Clinical manifestations

Presentation and course

Cramp-fasciculation syndrome. Cramp-fasciculation syndrome is a benign syndrome that presents with myalgia and cramps without weakness (27; 19). Examination may show fasciculations, myokymia, or both in muscles with an otherwise normal neuromuscular examination. The calves may become large.

Isaacs syndrome. Isaacs syndrome may affect patients at any age. It often manifests with generalized muscle stiffness that fluctuates but usually slowly worsens over the years. The stiffness persists during sleep (14; 01). On examination, there is continuous muscle twitching and undulation. Sometimes, muscle hypertrophy (mainly calf muscles) may be evident. The disorder varies significantly in severity. When severe, there is slowness of movement, and posture may be rigid. Trousseau and Chvostek signs may be present, and dysarthria and dysphagia may occur. Hyperhidrosis, sialorrhea, piloerection (goose flesh), and abdominal pain may also be present. Sensory manifestations are rare and include paresthesia and neuropathic pain.

Morvan syndrome. Morvan syndrome affects males more than females. It mimics Isaacs syndrome but includes additional features, such as neuropathic limb pain (likely due to involvement of small sensory fibers), sleep disturbances (mostly insomnia), and dysautonomia (11). Hyperhidrosis, tachycardia, arrhythmias, and urinary dysfunction are common dysautonomic symptoms. CNS features, including hallucinations, agitation, delirium, amnesia, and confusion, may also occur.

Limbic encephalitis. A discussion of the peripheral nerve hyperexcitability syndromes is not complete without addressing limbic encephalitis, which overlaps with peripheral nerve hyperexcitability syndromes (Table 1).

Table 1. Characteristic Clinical Findings in Patients with Peripheral Nerve Hyperexcitability Syndromes and Limbic Encephalitis

Autoimmune limbic encephalitis may be paraneoplastic or nonparaneoplastic, with significant overlap. The majority have antibodies towards intracellular antigens (eg, Hu, Ma2, or GAD65) or neuronal cell-surface proteins, ion channels, or receptors (such as N-methyl-d-aspartate receptor [NMDAR], VGKC-complex antibodies [including LGI1 and CASPR2], γ-aminobutyric acid type B receptor [GABABR], or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor [AMPAR]).

Limbic encephalitis associated with voltage-gated potassium channel-complex antibodies (VGKC-complex antibodies) is the second most frequent autoimmune encephalitis. This encephalitis is specifically associated with leucine-rich glioma-inactivated 1 (LGI1) antibody and less commonly with contactin-associated protein-like 2 (CASPR2). This predominantly CNS disorder frequently presents with multiple faciobrachial dystonic seizures before developing the amnestic and behavioral manifestations of limbic encephalitis (30). Dysautonomia, neuropathic pain, and peripheral nerve hyperexcitability (fasciculations, myokymia, and neuromyotonia) may accompany limbic encephalitis. This limbic encephalitis overlaps with peripheral nerve hyperexcitability syndromes, particularly Morvan syndrome. These peripheral manifestations are more commonly seen with CASPR2 than LGI1 antibodies. Additional diagnostic findings include MRI FLAIR-T2 imaging showing bilateral abnormalities highly restricted to the medial temporal lobes, CSF pleocytosis, and epileptic features or slow activity involving the temporal lobes on EEG.

Prognosis and complications

Peripheral nerve hyperexcitability syndromes have a favorable prognosis. Up to 80% of patients respond favorably to corticosteroids combined with a membrane stabilizer, such as carbamazepine or phenytoin. In the majority of patients, immunosuppressive therapy can be stopped in 1 to 5 years (18).

Biological basis

Etiology and pathogenesis

Voltage-gated potassium channels (VGKCs) are central to the pathophysiology of peripheral nerve hyperexcitability syndromes. Blockade of VGKCs increases nerve excitability and may lead to repetitive peripheral nerve discharges in peripheral nerve hyperexcitability disorders, including muscle cramps, muscle twitches, fasciculations, myokymia, and neuromyotonia.

Immunology and pathophysiology. Earlier clinical observations suggested an autoimmune pathogenesis to the peripheral nerve hyperexcitability syndromes. This included the strong association with other autoimmune disorders, mostly myasthenia gravis, but also Hashimoto thyroiditis, celiac disease, and connective tissue disorders.

Further investigations have confirmed the presence of IgG4 autoantibodies directed against voltage-gated potassium channel (VGKC) complex, specifically LGI1 and Caspr2. CASPR2 antibodies destabilize the voltage-gated potassium channel complex into the membrane, whereas LGI1 antibodies alter the binding of LGI1 with its postsynaptic cell membrane receptor, a disintegrin and metalloproteinase 22 (ADAM22). LGI1 protein has a predominant hippocampal localization, whereas CASPR2 is localized to the juxtaparanodal region of myelinated nerves, findings that explain the predilection of LGI1-positive patients to CNS manifestations and CASPR2 patients to peripheral nerve hyperexcitability syndrome manifestations (10).

Epidemiology

Peripheral nerve hyperexcitability syndromes are rare, and their incidence is not known. The annual incidence of anti-LGI1 encephalitis in the Netherlands is 0.83 per million (31).

Heredity. Episodic ataxia type 1 is an inherited channelopathy disorder associated with peripheral nerve hyperexcitability manifestations. It is autosomal dominant and mapped to chromosome 12p13; the responsible gene is KCNA1 (04). All mutations impair Kv1.1 function, a delayed-rectifier potassium channel responsible for repolarizing nerves after depolarization. This potassium channel is abundantly expressed in the cerebellum and in motor axons, resulting in increased neuronal excitability.

Episodic ataxia type 1 often manifests before the age of 20. It is characterized by brief episodes of ataxia, dysarthria, coarse tremor, dizziness or vertigo, and muscle stiffness, weakness, and twitching (16). Nausea, vomiting, and headache are rare. The attacks are often precipitated by physical exertion, emotional stress, or environmental temperature. They usually last a few minutes to, rarely, hours and range from daily to monthly. About 20% of patients with episodic ataxia type 1 accumulate persistent cerebellar ataxia (08).

Myokymia is usually persistent at baseline but worsens during the attacks. It is not clear whether the tremors and muscle twitching represent exacerbation of interictal myokymia. Myokymia may be detected clinically or may only be apparent by needle EMG, which often shows both myokymic and neuromyotonic discharges.

Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of the ataxic attacks in some patients. Carbamazepine and valproic acid are sometimes effective (16). Avoiding stress, abrupt movements, loud noises, and caffeine intake are important measures to reduce the severity and frequency of attacks.

An axonal, predominantly motor Charcot-Marie-Tooth disease is an autosomal recessive neuropathy associated with neuromyotonia, which is present, at least electrically, in 70% to 80% of patients (25). It is caused by the loss-of-function mutations in histidine triad nucleotide binding protein 1 (HINT1), which is ubiquitously expressed in the peripheral nerves and may have a role in signaling and transcriptional pathways. HINT1-related hereditary neuropathy often presents in the first 1 to 2 decades of life with gait disorder and distal leg and hand weakness and atrophy, with frequent hand contractures. There are often muscle cramps and stiffness, particularly in the hands. Sensory loss is subtle or absent. EMG shows both neuromyotonic and myokymic discharges, which, when present, distinguish this hereditary neuropathy from other types of Charcot-Marie-Tooth disease. The disorder is slowly progressive.

Differential diagnosis

Confusing conditions

Muscle stiffness is a common presenting symptom and is often caused by a variety of peripheral nervous system disorders, such as myopathies and peripheral nerve hyperexcitability syndromes, and central nervous system disorders, such as stiff-person syndrome.

Nondystrophic myotonias, specifically myotonia congenita, often present with muscle stiffness that manifests when attempting to initiate movement after a period of rest and diminishes with repeated activity and muscle contractions (26). Needle EMG shows prominent myotonic discharges without myopathic motor unit action potential changes.

Dystrophic myotonias, including myotonic dystrophy type 1 and type 2, often present with muscle weakness but may have stiffness and muscle pain. These disorders have frequent nonmuscular manifestations that help establish the diagnosis, including cataracts, cardiac conduction defects, balding, temporal atrophy, and characteristic hatchet facies (26). The needle EMG shows characteristic myotonic discharges as well as short duration, low-amplitude, and polyphasic motor unit action potentials.

Schwartz-Jampel syndrome, or chondrodystrophic myotonia, is a rare autosomal recessive disorder characterized by the triad of myotonia, facial dysmorphism, and skeletal deformities. Common features include muscle stiffness, hypertrophy, and contractures as well as clinical myotonia (02). Other features are facial dysmorphisms, including puckered-small mouth, blepharophimosis and blepharospasm, and skeletal abnormalities, including short stature, kyphosis, hip dysplasias, and pseudofractures. Muscle enzymes are normal or slightly elevated. Nerve conduction studies are normal. Needle EMG reveals continuous myotonic discharges at rest. The disorder results from mutations in the HSPG2 gene in chromosome 1p34-36.1, which encodes perlecan, a major component of basement membranes.

Rippling muscle disease is a benign myopathy with symptoms and signs of muscular hyperexcitability. The typical finding is a rolling, wave-like mounding of muscle provoked by mechanical stimuli and stretch that is electrically silent on needle EMG recording (29). The disorder has immune associations, including acetylcholine receptor–antibody positive myasthenia gravis and thymoma. Some patients have autoantibodies to caveolae-associated protein 4 (cavin-4) (06). Other patients with rippling muscle disease have mutations in the gene encoding caveolin-3 (CAV3), a membrane-associated protein localized to skeletal muscle fibers, or, less frequently, cavin-1 genes. Muscle biopsies demonstrate a mosaic or diffuse pattern of caveolin-3 deficiency.

Stiff-person syndrome is a central nervous system disorder characterized by progressive and fluctuating muscle stiffness, with painful muscle spasms in the limbs, trunk, and neck (28). The disorder is associated with HLA phenotypes predisposing to type 1 diabetes, epilepsy, and other organ-specific autoimmunity. Affected muscles become tight and rock-hard during episodes. In severe cases, there is lumbar hyperlordosis and gait stiffness. In more than 70% of patients, antibodies are detected in serum directed against glutamic acid decarboxylase (GAD), the enzyme responsible for the biosynthesis of GABA. In about 5% of patients, anti-amphiphysin antibodies are seen in serum and CSF, and their presence in women can be associated with breast cancer. The needle EMG in stiff-person syndrome reveals nonspecific, continuous normal motor unit activity at rest. These manifestations are abolished by sleep, anesthesia, peripheral nerve blockade, and curare.

Associated or underlying disorders

A malignancy may precede or follow peripheral nerve hyperexcitability syndromes, mostly those with detectable VGKC-complex antibodies. The incidence of malignancy varies from 10% to 47% and occurs mostly in patients over 45 years of age (15). The majority of patients have thymoma, with occasional patients with lung or colon cancer.

Patients with peripheral nerve hyperexcitability syndromes, more specifically, Morvan syndrome and malignant thymoma, are often associated with acetylcholine receptor antibody-positive myasthenia gravis.

Diagnostic workup

The diagnosis of peripheral nerve hyperexcitability syndromes requires a high index of suspicion and is often supported by laboratory and electrophysiological findings.

Laboratory findings. The majority of patients with peripheral nerve hyperexcitability syndromes, mostly Isaacs syndrome and Morvan syndrome, and occasionally cramp-fasciculation syndrome, have Caspr2 autoimmunity, whereas patients with limbic encephalitis and epilepsy (mostly faciobrachial dystonic seizures) often have LGI1 autoimmunity. These antibodies target surface-exposed CASPR2 or LGI1 domains of voltage-gated potassium channel (VGKC). However, this is not exclusive; significant overlap exists, with neuropathic pain, cerebellar syndrome, and epilepsy frequently occurring in a significant number of patients with Caspr2 autoimmunity and peripheral nerve hyperexcitability syndromes occurring in some patients with LGI1 autoimmunity.

Voltage-gated potassium channel (VGKC)-complex antibodies with LGI1 or CASPR2 reactivity are more specific and appear to be directly pathogenic compared to VGKC antibodies. Low-level VGKC-complex antibodies and VGKC antibodies are less specific and present in a variety of nonspecific disorders (15; 21). Among sera with positive VGKC antibodies, only 15% have LGI1 and CASPR2 pathogenic antibodies (21). Hence, it is recommended to test only for LGI1 and CASPR2 antibodies and not VGKC antibodies.

Electrophysiological findings. The electrophysiological findings of peripheral nerve hyperexcitability syndromes are the core findings in the diagnosis of peripheral nerve hyperexcitability syndromes. This includes findings on nerve conduction studies and needle electromyographic (EMG) examination.

Needle EMG. A variety of spontaneous motor unit activities are seen with peripheral nerve hyperexcitability syndromes on needle EMG. This mostly includes fasciculation potentials, doublets/triplets/multiplets, myokymic discharges, and neuromyotonic discharges (17). These abnormal discharges originate from one or more segments of the peripheral motor axon (09). They are not blocked by general anesthesia but are eliminated by neuromuscular junction blockade.

Fasciculation potentials are spontaneous (involuntary) discharges of individual motor units. They originate from the anterior horn cell or motor axon anywhere along its length. Fasciculation potentials fire randomly and irregularly, with variable waveform morphology and at a much slower firing rate than voluntary motor unit action potentials. They may be associated with a visible muscle twitch and, rarely, in slight movements of small joints in the fingers or toes. When abundant, fasciculation potentials give a “popping corn” sound on the EMG loudspeaker.

Doublets, triplets, and multiplets are spontaneous motor unit action potentials that fire in groups of two, three, or multiple potentials. They have the same significance as fasciculations.

A myokymic discharge is a grouped discharge of one or a few motor unit action potentials occurring spontaneously and repetitively in a quasi-rhythmical fashion at rates of 1 to 5 Hz, which gives the myokymic discharge the sound of “marching soldiers” on the loudspeaker. The burst is composed of about 2 to 15 spikes, with frequent variability in the number of spikes per discharge.

A neuromyotonic discharge includes bursts of a single motor unit action potential firing at very high frequency of 150 to 250 Hz for several seconds, often starting and stopping abruptly, and with decrementing amplitudes and frequency.

Both neuromyotonic and myokymic discharges may be detected in patients with peripheral nerve hyperexcitability syndromes, including Isaacs and Morvan syndromes, as well as in limbic encephalitis. However, neuromyotonic discharges are more common and specific for the peripheral nerve hyperexcitability syndromes, whereas myokymic discharges occur in many other settings. Myokymic discharges may be seen either focally or in a more generalized fashion in many other peripheral nerve disorders. This includes radiation plexopathy, carpal tunnel syndrome, Guillain-Barré syndrome, gold toxicity, pontine glioma, and multiple sclerosis (Table 2).

Table 2. Causes of Myokymia

Nerve conduction studies. The findings on nerve conduction studies have generally been ignored. Stimulus induced after discharges (SIAD) are repetitive or sustained firing of action potentials that occur after supramaximal stimulation of motor nerves and persist beyond stimulus cessation. These repetitive late potentials are seen following the initial compound muscle action potential. They are detected in 15% to 40% of patients with peripheral nerve hyperexcitability syndromes during routine motor nerve conduction studies. However, they are seen in up to 75% when higher gain setting (200 uV/division) and time base (20 ms/division) are utilized, such as during F wave studies (03; 22). SIADs are best seen during tibial F wave studies.

SIAD is best measured as the mean F wave duration as a marker of excitability of the peripheral nerve. This is markedly prolonged in peripheral nerve hyperexcitability syndromes, averaging 54.2 +/- 11.0 msec, compared to controls (16.8 +/- 1.8 msec) (22). SIAD are reported to be more sensitive than abnormal spontaneous firing on EMG (24; 22). However, SIADs following repetitive nerve stimulation at various frequencies (between 2 and 20 Hz) in patients with peripheral nerve hyperexcitability syndromes may not necessarily distinguish patients with peripheral nerve hyperexcitability from controls and is under debate.

Management

The management of peripheral nerve hyperexcitability syndromes includes symptomatic treatment, immunomodulation treatment, and malignancy detection and therapy (07).

Symptomatic treatment is designed to reduce spontaneous peripheral nerve discharges by altering their channel properties (Table 3). Membrane-stabilizing agents, such as sodium channel-blocking agents and, more specifically, carbamazepine or phenytoin, are the most effective in reducing muscle stiffness, twitching, and cramps. Carbamazepine at 200 to 400 mg/day in divided doses, with a maximum daily dose of 1600 mg, is often successful. Adverse effects include hyponatremia, blood dyscrasias, and hepatotoxicity. Phenytoin at a single daily dose of 300 to 600 mg is a good alternative to carbamazepine. Adverse effects include blood dyscrasias, osteoporosis, and gingival hypertrophy. Other sodium channel-blocking agents, such as lamotrigine, lacosamide, valproate, and oxcarbazepine, may also be used. Gabapentinoids, such as gabapentin and pregabalin, are also used and can be effective in symptoms relief. These agents possess membrane-stabilizing effects by direct/indirect action on sodium channels and inhibition of neuronal hyperactivity. Mexiletine, dantrolene, baclofen, and acetazolamide have been used with variable success.

Corticosteroids are also effective. The majority of patients (about 80%) respond favorably to corticosteroids combined with a membrane stabilizer (18). Oral corticosteroids are often satisfactory, but in severe nonambulatory patients, intravenous methylprednisolone is recommended initially and then switched to an oral corticosteroid after 3 to 5 days. This could also later be switched to a steroid-sparing agent, such as azathioprine, mycophenolate, cyclosporine, or cyclophosphamide.

Immunomodulation and more aggressive immunosuppressive therapies are usually reserved for patients who are nonresponders to corticosteroids combined with a membrane stabilizer or those with severe motor, autonomic, or CNS symptoms. Intravenous immunoglobulin, plasmapheresis, and rituximab have all been used and are reported to be effective (23). Maintenance therapy with immunosuppressive therapy or combination therapy is often needed to avoid the recurrence of symptoms. However, in the majority of patients, immunosuppressive therapy could be stopped in 1 to 5 years.

Search, detection, and treatment of underlying malignancy, specifically thymoma, is indicated and help to alleviate the manifestations of the underlying peripheral nerve hyperexcitability syndrome.

Table 3. Symptomatic Treatment of Peripheral Nerve Hyperexcitability Syndromes

Outcomes

Peripheral nerve hyperexcitability syndromes are treatable disorders, and three quarters of patients respond to symptomatic and immunomodulation therapy, or both. A relapse may occur in up to a quarter of patients (31). Patients with LGI1 antibodies and CNS manifestations may have residual memory loss (30).