Riboflavin responsive multiple acyl-CoA dehydrogenase deficiency: functional evaluation of recovery after high dose vitamin supplementation.

The effect of riboflavin supplementation on muscle performance and exercise metabolism was investigated in four patients with multiple acyl-coenzyme A dehydrogenase deficiency (MAD). Maximum oxygen consumption and endurance measurements were performed to assess the patients' aerobic capacity and energy metabolism during exercise. They were tested before and after treatment with pharmacological doses of riboflavin. The initially low maximum oxygen consumption and high levels of blood lactate during submaximal exercise suggest that the oxidation of both fatty acids and carbohydrates was severely impaired. All four patients experienced a dramatic improvement in aerobic performance under riboflavin supplementation.

A short plasma exchange protocol is effective in severe myasthenia gravis.

Plasma exchange has been reported to be a successful therapeutic procedure for the treatment of severely compromised myasthenic patients, but the optimal regimen in terms of costs or clinical benefit has not so far been determined. We have investigated the efficacy of a short plasmapheresis protocol of two exchanges 1 day apart in a series of 70 patients with severe forms of myasthenia gravis. Patients were evaluated before and 7 days after the first exchange. A positive outcome was observed in 70% of the plasma exchange cycles performed. Disease severity did not seem to be a negative prognostic factor for the efficacy of this short protocol, which was well tolerated by patients. In only 1 case were major side-effects observed. In spite of its short duration, the exchange treatment plus concomitant immunosuppressive drug therapy was not followed by early clinical deterioration.

A multicentre follow-up study of 1152 patients with myasthenia gravis in Italy.

A multicentre retrospective study was carried out on the characteristics and course of myasthenia gravis (MG) in Italy. Data from 1152 patients, fairly representative of the myasthenic population seeking medical advice, were analysed for diagnostic criteria, clinical aspects and therapeutic approaches. Mean follow-up was 4.9 years. The disease was correctly diagnosed within 2 years of the onset in 80% of cases. Onset of symptoms peaked in the second and third decade in females and fell between 20 and 59 years in males. At first observation 87% of the patients had generalized MG. Maximal worsening was observed within 3 years in 77% of patients. At the last follow-up, 35% of cases were symptom-free (pharmacological remission 24%, remission without treatment 11%). The more severe the disease at the first observation and at the maximal worsening of symptoms, the lower was the proportion of remissions. Steroids were given in 54% and immunosuppressants in 18%. Thymectomy was performed in 72%, mostly in women, younger than age 40, and with generalized MG. Thymectomy seemed to improve the course of the disease, mostly in patients operated on shortly after diagnosis and those with generalized mild-to-moderate disease and with a normally involuted thymus. MG was lethal in 4% of patients, principally men, older than 40, in grade 3 or worse at first observation, with a short history of disease, and with thymona.

[Muscle weakness and intolerance to exercise in mitochondrial myopathies]. / Valutazione della forza e dell'energetica muscolare nelle miopatie mitocondriali.

Muscle weakness and intolerance to exercise are two of the main features commonly shown by patients affected by mitochondrial myopathies. In order to obtain an objective and quantitative evaluation of muscle weakness and endurance, we studied an evaluation protocol devoted to the assessment of 1) muscle strength by the isokinetic ergometer and 2) the metabolic aspects of exercise by means of Maximal Oxygen Consumption and endurance by a Steady State Submaximal exercise evaluation. The protocol has been applied to the study of patients affected by mitochondrial diseases and proved to be a reliable method to quantitate the defect in the oxidation pathways, either before or during the therapeutic follow-up.

Normalization of short-chain acylcoenzyme A dehydrogenase after riboflavin treatment in a girl with multiple acylcoenzyme A dehydrogenase-deficient myopathy.

A 12-year-old girl was shown to have carnitine-deficient lipid storage myopathy and organic aciduria compatible with multiple acylcoenzyme A (acyl-CoA) dehydrogenase deficiency. In muscle mitochondria, activities of both short-chain acyl-CoA dehydrogenase (SCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) were 35% of normal. Antibodies against purified SCAD, MCAD, and electron-transfer flavoprotein were used for detection of cross-reacting material (CRM) in the patient's mitochondria. Western blot analysis showed absence of SCAD-CRM, reduced amounts of MCAD-CRM, and normal amounts of electron-transfer flavoprotein-CRM. The patient, who was unresponsive to treatment with oral carnitine, improved dramatically with daily administration of 100 mg oral riboflavin. Increase in muscle bulk and strength and resolution of the organic aciduria were associated with normalization of SCAD activity and "reappearance" of SCAD-CRM. In contrast, both MCAD activity and MCAD-CRM remained lower than normal. These results suggest that in some patients with multiple acyl-CoA dehydrogenase deficiency riboflavin supplementation may be effective in restoring the activity of SCAD, and possibly of other mitochondrial flavin-dependent enzymes.

Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis.

Azathioprine (Aza) has been used alone or in combination with steroids for two groups of myasthenic patients. Positive responses were noted in 75% of patients on Aza alone and in 70% receiving the combined regimen. The clinical course of the two groups differed in terms of respiratory crisis and need for plasma exchange. With an appropriate Aza administration schedule side-effects were not a limiting factor to its use. Aza treatment induced a reduction in anti-AchR-antibody level that was correlated with clinical improvement and greatly decreased the need for steroids.

Anti AChR antibody: relevance to diagnosis and clinical aspects of myasthenia gravis.

227 sera from myasthenic patients were tested for the presence of anti-AChR antibodies (anti-AChR Abs) by mean of a fetal calf receptor (Fc-AChR); 73.5% of cases proved positive with this method. Significant correlations were found between presence of anti-Fc-AChr Abs and various clinical aspects such as: clinical stage and duration of disease; moreover significantly higher than the median titers were found among younger patients (i.e. age less than 40 yrs).

Single donor plasma in therapeutic plasma exchange for myasthenia gravis.

Thirty-seven myasthenic patients were treated with therapeutic plasma exchange (TPE) on different performance schedules using either random or single donor plasma. The two schedules had the same effects in terms of efficacy but single donor replacement gave significantly less side effects in the short and long term. A two exchange procedure on alternate days associated with immunosuppression seems to be an optimal schedule for the treatment of myasthenic patients. A single donor two-exchange on alternate days procedure appears to be safe, useful and can be repeated in patients who need frequent TPE.

Porphyric neuropathy: a clinical, neurophysiological and morphological study.

A case of neuropathy in the course of an attack of acute intermittent porphyria was studied from the neurophysiological and morphological points of view. The neurophysiological findings (acute neuropathy with almost complete denervation despite normal or slightly reduced conduction velocity) and the morphological findings (no segmental demyelination after teasing, conservation of the linear fiber diameter/internodal distance ratio, mainly axonal damage on ultrastructural study) seem to indicate that the disease process is chiefly an axonal neuropathy.

Thymectomy for myasthenia gravis: a fourteen-year experience.

Over the last 14 years we have thymectomized 106 myasthenic patients, 62 by transcervical and 44 by transsternal approach. At the end of the follow-up 49 patients (46.2%) had improved, 12 of these (11.2%) being in remission. Our data supply no guidance regarding the prognosis of individual patients at the time of thymectomy. In our hands neither operation seemed to modify the natural course of myasthenia gravis.

Freeze-fracture analysis of the muscle fiber plasma membrane in Duchenne dystrophy.

The intramembrane particle density in freeze-fractured muscle fiber plasma membranes did not differ in 4 patients with Duchenne dystrophy and 4 normal subjects. However, we confirmed reported loss of orthogonal arrays and increased density of caveolae in dystrophic muscle.

Treatment of deep brain abscesses by stereotactic implantation of an intracavitary device for evacuation and local application of antibiotics.

Complete recovery from deep brain abscesses was achieved in four patients treated by a specialized stereotactic method. In one patient the lesion was in the right thalamus, in two patients within the brain stem and in one case in the right rolandic cortex. The technique consists in the stereotactic implantation of a chronic intracavitary catheter connected to a subcutaneous reservoir to allow postoperative multiple evacuations and local antibiotic irrigations. Serial CT scan examinations guided the timing of intracavitary treatment and the removal of the catheter. No recurrence developed. The diagnostic and therapeutic advantages of this stereotactic technique are emphasized.

Studies on terminal deoxynucleotidyl transferase and adenosine deaminase in myasthenic thymus.

Thymic function in myasthenic patients was examined using two biochemical markers which specifically define a population of cortisone-sensitive cortical thymocytes. The enzymatic activities of terminal deoxynucleotidyl transferase (TdT) and adenosine deaminase (ADA) were determined in 13 samples. High contents of both enzymes were found in young patients. The enzymatic activities were easily detectable also in the oldest patients, despite the morphological involution and the decrease in TdT which are known to occur with age in the normal thymus. TdT and ADA-containing cells were almost completely depleted in all the 3 treated patients by the corticosteroid treatment which provides a non-surgical alternative to the elimination of this lymphoid population by thymectomy. The persistence of TdT and ADA activity in old age, and their inhibition by the corticosteroid treatment.

Myasthenia gravis: prolonged treatment with steroids.

We have evaluated chronic corticosteroid treatment in 60 myasthenic patients; 92% were followed for more than 3 years and 82% longer than 4 years. Improvement was noted in 72% of the patients. The best results were seen in those whose symptoms started after the age of 40 years. There was a correlation between the starting dose of prednisone and the rate of improvement. Complete withdrawal of steroids was possible only for 3 patients.

Absence of decremental response in decentralized muscles of a myasthenic patient.

Decentralized muscles of patients with upper motoneurone lesions may show anomalous responses to drugs acting on acetylcholine receptors. We compared the effects produced by repetitive nerve stimulation on normal and decentralized muscles of a patient with myasthenia gravis admitted to our Institute for a right hemiparesis. A myasthenic response was observed on the left (unaffected) deltoid muscle and a normal response on the opposite (paretic) side. It is suggested that decentralization might alter the functional properties of junctional receptors.

Cellular and humoral immunity to acetylcholine receptor in myasthenia gravis.

At the same time in 21 myasthenic patients we measured a. the cellular immune response against acetylcholine receptor (AChR) of peripheral lymphocytes, T lymphocytes and non rosette forming lymphocytes (50% B lymphocytes); b. the antibodies to AChR and c. the antigenic modulation activity of their sera on rat myotube AChR. At least one of these parameters was positive in each patient and this further supports the relevance of the immune response to acetylcholine receptor in myasthenia gravis. Strict correlations between the response of lymphocytes, antigenic modulation, antibody titer and disease severity were not evident.

Systemic carnitine deficiency with peripheral nerve involvement morphological and biochemical study.

The patient, a 31-year-old woman, suffered from a weakness of the proximal muscles which subsequently worsened involving the spinal and neck muscles. During the hospitalization, the patient displayed a "burning feet" syndrome. Lab tests showed a moderate increase in CPK, Aldolase, SGPT, SGOT, lactic and pyruvic acids. Needle EMG was interpreted as "myopathic" but a marked reduction of sensitive action potentials was also detected. Muscle biopsy showed neutral lipid accumulation in muscle fibers, many small angular fibers, probably denervated ones were also evident. A liver biopsy showed fatty accumulation in hepatocytes. Free carnitine was extremely reduced in muscle and liver and just below normal level in plasma while there was a tenfold elevation of long-chain carnitine esters in plasma too. The mechanism by which carnitine deficiency can cause both neural and muscular alterations and in particular the role of carnitine in glucose metabolism is discussed.

"Carnitine deficient" myopathy and cardiomyopathy with fatal outcome.

A 13-year-old boy with a mild limb girdle muscular weakness had a massive rhabdomyolysis and cardiac arrest after general anesthesia. A congestive cardiomyopathy then developed. Muscle biopsy revealed an unspecific "myopathic" degeneration of muscle fibers and a slight accumulation of lipid droplets. Carnitine content was markedly reduced in muscle and moderately in plasma. Both prednisone and carnitine therapies were unable to improve the heart insufficiency, and the patient died 1 year after the acute episode of rhabdomyolysis.