Effect of 3,4-diaminopyridine on the time course of decay of compound muscle action potential augmentation in the Lambert–Eaton myasthenic syndrome

3,4-Diaminopyridine (3,4-DAP) is known to be beneficial in the symptomatic treatment of the Lambert–Eaton myasthenic syndrome (LEMS). The effects of 3,4-DAP on the decay of postexercise augmentation were observed in 6 patients with LEMS. After 10 s maximal voluntary contraction, the amplitude of the compound muscle action potential (CMAP) recorded from abductor digiti minimi decayed exponentially after an initial rise. The rate of decay in CMAP amplitude was increased after treatment with 3,4-DAP, suggesting that this drug has an effect on the efflux of calcium ions from the presynaptic nerve terminal. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1196–1198, 1998.     

Voluntary contraction and responses to submaximal cervical nerve root stimulation

Voluntary contraction of hand muscles increases compound muscle action potential (CMAP) amplitudes evoked by submaximal electrical percutaneous cervical stimulation (EPCS). This has been reported to be due to an intraspinal, presynaptic mechanism. We studied the effects of voluntary contraction on hypothenar CMAP amplitudes in 5 volunteers following electrical peripheral nerve stimulation at the wrist, EPCS, magnetic stimulation at the neck and the effects of a conditioning subthreshold cortical magnetic stimulus on CMAPs evoked by EPCS at rest. CMAP amplitudes increased with voluntary contraction of the target muscle, regardless of type or location of stimulus (P < 0.001). No increase in CMAP amplitude occurred when a conditioning transcranial stimulus was employed with EPCS (P = 0.35). Our findings indicate a peripheral rather than central mechanism underlies this effect of voluntary contraction. It is probably related to the recruitment order of motor axons, comparing voluntary activation with electrical or magnetic stimulation. © 1994 John Wiley & Sons, Inc.     

Cerebellar ataxia in non-paraneoplastic Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the neuromuscular junction that rarely is associated with cerebellar ataxia (CA). We describe two patients with non-paraneoplastic LEMS associated with CA who showed high levels of anti-P/Q-type voltage-gated calcium channels antibodies in the serum and cerebrospinal fluid, and reduced CMAP with increment after brief maximum voluntary contraction in electrophysiological studies. We suggest that LEMS should be considered in the differential diagnosis of patients with CA.     

Distribution of electrophysiological abnormality in Lambert-Eaton myasthenic syndrome

OBJECTIVE—Toassess the distribution of electrophysiological abnormality inLambert-Eaton myasthenic syndrome (LEMS) to identify the most sensitivemuscle to use in routine examination.
METHODS—Surfacerecorded compound muscle action potential (CMAP) amplitudes were madefrom abductor digiti minimi, abductor pollicis brevis, anconeus, bicepsbrachii, and trapezius in 10 patients with LEMS. The effect of3,4-diaminopyridine (3,4-DAP) was recorded in each muscle in ninepatients. CMAP amplitudes were measured at rest and immediately after10 seconds maximal voluntary contraction in each muscle. Values werecompared with results obtained from 12 healthy controls.
RESULTS—Resting CMAPamplitudes were reduced in at least one muscle in all patients comparedwith controls, most markedly in abductor digiti minimi and anconeus.The administration of 3,4-DAP resulted in significantly improvedresting CMAP amplitudes in trapezius only. After maximal voluntarymuscle contraction, characteristic increments in CMAP amplitude of over100% above resting values were seen in abductor digiti minimi andabductor pollicis brevis in seven patients, anconeus and biceps brachiiin five patients. No patient had this level of increment in trapezius.
CONCLUSION—Despitepredominantly proximal limb weakness seen clinically in patientswith LEMS, the most sensitive muscles for detecting characteristicelectrophysiological abnormalities of low resting CMAP amplitude andincrement of over 100% after 10 seconds maximal voluntarycontraction are abductor digiti minimi, abductor pollicis brevis, and anconeus.

     

Diverse electrophysiological spectrum of the Lambert-Eaton myasthenic syndrome

Among 13 patients with the Lambert-Eaton myathenic syndrome (LEMS), three different patterns on the repetitive nerve stimulation test were observed at the time of initial testing. Type 1 pattern, seen in one patient, had low normal CMAP amplitude, decremental response at the low rate of stimulation (LRS), and relatively normal response at the high rate of stimulation (HRS). Type 2, seen in nine patients, had the classical triad: low CMAP amplitude, decremental response at LRS, and incremental response at HRS. Type 3, seen in three patients, showed low CMAP amplitude, decremental response at LRS, and initial decremental response at HRS. We believe that these three patterns represent different degrees of blocking in LEMS, from the mildest in type 1 to the most severe in type 3. Since types 1 and 3 can be misinterpreted as myasthenia gravis patterns, they must be recognized in LEMS and an incremental response documented by prolonged stimulation at HRS.     

Single fiber EMG and repetitive stimulation of the same muscle in myasthenia gravis

We performed RNS and SFEMG studies of the same muscle in 46 patients with myasthenia gravis. Maximum decrement to 3–5-Hz stimulation before and after maximum voluntary exercise, percentage of action potential pairs with increased jitter and blocking, and mean MCD in each study were compared. A significant decrement (> 10% decrease in CMAP area or amplitude between the first and fourth response) was never found without increased jitter and impulse blocking on SFEMG. Increased jitter, blocking, and mean MCD were each correlated with maximum decrement (r > 0.61, P < 0.0001). We conclude that decrement to RNS and impulse blocking on SFEMG result from the same physiologic phenomenon, and that SFEMG is more sensitive at detecting disordered neuromuscular transmission given its ability to detect impulse blocking at levels below the resolution of RNS and increased neuromuscular jitter when there is not blocking. © 1994 John Wiley & Sons, Inc.     

Practical aspects of 3,4-diaminopyridine treatment of the Lambert-Eaton myasthenic syndrome

3,4-Diaminopyridine (3,4-DAP) given alone or combined with pyridostigmine is the recommended basic therapy in the Lambert-Eaton myasthenic syndrome (LEMS). We present and exemplify our routine test protocol for monitoring drug introduction and treatment regimen of cholinergic drugs in LEMS. The individual drug responses vary and no recommended standard doses exist. Routine electrophysiological repetitive nerve stimulation studies recording amplitude of initial compound muscle action potential (CMAP) in thenar muscles correlate excellently with clinical myasthenic muscle power tests in clinically affected muscle groups. Therefore repetitive clinical muscle power tests, that often are complicated by painful myalgia and activation potentiation, can be replaced by recordings of CMAP in the introduction and clinical follow up of cholinergic drug treatment in LEMS. Also, adverse effects and other treatment problems from the experience of continuous treatment of 19 LEMS patients with 3,4-DAP for up to 10 years are presented.     

Electrophysiologic data on myasthenic syndromes of the Lambert-Eaton type. A series of 23 cases]

The electrophysiological data of 23 adult patients with Lambert-Eaton myasthenic syndrome (LEMS) have been reviewed. Lung carcinoma was disclosed in 17. In six cases with an EMG follow-up ranging between one and 17 years no carcinoma was detected. The results of repetitive nerve stimulation test (RNS) were not statistically different between the 2 groups. Low CMAP ulnar amplitude was present in all patients (mean: 1.7 mV). Decremental response at low rate of stimulation (3 Hz) was present in 17/20 (means: 30%). An abnormal incremental response at high rate of stimulation was present in all cases (mean: 826%). The authors emphasize the interest of a 50 Hz stimulation for 4 s. Increase of the 'F-wave' amplitude was noticed in some cases. Electrophysiological changes suggestive of an associated mild neuropathy were noticed in eight patients but H-reflex was present in 3/3 cases. SFEMG abnormalities were found in 6/6 cases. In one case, stimulated SFEMG showed more blockings and an increased jitter with low rate of stimulation. In one case the electrical pattern of RNS could be misinterpreted as myasthenia gravis in one tested muscle only. The author's results suggest that CMAP amplitude and RNS test could be used to appreciate the short-term improvement of LEMS with treatment and in some cases for the long-term follow-up.     

Axonal function and activity-dependent excitability changes in myotonic dystrophy

To investigate peripheral nerve function and its potential contribution to symptoms of weakness in myotonic dystrophy type 1 (MD), nerve excitability was assessed in 12 MD patients. Compound muscle action potentials (CMAPs) were recorded at rest from abductor pollicis brevis (APB) following stimulation of the median nerve. Stimulus-response behavior, threshold electrotonus, a current-threshold relationship, and recovery cycles were successfully recorded in each patient. Compared with controls, there was significant reduction in CMAP amplitude in MD patients. This was accompanied by reduction in depolarizing threshold electrotonus and an increase in refractoriness and in the duration of the relative refractory period. To determine whether alteration in axonal resting membrane potential was a factor underlying these changes, axonal excitability was assessed following maximal contraction of APB for 60 seconds. Following contraction, there was reduction in CMAP amplitude for a submaximal stimulus (by 51.5+/-11.8%) and an increase in super-excitability (of 22.2+/-12.0%), consistent with activity-dependent hyperpolarization, with a greater increase in threshold for MD patients compared to controls (MD group, 22.3+/-5.1%; controls, 11.7+/-2.1%; P<0.04) and prolonged recovery to baseline. The present study has established that greater activity-dependent changes in excitability may be induced in MD patients by maximal voluntary contraction when compared to controls. The excitability changes and prolonged recovery of threshold following contraction are likely to contribute to symptoms of fatigue and weakness in MD patients.     

Motor potentials evoked by magnetic stimulation of the motor cortex in normal subjects and patients with motor disorders.

Motor evoked potentials (MEPs) elicited by magnetic coil stimulation of motor cortex were studied at rest and during maximum voluntary muscle contraction in 20 normal subjects and 42 patients with motor disorders. MEP parameters employed in this study included: onset latency, amplitude, MEP/M wave amplitude ratio and background EMG/MEP area ratio. Maximum voluntary contraction increased the amplitude of MEPs compared to the size of M waves elicited by peripheral nerve stimulation. A reduced MEP/M wave amplitude ratio had a higher correlation with pyramidal tract involvement than did a prolonged MEP onset latency. Analysis of MEP parameters may help in the differential diagnosis of cerebral infarction, ALS and cervical spondylotic radiculomyelopathy. The inhibitory period which follows MEPs during voluntary contraction was observed in all subjects; the mean duration in normal subjects was 126.6 +/- 29.5 msec. The mean duration of the inhibitory period in patients with cerebral infarction, ALS and cervical spondylotic radiculomyelopathy was 73.9 +/- 41.7 msec, 79.5 +/- 54.5 msec and 85.1 +/- 36.5 msec, respectively. These values were significantly shorter than in normal subjects.     

Lambert-Eaton syndrome: clinical and electrophysiological study of 18 cases associated with lung cancer]

The clinical and electrophysiological data of 18 consecutive adult patients with paraneoplastic Lambert-Eaton myasthenic syndrome (LMES) have been reviewed. The cancer associated with LEMS was small-cell lung carcinoma (SCLC) in 15 cases and epidermoid lung carcinoma in 3 cases. The main clinical neurological features were proximal lower limb weakness (100%), depressed tendon reflexes (94%) and dryness of the mouth (66%). The results of repetitive nerve stimulation (RNS) were not statistically different in the paraneoplastic LEMS group and in a group of 6 LMS patients in whom no carcinoma had been detected. Low-amplitude compound muscle action potential (CMAP) was present in all cases; decremental response at low stimulation rates was present in 13/15 cases. An abnormal incremental response at high stimulation rates was observed in all cases. A close correlation between CMAP amplitude and clinical condition was found in 4 cases during the long-term follow-up. In one patient the RNS electrical pattern could be misinterpreted as myasthenia gravis in only one muscle tested. We underline the usefulness of a 50 Hz stimulation during 4 seconds to establish the diagnosis unequivocally, and that of post-exercise facilitation in routine detection among an SCLC population. Our results suggest that CAMP amplitude and RNS test could be used to evaluate the short-term improvement of LMS under treatment and, in some cases, for the long-term follow-up. The infraclinical axonal neuropathy detected in 8 patients probably was another associated autoimmune paraneoplastic complication.     

Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer

OBJECTIVES: To determine the prognosis in patients with Lambert-Eaton myasthenic syndrome (LEMS) without small cell lung cancer (SCLC), and to analyse longitudinal clinical, electrophysiological, and immunological data on each patient to establish prognostic factors for long term outcome. METHODS: The retrospective and part prospective study of 47 patients with LEMS was undertaken from data recorded during visits to a specialist neuromuscular clinic. Serial measurements of muscle strength score in shoulder abduction, elbow extension and hip flexion, compound muscle action potential (CMAP) amplitude, and postcontraction increment in abductor digiti minimi (ADM), and anti-P/Q-type voltage gated calcium channel (VGCC) antibody titre were made at each visit. RESULTS: Muscle strength scores were improved in 88% of patients after a median duration of immunosuppressive treatment of 6 years (range 1.3 to 17 years); anti-VGCC antibody titres fell in 52% after treatment; and mean resting CMAP amplitude improved from 2.7 mV initially to 8.8 mV after 2 years of treatment p<0.001). Initial pretreatment anti-VGCC antibody titre did not correlate significantly with either CMAP amplitude, CMAP increment, or clinical score: from serial measurements made during follow up, significant correlation between antibody titre and CMAP amplitude was seen in only two patients. Sustained clinical remission was achieved by 20 (43%) of whom only four remained in remission without the need for immunosuppression. Using a Cox proportional hazards model, the only independent predictor of sustained clinical remission was initial pretreatment clinical score (p=0.03). Lymphoma presented in three patients during the study. CONCLUSIONS: The prognosis in patients with LEMS without SCLC is favourable, although patients often need significant doses of immunosuppressive treatment to remain clinically stable. Only initial clinical muscle strength measurements and not anti-VGCC antibody titres or electrophysiological recordings are predictive of long term outcome.     

Serial neurophysiological studies of intramuscular botulinum-A toxin in humans

To characterize the time course of intramuscular botulinum toxin–induced paresis, we serially performed electrophysiological measurements and recorded the sonographic size of an extensor digitorum brevis (EDB) muscle in 10 human subjects before and after injecting the EDB with 10 units of botulinum-A toxin. All EDB CMAPs decreased within 48 h, with peak decline at day 21 (8.3 ± 3.1 mV to 3.0 ± 0.9 mV). Decline of mean rectified voltage during maximal voluntary contraction of the EDB paralleled the change in CMAP amplitude. Average decrements to 2-Hz repetitive stimulation never exceeded 6% (day 42) and exercise failed to facilitate Significantly CMAP amplitude. Atrophy peaked at day 42. The F-wave to M-wave ratio increased at day 2; silent periods did not change. Our findings confirm a primary peripheral action of the toxin, but a superimposed, transient central effect of the drug cannot be excluded. Intramuscular injections into EDB provide a useful model for studying chemodenervation effects. © 1994 John Wiley & Sons, Inc.     

Trigeminal nerve repetitive stimulation in myasthenia gravis

The aim of this study was to evaluate the utility of repetitive nerve stimulation (RNS) of the trigeminal nerve in assessing patients with myasthenia gravis (MG). In 26 normal controls and 21 patients with myasthenia gravis (MG), 2-Hz repetitive stimulation of the trigeminal nerve was performed using a monopolar needle for percutaneous nerve stimulation and recording over the surface of the masseter. In the MG patients, repetitive stimulation of the ulnar, spinal accessory, and facial nerves was also performed. The mean percent decrement in the compound muscle action potential (CMAP) amplitude among the different nerves at rest were: ulnar, 4.3%; spinal accessory, 10.1%; facial, 14%; and trigeminal, 17.3%. The facial nerve demonstrated abnormal decrement in 57% of all patients, compared with the spinal accessory (48%), trigeminal (43%), and ulnar (20%) nerves. All patients tolerated trigeminal RNS better than or as well as facial RNS. The study demonstrates that trigeminal RNS is a safe, reliable, efficient, and well-tolerated technique that provides another cranial nerve-muscle combination that can be used to supplement repetitive stimulation of other limb or cranial nerves in the evaluation of patients with bulbar or generalized MG.     

Twitch potentiation induced by stimulated and voluntary isometric contractions at various torque levels in human knee extensor muscles

The purpose of this study was to compare the extent of twitch potentiation (TP) after stimulated or voluntary contractions at identical intensities for the human knee extensor muscles. Isometric knee extensions of 10 s were performed at 20%, 40%, and 60% of maximal voluntary contraction (MVC) torque level, through percutaneous electrical stimulation of the quadriceps at 80 Hz or voluntary contraction. Twitch responses were evoked by stimulating the femoral nerve percutaneously with supramaximal intensity. The extent of TP after the stimulated contraction was greater than that after the voluntary contraction at the 20% MVC torque level, whereas a stimulated contraction induced a smaller extent of TP than did a voluntary contraction at contraction intensities higher than 40% MVC. We suggest that this contraction intensity dependence of differences in TP after stimulated and voluntary isometric conditioning contractions is responsible for differences in the recruitment pattern of motor units during the conditioning contractions.     

Compound muscle action potentials during repetitive nerve stimulation

When using repetitive nerve stimulation to examine neuromuscular transmission, the change in compound muscle action potential (CMAP) size is usually assessed by measurement of negative-peak or peak-to-peak amplitude. Technological developments now allow automatic measurement of CMAP area, but some patients show increment of CMAP amplitude and decrement of CMAP area. This study systematically analyzed the changes in these CMAP parameters in 23 neurologically healthy subjects. CMAPs were recorded when the ulnar nerve was stimulated at frequencies of 1, 2, 5, 10, 20, 30, and 50 HZ (five pulses per train). CMAP amplitude showed significant increment within a train when stimulus frequency was above 5 HZ (probably due to increased muscle-fiber conduction velocity), whereas CMAP area hardly changed at any frequencies. Measurement of CMAP area produces less ambiguous results than amplitude measurement in repetitive nerve stimulation studies.     

Electrophysiological differences in seropositive and seronegative Lambert-Eaton myasthenic syndrome

In order to determine whether there is any difference between voltage-gated calcium-channel antibody (VGCC-Ab)-positive and -negative groups in Lambert-Eaton myasthenic syndrome (LEMS), we compared the clinical and electrophysiological features between 13 patients with VGCC-Ab and 6 VGCC-Ab-negative patients. No obvious difference was observed in the various clinical features or findings on single-fiber electromyography between seropositive and seronegative cases. In seropositive cases, the compound muscle action potential (CMAP) amplitude was lower but the increment on post-exercise facilitation (PEF) and high-rate stimulation (HRS) was significantly higher than in the seronegative group, indicating that the repetitive nerve stimulation (RNS) test in the seropositive group is more typical of LEMS and more severe. A 100% increment as the diagnostic criterion in the routine RNS test was satisfied in all seropositive cases but in only three seronegative cases, whereas a 60% increment as the diagnostic criterion was found in all seronegative cases. The classic triad (low CMAP amplitude, decrement at low rate of stimulation, and increment at PEF or HRS) of RNS is rare, adding to the difficulty in diagnosing LEMS in the seronegative group, and making a 60% increment criterion more critical for the diagnosis of this disorder.     

Neuromuscular transmission failure due to common krait (Bungarus caeruleus) envenomation

Neurophysiological studies were performed in 12 patients with neuromuscular paralysis due to envenomation by the common krait (Bungarus caeruleus). All patients presented with an acute, reversible, oculofaciobulbar paresis. In addition, 7 patients had weakness of the limb muscles and 4 required assisted mechanical ventilation. Neurophysiological abnormalities included: (1) a reduction in the amplitude of the median-elicited compound muscle action potential (CMAP) in 4 patients; and (2) a decremental response (>10%) to 3-Hz repetitive nerve stimulation (RNS) in 4 patients. With 1 exception, these abnormalities were noted only in clinically weak muscles. The administration of edrophonium to 6 patients produced an insignificant increase in CMAP amplitudes as well as partial (not significant) improvement in the decremental response to 3-Hz RNS. Neurophysiological studies were performed in 2 patients before and after the administration of 20 mL of polyvalent antivenom. A decrease in amplitude of the median-elicited CMAP amplitude occurred after the administration of antivenom. In 1 patient, administered 100 mL of antivenom, the median-elicited CMAP amplitude increased and the decrement to 3-Hz RNS decreased. Neurophysiological studies can provide useful information regarding the nature, severity, and therapy of the neuroparalytic syndrome of krait envenomation.     

What is the best diagnostic index of conduction block and temporal dispersion?

In order to find the best diagnostic index of conduction block and abnormal temporal dispersion, the amplitude, duration, and area of the compound muscle action potentials (CMAP) were studied in 40 normal controls and 28 patients with acquired demyelinating neuropathies. In the normal subjects, there was a substantial difference among the various nerves in the degree of CMAP amplitude reduction and CMAP duration prolongation with proximal stimulation, and thus different criteria should be used for conduction block or abnormal temporal dispersion for a given nerve. In 28 patients with demyelinating neuropathy, 58 of 207 (28%) tested nerve segments showed nerve conduction velocity (NCV) evidence of demyelination. To identify “demyelination” in these segments, conduction block was best detected by the total area method in 71% of cases, and abnormal temporal dispersion was bast by the negative-peak duration method. This study showed that the best diagnostic index for conduction block is the total area method and for abnormal temporal dispersion, the negative-peak duration method. © 1994 John & Sons, Inc.     

Exercise test in muscle channelopathies and other muscle disorders

We studied the percentage change in compound muscle action potential (CMAP) amplitude and area during and after a 5-min maximal contraction of the muscle. The exercise test (ET) was performed on 64 patients with different muscle disorders and on 46 normal controls. The range of normal ET values was defined as the mean + 2 SD of the control values. The mean sensitivity of the test was 63% in the whole group with ion channel muscle disorders, the highest sensitivity being seen in primary periodic paralysis (81%) and the lowest in chloride channelopathies (17%). In thyrotoxic periodic paralysis, the ET was abnormal in the three of the four patients studied. In patients with myotonic dystrophy, a smaller than normal increase in CMAP amplitude occurred during and after exercise, whereas in proximal myotonic myopathy a normal initial increase in CMAP amplitude was followed by an abnormal decrement. We conclude that the ET can be of use in confirming abnormal muscle membrane excitability in patients with calcium and sodium channelopathies and thyrotoxic periodic paralysis. In chloride channelopathy, the test may also be abnormal, but shows no, or only a small, increase in amplitude or area in the immediate postexercise period. The test may also be abnormal in proximal myotonic myopathy, but is normal in myotonic dystrophy.