Rev. Neurosci. 2015; 26(2): 239–251

Cem Ismail Küçükali*, Murat Kürtüncü, Halil İbrahim Akçay, Erdem Tüzün and Ali Emre Öge

Peripheral nerve hyperexcitability syndromes Abstract: Peripheral nerve hyperexcitability (PNH) syndromes can be subclassified as primary and secondary. The main primary PNH syndromes are neuromyotonia, cramp-fasciculation syndrome (CFS), and Morvan’s syndrome, which cause widespread symptoms and signs without the association of an evident peripheral nerve disease. Their major symptoms are muscle twitching and stiffness, which differ only in severity between neuromyotonia and CFS. Cramps, pseudomyotonia, hyperhidrosis, and some other autonomic abnormalities, as well as mild positive sensory phenomena, can be seen in several patients. Symptoms reflecting the involvement of the central nervous system occur in Morvan’s syndrome. Secondary PNH syndromes are generally seen in patients with focal or diffuse diseases affecting the peripheral nervous system. The PNH-related symptoms and signs are generally found incidentally during clinical or electrodiagnostic examinations. The electrophysiological findings that are very useful in the diagnosis of PNH are myokymic and neuromyotonic discharges in needle electromyography along with some additional indicators of increased nerve fiber excitability. Based on clinicopathological and etiological associations, PNH syndromes can also be classified as immune mediated, genetic, and those caused by other miscellaneous factors. There has been an increasing awareness on the role of voltage-gated potassium channel complex autoimmunity in primary PNH pathogenesis. Then again, a long list of toxic compounds and genetic factors has also been implicated in development of PNH. The management of primary PNH syndromes comprises symptomatic treatment with anticonvulsant drugs, immune modulation if necessary, and treatment of possible associated dysimmune and/or malignant conditions. Keywords: cramp fasciculation syndrome; myokymia; neuromyotonia; peripheral nerve hyperexcitability.

*Corresponding author: Cem Ismail Küçükali, Department of Neuroscience, Institute for Experimental Medical Research, Istanbul University, Istanbul 34390, Turkey, e-mail: [email protected] Erdem Tüzün: Department of Neuroscience, Institute for Experimental Medical Research, Istanbul University, Istanbul 34390, Turkey Murat Kürtüncü, Halil İbrahim Akçay and Ali Emre Öge: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34390, Turkey

DOI 10.1515/revneuro-2014-0066 Received September 16, 2014; accepted November 4, 2014; previously published online February 14, 2015

Introduction Peripheral nerve hyperexcitability (PNH) syndromes are caused by spontaneous discharges originating from the motor nerve fibers, which lead to increased activity of the muscles. The bioelectrical consequences of this increased activity can usually be recorded electrophysiologically. Although an ectopic electrical activity is also present in the sensory nerves causing positive sensory symptoms, such as pain and paresthesia in peripheral neuropathies, these sensory phenomena are more difficult to be studied electrophysiologically and are not solely categorized as PNH (Caress and Walker, 2002). PNH syndromes might be divided, somewhat artificially, into two categories as primary and secondary syndromes (Table 1). Primary PNH syndromes cause widespread symptoms and signs while there is no evident peripheral nerve disease. Nerve conduction studies reveal abnormalities compatible with a mild polyneuropathy in only a fraction of the patients with primary PNH (Deymeer et  al., 1998; Maddison, 2006; Rubio-Agusti et  al., 2011). The pathological mechanisms responsible for the disorders in some patients of this category have been shown to be initiated by autoimmune processes directed against the ion channels located mostly in the terminal segments of the peripheral nerves. Secondary PNH syndromes, on the other hand, are one of the consequences of the recognized diseases that can affect the peripheral nerves either in a diffuse manner, as seen in inflammatory demyelinating polyneuropathies, or focally, like entrapment or radiation induced neuropathies (Gutmann et  al., 2001a; Gutmann and Gutmann, 2004; Maddison, 2006). The symptoms and signs of PNH syndromes in this second category generally do not lead the patient to seek medical help and are usually found incidentally during the clinical examination or electrophysiological study. Alternatively, PNH syndromes can also be classified as immune-mediated, genetic, and those caused by other miscellaneous factors based on clinicopathological and etiological associations (Table 1).

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240      C.I. Küçükali et al.: Peripheral nerve hyperexcitability syndromes Table 1 Classification of PNH syndromes according to clinicopathological and etiological associations. 1. Immune mediated a. Isolated (primary/idiopathic) b. Paraneoplastic: thymoma, small cell lung carcinoma, adenocarcinoma, lymphoma, and other hematological malignancies (Viallard et al., 2005; Irani et al., 2010; Rana et al., 2012) c.  Associated with other autoimmune diseases (e.g., myasthenia gravis, chronic inflammatory demyelinating neuropathy, rheumatoid arthritis, autoimmune thyroid disease, systemic lupus erythematosus, penicillaminetreatment-induced autoimmune conditions) (Reeback et al., 1979; Van Zandycke et al., 1982; Auger, 1994; Odabasi et al., 1996; Le Gars et al., 1997; Mygland et al., 2000; Hart et al., 2002; Maddison, 2006; O’Sullivan et al., 2007) 2. Gene mutations and hereditary diseases a. VGKC (KCNA1) mutations (Browne et al., 1994)   Sporadic forms   Familial episodic ataxia type 1 b. Hereditary neuropathies (e.g., associated with mutations of molecules such as peripheral myelin protein 22 and encoding histidine triad nucleotide-binding protein 1 defined in experimental animals and/or patients) (Toyka et al., 1997; Zhao et al., 2014) c. Spinal muscular atrophy (Lance, 1998) d. Schwartz-Jampel syndrome (Echaniz-Laguna et al., 2009; Bauché et al., 2013) 3. Other causes a. Toxins and drugs: herbicide, insecticide, toluene, alcohol, snake venom, gold (Devathasan et al., 1984; Petiot et al., 1993; Caress and Walker, 2002; Maddison, 2006) b. Idiopathic peripheral neuropathy (Hart et al., 2002; NewsomDavis et al., 2003) c.  Anterior horn cell degeneration as part of motor neuron disease (Kleine et al., 2008b; Eisen, 2009) d. Neuromyotonia induced by staphylococcal infection, human papilloma virus, and wasp sting presumably via autoimmune mechanisms (Maddison et al., 1998; Turner et al., 2006; Cerami et al., 2013)

Clinical characteristics The syndrome that is currently known as ‘neuromyotonia’ was initially described by Isaacs, who reported two cases in 1961. He appropriately localized the source of peripheral nerve activity leading to the clinical syndrome, which he named as the ‘syndrome of continuous muscle fiber activity’ (Isaacs, 1961, 1967). The disorder is currently referred as Isaacs’ syndrome or neuromyotonia as suggested by Mertens and Zschocke (Gutmann et al., 2001a). The main symptoms of neuromyotonia are muscle twitching and stiffness, which generally evolve over months (Gutmann et al., 2001a; Maddison, 2006; Merchut,

2010). The twitches often consist of irregular asynchronous undulation of groups of muscle fibers, giving the appearance of worms moving beneath the skin (myokymia). Sometimes, frequent fasciculations can also be recognized. Although the usual location of the twitches is the extremities, they can also be seen over the face and the truncal muscles. In most of the cases, muscle stiffness and cramps occur in the extremities and less frequently disseminate to the girdle and trunk muscles. Muscle stiffness may be so strong that it can nearly fix the hands and arms in certain postures and make them almost unusable. Likewise, the stiffness in the legs may cause difficulty in walking. In the most common clinical presentation of the disorder, the symptoms are more severe in the distal extremities with predominating muscle stiffness, whereas myokymia can easily be observed in the proximal muscles that bear less severe stiffness (Deymeer et  al., 1998; Maddison, 2006; Maddison et  al., 2006; Merchut, 2010). Hyperlordosis and respiratory difficulty due to the involvement of axial muscles, as well as a rare grinning appearance caused by the participation of facial muscles, can be observed (Gutmann and Gutmann, 2004; ­Maddison, 2006). A difficulty in relaxing voluntarily contracted muscles can be found in some cases. Since this symptom is not associated with percussion myotonia, it is named as pseudomyotonia (Maddison, 2006). Hyperhidrosis is present in most of the subjects, and it is thought to be caused by excessive muscle fiber activity (Maddison, 2006). However, involvement of the autonomic fibers has also been implicated for this symptom, which seems reasonable especially when the presence of various other autonomic signs seen in Morvan’s syndrome is considered (see below) (Merchut, 2010; Abou-Zeid et  al., 2012). Muscle fiber hyperactivity also causes hypertrophic appearance of the muscles in some patients, prevalently in the calf and forearm regions. The exact cause of the muscle weakness reported in some rare patients has not been understood so far. Also, tendon reflexes may not be elicited in some cases due to relaxation difficulty (Deymeer et  al., 1998; Maddison, 2006). Sensory symptoms, usually occurring as episodes of positive phenomena (paresthesia or electrical feelings) or less frequently as transient numbness, in various distributions involving the arms, body, and neck are encountered nearly in one third of the patients. These symptoms might occur spontaneously or might be triggered with motor activity. Some patients display Tinel’s sign, and some cases may experience sensory symptoms so severely that differentiation from polyneuropathies may be very difficult, particularly when electrophysiological findings suggesting a mild polyneuropathy are present (Vincent et al., 1998; Herskovitz et al., 2005; Merchut, 2010).

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Although the main symptoms of neuromyotonia usually develop insidiously over months and have a protracted course thereafter, some rare cases have been reported with attacks of episodic stiffness or hyperhidrosis, which can be extended over many years before the diagnosis is established (Gomez-Choco et al., 2005; Ganos et al., 2011; Pulkes et al., 2012). In 1991, Tahmoush et al. drew attention to cases with complaints of cramps, twitches, and stiffness in their muscles, the last of which was never as severe as that seen in neuromyotonia. In this ‘cramp-fasciculation syndrome’ (CFS), there is usually no clinical abnormality except fasciculations, occasional myokymias, and easily provoked cramps. Needle electromyography (EMG) reveals similar but less abundant discharges as compared to those seen in neuromyotonia, with the preponderance of fasciculations. CFS patients have been shown to display similar immune mechanisms as neuromyotonia patients, and the difference of CFS from neuromyotonia is suggested to be only a matter of severity (Figure 1) (Hart et al., 2002; Maddison, 2006). There are cases presenting with symptoms of central nervous system involvement such as hallucinations, confusion, and insomnia along with neuromyotonia and autonomic symptoms (Merchut, 2010). There

is strong evidence that the syndrome first described by A.M. Morvan in 1870 as la chore’e fibrillaire, which is currently known as Morvan’s syndrome, is caused by similar immune mechanisms as those operating in neuromyotonia with a tendency to affect the central nervous system, and thus, this syndrome occupies a place between autoimmune limbic encephalitis and neuromyotonia (Josephs et al., 2004; Takahashi et al., 2008). Autonomic symptoms are encountered in neuromyotonia patients and majority of Morvan’s syndrome patients. Hyperhidrosis, cardiovascular (e.g., tachycardia, hypertension), and gastrointestinal (e.g., constipation, diarrhea) disturbances are the most common forms of dysautonomia in PNH syndromes. Urinary disturbances, hypersalivation, lacrimation, and impotence may also be observed (Hart et al., 2002; Lee et al., 2013). As a rare manifestation, neuromyotonia patients might also display swallowing difficulty and bronchospasm, suggesting involvement of autonomic motor fibers destined to the esophagus and bronchi, respectively (Braune et al., 1998; Entrambasaguas et  al., 2006). It can be expected that ongoing immunological studies focusing on different antigenic targets may illuminate mechanisms leading to the above-mentioned different phenotypes and the various clinical phenomena presented by PNH patients.

Figure 1 A general review of the PNH syndromes. A spectrum of abnormal spontaneous activities, from fasciculation to myokymias and, eventually, to cramp activities, is observed in PNH syndromes. More abundant discharges (dis.) with higher frequencies lead to more stiff muscles, and the resultant symptoms vary between fasciculations and severe stiffness. These symptoms might possibly be encountered in both primary and secondary PNH disorders.

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242      C.I. Küçükali et al.: Peripheral nerve hyperexcitability syndromes

Electrophysiological findings The major electrophysiological findings are spontaneous myokymic and neuromyotonic discharges in needle EMG. These are composed of single motor unit potentials (MUPs) or parts of MUPs repeating in bursts of two (doublets), three (triplets), or multiple (multiplets) discharges. The firing frequency of the potentials in a burst is widely variable, usually between 5 and 300 Hz. Neuromyotonic discharges are composed of multiple potentials discharging in higher frequencies (150–300 Hz). Their onsets and ends are abrupt with a frequent waning of the amplitude at the beginning of the discharge (Figures 1 and 2A). The discharge groups (bursts) repeat semirhythmically with short (  10 s) interburst intervals. There are usually short intervals between the bursts composed of a few potentials, whereas those between the bursts of numerous potentials or between the neuromyotonic potentials are longer (Gutmann and Gutmann, 2004; Maddison, 2006; Maddison et  al., 2006; Kleine et  al., 2008a). Fasciculations and fibrillation potentials are also seen in these disorders (Maddison, 2006). Neuromyotonic discharges can be discriminated from complex repetitive discharges (CRDs) as follows: (i) they have a tendency to repeat semirhythmically (CRDs are usually random), (ii) they have longer durations, and (iii) the waning at the beginning of the discharge is fairly typical. However, it may be difficult to differentiate neuromyotonic discharges from CRDs, especially if they have similar durations. In that case, they have to be differentiated in the context of the general appearance of spontaneous activity; e.g., the presence of frequent fasciculations and myokymic discharges favors neuromyotonic discharges. The abnormal spontaneous EMG activity of PNH is usually accentuated by voluntary muscle contraction or ischemia (Maddison, 2006). Myokymic potentials are composed of fewer potentials (usually as doublets or triplets), and their intraburst frequency is lower (50–150 Hz) (Figure 1). In a burst, the interpotential interval between the last two potentials is longer than that measured between the potentials at the beginning. This reflects slow potassium conductivity dependent recovery process of the nerve membrane (Figure 2B) (Kleine et al., 2008a). There are no major differences between the quality of the discharges observed in twitching muscles or in the muscles that bear the stiffness primarily. The discharges are much more dense in the muscles with predominant stiffness, and it is generally impossible to discriminate a calm period in the EMG screen. In contrast, the pathological spontaneous activity is more sparse in twitching muscles with less stiffness, usually permitting to see the

Figure 2 Examples for the electrophysiological findings of various PNH syndromes. (A) Neuromyotonic discharge in needle EMG. Please note the abrupt onset and end of the high-frequency discharge, the typical amplitude loss at its beginning, and fasciculations before and after the neuromyotonic discharge. (B) Doublet and triplet myokymic discharges in a patient with CFS. (C) Doublet, triplet, and multiplet rhythmical discharges in tetany. (D) Typical discharges recorded from a patient with Schwartz-Jampel syndrome.

baseline between the semirhythmically bursting potentials. These two patterns of spontaneous EMG activity can be observed in the same patient, in whom the second pattern may be observed in the twitching proximal muscles while the first one predominates in apparently rigid distal muscles (Maddison, 2006). This characteristic distribution of the symptoms, which appears to be dependent on the length of the nerves, may probably suggest that abnormal discharges can arise from every point of the motor axon, most probably, however, from the distal segments (Merchut, 2010). There are also no substantial differences between the discharges observed in neuromyotonia and CFS. The pathological spontaneous activity is considered to originate from comparable segments of the peripheral

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nerve fibers and is generated by similar mechanisms (Figure 1). However, it must be remembered that neuromyotonic discharges are seen mainly in patients with neuromyotonia in whom myokymic and other discharges are also seen more densely. On the other hand, rhythmicsemirhythmic fasciculations and rare myokymic potentials with a less dense discharge pattern predominate in CFS (Gutmann et  al., 2001b; Caress and Walker, 2002; Gutmann and Gutmann, 2004; Maddison, 2006). After showing in his cases that the abnormal activity did not abolish with sleep, general anesthesia, and anesthetic blocks of the peripheral nerve trunks and was diminished by injection of curare or similar postsynaptic blockers, Isaacs (1961, 1967) proposed the terminal segments of the peripheral nerve fibers as the site of origin of the pathological discharges. The common view on this subject did not change in the subsequent era and was confirmed in different ways; e.g., the report of two neuromyotonia cases whose anesthetic nerve block-resistant discharges disappeared after intramuscular injections of botulinium toxin, which has a presynaptic mechanism of action, contributed to restrict the site of discharges to the terminal presynaptic segments of the motor nerve fibers (Deymeer et al., 1998; Arimura et al., 2005). In CFS cases with mild clinical and EMG findings, some other electrophysiological methods can be used in order to substantiate the presence of PNH. In motor conduction or F wave studies, recording the afterpotentials or

cramp discharges following the compound muscle action potentials elicited by supramaximal peripheral nerve stimulation can be useful (Figure 3) (Tahmoush et  al., 1991). Giving a train of nearly five supramaximal stimuli may facilitate these afterdischarges. However, it should be kept in mind that afterpotentials can also be observed in normal individuals by applying high-frequency trains. In studies performed in normal subjects and in patients with PNH and peripheral neuropathy, it has been proposed that CFS cases can be discriminated with reasonably high sensitivity and specificity by using repetitive trains of   ≤  10 Hz (Benatar et al., 2004; Bodkin et al., 2009). The highest positive results have been reported with recordings obtained from the muscles of the sole. Therefore, it can be recommended to begin the test with tibial nerve stimulation while recording from the abductor hallucis muscle with trains of five at 1 Hz, and in case of negative results, the test can be repeated with higher frequencies until 5 Hz, by leaving convenient intervals between the trials (Benatar et al., 2004; Harrison and Benatar, 2007). Although motor and sensory nerve conduction studies in patients with neuromyotonia or CFS are generally normal, abnormalities indicating a mild axonal neuropathy can be found in some patients (Maddison, 2006). It is possible that these axonal abnormalities are the primary pathology that leads to PNH, or alternatively, the immunologically mediated injury of axonal membrane can result in both PNH and axonopathy. There is some recent

Figure 3 After potentials that follow the compound muscle action potentials elicited by single supramaximal electrical stimulations of the relevant nerves in a patient with CFS. Ulnar nerve stimulation and abductor minimi recording on the left, tibial nerve stimulation, and abductor hallucis recording on the right figure. Compound muscle action potentials do not fit the frames due to high sensitivity recording for identification of the after discharges. R, right; ADM, abductor digiti minimi muscle; AH, abductor hallucis muscle.

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244      C.I. Küçükali et al.: Peripheral nerve hyperexcitability syndromes evidence supporting the second hypothesis (Rubio-Agusti et al., 2011). Serum creatine kinase levels are also elevated in a high proportion of the cases, reflecting the presence of an inflammatory or nonspecific muscle damage that has been histopathologically found in some patients (Merchut, 2010; Rubio-Agusti et al., 2011). Macro-EMG in two patients with neuromyotonia has revealed that macro-MUPs triggered by spontaneous discharges were smaller than those triggered by voluntary activation, providing an additional evidence that the main generator site in neuromyotonia is distal arborizations of the motor nerves (Arimura et al., 2005).

Pathogenesis Autoimmune factors associated with PNH The research accomplished in the last two decades has provided strong evidence that generalized neuromyotonia, which was formerly called as ‘primary’ or ‘idiopathic’, has generally an autoimmune origin. Moreover, it has been shown that in most of the cases, this autoimmune mechanism causes the disease by disturbing the function of voltage-gated potassium channels (VGKC) (Newsom-Davis and Mills, 1993; Odabasi et al., 1996; Vincent et al., 1998; Nagado et al., 1999; Hart et al., 2002; Newsom-Davis et al., 2003). Neuromyotonia patients often present with other autoimmune diseases such as Graves disease, systemic lupus erythematosus, rheumatoid arthritis, and myasthenia gravis (Le Gars et al., 1997; Mygland et al., 2000; Hart et  al., 2002; O’Sullivan et  al., 2007). Moreover, penicillamine treatment, which is known to trigger several autoimmune diseases such as myasthenia gravis, might also induce neuromyotonia symptoms (Reeback et  al., 1979). Some neuromyotonia patients exhibit increased cerebrospinal fluid immunoglobulin G (IgG) index values and oligoclonal bands, suggesting intrathecal autoantibody production (Newsom-Davis and Mills, 1993). Thymoma, another characteristic accompaniment for autoimmune diseases, is detected roughly in 20% of neuromyotonia patients, and some of these patients also develop myasthenia gravis and acetylcholine receptor antibodies (Halbach et al., 1987; Helm et al., 2008). Other tumor types such as small cell lung cancer might be detected in neuromyotonia cases, supporting the paraneoplastic autoimmune origin of this disease (Hart et  al., 2002; Newsom-Davis et al., 2003; Viallard et al., 2005). Initial clues for the involvement of a humoral factor in neuromyotonia pathogenesis have emerged from treatment

trials. Long before demonstration of autoantibodies, antibody-depleting treatment methods such as plasma exchange (PE) have been shown to ameliorate clinical and electrophysiological findings of PNH syndromes (NewsomDavis and Mills, 1993). Although passive transfer of serum IgG from neuromyotonia patients has not induced overt clinical findings, isolated phrenic nerve and diaphragm preparations of IgG-injected mice have shown increased acetylcholine quanta release per nerve impulse (Shillito et  al., 1995). Additionally, administration of IgG isolated from neuromyotonia patients onto dorsal ganglion-derived cultured neuronal cells has led to increased electrophysiological activity and reduced potassium channel currents (Shillito et  al., 1995). Overall, these findings have implicated the presence of serum IgGs causing neuronal hyperexcitability in neuromyotonia patients. VGKCs are abundantly expressed at the cell body membrane, axons, and nerve terminals of both central and peripheral nervous system neurons and are known to significantly contribute to repolarization and maintenance of the resting membrane potential. Inhibition of neuronal potassium channels with toxins or chemicals such as α-dendrotoxin and 3,4-diaminopyridine leads to increased membrane excitability and spontaneous action potential discharges. Mutations of the VGKC subunits are among the leading causes of hereditary neuromyotonia as well as familial episodic ataxia/myokymia syndrome (Baker et al., 1987; Wang et al., 1993; Browne et al., 1994; Boland et al., 1999; Gutman et al., 2005). Therefore, not surprisingly, antibodies that immunoprecipitate [125I]-α-dendrotoxin-labeled VGKCs extracted from mammalian brain tissue have been identified in patients with neuromyotonia, CFS, Morvan’s syndrome, and limbic encephalitis and more rarely with other neurological disorders such as adult-onset epilepsy, intestinal pseudo-obstruction, and immune-mediated polyneuropathies (Tan et al., 2008; Irani et al., 2010, 2012; Lancaster et al., 2011; Lee et al., 2013; Liewluck et al., 2014). These antibodies have been found in about 30–40% of neuromyotonia cases, and notably, PNH patients with multiple myokymic discharges have been shown to be more likely to exhibit VGKC antibodies than those with normal needle EMG results (Hart et al., 2002). Since dendrotoxin avidly interacts with VGKC Kv1 subunits, these antibodies were long assumed to interact directly with the VGKC subunits (Buckley et al., 2001; Harvey and Robertson, 2004; Vincent et  al., 2004; Tan et  al., 2008). However, recent immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with VGKC antibodies predominantly react with two proteins that are complexed with potassium

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channels on the neuronal membrane: contactin-associated protein-2 (CASPR2), which is localized at the juxtaparanodes of myelinated axons, and leucine-rich, glioma inactivated 1 (LGI1), a neuronal secreted protein that interacts with presynaptic ‘a disintegrin and metalloprotease domain’ (ADAM) 23 and postsynaptic ADAM 22 and is most strongly expressed in the hippocampus. Antibodies directed against Tag-1/contactin-2 (associated with CASPR2) and the potassium channel Kv1 subunits are detected only in a small minority of patients with VGKCcomplex antibodies (Figure 4) (Irani et al., 2010; Lai et al., 2010; Lancaster et al., 2011). CASPR2 and LGI1 antibodies are detected individually or together in neuromyotonia, Morvan’s syndrome, and limbic encephalitis patients in varying frequencies. While CASPR2 antibody is more frequently associated with neuromyotonia or Morvan’s syndrome, LGI1 antibody is generally found in limbic encephalitis patients. Moreover, CASPR2 is more often associated with an underlying neoplasm (mostly thymomas) and accompanying autoimmune disorders such as myasthenia gravis (Irani et al., 2010; Vincent and Irani, 2010). Morvan’s syndrome patients are typically male patients ( > 90%) with VGKCcomplex antibodies (roughly 80%) and thymoma (about half of the patients) (Irani et  al., 2012; Lee et  al., 2013). In contrast, VGKC-complex antibodies are found much more rarely in CFS patients, and these patients display malignancies very infrequently. Moreover, antibodies of the seropositive CFS patients are mostly directed against uncharacterized VGKC-complex proteins and rarely against LGI1 or CASPR2 (Liewluck et al., 2014). CASPR2 antibody can also be detected in patients with symptoms suggestive of motor neuron disease and acute or chronic axonal sensorimotor polyneuropathy presenting with electrophysiological findings that are suggestive of PNH (e.g., widespread fasciculations, fibrillation potentials, spontaneous motor unit discharges). These patients may or may not display typical neuromyotonic discharges described above. While these patients generally have neuromyotonia or other PNH symptoms, some CASPR2 antibody positive polyneuropathy patients may not exhibit PNH-related symptoms such as fasciculations, cramps, and autonomic symptoms (Lancaster et al., 2011; Tüzün et al., 2013). Notably, CASPR2-deficient mice display normal nerve conduction study values, suggesting that other as yet uncharacterized antibodies found in CASPR2-antibody-positive sera might be causing polyneuropathy symptoms (Poliak et  al., 2003). VGKC-complex autoantibodies have been defined in neuromyotonia patients stung by a wasp, exposed to staphylococcus septicemia or human papilloma virus vaccination, suggesting

Figure 4 Schematic illustration of VGKC-complex proteins (Kv1 subunits of VGKC, leucine-rich glioma inactivated 1 [LGI1], contactinassociated protein-2 [CASPR2], and contactin-2) that are coimmunoprecipitated in the α-dendrotoxin radioimmunoassay and are commonly targeted by the primary PNH patients’ antibodies. LGI1 antibodies inhibit the interaction between LGI1 and ADAM (a disintegrin and metalloprotease domain) proteins. Membrane topology with the membrane spanning segments (S1–S6) and the pore region (P) is noted. Based on data from Vincent et al. (2011) and Boland et al. (1999).

that certain microorganisms and venoms might induce VGKC autoimmunity (Maddison et al., 1998; Turner et al., 2006; Cerami et al., 2013). Regardless of the clinical syndrome, both LGI1- and CASPR2-antibody-positive patients give good response to immunotherapies including corticosteroids, intravenous immunoglobulins (IVIg), and PE, and antibody levels are reduced in parallel with clinical and electrophysiological amelioration (Vincent et al., 2004; Irani et al., 2010). However, patients with thymoma have a relatively poor prognosis (Irani et al., 2010). Based on the positive response to immunotherapy in most CASPR2- and LGI1-antibody-positive patients, clinical symptoms are most likely induced in VGKC-complex-antibody-positive patients by functional neuronal dysfunction caused by antibody-mediated downregulation of VGKC currents and reduced repolarization (Tomimitsu et  al., 2004). In vitro studies have shown that LGI1 antibodies disrupt the interaction between LGI1 and ADAM22/23 and reduce α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor expression (Ohkawa et  al., 2013). Although VGKC-complex antibodies are

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246      C.I. Küçükali et al.: Peripheral nerve hyperexcitability syndromes mostly of the noncomplement fixing IgG4 isotype (Vincent et al., 2011), complement deposits have been detected in the brain specimens of VGKC-complex-antibody-positive encephalitis patients, suggesting that complement mediated neuronal destruction might also have a pathogenic significance in central nervous system complications of VGKC autoimmunity (Bien et  al., 2012). However, there is no direct evidence for the involvement of complement activation in PNH syndromes. Mechanisms by which CASPR2 antibodies exert their pathogenicity still need to be characterized. Notably, myasthenia gravis patients with muscle-specific kinase antibody and without VGKCcomplex antibodies have recently been shown to display clinical and electropyhsiological findings of PNH, suggesting that there might be many other PNH-related antibodies pending to be characterized (Simon et al., 2013).

Genetic factors and other conditions associated with PNH In a small number of the cases with neuromyotonia, genetic mutations (mainly of the potassium channel subunits), exposure to toxic chemicals or drugs, and

coexistence of acquired or hereditary neuropathies and lower motor neuron diseases have been reported (Table 1) (Devathasan et al., 1984; Petiot et al., 1993; Odabasi et al., 1996; Toyka et al., 1997; Lance, 1998; Zhao et al., 2014). Experimental animals with VGKC subunit Kv1.1 mutations display neuromyotonic and myokymic discharges with the same frequencies and phenotypes observed in PNH patients. Further supporting the role of VGKC-complex in PNH syndromes, transfection of Xenopus oocytes with mutated Kv1.1 subunit channels leads to significantly smaller VGKC currents, as compared to those transfected with wild-type Kv1.1 channels (Ishida et al., 2012). It is possible to observe neuromyotonic and myokymic potentials electromyographically (and the muscle twitches and myokymias they cause clinically) in some patients with diffuse and focal peripheral nerve diseases. Furthermore, the immunological mechanisms that cause PNH are not present in these patients. As seen in Figure 5, the most common feature in these conditions is focal or widespread segmental demyelination of the peripheral nerves. It has been proposed that the pathological discharges originate from the demyelinated segment or from any point of the nerve membrane distal to that segment. Inflammatory demyelinating polyneuropathies

Figure 5 In primary PNH, the pathological processes are mainly immune mediated and affect the function of VGKCs. The most frequent causes of secondary PNH syndromes are segmental/multisegmental demyelination of the peripheral nerves and ­metabolic changes in the microenvironment of the nerves. The exact mechanisms of PNH in amyotrophic lateral sclerosis (ALS) remain to be determined. PNS, peripheral nervous system; CNS, central nervous system; CFS, cramp fasciculation syndrome.

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C.I. Küçükali et al.: Peripheral nerve hyperexcitability syndromes      247

(Guillain-Barré syndrome [GBS], chronic inflammatory demyelinating polyneuropathy, and the other chronic forms with multifocal involvement), some hereditary demyelinating neuropathies, radiation neuropathies, and entrapment neuropathies (myokymic discharges observed in the muscles innervated by the branches distal to the injury site) can be placed in this list (Van Zandycke et al., 1982; Auger, 1994; Boyaciyan et al., 1996; Oge et al., 1996). Facial myokymias caused by segmental demyelinating lesions of the facial nerve such as those seen in GBS or tumor compression can be included in the same list. However, facial myokymia observed in patients with intrinsic brainstem lesions (multiple sclerosis plaques or other causes) is caused by nuclear hyperexcitability and characterized by a different kind of abnormal EMG activity (Oge et  al., 2005). There are focal demyelinating lesions of the facial or trigeminal nerves in patients with hemifacial and hemimasticatory spasms. However, the electrical discharges and the resulting abnormal movements are different in these disorders; e.g., tonic-clonic spasms of the mimic muscles are seen in the former and abnormal undulating movements of the masticatory muscles are observed in the latter. On the other hand, persistent facial myokymia associated with VGKC-complex antibodies has been reported, implying that this symptom can also occur as a mild and localized form of primary PNH syndromes (Gutmann et al., 2001b). Fasciculations, myokymias, and cramps, which occur with the intensification of the former two, may arise from the changes of the chemical microenvironment of the peripheral nerves. These can result from physiological (exercise or pregnancy) or pathophysiological (dehydration or tetany) conditions (Zambelis et al., 2009). Doublet and triplet discharges of the evolving tetany are very typical, which are followed by an interference pattern when the cramps occur (Figure 2C). Amyotrophic lateral sclerosis (ALS) is one of the clinical conditions in which fasciculations are most commonly encountered. It has been claimed that some of the fasciculations in ALS originate from the peripheral motor neurons, some from the motor axons, and the others from the motor cortex (Kleine et al., 2008b; Eisen, 2009). The fasciculations of ALS can partially be differentiated from those observed in PNH by their complex shapes and nonrhythmiticity. On the other hand, PNH can be discriminated in EMG examination by the simple shapes of the fasciculation potentials and the normal MUP activity with voluntary contraction without neurogenic changes. However, an ‘intermediate syndrome’ has been reported in which the initial clinical and electrophysiological findings of CFS were followed by limited progressive lower

motor neuron loss, emphasizing the difficulty of discriminating autoimmune PNH disorders from motor neuron diseases in at least some of the patients (De Carvalho and Swash, 2011). Lastly, some conditions need to be mentioned due to their potential of being classified as PNH because of some peculiar aspects of their characteristics. Some patients with ‘painful legs and moving toes’ syndrome have rhythmic-semirhythmic discharges in their muscles in the EMG examinations (Hassan et  al., 2012). It can be considered that this etiologically nonhomogenous syndrome can be formed by mechanisms similar to those seen in PNH in a fraction of the patients. Recently, it was claimed that the typical electrical discharges of the Schwartz-Jampel syndrome arise from the peripheral nerves, which show preterminal nerve and neuromuscular junction remodeling (Figure 2D) (Echaniz-Laguna et  al., 2009; Bauché et  al., 2013). It would be necessary to include this syndrome among the secondary PNH syndromes if this claim is proven to be true in the future. However, the fixed frequencies of the discharges and the low jitter between them weaken the probability of their peripheral axonal origination.

Management The management of primary PNH syndromes can be discussed in two sections. The first section consists of symptomatic treatment with antiepileptics that should be considered for all patients, if symptoms are severe enough to interfere with daily activities. Symptoms and signs of neuromyotonia and CFS usually respond well to phenytoin and carbamazepine. These drugs presumably decrease the abnormal activity by their effects on the voltage-gated sodium channels (Maddison, 2006; Merchut, 2010). The response to valproate, lamotrigine, and acetazolamide is also good. Recently, the effectiveness of gabapentin and mexiletine in alleviation of symptoms was reported (Caress and Walker, 2002; Dhand, 2006; Ganos et al., 2011). Symptomatic treatment of PNH with these drugs should be used in patients with severe disturbing symptoms. However, if symptoms are mild, the course of the disease is prolonged, and response to the drugs administered in rational doses is insufficient, symptomatic treatment can be refrained by informing the patient about the expected benign course of the disorder. The accumulating evidence on the autoimmune origins of the primary PNH syndromes has brought up the immunomodulatory treatments. Patients responding to prednisone and azathioprine treatment have been

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248      C.I. Küçükali et al.: Peripheral nerve hyperexcitability syndromes frequently reported. PE, IVIg, or high doses of intravenous prednisone can be used in patients with a rapid course and severe symptoms. Although satisfactory results can be obtained by these treatments in some cases, in others, immunomodulatory treatments do not provide an effect more than that obtained by the symptomatic treatment alone (Maddison, 2006; Skeie et al., 2006; Feasby et al., 2007; Elovaara et al., 2008). On the other hand, in some patients whose symptoms cannot be kept under control with symptomatic treatment, immunomodulatory treatment is needed for both induction of remission (e.g., with IVIg or PE) and maintenance of the response (e.g., with oral steroids and/or other oral immunosuppressants). This is most probably valid in patients with severe symptoms and signs, especially those with Morvan’s syndrome (Merchut, 2010; Kim et al., 2013a,b). It has been recommended to be careful in neuromyotonia patients who will be given general anesthesia because of the likely hypersensitivity to muscle relaxants due to downregulation of acetylcholine receptors in response to chronic high agonist (acetylcholine) concentrations (Ginsburg et al., 2009; Kim et al., 2013a,b). Because of the known association of PNH and malignant tumors (primarily thymomas, lung carcinomas, and less frequently lymphomas) and other autoimmune diseases (myasthenia gravis and others), it is important to perform clinical investigations to search for these disorders (and to treat them accordingly) if they already have not become overt before the diagnosis of PNH (Maddison, 2006). Thymoma probably represents the most important association for PNH, since it is the most common tumor associated with PNH syndromes. The probability of its occurrence increases if symptoms of myasthenia gravis are present. PNH symptoms and signs can herald the recurrence of a previously treated thymoma (Skeie et al., 2006; Abou-Zeid et al., 2012; Rana et al., 2012; Fleisher et al., 2013).

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