Fasciculations and cramps: how benign? Report of four cases progressing to ALS

Clinical diagnosis of amyotrophic lateral sclerosis (ALS) in patients presenting with cramps and fasciculations may not be evident at the first consultation. Sequential reviews, clinical and neurophysiological, form an important part of clinical practice in such cases. Recent attempts to delineate a more benign group with cramps and fasciculations have lacked information on the long term profile, both clinical and neurophysiological. Four patients who were initially diagnosed as suffering from benign cramps and fasciculations, but who subsequently progressed to ALS, are described. We propose that a diagnosis of benign cramps and fasciculations should not be considered secure without a minimum follow up of 4–5 years.     

Repetitive nerve stimulation for the evaluation of peripheral nerve hyperexcitability

OBJECTIVE: To examine the utility of repetitive nerve stimulation (RNS) in the evaluation of peripheral nerve hyperexcitability (PNH). BACKGROUND: PNH describes a group of disorders characterized by muscle cramps, twitching and stiffness. When severe, PNH may be characterized by the presence of continuous muscle fiber activity on routine needle electromyography (EMG). In milder forms of the disease, nerve hyperexcitability may be evidenced by the presence of after-discharges or cramp potentials following RNS. METHODS: Fifty-four patients were prospectively recruited and classified into one of three groups-PNH, other neuromuscular disease and controls. We recorded and quantified the after-discharges and cramp potentials following RNS at 1, 5, 10 and 30 Hz. RESULTS: The proportion of nerves with after-discharges and/or cramp potentials was significantly greater in the PNH group than the control group at both 5 Hz (p=0.03) and 10 Hz (p=0.01), as well as in the neuromuscular disease group compared to controls at 5 Hz (p=0.02). There was also a significant concordance between complaints of muscle cramps and fasciculations and the finding of after-discharges and/or cramp potentials at both 5 Hz (p=0.005) and 10 Hz (p=0.004). At a stimulation frequency of 10 Hz, the sensitivity of RNS for the diagnosis of PNH (primary or secondary) was 79% and the specificity was 88%. CONCLUSION: Our findings suggest that RNS at or below a stimulation frequency of 10 Hz (when positive) is a useful test for the diagnosis of PNH, whether it is primary or secondary.     

Cramp-fasciculation syndrome: a treatable hyperexcitable peripheral nerve disorder.

We report nine patients with muscle aching, cramps, stiffness, exercise intolerance, and peripheral nerve hyperexcitability. Neurologic examination showed calf fasciculations in seven, quadriceps myokymia in two, and deltoid myokymia in one patient. Two patients had mild increase in serum creatine kinase. Muscle biopsy showed either no abnormality (three patients) or mild neurogenic changes (four patients). Fasciculations were the only abnormality on routine electrodiagnostic studies. Supramaximal stimulation of the median, ulnar, peroneal, and posterior tibial nerves at frequencies of 0.5, 1, 2, and 5 Hz produced showers of electrical potentials following the M response in at least one nerve. In three patients, the fasciculations and evoked electrical potentials were abolished by regional application of curare but not nerve block. Carbamazepine therapy caused moderate-to-marked reduction of symptoms and nerve hyperexcitability. We designate this hyperexcitable peripheral nerve disorder as the "cramp-fasciculation syndrome."     

Musculoskeletal pain in patients with myotonic dystrophy type 2

BACKGROUND: Myotonic dystrophy type 2/proximal myotonic myopathy (DM2/PROMM) is an autosomal dominant multisystem disorder. Musculoskeletal pain is one of its frequent symptoms but also occurs in other chronic noninflammatory muscle disorders (OMD). OBJECTIVES: To characterize the phenotype of DM2/PROMM-associated musculoskeletal pain and to test whether it shows features distinct from OMD. SETTING: Outpatient clinic for patients with neuromuscular disorders, university hospital. PATIENTS: Twenty-four patients with DM2/PROMM (12 women and 12 men; median age, 57 years) and 24 age- and sex-matched patients with OMD consecutively recruited during a 3-year period were examined for musculoskeletal pain. METHODS: Standardized pain assessment; McGill Pain Questionnaire; depression score; and quantification of pain thresholds to blunt pressure on limb muscles with analgometer. RESULTS: Unlike patients with OMD who have musculoskeletal pain, patients with DM2/PROMM distinguished a wide spectrum of coexisting pain types. The major pain type in patients with DM2/PROMM was exercise-related, temperature-modulated, and palpation-induced, whereas, cramps were rare. In 8 of the patients with DM2/PROMM and in 3 of the patients with OMD, musculoskeletal pain was the most disabling symptom. CONCLUSION: Besides many similarities, DM2/PROMM-associated musculoskeletal pain shows features distinct from OMD.     

Abnormal hyperexcitability in ALS]

The defect of neuromuscular transmission is one of the important signs in ALS. The amplitude of a single motor unit potential from patients with ALS often decrease during tonic voluntary contraction. This phenomenon is closely correlated with fatigue seen in the patient. Overfunctioning of Ach release in the nerve terminal might cause the failure of neuromuscular transmission in ALS. Fasciculations is an another characteristic sign and considered mainly to be peripheral axons in origin. It is postulated that the dysfunction of potassium channel in ALS axons makes the hyperexcitability of the axon membrane, causing fasciculations. Magnetic cortical stimulation sometimes evokes the same potentials as fasciculations, implying the hyperexcitability might be present also in spinal motoneurons or even in pyramidal neurons in ALS. All of these findings lead to the hypothesis that hyperexcitability or overactivity of central and peripheral motoneurons is an essential feature in ALS.     

Muscle‐specific kinase antibodies: A novel cause of peripheral nerve hyperexcitability?

Introduction: Antibodies that target the postsynaptic neuromuscular junction (NMJ) protein, muscle‐specific kinase (MuSK), have been associated with myasthenia gravis (MG), often with cramps and fasciculations, after administration of acetylcholinesterase inhibitors (AChE‐I). Methods: In this report, 2 patients are described with elevated MuSK antibodies and evidence of peripheral nerve hyperexcitability (PNH) unrelated to AChE‐I medication. Results: Patient 1 presented with facial neuromyotonia and fasciculations, without overt weakness. EMG studies demonstrated myokymic discharges in facial muscles, with bursts of discharges after voluntary activation, and widespread fasciculation potentials in limb muscles. Patient 2 presented with bulbar weakness and fasciculations in the tongue and limbs, initially diagnosed as bulbar‐onset amyotrophic lateral sclerosis. Subsequent investigation identified the presence of MuSK antibodies. Conclusions: We hypothesize that MuSK antibodies may induce these phenotypes through disruptive actions at the NMJ, in particular the binding of acetylcholinesterase (AChE) to MuSK via its collagen Q (ColQ) tail, producing a reduction in synaptic AChE activity. Muscle Nerve 48:819–823, 2013     

Fatigue and abnormal neuromuscular transmission in Kennedy's disease

We describe a patient with Kennedy's disease (X-linked bulbospinal neuronopathy) who experienced leg muscle fatigue with long-distance running. The patient also reported muscle twitching involving the face and extremities and long-standing muscle cramps. Aside from mild facial and tongue weakness (and fasciculations), his examination was normal, including completely preserved muscle strength in the extremities. Electrodiagnostic evaluation revealed evidence for a chronic motor axonopathy/neuronopathy and abnormal sensory nerve action potentials. In addition, repetitive nerve stimulation studies were normal, but neuromuscular jitter tested in the same muscle was markedly abnormal. The normal clinical strength and repetitive nerve stimulation studies in a muscle showing markedly increased neuromuscular jitter suggested a mechanism for this patient's symptoms of muscle fatigue, related to failure of neuromuscular transmission at a critical number of endplates during extremes of physical activity.     

Accuracy of repetitive nerve stimulation for diagnosis of the cramp-fasciculation syndrome

The goal of this retrospective cohort study was to test the hypothesis that the cramp-fasciculation syndrome (CFS) represents a disorder of peripheral nerve hyperexcitability and to evaluate the accuracy of repetitive nerve stimulation (RNS) for its diagnosis. A consecutive series of 108 patients were evaluated with posterior tibial RNS at 1, 2, and 5 HZ. Abnormal peripheral nerve excitability was defined by the presence of afterdischarges, cramp potentials, or continuous motor unit activity. RNS demonstrated abnormal nerve hyperexcitability in 29 of 36 subjects (81%) with CFS, defined operationally by the presence of both muscle cramps and fasciculations. Based on receiver operating characteristic (ROC) curve analysis, tibial RNS correctly classified the presence or absence of CFS in 75% of subjects. These results suggest that CFS represents a form of peripheral nerve hyperexcitability and, furthermore, that RNS is a clinically useful test for CFS.     

Interspike interval analysis in a patient with peripheral nerve hyperexcitability and potassium channel antibodies

Neuromyotonia or Isaacs' syndrome is a rare peripheral nerve hyperexcitability disorder caused by antibodies against potassium channels of myelinated axons. We present the high-density surface electromyographic (EMG) recordings of a patient with fasciculations and cramps due to neuromyotonia. To characterize the time course of hyperexcitability, we analyzed the interspike intervals (ISIs) between fasciculation potentials, doublet, and multiplet discharges. ISI duration increased within each burst. The ISI histograms found can be explained by the recovery cycle of the myelinated axon and its dependency on the slow potassium conductance. We conclude that ISI analysis is a useful tool to understand the membrane dynamics underlying abnormal motor unit activity.     

Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome

BACKGROUND: Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of alpha-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual alpha-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life. OBJECTIVE: To expand the later-onset Fabry phenotype to include cramp-fasciculation syndrome without small-fiber neuropathy. METHODS: A 34-year-old man who presented with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs, and his similarly affected mother, were evaluated. Clinical, biochemical, and molecular studies were performed. RESULTS: Clinical evaluation suggested the diagnosis of Fabry disease, which was confirmed by reduced plasma and leukocyte alpha-galactosidase A activities (8.8% and 13.4% of normal, respectively) due to a missense A143T mutation. His mother was heterozygous for the A143T mutation. CONCLUSION: The presentation of cramps and fasciculations without apparent small-fiber neuropathy expands the phenotype of later-onset Fabry disease.     

Ectopic impulse generation in peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis

Objective

To elucidate differences in the distribution and firing frequency of fasciculations between peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis (ALS) and to explore the generator site of fasciculations.

The muscular pain-fasciculation syndrome

Five cases of a chronic neuromuscular syndrome consisted of muscular aching and sometimes burning pain, fasciculations, cramps, fatigue, and occasional paresthesia. The disorder affected the legs and, less commonly, the girdle, trunk, and arm muscles. The symptoms were enhanced by physical activity and were usually improved by rest. Neither muscular wasting nor weakness was found, although the condition was present for an average of 4.7 years and, in one patient, as long as 10 years. Electrophysiologic studies showed motor abnormalities indicative of axonal degeneration and muscle fiber denervation, most marked in the legs. Light microscopy of skeletal muscle and spinal cord in one case disclosed evidence of mild denervation atrophy in muscle, but no loss of anterior horn cells. The findings are compatible with a benign polyneuropathy.     

Bronchial involvement in the cramp-fasciculation syndrome

BACKGROUND/AIMS: Cramp-fasciculation syndrome (CFS) is an acquired, chronic, usually benign and rather heterogeneous condition with isolated fasciculations and muscle cramps generally induced by physical exercise. They commonly involve calf and quadriceps muscles. The pathophysiology of CFS is related to peripheral nerve hyperexcitability, most often located at the motor nerve terminal or intramuscular arborization. METHODS: A 21-year-old man presented with a progressive syndrome of bronchospasm, cramps and muscle twitches related to physical exercise. Spirography showed bronchial hyperresponsiveness, so he received inhaled corticosteroids and beta2-agonists that improved respiratory symptoms. Electrodiagnostic studies were consistent with CFS. Gabapentin was then introduced. RESULTS: Both respiratory and muscle symptoms improved. A new spirogram after all inhaled medication had been discontinued was normal. CONCLUSION: This picture suggests a concomitant involvement of the peripheral motor nerves of both skeletal and airway autonomic smooth muscle, a presentation not previously reported in CFS.     

Motor neuron disease following generalized fasciculations and cramps

We report a case of motor neuron disease in which fasciculations and cramps progressed generally before the development of muscle wasting. After involvement of the upper and lower motor neurons became clinically manifest, widespread fasciculations and cramps persisted and accompanied pseudotetany. The present case suggests that spinal cord pathology of motor neuron disease can cause the abnormal excitability of the motor neurons, resulting in the development of generalized fasciculations and cramps.     

Estimation of the frequency of the muscular pain-fasciculation syndrome and the muscular cramp-fasciculation syndrome in the adult population

Summary A nationwide two-phase survey was carried out of the adult population of the Netherlands regarding fasciculation, muscle pain and muscle cramp. We conducted a population-based telephone interview with 780 Dutch adults, followed by a questionnaire covering more clinical details, filled out by 311 subjects, who had been interviewed by telephone previously. From these data the frequencies of fasciculation (men 50%, women 61%), muscle cramp (men 28%, women 42%) and muscle pain (men 48%, women 60%) in the Dutch adult population in 1988 were estimated. The combined occurrence of frequent fasciculation and frequent muscle cramp as well as of frequent fasciculation and frequent muscle pain was reported only sporadically. Although the muscular painfasciculation syndrome and the muscular cramp-fasciculation syndrome represent combinations of common neuromuscular phenomena, their occurrence in the general population proved to be rare. This finding supports their clinical identity as distinct motor unit hyperactivity syndromes rather than mere coincidences of fasciculation, muscle cramp and muscle pain.     

From benign fasciculations and cramps to motor neuron disease

Fasciculations and cramps may occur in motor neuron disease or as part of a more benign syndrome. A man with apparently benign fasciculations and cramps for 4 years developed progressive muscle weakness and wasting. Such a previously undocumented evolution of benign fasciculations and cramps to motor neuron disease may further implicate anterior horn cell dysfunction in the pathogenesis of muscle fasciculation-cramp syndromes.     

Syndromes of abnormal muscular activity: overlap between continuous muscle fibre activity and the stiff man syndrome.

Four patients with muscular pain, fasciculations, contractures or cramps are presented. Evidence of peripheral nerve involvement was revealed by electromyography and nerve conduction studies. Muscle biopsy showed mild signs of denervation and reinnervation and, at electron microscopy, dilatations of terminal cisternae were found. All patients showed a remarkable improvement after therapy with diphenylhydantoin or carbamazepine. These clinical, neurophysiological and morphological data underline the role of peripheral nerve pathology in various syndromes of abnormal continuous muscular activity.     

Isaacs syndrome: A review

Isaacs syndrome is a peripheral nerve hyperexcitability (PNH) syndrome that presents as continuous motor activity. Clinical findings include cramps, fasciculations, and myokymia. Electrodiagnosis plays a key role in diagnosis by demonstrating after‐discharges on nerve conduction studies, and fasciculation potentials, myokymic discharges, neuromyotonic discharges, and other types of abnormal spontaneous activity on needle examination. Etiopathogenesis involves the interaction of genetic, autoimmune, and paraneoplastic factors, which requires a broad‐ranging evaluation for underlying causes. Initial treatment is symptomatic, but immune therapy is often needed and can be effective. The purpose of this review is to describe the syndrome and its pathogenesis, assist the reader in evaluating patients with suspected Isaacs syndrome and distinguishing it from other disorders of PNH, and suggest an approach to management, including both symptomatic and immunomodulating therapy. Muscle Nerve 52 : 5–12, 2015     

Kennedy disease in two sisters with biallelic CAG expansions of the androgen receptor gene

We present a retrospective 21-year follow-up of two sisters with X-linked biallelic CAG expansions in the androgen receptor (AR) gene causing Kennedy disease. Two sisters inherited CAG expansions from their mother who was a carrier and their father who had Kennedy disease. Genetic testing revealed alleles comprising 43/45, and 43/43 CAG repeats in the younger and older sister, respectively. They were referred to a neurologist for further evaluation. Both reported similar symptoms with chronic backache, pain and cramps in upper- and lower extremities, and fasciculations in their faces and extremities. Neurological examination demonstrated postural hand tremor in both and EMG revealed chronic neurogenic changes. Reevaluation of the patients at ages 74 and 83 showed slight progression of clinical manifestations. As opposed to male patients, these two females showed minimal disease progression and have maintained normal level of function into old age.     

Post-poliomyelitis syndrome: 29 cases]

The post-polio syndrome refers to new neuromuscular symptoms developed by some patients many years after recovery from acute poliomyelitis. Several groups were separated: musculo-skeletal symptoms (different from a new spinal cord disease), infraclinical signs (EMG), post-polio muscular atrophy (new lower motor neuron objective signs) with several subgroups: cramps and fasciculations, benign focal weakness and atrophy (in previously affected muscles or in unaffected muscles), progressive spinal muscular atrophy. The following examination were performed in some cases, but not all, in this retrospective study: muscle CT scan, conventional electromyography (EMG), quantifying-EMG, macro-EMG and single-fiber EMG. The serum titers of neutralising antibodies to polio virus type 1, type 2 and type 3 were negative. No oligoclonal bands were found in the CSF from 6 patients screened by electrophoresis immunoelectrophoresis. Serum creatine kinase or aldolase was high in 6 patients. The same unusual features in this syndrome were observed on muscle biopsies: muscular hypertrophy and interstitial eosinophils; two patients had rimmed vacuoles in the muscle fibers.