Phenotypic variability in Bartter syndrome type I.

Limited phenotypic variability has been reported in patients with Bartter syndrome type I, with mutations in the Na-K-2Cl cotransporter gene (BSC). The diagnosis of this hereditary renal tubular disorder is usually made in the antenatal-neonatal period, due to the presence of polyhydramnios, premature delivery, hypokalemia, metabolic alkalosis, hypercalciuria, and nephrocalcinosis. Among nine children with hypercalciuria and nephrocalcinosis, we identified new mutations consistent with a loss of function of the mutant allele of the BSC gene in five. Three of the five cases with BSC gene mutations were unusual due to the absence of hypokalemia and metabolic alkalosis in the first years of life. The diagnosis of incomplete distal renal tubular acidosis was considered before molecular evaluation. Three additional patients with hypokalemia and hypercalciuria, but without nephrocalcinosis in the first two and with metabolic acidosis instead of alkalosis in the third, were studied. Two demonstrated the same missense mutation A555T in the BSC gene as one patient of the previous group, suggesting a single common ancestor. The third patient presented with severe hypernatremia and hyperchloremia for about 2 months, and a diagnosis of nephrogenic diabetes insipidus was hypothesized until the diagnosis of Bartter syndrome type I was established by molecular evaluation. We conclude that in some patients with Bartter syndrome type I, hypokalemia and/or metabolic alkalosis may be absent in the first years of life and persistent metabolic acidosis or hypernatremia and hyperchloremia may also be present. Molecular evaluation can definitely establish the diagnosis of atypical cases of this complex hereditary tubular disorder, which, in our experience, may exhibit phenotypic variability.

Botulinum toxin restores presynaptic inhibition of group Ia afferents in patients with essential tremor.

We studied the effect of botulinum toxin A injection on the abnormal presynaptic phase of reciprocal inhibition between forearm antagonist muscles in patients with essential tremor. Ten patients with essential tremor were investigated before and 1 month after botulinum injection. Reciprocal inhibition was studied by conditioning the H reflex in forearm flexors with a radial-nerve stimulus delivered at a range of time intervals. Botulinum toxin produced a significant functional improvement in tremor (about 20%). Before botulinum toxin injection, patients had a reduced presynaptic phase of reciprocal inhibition. After botulinum toxin this phase was significantly more pronounced. The normal early disynaptic phase of reciprocal inhibition was normal before and after botulinum treatment. Although botulinum treatment reduced the size of the H reflex and the M wave to a similar extent, it left the H/M ratio unchanged. These findings show that botulinum toxin treatment restores presynaptic inhibition between forearm antagonist muscles. The results are also consistent with botulinum toxin having a beneficial effect in patients with essential tremor. Both effects probably depend upon the toxin's concurrent action on the extrafusal and intrafusal motor end-plates, the latter resulting in decreased spindle afferent input to the spinal cord.

Reciprocal inhibition in forearm muscles in patients with essential tremor.

Reciprocal inhibition of the H-reflex in the forearm flexor muscles was studied in 11 patients with essential tremor and in 10 normal controls. Whereas patients and controls had a similar first, disynaptic phase of reciprocal inhibition, patients had a significantly reduced second phase. Patients with more severe functional impairment had more pronounced abnormalities of reciprocal inhibition. Abnormalities of reciprocal inhibition may play a role in the pathophysiology of essential tremor and probably arise from defective suprasegmental control.

Autosomal recessive distal muscular dystrophy.

The "distal myopathies" include autosomal dominant, autosomal recessive, and sporadic disorders. Two of the recessive disorders are considered to be definitive entities: Miyoshi's myopathy, which has an early adult onset and first involves the calf muscles, and distal myopathy with rimmed vacuoles. We here describe the cases of two sisters and compare them with previously reported cases. The disorder in our patients is characterised by: a) autosomal recessive inheritance; b) onset in early adult life; c) initial involvement of the tibialis anterior and peroneal muscles; d) subsequent involvement of the calf muscles spreading to the proximal muscles of the legs and, later, the arms; e) a moderately disabling evolution over a period of 10-12 years; f) marked and stably high serum levels of CK and other enzymes; g) EMG evidence of myopathic damage, with fibrillation at rest; and h) a histological picture of dystrophic myopathy, with atrophy of mainly type 2 fibres. We think that this syndrome is different from the two forms of autosomal recessive distal myopathy mentioned above.

Effects of transcranial electrical and magnetic stimulation on reciprocal inhibition in the human arm.

We studied the effects of transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS), delivered at intensities below the threshold for evoking an electromyographic response, on the disynaptic and presynaptic phases of reciprocal inhibition in 8 healthy subjects. After TES, the H-reflex evoked in the flexor carpi radialis (FCR) muscle was strongly facilitated when the cortical stimulus was given 4.0-4.5 ms after the test stimulus (median nerve stimulus). TES reduced the disynaptic phase of reciprocal inhibition most strongly when the cortical stimulus followed the test stimulus by 3.0-3.5 ms. TES also reduced presynaptic inhibition, but with a time course that was identical to that of the facilitation of the uninhibited H-reflex. After subthreshold TMS, the facilitation of the H-reflex showed at least 2 peaks, one occurring when the cortical stimulus was given 2 ms after the test stimulus and the other when the cortical stimulus followed the test stimulus by 0.5 to -1.5 ms. The effects of TMS on the 2 phases of reciprocal inhibition were similar, and in both cases the disinhibitory effects had essentially the same time course as the facilitatory effect of TMS on the uninhibited H-reflex. The different effects of TES on the 2 phases of reciprocal inhibition provide evidence of the presynaptic nature of the second phase. The absence of a difference in the effect of TMS on the 2 phases could be due to the more temporally dispersed descending volley after TMS.

Decreased postexercise facilitation of motor evoked potentials in patients with chronic fatigue syndrome or depression.

We studied the effects of exercise on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in 18 normal (control) subjects, 12 patients with chronic fatigue syndrome, and 10 depressed patients. Subjects performed repeated sets of isometric exercise of the extensor carpi radialis muscle until they were unable to maintain half maximal force. MEPs were recorded before and after each exercise set and for up to 30 minutes after the last set. The mean amplitude of MEPs recorded from the resting muscle immediately after each exercise set was 218% of the mean pre-exercise MEP amplitude in normal subjects, 126% in chronic fatigue patients, and 155% in depressed patients, indicating postexercise MEP facilitation in all three groups. The increases in the patient groups, however, were significantly lower than normal. The mean amplitudes of MEPs recorded within the first few minutes after the last exercise sets in all three groups were approximately half their mean pre-exercise MEP amplitudes. This postexercise MEP depression was similar in all groups. We conclude that postexercise cortical excitability is significantly reduced in patients with chronic fatigue syndrome and in depressed patients compared with that of normal subjects.

Abnormal cortical motor excitability in dystonia.

To assess the excitability of the motor system, we studied 11 patients with task-specific dystonia and 11 age-matched normal subjects. The dominant side was affected in nine of the patients. We delivered transcranial magnetic stimuli at different stimulus intensities and with different levels of muscle facilitation to the side contralateral to the side of electromyographic recording, and recorded motor evoked potentials (MEPs) from the flexor carpi radialis muscles bilaterally. The threshold intensity for eliciting MEPs at rest did not differ between patients and normal subjects. We compared the affected side in patients with the dominant side in normal subjects. With facilitation, the percentage of the area of the MEP to the M wave (MEP area%) was similar in both groups at low stimulus intensities, but with increasing stimulus intensity the increase in the MEP area% was greater in patients than in normal subjects (ANOVA, p < 0.001). The increase in MEP area% was similar in both groups with increasing facilitation levels. The duration of the silent period was similar in patients and normal subjects. We conclude that cortical motor excitability is increased in dystonia.

Characterization of postexercise facilitation and depression of motor evoked potentials to transcranial magnetic stimulation.

We studied the effects of exercise on motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES). Subjects performed 30-second periods of isometric exercise of the extensor carpi radialis until fatigue, which was defined as the inability to maintain half maximum force. The amplitude of MEPs to TMS recorded from the resting muscle after each exercise period was on average more than twice the pre-exercise value (postexercise MEP facilitation). After fatigue occurred, the MEP amplitudes were approximately 60% of the pre-exercise value (postexercise MEP depression). There was a gradual recovery of the depressed MEPs to pre-exercise values over several minutes of rest. Postexercise MEP facilitation was constant when exercise intensity ranged from 10 to 50% of maximum voluntary contraction and it decayed to baseline over several minutes after the end of exercise. There was no postexercise MEP facilitation to TES. We hypothesize that both postexercise MEP facilitation and MEP depression are due to intracortical mechanisms.

Responses to paired transcranial magnetic stimuli in resting, active, and recently activated muscles.

Transcranial magnetic stimulation (TMS) causes the corticospinal system to become refractory to subsequent stimuli for up to 200 ms. We examined the phenomenon of paired pulse inhibition with TMS under conditions of rest, ongoing voluntary activation (isometric force generation), and at variable delays following activation (postactivation) of the wrist extensors of seven normal subjects. Paired stimuli were delivered to the motor cortex with a circular coil at 1.1 times motor evoked potential (MEP) threshold, with various interstimulus intervals. Voluntary activation caused a marked decrease in the variability of the ratio of the amplitude of the MEP evoked by the test pulse to that of the MEP evoked by the conditioning pulse. Marked inhibition of the MEP evoked by the test pulse was still present. Postactivation, however, caused a dramatic reversal of the inhibitory effect of the conditioning pulse in all subjects at interstimulus intervals ranging from 40 to 120 ms. This effect lasted for up to 10 s following the cessation of activation. MEPs to transcranial electrical stimulation were also inhibited by conditioning TMS, but postactivation did not reverse this inhibition, indicating that the reversal of paired pulse inhibition is intracortical. We conjecture that paired pulse inhibition reflects activity of inhibitory interneurons or inhibitory connections between cortical output cells that are inactivated in the postactivation state.

Cortical modulation of spinal excitability: an F-wave study.

F-waves are known to be highly sensitive to changes in the excitatory state of the spinal cord. This paper describes the effects of subthreshold transcranial magnetic stimulation on the F-waves evoked in hand and foot muscles. In the abductor pollicis brevis muscle, the F-wave was significantly enhanced when the cortical stimulus was given with a delay corresponding approximately to the expected time of collision, i.e., the difference between the mean latency of the F-wave and the mean latency of the motor evoked potential. A second, usually larger facilitatory phase follows the first phase after 2-3 msec, and later peaks of enhancement often occurred. After the enhancement periods, a significant inhibition of the F-wave was usually observed. In the extensor digitorum brevis muscle, the first facilitatory phase was observed some milliseconds earlier than expected in 4 of 5 subjects, and the inhibitory phase was less pronounced. We argue that the sequential arrival of I-waves at the spinal segment could be responsible for the changes observed in the F-wave recorded from the small hand muscle. In the foot muscle, anatomical and technical factors could contribute to the generation of a D-wave. The strong inhibition observed in the F-wave recorded from the hand muscle is likely to be due to the arrival on alpha-motoneurons of inhibitory postsynaptic potentials (IPSPs) generated by the cortical stimulus. Our data show that the F-wave ia a probe for changes in the spinal cord excitatory state.

Infantile autosomal dominant distal myopathy.

INTRODUCTION: Distal myopathies are currently regarded as a non-homogeneous group of disorders including different autosomal dominant, recessive and sporadic forms. MATERIAL AND METHODS: The cases of a mother and her son and daughter are described and compared to previously reported cases from 4 families. Despite minor differences, the clinical picture is remarkably homogeneous, both within the same family and among different families. CONCLUSION: A distinct clinical form can be identified including: a) autosomal dominant inheritance; b) onset in infancy or childhood with peroneal muscles weakness; c) not disabling evolution in spite of possible late involvement of muscles others than tibio-peroneal; d) usually normal serum CK and other muscle enzymes; e) EMG evidence of primary myogenic damage; f) morphological findings of non-specific myopathy. Because of the benign evolution and the absence of true dystrophic changes in most biopsies we suggest the term infantile autosomal dominant distal myopathy should be preferred to infantile autosomal dominant distal muscular dystrophy.

Physiological effects produced by botulinum toxin treatment of upper limb dystonia. Changes in reciprocal inhibition between forearm muscles.

Patients with upper limb dystonia have abnormal reciprocal inhibition between flexor and extensor forearm muscles. To see whether botulinum toxin treatment alters segmental motor system function, we studied reciprocal inhibition between forearm flexor and extensor muscles, before and after botulinum toxin injection in forearm muscles in 12 patients with upper limb dystonia. Reciprocal inhibition was studied by conditioning the H reflex in forearm flexors with a radial nerve stimulus delivered at a range of time intervals. Botulinum toxin injection improved upper limb dystonia. Before botulinum toxin injection, the dystonic patients had a decreased second phase of reciprocal inhibition. After botulinum toxin injections this second abnormal phase of reciprocal inhibition increased. Botulinum toxin did not change the first phase of reciprocal inhibition. Botulinum toxin treatment also reduced the M wave and the H reflex by a similar amount but left the Hmax:Mmax ratio unchanged. Ample evidence has shown that the therapeutic effects of botulinum toxin in dystonia depend mainly on its neuromuscular junction blocking action. Our data now suggest a concurrent indirect effect on spinal cord circuitry, probably through the action of botulinum toxin on the intrafusal neuromuscular junction.

The effect of hyperventilation on motor cortical inhibition in humans: a study of the electromyographic silent period evoked by transcranial brain stimulation.

We studied the effects of hyperventilation under control of the end-tidal PCO2, on the electromyographic silent period evoked by transcranial magnetic brain stimulation and by peripheral nerve stimulation. We also studied the effects of hyperventilation on the threshold, latency and amplitude of motor potentials. Hyperventilation significantly reduced the duration of the cortical silent period, but did not affect the length of the peripheral silent period. Neither did it alter the latency, amplitude or threshold of the motor potentials. These findings suggest that hyperventilation selectively depresses motor cortical inhibition in humans.

Effects of transcranial magnetic stimulation on single and sequential arm movements.

We studied in humans the effects of transcranial stimulation of cortical motor areas on the execution of single and sequential rapid arm movements. In a reaction time paradigm with an auditory "go" signal, stimulation given after an auditory tone and before the start of movements delayed the onset but did not affect the subsequent performance of single or sequential movements; high intensities of cortical stimulation determined a long-lasting inhibition of movements. Cortical stimulation given during the execution of a sequential movement temporarily interrupted the movements. Reaction time was not prolonged and movements were not inhibited when cortical stimulation was delivered before the auditory tone and the start of movement. Neither electrical stimulation of the corticospinal tracts at the cervico medullary junction nor magnetic stimulation of the cervical roots delayed the onset or interrupted the execution of movements. Transcranial stimulation affects the performance of both single and sequential movements, through cortical mechanisms that interfere with the transfer of the motor program from other cortical structures to the motor cortex.

Botulinum toxin treatment in patients with focal dystonia and hemifacial spasm. A multicenter study of the Italian Movement Disorder Group.

In six Centers belonging to the Italian Movement Disorder Study Group, the efficacy of botulinum toxin treatment was evaluated in an open collaborative study in 251 patients with focal dystonia and hemifacial spasm. The percentage of functional improvement ranged from 66% to 81% in patients with blepharospasm, from 40% to 51% in patients with spasmodic torticollis and from 73% to 81% in those with hemifacial spasm. Good results were also obtained in patients with oromandibular dystonia, laryngeal dystonia and writer's cramp. Side effects were mild and transient. Local botulinum toxin injection is the first choice symptomatic treatment in focal dystonia and hemifacial spasm.

Electrical and magnetic transcranial stimulation in patients with corticospinal damage due to stroke or motor neurone disease.

Twenty patients with hemiplegia and 13 patients with motor neurone disease were studied with electrical and magnetic transcranial stimulation. Motor evoked potentials were recorded from the biceps, thenar and tibialis anterior muscles. In both groups of patients magnetic stimulation with a Novametrix stimulator revealed fewer abnormalities than electrical stimulation with a Digitimer D180 stimulator. In patients with hemiplegia, motor evoked potentials after electrical stimulation were absent in 70% of muscles, delayed in 22% and normal in 8%; after magnetic stimulation, they were absent in 53% of muscles, delayed in 28% and normal in 19%. In patients with motor neurone disease, motor evoked potentials after electrical stimulation were absent in 62% of muscles, delayed in 10%, and normal in 29%; after magnetic stimulation, they were absent in 45% of muscles, delayed in 15%, and normal in 40%. The reason why magnetic stimulation reveals fewer abnormalities than electrical stimulation could be that magnetic stimulation repetitively discharges the pyramidal cells and, because of temporal summation mechanisms, produces more powerful excitatory potentials at the lower motoneurone synapse.

Corticobulbar and corticospinal projections to neck muscle motoneurons in man. A functional study with magnetic and electric transcranial brain stimulation.

The cortical projections to neck muscle motoneurons were studied in normal subjects by electrical and magnetic transcranial brain stimulation. After magnetic stimulation with a large coil, motor evoked potentials were present in about 20% of relaxed and 100% of contracting neck muscles. The latency of these responses was short: about 7 ms in the sternomastoid and splenius and 9 ms in the trapezius muscles. Subtraction of the M-wave latency after stimulation of the accessory nerve at the skull base resulted in a central latency of about 4.5 ms. We suggest that rapid cortical projections connect with neck muscle motoneurons mono or disynaptically. The latency difference between the responses after electrical and magnetic stimulation was smaller in neck than in limb muscles but similar to that seen in masticatory muscles. A small magnetic coil was used to study the pattern of functional lateralization of cortical projections to neck muscle motoneurons; the projections for the sternomastoid and splenius are bilateral but predominantly contralateral, whereas those for the trapezius are exclusively contralateral.