Muscle & Nerve

MUSCLE & NERVE

Invited Review

Pathophysiology of Immune-Mediated Demyelinating Neuropathies—Part II: Neurology

Hessel Franssen, MD, PhD, and Dirk C.G. Straver, MD

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CME Credit Available Free to AANEM members See instructions on the Journal CME Guide page. Pathophysiology of Immune-Mediated Demyelinating Neuropathies — Part II: Neurology Hessel Franssen, MD, PhD, and Dirk C.G. Straver, MD Department of Neurology, Section Neuromuscular Disorders, F02.230, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands

No one involved in the planning of this CME activity had any relevant financial relationships to disclose. (Authors/Faculty had nothing to disclose)

Reviewed and accepted by the 2013-2014 Monograph/Issues and Opinion Committee of the American Association of Neuromuscular & Electrodiagnostic Medicine

Certified for CME credit 01/2014 – 01/2017

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The ideas and opinions in this monograph are solely those of the author and do not necessarily represent those of the AANEM. AANEM Invited Review #46 CME STUDY GUIDE Pathophysiology of Immune-Mediated Demyelinating Neuropathies — Part II: Neurology

Hessel Franssen, MD, PhD, and Dirk C.G. Straver, MD Department of Neurology, Section Neuromuscular Disorders, F02.230, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands

EDUCATIONAL OBJECTIVES Upon completion of this monograph, the reader will acquire skills to: (1) review the pathophysiology of Guillian-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, anti-myelin associated glycoprotein neuropathy, and POEMS syndrome and (2) receognize the pathophysiology of select immune-mediated demyelinating neuropathies

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Monographs published by the AANEM are reviewed every 3 years by the AAEM Education Committee for their scientific relevance. CME credit is granted for 3 years from the date of publish, review, or revision date. Individuals requesting credit for monographs that have been discontinued will be notified that CME credit is no longer available.

INSTRUCTIONS The reader should carefully and thoroughly study the monograph. If further clarification is needed, the references should be consulted. Do not neglect illustrative material. To obtain CME: 1. Go to www.aanem.org/Marketplace. 2. Add specific Journal Review to cart. 3. Checkout - Upon checkout an email will be sent directly to you with a CME survey link. - Click on the link; complete the survey; and print your transcript. - AANEM’s CME transcripts will update automatically. INVITED REVIEW PATHOPHYSIOLOGY OF IMMUNE-MEDIATED DEMYELINATING NEUROPATHIES—PART II: NEUROLOGY HESSEL FRANSSEN, MD, PhD, and DIRK C.G. STRAVER, MD Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Accepted 26 August 2013

ABSTRACT: In the second part of this review we deal with the (IUPHAR) Compendium of Voltage-Gated Ion clinical aspects of immune-mediated demyelinating neuropathies. 2 We describe the relationship between pathophysiology and Channels. symptoms and discuss the pathophysiology of specific disease entities, including Guillain–Barre syndrome, chronic inflammatory RELATIONSHIP BETWEEN PATHOPHYSIOLOGY AND demyelinating polyneuropathy, multifocal motor neuropathy, SYMPTOMS IN IMMUNE-MEDIATED NEUROPATHY anti–myelin-associated glycoprotein neuropathy, and POEMS syndrome. Selective Involvement of Motor Nerve Fibers and Pure Muscle Nerve 000:000–000, 2013 Motor Neuropathy. Selective involvement of motor axons at the peripheral nerve level, such as in MMN and AMAN, is not well understood, because individ- ual peripheral nerve fascicles contain motor as well In the accompanying article (part I), we discussed as sensory axons.3 The research to explain this selec- the normal physiology of myelinated axons and tivity was directed to differences in immunological the pathophysiology of immune-mediated neuropa- and ion channel properties between motor and sen- thies.1 In this article we deal with the relationship sory fibers. One of the problems in immunological between pathophysiology and symptoms and spe- research is that motor and sensory axons can only cific disease entities. The latter include Guillain– be distinguished with certainty at the root level. Barre syndrome (GBS), chronic inflammatory With less certainty, peripheral nerve motor axons demyelinating polyneuropathy (CIDP), multifocal can be identified by staining of cholinacetyltransfer- motor neuropathy (MMN), anti–myelin-associated ase (ChAT), which is expressed on the axolemma of glycoprotein (MAG) neuropathy, and the syn- motor axons only. ChAT expression varies, however, drome of polyneuropathy, organomegaly, endocri- so that motor axons with weak staining cannot nopathy, M-protein, and skin changes (POEMS always be distinguished from sensory axons that do syndrome). The GBS subtypes acute inflammatory not stain (reviewed by Castro et al.4). demyelinating polyneuropathy (AIDP) and acute The amount of antigen may differ between motor axonal neuropathy (AMAN) will both be motor and sensory axons. One study showed that discussed, because their features overlap and human lumbar motor root fibers contained more because AMAN also affects paranodal myelin and GM1 than sensory root fibers, suggesting that molecules which connect terminal Schwann cell motor fibers are more vulnerable to anti- loops to the axon. Ion channels are named by the ganglioside antibodies due to a higher amount of channel name (not the gene name) as given in antigen.5 However, other studies did not confirm the International Union of Pharmacology this difference.6–8 Motor fibers may be targeted selectively Abbreviations: AIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor and sensory because their gangliosides have a slightly different axonal neuropathy; Caspr-2, contactin-associated protein-2; ChAT, choli- molecular composition than the same type of gan- nacetyltransferase; CIDP, chronic inflammatory demyelinating polyneuropathy; CMAP, compound muscle action potential; DML, distal motor glioside in sensory fibers. The ceramide portion of latency; GBS, Guillain–Barre syndrome; HCN, hyperpolarization-activated gangliosides GM1, GD1a, and GD1b in motor roots cyclic nucleotide-gated; IVIg, intravenous immunoglobulin; MAG, myelin- associated glycoprotein; MCV, motor conduction velocity; MMN, multifocal contains fewer long-chain fatty acid chains than motor neuropathy; NCS, nerve conduction studies; P0, protein zero; the ceramide portion in sensory roots.9 This differ- PMP22, peripheral myelin protein-22; POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; PSMA, progressive ence, however, does not immediately explain selec- spinal muscular atrophy; SDTC, strength–duration time constant; TAG-1, tive motor involvement, because the ceramide transient axonal glycoprotein-1; VEGF, vascular endothelial growth factor Key words: anti–myelin-associated glycoprotein neuropathy; chronic portion lies in the bilipid membrane, whereas the inflammatory demyelinating polyradiculoneuropathy; Guillain–Barre syn- antibodies bind to the extracellular sugar residues drome; multifocal motor neuropathy; pathophysiology This study was supported by a grant from the Prinses Beatrix Spierfonds of gangliosides. However, the different ceramide (to D.C.G.S). portion in motor axons may change the 3- Correspondence to: H. Franssen; e-mail: [email protected] dimensional configuration of the extracellular VC 2013 Wiley Periodicals, Inc. Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary. sugar portion to make it more susceptible to anti- com). DOI 10.1002/mus.24068 GM1 antibody binding. Several studies showed that

Demyelinating Neuropathies MUSCLE & NERVE Month 2013 1 ganglioside GD1a is selectively targeted in motor fibers. Immunostaining of cross-sectioned fibers by high-affinity IgG anti-GD1a antibodies showed more prominent binding to human motor than to sensory roots, despite the finding that the quantitative GD1a content was similar in motor and sensory roots.8 Also, high-titer anti-GD1a antibodies from a patient with AMAN bound to the nodal region of human motor root fibers but not to that of sensory root fibers.10 Finally, motor axons in the phrenic nerve were more sensitive to GD1a- induced injury by membrane attack complex than sensory axons in the sural nerve.11 Other studies, however, did not support the predominant binding of anti-ganglioside antibodies to motor fibers. One study showed that anti-GM1 antibodies bound equally to motor and sensory root fibers, and another showed that anti-GM1 antibodies from a GBS patient bound more strongly to purified GM1 of sensory rather than motor roots.7,8 Differences in biophysical properties may render motor axons more vulnerable to conduction block than sensory axons when a mixed nerve is affected. Excitability studies have shown that motor axons have a smaller strength–duration time constant (SDTC) and larger rheobase than sensory axons.12 SDTC and rheobase are both derived from the relationship between current strength (I) and duration (t) of stimuli that evoke a predefined nerve response (e.g., a target compound muscle action potential of 50% of maximal). On empirical grounds, the I–t relation is hyperbolic, revealing that stimuli with smaller I values require larger t values (and vice versa) to evoke similar nerve responses. In the I–t relation, rheobase is the theoretical I needed to evoke the response if t is infinitely long, although it should be stressed that strength–duration properties are only valid for short-duration stimuli. SDTC, or chronaxie, is the value of t when I is twice rheo- FIGURE 1. Proposed mechanisms of conduction block in multi- base. Because stimulus charge (Q) 5 I Á t, the I–t focal motor neuropathy (MMN). Dotted lines depict failed generation of inward Na1 current at the node-to-be-activated. (A) relation can be recalculated into a Q–t relation, Demyelination, leading to a reduction in driving current available which is linear and more convenient to analyze. at the node-to-be-activated. This causes block if safety factor SDTC is then given by the x-intercept and rheo- [the ratio: (available driving current) / (required driving current for base by the slope.13 SDTC reflects: (i) the small excitation of a node)] falls below unity. (B) Abnormal resting capacitance of the nodal membrane; and (ii) the membrane potential. Hyperpolarization causes an increase in 1 required driving current and a decrease in safety factor. Depola- amount of persistent Na current. rization will cause inactivation of nodal Na1 channels. (C) Dis- The smaller SDTC in motor axons reflects a ruption of nodal Na1 channels, causing impaired inward Na1 smaller persistent Na1 current because the passive current despite adequate nodal depolarization. nodal properties are similar between motor and sensory axons.14 When the safety factor is reduced due to demyelination (Fig. 1A), conduction may larizing parts of threshold electrotonus and I/V be blocked in motor axons, but may just be main- relation reveal less hyperpolarization-activated tained in sensory axons, because their relatively cyclic nucleotide–gated (HCN) channel activity in large persistent Na1 current contributes to excit- motor than in sensory axons.15 Thus, when nerve ability. The concept of safety factor was discussed pathology results in hyperpolarized axons, only in part I of this review.1 Furthermore, the hyperpo- motor axons may develop hyperpolarizing block,

2 Demyelinating Neuropathies MUSCLE & NERVE Month 2013 because their hyperpolarization is less well counter- axons.20,21 Because conduction failure occurred at acted by HCN channel activity. Finally, refractori- interstimulus intervals that were considerably lon- ness, superexcitability, and subexcitability are all ger than the refractory period, another mechanism more pronounced in motor than in sensory than that responsible for the refractory period axons.12 The mechanism of this difference is not must be involved. well established, but as it concerns all recovery Sustained firing of action potentials induces cycle parameters, its cause may lie in the initial several changes, each of which may cause an addi- event leading to the recovery cycle; that is, the first tional reduction in the already diminished safety change induced by the action potential. A possible factor of demyelinated axons. Short trains of 10– factor may be the longer duration of action poten- 20 impulses cause brief hyperpolarization, because tials in motor versus sensory fibers, as demon- the subexcitable periods after each action poten- strated in the frog.16 The longer duration is due to tial summate.22,23 More prolonged repetitive firing a greater amount of transient, but slowly inactivat- may cause an increase in extra-axonal K1 concen- 1 ing, Na current in motor nodes so that, for each tration and lead to reduced Ek and depolarization action potential, more Na1 ions enter in motor that may first decrease threshold, but ultimately than in sensory axons. It is unclear whether the lead to Na1 channel inactivation and increased difference in action potential size renders motor threshold (Fig. 1B).24,25 Sustained firing also axons more susceptible to conduction block due increases intra-axonal Na1 concentration, which to demyelination. On the one hand, short lasting produces a decreased Na1 concentration gradient, nerve activity leads to summation of subexcitability, decreased Na1 influx during an action potential, and as this is more pronounced in motor axons, and decreased driving current.19 The most impor- short lasting activity-dependent hyperpolarization tant mechanism for rate-dependent block is hyper- will therefore be greater and the safety factor polarization induced by increased activity of the smaller in motor versus sensory axons. On the electrogenic Na1/K1 pump. The latter arises other hand, the larger size of action potentials in because the pump is driven by the large amount motor axons is advantageous, as this contributes to of Na1 ions entering the axon during repetitive the safety factor. firing. The main arguments in favor of this mechanism are that blocking neither arose after Rate-Dependent Block and Activity-Dependent replacement of Na1 ions by Li1 ions in the Weakness. Decreased muscle strength in polyneu- medium nor after topical application of the Na1/ ropathy is usually attributed to loss of axons or K1 pump blocker ouabain.20,21 To depolarize persistent conduction block. It is, however, difficult these hyperpolarized axons to threshold, a larger- to ascribe weakness to one of these mechanisms, than-normal potential difference has to be over- because both may occur in patients with immune- come, which requires extra driving current. In the mediated demyelinating neuropathy. For instance, case of demyelination, this may not be available in a group of MMN patients, loss of axons and not due to leakage of driving current so that conduc- conduction block was the single independent tion may become blocked. In normal subjects, determinant for muscle weakness, despite the fact maximal voluntary contraction induced excitability that all patients had evidence of conduction changes consistent with hyperpolarization block.17 To complicate matters further, other (increased threshold, increased superexcitability, mechanisms may give rise to weakness as well. decreased SDTC), but also increased refractoriness Increased temporal dispersion may desynchronize immediately after maximal voluntary contraction activation of motor units, thereby impairing maxi- that could not be explained by hyperpolariza- mal force production.18 Sustained nerve activity tion.26,27 The increased refractoriness was possibly may induce blocking in axons that were not related to transmission failure in distal axon blocked during short-lasting activity. The latter branches. mechanism, discussed here, is known as rate- In MMN and CIDP patients, rate-dependent dependent block and may produce a temporary block was sought by recording compound muscle increase in weakness after exercise and possibly action potentials (CMAPs) before maximal volun- contribute to fatigue. When single demyelinated tary contraction and at several time-points there- motor axons are stimulated for several minutes at after.28–31 In 2 studies, a specially designed non-physiological frequencies of 80–100 HZ, inter- excitability protocol assessed threshold, superexcit- nodal conduction time gradually increases until ability, and SDTC at 10-s intervals to allow for accu- conduction becomes intermittent or blocked.19 rate following of membrane potential changes.28,29 This rate-dependent block was also demonstrated Maximal voluntary contraction induced a CMAP during stimulation at frequencies of 10–50 HZ, decrease lasting up to 3 minutes. In 1 patient, the which are in the physiological range for motor CMAP evoked proximal to a demyelinating lesion

Demyelinating Neuropathies MUSCLE & NERVE Month 2013 3 was abolished temporarily after maximal voluntary daily life. In clinical research, rate-dependent block contraction, whereas the distal CMAP remained was usually assessed after 1 minute of maximal vol- unchanged.28 These findings were attributed to untary contraction. Again, this hardly occurs in the previously described mechanism for rate- daily life, because forceful muscle contraction is dependent block, because it was paralleled by usually maximal for only a few seconds. changes in excitability indices consistent with rate- dependent hyperpolarization (increase in thresh- Heat Block and Heat Paresis. It is well known that old and superexcitability, decrease in SDTC). symptoms in multiple sclerosis may worsen after a These studies suffered from methodological hot bath.36 In demyelinating neuropathies similar problems, however. In most patients, proximal effects were described. In a patient with CIDP, CMAPs were evoked by magnetic cervical stimula- symptoms considerably increased during fever.37 tion. This carries the risk of being submaximal, Several studies indicated that this so-called “heat and the risk is increased further if activity has paresis” is likely caused by development of conduc- induced hyperpolarization of the axons under tion block in demyelinated axons (heat block). In investigation. The CMAP decrease induced by max- single demyelinated axons, conduction was imal voluntary contraction may therefore be due blocked by a minor temperature increase of 0.5C to submaximal stimulation caused by hyperpolar- and was restored subsequently when temperature ization and not by rate-dependent block. Further- was decreased by 0.5C.38 In 7 patients with various more, criteria for rate-dependent block were not demyelinating neuropathies (CIDP, MMN, or ulnar defined. Because maximal voluntary contraction nerve entrapment at the elbow) neurological defi- also induces temporal dispersion of nerve action cits and signs of conduction block on conventional potentials, assessment of block from the summated nerve conduction studies (NCS) increased after activity of several axons, as is done in CMAP warming to 40C and decreased after cooling to recording, requires criteria to distinguish temporal 20C.39 dispersion from block.30,32,33 Subsequent studies of Heat block is caused by the unfavorable combi- a larger number of nerves in patients with MMN nation of demyelination and temperature increase. or CIDP employed supramaximal electrical stimula- Demyelination results in leakage of the driving cur- tion up to the Erb point and adopted a predefined rent through the demyelinated part of the inter- criterion for activity-dependent block that was node adjacent to the node-to-be-activated. This based on simulations.32,33 The studies showed that leakage leaves less driving current available to maximal voluntary contraction induced increased depolarize the node-to-be-activated. Temperature segmental duration prolongation, indicating increase decreases amplitude and duration of the increased temporal dispersion. Rate-dependent action potential at the active node so that the driv- block according to the predefined criterion was ing current at the node-to-be-activated decreases not observed, except in a nerve segment of a further.40 At critically demyelinated internodes, the patient with CIDP. In agreement with these latter additional reduction in the already diminished studies, high-frequency electrical stimulation of sin- driving current decreases the safety factor below gle sensory axons in CIDP patients induced slow- unity so that conduction will be blocked. ing but no conduction block.34 The decrease in action potential amplitude and A major problem in assessing rate-dependent duration occurring with temperature increase can block by means of CMAP recording is that maxi- be attributed to several factors. First, the time dur- mal voluntary contraction may induce a CMAP ing which Na1 channels are open in response to increase that lasts several minutes. Previously this depolarization (Na1 channel open time) is was only observed in normal subjects and patients shorter. This is because the Q10 of the rate con- with motor neuron disease, but not in MMN or stant for activation of Na1 permeability is smaller CIDP.31 Subsequent studies, however, showed that than that for inactivation.41 Therefore, at higher it also occurred in many demyelinated and non- temperatures, Na1 activation is slightly faster, but demyelinated nerves of MMN and CIDP Na1 inactivation is markedly faster, resulting in patients.32,33 The most likely mechanism for the shortened open time and, consequently, fewer CMAP increase is that voluntary muscle contrac- Na1 ions entering the axon during an action tion increases muscle Na1/K1 pump activity lead- potential. Ultimately, this mechanism may lead to ing to muscle fiber hyperpolarization and larger some Na1 channels entering the fast inactivated muscle fiber action potentials.35 state before they open.42 When, however, tempera- The findings just described raise doubt as to ture in myelinated mammalian axons was raised whether rate-dependent block is clinically relevant. from 20Cto37C, peak Na1 current did not In some single axon recordings it was only decrease but increased slightly.43 This suggests that observed at axonal firing rates that do not occur in other mechanisms also affect driving current when

4 Demyelinating Neuropathies MUSCLE & NERVE Month 2013 temperature is changed, such as alterations in leak- reduced inward current at the active node and a age conductance, bilipid membrane structure, axo- decreased driving current at the node-to-be-acti- 41 1 1 nal resistance, and ENa. Second, the capacitive vated. Thermal reduction in Na /K pump activ- current leak across the internode increases with ity possibly contributes to cold block, as it leads to temperature, resulting in less driving current being depolarization and an increased proportion of available to depolarize the node-to-be-activated. inactivated Na1 channels, making it impossible to 1 Third, the rate constant an for fast K current acti- attain sufficient action current for an action poten- vation increases more prominently with tempera- tial (Fig. 1B). Cold block in demyelinating neuro- 1 ture than the rate constant am for transient Na pathies arises at higher temperatures (up to 16 C) current activation. This was shown for both axonal due to the unfavorable combination of 2 factors and muscle currents.44,45 It implies that an that lead to a reduced driving current: leakage increase in temperature results in faster opening through the damaged myelin and reduced action of both ion channel types, but that this effect is current.53 more prominent in K1 channels (which oppose Complaints of increased weakness during cold the action potential) than in Na1 channels (which were reported initially in a case of MMN.54 Subse- initiate the action potential). In normal mamma- quently, symptoms of cold paresis and heat paresis lian myelinated axons, this difference in rate con- were analyzed by questionnaire in patients with stants is irrelevant, because fast K1 currents are MMN, CIDP, progressive spinal muscular atrophy mediated by juxtaparanodal K1 channels. These (PSMA), and chronic idiopathic axonal polyneu- are covered by myelin and therefore they have no ropathy.55 Cold paresis was experienced by a pro- role in action potential termination.46 When juxta- portion of patients in each group and was paranodal fast K1 channels are exposed by demye- reported more frequently than heat paresis. Most lination, however, they will contribute to action importantly, symptoms of cold paresis occurred potential termination, and, because this contribu- most frequently in MMN (83%), and the odds of tion increases with temperature, they contribute to experiencing cold paresis were 4–6-fold greater for heat block. MMN than for CIDP or PSMA patients. As this The blocking temperature of demyelinated study only assessed subjective symptoms of weak- axons was shown to rise after application of 4-ami- ness, it is necessary to perform force measurements nopyridine.47 This was attributed to an increase in to determine whether cold also induces an objec- safety factor due to augmentation of the driving tive increase of weakness in MMN patients. current, because this was no longer counteracted Although MMN is regarded as a disorder in by K1 channels exposed by demyelination. which demyelination plays a role, cold paresis can- In normal nerves the maximal conduction veloc- not be explained by the previously described ity increases approximately linearly with tempera- demyelinative conduction block, as this should dis- ture over a wide range of temperatures until, at appear in cold (see previous section on heat temperatures >45C, conduction is blocked.48 This block). It was therefore hypothesized that cold relationship is expressed by the ratio between con- paresis in MMN was not related to demyelination, duction velocity increase (Dv) and temperature but to inflammatory nerve lesions where axons are increase (DT). For upper limb nerves Dv/DT is depolarized but just able to conduct impulses at approximately 2.2 m/s/C.49 In experimental and ambient temperature. In these lesions, thermal human demyelinating neuropathies, however, the reduction of Na1/K1 pump activity due to cooling normal relationship between conduction velocity may induce additional depolarization and depola- and temperature is lost, and Dv/DT is rizing block, because long-standing depolarization decreased.50,51 Furthermore, the value of Dv/DT yields Na1 channel inactivation.54 The hypothesis decreases linearly with the conduction velocity at predicts that the Na1/K1 pump inhibitor digitalis 37C, so that markedly reduced conduction veloc- will aggravate depolarization in MMN. In a patient ities hardly increase when temperature is increased. with MMN, however, administration of digitalis The relationships between the amount of demyelin- resulted in paradoxical fanning-out of threshold ation, influence of temperature, and conduction electrotonus that is consistent with more hyperpo- velocity were simulated, but the determinants for larization rather than depolarization.54 A possible the decrease in dv/DT were not elucidated.52 explanation was that digitalis only gained access to the lesion site where the blood–nerve barrier is Cold Block and Cold Paresis. Animal studies indi- impaired and where it increased depolarization; at cate that cooling of axons below 5–8C induces perilesional sites with intact barrier, electrogenic conduction block.53 This type of block arises pump activity was increased to remove the because, at these temperatures, nodal Na1 channel increased Na1 load from the lesion site, yielding activation slows down considerably, yielding a hyperpolarization.

Demyelinating Neuropathies MUSCLE & NERVE Month 2013 5 Some steps of the hypothesis for cold paresis 4 weeks. Recovery may be complete or partial. The were supported by experiments. First, excitability subtypes of GBS include AIDP, AMAN, acute studies revealed that stepwise cooling of the motor and sensory axonal neuropathy (AMSAN), median nerve in normal subjects from 37Cto acute sensory axonal neuropathy (ASAN), and 25C, 20C, and 15C resulted in progressive axo- Miller–Fisher syndrome. AIDP is the major subtype nal depolarization that was best explained by ther- of GBS in Europe and North America, but it mal reduction in Na1/K1 pump activity.56 Muscle occurs more rarely in northern China and Japan, strength remained normal at 25C, but decreased where axonal forms are found in up to 50% of progressively with cooling from 20Cto15C, pos- patients.63,64 AMAN, AMSAN, and Miller–Fisher sibly due to impaired conduction in axons or mus- syndrome are associated with antibodies against cle fibers. Second, animal models of inflammatory peripheral nerve gangliosides. spinal root lesions indicated that inflammation Electrophysiology is an important clinical tool may induce nitric oxide–mediated mitochondrial for distinguishing demyelinating and axonal sub- dysfunction, energy depletion of the ATPase- types, because it may reveal demyelination, loss of dependent Na1/K1 pump, and axonal depolariza- motor axons only, loss of sensory axons only, or tion.57 Third, in some nerves of MMN patients, mixed loss.65 Unfortunately, the interpretation of axons may be permanently depolarized.58 NCS in an acute neuropathy like GBS is not straight- Alternatively, cold paresis may be due to cool- forward. First, in most criteria for GBS, except those ing of muscle. In normal mammalian skeletal mus- described by Ho et al.,63 conduction block is consid- cle fibers, cooling results in decreased availability ered supportive of demyelination and AIDP.65–68 of excitable muscle Na1 channels (which are of Short-lasting conduction block that resolves without the Nav1.4 subtype, having slightly different bio- temporal dispersion has also been observed in early physical properties than the axonal Nav1.6 sub- stages of a GBS subtype associated with anti- type2), because the proportion of Na1 channels in ganglioside antibodies that resembled AMAN.69 This the slow inactivated state increases with decreasing suggests that the block is due to nodal Na1 channel temperature.45 Among patients, two-thirds of dysfunction rather than demyelination. Therefore, patients with distal upper limb muscular atrophy the finding of conduction block in itself cannot be (Hirayama disease) and 83% of patients with MMN attributed simply to a particular subtype. Second, reported cold paresis.55,59 Hirayama disease is a classification depends on the timing of NCS relative disorder that affects peripheral motor neurons in to disease onset. Serial NCS lead to reclassification the anterior horn of the cervical cord and leads to in as many as 40% of patients, especially from AIDP denervation and weakness of hand muscles.59 NCS to an axonal form.69,70 Thus, classification may differ in 11 patients with Hirayama disease, and 1 patient between studies that employ single or repeated NCS. with hypothenar atrophy due to ulnar neuropathy Third, criteria for demyelinative slowing differ showed cold induced excessive conduction delay among studies so that they cannot always be com- and waning of the compound muscle action poten- pared. For motor conduction velocity (MCV) to be 60,61 tial during 20-HZ repetitive stimulation. These consistent with demyelination, values of 95%, 90%, findings were attributed to increased sensitivity of 80%, 75%, and 70% of the lower limit of normal, reinnervated muscle fibers to develop depolarizing and 60% of the normal mean, have been proposed conduction block in cold. This mechanism may be for GBS.71 The 60% value is based on evidence related to the previously described increased pro- obtained by determining the velocity that distin- portion of muscle Na1 channels in the slow inacti- guishes hereditary axonal and demyelinating neu- vated state. The possibility that this mechanism ropathy or by assessing the slowest MCV in lower may also occur in MMN is supported by extensive motor neuron disease and assuming that MCVs needle electromyography studies in 20 MMN below this value reflect demyelination (reviewed by patients, which showed prominent signs of reinner- van Asseldonk et al.72). Evidence for the other values vation consistent with collateral sprouting in most cannot be found in the literature, although their muscles.17 Also, pathological studies of motor diagnostic value was assessed by aposteriorievaluation nerves in MMN revealed prominent axon loss, of the sensitivity and specificity of entire criteria sets, which may have led to collateral sprouting and in which MCV was a feature. This procedure is not reinnervated muscle fibers.62 suitable to assess cut-off criteria for a single NCS vari- able like MCV. There is, however, a need for liberal FINDINGS IN PATIENTS cut-off criteria, because the evidence-based criteria GBS: General. GBS is a self-limited acute neuropa- may be too strict to detect slight demyelination. thy; it is characterized by flaccid paralysis, are- The cerebrospinal fluid (CSF) of patients with flexia, ataxia, and sensory deficits that start 1–3 unspecified GBS was shown to contain the endoge- weeks after an infection and reach a nadir within nous pentapeptide QYNAD that, when applied to

6 Demyelinating Neuropathies MUSCLE & NERVE Month 2013 rat sciatic nerve, induces acute conduction block site and the muscle.66 Axon loss, as revealed by on whole nerve recording.73 Application of persistent low distal CMAPs, may occur in severe QYNAD to neuron-like cells shifts the steady-state cases. inactivation curve of whole-cell recorded Na1 cur- Excitability indices have been found to be nor- rents to more hyperpolarized membrane poten- mal in AIDP.85,86 This finding was unexpected, tials, indicating decreased availability of Na1 because paranodal demyelination should have current over a range of membrane potential val- resulted in prolonged SDTC due to enlargement ues.74 However, patch-clamping showed that of the nodal area and because activity of exposed QYNAD has no effect on currents generated by dif- juxtaparanodal fast K1 channels should have lim- ferent Na1 channel subtypes, including Nav1.6, ited superexcitability.87 Stimulus–response curves the most important subtype at the node of Ranv- of motor axons were normal in AIDP.88 In another ier.75 It is therefore unclear whether QYNAD con- study using finer current-steps, stimulus–response tributes to impaired impulse propagation or curves were found to be abnormal, but the subtype clinical deficits. of GBS was not specified.89 Recordings from single cutaneous afferents GBS: AIDP. Postmortem studies in AIDP have during the recovery phase showed abnormalities shown multifocal T-lymphocyte infiltration in nerves that were restricted to patients with marked clini- and invasion of the myelin sheath by macrophages, cal sensory deficits.90 Furthermore, at least 50% of yielding segmental demyelination and denuded the units had to be abnormal before marked clini- axons.76,77 In severe lesions, axons are damaged as cal symptoms occurred. Abnormal discharge pat- well. These findings may represent cellular immu- terns included solitary action potentials upon nity in which macrophages are targeted to antigens stimulation instead of bursts, failure to follow stim- on the Schwann cell surface by T cells.65 Autopsy uli, and spontaneous activity; thresholds and con- studies done in early stages of AIDP have shown acti- duction velocities were normal. It was suggested vated complement and membrane attack complex that the failure to react properly to stimuli on outer myelin layers prior to invasion of the mye- reflected rate-dependent block due to demyelin- lin sheath by macrophages, and completely demyeli- ation or remyelination and that this failure con- nated axons were scarce.78,79 This suggests humoral tributed to clinical sensory symptoms and deficits. immunity in early AIDP with binding of antibodies to Schwann cell epitopes and complement mediated GBS: AMAN. AMAN is associated with a preceding myelin damage. The temporal evolution of GBS also infection with C. jejuni and IgG antibodies against suggests humoral, rather than cellular immunity.80 gangliosides. Antibodies are directed against GM1 Antibodies against myelin protein zero (P0) or in 64% of patients, GM1b in 66%, GD1a in 45%, peripheral myelin protein 22 (PMP22) have been and GalNac-GD1a in 33%.65 Sera of some GBS reported in AIDP, but only in a small proportion of patients do not react with single gangliosides, but patients.81 Anti-ganglioside antibodies were also only with complexes consisting of 2 different gan- reported in patients supposed to have AIDP but, as gliosides, suggesting that they form unique confor- these cases were associated with Campylobacter jejuni mational epitopes.91,92 Reactive complexes have infection or pure motor GBS, patients may actually included GD1a/GD1b, GD1b/GT1b, GM1/GD1a, have had AMAN.77 Increased endoneurial fluid and GM1/LM1. AMAN is likely caused by antibod- pressure due to inflammation in nerve trunks likely ies against the bacterial wall of a specific genotype contributes to the development of axonal degenera- of C. jejuni that cross-react with these peripheral tion in AIDP.82 nerve gangliosides.93 Injection of rabbits with Electrophysiology performed within 2–15 days GM1 or GM1-like components of C. jejuni causes after onset may show motor conduction block or acute flaccid paralysis with anti-GM1 IgG antibod- slowing consistent with stringent criteria for demy- ies and pathological findings that strongly resem- elination in approximately 60% of patients.67 ble those in AMAN. This model is considered Demyelinative NCS abnormalities become most appropriate for the human disease.94 The associa- prominent 4–8 weeks after onset, and recovery tion between C. jejuni infections and AMAN is starts after 6–10 weeks.66,83 Conduction block strong but possibly not exclusive, because a small resolves with appearance of CMAPs with slow ini- number of patients have an AIDP phenotype on tial components and increased duration on stimu- electrophysiology.68 lation proximal to the site of block, consistent with Autopsy studies in fatal human AMAN showed remyelinating slowly conducting axons.66,84 This nodal lengthening, nodal IgG and complement sequence also occurs with distally evoked CMAPs, depositions, invasion of the space between nodes indicating restoration of demyelinative conduction and Schwann cell processes by macrophages, and block in the segment between the distal stimulus axonal degeneration; demyelination and

Demyelinating Neuropathies MUSCLE & NERVE Month 2013 7 lymphocyte infiltration were scarce.79,95 These find- assessed by 2 supramaximal stimuli (instead of a ings are consistent with antibody-mediated supramaximal conditioning stimulus followed by a humoral immunity rather than with cellular immu- test stimulus tracking a 40% CMAP), the duration nity. It is likely that the Fc receptors of activated of the refractory period was increased.100 Abnor- macrophages are targeted to autoantibodies bound mal excitability indices usually reflect axonal mem- to gangliosides on the axolemma. Although these brane dysfunction at the stimulus site. Because the findings prove that the immune attack is directed recovery cycle curves in AMAN differed from those at the node, Schwann cells may possibly be observed in other conditions with prolonged involved as well, because their surface expresses a refractory period, such as during application of small amount of GM1. depolarizing currents, ischemia, or cooling, the NCS may show low CMAPs on distal stimulation investigators suggested that they reflect conduction and normal thresholds, which are usually inter- failure of the second impulse distal to the wrist; for preted as indicating permanent axon loss and instance, in distal axon branches, rather than Na1 poor prognosis. Serial studies, however, revealed channel dysfunction at the wrist. It was considered that this vision needs to be modified. NCS per- unlikely that these changes were related to axonal formed in the first week of GBS with IgG anti- degeneration, because the recovery cycle was nor- ganglioside antibodies showed decreased distal mal in other diseases with axonal degeneration. CMAPs, prolonged distal motor latency (DML), Therefore, the biophysical basis of the abnormal conduction block, and conduction slowing in fore- recovery cycle in AMAN was assumed to be Na1 arm segments.69,96 Thereafter, 2 patterns were channel blocking, occupation of the nodal gap by observed. In some patients, distal and proximal invading macrophages yielding an increased resist- CMAPs were persistently decreased as is consistent ance for nodal currents, or paranodal myelin with axonal degeneration; these patients had a detachment yielding short-circuited nodal cur- poor outcome. In other patients, however, DMLs rents.85 An argument against the first assumption and distal CMAP amplitudes normalized (indicat- is that Na1 channel blocking by tetrodotoxin yields ing resolution of distal conduction block), and abnormalities distinct from AMAN, including conduction block in the forearm disappeared with- decreased refractoriness and threshold electroto- out signs of temporal dispersion. These changes nus abnormalities.101 Furthermore, in a patient occurred within days after onset. Some patients with acute motor conduction block neuropathy, were classified initially as having AIDP. The fast excitability studies, including the refractory period, recovery was explained by temporary loss of nodal were completely normal.102 Na1 channel function related to the autoimmune The effects of anti-ganglioside antibodies on process.69 Remyelination was considered unlikely the neuromuscular synapse, as found in ex vivo because, in AIDP, recovery is associated with studies, may also occur in human GBS. Single-fiber appearance of increased temporal dispersion and electromyography in patients with antibodies to starts after 6–10 weeks.66 Axonal regeneration after GM1, GM2, GD1a, or GD1b showed single impulse distal degeneration of motor axon terminal blocking and concomitant impulse blocking of 2 branches was also considered unlikely, because this muscle fibers with normal or slightly increased jit- starts after 2–4 weeks.97 ter values. These findings are consistent with dys- In other patients with acute motor GBS, distal function of neuromuscular synapses and axon CMAPs and conduction block in forearm and branches.103 Other types of electrophysiological elbow segments have resolved without signs of tem- abnormalities in GBS associated with several types poral dispersion, albeit after 2–5 weeks, which is of anti-ganglioside antibodies included decrement, later than in patients in the Kuwabara et al. study; increment, markedly increased jitter, and approximately half of these patients had anti- decreased CMAPs (reviewed by Plomp and Willi- ganglioside antibodies.96,98 This pattern was son104). These abnormalities may reflect primary labeled acute motor conduction block neuropathy and neuromuscular synapse pathology but may also be was considered to be related to AMAN and to be secondary to axonal degeneration. due to an antibody-mediated attack on nodal gangliosides. CIDP. CIDP is characterized by progressive sensori- Excitability studies of the median nerve at the motor, mainly motor, or purely sensory deficits that wrist in AMAN were normal, except for the recov- progress over >2 months. The course is relapsing– ery cycle, which showed an abrupt increase in remitting, gradually worsening, or stepwise worsen- threshold at short interstimulus intervals of 2.0–2.5 ing. The distribution can be diffuse or mainly distal, ms without an accompanying increase in refractory or may predominantly affect upper extremities. period, a finding not observed in sensory Pathological studies of roots, plexuses, and axons.99,100 When, however, refractoriness was nerves showed loss of myelinated fibers, onion

8 Demyelinating Neuropathies MUSCLE & NERVE Month 2013 bulbs, axonal degeneration, endoneurial or sub- distribution so that axons are less well protected perineurial edema, and infiltrates. Teased fiber against the effects of demyelination. In nerve biop- preparations showed denuded axons, thinly sies of CIDP patients, several genes related to pain myelinated axons, and paranodal demyelin- mediation, immunity, inflammation, and remyeli- ation.105–107 Electron microscopy of longitudinal nation are up- or downregulated.118 In turn, sections of superficial fibular nerve axons showed inflammation may induce expression of other sub- multivesicular bodies in paranodal loops, vacuoles types of voltage-gated Na1 channel subtypes in in Schwann cell cytoplasm, and vacuoles in axo- dorsal root ganglia that are normally expressed.119 plasm.108 Immunohistochemistry revealed that the These alternative subtypes may induce abnormal normal staining of Nav and Kv7.2, the slow K1 firing patterns and result in pain sensations. channel, at the node and of contactin-associated Excitability studies of the median nerve at the protein-2 (Caspr-2) at the paranode could be lost wrist in CIDP patients have shown increased and was replaced by spots or diffuse reactivity of thresholds in stimulus–response curves.86,88,120 Caspr-2, Nav, and Kv7.2 along the internodal axo- Other excitability indices were also altered, but lemma; Caspr-2 staining was of a higher than nor- were not consistent between studies. This variabili- mal intensity. These findings were considered to ty may be related to differences in disease charac- reflect loss of axon–Schwann cell contact. They teristics, as threshold electrotonus abnormalities resemble the focal expression of Nav channels were greater in patients with severe disability, long observed during recovery from experimental aller- disease duration, and marked slowing on NCS.86 gic neuritis.109 The abnormality consisted of increased threshold The pathogenesis of CIDP is poorly under- change in hyperpolarizing threshold electrotonus stood. Cellular immunity is suggested by the find- of which the mechanism is unknown. In 2 studies, ing that demyelination is mediated by invasion and SDTC was decreased and rheobase increased, stripping (delamination) of myelin lamellae by T which is consistent with increased thresholds to cells and macrophages.106 Humoral immunity is nerve stimulation.120,121 The decreased SDTC was, suggested by induction of demyelination in ani- however, unexpected, because exposure of addi- mals by IgG or sera from CIDP patients and by the tional axon membrane by paranodal demyelination finding of antibodies against P0, myelin P2 pro- would have increased nodal capacitance and, tein, PMP22, or neurofascin in a minority of therefore, would have increased the passive com- patients.110–112 Myelinated nerve fibers of CIDP ponent of SDTC. This may reflect a decrease in patients showed immunoglobulin and complement persistent Na1 current density due to nodal deposits, also indicating an antibody-mediated enlargement or short-circuiting of applied current process.113 by inflammatory edema. Several studies suggested that genetically deter- Excitability tests of motor axons at the wrist mined factors in the immune system and other were compared before and after IVIg treatment for genetic factors contribute to development of CIDP.121,122 Immediately after IVIg infusion the CIDP. B cells in CIDP patients exhibit impaired following changes were noted: stimulus–response expression of the inhibitory Fc-gamma receptor curve thresholds decreased; SDTC shortened; IIB, which is critical for the balance between toler- accommodation during depolarizing threshold ance and autoimmunity.114 Apoptosis of T cells by electrotonus increased; and absolute super- and expression of the Fas receptor on their membrane subexcitability values decreased. During the weeks is impaired in CIDP, suggesting a defect in switch- thereafter, these indices slowly reverted to pre- ing off the immune response; the impairment is infusion values. Because the changes occurred too more pronounced in patients with a progressive rapidly to be explained by remyelination or axonal course and axonal damage on needle electromyog- regeneration, they may indicate that IVIg normal- raphy.115 In CIDP, the SH2DA gene has a low ized axon membrane function by an unknown number of GA repeats that may result in defective effect on ion channels and pumps. After an aver- elimination of activated T cells.116 Single- age of 15 months of IVIg courses, excitability indi- nucleotide polymorphisms affecting the N-terminal ces approached normal values and weakness fragment of the paranodal adhesion molecule tran- decreased. The excitability changes after IVIg sug- sient axonal glycoprotein-1 (TAG-1) are associated gest that motor axons were hyperpolarized prior to with unresponsiveness to intravenous immunoglo- treatment and that IVIg shifted resting membrane bulins (IVIg).117 Because TAG-1 is essential for potential toward more depolarized values. Only proper location of juxtaparanodal K1 channels, the short-term decrease in SDTC cannot be and because axonal dysfunction contributes to explained by a depolarizing shift in resting mem- IVIg unresponsiveness, it has been suggested that brane potential, because this should have TAG-1 mutations may unfavorably alter K1 channel increased SDTC. The hyperpolarization before

Demyelinating Neuropathies MUSCLE & NERVE Month 2013 9 IVIg treatment may have been caused by remyeli- verse sections and teased fiber preparations nation with short internodes, because shorter showed virtually no demyelination and only axonal internodal distance implies greater numbers of degeneration, suggesting that the primary pathol- nodes, Na1 channels, Na1 influx, and, conse- ogy in MMN affects axons rather than the myelin quently, more electrogenic Na1/K1 pump sheath. In 2 patients, small perivascular lymphocyte activity.123 infiltrates were seen, possibly reflecting an inflam- To determine whether conduction block can matory process.62 be precipitated by changing resting membrane IgM anti-antibodies against GM1 were found in potential in axons with reduced safety factor due 20–80% of patients with MMN, but they were also to demyelination, excitability studies were per- found in patients with other disorders, including formed in CIDP patients during ischemia induced motor neuron disease.131 Nevertheless, anti-GM1 by cuff inflation and in the post-ischemic antibodies may play a role in the pathogenesis of period.124 In CIDP, CMAPs decreased during and MMN because: (i) high-titer antibodies are specific after ischemia. Because this was not observed in for MMN; (ii) patients with antibodies have more normal subjects, it was attributed to conduction weakness and evidence of axon loss on NCS than block. Ischemia gives rise to Na1/K1 pump failure, patients without antibodies; and (iii) most anti- loss of ionic concentration gradients, depolariza- GM1 containing sera of MMN patients activate the tion, and Na1 channel inactivation.125 The latter classical complement pathway.132,133 Serum IgM decreases the safety factor, because fewer Na1 from patients with MMN bound more strongly to a channels are available for impulse generation. lipid mixture containing GM1, galactocerebroside, Release of ischemia increases Na1/K1 pump activ- and cholesterol than to GM1 alone, indicating that ity, because the ionic imbalance drives the pump the lipid environment of GM1 influences its bind- to restore ionic concentration gradients. Because ing to IgM.134 However, anti-GM1 antibodies can- the pump is electrogenic, hyperpolarization not be detected in approximately 40% of MMN ensues. Hyperpolarization also reduces the safety patients, so other antigens may be targeted in factor, because more driving current is needed to these patients.132 The IgM of some MMN patients overcome the large potential difference and gener- reacted to disulfated heparin disaccharide, but the ate sufficient nodal depolarization for impulse gen- significance of this finding is unclear, as it is eration. In normal subjects, the safety factor is unknown where this substance is present on nerve sufficiently large to ensure impulse transmission fibers.131 despite these changes in resting membrane poten- In patients with MMN, focal polarizing currents tial. In CIDP, however, the safety factor is already were applied at the site of conduction block, and reduced due to demyelination, and the additional the effect on the CMAP evoked proximal to the reduction due to de- or hyperpolarization will block was measured.58 In 2 nerves, the CMAP induce conduction block. increased during application of a hyperpolarizing current. This was considered to be consistent with MMN. MMN is characterized by asymmetric lower the disappearance of block in axons that were motor neuron weakness, often more prominent in depolarized prior to application of the polarizing upper than in lower limbs. Patients may suffer currents. In 3 other nerves the CMAP increased from cold paresis, heat paresis, or both (see after application of a depolarizing current, suggest- above). In typical cases, motor NCS reveal conduc- ing that the block was caused by focal hyperpolar- tion block, marked slowing, or both, whereas sen- ization of axons. In 1 nerve, the proximally evoked sory conduction in the same nerve segment is CMAP decreased during depolarizing as well as normal.126 It remains unclear whether motor con- during hyperpolarizing currents, suggesting that duction block and slowing represent paranodal depolarized axons and hyperpolarized axons may demyelination, segmental demyelination, changes coexist within a nerve. The latter finding illustrates in resting membrane potential, or ion channel dys- the potential weakness of compound action poten- function at the node of Ranvier (Fig. 1).127 tial recordings; if the axons within a nerve are Pathological studies of nerves containing motor affected by different disease mechanisms, the net axons were performed on biopsy specimens taken result may be no change at all, or an average from forearm nerves, the brachial plexus, or the change from which it is impossible to derive the obturator nerve.62,128–130 Transverse sections pathophysiological events. showed thinly myelinated axons and small onion Excitability studies in MMN patients that have bulbs, consistent with demyelination and remyeli- been performed distal to sites with motor conduc- nation, as well as loss of myelinated axons and tion block have shown fanning-out of threshold regenerative clusters, consistent with axonal degen- electrotonus, decreased I/V slope, decreased refrac- eration and regeneration.128,129 In 1 study, trans- toriness, and increased superexcitability.135 The

10 Demyelinating Neuropathies MUSCLE & NERVE Month 2013 FIGURE 2. Myelin-associated glycoprotein (MAG) function and axon diameter. Left: normal axon; by means of Schwann cell–axon signaling, MAG induces neurofilament sidearm phosphorylation; the negatively charged phosphate groups repel each other, ensuring neurofilament spacing and maintenance of axon diameter. Right: anti-MAG neuropathy; MAG function is impaired by anti-MAG antibodies; neurofilament sidearms are dephosphorylated, resulting in neurofilament clustering and failure to maintain axon diameter.

abnormalities resemble those encountered during After IVIg treatment, SDTC decreased and rheo- application of hyperpolarizing current to a nerve base increased within 3–5 days, which is too early and suggest that some axons in MMN are hyperpo- to be explained by remyelination or axonal regen- larized. This was supported by the return to nor- eration.122 The investigators suggested that the mal of variables dependent on Na1 channel decrease in SDTC reflected a decrease in persistent function and variables dependent on K1 channel Na1 current. Such an effect of IVIg may be benefi- function during application of a depolarizing DC cial for axonal survival, because it limits intra- current at the site of stimulation. To explain the axonal Na1 accumulation. Excessive Na1 accumu- focal hyperpolarization, the following was hypothe- lation may induce reversal of the Na1/Ca11 sized: At the site of the lesion with conduction exchanger, resulting in Na1 being extruded from block, Na1/K1 pump activity is blocked due to the axon in exchange for Ca11, increase in intra- edema or antibodies; this causes permanent depo- axonal Ca11 concentration from nanomolar to larization, which, in turn, yields continuous Na1 micromolar values, and Ca11-mediated axonal influx through persistent Na1 channels; the accu- degeneration.138 Because, however, not all excit- mulated Na1 ions are removed at adjacent healthy ability variables were investigated, the decrease in parts of the axon by increased activity of the elec- SDTC may also have been secondary to a change trogenic Na1/K1 pump, yielding hyperpolarization in membrane potential. distal to the lesion. Excitability tests in unaffected nerves of MMN patients were essentially normal, Anti-MAG Neuropathy. Anti-MAG neuropathy is indicating that axonal membrane dysfunction is associated with IgM antibodies against MAG. It is not generalized in MMN.136 Another study indi- characterized by slowly progressing symmetrical cated decreased SDTC outside of sites with con- sensorimotor deficits and sometimes severe sensory duction block, but the excitability protocol was ataxia. The IgM is likely to be the pathogenic fac- limited and did not involve threshold tracking.137 tor, because the antibodies are directed against

Demyelinating Neuropathies MUSCLE & NERVE Month 2013 11 FIGURE 3. Relation of nerve length and normalized distal motor latency (DML) in IgM neuropathy (green bars) and chronic inflammatory demyelinating neuropathy (CIDP, blue bars). DML was measured from the median nerve to flexor carpi radialis muscle (short nerve length), median nerve to abductor pollicis brevis muscle (intermediate nerve length), and tibial nerve to abductor hallucis muscle (long nerve length). Nerve length dependence of DML in IgM neuropathy is more pronounced than in CIDP.

MAG, and passive transfer of human IgM anti- between the phosphate groups induce spacing MAG antibodies to chickens produces a neuropa- between neurofilament sidearms so that axon thy with the same pathological features as in diameter is maintained (Fig. 2). Consistent with humans, including demyelination, widening this function, local axon diameter increases with between myelin lamellae, and IgM deposits.139 A the amount of MAG expression, and MAG-null drug treatment with convincing efficacy is not mice demonstrate demyelination and small axon available.140,141 caliber.144–146 The axolemmal receptors that inter- The transmembrane glycoprotein MAG is act with MAG possibly include Nogo, neurotro- located in non-compact myelin, including parano- phins, glycoproteins, and gangliosides (reviewed by dal loops, the area apposing the axon, and along- Steck et al.147). Third, MAG protects the axon side Schmidt–Lanterman incisures. MAG consists against degeneration induced by toxic substances, of 5 extracellular immunoglobulin-like domains to possibly through signaling between the extracellu- which sugar residues are attached, a single trans- lar MAG component and axolemmal ganglio- membrane segment, and a cytoplasmic tail. The sides.148 Fourth, in the mature central nervous sugar residues form the HNK-1 epitope, which is system, it inhibits elongation of axonal growth the antigen for anti-MAG antibodies and which is cones during regeneration by signaling to recep- also expressed by P0, PMP22, and sulfated glyco- tors on the axolemma.149 Potentially, anti-MAG lipids (reviewed by Quarles and Weiss142 and Latov antibodies may impair any of these actions. and Renaud143). MAG has 4 known actions. First, Pathological studies of distal sensory lower limb it ensures adhesion and spacing of non-compact nerves have shown IgM deposits in the myelin myelin lamellae by homologous adhesion between sheath, demyelination, axon loss, and widening extracellular MAG residues of adjacent Schwann between myelin lamellae. The myelin widening cell membranes. Second, it maintains axon diame- increased with the depth of IgM penetration, sug- ter by promoting attachment of negatively charged gesting that the antibodies cause loss of the role of phosphate groups to the side arms of medium and MAG in adhesion between lamellae.150 The IgM heavy axonal neurofilaments. The repelling forces deposits are found in non-compact myelin where

12 Demyelinating Neuropathies MUSCLE & NERVE Month 2013 MAG is localized, but also in compact myelin, indi- more vulnerable to anti-MAG antibodies, either cating that the IgM is not only directed to MAG due to a more permeable blood–nerve barrier or but also to other molecules that bear the HNK-1 to more prominent MAG expression. Although it epitope. Terminal complement was found near is unknown whether this also holds true for large- blood vessels but not in the myelin, suggesting that diameter motor and sensory axons, it may explain complement may be involved in the initial injury why distal axons are affected predominantly in of the Schwann cell basement membrane, but not anti-MAG neuropathy. Alternatively, impairment of in demyelination.150 Sural nerve biopsies revealed neurofilament phosphorylation by anti-MAG anti- a decreased nearest neighbor distance between bodies may cause neurofilament accumulation, axonal neurofilaments, consistent with impairment which may impair axonal transport and induce of the role of MAG in maintaining neurofilament axonal degeneration that is more prominent in phosphorylation.151 In earlier studies, it was more distal parts of longer axons.151 Moreover, hypothesized that the primary pathology in anti- neurofilament clustering may also yield an MAG neuropathy is axonal and, given the role of increased longitudinal intra-axonal resistance. MAG in Schwann cell to axon signaling, this can- Computer simulations have shown that this resist- not be ruled out. In 1 patient, autopsy showed gen- ance is one of the most important determinants eralized IgM deposits in roots and peripheral for conduction velocity, so that neurofilament clus- nerves, but axon loss was limited to the sciatic tering may contribute to distal conduction slowing nerve and demyelination to the sural nerve.152 in patients with anti-MAG neuropathy.17,159 These findings were suggested to reflect a sequence found after axotomy in cats.153 This con- POEMS Syndrome. The full clinical picture of sisted of primary distal axon atrophy, followed by POEMS syndrome comprises polyneuropathy, orga- secondary myelin wrinkling, nodal lengthening, nomegaly, endocrinopathy, M-protein (IgG or and internodal demyelination. The axotomy model IgA), skin changes, massive peripheral edema, was, however, based on acute injury, and it is pleural effusion, pulmonary hypertension, ascites, uncertain whether it can be applied to a chronic and thromboembolic events. The polyneuropathy disorder like anti-MAG neuropathy. is progressive and, in approximately 50% of NCS in typical cases show prolonged DMLs patients, is the initial and only sign. One of its fea- consistent with demyelination, less pronounced tures is severe pain in the feet. POEMS syndrome slowing in adjacent forearm and lower leg seg- is associated with overproduction of vascular endo- ments, and decreased CMAPs and sensory nerve thelial growth factor (VEGF) by monoclonal action potentials in lower limbs, consistent with plasma cells, which results in elevated serum VEGF axon loss.154 This pattern is considered unique for levels, vascular permeability, and neovasculariza- anti-MAG neuropathy, as it does not occur in other tion.160 Treatment is essential and is directed at demyelinating neuropathies such as CIDP and decreasing VEGF levels by chemotherapy, autolo- MMN and not in axonal neuropathies such as dia- gous blood stem cell transplantation, or thalido- betic neuropathy, where DMLs are not consistent mide. Untreated patients die from multiorgan with demyelination.155–157 Standardized motor and failure. sensory NCS in nerves with short, medium-length, Pathological studies have shown VEGF staining and long axons, revealed that DMLs were more in endoneurial vessels, epineurial vessels, and prolonged, and signs of axon loss were more Schwann cells; endoneurial edema; loss of small prominent in nerves with longer axons (Fig. 3).17 myelinated axons with preserved unmyelinated The combination of length dependence of both axons; segmental demyelination; widened nodal axon loss and distal demyelination was not present areas; loosening of inner and outer myelin lamel- in disease controls with CIDP and normal controls. lae; and decreased number of neurofilaments.161– Length dependence, however, is known to be a 163 The loss of small myelinated axons correlates feature of axonal polyneuropathies, where it can with the presence of pain, suggesting loss of inhibi- be explained by the vulnerability of longer axons tory functions that are normally mediated by to a generalized disease process. Length depend- myelinated axons. ence of features consistent with demyelination is NCS show slowing consistent with demyelin- not well understood, and several mechanisms have ation in forearm and upper arm segments and been proposed. In patients with anti-MAG neurop- signs of axon loss in lower limb nerves; DMLs are athy, skin biopsies reveal IgM deposits in small less prominently slowed, and conduction block is myelinated axons that are more prominent in rare.164 Taken together, the pathological and elec- biopsies taken from the distal part of extremities trophysiological findings suggest that POEMS syn- than in biopsies taken from the proximal part.158 drome affects predominantly intermediate nerve This suggests that the distal part of nerve fibers is segments and nerve trunks by VEGF-mediated

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