Neuromuscular Disorders 2/E

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.^13–17 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.

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

By localization

Spinal cord

• Stiff-person syndrome

• Tetanus

• Demyelination (e.g., multiple sclerosis)

Anterior horn cell diseases

• ALS

• X-linked bulbospinal muscular atrophy

• Post-polio muscular atrophy

Radiculopathy

• Compressive—discogenic/spondylotic, tumor

• Tumor infiltration

• Nonstructural (e.g., diabetes mellitus, sarcoidosis, infection, radiation-induced)

Nerve

• Multifocal motor neuropathy

• Cramp fasciculation syndrome

• Tetany

• Palmaris brevis syndrome

Muscle

• Brody disease

• Myotonic disorders

• Metabolic muscle diseases (glycogen storage, lipid storage, mitochondrial)

• Dystrophinopathy

Uncertain

• Satoyoshi syndrome

By etiology

Benign

• Advanced age

• Post-exercise

• Pregnancy

Metabolic

• Hypothyroidism

• Hypoadrenalism

• Uremia

• Cirrhosis

• Dialysis

• Dehydration with electrolyte loss

Medication (common)

• Diuretics

• Cholesterol-lowering agents

• β-adrenergic agonists

• H2 receptor blockers

• Nifedipine

• Ethanol

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 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.

ISAACS SYNDROME OR NEUROMYOTONIA

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

By localization

Neuronopathies

• ALS

Neuropathies

• Charcot–Marie Tooth disease

• Guillain–Barré syndrome

• Chronic inflammatory demyelinating polyneuropathy

• Isaacs syndrome

Disorders of neuromuscular transmission

• Myasthenia gravis

By etiology

Radiation

• Brain

• Head and neck

Neoplasia

• Small-cell carcinoma of the lung

• Thymoma

• Hodgkin disease

Drugs

• Penicillamine

Immune mediated

• Primary systemic sclerosis

• Bone marrow transplantation

Familial

• Autosomal dominant neuromyotonia

Amyloidosis

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).

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.

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

Support for the clinical observations of paresthesias, sensory neuropathy, or neuropathic pain syndromes in IS patients comes from passive transfer experiments that have demonstrated increased quantal content and repetitive firing of dorsal root ganglia cells in mice injected with sera from patients with IS.⁷⁸

TREATMENT

Various forms of immunotherapy have partial efficacy in patients with IS. There is no standard algorithm. As a general rule, treatment protocols couple symptomatic treatment with immunosuppression. Plasma exchange (PLEX) and intravenous immunoglobulin (IVIG) are generally considered to have a faster onset of action than oral immunomodulating drugs. Although either may be effective, there is a general consensus that PLEX is the more effective of the two in IS. Azathioprine or corticosteroid treatment are usually utilized in addition in an attempt to avoid the inconvenience and cost associated with maintenance IVIG or PLEX.^{9,81,98–102} Rituximab may be a reasonable option in refractory cases of Isaacs syndrome; this may be more cost-effective than frequent maintenance courses of IVIG or PLEX, but one needs to consider the small but consequential risk of infection, including progressive multifocal leukoencephalopathy.

Symptomatic treatment with antiepileptic medications that block sodium channels such as phenytoin or carbamazepine or decrease neuronal excitability through other mechanisms (e.g., baclofen, mexiletine, valproic acid, and gabapentin) may provide some measure of symptomatic relief.^{9,76,82,84,89} As in other autoimmune diseases, patients may seemingly enter a period of protracted remission following treatment, require prolonged maintenance therapy, or succumb if treatments are ineffective or complications of the disease ensue.

TETANUS

CLINICAL FEATURES

Despite their entirely different causes and mechanisms, both tetanus and tetany are derived from the Greek word for spasm, that is, tetanos. Like the SPS, tetanus is a disorder of sustained muscle rigidity with superimposed painful spasms. The natural history of tetanus consists of an incubation period varying from a few days to weeks with a mean of 8 days.¹⁰³ A shorter duration between exposure and symptom onset portends the development of severe disease with intense spasms and bulbar symptoms. Once begun, the clinical manifestations tend to progress for 10-14 days. If the patient avoids secondary complications of the illness and survives, recovery typically begins approximately a month after symptom onset and is often complete. However, the mortality rate may be as high as 30% particularly in neonates, in older patients with co-morbidities, and in locations where supportive medical care may be limited.¹⁰⁴

Uncommonly, tetanus may result from anaerobic infection of the middle ear or paranasal sinuses.^103,104 This may result in “local” tetanus, producing trismus as well as motor cranial nerve dysfunction as described, potentially including ophthalmoparesis. Tetanus may also proliferate in the uterus and represents a feared complication of parturition or abortion in nonhygienic facilities.

Neonatal tetanus is predominantly a disease of underdeveloped countries.^103,104 It typically originates from an umbilical stump infection in a child born of an unimmunized mother. Local customs that include application of substances to the umbilical stump that unknowingly harbor spores may contribute to risk of the disease. Symptom onset is typically within the first 2 weeks of life, manifesting as a poorly feeding infant with prominent muscle twitching. Changes in cranial musculature provide valuable clues. The jaw may clamp tight on a finger placed in the mouth. The upper lip stiffens, the eyelids are closed tightly, and the forehead is continuously wrinkled. Mortality in neonatal tetanus is high. Neonatal tetanus accounted for two-thirds of the 300,000 deaths attributed to tetanus worldwide in the year 2000.¹⁰⁵

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The early involvement of cranial muscles is presumptively due to their shorter length and early arrival of neurotoxin to brainstem via this retrograde transport mechanism. Cranial, trunk, and limb muscles are usually affected in that order presumably due to the relationship of nerve length and retrograde neurotoxin transport. Recovery from tetanus is dependent on the genesis of new presynaptic nerve terminals of inhibitory interneurons.^103,110

TREATMENT

The primary treatment strategy for tetanus is prevention. Tetanus is an uncommon illness due to the existence of effective vaccination programs. During a 2-year period in the United States in the 1990s, only 124 cases were reported.¹⁰⁴ To further amplify the efficacy of prevention, a vaccination program for pregnant women with tetanus toxoid in India reduced the annual number of cases of neonatal tetanus from 9313 to 653 over a 21-year period of time.¹¹¹ Although vaccination is extremely effective, rare individuals may develop tetanus even with a complete and up-to-date tetanus vaccination program and demonstration of pre-existing tetanus antibodies.¹¹² In countries where vaccination programs and medical access are limited, neonatal tetanus is more prevalent. In developed countries, the incidence of tetanus is higher in older individuals. Waning immunity from remote immunization may play a significant role in this observation.¹⁰³

Vaccination against tetanus can be delivered either passively (tetanus toxoid) or actively (tetanus-specific immunoglobulin). The former, developed in the 1940s, is the preferred vaccination method. Primary vaccination for infants consists of five doses of tetanus toxoid delivered at 2, 4, and 6 months of age, as well as at 15–18 months and 4–6 years. The fifth dose is not required if the fourth was received after age 4. Typically, tetanus toxoid is combined with pertussis and diphtheria vaccines for the first five doses. Following these initial five doses, pertussis is deleted and tetanus toxoid/diphtheria boosters are recommended at 10-year intervals.

Primary vaccination is indicated in adults when their childhood vaccination history is uncertain or in a bone marrow transplant is planned.¹⁰⁴ It consists of three injections, the first two of which are separated by a minimum of 4 weeks, and the last dose done 6–12 months subsequent to the second. In individuals who have received a “clean” wound, vaccination is considered adequate if previously vaccinated and if a tetanus booster has been received within 10 years. In the setting of a “dirty” wound, a booster within 5 years would be considered with adequate primary vaccination. In a patient who has been wounded, whose tetanus immunization has “expired” or their immune status compromised by HIV infection, dialysis, chronic chloroquine exposure (and potentially other immunosuppressant agents), both primary vaccination with tetanus toxoid and human tetanus immunoglobulin (250 units intramuscularly) should be administered at different sites.

With the development of symptomatic tetanus, the goals are to: (1) limit further production of tetanospasmin by wound debridement and antimicrobial therapy, (2) neutralize if possible, the effects of existing, unbound toxin by active immunization, (3) provide symptomatic treatment of painful spasms, impaired ventilation, and swallowing; and (4) treat symptoms referable to dysautonomia. Patients with tetanus without obvious wounds should have orifices examined, such as the external ear or rectum, with removal of foreign bodies if relevant. Patients with tetanus should be considered for early lumbar puncture if indicated, and particularly prophylactic intubation and enteral feeding tube placement as both are frequently required and become technically difficult once rigidity and spasms begin in earnest.

Elimination of the toxin source involves removal of any foreign body, debridement of any necrotic tissue, and delivery of antibiotics with anaerobic efficacy. The latter is recommended despite absence of proven efficacy. Metronidazole, penicillin, third-generation cephalosporins, clindamycin, or erythromycin are typically administered and may reduce the need for muscle relaxants and sedatives. Penicillin G is given in doses ranging from 10–12 million units per day. Metronidazole appears to be equally effective and may be preferential in view of penicillin’s stimulatory effect on the cortex. The customary dose is 500 mg IV q6h for 7–10 days.

Conversely, neutralization of unbound circulating toxin has documented efficacy in shortening disease duration and improving recovery rates.¹⁰⁴ Human tetanus immune globulin should be administered at a dose of 500 units intramuscularly as soon as possible, ideally before the wound is manipulated. The addition of intrathecal (1000 units) to intramuscular administration appears to result in even better outcomes.¹¹³ Equine-derived tetanus immune globulin may be used if human-derived immune globulin is not available. Infection with C. tetani does not stimulate active immunity by the host.

TETANY

CLINICAL FEATURES

Tetany is a disorder of nerve hyperexcitability provoked by hypocalcemia with or without vitamin D deficiency, hypomagnesemia or alkalosis. The syndrome has both motor and sensory features and is characterized by the development of paresthesias which initially occur in the digits and in a circumoral distribution. The paresthesias may in some cases have a lateralized preponderance and may spread to the proximal extremities. Paresthesias are followed by manifestations of motor nerve hyperactivity manifesting as spasmodic muscle contraction resulting in characteristic patterns of extremity posturing. The most characteristic of these is “carpal spasm” consisting of a “fisted” posture with the thumb adducted against the palm covered by fingers that are flexed at the metacarpophalangeal joints, extended at the proximal interphalangeal joints and adducted against each other. In more severe cases, the wrists and elbows may assume a flexed posture as well. In the lower extremities, the pedal portion of carpal pedal spasm, the tendency is for the toes to flex and the ankle to assume the equinovarus posture, that is, plantar flexed and inverted. Unlike tetanus, the effects of tetany are more pronounced in limb as opposed to cranial and axial muscles and influence sensory as well as motor function due to their peripheral nerve effects. In severe cases however, laryngospasm may occur and trunk muscles may be affected potentially resulting in opisthotonus.¹

Carpal spasm may be elicited in patients at risk by inflating a blood pressure cuff to greater than systolic blood pressure for ≤3 minutes (Trousseau sign). Spasm of facial muscles may be provoked in these patients by digital percussion of the facial nerve at the angle of the jaw (Chvostek sign).

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Tetany is diagnosed by recognition of the characteristic pattern of paresthesias, typical hand-and-foot postures, and a positive response to the provocative maneuvers described above. The diagnosis is further supported by identification of reduced serum levels of ionized calcium or magnesium. Cases of normocalcemic, normomagnesemic tetany do however occur.¹¹⁶ Cases in which reduced ionized calcium has been detected in arterial but not venous blood have been described as well.

The differential diagnosis of tetany once again includes any disorder that produces cramps or cramp-like painful muscle contractions. Diagnostic considerations should include consideration of drug-induced tetany, typically resulting from alterations in magnesium homeostasis. Potential offenders include proton pump inhibitors, diuretics, epidermal growth factor receptor modulators, some antimicrobials and chemotherapeutic agents, and of particular interest to neuromuscular clinicians, calcineurin inhibitors such as tacrolimus and certain monoclonal antibodies including bevacizumab.^117–119

LABORATORY FEATURES

All patients with unwanted muscle contractions should have ionized calcium, 25 hydroxy-vitamin D and magnesium levels assessed in their serum. Tetany induced by hyperventilation will be associated with an arterial blood gas pattern consistent with acute respiratory alkalosis (i.e., a reduced PCO2 and elevated pH). The EDX signature of tetany is grouped discharges that may occur spontaneously (myokymic discharges) or in response to voluntary activation (multiplets).

PATHOGENESIS

TREATMENT

The treatment of tetany involves recognition and correction of hypocalcemia and/or hypomagnesemia if detectable. With symptomatic hypocalcemia, the goal is to elevate the corrected serum calcium to >7.0 mg/dl. This can be accomplished by infusions of calcium gluconate at doses of 15–20 meq/kg delivered over 4–6 hours. Conditions causing chronic hypocalcemia can be managed with 1–3 g of elemental calcium replacement a day. In the case of acute symptomatic hypomagnesemia, magnesium sulfate can be delivered either intramuscularly or intravenously. The intravenous dose is typically a bolus of 4–6 g followed by 2–3 g per hour as required. Vitamin D deficiency is treated with oral replacement. Vitamin D2 is the most economic way to accomplish this at daily doses of 25,000 to 150,000 IU. If hyperventilation is the cause, breathing into a paper bag will address this problem acutely. Addressing the underlying cause of hyperventilation is important if a patient is repeatedly symptomatic. Drugs that potentially cause symptomatic hypomagnesemia should be removed if possible with consideration of patient comorbidities.

SATOYOSHI SYNDROME

CLINICAL FEATURES

Satoyoshi syndrome is a rare, presumed autoimmune disorder, predominantly affecting individuals in the first two decades of life.^1,121–125 Females are affected twice as frequently as males. Satoyoshi syndrome occurs worldwide but appears to have the greatest prevalence in Japan.¹²² It is characterized by painful muscle spasms of the extremities, typically beginning in the legs, but progressing to involve the entire body including the trunk, neck, and masticatory muscles. In Japan, it has been also referred to as “komuragaeri” (calf-spasm) disease.¹²⁵ The spasms, like those of IS are commonly provoked by movement, persist during sleep and interfere with gait.^122,125 Unlike IS adventitious muscle movements such as myokymia and fasciculations are not described.^123,124 The spasms commonly distort posture, typically last for a few minutes and recur after short intervals. Although these paroxysms may be the sole manifestation of Satoyoshi syndrome, the syndrome is best conceptualized as a multisystem disorder associated with alopecia, diarrhea, and short stature. Short stature may occur as a result of impaired nutrition and/or endocrine abnormalities that may include amenorrhea as well as growth retardation.^123,127 The amenorrhea, at least in some cases, is a consequence of hypergonadotropic hypogonadism and primary ovarian failure.³² Bony deformities may occur in Satoyoshi syndrome. They have been hypothesized to result from the influence of repeated forceful muscle spasm on developing bone.¹²² Life expectancy is reduced attributed predominantly to nutritional deficiency.^122,125

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Satoyoshi syndrome remains a clinical diagnosis, suspected when movement-related painful muscle spasms develop in children and adolescents, accompanied by alopecia, diarrhea, short stature, and in post-pubescent females, amenorrhea. The laboratory abnormalities and responsiveness to immunomodulating treatment described below provide diagnostic support.

LABORATORY FEATURES

Lab testing results may reflect malnutrition or malabsorption. Consistent with this conclusion are duodenal imaging abnormalities felt to be consistent with chronic inflammatory change. Endoscopy may demonstrate atrophic gastric mucosa and multiple ulcerations.^125,126 X-rays may reveal osteolytic lesions of the epiphysis and metaphysis of bone.¹²² Serum CK levels may be elevated.^125,126,128 The serum IgE level has been elevated in at least two cases.^127,128 In post-pubescent females, levels of sex hormones may be reduced and gonadotropin levels elevated.¹²² Although a number of circulating autoantibodies including those directed at the acetylcholine receptor and GAD enzyme have been anecdotally reported, there has been no consistent pattern identified to date.^126,128 Despite the presence of acetylcholine receptor antibodies in some cases, we are unaware of any reports of Satoyoshi syndrome associated with thymic abnormality. As titers of GAD autoantibodies are frequently elevated in high titers in the SPS, the significance of low-level titers of these antibodies in Satoyoshi syndrome awaits further clarification. Routine EDX studies done in Satoyoshi syndrome patients when muscles are quiescent are normal. Surface EMG recordings during involuntary muscle contraction reveals high amplitude, synchronous motor unit discharges that are pervasive throughout the entire muscle belly.¹²⁸

HISTOPATHOLOGY

PATHOGENESIS

Satoyoshi syndrome is suspected to have an autoimmune mechanism. Other autoimmune diseases such as myasthenia, idiopathic thrombocytopenia, and immune-mediated nephropathies appear to occur with increased frequency in Satoyoshi syndrome.¹²⁵ As previously mentioned, a nonspecific pattern of autoantibodies may be identified in the serum of Satoyoshi syndrome patients. A single report has described a circulating antibody reacting to a 90-kDa protein found in the brain, stomach, and duodenum but not the uterus.¹²⁵

The pathophysiology of muscle contraction in Satoyoshi syndrome is unknown. It appears to differ from cramps in that surface EMG recordings of motor unit discharges are synchronous, not random, and occur in uniform rather than a migrating pattern throughout the muscle belly.

TREATMENT

In view of its rarity, there is no standardized approach to the treatment of Satoyoshi syndrome. A variety of agents have been used unsuccessfully for the treatment of spasms. Botulinum toxin may be locally effective (e.g., masticatory spasm) but is impractical for widespread application. Carbamazepine was effective in at least one case whereas baclofen provided no benefit.¹²² Case reports suggest that immunomodulation may favorably alter the natural history of the disease in some but not all cases. Significantly beneficial responses to muscle spasms, alopecia and gastrointestinal symptoms have been reported with tacrolimus, methotrexate, corticosteroids, and IVIG.^122,125,126 Conversely, both corticosteroids and IVIG have been reported to be ineffective.^{122,126,128–130} Appropriate hormonal replacement may be considered.

STIFF-PERSON SYNDROME

CLINICAL FEATURES

Moersch and Woltman described the stiff-man syndrome in 1956 based on their experience with 14 patients afflicted with a syndrome of fluctuating but progressive muscle rigidity and spasm that preferentially affected the axial muscles.¹³¹ For multiple reasons including its greater prevalence in women, this disorder is now commonly referred to as the SPS.^132–134

Unlike most of the other most of the disorders considered in this chapter, SPS is a CNS disorder, best conceptualized in our minds as a encephalomyelopathy in which the myelopathic features predominate in most cases.^132,135,136 Like other autoimmune and paraneoplastic disorders, the onset is often acute–subacute although it may go undiagnosed for years.¹³⁷ SPS affects women twice as frequently as men with a median onset of 35–40 years of age.^137,138 The best estimate of prevalence is less than 1 × 10⁶.¹³⁴ In view of its rarity and the often protean nature of its onset symptoms, for example, low back pain, the diagnosis may be delayed by an average of 6 years following symptom onset.^132,134

In the classic form of the disease, the initial symptom is typically painful muscle stiffness in the lumbosacral and abdominal regions.^{135,136,139,140} One of the key features of SPS is the propensity for agonist and antagonist muscles to be affected simultaneously. As the disease progresses, there is a propensity for the muscle rigidity to spread to involve the proximal muscles of the lower extremities. Eventually, any muscle under voluntary control may be affected. Limb involvement may be symmetric or asymmetric. Falls constitute a significant risk and source of morbidity. Fear of falling is a significant source of anxiety for these patients.

At onset, paroxysmal muscle spasms are the norm. They usually become more persistent as the disease worsens if left untreated. These spasms, superimposed upon baseline muscle stiffness, may begin abruptly, last for seconds to minutes as individual events, and may recur in clusters that may persist for hours.^{134,141–143} They are often provoked or intensified by movement, by tactile, emotional, or auditory stimuli, or by cold weather or intercurrent infection.¹⁴⁴ The spasms may be powerful enough to break bones, dislocate joints, or incite rhabdomyolysis. The spasms may be so dramatic as to mimic the opisthotonic posturing of tetanus.^134,145 Unlike IS, spasms are typically diminished if not alleviated by general anesthesia, benzodiazepines, and sleep.¹³⁵ The paroxysms of SPS may be associated with adrenergic symptoms of dysautonomia including diaphoresis, hypertension, tachycardia, tachypnea, and pupillary dilatation.¹³³ Rarely, the dysautonomia may result in sudden death.^134,146,147

Like many clinical syndromes, the clinical manifestations of SPS may be heterogeneous.¹⁴⁸ Focal presentations have been referred to as “stiff-limb” syndrome.^{137,148–152} Focal onset SPS may or may not progress to more generalized disorder. If the phenotype remains focal, SPS may not be readily suspected. Cervical involvement may result in restricted head movement. Thoracoabdominal rigidity may result in symptoms whose mechanism may not be initially recognized as being related to restricted muscle movement including ventilatory insufficiency (dyspnea on exertion, orthopnea, exercise intolerance, inability to swim underwater) and impaired gastric distention (early satiety). Facial involvement resulting in facial masking has been described in some cases, leading to the erroneous diagnosis of Parkinson disease.¹³² Dysphagia, dysarthria, and disordered ocular motility have been rarely described without overt encephalitis.¹⁴⁷ Whether these represent limited forms of brainstem encephalitis is uncertain. Alternatively, myasthenia should be considered with the development of oculobulbar symptoms in SPS.¹³⁴

Although rare, the existence of a progressive encephalomyelitis with rigidity and myoclonus variant of this disease (PERM) or “jerking stiff-man syndrome” lends further support for this hypothesis.^{134,135,148,149–151} In this syndrome, progressive rigidity progresses within weeks to years to include cognitive impairment. Associated features include myoclonus, nystagmus, opsoclonus, impaired ocular motility, dysarthria, and dysphagia. Seizures may occur in up to 10% of cases.¹⁶⁰ Other encephalopathic manifestations of SPS have been described including a subacute cerebellar syndrome, brainstem encephalitis, temporal lobe epilepsy, dystonia, and retinopathy.¹³⁵ Of these, the cerebellar syndrome appears to be the most prevalent. It is characterized by prominent ataxia, dysarthria, and eye movement abnormalities superimposed on muscle stiffness and spasms.¹³⁶ Peripheral neuropathy and motor neuronopathy have also been reported to occur as part of the PERM complex.¹³⁷ The course of PERM is relentless. Death may occur within weeks to months of brain involvement.

The clinical examination of the “typical” SPS patient often reveals accentuation of the normal lumbar lordosis with resultant restriction of spine mobility. As a result, a patient’s lower back may fail to flatten and contact the bed when lying supine. Their ability to touch their toes may be severely restricted similar to an spondyloarthropathy patient. In SPS however, the lumbar lordotic curve is increased rather than decreased both in the upright and attempted flexed positions. Although nonspecific, the paraspinal muscles in SPS are typically indurated to palpation. As a result, the patient’s flexibility, mobility, and ambulation are hampered. The patient’s gait may be described as stiff, robotic, and spastic in nature. In addition to abnormal axial postures, other abnormal postures during spasms may include extension and slight abduction of the leg, inversion and plantar flexion of the foot that may be mistaken as foot drop, or pronation and extension of the upper extremity.^134,136 Deep tendon reflexes are commonly increased and sustained ankle clonus and Babinski signs may occur.¹³⁷ A triple flexion response in response to lower extremity stimulation may be observed.¹³⁴ The head retraction reflex is a bedside test that can be utilized in an SPS suspect.²⁰ It is positive in 50% or more of SPS or PERM patients but is nonspecific and may occur in other CNS disorders of hyperexcitability as well. A positive response is contraction of neck muscles, with or without head movement, in response to a gentle tap to the glabella, bridge of the nose, lip or cheek in a patient whose eyes are closed.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of SPS is typically arrived at by recognition of the clinical features, coupled with a typical antibody profile, electrophysiologic support when necessary, and benzodiazepine responsiveness. The latter provides both diagnostic and therapeutic benefits.¹³⁴ In typical cases, signs and symptoms of either lower motor neuron, sensory, or cognitive involvement should dissuade the clinician from the diagnosis. Some have suggested that pyramidal and extrapyramidal features are atypical in SPS ¹³⁴, although that has not been our experience or the experience of others.^137,146 A number of our cases have been referred by neurosurgeons for myelopathic phenotypes associated with negative spinal cord imaging.

The diagnosis of SPS is confirmed, in the appropriate clinical context, by the demonstration of GAD-65 or amphiphysin autoantibodies in significant titres the serum or CSF. GAD-65 autoantibodies in SPS, unlike diabetes, are typically found in high titers. They also differ from diabetes in that they are typically directed toward the amino terminus of the molecule.^135,161,162 In patients who are GAD-65 seronegative, other less specific markers of autoimmunity including oligoclonal banding in the CSF and the presence of other serum autoantibodies offer diagnostic support. Many have described the value of EMG in demonstrating involuntary activation of MUAPs simultaneously in agonist/antagonist muscle pairs. In our experience, we have not found this to be either sensitive or specific enough to utilize as a major determinant in the decision to initiate immunomodulating treatment in a patient with suspected SPS who is seronegative. Other testing, particularly spinal cord imaging and CSF analysis, may be required to exclude the other differential diagnostic considerations listed below.

The differential diagnosis of SPS includes many of the other disorders listed in this chapter particularly IS, chronic tetanus, Brody syndrome, Satoyoshi syndrome, and in children, hyperekplexia. Other compressive and noncompressive myelopathies including primary lateral sclerosis, primary progressive MS, neuromyelitis optica, and retroviral infection with HTLV-1 bear some resemblance to SPS. Extrapyramidal disorders, particularly those with dystonia should be considered as well. In individuals who develop symptoms of intracranial disease in addition to their stiffness, Morvan syndrome and other autoimmune often paraneoplastic causes of limbic encephalitis including those associated with Hu, Ri, VGKC, and n-methyl d-aspartic acid (NMDA) receptor autoantibodies should be considered. Although patients with SPS may be mislabeled as psychogenic, the opposite misdiagnosis may occur as well as psychogenic patients with muscle pain and unusual postures may be considered to have SPS.¹³⁸

Other nonparaneoplastic autoimmune disorders both within and outside of the nervous system associate with SPS. This is particularly true in those who possess GAD antibodies. These comorbidities may include encephalomyelitis with seizures, cerebellitis, myasthenia gravis, hypo- and hyper-thyroidism, pernicious anemia, celiac disease, adrenal insufficiency, systemic lupus erythematosus, rheumatoid arthritis, ovarian failure, and vitiligo.^{132,134,165,166} Diabetes mellitus is particularly prevalent and may exist in up to 70% of patients with SPS.¹⁶⁰

The decision regarding potential evaluation for underlying malignancy should probably depend on the context of the individual patient. The presence of amphiphysin antibodies, a strong family history of breast or ovarian cancer or smoking, and predominant upper extremity or cranial nerve involvement are features that will increase the diagnostic yield of identifying an underlying malignancy.^60,134,164 In an environment where neither cost nor availability are considerations, 18 F fluorodeoxyglucose positron emission tomography (FDG PET) scanning would represent the presumed screening method of choice to search for an occult malignancy.

LABORATORY FEATURES

The association of GAD autoantibodies and SPS was first reported in 1988.¹⁶⁷ Antibodies directed against the 65KD isoform of GAD (GAD-65) may be found in high titer in 85% of SPS patients as opposed to the other isoform, GAD-67 for which autoantibodies are present in less than 50% of affected individuals.^{135,136,167,168} If only patients with the classic phenotype are considered, the prevalence of anti-GAD antibodies in SPS may exceed 90%.¹⁴⁸ GAD-65 autoantibodies in high titre typically designated as >20 nmol/L are found in only 1% of normal individuals and 5% of patients with other neurologic diseases.¹³⁸ GAD-65 autoantibodies are also demonstrable in the CSF in 75% of cases.^135,169 They are present in the CSF in lower titer than in serum but with a 10-fold increase when indexed against serum implicating intrathecal synthesis.¹³⁵ Patients with the rare PERM phenotype may be seropositive or seronegative. In addition to GAD-65, autoantibodies directed against the glycine receptor alpha-1 subunit (GLRA1) and the NMDA receptors have been reported in this illness.¹⁵⁵

Although commonly assayed by immunocytochemical technique, the greatest sensitivity in GAD-65 autoantibody detection is achieved with radioimmunoassay.¹³⁵ GAD autoantibodies are not specific for SPS and are found in approximately 5% of individuals with other neurologic disorders. These include individuals with cerebellar ataxia, palatal myoclonus, limbic encephalitis, localization-related epilepsy, and ceroid lipofuscinosis. ^134,135,138 GAD-65 autoantibody titers do not correlate with disease severity, duration, or treatment responsiveness.¹⁷⁰

Paraneoplastic SPS is more commonly associated with autoantibodies directed against amphiphysin than GAD-65.^{135,136,145,163,164} Amphiphysin antibodies are found in approximately 5% of SPS cases, almost always in women. There is a considerable overlap between paraneoplastic SPS and amphiphysin-positive SPS but they are not synonymous. Amphiphysin autoantibodies may occur in other non-SPS paraneoplastic syndromes including limbic encephalitis, cerebellar degeneration, and sensory neuronopathy.¹³⁶ Conversely, paraneoplastic SPS may rarely associate with other autoantibodies. GAD-65 autoantibodies may occur rarely in individuals with SPS who have an underlying malignancy such as renal cancer or thymoma.^{135,152,169–171} The encephalomyelitic form of SPS with opsoclonus may have anti-Ri antibodies, often associated with adenocarcinoma of the lung. There have been individual case reports linking paraneoplastic SPS with gephyrin (GHPN) autoantibodies.^136,172,173 Amphiphysin and GAD-65 autoantibodies virtually never coexist.

Oligoclonal bands in the CSF are common in SPS.¹⁷⁴ Their presence may provide valuable support for the diagnosis of SPS in an individual who does not possess the more specific biomarkers of anti-GAD or amphiphysin antibodies in either serum or their CSF. Other organ-specific autobodies may be found in SPS including anti-thyroid, anti-intrinsic factor, anti-nuclear, anti-RNP, and anti-gliadin.¹³⁵ Routine testing for these less specific autoantibodies is not generally recommended as they are more likely representative of an underlying autoimmune diathesis than indicative of SPS.

Regarding EDX evaluation of the SPS patient, routine nerve conduction studies are normal. Needle electromyography of symptomatic muscles will reveal MUAPs with normal morphology and firing rates. The only difference between SPS and normal patients is that these MUAPs fire involuntarily and simultaneously in both agonist and antagonist muscle groups. This pattern must be interpreted with caution however, as spontaneously firing MUAPs in a single muscle is commonplace in a normal, tense individual. In addition, it is possible for a normal individual to consciously activate agonist and antagonist and feign this pattern of abnormality should they be incented to do so. In our opinion, the greatest value of EDX in a suspected SPS patient is to exclude the waveforms that characterize other disorders that should be considered in the SPS differential diagnosis.

MR imaging of the brain and spinal cord in SPS patients is usually normal.^136,176 Specifically, SPS patients with cerebellar syndromes do not demonstrate cerebellar atrophy.¹³⁶ MR spectroscopy however, may demonstrate a significant regional decrease in GABA levels in the motor cortices in these patients.^136,176,177

HISTOPATHOLOGY

Histologic findings in SPS are limited and inconsistent, thus suggesting a predominantly physiologic rather than histologic pathogenesis.^{131,134,178–180} Postmortem examination may reveal loss of anterior horn cells, interneurons, and small alpha and gamma motor neurons within the spinal cord or cerebellum but these findings are inconsistent.¹³⁸ More overt pathology is seen in PERM where perivascular inflammation in the cord, brain, and brainstem may be identified.^{134,154,173–182}

PATHOGENESIS

Current consensus holds that SPS is an autoimmune disease, related to circulating autoantibodies to proteins involved in gamma amino butyric acid (GABA) neurotransmission, resulting in impaired GABAergic inhibition of α-motor neurons within the brain and spinal cord. The exact pathogenic mechanisms, specifically whether these autoantibodies are causal, remains unknown.¹³⁸

l-Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to gaba-Aminobutyric acid (GABA). GAD is widely prevalent in the cytosol, specifically the inner surface of synaptic vesicles of GABA secreting neurons within the CNS.¹³⁸ GABA is the major inhibitory neurotransmitter within the forebrain whereas both GABA and glycine serve in this capacity within the spinal cord. There are other proteins relevant to SPS and CNS, which causes neuromuscular hyperexcitability.¹⁸³ Amphiphysin is another cytosolic presynaptic protein that is responsible for the retrieval of the vesicular protein following GABA exocytosis.¹³⁵ GABA-receptor-associated protein (GABARAP) is a postsynaptic protein that stabilizes and surface expression of GABA-A receptors as well as modulating their conductance.¹³⁶ Approximately 65–70% of GAD-65 seropositive SPS patients will have antibodies that react with this protein.^135,136 These antibodies inhibit the surface expression and impair the stability of GABA-A receptors.¹³⁶ Gephyrin is a postsynaptic protein responsible for the clustering of glycine receptors in the spinal cord and GABA-A receptors within the brain, essential for their proper functioning.¹³⁶ Accordingly, knockout of the GHPN gene in mice results in an SPS phenotype.

The exact roles of the autoantibodies remain however, uncertain. GAD-65 specific autoantibodies harvested from SPS patients inhibit GAD activity and GABA synthesis in vitro.¹⁸² They are presumed to adversely affect inhibitory GABA interneurons in the spinal gray matter and cortex, leading to continuous tonic firing of α-motor neurons.^134,184,185 Given the logic of this hypothesis, the high prevalence of GAD-65 autoantibodies in high-titer in SPS patients, and their apparent intrathecal synthesis, it is tempting to suggest that GAD-65 have a direct pathogenic role. Inhibition of GABA synthesis and interference with GABA vesicle exocytosis are proposed mechanisms.¹³⁵

There are however, conflicting observations. As GAD-65, as well as amphiphysin and GHPN, are cytosolic proteins, it is unlikely to be recognized by the immune system unless GAD were to migrate to the cell surface. In addition, neither infants with transient autoantibodies transferred from mothers with GAD65 seropositive SPS, nor mice who have received passively transferred GAD-65 autoantibodies develop disease.¹³⁵

Paraneoplastic SPS occurs primarily in individuals with autoantibodies directed against amphiphysin, or rarely in patients with GAD-65, Ri, or GHPN autoantibodies.^{134,135,163,164} A causal relationship between amphiphysin autoantibodies and SPS is supported by the production of a similar clinical response in animals to whom these autoantibodies have been passively transferred.¹³⁵ Response to immune-modulating treatment in some cases offers further support for the autoimmune hypothesis in amphiphysin-associated SPS. As one other potential paraneoplastic association in SPS, GAD-65 is a protein also expressed in thymic tissue, providing a potential pathogenic link between SPS and thymic pathology.¹³⁷

Autoimmunity may not represent an isolated disease mechanism in SPS. There may be an additional genetic predisposition based on major histocompatibility genotype. The DQβ1*0201 allele is present in approximately 70% of patients and along with the DRβ1 allele is closely associated with SPS.¹³⁶ This is also a prevalent allele in patients with diabetes without SPS. Conversely, the presence of the DQB1*0602 allele seems to be protective.¹³⁵

TREATMENT

The treatment of SPS involves the use of both symptomatic agents to enhance GABAergic influences and immunomodulating treatments aimed at the presumed autoimmune basis of the disease.135,136 In the case of paraneoplastic SPS, treatment and if possible eradication of the underlying tumor represent the initial therapeutic goal. Patients are typically treatment responsive although complete eradication of symptoms is the exception rather than the rule. A significant portion of affected individuals remain dependent on others for at least some activities of daily living.¹³⁶

Benzodiazepines have been the historical mainstay of symptomatic treatment. Patients require and are tolerant of large doses, with a median daily diazepam dose of 40 mg required to provide efficacy without excessive side effect. Although many SPS patients tolerate doses of benzodiazepines that normal patients would not, unwanted CNS side effects still represent a limitation of this therapy. Antispasticity drugs provide a second line of symptomatic treatment. Baclofen, tizanidine, and dantrolene have been used with some success although our experience has not been as rewarding as suggested in the literature.¹³⁶ Baclofen can also be used intrathecally and has been shown to have some benefit in controlled trials but is associated with the potential risk of significant complication.^136,185 A number of anticonvulsants with mechanisms of action that augment GABA effect have been tried with anecdotal report of benefit including gabapentin, valproic acid, levetiracetam, vigabatrin, and tiagabine. Botulinum toxin may benefit individual patients as well but is limited by its cost, and the need for large doses to adequately address large axial muscle groups.

Of the immunomodulating agents, only IVIG and rituximab have been studied in clinical trials in SPS. To the best of our knowledge, the rituximab trial conducted at the NIH is yet to be published. The rituximab trial was prompted by its relevant mechanism of action as well as by case reports of beneficial and protracted responses to rituximab.^186–188 The IVIG trial involved 16 patients and reported improved morbidity and reduction in GAD autoantibody titers with treatment.¹⁸⁹

There have been many reports describing anecdotal responses to other immunomodulating therapies but a limited evidence basis by which to judge efficacy. In general, efforts to assess treatment efficacy in SPS are hampered not only by the rarity of the condition but by the lack of adequate parameters by which to measure it. PLEX has benefited some patients. Corticosteroids are less attractive than in other diseases, in view of the high concordance of diabetes. Azathioprine, methotrexate, and mycophenolate have been tried. Anecdotally, we have been impressed that corticosteroids and mycophenolate have modest benefit with clinical improvement upon exposure and demonstration of worsening that is chronologically related to drug withdrawal after the patient has experienced long periods of drug-related stability. As in other paraneoplastic syndromes, successful treatment of the underlying malignancy may lessen the morbidity of the associated SPS. As paraneoplastic SPS is uncommon the theoretical concern that immunomodulating agents might promote growth of an occult cancer by reducing immune surveillance is of less concern than in disorders such as the Lambert–Eaton myasthenic syndrome.

HYPEREKPLEXIA

CLINICAL FEATURES

Hyperekplexia originates from the Greek ekplexis meaning surprise, an apt description for the exaggerated startle response that characterizes the syndrome. It is characterized by nonepileptic, paroxysmal rigidity and hyperreflexia in response to external, often auditory stimuli. The startle response frequently includes eye blinking and trunk flexion similar to a salaam attack in West syndrome. Voluntary movement is typically precluded during the spasm. Hyperekplexia is typically a newborn disorder but often persists to some degree during adult life. Affected adults often experience drop attacks as their major manifestation. Occasionally, onset may be delayed. In neonates, it may be provoked by handling. Child care such as changing a diaper may be impaired do to the inability to passively abduct the legs. The spasms tend to disappear during sleep but may occur at night during arousals. The examination of the hyperekplectic individual may reveal an exaggerated head retraction response as is described above in the SPS. Gentle tapping of the tip of the nose will elicit a startle response in affected babies. The severity of hyperekplexia varies and in extreme cases, it can result in neonatal cardiac arrest and death.¹⁹⁰

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of hyperekplexia is based on the appropriate clinical syndrome beginning in infancy, associated with normal electroencephalography, supported by family history, and confirmed when possible by genotyping. Of the disorders described in this chapter, hyperekplexia bears the closest resemblance to the SPS or childhood tetanus. At one time, hyperekplexia was referred to as stiff-baby syndrome. Undoubtedly the most prevalent and difficult differential diagnostic consideration from a clinical perspective in infancy is infantile spasms associated with the West syndrome. Consciousness is not altered in most hyperekplexia attacks as it is in the seizures of infantile spasm but this may not be clinically apparent in infancy. Mutations of the rho guanine nuclear exchange factor 9 (ARHGEF9) gene described below are an exception, resulting in hyperekplexia coupled with an early infantile epileptic encephalopathy. Cerebral palsy or other causes of spastic quadriplegia, a tic disorder or adverse reaction to neuroleptics are other differential diagnostic considerations. As it may also produce stimulus-related falls, cataplexy may be confused with hyperekplexia in the absence of a detailed history.

LABORATORY FEATURES

PATHOGENESIS

There are currently five known gene mutations that result in a hyperekplexia phenotype.¹⁹² Of these, mutations of the glycine receptor alpha-1subunit (GLRA-1) accounts for 80% of cases. Other responsible mutations include the glycine receptor beta subunit (GLRB), the GHPN, and solute carrier family 6 (SLC6A5) genes. The latter encodes a presynaptic glycine transporter. Mutations of the rho guanine nuclear exchange factor 9 (ARHGEF9) gene alter the synthesis of the protein collybistin whose function is to interact with the protein GHPN whose function in CNS inhibition will be described below.

Like SPS, hyperekplexia is presumed to have a CNS localization. The startle response is thought to originate from an established neural network within the pontomedullary reticular formation with the response becoming manifest when normal inhibitory influences are lacking.

TREATMENT

There have been no studies addressing therapeutic intervention in hyperekplexia. Clonazepam has been reported to have a beneficial effect. Phenytoin, carbamazepine, piracetam, clobazam, vigabatrin, phenobarbital, 5-hydroxytryptophan, and diazepam have been used anecdotally with uncertain benefit. Positioning a child in a flexed, fetal position may abort a spasm.

SUMMARY

With the exception of cramps and fasciculations, the disorders described in this chapter are uncommon. Most of these disorders have, to some extent, 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 EDX features of each syndrome. Many of these disorders appear to have an autoimmune pathogenesis, some of which are in turn related to underlying malignancies. No singular treatment paradigm exists for any of these disorders. In many cases, both immunomodulating therapies and symptomatic measures will provide relief from disease morbidity.

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CHAPTER 10Disorders of Motor Nerve Hyperactivity

CRAMPS, FASCICULATIONS, AND THE CRAMP–FASCICULATION SYNDROME

CLINICAL FEATURES

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

LABORATORY FEATURES

HISTOPATHOLOGY

PATHOGENESIS

TREATMENT

ISAACS SYNDROME OR NEUROMYOTONIA

CLINICAL FEATURES

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

LABORATORY FEATURES

HISTOPATHOLOGY

PATHOGENESIS

TREATMENT

TETANUS

CLINICAL FEATURES

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

LABORATORY FEATURES

PATHOGENESIS

TREATMENT

TETANY

CLINICAL FEATURES

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

LABORATORY FEATURES

PATHOGENESIS

TREATMENT

SATOYOSHI SYNDROME

CLINICAL FEATURES

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

LABORATORY FEATURES

HISTOPATHOLOGY

PATHOGENESIS

TREATMENT

STIFF-PERSON SYNDROME

CLINICAL FEATURES

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

LABORATORY FEATURES

HISTOPATHOLOGY

PATHOGENESIS

TREATMENT

HYPEREKPLEXIA

CLINICAL FEATURES

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

LABORATORY FEATURES

HISTOPATHOLOGY

PATHOGENESIS

TREATMENT

SUMMARY

REFERENCES

CHAPTER 10

Disorders of Motor Nerve Hyperactivity