Complaints referable to muscle such as pain, spasm, stiffness, fatigue and/or abnormal movements within a muscle are commonplace in the practice of medicine. As the cause is often elusive, both patients and physicians may become frustrated as many with these complaints will remain undiagnosed despite thorough investigation. There are many sources for this diagnostic elusiveness. With the exception of cramps and fasciculations, the disorders described in this chapter are uncommon. In addition, most of the disorders that will be described have nonspecific and overlapping clinical features. Successful diagnosis requires a heightened index of clinical suspicion, detailed knowledge concerning each disorder’s phenotypic characteristics, and awareness of the serologic and electrodiagnostic (EDX) features of each syndrome.

Motor nerve hyperactivity disorders frequently result in reduced exercise intolerance and impaired mobility. They originate from numerous central and neuromuscular system localizations. This chapter will restrict itself to disorders thought to originate from motor nerves and the upper motor neurons that control them. Cramps, fasciculations, tetany, tetanus, the cramp–fasciculation syndrome (CFS), Isaacs syndrome (IS), Satoyoshi syndrome, stiff person syndrome (SPS) and hyperekplexia will all be discussed. As the differential diagnosis of many of these disorders overlaps, the majority of the differential diagnostic considerations will be primarily emphasized in the first section devoted to muscle cramping.

Historical writings on motor nerve hyperactivity disorders have been potentially confusing. Different names have been used for the same syndrome. Nomenclature to describe clinical observations has overlapped with that used to describe frequently associated electromyographic waveforms. In an attempt to avoid this, and as neurologists deeply appreciative of history and those who created it, we will be preferentially referring to these syndromes by their eponyms whenever appropriate. We will also follow the suggestion of Gutmann et al.¹ by using a single term (e.g., fasciculations, myokymia) to refer to clinically observed phenomenon and refer to EDX waveforms as potentials or discharges (e.g., fasciculations potentials, myokymic discharges).

CLINICAL FEATURES

Cramps refer to a sudden, involuntary, and painful shortening of an entire muscle belly accompanied by a squeezing sensation and visible, palpable muscle induration. As cramps tend to incorporate multiple if not all the motor units in one or more muscles, they typically generate sufficient force to induce abnormal posturing of relevant joints. Cramps are characteristically relieved by massage or stretching. They have a tendency to recur if the muscle is prematurely returned to its unstretched position. They will spontaneously remit within minutes in most cases.

Cramps occur commonly. Their prevalence in a “normal” population is estimated at 35% in one study and in 95% of young, healthy people who recently initiated exercise in another.^2,3 Their prevalence is increased in the elderly, in pregnant females, and subsequent to exercise in those who have recently begun unaccustomed activity. Cramps are a considerable source of morbidity for afflicted individuals, particularly if nocturnal. In the majority of cases however, they are unassociated with serious disease and considered benign. Benign cramps are most prevalent in the calf. Familial cramp syndromes have been reported.

Pathologic cramps as a symptom of an underlying neuromuscular disease occur less frequently. Although potentially representative of nerve or nerve root diseases, their most notorious if not frequent association is with the motor neuron diseases (MND). Cramps may represent an early symptom in amyotrophic lateral sclerosis (ALS) X-linked bulbospinal atrophy or multifocal motor neuropathy.^4,5 In MND, they are frequently mentioned in passing and represent a minor component of the illness in most but may represent a significant source of morbidity in some. Like fasciculations, they tend to dissipate as the disease progresses.

In general, benign cramps occur at rest or following exercise. In our experience, cramping provoked by manual muscle testing occurs with some regularity in MND patients. Exertional cramping during protracted or intense exercise is more typically associated with metabolic muscle disease and has been reported as an uncommon phenotype of Becker muscular dystrophy.⁶

Fasciculations, unlike cramps, represent the discreet, random contraction of the muscle fibers in an individual motor unit. Unlike cramps, the patient may not be aware of them. As fasciculations represent activation of a single motor unit, movement at a relevant joint is uncommon. In our experience, if movement at a joint if occurs, it tends to be seen in situations where reinnervated and enlarged motor units act on a small joint, for example, the first dorsal interosseous on the metacarpophalangeal joint of the index finger. Fasciculations, when occurring in isolation, are typically benign. Characteristics of benign fasciculations are their tendency to occur repetitively for seconds at a single site, in a single muscle.⁶ Fasciculations occurring in multiple locations in one muscle or multiple muscles simultaneously is disconcerting as is the concomitant finding of weakness, atrophy or hyperreflexia.

Cramps and fasciculations occurring in concert are also a cause for concern and increase the likelihood of an underlying neuromuscular disease, particularly when not localized to a singular muscle like the calf. This association may suggest CFS in which patients experience myalgias, cramps, stiffness, myokymia, and fasciculations that occur in some combination. The symptoms of CFS are frequently provoked by exercise and promote exercise intolerance. Eight of nine initially reported cases were considered vocationally disabled.⁷ In our estimation, CFS may be conceptualized as a limited expression of IS with which it may share not only clinical but serologic and/or electrophysiologic features.^8,9 Further support for the association is provided by the observation that some patients with CFS have features of an encephalopathy analogous to Morvan syndrome, an IS variant.¹⁰

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Muscle cramps remain a largely clinical diagnosis dependent for the most part on patient description. Differential diagnostic strategies are twofold: (1) to distinguish cramps from other causes of unwanted muscle contraction and pain and (2) to identify an underlying cause for the cramping. Cramps represent one of many potential causes of myalgia or muscle pain.

The differential diagnosis of cramps includes disorders originating from the central nervous system (CNS) and other neuromuscular locations. Although the mechanism of unwanted muscle activation is not fully understood in many of the following disorders, it may be accurate to conceptualize neural disorders of involuntary muscle contraction as positive events resulting from a lower threshold for nerve activation or prolonged depolarization. In contrast, myopathies producing unwanted muscle contraction may be considered as a negative phenomenon, that is, a failure of muscle relaxation after voluntary activation. Myopathies capable of producing involuntary muscle contraction, myalgia or/and stiffness will be covered more extensively in later chapters of this text but will be briefly mentioned here for completeness.

Myotonia may be considered as the prototypic disorder of failed muscle relaxation. Myotonia differs from benign cramps in that it is typically painless and provoked by muscle activation. Myotonia is characterized by a completely different EDX signature, that is, myotonic as opposed to cramp discharges demonstrable with needle electromyography.

As described above, metabolic myopathies may produce unwanted muscle contraction, induration and myalgia by physiologic contracture. These inherited defects result in most cases from impaired glycogen or lipid metabolism, leading to muscle energy failure, and resulting in painful muscle shortening. Intense or protracted exercise is typically required to deplete readily available muscle fuel sources and provoke contractures. Physiologic contractures are also distinguished from cramps by their EDX signature of electrical silence which is also a feature of rippling muscle and Brody diseases.

Rippling muscle disease (RMD) is clinically defined by observation of wave-like rippling of muscles, typically provoked by muscle stretch or percussion. Patients may complain of muscle stiffness and muscle hypertrophy may be observed on examination.¹¹ RMD can be inherited in an autosomal dominant fashion caused by mutations of the caveolin-3 gene. The reader is referred to Chapter 27 for further discussion regarding the evaluation of the numerous phenotypes associated with mutations of this gene, including LGMD1 C. RMD may occur as an autoimmune disorder as well with clinical, EDX and serologic manifestations that overlap with other motor nerve hyperactivity disorders. This belief is based upon an apparent association with myasthenia gravis, thymoma and detection of autoantibodies such as acetylcholine receptor binding (AChRB), voltage-gated potassium channel (VGKC) or neuronal ganglionic acetylcholine receptor (NGAChR).^10–12 Unlike disorders of motor nerve hyperactivity, the EDX signature of rippling muscles is electrical silence. The EDX examination, however, may identify features of an underlying myopathy.^10,11 Patients with RMS typically have a 3–25-fold increase in their serum CK levels.¹¹

Brody disease is another rare inherited myopathy producing physiologic contractures through disruption of calcium reuptake within the sarcoplasmic reticulum of muscle.^13,14–17 It results from a mutation in the in the fast-twitch skeletal muscle sarcoplasmic reticulum Ca–ATPase gene (SERCA1) in some but not all cases.^17,18 Its morbidity stems from impaired muscle relaxation that is exercise-induced, associated with stiffness affecting muscle of the limbs and face. A more detailed description may be found in the chapter describing the nondystrophic myotonias. Cold may aggravate the symptoms of Brody disease as it may aggravate the stiffness associated with myotonic disorders.

Malignant hyperthermia and neuroleptic malignant syndrome are other disorders resulting in unwanted muscle rigidity, typically recognized by associated signs and symptoms and the context in which they occur. Malignant hyperthermia is an inherited disorder and like Brody disease represents disordered sarcoplasmic reticulum function. The neuroleptic malignant syndrome appears to be related to dopaminergic receptor dysfunction, presumably within the CNS.

The palmaris brevis syndrome is characterized by a spontaneous, irregular, nonpainful contraction of the palmaris brevis muscle resulting in “wrinkling” motions of the palm.¹⁹ It has been associated with C8-T1 radiculopathy, pathology of the deep branch of the ulnar nerve in Guyon canal, and occupational risk. The EDX features of the palmaris brevis syndrome have been reported as spontaneous rapid discharges of single MUAPs of normal morphology and myokymic discharges associated with normal motor and sensory conduction studies.

Focal dystonias such as writer’s cramp produce unwanted muscle contraction and are uncomfortable although are typically not as painful as cramps. They are most readily identified by the characteristic activities that provoke them.

The characteristic features of all of these disorders are involuntary muscle contraction and the stiffness that may accompany it. Many of these disorders are accompanied by discomfort or pain. The differential diagnosis of disorders that are dominated by generalized or focal myalgias, unassociated with unwanted muscle contraction, stiffness and movement is far more extensive and exceeds the scope of this book. The reader is referred to an excellent review article on cramps for a comprehensive list of these conditions.²

The differential diagnosis of cramps also has to take into consideration whether the cramps are primary or secondary in their etiology. The latter is defined by their association with another underlying illness. Primary cramping occurs with the greatest frequency in calf and intrinsic foot muscles and as previously mentioned in older individuals, often at rest (particularly at night) or following unaccustomed exercise.² Volume depletion is generally considered a benign cause of cramping that may be related in turn to exercise, hemodialysis, emesis, diarrhea, and diuretic use.

Secondary cramping (Table 10-1) associates with a variety of toxic or metabolic disturbances and the MNDs. These associated conditions are identified through careful history taking, and by clinical, EDX, and judicious laboratory assessment. Metabolic conditions associated with cramping include hypoadrenalism, hypothyroidism, pregnancy, uremia, and cirrhosis. Cramps may also be hereditary in nature, either related or unrelated to a definable disease. Cramps may be provoked by a number of medications (Table 10-1). Finally, cramps and fasciculations are most commonly associated with disorders of anterior horn cells and to a lesser extent neuropathy and radiculopathy.²

LABORATORY FEATURES

The EDX evaluation of patients with suspected cramps is done primarily to exclude secondary causes of cramping such as MND or to identify other forms of spontaneous discharges that might suggest an alternative cause of motor nerve hyperactivity. The EDX signature of cramping is the cramp discharge, an involuntary, often irregular and “sputtering” discharge of multiple, normal appearing motor unit action potentials (MUAPs). Cramp discharges begin abruptly and fire at a collective frequency of up to 150 Hz.²⁰ Cramp discharges are most commonly encountered in normal individuals during activation of the gastrocnemius muscle. They are usually readily identifiable by both their morphologic characteristics and firing pattern. The discharges are made up of multiple, normal MUAPs. Like the cramp itself, the number of MUAPs contributing to the cramp discharge builds up and then dissipates. Fasciculation potentials may be recognizable both at the initial and terminal portions of cramp potentials.

In SPS and tetanus, the MUAP is typically less dense and more continuous without the aforementioned crescendo decrescendo pattern. A more commonly occurring potential EDX mimic of cramp potentials is normal, voluntarily activated MUAPs in patients who have an underlying tremor or are experiencing respiratory alkalosis related to anxiety or hyperventilation. MUAPs in this situation are also normal but differ as they are voluntarily activated and discharge in clusters. Once again, the similarities are based on waveform morphology, not firing pattern. End-plate potentials are the waveform most likely to be confused with cramp discharges based upon firing pattern. They discharge with the same sputtering pattern as cramp discharges but their waveform morphology is readily distinguishable.

The EDX signatures of other disorders of muscle induration and stiffness when symptomatic are typically distinctive. They include the electrical silence of the muscle diseases as described above, the myotonic discharges seen in the myotonic disorders, and the myokymic, grouped and neuromyotonic discharges characteristic of IS.

In a patient with true cramps, it would be reasonable to obtain blood for thyroid stimulating hormone (TSH), creatinine, magnesium, and calcium as well as to assess for orthostatic hypotension and serum potassium as screening tests for adrenal insufficiency. Genetic testing for familial forms of MND (ALS, pediatric and adult spinal muscular atrophy) may be considered if warranted by clinical and EDX context. An elevation in serum CK in a patient with cramping may be more confounding than helpful. If cramps are persistent, an elevation of serum CK may occur and may take 3–8 days to normalize.²¹ This is important to recognize so as to not assume CK elevations in this setting implicate an underlying MND.

Fasciculation potentials are readily recognized electromyographically by their morphology and firing pattern. They are MUAPs that fire individually in a random fashion unlike those that are voluntarily activated (Fig. 10-1). Consecutive fasciculation potentials usually represent different motor units. Like fasciculations, the distinction between benign and pathologic fasciculation potentials is in a large part determined by the clinical and electrophysiologic company that they keep. Attempts to assign pathologic significance to fasciculation potentials based on their morphology has been described, but in our opinion is of more academic than pragmatic clinical interest.^22–24 Unlike many of the other disorders described in this chapter, fasciculations occurring in isolation do not appear to have an autoimmune etiology. In one study, no patient with benign fasciculations had autoantibodies directed against either the VGKC or NGAChR that may be found in other disorders of motor nerve hyperactivity described in this chapter.¹⁰ Unless there is clinical or EDX suspicion of a secondary cause for fasciculations, no blood work is required.

The EDX findings in CFS include fasciculation potentials, cramp discharges, multiplets and even neuromyotonic discharges.⁹ In addition, repetitive stimulation of peripheral nerves may produce afterdischarges in some cases in a manner similar to IS although the specificity of these after-discharges has been called into question (Fig. 10-2).^8,25 Other EDX abnormalities including myokymic and complex repetitive discharges; fibrillation potentials and positive waves; and morphological changes of MUAPs suggesting chronic partial denervation and reinnervation are typically notable for their absence.^7,26 Patients with CFS may possess circulating VGKC (16%) or neuronal ganglionic NGAChR (6%) antibodies.^9,10,27–29

In patients with complaints of cramps and/or fasciculations, it is our tendency to be conservative in our testing unless there are historical or examination features of concern. A family history suggestive of neuromuscular disease, visible fasciculations or other adventitious movements of muscle such as myokymia or muscle weakness/atrophy would be indications for EDX testing. We would reserve autoantibody testing for patients who complain of muscle stiffness in the absence of apparent extrapyramidal disease, particularly if associated with either clinical or EDX evidence of motor nerve hyperactivity such as widespread cramps or cramp potentials, fasciculations or fasciculation potentials, myokymia or myokymia discharges, spontaneously discharging high-frequency multiplets or neuromyotonic discharges.

HISTOPATHOLOGY

Patients with CFS may have features of neurogenic atrophy with muscle biopsy.⁷ As neurogenic atrophy can be accurately and less invasively be predicted by electromyographic examination, and as muscle biopsy rarely identifies the etiology of the neurogenic condition, muscle biopsy is uncommonly performed in these patients.

PATHOGENESIS

The weight of experimental evidence supports a neurogenic origin for both cramps and fasciculations.² Specifically, the generator appears to be located within distal nerve terminals. There are a number of lines of evidence to support this. Cramps can be provoked in normal humans by repetitive stimulation of motor nerves distal to a complete, pharmacologically induced nerve block.³⁰ Cramps are often preceded and followed by fasciculation potentials implicating a shared generator. The waveform morphology of cramp potentials is that of MUAP. This does not preclude a CNS generator but diminishes the likelihood of a muscle or neuromuscular generator. Cramps may seemingly occur in a single muscle at any given time, sparing other muscles in the same myotome, making a CNS generator unlikely.

Even though cramps occur more commonly in patients who are pregnant or who exercise, no measurable metabolic differences have been identified in either group compared to those who do not experience cramping.² Cramping has been precipitated by infusion of hypotonic fluids implicating fluid or solute movement between extracellular and intracellular compartments as the causative mechanism.²

TREATMENT

Evidence to guide clinicians in the prevention and treatment of cramps is limited and may be reviewed in an American Academy of Neurology (AAN) evidence-based publication.³¹ Prevention of cramping related to exertion and fluid loss can be attempted with the prophylactic use of salt tablets, hydration, and routine or pre-/post-exercise stretching. Successful prevention of cramps occurring under other circumstances may be achieved with the avoidance of offending drugs or when necessary, by using prophylactic medication.^2,31 Typically, these agents are dispensed preferentially at night, as sleep interruption is usually the most bothersome source of morbidity. Medications that have been used for this purpose are reviewed in Table 10-2. Of these, only quinine sulfate has achieved level A support as an efficacious treatment.³¹

Unfortunately, the FDA considers the use of quinine to be associated with unacceptable risk for any condition except malaria.³² The incidence of serious side effects with quinine is estimated at 2–4%.³¹ The official position of the AAN regarding quinidine, which can still be prescribed as Qualquin®, is that “select patients can be considered for an individual therapeutic trial once potential side effects are taken into account.”³¹ The AAN suggests that quinine be utilized in the setting of significant cramp morbidity and failure of other agents. Unfortunately, other agents possess only anecdotal or equivocal efficacy (Table 10-2).

The traditional approach to the treatment of symptomatic cramps if related to dehydration or exercise includes intravenous saline (not dextrose) solutions with electrolyte replacement.^2,31 An acute cramp can usually be aborted by stretching the involved muscle(s) although this will not necessarily prevent recurrence.

In our experience, patients who are psychologically troubled by an apparent benign fasciculation syndrome are reassured by providing them with a copy of the notable Mayo Clinic manuscript describing what is almost always a benign natural history.³³ Patients with CFS typically respond to treatment with anticonvulsants such as carbamazepine or phenytoin, again demonstrating similarities to IS.

This syndrome was first described by Denny-Brown in 1948.³⁴ Its eponym, IS, originates from the description of two patients by Isaacs in 1961 manifesting as progressive muscle stiffness associated with continuous muscle fiber activity.³⁵ IS or acquired neuromyotonia as it is commonly referred to, has also been referred to as the syndrome of continuous muscle fiber activity, normocalcemic tetany, armadillo disease, quantal squander, or generalized or undulating myokymia. Like many clinical syndromes associated with ion channel dysfunction, it may occur as either an autoimmune or a hereditary disorder. Autoimmune IS is the more common form of the disease, with or without an associated neoplasm (Table 10-3).^9,10,36,37

CLINICAL FEATURES

IS may affect individuals of any age including neonates but is most commonly a disorder of adolescents and young adults.³⁸ The cardinal clinical feature is muscle stiffness, typically provoked by use, resulting from motor nerve hyperactivity and the associated involuntary and undesired muscle contraction.^{2,9,27,35,36,41,42} A very characteristic feature is the adventitious movements that are observed in muscles, notably continuous muscle undulation or rippling (myokymia) and intermittent, focal muscle twitching (fasciculations).

The stiffness of IS has been referred to as pseudomyotonia. The use of this term is discouraged by the American Association of Neuromuscular and Electrodiagnostic Medicine and is considered ambiguous by many neuromuscular experts. Nonetheless, it is a term that is difficult to ignore in this context as pseudomyotonia has been used by many IS authors to describe a clinical phenomenon that mimics clinical myotonia. Pseudo-myotonia is distinguished from myotonia as pseudo-myotonic stiffness does not typically diminish with repetitive muscle use or during sleep and although provoked by muscle activation, is not provoked by muscle percussion.³⁶ Most importantly, unlike true myotonia, the unwanted muscle contractions of pseudo-myotonia are not associated with myotonic discharges. The involuntary contraction of pseudo-myotonia is associated with the spontaneous discharge of MUAPs in the form of one or more of the following: fasciculation potentials, myokymic discharges or erratic bursts known as multiplets. “Pseudomyotonia” often results in abnormal posturing mimicking the joint positioning of tetany such as carpopedal spasm, plantar flexion of the foot at the ankle, enhanced spinal curvature, facial grimacing, and flexion of the elbows, wrists, hips, and knee.^39,40

In contrast to the SPS, adventitious movements are highly characteristic and these movements as well as muscle stiffness tends to be more generalized at onset, affecting the limb as well as trunk muscles. From an EDX standpoint, distal muscles are more likely than proximal muscles to display abnormal spontaneous discharges.⁴³ In addition to the continuous muscle fiber activity, muscle hypertrophy, hyperhidrosis, and weight loss are frequent concomitants, all of which may result from excessive muscular activity.¹⁰ Symptoms of dysautonomia occur in as many as 93% of patients with concomitant CNS involvement (see below).^9,36,44

The signs and symptoms of IS may be generalized or focal in distribution. In addition to the limbs and trunk, the tongue, face, and pharynx may be involved resulting in difficulty in speaking (hoarseness or dysarthria) and swallowing. Dyspnea, believed to result from stiffness of chest wall muscles, was a prominent symptom in Isaacs’ initial cases.³⁵ Ocular neuromyotonia has been implicated as a cause of intermittent, spasmodic diplopia, occurring either spontaneously or in response to sustained eccentric gaze.^45–47 Ocular neuromyotonia may occur either as a component of the IS or as an isolated event following parasellar radiation. Involuntary finger flexion has also been described as an isolated manifestation of this syndrome.^48,49

The physical examination of the IS patient may include observations of stiff posture with slight trunk flexion, shoulder elevation and abduction, and elbow flexion.⁴⁰ Widespread fasciculations and myokymia are seen and appear as continuous undulating or quivering of the underlying muscles.⁵⁰ These adventitious movements may be particularly prominent in the facial, pectoral, and calf muscles and may be provoked by muscle contraction. Pseudomyotonia, like myotonia may be demonstrable as delayed relaxation of eye or hand opening following forceful eye closure or a strong grip. Length-dependent sensory loss, weakness and reflex loss are indicative of axonal polyneuropathy which occurs in approximately a third of cases.^51–53 Diminished or lost deep tendon reflexes provide another distinguishing feature from the SPS. Muscle hypertrophy may be focal or generalized.⁵⁴ The trapezius muscles may appear particularly prominent when the patient is viewed from the front.³⁵ Chvostek and Trousseau signs may be appreciated despite normal calcium levels.^55,56

IS may occur in association with other neurologic manifestations. Morvan syndrome, the most notable example of this, refers to CNS involvement occurring with peripheral neuromuscular hyperexcitability.⁴⁴ The encephalopathy of Morvan syndrome manifests as confusion, agitation, insomnia, amnesia, and hallucinations.^9,35,57,58 Seizures occur in approximately a third of cases.⁴⁴ To clarify terms, the phenotype of limbic encephalitis is considered synonymous with the CNS component of Morvan syndrome, the difference in the two disorders being the absence of peripheral manifestations (neuromyotonia) in limbic encephalitis.⁵⁹ Morvan syndrome occurs almost exclusively in males.^37,44 Despite its responsiveness to immunomodulating treatment in some cases, the natural history is variable. Cases associated with thymoma frequently have an unsatisfactory outcome.

Nonspecific complaints of numbness and paresthesia may represent either an axonal peripheral neuropathy that occurs with some frequency or persistent depolarization of sensory nerves.^44,51 The latter concept is supported by microneurographic recordings demonstrating the same spontaneous activity of sensory axons that occurs in their motor counterparts.⁵⁵ Neuropathic pain syndromes also appear linked to Morvan syndrome, with both overlapping clinical and serologic profiles.⁴⁴

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of IS is established by the clinical features, supported by the characteristic EDX findings, and in many cases, the presence of autoantibodies. The differential diagnosis of IS needs to be considered in three domains: disorders that mimic the clinical phenotype, disorders that appear to occur at increased frequency in patients with either IS or Morvan syndrome and disorders that share the EDX features of the disorder (Table 10-3).

The differential diagnosis of IS consists largely of the other disorders discussed in this chapter, as well as those previously summarized in the cramps and fasciculations section. Causes of muscle stiffness that originate from the extrapyramidal system are beyond the scope of this book. The differential diagnosis of each of the EDX features that may be seen in IS patients (fasciculation potentials, cramp, myokymic and neuromyotonic discharges, multiplets) can be found in appropriate tables in Chapter 2.

It is somewhat difficult and artificial to distinguish diseases occurring at increased frequency in IS secondary causes of IS and secondary causes of neuromyotonic discharges. Myasthenia gravis has been reported to occur in 9% of patients with neuromyotonia. The vast majority of patients with myasthenia and neuromyotonia will have the traditional binding autoantibodies in their serum directed against the nicotinic acetylcholine receptor.¹⁰ Neoplasms, particularly thymoma, may be found in as many as 40% of patients. Small cell carcinoma of the lung, Hodgkin lymphoma, and rarely plasmacytoma, ovarian, renal, bladder, and thyroid cancers occur as comorbidities in both IS and Morvan syndrome.^{9,10,44,51,52,60–64} Like other paraneoplastic disorders, IS may precede the recognition of lung cancer by years.²⁷

Neuromyotonic discharges do not occur as a universal feature of IS nor are they unique to this disorder. They can occur as a consequence of radiation injury to affected nerves.^45,46 Neuromyotonic discharges have been reported as an association with certain neuropathies, particularly those with strong demyelinating characteristics such as Charcot–Marie–Tooth disease, Guillain–Barré syndrome, and chronic inflammatory demyelinating polyradiculoneuropathy. They have been rarely described in association with ALS, amyloidosis, and rattlesnake envenomation as well as disorders also felt to have autoimmune mechanisms such as primary systemic sclerosis, systemic lupus, celiac disease, bone marrow transplantation, graft versus host disease, and penicillamine therapy.^{9,36,40,55–76} Autosomal dominant heritable neuromyotonia has been described.⁷⁶

LABORATORY FEATURES

An autoimmune basis for Isaacs and Morvan syndromes is strongly supported by the recognition that VGKC antibodies occur in both the serum and cerebrospinal fluid (CSF) in many of these patients.^{9,27,44,77,78} These autoantibodies have been demonstrated in 54% of IS patients and 79% of Morvan syndrome patients.^10,44 Although these antibodies appear to be most closely associated with these two disorders, they may occur with many other neurologic phenotypes including limbic encephalitis.^79,80 Other neuronal and often paraneoplastic antibodies (notably NGAChR, CRMP-5, amphiphysin, and antinuclear neuronal type 4 have been identified in a small portion of the Isaacs and Morvan syndrome patients.¹⁰ Patients may have other markers of autoimmunity including increased protein, immunoglobulins, and oligoclonal bands within the CSF.⁹ Serum abnormalities including elevated CK levels in IS and hyponatremia in Morvan syndrome.^44,51,80

Motor and sensory nerve conduction studies (NCS) are often normal in patients with the idiopathic or familial form of IS although may indicate a concomitant polyneuropathy in some patients.^{9,40,42,55,56,81–83} If one looks closely however, repetitive afterdischarges are often evident following standard motor conduction and F-wave studies similar to what may be identified in organophosphate poisoning (Fig. 10-2).^76,84 Microneurographic recordings demonstrate afterdischarges in sensory as well as motor nerve fibers.⁵⁴

Multiple potential types of abnormal EDX spontaneous activity characterize IS.^{9,43,75,82,85,86} Neuromyotonic, myokymic or cramps discharges, fasciculation or fibrillation potentials and positive sharp waves may occur individually or in combination.^9,43 One of the most characteristic EDX signatures of IS are spontaneous bursts of grouped MUAPs known as multiplets.⁴³ These are similar in appearance to myokymic discharges but are distinguished by their random rather than semi-rhythmic discharge pattern and by their faster intraburst frequency. Myokymic discharges typically have slower intrabursts discharge frequencies. The discharge frequency is always <150 Hz and is more typically in the 40–80 Hz range.⁸⁷ Although there is some overlap, the intraburst discharge frequency of multiplets is typically higher and overlaps with the neuromyotonic discharge range, reaching 350 Hz in some cases.⁴³

Neuromyotonic discharges, the EDX signature of IS, is a term that was presumably coined to recognize both their neural origin and their association with the clinical phenomenon of pseudomyotonia.¹ As previously mentioned, they are neither a particularly sensitive or specific for Isaacs syndrome. They may be found in any muscle including those of the face and extraocular muscles.^26,86 These discharges are provoked by needle movement or muscle contraction. They represent high-frequency discharges of single MUAPs that occur at random intervals with intradischarge frequencies of greater than 150 Hz and up to 500 Hz or intraspike intervals in the 2–5 ms range.⁸⁷ They cannot sustain themselves at these frequencies and rapidly dissipate in a decrescendo pattern.⁸⁷ It is this decrescendo pattern that distinguishes them from multiplets. They begin and end abruptly with a duration measured in seconds (Fig. 10-3). The resultant sound has been described as “pinging” or likened to the scream of a Formula 1 engine.

Myokymic discharges are seen at a greater frequency in IS than neuromyotonic discharges.⁴⁰ Their distinction from neuromyotonic discharges may be artificial in that each individual burst of discharges are felt to originate from motor nerve and are constituted from individual MUAPs.¹ Myokymic discharges are considered different from neuromyotonic discharges by their intraburst frequency as described above, by their firing pattern, and by the diseases they associate with. They are defined and recognized as spontaneously firing grouped discharges that occur in a repetitive, semi-rhythmic pattern with intervening periods of electrical silence (Fig. 10-4), thus differing from the singular decrescendo burst of a neuromyotonic discharge. Their intradischarge frequency is considerably slower than neuromyotonic discharges.²⁶ The associated sound has been likened to troops marching in unison.

The EDX of IS as described in the literature focuses on abnormal spontaneous activity. In part, this is because the abnormal spontaneous discharges may obscure the visualization of voluntarily activated MUAPs. MUAP analysis may also be confounded by the coexistence of either peripheral neuropathy or myasthenia. MUAPs in IS may be normal or may fire in multiplets, in a manner reminiscent of tetany.²³

MR imaging of the brain in Morvan syndrome is typically normal whereas positron emission tomography (PET) scanning routinely demonstrates focal or generalized hypometabolism.⁴⁴ Elevated CSF protein levels, lymphocytic pleocytosis, and/or oligoclonal banding are found in approximately half of Morvan syndrome patients.⁴⁴ Imaging of the chest is recommended to address the potential for thymoma, lung cancer, or lymphoma.

HISTOPATHOLOGY

Neither nerve nor muscle biopsy are routinely performed in suspected IS cases. If performed, sural nerve biopsies may be normal or reveal evidence of a concomitant neuropathy with a reduction in myelinated fibers numbers or evidence of demyelination.⁵⁵ Grouped atrophy and fiber-type grouping that may be demonstrable on muscle biopsy is also consistent with a peripheral neuropathy.^56,88–90 Histopathologic evidence of an inflammatory myopathy has been reported.⁵¹

PATHOGENESIS

IS is a disorder that appears to originate from terminal nerve twigs or the neuromuscular junction.³⁶ Neuromyotonic discharges are abolished by curare or botulinum toxin and persist following general or spinal anesthesia, and in most cases, proximal nerve block.^9,36,91 In some cases however, discharges appear to originate from more proximal aspects of nerve.^{36,83,86,90,92,93} These observations would be consistent with the presumed autoimmune mechanisms described below as antibodies would have the greatest access to nerve at terminal twigs and roots where the blood–nerve barrier is least well established. The observation that neuromyotonic discharges have been reported to occur in both acquired and hereditary demyelinating neuropathies begs the question as to whether ephaptic transmission may facilitate the generation of these discharges. Conversely, the prevalence of axonopathy in IS provokes the syllogistic question as to whether the axonopathy promotes or results from the peripheral nerve hyperexcitability of neuromyotonia.⁵¹

The demonstration of VGKC antibodies in the serum and CSF of IS patients in 1995 and reinforced in numerous subsequent publications have provided both incontrovertible evidence of autoimmunity and a potential pathophysiological explanation for peripheral nerve hyperexcitability.^{9,36,78,80,94} Blocking these ion channels, localized to the juxtaparanodal region of both PNS and CNS axons reduces the hyperpolarizing effect of channel activation, preventing the nerve action potential from dissipating and leading to retrograde depolarization of certain terminal twigs and reactivation of other terminal twigs belonging to the same motor unit.^36,59,95

Initial experiments demonstrated that divalent VGKC antibodies appeared to accelerate and degrade potassium channels by a cross-linking mechanism independent of complement.⁹⁶ Subsequent observations however, have shown that VGKC autoantibodies do not appear to directly adversely affect potassium channels although do reduce potassium channel current amplitude after prolonged exposure.⁵⁹ Other more specific target antigens that indirectly influence potassium channel function in Isaacs and Morvan syndrome patients have been sought for and found. These include contactin-associated protein-like 2 (CASPR2), leucine-rich glioma inactivated (LGi1), and contactin-2 antigens.^44,80,97 These have been referred to as VGKC-complex proteins.⁸⁰ CASPR2 appears to concentrate VGKC in the juxtaparanodal regions of both peripheral and CNS axons. CASPR2 autoantibodies may lead to potassium channel dysfunction through impaired clustering and appears to be the principle antigenic target in neuromyotonia.⁹⁷ LGl1 on the other hand appears to be the principle antigenic target in limbic encephalitis. That it localizes to specific brain regions in experimental animals may well explain the selected vulnerability of certain neuronal populations and the nature of the characteristic clinical manifestations of Morvan syndrome.⁴⁴