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Friedreich's ataxia (FRDA), the most common autosomal recessively inherited ataxia, is due to a homozygous GAA triplet repeat expansion in the first intron of the FRDA gene in about 96% of patients. Approximately 4% of FRDA patients are compound heterozygotes with a GAA repeat expansion in one allele and a point mutation in the coding region of the second allele. To reinvestigate the mutation spectrum, we searched for mutations including exon deletions in six patients heterozygous for the GAA repeat expansion and found two unknown missense mutations, p.Asn146Lys and p.Leu186Arg, in trans to the expanded FRDA allele. Interestingly, we detected a heterozygous 2776 bp deletion including exon 5a in one of our patients. This deletion removes 50 of the 210 residues of the frataxin. Furthermore, since no FRDA case with two-point mutations is known, we screened eight patients with FRDA phenotype but GAA alleles within the normal range but did not reveal a mutation within the FRDA gene. In addition, DNA polymorphisms have been found in four out of 100 control individuals in this study.

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OBJECTIVE: Spasms in patients with generalized tetanus can be suppressed by a spinal intrathecal infusion of baclofen. We report on four patients and review reported cases treated by this method elsewhere. DESIGN: Intrathecal baclofen infusion was started with a bolus dose (300-500 micrograms) and continued at a steady rate of 500-1000 micrograms/day. The dose was increased in daily steps as needed. RESULTS: Doses of baclofen of 500, 1000, or 2000 micrograms/day were effective in three patients, while 1500 micrograms/day was insufficient in the fourth. Bradycardia and hypotonia occurred in one patient at a dose of 2000 micrograms/day but resolved after the dose was reduced to 1500 micrograms/day. Another patient developed hypotonia when a bolus of 500 micrograms was given after a steady infusion of 1500 micrograms/day. Voluntary movements were preserved in one and returned in two patients when sedation, induced by initial diazepam infusions, receded. The fourth patient needed diazepam during most of the treatment with intrathecal baclofen and required mechanical ventilation while being treated with baclofen. CONCLUSIONS: A catheter position higher than T11 would possibly have yielded better results. It may be necessary to adapt the dose during the course of the illness. The preservation of respiratory drive and voluntary movements is the main advantage of treating tetanus with intrathecal baclofen. Additionally it helps to reduce sympathetic hyperactivity. Mortality may thereby be reduced.

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In patients with predominantly focal spasticity, oral antispastic drugs are relatively ineffective or cause unwanted side effects of central origin. Therefore we treated patients disabled by focal spasticity with local injections of Botulinum-Toxin A (Porton Products BOTOX). Efficacy, dosage, side-effects and injection technique were examined. 11 patients (mean age 48 years) with severe focal spasticity of the flexor muscles of the hand and arm (5 patients), the adductor muscles of the legs (5) or the plantar flexors of the foot (1) due to multiple sclerosis, cervical myelopathy or stroke-related hemi-paresis were treated with BOTOX. Rating scales, including Ashford spasticity scale, pain scale and a hygienic rating scale, were used to evaluate the efficacy. 25 to 30 ng (1000-1200 MU Porton) were injected in the flexor group of the hand or arm and 42 to 50 ng (1680-2000 MU Porton) BOTOX in the adductor group of one leg. 10 of the patients showed an improvement of at least one point on the scales for spasticity, pain and hygiene. Effects could be observed after 4-7 days and lasted for 6-13 weeks. There were no unwanted side-effects. We conclude that BOTOX is an alternative to the systemic application of antispastic drugs. Focal spasticity and pain can be successfully reduced and hygienic care is facilitated.

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It was recently suggested that a premotion silent period in isometrically loaded agonist muscle reflects transition process in switching motor program from an isometric to an isotonic condition. To test this hypothesis we investigated changes in EMG activity of a biceps muscle during motor preparatory phase in an entirely isometric paradigm. Five healthy volunteers produced rapid isometric elbow flexions superimposed on a slightly sustained contraction during self-paced and reaction time conditions. In addition to surface EMG, single motor units were recorded in agonist muscle prior to a rapid contraction. Silent period was found in responses of three out of five subjects, whereas inhibition of some but not all tonically active motor units was observed in all studied subjects prior to the phasic EMG burst. Inhibition of motor unit activity occurred more often in self-paced than reaction time contractions. Our results indicate that inhibition is not always powerful enough to produce a complete electrical silence, and weaker inhibitory effects were observed as a declining number of firing motor units. We conclude that the silent period or depression of the EMG activity is associated with changes in motor program from tonic to phasic muscle activation and is not merely a consequence of changes from an isometric to an isotonic condition.

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Paired motor unit discharges (PDs), i.e., two discharges of the same motor unit (MU) with short interval, and their relation to tremor amplitude were studied in the first dorsal interosseous muscle (FDI) of patients with parkinsonian or essential tremor and in normal subjects mimicking tremor. In both pathological and voluntary tremor, interdischarge intervals of PDs were inversely correlated with the amplitude of the subsequent tremor beat, i.e., PDs with shorter intervals were followed by higher tremor beats. To further assess their mechanical impact, PDs were simulated by applying paired stimuli to MUs of the FDI in normal subjects using intramuscular microstimulation. Following paired stimuli, summation of twitch responses was more than linear. This was also the case with the paired stimuli applied at a tremor-like repetition rate (5 Hz). These findings stress the importance of PDs for tremor expression.

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In multiple sclerosis and stroke the muscle responses to transcranial magnetic stimulation are frequently delayed, reduced in amplitude or absent. To investigate the underlying pathophysiological mechanisms, responses of single motor units to transcranial magnetic stimulation were analysed using peri-stimulus time histograms. The following response patterns were detected: 1. prolongation of latency and duration of the primary peak which occurs in healthy controls 17 to 30 ms after the stimulus and has a duration of 2 to 8 ms, 2. lack of an excitatory response, 3. prolongation of the interval between sub-peaks within the primary peak and 4. multimodal responses. Possible mechanisms for these changes are: reduction and dispersion of conduction velocities in corticospinal axons associated with impaired summation of excitatory post-synaptic potentials at the spinal motoneurone, frequency-dependent or complete conduction block in corticospinal neurones and compensatory activation of other descending motor pathways.

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Macro-EMG potentials (MEP)s and twitch contractions (spike-triggered-averaging) of single motor units (MUs) have been recorded in the first dorsal interosseus muscle (FDI) of 10 control subjects and 20 patients with amyotrophic lateral sclerosis (ALS). MUs over the full range of voluntary recruitment thresholds were studied. Patients with slightly affected FDIs (5) mainly showed MUs with enlarged MEPs and increased twitch forces. In contrast, the patients with more severely affected FDIs (15) revealed decreased twitch forces, especially in the MUs with higher thresholds. The corresponding MEPs could be enlarged as well as normal. It appears that MU sprouting and the resulting increase of twitch force can compensate for the loss of motoneuron in early stages of ALS. In more advanced stages, however, a decline of the force of the surviving MUs, especially of those with higher thresholds, seems to contribute to the progressive muscle weakness, in addition to the corticospinal degeneration and the reduction in the number of motoneurons.

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Single motor units (MUs) were studied in the first dorsal interosseus muscle of 7 patients with slight partial denervation and in 10 controls. MU action potentials were recorded using the macro-EMG technique and their size was taken to assess collateral nerve sprouting. Simultaneously, the muscle force was monitored to determine the voluntary recruitment thresholds of the MUs and spike-triggered-averaging was applied to measure their twitch forces. At comparable force recruitment thresholds, both macro-EMG potentials and twitch forces were increased in the patients. We conclude, that collateral nerve sprouting increases MU force and can compensate for MU loss.

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