Sustained rises in serum thyrotropin, thyroxine, and triiodothyronine during long term, continuous thyrotropin-releasing hormone treatment in patients with amyotrophic lateral sclerosis.

In a pilot therapeutic trial, four patients with amyotrophic lateral sclerosis (ALS) were treated with long term, continuous infusions of TRH, three intrathecally and one epidurally. They had prompt increases in serum TSH and thyroid hormone concentrations, averaging 120% for TSH, 49% for serum T4, 68% for the serum free T4 index, 49% for serum T3, and 67% for the serum free T3 index. These elevations were statistically significant for all but serum T3 and persisted for the duration of treatment (4-7 months). Mean values during treatment were near the upper limit of normal for each of these hormone measurements. After TRH withdrawal, serum TSH fell transiently below the normal range. A comparison group of four patients with ALS treated by twice weekly intrathecal bolus doses of TRH had no significant changes in serum TSH, T4, or T3. During continuous TRH treatment, the responsiveness of both TSH and PRL to a standard iv TRH stimulation test was blunted, but not abolished. Basal serum PRL was occasionally elevated in the two women during continuous TRH treatment, but was normal in the men, and serum GH was normal in all patients. In the patients receiving continuous TRH treatment, indexes of end-organ effects of thyroid hormone were inconclusive; none had a rise in serum ferritin, one of four had a rise in serum sex hormone-binding globulin, and three had increased creatinuria. These results provide direct evidence in man that chronic TRH administration can cause modest sustained increases in serum TSH and thyroid hormones, though the metabolic consequences of these changes are uncertain, and appears to raise the set-point of the pituitary-thyroid axis, i.e. the serum T4 and T3 concentrations needed for a given degree of suppression of basal TSH secretion.

Dominant inheritance of McArdle syndrome.

Myophosphorylase deficiency (McArdle syndrome) is an uncommon condition characterized by exercise intolerance, muscle cramping, and myoglobinuria. Although the original report by McArdle dealt with a sporadic case, subsequent cases reported in the literature show high familial incidence and consanguinity, implying that the defect is transmitted as a rare recessive gene or a possible sex-limited mode of inheritance. The present report describes the clinical, histoenzymatic, and biochemical findings in a 40-year-old woman with myophosphorylase deficiency. The family history reveals that four other members are also affected: an older sister, a younger brother, a 10-year-old son, and her 75-year-old mother, and possibly her maternal grandmother. Because of this particular pattern of direct transmission in this family, a dominant inheritance is postulated.

Effects of nerve stimulation on human muscle.

A phasic program of femoral nerve stimulation was used to reduce refractory knee flexion contractures in five patients. In one, rectus femoris was tenotomized before starting stimulation to reduce hip flexion contracture. Muscle biopsies were performed before and after 5 to 12 weeks of intermittent stimulation at separated sites on the same muscle. In the four patients where muscle contraction was isometric, type I fibers increased 3.7%, 6.4%, 48.4%, anand 30.4%, respectively. Both fiber types in each patient showed an increase in size ( p less than .001). In the tenotomized muscle, where contraction was isotonic at a shortened length, the proportion of type I fibers decreased from 40.2% to 25.4%, and their mean diameter also decreased (p less than .001). These observations suggest that the physical conditions of contraction may be more important than the pattern of neuronal discharge in determining the metabolic profile of human muscle fibers.

The global burden of disease study: implications for neurology.

Because of the epidemiological transition, the global burden of illness has changed. Several factors have contributed to this change, including improvements in maternal and child health, increasing age of populations, and newly recognized disorders of the nervous system. It is now evident that neurologic disorders have emerged as priority health problems worldwide. This is reflected in the Global Burden of Disease Study, jointly published by the World Health Organization and other groups. The proportionate share of the total global burden of disease resulting from neuropsychiatric disorders is projected to rise to 14.7% by 2020. Although neurologic and psychiatric disorders comprise only 1.4% of all deaths, they account for a remarkable 28% of all years of life lived with a disability. This study provides compelling evidence that one cannot assess the neurologic health status of a population by examining mortality statistics alone. Health ministries worldwide must prioritize neurologic disorders, and neurologists must be prepared to provide care for increased numbers of people individually and in population groups.

Plasmapheresis with immunosuppression in amyotrophic lateral sclerosis.

Four patients with amyotrophic lateral sclerosis and one with progressive muscular atrophy were treated with large-volume plasmapheresis combined with immunosuppression. Assessment of muscle strength and functional ability was performed during a period of time ranging from 6.2 to 13 months. Patients were compared with a clinically matched control group. Both treated and untreated patients continued to show similar deterioration. The results of this study failed to show any therapeutic benefit of plasmapheresis with immunosuppression in patients with amyotrophic lateral sclerosis.

The effects of acute and chronic ethanol administration on twitch and tetanic force production by rat gastrocnemius muscle in situ.

The effects of acute ethanol injection on force production were measured in normal and chronic alcoholic rats. Acutely injected normal rats, acutely injected chronic alcoholic rats, and noninjected chronic alcoholic rats were compared with control groups: normal nonalcoholic rats and a dietetically deprived control group. Acute ethanol injection increased twitch force in normal rats but not in chronic alcoholic rats. Chronic alcohol ingestion caused a decrease in maximal twitch and tetanic tension. The dietetically deprived control group developed less maximal tetanic force, with no significant decrease in maximal twitch force. Chronic alcohol ingestion seemed to decrease maximal twitch tension, whereas the decrease in maximal tetanic could be attributed to the effects of malnutrition.

Serum creatine phosphokinase levels and prednisone treated muscle weakness.

Evidence is cited from the literature and from personal experience with the "inflammatory" form of facioscapulohumeral syndrome that the creatine phosphokinase reduction occurring during pharmacologic treatment of various neuromuscular diseases does not necessarily imply therapeutic benefit.

Tubular aggregates in subclinical alcoholic myopathy.

A 34-year-old chronic alcoholic with acute alcoholic intoxication was found to have extensive aggregates on muscle biopsy performed 48 hours after admission. Forearm ischemic exercise failed to demonstrate normal generation of lactic acid. Pathologic changes in the muscle biopsy consisted of subsarcolemmal accumulations of bright purple-red material with trichrome reaction. This material stained darkly with NADH-TR but was unstained with myofibrillar ATPase and Pas. Ultrastructural studies revealed that these regions contained tubular aggregates. A second biopsy 7 days later failed to demonstrate any significant abnormalities. Two weeks later, lactate generation was normal. Previous observations by other authors that tubular aggregates may be concerned with correction of metabolic defect or detoxification of endogenous toxins could apply in our case.

Experimental serotonin myopathy.

One hundred and eight Wistar rats were injected with serotonin (20 mg per kilogram of body weight intraperitoneally) or imipramine hydrochloride (20 mg per kilogram intraperitoneally), or both, in a single cycle or in multiple (up to 18 weeks) weekly cycles. In contrast to previous reports, a characteristic myopathy was produced with serotonin alone, identical to that produced by serotonin and imipramine in combination. Imipramine alone produced no significant change. The myopathy produced was characterized by (1) preferential damage to myofibers with high oxidative capacity (types I and IIA), (2) prominent regenerative activity occurring as early as 48 hours, and (3) degeneratio of capillary endothelium (thickening, vacuolar degeneration, proliferation of marginal folds, dissolution of mitochondria). Small groups of degenerating fibers and increased connective tissue were not observed. There was no loss of myofibers or fat replacement. The changes suggested repeated acute insults followed the complete recovery. These observations suggest that although the pathogenesis of serotonin and serotonin-imipramine myopathy is primarily ischemic, it is not a satisfactory model of human Duchenne muscular dystrophy.

Pharmacokinetics of intrathecal thyrotropin-releasing hormone.

An investigation of the efficacy of thyrotropin-releasing hormone in amyotrophic lateral sclerosis included study of the intrathecal pharmacokinetics of this neuropeptide. Its mean elimination half-life in CSF was 0.90 hours and was monoexponential. During a 2-hour infusion, 2.75% crossed the CSF/blood-brain barrier. Infusion for 12 months with an implanted pump in three patients at a rate of 3 mg/24 hr resulted in a mean CSF steady state of 2.88, 2.42, and 2.74 micrograms/ml, respectively. Pharmacokinetic data were similar at 6 and 12 months. This is an effective system with potential uses in the treatment of other degenerative diseases.

Dystonic postures generated from complex repetitive discharges.

We report a woman with a chronic inflammatory myopathy who developed muscle stiffness and dystonic postures of both upper extremities. Electromyography demonstrated that involuntary complex repetitive discharges of muscle caused the posture. Rare cases of dystonic posturing may be of peripheral, and not central system, origin.

Needle muscle biopsy with the automatic Biopty instrument.

Needle muscle biopsies are less traumatic and easier to do than open biopsies, but their main disadvantage is the small specimen size. One hundred and five patients underwent needle biopsies with a 14-gauge spring-loaded device that guillotines the muscle automatically (Bard Radiology). Fifty patients had more than one muscle biopsy. One hundred and forty-six of 155 specimens contained over 200 muscle fibers, some as many as 500 fibers. Having evaluated various needles, we found the Bard Biopty instrument more efficient than manual needles and open biopsy techniques, and it provides muscle specimens for pathologic interpretation that are comparable with open surgical procedures.

Familial amyloidosis with cranial neuropathy and corneal lattice dystrophy.

A 64-year-old woman had bilateral facial weakness, mild peripheral neuropathy, incoordination, and impaired balance. A corneal transplant had been performed for corneal lattice dystrophy. Sural nerve biopsy showed mild axonal neuropathy with deposits of amyloid in the perineurium. Histochemical studies showed amyloid protein AA in the nerve, but not in cornea or muscle.

Amyotrophic lateral sclerosis: thyrotropin-releasing hormone and histidyl proline diketopiperazine in the spinal cord and cerebrospinal fluid.

In spinal cords from seven amyotrophic lateral sclerosis (ALS) patients and four controls, we found no difference in thyrotropin-releasing hormone (TRH) concentration relative to protein content, but there was a reduction per tissue wet weight in ALS. Immunohistochemical localization of TRH in ALS cord was unaltered. Histidyl proline diketopiperazine (HisPro-DKP), a possible metabolite of TRH, was significantly elevated per protein content in ALS. CSF levels of TRH and HisPro-DKP were unchanged. These findings suggest that TRH neurons are not primarily affected in ALS, but TRH and tissue protein are lost together as the disease progresses.

Total body irradiation not effective in inclusion body myositis.

Four patients with inclusion body myositis were treated with 150 rad of total body irradiation given in 5 weeks. One patient responded subjectively and transiently, but no patient showed clear benefit. This treatment is not recommended for inclusion body myositis.

Quantitative motor assessment in amyotrophic lateral sclerosis.

Reliable measurements are needed to document the natural history of ALS and to determine therapeutic efficacy. We have devised a standardized protocol that generates interval data sensitive to change-the Tufts Quantitative Neuromuscular Exam (TQNE). The TQNE consists of the following four major categories: pulmonary function, oropharyngeal function, timed functional activities, and isometric strength using an electronic strain gauge. The 29-item exam takes about 1 hour to administer and has excellent test-retest reliability.

The natural history of amyotrophic lateral sclerosis and the use of natural history controls in therapeutic trials.

We analyzed the natural history of amyotrophic lateral sclerosis in 277 patients. Our goal was to develop a better understanding of the clinical disease and thus improve the design of therapeutic trials. The Tufts Quantitative Neuromuscular Exam (TQNE) was used as the primary assessment instrument. Our analysis suggested that although more observations are desirable, six monthly TQNEs were adequate to establish the rate of disease progression. We observed a spectrum of deterioration rates without definable subgroups. The striking linearity of deterioration was confirmed. We found a high correlation between deterioration rates in arm and leg strength for individual patients, but a wide range between different patients. Sex and the age at clinical onset did not affect the deterioration rate. As compared with patients without a positive family history, those with other affected family members had a slower loss in arm but not leg strength. We propose that natural history controls can be used effectively in the design of ALS therapeutic trials.

Retrograde axonal transport of lead in rat sciatic nerve.

A wavelike pattern of retrograde axonal transport of lead was demonstrated in rat sciatic nerve after injection of 203Pb into the triceps surae muscle. The transport rate was about 10 mm per day, and the lead reached the spinal cord by 9 days after injection. The distribution of lead within the spinal cord indicated the possibility of retrograde axonal transport in the upper and lower motor neurons, which might explain how lead enters the central nervous system and could be related to the postulated role of lead in causing amyotrophic lateral sclerosis. Lead may be useful in investigating retrograde transport experimentally.

Familial myoadenylate deaminase deficiency and exertional myalgia.

In 14 members of four families with a hereditary syndrome of exertional myalgia, five of eight muscle biopsies from symptomatic individuals showed histochemical and biochemical absence of myoadenylate deaminase (MADA). In the others, MADA biochemical activity was normal in two and reduced but not absent (intermediate level) in one. Asymptomatic relatives had normal histochemical MADA activity, but three had intermediate biochemical levels. In a survey of 302 routine muscle biopsies, 3 of 36 patient with myalgia had absence of MADA. Three of 266 biopsied for other conditions were MADA-deficient. Despite some inconsistencies, MADA deficiency seems to be relevant to this clinical syndrome.

Use of composite scores (megascores) to measure deficit in amyotrophic lateral sclerosis.

The Tufts Quantitative Neuromuscular Exam (TQNE) consists of 28 items that were designed to measure voluntary motor deficit in amyotrophic lateral sclerosis (ALS) and related diseases. Individual raw data were converted to Z scores for standardization and then grouped into five megascores with statistical and clinical relevance. The derived megascores were Mega 1, pulmonary function; Mega 2, bulbar function; Mega 3, timed hand activities; Mega 4, isometric arm strength; and Mega 5, isometric leg strength. Megascores should enhance the usefulness of testing in therapeutic trials and in analyzing the natural history of ALS and related diseases.