Evaluation of fatigue in Parkinson''s disease patients with stimulated single fiber electromyography

OBJECTIVES: Fatigue is a disabling and dopa-resistant symptom in Parkinson's disease (PD). Pathological studies have shown that both peripheral and central cholinergic systems are involved in PD. Electrophysiological investigation showed decremental muscle responses following repetitive nerve stimulation (RNS). We hypothesized that fatigue in PD patients may be secondary to cholinergic defect at the neuromuscular level. MATERIAL AND METHODS: Twenty PD patients with disabling fatigue symptoms were enrolled. We used stimulated single fiber electromyography (s-SFEMG) to evaluate the neuromuscular junction of these patients. For every patient, at least 15 muscle fibers were tested at the rate of 10 Hz with the method described by Trontelj et al. The individual mean consecutive difference (i-MCD) was obtained from 100 constant consecutive single fiber potentials. The i-MCD values in each patient were averaged to obtain the mean MCD (m-MCD). RESULTS: None of the 20 PD patients with disabling fatigue symptoms had an m-MCD over 29 micros or more than 10% of the i-MCD values over 41 micros. The neuromuscular junction was intact in terms of normal jitter (expressed as MCD) and an absence of blocking. CONCLUSION: Our findings indicate that the cholinergic system at the neuromuscular level is not affected in PD patients with fatigue symptoms.     

A congenital myasthenic syndrome refractory to acetylcholinesterase inhibitors.

We studied 4 siblings (3 men and 1 woman), ages 22 to 43 years, with congenital ptosis, external ophthalmoplegia, proximal muscle weakness and fatigability unresponsive to acetylcholinesterase (AChE) inhibitors. Repetitive nerve stimulation showed a significant compound muscle action potential (CMAP) area decrement at 2 or 3 Hz. Nerve conduction studies and concentric needle electromyography were normal, and repetitive CMAPs to single nerve stimulation were not observed. Voluntary single fiber electromyography (SFEMG) showed increased jitter and blocking. Assessment of individual end-plates using SFEMG with intramuscular axonal microstimulation showed no uniform relationship between jitter and the rate of stimulation, consistent with a postsynaptic defect of neuromuscular transmission. Edrophonium eliminated the decremental response to repetitive nerve stimulation, but caused no significant clinical improvement, suggesting an additional mechanism for weakness in these patients.     

AAEE minimonograph #25: Single-fiber electromyography in myasthenia gravis

Single-fiber electromyography (SFEMG) demonstrates abnormal jitter in virtually all (99%) patients with myasthenia gravis (MG). One muscle, the extensor digitorum communis, is abnormal in most patients with this disease, but to obtain the maximum diagnostic sensitivity, it may be necessary to examine other muscles, especially ones that are more involved clinically. There is no one muscle that will be more abnormal in every patient with MG. The muscle(s) to be tested must be selected based on the distribution of weakness in the individual patient. Abnormal jitter is also seen in diseases of nerve and muscle; these diseases must be excluded by other electrophysiologic and clinical examinations before diagnosing MG. If neuronal or myopathic disease is present, increased jitter does not indicate that MG is also present. However, if jitter is normal in a muscle with definite weakness, the weakness is not due to MG. When abnormal neuromuscular transmission has been demonstrated by repetitive nerve stimulation, the finding of abnormal jitter does not add to the diagnosis, though it may be useful in providing baseline values for comparison with the results of subsequent studies. SFEMG is most valuable clinically in the patient with suspected MG in whom other tests of neuromuscular transmission and antiacetylcholine receptor antibody titers are normal. Serial measurements of jitter can be useful in following the course of disease and in assessing the effect of treatment, but the results from these studies must always be interpreted in light of the overall clinical picture.     

Stimulated single-fiber electromyography in Lambert-Eaton myasthenic syndrome.

The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission. Electrodiagnosis is confirmed by an increase in compound muscle action potential amplitude during high-frequency repetitive nerve stimulation or following brief exercise. We describe the results of stimulated single-fiber electromyography in 4 patients with disorders of neuromuscular transmission: LEMS (2), LEMS/myasthenia gravis (MG) overlap (1), and MG (1). Stimulated SFEMG was performed in the extensor digitorum communis muscle with axonal intramuscular suprathreshold stimulation at low and high rates. In all 4 patients, a rate dependence of jitter was found. In LEMS and LEMS/MG, jitter and blocking improved with high stimulation rates, as compared with the opposite effect in MG. We conclude that stimulated SFEMG is a valuable technique in the diagnosis of LEMS.     

Dysfunction at the motor end-plate and axon membrane in Guillain-Barré syndrome: a single-fiber EMG study

In nine patients with Guillain-Barré syndrome (GBS), stimulation single-fiber electromyography (SFEMG) and serological studies were performed in the acute stage of the illness. Increased jitter and intermittent blocking of muscle fiber action potentials occurred to a varying degree in all patients. Five patients had elevated titers of antiganglioside antibodies. The most remarkable EMG phenomenon was the occurrence in all patients of impulse blocking at normal or slightly increased jitter. The assumption that this phenomenon was due to an axolemmal dysfunction was confirmed by the occurrence in two patients of concomitant blocking of two muscle fiber action potentials at strictly normal jitter values. In one patient this sign of axonal dysfunction was demonstrated with SFEMG at voluntary activation. In another patient, concomitant blocking was associated with greatly increased but completely independent jitter of both components. The results of this study show that both a disorder of neuromuscular transmission and an axolemmal dysfunction play a role in the pathophysiology of GBS.     

Myasthenia gravis presenting as weakness after magnesium administration

We studied a patient with no prior history of neuromuscular disease who became virtually quadriplegic after parenteral magnesium administration for preeclampsia. The serum magnesium concentration was 3.0 mEq/L, which is usually well tolerated. The magnesium was stopped and she recovered over a few days. While she was weak, 2-Hz repetitive stimulation revealed a decrement without significant facilitation at rapid rates or after exercise, suggesting postsynaptic neuromuscular blockade. After her strength returned, repetitive stimulation was normal, but single fiber EMG revealed increased jitter and blocking. Her acetylcholine receptor antibody level was markedly elevated. Although paralysis after magnesium administration has been described in patients with known myasthenia gravis, it has not previously been reported to be the initial or only manifestation of the disease. Patients who are unusually sensitive to the neuromuscular effects of magnesium should be suspected of having an underlying disorder of neuromuscular transmission.     

Mechanisms of fatigue in normal intercostal muscle and muscle from patients with myasthenia gravis

Fatigue mechanisms in normal intercostal muscle and muscle from patients with myasthenia gravis (MG) were evaluated by monitoring the compound muscle action potential (CMAP) and tetanic tension responses to repetitive nerve or muscle stimulation in vitro. When fatigue was induced by nerve stimulation at 30 Hz for 0.5 s every 2.5 s, about half of the original tension decreased after 30 min in normal muscle and 5 min in MG muscle. Analysis of the changes in area of CMAPs and tension indicated that impairment of neuromuscular transmission, muscle membrane excitation, and excitation-contraction (E-C) coupling and contractility accounted for 40%, 29%, and 31% of fatigue in normal muscle, and 83%, 0%, and 17% of fatigue in MG muscle. When fatigue was induced by muscle stimulation at 30 Hz, tension declined by a quarter after 30 min in normal muscle, but by a half after 17 min in MG muscle. Impairment of muscle membrane excitation and E-C coupling and contractility accounted for 58% and 42% of fatigue in normal muscle, and 22% and 78% of fatigue in MG muscle. Thus, fatigue of normal muscle is caused by impairment of at least four processes, and enhanced fatigue of MG muscle is caused by greater impairment of neuromuscular transmission, E-C coupling, and contractility. © 1993 John Wiley & Sons, Inc.     

Cephalic tetanus studied with single fibre EMG.

In a case of cephalic tetanus with left facial spasms and trismus, the repetitive stimulation of the left facial nerve at 3, 10 and 20 Hz showed no facilitation or decrement. The amplitudes of the blink reflex were 50% lower on the affected side. The silent period of the masseter muscles was shortened. Concentric needle examination of the masseters and left facial EMG of the left frontalis muscle showed increased jitter and blocking in a significant proportion of the recorded potentials. Both jitter and blocking improved on higher innervation rates. All electrophysiological findings were normal on the second examination when the patient was asymptomatic. The single fibre EMG findings point to a presynaptic defect in the neuromuscular transmission in human tetanus.     

Facioscapulohumeral dystrophy: jitter in facial muscles.

Motor end plate jitter was studied by single fibre EMG in the orbicularis oculi muscle of eight patients with facioscapulohumeral dystrophy activated by extramuscular nerve stimulation. The jitter was found to be slightly larger in comparison with the normal controls, although still within the normal limits in each patient. The findings are considered to indicate absence of any significant neuromuscular transmission disturbance, inflammatory or regenerative process, or reinnervation in progress. There was no evidence of muscle fibre conduction abnormality even in very weak muscle.     

Peripheral mechanisms of fatigue in muscles of normal and dystrophic mice.

We evaluated the contribution of different processes to fatigue of normal and dystrophic mouse muscles using an in vitro electromyography chamber. Fatigue was induced by repetitive nerve stimulation at 30 Hz for 0.5 s, every 2.5 s until tension decreased by about 50%. We monitored the compound nerve action potential (AP), compound muscle AP, and isometric tension responses to nerve stimulation, and compound muscle AP and tension responses to direct muscle stimulation. In normal mice, about 50% reduction in nerve-evoked tension occurred by 2.4 min in extensor digitorum longus (EDL), 4.8 min in diaphragm, and 9 min in soleus. Analysis of the responses revealed that the fatigue was caused by failure of more than one process in all muscles, and failure of nerve conduction did not contribute to fatigue in any muscle. Failure of neuromuscular transmission, muscle membrane excitation, and excitation-contraction (E-C) coupling and contractility accounted for 55, 45, and 0%, respectively, of the fatigue in EDL, for 21, 74, and 5% of the fatigue in diaphragm, and for 2, 54, and 44% of the fatigue in soleus. In dystrophic mice, while about 50% reduction in nerve-evoked tension occurred by 8.1 min in EDL and 5.6 min in diaphragm, only 29% reduction in tension occurred by 80 min in soleus. Failure of neuromuscular transmission, muscle membrane excitation, E-C coupling and contractility accounted for 22, 63 and 15% of the fatigue in EDL, for 21, 79, and 0% of the fatigue in diaphragm, and for 15, 59, and 26% of the fatigue in soleus. The proportion of slow-twitch oxidative fibers was more than normal in dystrophic EDL, but the same as normal in dystrophic diaphragm and soleus. The slower onset of fatigue was attributable to lesser failure of neuromuscular transmission in dystrophic EDL, and to lesser failure of E-C coupling and contractility in dystrophic soleus.     

Single‐fiber EMG with concentric electrodes in lambert‐eaton myasthenia

Introduction: We analyzed jitter recordings made with concentric needle electrode (CNE) single‐fiber electromyography (SFEMG) in Lambert‐Eaton myasthenia (LEM). Methods: Fifteen subjects diagnosed with LEM were studied using CNE‐SFEMG in the extensor digitorum (ED) and tibialis anterior (TA) muscles. CNE‐SFEMG in the ED and TA was also used to evaluate 12 and 10 healthy controls (HCs), respectively. Results: Ten men and 5 women were diagnosed with LEM based on an increase of 100% in compound muscle action potential amplitude during 50 Hz repetitive nerve stimulation. All patients exhibited markedly greater jitter in the ED (88.8 ± 23.2 µs) and TA (92.2 ± 30.2 µs) than HCs (28.3 ± 3.4 µs and 30.9 ± 5.1 µs, respectively). Conclusions: CNE‐SFEMG is sensitive for discovering abnormalities in neuromuscular transmission in LEM. Muscle Nerve 56 : 253–257, 2017     

Botulinum neurotoxin‐A does not spread to distant muscles after intragastric injection: A double‐blind single‐fiber electromyography study

The purpose of this study was to perform a careful neurophysiological examination to identify subclinical signs of botulinum toxin spread distant to the injection site following intragastric injection for obesity treatment. Single‐fiber electromyography of extensor digitorum communis and repetitive stimulation of abductor digiti minimi were performed before and 8 days after multiple intragastric injections of botulinum toxin A (Botox, 200 U per patient) or placebo. The study was performed in a randomized double‐blind fashion. No patient in either group displayed results indicative of neuromuscular dysfunction either before or after the treatment. No significant change in muscle jitter was observed when comparing baseline with the after‐treatment evaluation in either group, and no significant differences between groups were observed. After intragastric botulinum toxin injection no subclinical sign of distant spread was observed. Muscle Nerve, 2010     

Local cooling in myasthenia. Improvement of neuromuscular failure.

Weak myasthenic muscles were tested by nerve stimulation both at normal temperature and after local cooling that was accomplished by exposing the skin to ice bags or cold paraffin oil. Reduction of intramuscular temperature from 35 C to 28 C increased the voltage of the bellytendon electrical response, the force of the tetanus elicited by 10/sec or 20/sec nerve stimulation. The myasthenic decrement of successive muscle responses was less marked after cooling, as were "delayed rundown" and "postactivation exhaustion." All these effects were reversed on rewarming the muscle. The abnormal neuromuscular jitter in motor-unit components was also reduced by local cooling. These observations may explain why diagnostic application of repetitive stimulation may be false-negative; muscle temperature must be controlled.     

Concurrent chronic motor axonal polyneuropathy and synaptic impairment of neuromuscular junction

Polyneuropathies may exhibits clinical, electrophysiologic signs of neuromuscular junction impairment. Distal motor nerve terminals and neuromuscular junction contain pre or postsynaptically specific targets for circulating autoantibodies, if present in neuropathies. Motor nerve terminal blockade either reversible or permanent is a putative factor of muscle weakness. A 59-year-old patient exhibited oropharyngeal, facial, extremity weakness, fluctuating fatigability, and areflexia. Elecectrophysiologic studies showed purely motor axonal polyneuropathy. Thenar, facial slow rate repetitive stimulation revealed up to 47% decrement of compound muscle action potential size. Single fiber electromyography on voluntary activation confirmed increased jitter and impulse blocking in all muscles examined in one third of the fibers. Repeated testings for antibodies to gangliosides, acetylcholine, muscle tyrosine kinase receptors, voltage-gated calcium channels were negative. Oral pyridostigmine bromide improved bulbar symptoms. Pulse intravenous immunoglobulin, oral steroids, and azathioprine had steady benefit. Impairment of neuromuscular transmission if occurring in chronic axonal neuropathies highlights mechanisms and significance of neuromuscular chronic "synaptopathies."     

Longitudinal neurophysiological assessment of intramuscular type-A botulin toxin in healthy humans

The aim of this study is to assess the neurophysiological abnormalities of type A botulin toxin-infiltrated human muscle, and their evolution over time. Seried cMAP measurements, 3 and 20 Hz repetitive nerve stimulation, EMG, SFEMG over 3 months from toxin injection. Our findings consist in lack of decrement with 3 Hz repetitive nerve stimulation and facilitation with 20 Hz repetitive nerve stimulation; progressive increasing of jitter; early appearance of fibrillations; small and short motor unit action potential in the first 3 weeks, followed by increasing of MUAP amplitude and duration, with polyphasic morphology. Although claimed as highly specific and sensible, neuromuscular junction facilitation is an inconstant finding in human botulism. Therefore, lack of neuromuscular junction facilitation cannot exclude a diagnosis of botulism. Our findings are compatible with a process of acute denervation followed by distal reinnervation, favored by terminal nerve sprouting.     

HTLV‐1–associated myelopathy/tropical spastic paraparesis and peripheral neuropathy following live‐donor renal transplantation

Introduction: Our aim in this study was to provide an updated literature review of electrodiagnostic testing in myasthenia gravis and Lambert–Eaton myasthenic syndrome. Methods: A systematic review of the recent literature was performed using the following key words: myasthenia gravis (MG); Lambert–Eaton myasthenic syndrome (LEMS); electromyography (EMG); repetitive nerve stimulation (RNS); single‐fiber electromyography (SFEMG); nerve conduction study; and normative values. Results: Several articles supported testing of facial, bulbar, and respiratory muscles in the diagnosis of neuromuscular junction (NMJ) disorders, including muscle‐specific kinase antibody (MuSK)‐seropositive MG. Several articles supported use of concentric needle EMG as an alternative to SFEMG jitter in disorders of neuromuscular transmission. A limited number of articles addressed measurement of area (vs. amplitude) decrement in RNS and decreasing the threshold of post‐exercise facilitation. Conclusions: Electrodiagnostic testing continues to be useful for diagnosis of MG and LEMS, although the quality of the evidence is not great. This literature review summarizes RNS and jitter measurement of facial and respiratory muscles and use of concentric needle EMG for SFEMG. Muscle Nerve 52:455–462, 2015     

A comparison of stapedial reflex fatigue with repetitive stimulation and single-fiber EMG in myasthenia gravis

The pattern of stapedial reflex fatigue in response to pulsed acoustic stimulation was measured and compared to results of repetitive nerve stimulation and single-fiber electromyography (EMG) in 89 patients with myasthenia gravis. Studies were also made on 22 patients with other neuromuscular disorders and 40 control subjects with no evidence of neuromuscular impairment. Stapedial reflex fatigue exceeded normal control values in 84% of the patients with myasthenia gravis. Repetitive stimulation and single-fiber EMG measurements were abnormal in 56% and 91% of this same population, respectively. Stapedial reflex abnormalities were most prevalent in patients with mild forms of myasthenia (predominantly ocular or oropharyngeal weakness). Of 22 nonmyasthenic patients with neuromuscular disease tested, 6 had abnormal stapedial reflex fatigue according to our normal values, indicating that this form of testing also detects other diseases of the motor unit. The measurement of stapedial reflex fatigue is painless, is easy to perform, and requires minimal patient cooperation. Due to the relatively high occurrence of abnormal stapedial reflex fatigue in patients with myasthenia gravis, this procedure appears to have considerable potential value in screening and monitoring patients for the presence of defects in neuromuscular transmission.     

Single‐fiber EMG and clinical correlation in Lambert‐Eaton myasthenic syndrome

Objectives: We analyzed 82 single‐fiber EMG (SFEMG) tests in the extensor digitorum communis muscle in 30 Lambert‐Eaton myasthenic syndrome (LEMS) patients to study the relationship between electrodiagnostic findings and clinical severity. Methods: The repetitive nerve stimulation test was performed in the abductor digiti quinti and flexor carpi ulnaris muscles. SFEMG was performed in the extensor digitorum communis muscle using the conventional method. Results: Fiber density was normal in all patients. Jitter was abnormal in all patients at the first evaluation regardless of clinical severity. The jitter was increasingly abnormal with worsening disease severity. Mean MCD correlated well with clinical and electrophysiological severity. In 5 potential pairs in 3 patients, MCD analysis in relation to firing rate showed improvement with increasing firing rates, which is consistent with presynaptic neuromuscular transmission disorders. Conclusions: In all LEMS studies, SFEMG was abnormal on the first evaluation. The mean MCD correlated well with clinical and electrophysiological disease severity on the repetitive nerve stimulation test. Muscle Nerve 47: 664–667, 2013     

Neuromuscular transmission in rheumatoid arthritis, with and without penicillamine treatment

Electroneuromyographic studies were performed on patients with rheumatoid arthritis, some of whom were received penicillamine, to determine whether a subclinical defect of neuromuscular transmission existed. There were no significant differences between patients and controls with respect to nerve conduction studies or repetitive ulnar nerve stimulation. Four patients (three receiving penicillamine) demonstrated mild neurogenic changes distally on needle electromyography. Mean jitter was slightly higher for patients receiving penicillamine than in other patients or controls, but the differences were not significant. No significant correlations existed between of the studies and daily, cumulative, or average penicillamine dosage. A significant positive correlation (p less than 0.001) existed between jitter and duration of disease in patients receiving penicillamine. Results were consistent with the hypothesis that penicillamine predisposes certain individuals to develop myasthenia gravis rather than interfering directly with neuromuscular transmission.     

Muscle strength and fatigue in patients with generalized myasthenia gravis

Myasthenia gravis (MG) is characterized by fatigue and fluctuating muscle weakness resulting from impaired neuromuscular transmission (NMT). The objective of this study was to quantify, by direct measurement of muscle force, the strength and fatigue of patients with MG. A maximal voluntary isometric contraction protocol of shoulder abductors was used in conjunction with conventional fatigue and disease‐severity instruments. Results from patients with (D‐MG) and without (ND‐MG) decrement on repetitive nerve stimulation (RNS) of the spinal accessory and axillary nerves were compared with healthy controls. Patients with MG reported greater fatigue than controls. Muscle strength was lowest in the D‐MG group, followed by the ND‐MG group and controls. Normalized shoulder abduction fatigue and recovery values did not differ between the D‐MG and ND‐MG groups or controls. The RNS decrement appears to relate best to disease severity and muscle weakness but not to objective measures of fatigue in this population. Muscle Nerve, 2009