000), regardless of CMAP amplitude. This slowing in motor conduction velocity is also classically uniform in all segments (proximal, distal, and intermediate) of nerves studied, generalized and symmetrical, in contrast to the differential slowing and multifocal involvement in cases of acquired demyelinating neuropathy, as seen in CIDP (Lewis and Sumner, 1982). The uniform nature of this slowing also

makes other features of acquired demyelination, such as partial conduction block or temporal dispersion, less common, though cases of genetically confirmed CMT1A with these features have been reported (Hoogendijk et al., 1992; Oh, 1992). Prolongation of distal motor latencies may be the earliest feature of demyelination, being reported as abnormal in patients as young as 1 year of age, even prior to onset of motor conduction velocity slowing (Garcia et al., 2000). Other electrophysiologic features of demyelination, including prolonged F-wave minimal latencies, are often observed. Sensory responses are often absent in the lower extremities and when present are reduced in amplitude with prolonged peak latencies and slowed conduction velocities. Likewise, motor response amplitudes decline with age and disease duration (see Table 15.12) (Hattori, et al., 2003). Needle examination of distal muscles shows fibrillation potentials; voluntary activity is characterized by reduced recruitment of high-amplitude, longduration MUPs.

CMTX Specific electrophysiologic features help differentiate CMTX from CMT1A. Most important, the degree of motor conduction velocity slowing in male patients is often in an intermediate range, falling between the marked slowing typical of CMT1A patients and the near-normal conduction velocities seen in axonal CMT2 patients. Typical motor conduction velocities in the upper extremities are between 30 and 40 m/s. In females, who are often less affected, motor conduction velocities show even more mild degrees of slowing and may even be in the normal range (Hahn et al., 1990; Hattori, et al., 2003). An additional electrophysiologic feature of CMTX is a nonuniform, heterogeneity of motor conduction

Table 15.12 Nerve conductions in Charcot-Marie-Tooth disease Type 1A (PMP22 gene duplication), male, age 48

Sensory/ motor S S S S M

M

M

M M

Nerve/site Median—Digit II Ulnar—Digit V Radial—Forearm Sural—Calf Median Wrist Elbow Ulnar Wrist B. Elbow A. Elbow Peroneal Fib. Head Knee Peroneal Ankle Tibial Ankle

Recording site

Amplitude (uV,mV)

Normal (uV, mV)

Latency (ms)

Normal (ms)

Conduction velocity (m/s)

Normal (m/s)

F Wave Latency (ms)

Normal (ms)

Wrist Wrist Snuff Box Ankle

NR NR NR NR


12.0
10.0
15.0
4.0

NR NR NR NR

3.2 2.8 3.5 4.4

NR NR NR NR


49
49
49
49

— — — —

— — — —

APB APB

2.3 1.5


4.0
4.0

11.3 28.1

4.5

89.2

31.0

16.1


49

ADM ADM ADM

7.3 4.0 2.4


5.0
5.0
5.0

4.7 19.9 26.0

3.5


49
49

—

—

18.2 16.2

TA TA

4.8 4.2


5.0
5.0

8.2 12.7

6.6


39

—

—

22.3

EDB

NR


2.5

NR

6.6

—

—

NR

56.0

AH

NR


2.5

NR

6.6

—

—

NR

61.0

Motor conduction velocities are markedly and uniformly slow (between 16 and 22 m/s). Distal motor latencies and minimum F-wave latencies (when present) are likewise prolonged. The sensory responses are absent throughout (sural, median, ulnar, and radial); motor responses are affected in a length-dependent fashion (absent peroneal-EDB and tibial-AH, while preserved peroneal-tibialis anterior) stemming from the motor axon loss that occurs in the setting of longstanding disease.

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY velocity slowing between nerves as well as along individual nerves in select patients (Gutierrez et al., 2000). Motor conduction velocities may vary markedly (between 19 and 54 m/s) among nerves in affected male or female patients. Evaluation of the TLI, a metric that judges the uniformity of slowing between proximal and distal portions of a motor nerve, as discussed earlier, may likewise be quite variable, with both low and high values well beyond that found in CM1A, reflecting preferential slowing in both distal and proximal portions of individual nerves in some patients. Underscoring this heterogeneity of demyelination, poor concordance for motor conduction velocities among siblings has been reported (Hattori, et al., 2003). Similar to CMT1A, distal motor and sensory response amplitudes decline with increasing age and disease duration (Hattori, et al., 2003).

HNPP HNPP is characterized by conduction slowing, conduction block, and temporal dispersion across common sites of nerve entrapment. The most commonly affected nerves vary among studies but median neuropathy at the wrist, ulnar neuropathy at the cubital tunnel, and peroneal neuropathy at the fibular head are often cited (Amato et al., 1996; Hirota et al., 1996; PotulskaChromik et al., 2014). However, in both symptomatic patients and asymptomatic family members, evidence of a generalized polyneuropathy with some demyelinating features is often seen. In fact, an electrophysiologic picture of a generalized neuropathy with multiple concomitant entrapments should raise the index of suspicion for HNPP. Demyelination appears to be mostly distal, with prolonged distal motor latencies out of proportion to mild slowing in motor conduction velocities, and reduced terminal latency indices (Amato et al., 1996; PotulskaChromik et al., 2016). These findings are not dependent on the presence of entrapment neuropathy. Minimum F-wave latencies are often prolonged (Hirota et al., 1996). Sensory studies show prolonged peak latencies and slowed conduction velocities. Sensory and motor amplitudes may be normal or decreased (Amato et al., 1996).

CMT1B CMT1B patients may be divided into two distinct electrophysiologic populations (Hattori, et al., 2003). The first group shows great similarity to CMT1A with a uniform, primary demyelinating electrophysiologic pattern with upper extremity motor conduction velocities 38 m/s. The second group, with conduction velocities
38 m/s, has a more axonal electrophysiologic pattern.

263

Whether a patient expresses a primary axonal or demyelinating pattern appears related to the position of the mutation in the MPZ gene.

TOXIC DEMYELINATING NEUROPATHIES Toxic demyelinating neuropathies result from exposure to a variety of substances, including select medications (amiodarone), industrial agents (n-hexane), and environmental toxins (arsenic, Karwinskia humboldtiana fruit, saxitoxin, tetrodotoxin). Neuropathy as a result of any of these causes is uncommon, though it is important to be aware of such pathogens, as many of these neuropathies are reversible when the toxic agent is identified and removed. Our detailed understanding of the electrophysiologic features of toxic neuropathies falls far short of the more common forms discussed in earlier sections. What follows are some important clinical and electrophysiologic hallmarks for these varied toxic demyelinating neuropathies.

Medications Amiodarone is a class III antiarrhythmic agent used to treat both ventricular and atrial arrhythmias. A variety of neurotoxic complications are associated with amiodarone use, including tremor, ataxia, optic neuropathy, myopathy, and a polyneuropathy (Palakurthy et al., 1987). The polyneuropathy may mimic that of Guillain-Barre syndrome or may be more insidious in onset with chronic exposure to the drug. Case series with details of the electrophysiology of amiodarone-mediated neuropathy indicate a mixed picture of demyelinating and axonal features (Martinez-Arizala et al., 1983; Fraser et al., 1985; Palakurthy et al., 1987). Sensory responses are typically absent or attenuated in amplitude with prolonged peak latencies. Distal motor latencies are prolonged in the lower more than upper extremities, with mild to moderate slowing of conduction velocities (in some cases, firmly in the demyelinating range) (Charness et al., 1984). Needle examination will often show active denervation (Martinez-Arizala et al., 1983), underscoring the motor axonopathy component of this toxic neuropathy. With discontinuation of the drug, amiodarone neuropathy improves clinically and electrophysiologically over months in most patients, though the improvement may be incomplete (Fraser et al., 1985).

Industrial agents Hexacarbons are currently used in industry as degreasing solvents, as well as in household glues; exposure (occupational or recreational) occurs via inhalation. Patients exposed to n-hexane report symmetric distal weakness

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in the legs, typically with variable sensory symptoms such as paresthesias or burning pain (Herskowitz et al., 1971; Paulson and Waylonis, 1976). On examination, distal more than proximal leg weakness is observed, along with reduced vibratory sensation, and areflexia. Nerve conduction studies reveal variable results, with prolonged distal motor latencies and motor conduction velocities showing intermediate slowing (30 m/s in lower extremities; 40 m/s in upper extremities), or more marked slowing similar to that of inflammatory demyelinating polyneuropathies (Herskowitz et al., 1971; Paulson and Waylonis, 1976). Temporal dispersion and partial conduction block have also been reported in select patients (Paulson and Waylonis, 1976; Pastore et al., 2002). Needle electromyography shows a neurogenic pattern of reduced recruitment of MUPs. Abnormal spontaneous activity indicating acute denervation is also observed in distal muscles of the arms and legs. Peripheral nerve biopsies likewise show a mix of axonal degeneration and demyelination (Herskowitz et al., 1971).

Environmental exposures K. humboldtiana (also referred to as buckthorn, coyatillo, tullidora, wild cherry, and cacatsi) is found in southern and western Texas, the Caribbean, Central America, and parts of Columbia. Poisoning following ingestion of this plant’s black, ovoid, drupe fruit is associated with progressive, ascending weakness that, over days, may lead to areflexia and marked limb weakness. The clinical presentation closely mimics that of GBS with symmetric progressive weakness over days. In severe cases, tetraplegia, bulbar weakness, and respiratory failure leading to death may occur. However, with supportive care, a spontaneous recovery is likely. Children are most often affected in the setting of accidental ingestion, with symptom onset beginning within 2–3 weeks of exposure. Weakness may be preceded by respiratory or gastrointestinal symptoms (Martínez et al., 1998). Correct diagnosis can be challenging, especially when no historical cues suggesting fruit ingestion are available. CSF evaluation shows normal glucose, total protein, and no white cells. Serologic testing for the toxins of K. humboldtiana has been developed. Details regarding the abnormalities on nerve conduction studies and needle electromyography for K. humboldtiana neuropathy are quite sparse, as this is a relatively rare cause of neuropathy, further limited by its restriction to select areas of North, Central, and South America. Overall, neuropathy with marked demyelinating features has been observed. Motor studies will be abnormal with marked slowing in motor conduction velocities between 40% and 60% of the LLN, as well as prolonged distal motor latencies firmly in the

demyelinating range. In one series of 6 children affected by K. humboldtiana neuropathy, all 6 patients had 100% or greater prolongations in distal motor latencies (Martínez et al., 1998). F waves have been absent or have shown marked latency prolongation. The degree of reduction in distal CMAP amplitude will vary depending upon the severity of the illness; any diminution or loss in CMAP amplitude stems from demyelination (partial conduction block) or axonal degeneration, or both. With regard to the latter, serial needle electromyography may show abnormal spontaneous activity indicative of acute denervation, but this is not thought to portend a poorer recovery. Nerve biopsies in both human and animal studies underscore the demyelinating nature of this neuropathy. Extensive segmental demyelination is typically observed, as is swelling of Schwann cells (Martínez et al., 1998). Axonal degeneration is mild in comparison and can be seen concurrent with demyelination or in the presence of intact myelin sheaths. Thus the targets of K. humboldtiana toxicity are likely both Schwann cells and axon elements. Arsenic is a heavy metal associated with homicidal and suicidal poisonings, industrial exposures (e.g., lead and copper smelting) and environmental exposures (e.g., contaminated well water, wood preservatives, and contaminated fossil fuels) (London and Albers, 2007). Acute exposure to arsenic is initially associated with gastrointestinal symptoms of nausea, vomiting, and diarrhea, then followed by multiorgan disease that may include skin desquamation as well as cardiac, hepatic, renal, and pulmonary dysfunction. Neuropathy may follow 7–14 days after arsenic exposure with sensory paresthesias and variable degrees of distal more than proximal weakness and areflexia. Neuropathy can progress to respiratory weakness and death in severe cases (Chhuttani et al., 1967). Electrophysiologic testing in arsenic neuropathy shows variable findings depending on the timing of studies. Early findings within 1 week of neuropathic symptom onset may mimic GBS, showing reduced or absent sensory responses, prolonged F-wave minimal latencies, and mild to moderate slowing in motor conduction velocities and partial conduction block, predominantly in the lower extremities. Over the ensuing 1–2 weeks, more marked motor conduction slowing and conduction block may be seen, along with progressive attenuation of distal CMAP amplitudes (Donofrio et al., 1987). Chronic exposure may appear as a symmetric sensorimotor axonal polyneuropathy suggestive of severe distal denervation. Electrophysiologic studies are not specific for arsenic toxicity, and serum studies are unreliable due to rapid clearance from the blood; 24-h urine arsenic levels and testing of hair or nails are of greater value (London and Albers, 2007).

CLINICAL NEUROPHYSIOLOGY OF DEMYELINATING POLYNEUROPATHY

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FURTHER READING Kaplan A, Brannagan TH (2017). Evaluation of patients with refractory chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 55 (4): 476–482.