Benedikt G.H. Schoser

Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease

Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.

Cerebral hyperperfusion injury after percutaneous transluminal angioplasty of extracranial arteries

Abstract Cerebral hyperperfusion syndrome after carotid endarterectomy (CEA) is a rare but well-known phenomenon. Percutaneous transluminal angioplasty (PTA) is being widely evaluated for treatment of selected stenoses of the extracranial arteries. Its benefits and risks still need to be established. Hyperperfusion injury (HI) after PTA of cerebral arteries has not been reported. We describe two patients with severe HI, one with a small putaminal haemorrhage and the other with diffuse basal subarachnoid haemorrhage. In both cases, a typical clinical hyperperfusion syndrome with headache, confusion, vomiting and seizures occurred. Patient 1 underwent PTA of the left carotid artery, both subclavian arteries and proximal vertebral arteries, patient 2 had carotid angioplasty only. Transcranial Doppler ultrasound displayed markedly elevated blood-flow velocities. HI may occur after PTA of extracranial arteries. The pathogenesis might be similar to reperfusion injury after CEA. Our findings suggest that: (1) HI may occur after PTA; (2) patients should be monitored after PTA for HI; (3) further risk factors for HI need to be identified.

Neuroprotection as Initial Therapy in Acute Stroke

Although a considerable body of scientific data is now available on neuroprotection in acute ischaemic stroke, this field is not yet established in clinical practice. At its third meeting, the European Ad Hoc Consensus Group considered the potential for neuroprotection in acute stroke and the practical problems attendant on the existence of a very limited therapeutic window before irreversible brain damage occurs, and came to the following conclusions. Neuroprotectants in Clinical Development: Convincing clinical evidence for an efficacious neuroprotective treatment in acute stroke is still required. Caution should be exercised in interpreting and extrapolating experimental results to stroke patients, who are a very heterogeneous group. The limitations of the time windows and the outcome measures chosen in trials of acute stroke therapy have an important influence on the results. The overall distribution of functional outcomes provides more statistical information than the proportion above a threshold outcome value. Neurological outcome should also be assessed. Neuroprotectants should not be tested clinically in phase II or phase III trials in a time window that exceeds those determined in experimental studies. The harmful effects of a drug in humans may override its neuroprotective potential determined in animals. Agents that act at several different levels in the ischaemic cascade may be more effective than those with a single mechanism of action. Current In-Hospital Management of Acute Stroke: The four major physiological variables that must be monitored and managed are blood pressure, arterial blood gas levels, body temperature, and glycaemia. The effects of controlling these physiological variables have not been studied in prospective trials, though they may all contribute to the outcome of acute ischaemic stroke and affect the duration of the therapeutic window. Optimal physiological parameters are inherently neuroprotective. Trials of new agents for the treatment of acute stroke should aim to maintain these physiological variables as close to normal as possible, and certainly within strictly defined limits. The Place of Neuroprotectants in Acute Stroke Management: Stroke patients are a very heterogeneous group with respect to stroke mechanisms and severity, general condition, age and co-morbidities. At the present time, the only firm guideline than can be proposed for patient selection is the need for early admission to enable neuroprotectant and/or thrombolytic treatment to be started as soon as possible within the therapeutic window. The severity of potential side-effects will largely determine who should assess a patient with suspected stroke and initiate treatment. There is little information on which to base the duration of neuroprotectant therapy, and more experimental data are needed. Even if prehospital treatment proves to be feasible, it should not replace comprehensive stroke management in a specialist hospital unit. Clinical trials of neuroprotectants should only be performed in stroke units. The combined approach of restoring blood flow and providing neuroprotection may be the most productive in human stroke, but current clinical trial design will have to change in order to test combination therapy. Important side-effects are those that interfere with any possible benefit or increase mortality. Pharmaco-Economic Aspects of Neuroprotectants: The early increase in hospital costs associated with neuroprotectant therapy may be balanced by the shorter length of hospital stay and lesser degree of disability of the surviving patients. The overall direct financial cost is highly dependent on the number of patients eligible for neuroprotectant therapy, which is itself dependent on the length of the therapeutic window and the severity of potential side-effects. A treatment that achieves a good functional outcome is the most cost-effective approach.

Clinical and Ultrasonic Long-Term Results of Percutaneous Transluminal Carotid Angioplasty

Experience of the long-term outcome of patients treated with carotid balloon angioplasty is limited. Therefore, we prospectively analyzed the ultrasonic and clinical features of 29 patients with complete follow-up data beyond 24 months, evaluated from 1989 through 1996 from our carotid angioplasty cohort of 106 patients. Mean follow-up time was 33 months. For up to 78 months postangioplasty, 23 patients with 24 angioplasties (77%) had no further neurological sequelae. Single ipsilateral amaurosis fugax or TIA events occurred in 3 patients. Recurrent ipsilateral amaurosis fugax or TIA events were noted twice in 2 patients. No patient suffered an ipsilateral stroke. Fifteen angioplasties (50%) remained with normal ultrasound (stenosis <50%), mild restenosis (50–70%) occurred in 12 angioplasties (40%), and severe restenosis (>70%) in 3 angioplasties (10%). Only in 2 of 15 patients clinical complications were related to the occurrence of ipsilateral restenosis above 50%. Until now, rigorous and careful evaluation of patients and clinical and ultrasonic follow-up have been essential for the estimation of the long-term efficacy of carotid angioplasty. It should be noted that carotid angioplasty is a new technique in evolution, with a high potential improving the technical results.

Novel missense mutation in the caveolin-3 gene in a Belgian family with rippling muscle disease

Rippling muscle disease (RMD) is a rare muscle disorder characterised by muscle stiffness, exercise induced myalgia, and cramp-like sensations. It is genetically heterogeneous and can be acquired, but most cases show autosomal dominant inheritance due to mutations in the caveolin-3 (CAV3) gene. We report a novel heterozygous missense mutation in CAV3 in a Belgian family with autosomal dominant RMD. A 40 year old woman complained of fatigue, exercise induced muscle pain, and muscle cramps since the age of 35. Neurological examination revealed percussion induced rapid muscle contractions (PIRCs) and localised muscle mounding on percussion; muscle rippling was not observed. Creatine kinase (CK) was elevated but electromyography and nerve conduction studies were normal. Fluorescence immunohistochemistry revealed reduced caveolin-3 and dysferlin staining in a quadriceps muscle biopsy. Western blot analysis confirmed severely reduced caveolin-3 levels, whereas dysferlin was normal. Sequence analysis of the two coding exons of CAV3 revealed a hitherto unreported heterozygous C82A transversion in the first exon, predicting a Pro28Thr amino acid exchange. Thr patient’s first degree relatives did not present with neuromuscular complaints, but PIRCs, muscle mounding, and muscle rippling were found in the mother, who also carried the CAV3 mutation.

Motor excitability in myopathy

OBJECTIVE To explore whether patients with myopathy present changes in motoneuronal excitability. METHODS Patients with well-defined myopathies were studied with single and paired pulse transcranial magnetic stimulations and electrical nerve stimulations to explore neuronal motor excitability. Motor-evoked potentials were recorded from the clinically unaffected first dorsal interosseous muscle (n=10) and the paretic deltoid muscle (n=8). RESULTS Compared to an age-matched healthy control group, myopathic patients showed a reduction of intracortical inhibition, enhancements of alpha-motoneuron excitability and increased amplitudes of motor-evoked potentials during target muscle contraction. These alterations were present in clinically affected and clinically unaffected muscles. CONCLUSION In myopathy, nervous system excitability may be altered, presenting as a motor disinhibition on cortical and subcortical levels.

Tenascin in denervated human muscle

Tenascin is a large oligomeric glycoprotein of the extracellular matrix. Its location is innervated muscle tissues. We investigated immunohistologically, using two monoclonal antibodies (mah) against Tenascin, biopsied denervated human muscle of children and adults. Tenascin was present in the interstitial space among denervated muscle fibres. Accumulation of Tenascin in denervated adult muscle tissue was frequent, accumulation in denervated muscle tissue of children was sparse and weak. The two antibodies reacted correspondingly. Tenascin was not only found in the vicinity of atrophic muscle fibres, but also close to normally sized fibres, suggesting an early stage of denervation even before reduction of muscle fibre volume.

Immunolocalization of tenascin-C in human type II fiber atrophy

AbstractTenascin-C is a multifunctional extracellular matrix glycoprotein with stimulatory and antiadhesive or inhibitory properties for axon growth. Its location and discontinous expression are restricted in innervated muscle tissues. Tenascin-C accumulated interstitially among human denervated muscle fibers and close to normal-sized fibers. To expand our knowledge of the expression of tenascin-C in human neuromuscular disorders, we investigated immunhistologically 20 human muscle specimens with type II myofiber atrophy of children and adults. Tenascin-C immunoreactivity in adult type II atrophy was frequent, and accumulation in children was sparse and weak. In both groups, tenascin-C immunoreactivity was found:1.Interstitially around normal-sized type II muscle fibers.2.Around atrophic type II muscle fibers.3.Around small-caliber myofibers with centrally located nuclei. These results indicate that tenascin-Cimmunoreactivity: (1) is detectable around early denervated and reinnervated muscle fibers and, therefore, (2) may reflect in part the molecularly ongoing process of denervation and reinnervation in human type II fiber atrophy.