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Peripheral nerve hyperexcitability
Handbook of Clinical Neurology, Vol. 161 (3rd series) Clinical Neurophysiology: Diseases and Disorders K.H. Levin and P. Chauvel, Editors https://doi.org/10.1016/B978-0-444-64142-7.00054-0 Copyright © 2019 Elsevier B.V. All rights reserved
Chapter 17
Peripheral nerve hyperexcitability BASHAR KATIRJI* Neuromuscular Center and EMG Laboratory, Neurological Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, United States
Abstract Neuromyotonic and myokymic discharges are abnormal electrical muscular discharges caused by ectopic discharges from motor axons and represent the hallmarks of peripheral nerve hyperexcitability. Neuromyotonic discharges are specific for peripheral nerve hyperexcitability syndromes, whereas myokymic discharges may occur either focally or in a more generalized fashion in many other peripheral nerve disorders. Isaacs syndrome and Morvan syndrome are rare acquired peripheral nerve hyperexcitability disorders that share common clinical features and are often associated with elevated voltage-gated potassium channel–complex antibodies. Central nervous system symptomatology is more common in Morvan syndrome, which also overlaps with limbic encephalitis. Cramp-fasciculation syndrome, a more common syndrome, may represent a milder form of peripheral nerve hyperexcitability. Peripheral nerve hyperexcitability syndromes should be distinguished from stiff person syndrome, myotonic disorders, and rippling muscle disease. When severe, Isaacs syndrome and Morvan syndrome may be disabling but often respond to membrane-stabilizing drugs and immunomodulatory treatments. The electrophysiologic features of these disorders are described.
Peripheral nerve hyperexcitability (PNH) is a term used to include a group of conditions with abnormal electrical discharges generated from motor axons and seen on needle electromyography (EMG). These disorders distinguish themselves from central nervous system disorders where muscle may exhibit stiffness, spasticity, or abnormal tone, and from muscle disorders where abnormal electrical discharges are generated from muscle fibers. Our understanding of the terminology, phenomenology, and neurophysiologic features of these disorders has been incomplete for several reasons: 1.
There are multiple terms used to describe these electrical findings, often used interchangeably and inconsistently in the medical literature. These include myokymic discharges, neuromyotonic discharges, continuous muscle fiber activity, continuous motor neuron discharges, and neurotonia. Neuromyotonic
and myokymic discharges are the preferred terms (Gutmann et al., 2001). These two discharges are related, and one or both may occur in patients with the PNH syndromes. 2. There are also multiple clinical terms used to describe the PNH syndromes. These include idiopathic generalized myokymia, acquired neuromyotonia, Isaacs syndrome, Armadillo syndrome, Morvan syndrome, Morvan’s fibrillary chorea, syndrome of continuous muscle fiber activity, and quantal squander. Isaacs syndrome and Morvan syndrome are the recommended terms for the two most common syndromes. 3. The clinical manifestations of the PNH syndromes have a wide spectrum. Some patients have benign “physiological” muscle twitches or night cramping while others have widespread muscle stiffness and delayed relaxation, which may be disabling and accompanied by dysautonomia or encephalopathy.
*Correspondence to: Bashar Katirji, MD, FACP, University Hospitals Cleveland Medical Center, Neurological Institute, Bolwell Health Center, Fifth floor, 11100 Euclid Avenue, Cleveland, OH 44106-5098, United States. Tel: +1-216-844-4854, Fax: +1-216983-0792, E-mail: [email protected]
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282 4.
A significant overlap in clinical presentations and pathophysiology exists among several of the beststudied PNH syndromes, namely Isaacs syndrome, Morvan syndrome, and cramp-fasciculation syndrome. This renders the distinction between these disorders difficult and raises the question as to whether these entities represent a single disorder with a spectrum of manifestations.
In this chapter, we will use the electrophysiologic terms neuromyotonic and myokymic discharges and the clinical designations of Isaacs syndrome and Morvan syndrome. We will describe insertional and spontaneous activity of muscle with special emphasis on the more specific electrical discharges associated with PNH syndromes. We will highlight the distinguishing features between these discharges and other muscle activity. We then will discuss the clinical manifestations of the various PNH syndromes and their differential diagnosis.
NORMAL MUSCLE INSERTIONAL AND SPONTANEOUS ACTIVITY At rest, muscle is silent. However, brief bursts of electrical discharges occur with needle electrode movement, slightly outlasting the movement of the needle, and usually not lasting more than 300 ms. This normal insertional activity appears as a cluster of positive or negative repetitive high-frequency spikes, which make a crisp static sound. If the needle electrode is inserted close to the motor endplate region and neuromuscular junctions, this usually triggers sharp pain and two types of normal endplate spontaneous activity that may be seen together or independently (Table 17.1):
Endplate spikes These are intermittent spikes representing discharges of individual muscle fibers generated by activation of intramuscular nerve terminals irritated by the needle. Endplate spikes sound like sputtering fat in a frying pan, and often have an initial negative deflection since the generator of the potential is usually underneath the needle’s tip. Endplate spikes fire irregularly at 5–50 Hz and measure 100–200 mV in amplitude and 3–4 ms in duration.
ABNORMAL MUSCLE INSERTIONAL AND SPONTANEOUS ACTIVITY IN PNH SYNDROMES Abnormal insertional and spontaneous activity includes a variety of discharges seen in a variety of neuropathic and myopathic disorders, including fibrillation potentials (brief spikes and positive waves), fasciculation potentials, doublets and triplets, complex repetitive discharges (CRD), myotonic discharges, and cramp discharges (see Table 17.1). These discharges are discussed in more detail in other chapters of this volume. Myokymic and neuromyotonic discharges fall into this category.
Myokymia and Myokymic Discharges DEFINITION In the late 1800s Kny and Schutze independently described focal myokymia and coined the term myokymia (myo ¼ muscle, kyma ¼ wave) (Kny, 1888; Schultze, 1895). In 1948, Denny-Brown and Foley first described generalized myokymia and identified the electrical correlate of this activity, consisting of continuous, irregular discharges from different motor units (DennyBrown and Foley, 1948). Clinically, myokymia refers to continuous, undulating muscle movements giving the appearance of a bag of worms beneath the skin. With needle EMG recording, a myokymic discharge is defined as one or a few motor unit action potential discharges that fire repetitively in a quasi-rhythmical fashion, sounding like “marching soldiers” in irregular step (Albers et al., 1981). Each discharge is composed of about 2–15 spikes with constant variability in the number of spikes per discharge and the interspike intervals as the discharge repeats itself (Fig. 17.1). The intraburst spike frequency is about 30–40 Hz, while the repeating discharge interval ranges from 1 to 5 Hz (Katirji et al., 2014). Myokymic discharges probably originate ectopically in motor nerve fibers and decrease in intensity with progressively distal nerve blocks (Harik et al., 1976). Their occurrence may be amplified by increased axonal excitability, such as after hyperventilation-induced hypocapnia.
DIFFERENTIAL DIAGNOSIS Considering other causes of myokymia
Endplate noise These potentials sounds like a seashell held to the ear, and are recurring irregular negative potentials, 10–50 mV in amplitude and 1–2 ms in duration. They are extracellularly recorded miniature endplate potentials triggered by spontaneous release of acetylcholine quanta at rest.
Both myokymic and neuromyotonic discharges may be found in patients with the clinical PNH syndromes (see the following). However, neuromyotonic discharges are specific for PNH syndromes, whereas myokymia and myokymic discharges occur either focally or in a more generalized fashion in many other peripheral nerve disorders (Albers et al., 1981; Jamieson and Katirji, 1994).
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Table 17.1 Normal and abnormal spontaneous discharges on needle EMG
EMG discharge
Generator/ source
Firing frequency
Stability/firing pattern
Normal spontaneous activity Endplate noise Neuromuscular 20–40 Hz Irregular junction Endplate spikes Terminal axon 5–50 Hz Irregular twigs Abnormal spontaneous discharges seen in peripheral nerve hyperexcitability Motor neuron/ 0.5–10 Hz Irregular Fasciculation potential axon Myokymic discharge Motor axon 1–5 Hz Stable, but number of intrabursts (interburst) potentials may 5–60 Hz change (intraburst) Neuromyotonic discharge
Motor axon
150–250 Hz
Cramp discharge
Motor neuron/ axon
20–150 Hz
Wax and wane in frequency and amplitude High-frequency motor unit action potential discharges
Abnormal spontaneous discharges seen in other disorders Myotonic discharge Muscle 20–50 Hz Wax and wane in membrane frequency and amplitude
Sound on loudspeaker
Clinical setting
Seashell
—
Sputtering fat in frying pan
—
Corn popping
Normal individuals Motor axon disorders Radiation plexopathy Carpal tunnel syndrome Isaacs syndrome Morvan syndrome Episodic ataxia 1 Isaacs syndrome Morvan syndrome Episodic ataxia 1 Normal individuals Motor axon disorders
Marching band
Pinging sound
Revving engine or dive bomber
Complex repetitive discharge
Muscle fiber
5–100 Hz
Regular and stable
Machine
Fibrillation potential/ positive wave
Muscle fiber
0.5–10 Hz
Regular and stable
Rain on tin roof or dull pops
Focal myokymia may be seen in facial muscles with brainstem glioma or multiple sclerosis, or in limb muscles such as in the thenar eminence with carpal tunnel syndrome. It may be present in a single extremity with radiation plexopathy or be generalized as encountered in association with gold toxicity, Guillain–Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and amyotrophic lateral sclerosis (Jamieson and Katirji, 1994; Table 17.2). Distinguishing myokymia from fasciculations While clinical myokymia is a continuous, rippling, undulating movement of muscle, fasciculation potentials are spontaneous, random, and irregular firing discharges of
Myotonic dystrophies Nondystrophic myotonias Pompe disease Schwartz–Jampel syndrome Myotubular myopathy Statins and colchicine Chronic myopathies and chronic neurogenic disorders (radiculopathy, polyneuropathy) Recent or ongoing denervation Necrotizing myopathy
individual motor units resulting in a visible muscle twitch that repeats sporadically and in a migratory fashion within a muscle belly. When recorded on EMG, fasciculation potentials have variable waveform morphology, are extremely irregular, and give a popping corn sound. Distinguishing facial myokymia from hemifacial spasm It may be difficult to clinically distinguish hemifacial spasm from facial myokymia, particularly when the hemifacial spasm is mild or restricted. Hemifacial spasm typically is unilateral and starts in the orbicularis oculi muscles, spreading slowly over years to other facial
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200 ms/D
Fig. 17.1. Myokymic discharge shown in a raster mode with a long sweep speed of 200 ms/division. Note that the number of potentials often changes from one burst to another, varying in this example from one to four potentials. Note also the relatively slow interburst frequency of about 2 Hz while the intraburst frequency is about 18–20 Hz. Reproduced from Katirji B. (2007). Electromyography in clinical practice, second edn. Philadelphia, PA: Mosby/Elsevier, with permission.
Table 17.2 Causes of myokymia and myokymic discharges Facial myokymia Multiple sclerosis Brainstem mass lesion (e.g., glioma) Cerebellopontine angle mass lesion Basilar invagination Syringobulbia Obstructive hydrocephalus Guillain–Barre syndrome Bell’s palsy Limb myokymia Radiation plexopathy Carpal tunnel syndrome Ulnar mononeuropathy Peripheral nerve injury Radiculopathy Generalized myokymia (with or without neuromyotonia) Peripheral nerve hyperexcitability syndromes (Isaacs and Morvan syndromes) Guillain–Barre syndrome Chronic inflammatory demyelinating polyneuropathy Charcot–Marie–Tooth disease Amyotrophic lateral sclerosis Thyrotoxicosis Heavy metal exposure (gold, platinum compounds, lithium, mercury, or manganese) Penicillamine therapy Timber rattlesnake envenomation
muscles. The episodes begin as brief clonic movements of involved muscles and become more tonic (Abbruzzese et al., 2011). Blink reflexes shows variable synkinesis with blink potentials abnormally recorded in lower facial muscles. Facial branch stimulation, such as the zygomatic and mandibular branches, often elicit a response in a muscle supplied by a different branch consistent with ephaptic transmission (Nielsen, 1985). Needle EMG shows irregular, brief, high-frequency bursts (150–400 Hz) of motor unit action potentials that are easily distinguishable from myokymic discharges. Distinguishing myokymic discharges from complex repetitive discharges A CRD is a waveform consisting of multiple distinct spikes, representing several linked muscle fibers, and often fires at a constant and fast rate of 30–50 Hz (Fig. 17.2). Individual CRDs can discharge at slow or extremely fast frequency, ranging from 5 to 100 Hz. The individual CRD ranges from 50 mV to 1 mV in amplitude and up to 50–100 ms in duration. CRD differs from myokymic discharge by remaining extremely uniform from one discharge to another, and by typically beginning and stopping abruptly (Katirji et al., 2014). CRDs produce a sound that mimics the sound of an idling motor boat engine. CRDs result from near-synchronous firing of a group of muscle fibers that communicates ephaptically. CRDs are nonspecific and are seen in a variety of chronic neurogenic and myopathic disorders.
PERIPHERAL NERVE HYPEREXCITABILITY 50 mV/D
285 50 ms/D
A 50 mV/D
50 ms/D
B Fig. 17.2. Complex repetitive discharge recorded from the deltoid muscle in a patient with chronic C6 radiculopathy. Note that the complex (circled) is stable and remains exactly the same between discharges, with a constant firing rate. In (A), the discharge is shown in a triggered raster, and in (B), the five rasters are superimposed. Note that the complex superimposes perfectly, reflecting its uniform configuration. Reproduced from Katirji B. (2007). Electromyography in clinical practice, second edn. Philadelphia, PA: Mosby/Elsevier, with permission..
Neuromyotonia and neuromyotonic discharges DEFINITION The term neuromyotonia was coined by Mertens and Zschocke to highlight the myotonia-like muscle spasms and the peripheral nerve origin (Mertens and Zschocke, 1965). Neuromyotonic discharges and myokymic
discharges are related and often seen together. Neuromyotonic discharges are more specific for PNH syndromes. In contrast, myokymic discharges are more common but less specific, since they occur in a variety of other entities (Table 17.2). Neuromyotonic discharges are rare discharges, characterized by motor units firing repetitively at very high frequency (150–250 Hz), either continuously or in
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100 mV 100 ms
Fig. 17.3. Neuromyotonic discharge. Note the decrementing response. The top is recorded with a long sweep speed of 100 ms/division while the insert is at a regular sweep speed of 10 ms/division. Note the very high-frequency (150–250 Hz) repetitive discharge of a single motor unit. Reproduced from Preston DC, Shapiro BE. (2013). Electromyography and neuromuscular disorders, third edn. London: Elsevier/Saunders, with permission.
recurring bursts with decrementing amplitudes and frequency (Katirji et al., 2014). This produces a “pinging sound” and a funnel or tornado shape when displayed with a longer sweep speed (such as 100 ms/division) (Fig. 17.3). The discharge continues during sleep, and diminishes in intensity with progressively distal nerve blocks, implicating a diffuse origin of the abnormal discharges. Neuromyotonic discharges are related pathophysiologically to myokymic discharges and do not significantly differ from them other than by their higher frequency and waning waveform amplitude (Gutmann et al., 2001). Neuromyotonic discharges are specifically seen in the PNH syndromes Isaacs syndrome, Morvan syndrome, and in episodic ataxia type 1.
Distinguishing neuromyotonia from central disorders
DIFFERENTIAL DIAGNOSIS
PNH syndromes may be inherited or acquired; there is increasing evidence that autoimmunity is the basis of many of the acquired cases. This has been more recently clarified by the identification of elevated voltage-gated potassium channel (VGKC) antibody titers in many of these patients (Irani et al., 2010; Paterson et al., 2014; Montojo et al., 2015). Although most of the symptoms are features of motor nerve hyperactivity, there is evidence of autonomic system and, in rare cases, sensory hyperactivity. The classical acquired PNH syndromes include Isaacs syndrome, Morvan syndrome, and cramp-fasciculation syndrome (CFS). The disorders in this group significantly overlap, and it is possible that they represent a single disorder with a wide range of manifestations and severity (Table 17.3). For example, Morvan syndrome and Isaacs syndrome share the same
Distinguishing neuromyotonia/neuromyotonic discharges from myotonia/myotonic discharges Myotonia presents clinically as poor muscle relaxation and may manifest with muscle stiffness mimicking PNH syndromes. Myotonic discharges are sustained runs of positive waves or brief sharp spikes initiated by needle insertion. Myotonic discharges typically wax and wane in amplitude and have a frequency of less than 100 Hz (Fig. 17.4), producing a characteristic sound of a revving motorcycle engine or dive-bomber. In contrast, neuromyotonia is composed of single motor unit repetitive discharges that decrement, firing at a high frequency of 150–250 Hz; neuromyotonia has a classic “pinging” sound and starts and stops abruptly and wanes in amplitude.
Several central nervous system disorders may produce muscle stiffness and abnormal muscle activity that mimic neuromyotonia. The majority of these disorders, such as stiff person syndrome, spasticity, and rigidity, have associated pyramidal or extrapyramidal signs, including hypertonia or hyperreflexia. On needle EMG, central nervous system (CNS) disorders are associated with normal-appearing motor unit action potentials that the patient has difficulty stopping voluntarily.
PERIPHERAL NERVE HYPEREXCITABILITY SYNDROMES
PERIPHERAL NERVE HYPEREXCITABILITY
287 50 mV 100 m
Fig. 17.4. Myotonic discharge recorded with a sweep speed of 100 ms/division. The arrow depicts the time of needle insertion that triggers the discharge from a muscle fiber. Note the waxing and waning of both amplitude and frequency. Reproduced from Preston DC, Shapiro BE. (2013). Electromyography and neuromuscular disorders, third edn. London: Elsevier/Saunders, with permission. Table 17.3 Characteristic clinical findings in patients with acquired peripheral nerve hyperexcitability syndromes Crampfasciculation Isaacs Morvan syndrome syndrome syndrome Muscle stiffness Muscle twitching Muscle cramps Fasciculation potentials Myokymic discharges Neuromyotonic discharges Autonomic features Agitation Memory loss Insomnia VGKC-complex antibodies
+ ++ ++ ++
++ ++ ++ + ++ ++
++ ++ ++ + ++ +++
+/-
++ +
++ ++ + + +
neuromuscular manifestations of muscle stiffness, muscle twitching, and autonomic disturbances, while Morvan syndrome has additional central nervous system manifestations (insomnia, memory loss, agitation, and hallucinations). Morvan syndrome may also overlap with limbic encephalitis. The majority of PNH syndromes are now considered to be due to potassium channelopathy. Anti-VGKC antibodies are in fact mainly directed at proteins surrounding the potassium channel, rather than the channel itself, and are thus better known as VGKC-complex antibodies. These cell-surface autoantibodies are directed against LGI-1 (leucine rich glioma inactivated protein 1) or CASPR2 (contact-associated protein-like 2) (Irani et al., 2010). The classic acquired PNH syndromes associated with high-level VGKC-complex antibodies include Isaacs syndrome, Morvan syndrome, limbic
encephalitis, and possibly CFS (Tan et al., 2008). High-level VGKC-complex antibodies have been seen occasionally in other patients with possible autoimmune disorder including cerebellar syndromes, intractable epilepsy, and pain syndromes, while low-level VGKCcomplex antibodies are less specific and present in a variety of nonautoimmune disorders (Paterson et al., 2014; Montojo et al., 2015). Most patient with acquired PNH syndromes have CASPR2 autoimmunity, while patients with limbic encephalitis have LGI1 autoimmunity. However, significant overlap exists, with neuropathic pain, cerebellar symptoms, and epilepsy frequently occurring in a significant number of patients with CASPR2 autoimmunity and PNH syndromes occurring in some patients with LGI1 autoimmunity. The treatment of autoimmune PNH syndromes is aimed at reducing spontaneous peripheral nerve discharges by altering their channel properties. Symptomatic treatment includes membrane-stabilizing drugs such as phenytoin or carbamazepine, which are often effective in reducing muscle stiffness, twitching, and cramps. In patients with severe manifestations and confirmed autoimmune origin, plasmapheresis, intravenous immunoglobulin, prednisone, or immunosuppressive agents may be beneficial. Other conditions rarely associated with PNH include anticholinesterase poisoning, chronic spinal muscular atrophies, inherited polyneuropathies, and heavy metal exposure such as gold, mercury, lithium, manganese, and platinum compounds (Caldron and Wilbourn, 1988; Haug et al., 1989; Wilson et al., 2002; Bolamperti et al., 2009; Zhou et al., 2014).
Isaacs syndrome (acquired neuromyotonia, idiopathic generalized myokymia) Isaacs syndrome affects patients at any age. It manifests with gradual onset of generalized muscle stiffness and
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slowness of movement. Dysarthria and dysphagia may occur. Hyperhidrosis, sialorrhea, piloerection, and abdominal pain are frequent. Paresthesia and neuropathic pain are rare. These symptoms vary significantly in severity among patients (Ahmed and Simmons, 2015). On examination, there is often continuous muscle twitching and undulation (myokymia), and sometimes muscle hypertrophy (mainly calf muscles). In severe cases, muscles and posture may be rigid, and Trousseau and Chvostek signs may also be present. Elevated voltagegated potassium channel–complex antibodies are evident in many patients. Needle EMG often shows fasciculations, myokymic discharges, neuromyotonic discharges, doublets and triplets. Symptoms may be disabling and warrant treatment. Symptomatic treatments with membranestabilizing drugs and immunomodulatory treatments may be required.
Morvan syndrome Morvan syndrome affects males much more than females and is sometimes associated with neoplasms, especially thymoma. Hyperhidrosis, tachycardia, arrhythmias, and urinary dysfunction are common (Irani et al., 2012). CNS features include hallucinations, agitation, delirium, and amnesia. Sleep disturbances including insomnia may be severe, mimicking fatal familial insomnia. Cerebrospinal fluid analysis may reveal an increased protein level and oligoclonal bands. Many of these features are common with limbic encephalitis, a CNS disorder associated with LGI1 antibodies. Morvan syndrome responds to immunomodulatory treatment.
Cramp-Fasciculation Syndrome Tahmoush et al. coined the term CFS to describe a benign clinical syndrome characterized by disabling muscle cramps, myalgia, and muscle twitches (Tahmoush et al., 1991). CFS is considered to represent the milder end of the spectrum of PNH disorders. Cramps occur most frequently in the legs but may include abdominal muscles or intrinsic foot muscles. Examination may show muscle fasciculations and calf hypertrophy without weakness. Needle examination demonstrates fasciculation potentials and sometimes myokymic discharges. Voltage-gated potassium channel–complex antibodies are sometimes elevated, but the target antigens within the VGKC complex (CASPR2 vs LGI1) remain unknown in most patients (Liewluck et al., 2014). CFS may be difficult to distinguish from benign fasciculation syndrome and common “physiologic” cramps, particularly in patients without VGKC antibodies.
Episodic ataxia type 1 Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia, dysarthria, coarse tremor, dizziness or vertigo, and muscle stiffness, weakness, and twitching (Jen et al., 2007). Nausea, vomiting, and headache occur rarely. Episodes can be precipitated by physical exertion, emotional stress, or environmental temperature. Attacks usually last a few minutes and rarely hours, ranging from daily to monthly. The onset of the first episode is typically in childhood, almost always before age 20. About 20% of patients with EA1 demonstrate progressive cerebellar ataxia (Graves et al., 2014). Myokymia is usually present at baseline, worsening during the attacks. It is not clear whether the tremors and muscle twitching represent exacerbation of baseline myokymia. Myokymia may be detected clinically or may only be apparent by needle EMG, which often shows both myokymic and neuromyotonic discharges. EA1 is inherited in an autosomal dominant manner. EA1 locus is mapped to chromosome 12p13 and the responsible gene was found to be KCNA1 (Chen et al., 2007). All mutations impair Kv1.1 function, a delayedrectifier potassium channel responsible for repolarizing nerves after depolarization. This potassium channel is abundantly expressed in the cerebellum and in motor axons, where increased neuronal excitability produces symptomatology. In contrast to EA1, episodic ataxia type 2 presents with longer episodes of ataxia and is not known to be associated with myokymia. The treatment of EA1 is mostly symptomatic. Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of the attacks of ataxia in some but not all affected individuals. Carbamazepine and valproic acid are sometimes effective (Jen et al., 2007). Behavioral measures including avoidance of stress, abrupt movements, loud noises, and caffeine intake are important to reduce severity and frequency of attacks.
DISORDERS MIMICKING PERIPHERAL NERVE HYPEREXCITABILITY SYNDROMES The accurate diagnosis of PNH syndromes requires a high index of suspicion, since muscle stiffness and twitching are common nonspecific symptoms associated with a variety of disorders. PNH syndromes are confirmed by the presence of neuromyotonic discharges, myokymic discharges, fasciculation potentials, or a combination of these discharges. PNH syndromes should be differentiated from myopathic disorders and CNS disorders that may cause muscle stiffness. The myotonias and stiff person syndrome have been described previously. A description of other mimics follows.
PERIPHERAL NERVE HYPEREXCITABILITY
Schwartz–Jampel syndrome (chondrodystrophic myotonia) Schwartz–Jampel syndrome is characterized by the triad of myotonia, facial dysmorphism, and skeletal deformities. Common features include muscle stiffness, muscle hypertrophy, contractures, and myotonia. Facial dysmorphisms include puckered-small mouth, blepharophimosis, and blepharospasm. Skeletal abnormalities include short stature, kyphosis, hip dysplasias, and pseudofractures (Giedion et al., 1997). Creatine kinase (CK) is usually normal or slightly elevated. Needle EMG reveals continuous myotonic discharges at rest. Schwartz–Jampel syndrome is a rare autosomal recessive disorder resulting from mutations in the HSPG2 gene in chromosome 1p34–36.1, which encodes perlecan, a major component of basement membranes.
Rippling muscle disease Rippling muscle disease (RMD) is a nonprogressive myopathy that manifests with muscle stiffness that may be painful, slowness of movements, and muscle cramps mostly at rest but sometimes during physical activity (Torbergsen, 2002). The symptoms appear in the first or second decade of life and follow a benign, stable course. The neuromuscular examination is normal except for muscle hypertrophy in some patients. Tapping on skeletal muscles with a reflex hammer typically produces local mounding of muscle (myoedema) that rolls like a wave (“rippling”). This is electrically silent during EMG recording. CK is often moderately elevated (<10 times normal). Muscle biopsy may be normal or shows mild nonspecific changes. The manifestations of RMD are likely due to muscular rather than peripheral nerve hyperexcitability. The pathophysiologic mechanism has not been clarified, although dysfunction in the sarcoplasmic reticulum and calcium release have been implicated. Most reported cases of RMD have an autosomal dominant inheritance pattern with variable penetrance. Mutations in the gene encoding caveolin-3 (CAV3), a membrane-associated protein localized to skeletal muscle fibers, is associated with RMD (Lo et al., 2011). In some patients, the disease may be autoimmune in nature, sometimes associated with myasthenia gravis, thymoma, or both, and responsive to immunotherapy (Schoser et al., 2009).
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Montojo MT, Petit-Pedrol M, Graus F et al. (2015). Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex. Neurologia 30 (5): 295–301. Nielsen VK (1985). Electrophysiology of the facial nerve in hemifacial spasm: ectopic/ephaptic excitation. Muscle Nerve 8 (7): 545–555. Paterson RW, Zandi MS, Armstrong R et al. (2014). Clinical relevance of positive voltage gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry 85: 625–630. Schoser B, Jacob S, Hilton-Jones D et al. (2009). Immunemediated rippling muscle disease with myasthenia gravis: a report of seven patients with long-term follow-up in two. Neuromuscul Disord 19: 223–228. Schultze F (1895). Beitrage zur musckelpathologie. Deutsch Ztschr fNervenh 6: 65–75. Tahmoush AJ, Alonso RJ, Thamoush GP et al. (1991). Cramp fasciculation syndrome: a treatable hyperexcitable peripheral nerve disorder. Neurology 41 (7): 1021–1024. Tan KM, Lennon VA, Klein CJ et al. (2008). Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 70: 1883–1890. Torbergsen T (2002). Rippling muscle disease: a review. Muscle Nerve 11 (Suppl): S103–S107.
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FURTHER READING Isaacs H (1961). Syndrome of continuous muscle fibre activity. J Neurol Neurosurg Psychiatry 24: 319–325. McKeon A, Robinson MT, McEvoy KM et al. (2012). Stiffman syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 69 (2): 230–238. Morvan A (1890). De la choree fibrillaire. Gazette Hebdomadaire Med. Chir. 27: 173–176. Ruff RL, Shapiro BE (2014). Disorders of skeletal muscle membrane excitability: myotonia congenita, paramyotonia congenita, periodic paralysis, and related syndromes. In: B KatirjiHJ Kaminski, RL Ruff (Eds.), Neuromuscular disorders in clinical practice, second edn. Springer, New York, pp. 1111–1147. Termsarasab T, Baajour W, Thammongkolchai T et al. (2014). The myotonic dystrophies. In: B Katirji, HJ Kaminski, RL Ruff (Eds.), Neuromuscular disorders in clinical practice, second edn. Springer, New York, pp. 1222–1238.
Chapter 17
Peripheral nerve hyperexcitability BASHAR KATIRJI* Neuromuscular Center and EMG Laboratory, Neurological Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, United States
Abstract Neuromyotonic and myokymic discharges are abnormal electrical muscular discharges caused by ectopic discharges from motor axons and represent the hallmarks of peripheral nerve hyperexcitability. Neuromyotonic discharges are specific for peripheral nerve hyperexcitability syndromes, whereas myokymic discharges may occur either focally or in a more generalized fashion in many other peripheral nerve disorders. Isaacs syndrome and Morvan syndrome are rare acquired peripheral nerve hyperexcitability disorders that share common clinical features and are often associated with elevated voltage-gated potassium channel–complex antibodies. Central nervous system symptomatology is more common in Morvan syndrome, which also overlaps with limbic encephalitis. Cramp-fasciculation syndrome, a more common syndrome, may represent a milder form of peripheral nerve hyperexcitability. Peripheral nerve hyperexcitability syndromes should be distinguished from stiff person syndrome, myotonic disorders, and rippling muscle disease. When severe, Isaacs syndrome and Morvan syndrome may be disabling but often respond to membrane-stabilizing drugs and immunomodulatory treatments. The electrophysiologic features of these disorders are described.
Peripheral nerve hyperexcitability (PNH) is a term used to include a group of conditions with abnormal electrical discharges generated from motor axons and seen on needle electromyography (EMG). These disorders distinguish themselves from central nervous system disorders where muscle may exhibit stiffness, spasticity, or abnormal tone, and from muscle disorders where abnormal electrical discharges are generated from muscle fibers. Our understanding of the terminology, phenomenology, and neurophysiologic features of these disorders has been incomplete for several reasons: 1.
There are multiple terms used to describe these electrical findings, often used interchangeably and inconsistently in the medical literature. These include myokymic discharges, neuromyotonic discharges, continuous muscle fiber activity, continuous motor neuron discharges, and neurotonia. Neuromyotonic
and myokymic discharges are the preferred terms (Gutmann et al., 2001). These two discharges are related, and one or both may occur in patients with the PNH syndromes. 2. There are also multiple clinical terms used to describe the PNH syndromes. These include idiopathic generalized myokymia, acquired neuromyotonia, Isaacs syndrome, Armadillo syndrome, Morvan syndrome, Morvan’s fibrillary chorea, syndrome of continuous muscle fiber activity, and quantal squander. Isaacs syndrome and Morvan syndrome are the recommended terms for the two most common syndromes. 3. The clinical manifestations of the PNH syndromes have a wide spectrum. Some patients have benign “physiological” muscle twitches or night cramping while others have widespread muscle stiffness and delayed relaxation, which may be disabling and accompanied by dysautonomia or encephalopathy.
*Correspondence to: Bashar Katirji, MD, FACP, University Hospitals Cleveland Medical Center, Neurological Institute, Bolwell Health Center, Fifth floor, 11100 Euclid Avenue, Cleveland, OH 44106-5098, United States. Tel: +1-216-844-4854, Fax: +1-216983-0792, E-mail: [email protected]
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282 4.
A significant overlap in clinical presentations and pathophysiology exists among several of the beststudied PNH syndromes, namely Isaacs syndrome, Morvan syndrome, and cramp-fasciculation syndrome. This renders the distinction between these disorders difficult and raises the question as to whether these entities represent a single disorder with a spectrum of manifestations.
In this chapter, we will use the electrophysiologic terms neuromyotonic and myokymic discharges and the clinical designations of Isaacs syndrome and Morvan syndrome. We will describe insertional and spontaneous activity of muscle with special emphasis on the more specific electrical discharges associated with PNH syndromes. We will highlight the distinguishing features between these discharges and other muscle activity. We then will discuss the clinical manifestations of the various PNH syndromes and their differential diagnosis.
NORMAL MUSCLE INSERTIONAL AND SPONTANEOUS ACTIVITY At rest, muscle is silent. However, brief bursts of electrical discharges occur with needle electrode movement, slightly outlasting the movement of the needle, and usually not lasting more than 300 ms. This normal insertional activity appears as a cluster of positive or negative repetitive high-frequency spikes, which make a crisp static sound. If the needle electrode is inserted close to the motor endplate region and neuromuscular junctions, this usually triggers sharp pain and two types of normal endplate spontaneous activity that may be seen together or independently (Table 17.1):
Endplate spikes These are intermittent spikes representing discharges of individual muscle fibers generated by activation of intramuscular nerve terminals irritated by the needle. Endplate spikes sound like sputtering fat in a frying pan, and often have an initial negative deflection since the generator of the potential is usually underneath the needle’s tip. Endplate spikes fire irregularly at 5–50 Hz and measure 100–200 mV in amplitude and 3–4 ms in duration.
ABNORMAL MUSCLE INSERTIONAL AND SPONTANEOUS ACTIVITY IN PNH SYNDROMES Abnormal insertional and spontaneous activity includes a variety of discharges seen in a variety of neuropathic and myopathic disorders, including fibrillation potentials (brief spikes and positive waves), fasciculation potentials, doublets and triplets, complex repetitive discharges (CRD), myotonic discharges, and cramp discharges (see Table 17.1). These discharges are discussed in more detail in other chapters of this volume. Myokymic and neuromyotonic discharges fall into this category.
Myokymia and Myokymic Discharges DEFINITION In the late 1800s Kny and Schutze independently described focal myokymia and coined the term myokymia (myo ¼ muscle, kyma ¼ wave) (Kny, 1888; Schultze, 1895). In 1948, Denny-Brown and Foley first described generalized myokymia and identified the electrical correlate of this activity, consisting of continuous, irregular discharges from different motor units (DennyBrown and Foley, 1948). Clinically, myokymia refers to continuous, undulating muscle movements giving the appearance of a bag of worms beneath the skin. With needle EMG recording, a myokymic discharge is defined as one or a few motor unit action potential discharges that fire repetitively in a quasi-rhythmical fashion, sounding like “marching soldiers” in irregular step (Albers et al., 1981). Each discharge is composed of about 2–15 spikes with constant variability in the number of spikes per discharge and the interspike intervals as the discharge repeats itself (Fig. 17.1). The intraburst spike frequency is about 30–40 Hz, while the repeating discharge interval ranges from 1 to 5 Hz (Katirji et al., 2014). Myokymic discharges probably originate ectopically in motor nerve fibers and decrease in intensity with progressively distal nerve blocks (Harik et al., 1976). Their occurrence may be amplified by increased axonal excitability, such as after hyperventilation-induced hypocapnia.
DIFFERENTIAL DIAGNOSIS Considering other causes of myokymia
Endplate noise These potentials sounds like a seashell held to the ear, and are recurring irregular negative potentials, 10–50 mV in amplitude and 1–2 ms in duration. They are extracellularly recorded miniature endplate potentials triggered by spontaneous release of acetylcholine quanta at rest.
Both myokymic and neuromyotonic discharges may be found in patients with the clinical PNH syndromes (see the following). However, neuromyotonic discharges are specific for PNH syndromes, whereas myokymia and myokymic discharges occur either focally or in a more generalized fashion in many other peripheral nerve disorders (Albers et al., 1981; Jamieson and Katirji, 1994).
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Table 17.1 Normal and abnormal spontaneous discharges on needle EMG
EMG discharge
Generator/ source
Firing frequency
Stability/firing pattern
Normal spontaneous activity Endplate noise Neuromuscular 20–40 Hz Irregular junction Endplate spikes Terminal axon 5–50 Hz Irregular twigs Abnormal spontaneous discharges seen in peripheral nerve hyperexcitability Motor neuron/ 0.5–10 Hz Irregular Fasciculation potential axon Myokymic discharge Motor axon 1–5 Hz Stable, but number of intrabursts (interburst) potentials may 5–60 Hz change (intraburst) Neuromyotonic discharge
Motor axon
150–250 Hz
Cramp discharge
Motor neuron/ axon
20–150 Hz
Wax and wane in frequency and amplitude High-frequency motor unit action potential discharges
Abnormal spontaneous discharges seen in other disorders Myotonic discharge Muscle 20–50 Hz Wax and wane in membrane frequency and amplitude
Sound on loudspeaker
Clinical setting
Seashell
—
Sputtering fat in frying pan
—
Corn popping
Normal individuals Motor axon disorders Radiation plexopathy Carpal tunnel syndrome Isaacs syndrome Morvan syndrome Episodic ataxia 1 Isaacs syndrome Morvan syndrome Episodic ataxia 1 Normal individuals Motor axon disorders
Marching band
Pinging sound
Revving engine or dive bomber
Complex repetitive discharge
Muscle fiber
5–100 Hz
Regular and stable
Machine
Fibrillation potential/ positive wave
Muscle fiber
0.5–10 Hz
Regular and stable
Rain on tin roof or dull pops
Focal myokymia may be seen in facial muscles with brainstem glioma or multiple sclerosis, or in limb muscles such as in the thenar eminence with carpal tunnel syndrome. It may be present in a single extremity with radiation plexopathy or be generalized as encountered in association with gold toxicity, Guillain–Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and amyotrophic lateral sclerosis (Jamieson and Katirji, 1994; Table 17.2). Distinguishing myokymia from fasciculations While clinical myokymia is a continuous, rippling, undulating movement of muscle, fasciculation potentials are spontaneous, random, and irregular firing discharges of
Myotonic dystrophies Nondystrophic myotonias Pompe disease Schwartz–Jampel syndrome Myotubular myopathy Statins and colchicine Chronic myopathies and chronic neurogenic disorders (radiculopathy, polyneuropathy) Recent or ongoing denervation Necrotizing myopathy
individual motor units resulting in a visible muscle twitch that repeats sporadically and in a migratory fashion within a muscle belly. When recorded on EMG, fasciculation potentials have variable waveform morphology, are extremely irregular, and give a popping corn sound. Distinguishing facial myokymia from hemifacial spasm It may be difficult to clinically distinguish hemifacial spasm from facial myokymia, particularly when the hemifacial spasm is mild or restricted. Hemifacial spasm typically is unilateral and starts in the orbicularis oculi muscles, spreading slowly over years to other facial
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200 ms/D
Fig. 17.1. Myokymic discharge shown in a raster mode with a long sweep speed of 200 ms/division. Note that the number of potentials often changes from one burst to another, varying in this example from one to four potentials. Note also the relatively slow interburst frequency of about 2 Hz while the intraburst frequency is about 18–20 Hz. Reproduced from Katirji B. (2007). Electromyography in clinical practice, second edn. Philadelphia, PA: Mosby/Elsevier, with permission.
Table 17.2 Causes of myokymia and myokymic discharges Facial myokymia Multiple sclerosis Brainstem mass lesion (e.g., glioma) Cerebellopontine angle mass lesion Basilar invagination Syringobulbia Obstructive hydrocephalus Guillain–Barre syndrome Bell’s palsy Limb myokymia Radiation plexopathy Carpal tunnel syndrome Ulnar mononeuropathy Peripheral nerve injury Radiculopathy Generalized myokymia (with or without neuromyotonia) Peripheral nerve hyperexcitability syndromes (Isaacs and Morvan syndromes) Guillain–Barre syndrome Chronic inflammatory demyelinating polyneuropathy Charcot–Marie–Tooth disease Amyotrophic lateral sclerosis Thyrotoxicosis Heavy metal exposure (gold, platinum compounds, lithium, mercury, or manganese) Penicillamine therapy Timber rattlesnake envenomation
muscles. The episodes begin as brief clonic movements of involved muscles and become more tonic (Abbruzzese et al., 2011). Blink reflexes shows variable synkinesis with blink potentials abnormally recorded in lower facial muscles. Facial branch stimulation, such as the zygomatic and mandibular branches, often elicit a response in a muscle supplied by a different branch consistent with ephaptic transmission (Nielsen, 1985). Needle EMG shows irregular, brief, high-frequency bursts (150–400 Hz) of motor unit action potentials that are easily distinguishable from myokymic discharges. Distinguishing myokymic discharges from complex repetitive discharges A CRD is a waveform consisting of multiple distinct spikes, representing several linked muscle fibers, and often fires at a constant and fast rate of 30–50 Hz (Fig. 17.2). Individual CRDs can discharge at slow or extremely fast frequency, ranging from 5 to 100 Hz. The individual CRD ranges from 50 mV to 1 mV in amplitude and up to 50–100 ms in duration. CRD differs from myokymic discharge by remaining extremely uniform from one discharge to another, and by typically beginning and stopping abruptly (Katirji et al., 2014). CRDs produce a sound that mimics the sound of an idling motor boat engine. CRDs result from near-synchronous firing of a group of muscle fibers that communicates ephaptically. CRDs are nonspecific and are seen in a variety of chronic neurogenic and myopathic disorders.
PERIPHERAL NERVE HYPEREXCITABILITY 50 mV/D
285 50 ms/D
A 50 mV/D
50 ms/D
B Fig. 17.2. Complex repetitive discharge recorded from the deltoid muscle in a patient with chronic C6 radiculopathy. Note that the complex (circled) is stable and remains exactly the same between discharges, with a constant firing rate. In (A), the discharge is shown in a triggered raster, and in (B), the five rasters are superimposed. Note that the complex superimposes perfectly, reflecting its uniform configuration. Reproduced from Katirji B. (2007). Electromyography in clinical practice, second edn. Philadelphia, PA: Mosby/Elsevier, with permission..
Neuromyotonia and neuromyotonic discharges DEFINITION The term neuromyotonia was coined by Mertens and Zschocke to highlight the myotonia-like muscle spasms and the peripheral nerve origin (Mertens and Zschocke, 1965). Neuromyotonic discharges and myokymic
discharges are related and often seen together. Neuromyotonic discharges are more specific for PNH syndromes. In contrast, myokymic discharges are more common but less specific, since they occur in a variety of other entities (Table 17.2). Neuromyotonic discharges are rare discharges, characterized by motor units firing repetitively at very high frequency (150–250 Hz), either continuously or in
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100 mV 100 ms
Fig. 17.3. Neuromyotonic discharge. Note the decrementing response. The top is recorded with a long sweep speed of 100 ms/division while the insert is at a regular sweep speed of 10 ms/division. Note the very high-frequency (150–250 Hz) repetitive discharge of a single motor unit. Reproduced from Preston DC, Shapiro BE. (2013). Electromyography and neuromuscular disorders, third edn. London: Elsevier/Saunders, with permission.
recurring bursts with decrementing amplitudes and frequency (Katirji et al., 2014). This produces a “pinging sound” and a funnel or tornado shape when displayed with a longer sweep speed (such as 100 ms/division) (Fig. 17.3). The discharge continues during sleep, and diminishes in intensity with progressively distal nerve blocks, implicating a diffuse origin of the abnormal discharges. Neuromyotonic discharges are related pathophysiologically to myokymic discharges and do not significantly differ from them other than by their higher frequency and waning waveform amplitude (Gutmann et al., 2001). Neuromyotonic discharges are specifically seen in the PNH syndromes Isaacs syndrome, Morvan syndrome, and in episodic ataxia type 1.
Distinguishing neuromyotonia from central disorders
DIFFERENTIAL DIAGNOSIS
PNH syndromes may be inherited or acquired; there is increasing evidence that autoimmunity is the basis of many of the acquired cases. This has been more recently clarified by the identification of elevated voltage-gated potassium channel (VGKC) antibody titers in many of these patients (Irani et al., 2010; Paterson et al., 2014; Montojo et al., 2015). Although most of the symptoms are features of motor nerve hyperactivity, there is evidence of autonomic system and, in rare cases, sensory hyperactivity. The classical acquired PNH syndromes include Isaacs syndrome, Morvan syndrome, and cramp-fasciculation syndrome (CFS). The disorders in this group significantly overlap, and it is possible that they represent a single disorder with a wide range of manifestations and severity (Table 17.3). For example, Morvan syndrome and Isaacs syndrome share the same
Distinguishing neuromyotonia/neuromyotonic discharges from myotonia/myotonic discharges Myotonia presents clinically as poor muscle relaxation and may manifest with muscle stiffness mimicking PNH syndromes. Myotonic discharges are sustained runs of positive waves or brief sharp spikes initiated by needle insertion. Myotonic discharges typically wax and wane in amplitude and have a frequency of less than 100 Hz (Fig. 17.4), producing a characteristic sound of a revving motorcycle engine or dive-bomber. In contrast, neuromyotonia is composed of single motor unit repetitive discharges that decrement, firing at a high frequency of 150–250 Hz; neuromyotonia has a classic “pinging” sound and starts and stops abruptly and wanes in amplitude.
Several central nervous system disorders may produce muscle stiffness and abnormal muscle activity that mimic neuromyotonia. The majority of these disorders, such as stiff person syndrome, spasticity, and rigidity, have associated pyramidal or extrapyramidal signs, including hypertonia or hyperreflexia. On needle EMG, central nervous system (CNS) disorders are associated with normal-appearing motor unit action potentials that the patient has difficulty stopping voluntarily.
PERIPHERAL NERVE HYPEREXCITABILITY SYNDROMES
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287 50 mV 100 m
Fig. 17.4. Myotonic discharge recorded with a sweep speed of 100 ms/division. The arrow depicts the time of needle insertion that triggers the discharge from a muscle fiber. Note the waxing and waning of both amplitude and frequency. Reproduced from Preston DC, Shapiro BE. (2013). Electromyography and neuromuscular disorders, third edn. London: Elsevier/Saunders, with permission. Table 17.3 Characteristic clinical findings in patients with acquired peripheral nerve hyperexcitability syndromes Crampfasciculation Isaacs Morvan syndrome syndrome syndrome Muscle stiffness Muscle twitching Muscle cramps Fasciculation potentials Myokymic discharges Neuromyotonic discharges Autonomic features Agitation Memory loss Insomnia VGKC-complex antibodies
+ ++ ++ ++
++ ++ ++ + ++ ++
++ ++ ++ + ++ +++
+/-
++ +
++ ++ + + +
neuromuscular manifestations of muscle stiffness, muscle twitching, and autonomic disturbances, while Morvan syndrome has additional central nervous system manifestations (insomnia, memory loss, agitation, and hallucinations). Morvan syndrome may also overlap with limbic encephalitis. The majority of PNH syndromes are now considered to be due to potassium channelopathy. Anti-VGKC antibodies are in fact mainly directed at proteins surrounding the potassium channel, rather than the channel itself, and are thus better known as VGKC-complex antibodies. These cell-surface autoantibodies are directed against LGI-1 (leucine rich glioma inactivated protein 1) or CASPR2 (contact-associated protein-like 2) (Irani et al., 2010). The classic acquired PNH syndromes associated with high-level VGKC-complex antibodies include Isaacs syndrome, Morvan syndrome, limbic
encephalitis, and possibly CFS (Tan et al., 2008). High-level VGKC-complex antibodies have been seen occasionally in other patients with possible autoimmune disorder including cerebellar syndromes, intractable epilepsy, and pain syndromes, while low-level VGKCcomplex antibodies are less specific and present in a variety of nonautoimmune disorders (Paterson et al., 2014; Montojo et al., 2015). Most patient with acquired PNH syndromes have CASPR2 autoimmunity, while patients with limbic encephalitis have LGI1 autoimmunity. However, significant overlap exists, with neuropathic pain, cerebellar symptoms, and epilepsy frequently occurring in a significant number of patients with CASPR2 autoimmunity and PNH syndromes occurring in some patients with LGI1 autoimmunity. The treatment of autoimmune PNH syndromes is aimed at reducing spontaneous peripheral nerve discharges by altering their channel properties. Symptomatic treatment includes membrane-stabilizing drugs such as phenytoin or carbamazepine, which are often effective in reducing muscle stiffness, twitching, and cramps. In patients with severe manifestations and confirmed autoimmune origin, plasmapheresis, intravenous immunoglobulin, prednisone, or immunosuppressive agents may be beneficial. Other conditions rarely associated with PNH include anticholinesterase poisoning, chronic spinal muscular atrophies, inherited polyneuropathies, and heavy metal exposure such as gold, mercury, lithium, manganese, and platinum compounds (Caldron and Wilbourn, 1988; Haug et al., 1989; Wilson et al., 2002; Bolamperti et al., 2009; Zhou et al., 2014).
Isaacs syndrome (acquired neuromyotonia, idiopathic generalized myokymia) Isaacs syndrome affects patients at any age. It manifests with gradual onset of generalized muscle stiffness and
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slowness of movement. Dysarthria and dysphagia may occur. Hyperhidrosis, sialorrhea, piloerection, and abdominal pain are frequent. Paresthesia and neuropathic pain are rare. These symptoms vary significantly in severity among patients (Ahmed and Simmons, 2015). On examination, there is often continuous muscle twitching and undulation (myokymia), and sometimes muscle hypertrophy (mainly calf muscles). In severe cases, muscles and posture may be rigid, and Trousseau and Chvostek signs may also be present. Elevated voltagegated potassium channel–complex antibodies are evident in many patients. Needle EMG often shows fasciculations, myokymic discharges, neuromyotonic discharges, doublets and triplets. Symptoms may be disabling and warrant treatment. Symptomatic treatments with membranestabilizing drugs and immunomodulatory treatments may be required.
Morvan syndrome Morvan syndrome affects males much more than females and is sometimes associated with neoplasms, especially thymoma. Hyperhidrosis, tachycardia, arrhythmias, and urinary dysfunction are common (Irani et al., 2012). CNS features include hallucinations, agitation, delirium, and amnesia. Sleep disturbances including insomnia may be severe, mimicking fatal familial insomnia. Cerebrospinal fluid analysis may reveal an increased protein level and oligoclonal bands. Many of these features are common with limbic encephalitis, a CNS disorder associated with LGI1 antibodies. Morvan syndrome responds to immunomodulatory treatment.
Cramp-Fasciculation Syndrome Tahmoush et al. coined the term CFS to describe a benign clinical syndrome characterized by disabling muscle cramps, myalgia, and muscle twitches (Tahmoush et al., 1991). CFS is considered to represent the milder end of the spectrum of PNH disorders. Cramps occur most frequently in the legs but may include abdominal muscles or intrinsic foot muscles. Examination may show muscle fasciculations and calf hypertrophy without weakness. Needle examination demonstrates fasciculation potentials and sometimes myokymic discharges. Voltage-gated potassium channel–complex antibodies are sometimes elevated, but the target antigens within the VGKC complex (CASPR2 vs LGI1) remain unknown in most patients (Liewluck et al., 2014). CFS may be difficult to distinguish from benign fasciculation syndrome and common “physiologic” cramps, particularly in patients without VGKC antibodies.
Episodic ataxia type 1 Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia, dysarthria, coarse tremor, dizziness or vertigo, and muscle stiffness, weakness, and twitching (Jen et al., 2007). Nausea, vomiting, and headache occur rarely. Episodes can be precipitated by physical exertion, emotional stress, or environmental temperature. Attacks usually last a few minutes and rarely hours, ranging from daily to monthly. The onset of the first episode is typically in childhood, almost always before age 20. About 20% of patients with EA1 demonstrate progressive cerebellar ataxia (Graves et al., 2014). Myokymia is usually present at baseline, worsening during the attacks. It is not clear whether the tremors and muscle twitching represent exacerbation of baseline myokymia. Myokymia may be detected clinically or may only be apparent by needle EMG, which often shows both myokymic and neuromyotonic discharges. EA1 is inherited in an autosomal dominant manner. EA1 locus is mapped to chromosome 12p13 and the responsible gene was found to be KCNA1 (Chen et al., 2007). All mutations impair Kv1.1 function, a delayedrectifier potassium channel responsible for repolarizing nerves after depolarization. This potassium channel is abundantly expressed in the cerebellum and in motor axons, where increased neuronal excitability produces symptomatology. In contrast to EA1, episodic ataxia type 2 presents with longer episodes of ataxia and is not known to be associated with myokymia. The treatment of EA1 is mostly symptomatic. Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of the attacks of ataxia in some but not all affected individuals. Carbamazepine and valproic acid are sometimes effective (Jen et al., 2007). Behavioral measures including avoidance of stress, abrupt movements, loud noises, and caffeine intake are important to reduce severity and frequency of attacks.
DISORDERS MIMICKING PERIPHERAL NERVE HYPEREXCITABILITY SYNDROMES The accurate diagnosis of PNH syndromes requires a high index of suspicion, since muscle stiffness and twitching are common nonspecific symptoms associated with a variety of disorders. PNH syndromes are confirmed by the presence of neuromyotonic discharges, myokymic discharges, fasciculation potentials, or a combination of these discharges. PNH syndromes should be differentiated from myopathic disorders and CNS disorders that may cause muscle stiffness. The myotonias and stiff person syndrome have been described previously. A description of other mimics follows.
PERIPHERAL NERVE HYPEREXCITABILITY
Schwartz–Jampel syndrome (chondrodystrophic myotonia) Schwartz–Jampel syndrome is characterized by the triad of myotonia, facial dysmorphism, and skeletal deformities. Common features include muscle stiffness, muscle hypertrophy, contractures, and myotonia. Facial dysmorphisms include puckered-small mouth, blepharophimosis, and blepharospasm. Skeletal abnormalities include short stature, kyphosis, hip dysplasias, and pseudofractures (Giedion et al., 1997). Creatine kinase (CK) is usually normal or slightly elevated. Needle EMG reveals continuous myotonic discharges at rest. Schwartz–Jampel syndrome is a rare autosomal recessive disorder resulting from mutations in the HSPG2 gene in chromosome 1p34–36.1, which encodes perlecan, a major component of basement membranes.
Rippling muscle disease Rippling muscle disease (RMD) is a nonprogressive myopathy that manifests with muscle stiffness that may be painful, slowness of movements, and muscle cramps mostly at rest but sometimes during physical activity (Torbergsen, 2002). The symptoms appear in the first or second decade of life and follow a benign, stable course. The neuromuscular examination is normal except for muscle hypertrophy in some patients. Tapping on skeletal muscles with a reflex hammer typically produces local mounding of muscle (myoedema) that rolls like a wave (“rippling”). This is electrically silent during EMG recording. CK is often moderately elevated (<10 times normal). Muscle biopsy may be normal or shows mild nonspecific changes. The manifestations of RMD are likely due to muscular rather than peripheral nerve hyperexcitability. The pathophysiologic mechanism has not been clarified, although dysfunction in the sarcoplasmic reticulum and calcium release have been implicated. Most reported cases of RMD have an autosomal dominant inheritance pattern with variable penetrance. Mutations in the gene encoding caveolin-3 (CAV3), a membrane-associated protein localized to skeletal muscle fibers, is associated with RMD (Lo et al., 2011). In some patients, the disease may be autoimmune in nature, sometimes associated with myasthenia gravis, thymoma, or both, and responsive to immunotherapy (Schoser et al., 2009).
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FURTHER READING Isaacs H (1961). Syndrome of continuous muscle fibre activity. J Neurol Neurosurg Psychiatry 24: 319–325. McKeon A, Robinson MT, McEvoy KM et al. (2012). Stiffman syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 69 (2): 230–238. Morvan A (1890). De la choree fibrillaire. Gazette Hebdomadaire Med. Chir. 27: 173–176. Ruff RL, Shapiro BE (2014). Disorders of skeletal muscle membrane excitability: myotonia congenita, paramyotonia congenita, periodic paralysis, and related syndromes. In: B KatirjiHJ Kaminski, RL Ruff (Eds.), Neuromuscular disorders in clinical practice, second edn. Springer, New York, pp. 1111–1147. Termsarasab T, Baajour W, Thammongkolchai T et al. (2014). The myotonic dystrophies. In: B Katirji, HJ Kaminski, RL Ruff (Eds.), Neuromuscular disorders in clinical practice, second edn. Springer, New York, pp. 1222–1238.