Skeletal muscle mitochondrial dysfunction in alternating hemiplegia of childhood

Alternating hemiplegia of childhood is an uncommon disease characterized by repeated, transient attacks of hemiplegia. Its pathophysiology is uncertain, but attention recently has focused on possible mitochondrial abnormalities. Using ³¹P magnetic resonance spectroscopy, we studied gastrocnemius muscle in 5 patients with alternating hemiplegia, aged 8 to 30 (mean, 18) years, at rest and during incremental aerobic exercise and recovery. There were no significant differences in resting muscle between patients and a control group aged 7 to 42 (mean, 19) years. Exercise performance was grossly impaired in the patients, the mean duration being 30% of normal. The total change in pH during exercise was somewhat less than in control subjects, while the changes in phosphocreatine concentration and intracellular ADP were similar. Thus the average overall rate of fall of phosphocreatine concentration during exercise was three-fold greater than in control subjects. However, the initial rate of ATP turNovemberer at the start of exercise (a measure of muscle mass and efficiency) was not abnormal. During recovery, both the initial rate of phosphocreatine resynthesis and the calculated mitochondrial capacity were reduced by about 35%. This mitochondrial defect probably explains most of the abnormalities seen during exercise.     

ERPs (N200, P300 and CNV) in alcoholics: relapse risk assessment]

The cognitive event-related potentials were studied in a group of 55 alcoholic patients, paired in age and sex with a group of 18 control subjects, using a protocol oddball (visual and auditory) and a protocol VCN Go/Nogo. The N200 obtained using an auditory oddball paradigm had lower amplitude in alcoholics than in controls. A significant amplitude decrease of visual P300 was also observed in alcoholic male subjects. There was however no difference in auditory P300 between alcoholics and control subjects. Using a Go/Nogo paradigm, a significant difference on the final part of the VCN appears between alcoholic and pilot subjects. In addition, the longitudinal follow-up of the same alcoholic patients showed an electrophysiological profile that allowed dividing them into two different groups. On the initial recording (17 days after weaning), the auditory oddball P300 amplitude was significantly higher at Cz and Pz among patients who relapsed during the 3 months follow-up. The same effect appeared on the CNV protocol, where the amplitude of P300 was higher in patients who subsequently relapsed than for those who remained abstinent. Cognitive ERPs may be clinically useful to improve the prediction of risk of relapse among alcoholic patients.     

The relationship between abstinence and Recovery of function in male alcoholics

Abstract

Recovery of information-processing skills following prolonged abstinence was studied in middle-aged (mean = 50 years) chronic alcoholics. A battery of neuropsychological tests was administered to 25 long-term abstinent (21.2 months) alcoholics, 25 short-term abstinent (1.6 months) alcoholics, and 25 non-alcoholic control subjects. While there was a tendency for LTA alcoholics to perform better than STA alcoholics on digit-symbol substitution tests, there was no evidence of recovery on short-term memory or paired-associate learning: both groups of alcoholics were equally impaired, compared to control subjects. This suggests that the typical alcoholic manifests subtle neuropsychological deficits despite 1–2 years of sobriety.     

Exploration of exercise intolerance by 31P NMR spectroscopy of calf muscles coupled with MRI and ergometry

One hundred patients presenting with exercise intolerance or rhabdomyolysis episodes have been examined successively by 31P Nuclear Magnetic Resonance Spectroscopy (MRS) of leg plantar flexor muscles with exercise test. In all cases a muscle biopsy was performed. At the end of investigations, diagnosis of a metabolic myopathy was made in 33 patients: glycogenolysis or glycolysis deficiency in 8 cases, mitochondrial myopathy in 24 cases and CPT II deficiency in one case. Muscular dystrophy or congenital myopathy were diagnosed in 6 cases. No precise etiology could be found in 30 patients with either high CK levels or muscle biopsy abnormalities. Seven patients had rhabdomyolysis related to excessive physical activities. Twenty-four patients had functional symptoms. The principal MRS parameters used for diagnosis were the values of intracellular pH at the end of exercise and the time constant of phosphocreatine resynthesis during recovery. Lack of acidosis after exercise was observed in all patients with blockade of glycogenolysis or glycolysis. A slowing in phosphocreatine resynthesis was found in 66 p.cent of patients with definite mitochondrial myopathy. The specificity of these parameters were respectively 92.4 p.cent and 85.5 p.cent for the two groups. In conclusion (31)P MRS allows the detection of muscular glycogenoses with a sensitivity close to 100 p.cent. However, its sensitivity was lower for the detection of mitochondrial myopathies, as is also known for the other in vivo metabolic investigations, reflecting the heterogeneity of expression of mitochondrial abnormalities in a given muscle. The integration of imaging in the examination protocol may help to orientate towards the diagnostic of a dystrophy in some patients.     

Short REM latency in primary alcoholic patients with secondary depression

Primary alcoholic patients with secondary depression had significantly shorter REM latency and less non-REM sleep than alcoholics without other psychiatric diagnoses and normal control subjects. Both patient groups had significantly longer sleep latency and less sleep efficiency, total sleep time, and delta sleep than control subjects.     

An unusual metabolic myopathy: a malate-aspartate shuttle defect

Studies on a 27-year-old man with a 3-year history of exercise-induced muscle pain, passage of red urine and elevated serum creatine kinase are described. Histological examination of a biopsy from quadriceps revealed non-specific myopathic changes with occasional clusters of subsarcolemmal mitochondria. The phosphorylase stain was normal. Phosphorous nuclear magnetic resonance (NMR) spectroscopy studies of gastrocnemius and flexor digitorum superficialis muscles showed no abnormalities at rest. During aerobic exercise there was an abnormally rapid decrease in phosphocreatine concentration but the pH remained within the normal range. There was a build-up of phosphomonoester (probably glucose 6-phosphate), usually indicative of a block in glycolysis. However, a primary defect in the glycolytic pathway seemed unlikely because muscle acidified normally during ischaemic exercise. Recovery from exercise was unusual in that phosphocreatine resynthesis and inorganic phosphate disappearance followed similar prolonged time courses (in control subjects the rate of inorganic phosphate disappearance was about twice as fast as the rate of phosphocreatine resynthesis). The transport of inorganic phosphate into the mitochondria appeared to be delayed. These slow recovery data suggested that oxidative metabolism was impaired. However, with all substrates tested, isolated muscle mitochondria had rates of oxygen uptake that were similar to control values, thereby ruling out a primary defect in mitochondrial respiration. A system involving several mitochondrial transport systems, the malate-aspartate shuttle, was measured. The activity in the patient's isolated mitochondria was less than 20% of the activity present in samples from control subjects. This patient is the only one so far reported with a defect involving the malate-aspartate shuttle system.     

Platelet monoamine oxidase in alcoholism

We studied platelet monamine oxidase (MAO) activity using 14C-tyramine as substrate in hospitalized alcoholic patients in the early phases of abstinence and in nonhospitalized normal control volunteers. Platelet MAO was determined in 75 patients (67 men, 8 women) with alcoholism and 123 normal control volunteers (52 men, 71 women). The platelet MAO activity in alcoholic patients was significantly lower than in normal control volunteers. We also observed that the mean platelet MAO activity in male alcoholics was significantly lower than in normal males. The analysis of platelet MAO in alcoholics revealed a mixture of two normal distributions. Alcoholic patients falling into the low MAO component were younger in age, with a lower age of onset of alcoholism, and had higher frequencies of family history of alcoholism. They thus resembled type II alcoholics described by other investigators. Platelet MAO may thus serve as a useful biological marker for subtyping alcoholism and identifying high-risk groups at an early stage. The findings of this study are consistent with previous reports of low platelet MAO activity in alcoholic patients.     

A volumetric MRI study of the hippocampus in type 1 and 2 alcoholism

In recent years, magnetic resonance imaging (MRI) of the hippocampus has been extensively studied on neurological and psychiatric disorders. Particularly in studies on schizophrenia and mood disorders, findings regarding the hippocampal involvement have been most controversial. Previously, minor volume loss of the hippocampus in alcoholism, a major comorbidity alongside psychiatric disorders, has been reported but no data exist on the hippocampal volumes in subtypes of alcoholism. In this study, MRI was used to measure volumes of the hippocampus in late-onset type 1 alcoholics and early-onset type 2 alcoholics. The type 2 alcoholic subjects were also violent offenders with antisocial personality disorder, derived from a forensic psychiatric sample. All were non-psychotic and legally competent. Normal volunteers, representing a wide age range, served as a controls group. Compared to the controls, the right, but not left, hippocampi were significantly smaller in both alcoholic groups. While there was no correlation between the hippocampal volumes with age in the control subjects, there was tendency towards decreased volumes with aging and also with the duration of alcoholism in the type 1 alcoholic subjects. Surprisingly, there was a significant positive correlation between the right hippocampal volume and age in the type 2 alcoholics. This study provides further in vivo evidence that type 1 alcoholism, in general, is associated with a minor loss in hippocampal volume. It is suggested that type 2 alcoholism, in general, similarly displays a minor decrease in hippocampal volume, but this decrease is unevenly distributed within the type 2 category, being weighted towards the younger subjects. These effects suggest differences between the two alcoholic groups, and raise the possibility that the observed effects within the type 2 category are due to other factors than the cumulative acquired effects related to alcohol abuse, such as primary personality psychopathology.     

Alteration of regional cerebral glucose metabolic rate in non-Korsakoff chronic alcoholism

That chronic alcoholism yields devastating effects to the central nervous systems of its victims is well known, but the actual physiologic mechanisms underlying that deterioration have yet to be completely identified. What is also known is that many chronic alcoholics seem to recover brain function after a protracted period of abstinence, but the actual mechanisms of that restoration are also not well understood. Using positron emission tomography with the tracer 11C-2-deoxy-D-glucose as a probe to measure regional cerebral metabolic rate of glucose (RCMRGlu), we compared the magnitudes of glucose consumption in 44 brain regions between a group of newly abstinent chronic alcoholics without Korsakoff's psychosis and a control group of normal nonalcoholic subjects whose range of age was that of the alcoholic group. We found that RCMRGlu measurements in the brains of alcoholics were significantly lower than in the brains of the control group, and that there were many fewer significant interregional correlations in the brains of the alcoholics than in the brains of the control group. We also found no significant correlation between age and global metabolic rate of glucose in either group. However, even though the number of alcoholic subjects was too few to allow a reliable statistical comparison, the measurements suggest that chronic alcoholics over the age of 50 years suffer a greater decrease of RCMRGlu values than do their counterparts under the age of 50 years. While resting in a bland environment, neither alcoholic nor control subjects were found to have significant differences in RCMRGlu values between their brain hemispheres. In contrast to this similarity, normal dextrous subjects responded to a nonverbal auditory stimulus by increasing the metabolic rate of glucose in their right hemispheres while eight of nine chronic alcoholics did not. The results of this pilot study point to arguments that the alcoholic brain metabolizes glucose at a lower rate than do normal brains, that there are fewer region-to-region functional relationships in the alcoholic brain than in the normal brain, and that alcoholics may be impaired in right hemispheric processing. In subsequent investigations, we will measure the metabolic changes that follow abstinence, if any, by tracking subjects throughout an interval of rehabilitation. Also, we intend to test the findings of this study by measuring greater numbers of alcoholic subjects to separate the consequences of measurement variability, age, and chance from the underlying biologic processes that seem to be affected by chronic alcoholism.     

The alcoholic's self-image: a comparative study between men and women

Self-image is a central problem in alcoholism. Most theories about the relationships between the self-image of alcoholics and their behaviour have been derived from -clinical observations rather than empirical research. Most observations have pointed out that alcoholics are prone to underevaluation of themselves and that low self-image is the basis of much of the problem drinker's behaviour. All the research on self-image has concluded that alcoholics have a lower self-image than non-alcoholics. Some empirical research has been conducted on the self-image of alcoholics; it has, however, been carried out only a few times, restricted to small samples, and concerned with a limited number of aspects of self-image. Moreover, most of these studies are not recent, and it seems that this area of research is not well covered. Even though the hypothesis of a bad self-image in alcoholics was validated by various older studies, the representation of alcoholism has since changed. Because of this evolution, the ways in which the disease has been viewed have changed. One can question to what extent changes in society can influence the self-image of alcoholics. This question seems all the more pertinent for alcoholic women, given the evolution of the female condition since the Seventies. The objectives of this study are to evaluate the self-image of alcoholics and non-alcoholics, and to compare the self-image of male and female alcoholics. Our hypotheses are that: 1) the self-image of an alcoholic is more negative than that of a non-alcoholic, and that: 2) female alcoholics have a more negative self-image than male alcoholics. Two groups of 30 subjects each were made up: a group of alcoholics recruited in an alcohol-dependency unit and a group of non-alcoholics recruited in a public place. The comparison of socio-demographic data between the alcoholic group and the control group does not show a significant difference except for age and level of schooling. The average age of the control group is younger than that of the alcoholic group. The level of schooling of the control group is higher than that of the alcoholic group. These differences can be explained by the mode of recruitment of the participants. The significant differences between the alcoholic men and women are at the level of the number of Years of alcoholism, the age at which the disorder began and the number of detoxification episodes. These differences are probably due to cultural background. Indeed, the age at which alcoholism begins is later in women and they consult more quickly than men. The two groups were assessed using the Tennessee Self Concept Scale and the Self Esteem Inventory. Other tests were used to control factors capable of influencing self-image (depression, socio-demographic data). The results show that the alcoholics have a more negative self-image than the control group. The alcoholics perceived themselves significantly less favourably on the identity (what I am), self-satisfaction (how I feel about myself), and behaviour (what I do) scores than did those in the control group. The alcoholics also saw themselves in a significantly more negative light than did those in the control group on the scores relating to physical self (body, health.), moral-ethical self (moral worth), personal self (evaluation of personality), family self (adequacy and value as a family member) and social self (adequacy and worth in interaction with others). The self-criticism subscale provided further evidence that the alcoholics were more open and self-critical than were those in the control group. Female alcoholics had a lower self-image than male alcoholics, but not in every aspect. There was a significant difference between the scores of alcoholic women and alcoholic men, for three of the subscales measured by the Tennessee Self Concept Scale: "general self-image", "personal self" and "self-criticism". The alcoholic women perceived themselves more negatively when it came to "self-satisfaction", "personal self" and "social self". They were however more positive than the men in the sectors of "identity", "behaviour", "physical self", "moral-ethical self", and "family self". The alcoholic men were more openly self-critical than the alcoholic women. Our results confirm the conclusions of empirical studies and of clinical observations. Alcoholics see themselves as generally inadequate and unworthy of respect. The changes in representations of this disease seem to have influenced the alcoholic's self-image, but it remains however very negative. The alcoholics'negative self-image is generalised and not specific to personality and behaviour. The -representation of alcoholism seems to have contributed to an improvement in the self-esteem and self-image of alcoholics, and in particular of female alcoholics. Even if the self-image of alcoholic women remains more negative than that of alcoholic men, it tends to bring back the self-image of alcoholic women to a level close to that of the men.     

Breakdown of adenine nucleotide pool in fatiguing skeletal muscle in McArdle's disease: a noninvasive 31P-MRS and EMG study

Energy metabolism and electrical muscle activity were studied in the calf muscles of 19 patients with proven McArdle's disease and in 25 healthy subjects. Phosphorus magnetic resonance spectroscopy and surface electromyography (S-EMG) were performed during two isometric muscle contractions of 3 min at 30% maximum voluntary contraction, one performed during normal perfusion and the other during applied ischemia. After about 1 min of ischemic muscle contraction in diseased muscle a significant acceleration in phosphocreatine breakdown was observed, along with a significant decrease in adenosine triphosphate. During both contractions the absence of glycolysis was shown by a significant alkalinization. Furthermore, in patients we observed a greater increase in the S-EMG amplitude than in control subjects. We conclude that early on during moderate exercise, a small number of muscle fibers reach metabolic depletion, indicated by a reduction in the adenine nucleotide pool. An increasing number of motor units, which are still in a high-energy state, are continuously recruited to compensate for muscle fatigue. This functional compartmentation may contribute to the pathophysiology of exercise intolerance in McArdle's disease.     

Craving for alcohol and dopamine receptor sensitivity in alcohol-dependent men and control subjects

Summary. Detoxified alcohol-dependent men and control subjects were repetitively exposed by sight and smell to either a neutral cue (tea) or an alcohol-related cue (their favourite alcoholic beverage) to provoke a maximum craving response. Additionally, their dopamine receptor sensitivity was evaluated by measuring growth hormone (HGH) response to stimulation with the dopamine receptor agonist apomorphine (APO). It was hypothesized that the subjects' desire to drink (craving) is related to their dopaminergic activity. In both groups, craving increased in the presence of the alcohol stimulus with significantly higher craving scores in alcoholics than in controls. However, in none of the groups and at no cue exposure did the craving response correlate with the individuals' dopaminergic activity as reflected by HGH release. Therefore, this study cannot add support to the hypothesis that craving for alcohol is associated with dopamine receptor sensitivity in abstinent alcoholics or healthy control subjects. Received June 16, 1999; accepted January 4, 2000     

Evidence of an abnormal intramuscular component of fatigue in multiple sclerosis

The goals of this study were to investigate muscle fatigue in patients with multiple sclerosis (MS), and to determine the relationships between muscle fatigue, clinical status, and perceived fatigue. The fatigability of the anterior tibial muscle was quantitated in patients and controls during 9 min of intermittent stimulation (used to eliminate central sources of muscle fatigue). During exercise, the decline in tetanic force, phosphocreatine, and intracellular pH was greater in patients than in controls. The compound muscle action potential amplitude did not decrease during exercise, indicating that there was no failure of neuromuscular transmission during fatigue. Thus, the excessive fatigue in MS developed from sources beyond the muscle membrane. Following exercise, the recovery of tetanic force was delayed in patients (a pattern that suggests abnormal excitation–contraction coupling), whereas the recovery of metabolites was complete in both groups. Muscular fatigue was correlated with clinical disability but not with perceived fatigue. These results suggests that fatigue in MS has both central (perception, upper motor neuron dysfunction) and peripheral (impaired metabolism and excitation–contraction coupling) components.© 1995 John Wiley &Sons, Inc.     

CSF gamma-aminobutyric acid in alcoholics and control subjects

Alcohol has widespread effects on the gamma-aminobutyric acid (GABA) system in the brain. This system in the brain is also postulated to have a role in anxiety, and alcoholics have been reported to have more anxiety disorders. Therefore, the authors undertook a study to compare CSF levels of GABA in abstinent alcoholic patients and normal control subjects. There was no significant difference between groups in CSF levels of GABA. Also, there was no significant difference in GABA level between alcoholic patients with histories of withdrawal seizures and those without such a history.     

Self-help groups reduce mortality risk: a 5-year follow-up study of alcoholics in the Tokyo metropolitan area

The present study aimed to determine whether alcoholics who attend self-help groups experience fewer deaths than those who do not. Subjects were patients from the Alcoholism Treatment Program (ATP) of Matsuzawa hospital. A cohort of alcoholic patients recruited into a prospective study was followed from April 1994 to March 1999. A total of 469 alcoholic patients met the International Classification of Diseases (10th edition) criteria for alcohol dependency. Of these, 94 patients refused to participate in the study, leaving a total of 375 participants. After discharge from the ATP and a complete explanation of the present study, subjects decided whether to attend a self-help group (SHG) or not. The SHG comprised 208 subjects, and the non-self-help group (NSHG) comprised 167 subjects. Outcomes were evaluated with regard to death during follow-up for a mean of 2.4 years. Death was ascertained through the records of the Setagaya Department of Health and Welfare center, Matsuzawa hospital and other hospitals, and through personal contact with informants, relatives, and significant others of subjects. Deaths were confirmed for 47 NSHG subjects and only five SHG subjects. NSHG displayed a significantly decreased cumulative survival compared with SHG (P < 0.0001). Cox proportion hazard analysis was used to examine variables that may help to predict mortality among alcoholics. Alcoholics who attended self-help groups differed from those who did not, with regard to mortality experience. Attending a self-help group represented the most important predictor of prognosis for alcoholics.     

Locus of control and drinking behavior in American Indian alcoholics and non-alcoholics

Many investigators have attempted to determine whether alcoholics differ from non-alcoholics in their perceived locus of control. The present study examined the responses of alcoholic and non-alcoholic American Indian males and females on Levenson's Multidimensional Locus of Control Scale. Subjects were 80 American Indian males and 40 American Indian females. All subjects were members of either an eastern (Cherokee) or western (Cheyenne) Oklahoma tribe. Results indicate no significant differences between the Cherokee male alcoholic and non-alcoholic group. Cheyenne male alcoholics reported significantly lower internal control scores than did Cheyenne male non-alcoholics. Within the female sample, alcohol use and tribal membership showed a significant interaction with locus of control. These findings suggest that locus of control may be a potentially useful clinical construct in the development of treatment plans and therapeutic issues for American Indian patients who are alcoholics.     

Brain stem auditory evoked responses in chronic alcoholics.

Brain stem auditory evoked responses (BAERs) were performed on 25 alcoholic patients with Wernicke-Korsakoff syndrome, 56 alcoholic patients without Wernicke-Korsakoff syndrome, 24 of whom had cerebellar ataxia, and 37 control subjects. Abnormal BAERs were found in 48% of patients with Wernicke-Korsakoff syndrome, in 25% of alcoholic patients without Wernicke-Korsakoff syndrome but with cerebellar ataxia, and in 13% of alcoholic patients without Wernicke-Korsakoff syndrome or ataxia. The mean value of the I-V interval was prolonged in all patient groups. There were more patients with prolonged I-V and I-III intervals in the Wernicke-Korsakoff syndrome group than in the group without the syndrome. The I-III interval was prolonged in 32% of those with Wernicke-Korsakoff syndrome but in only 6% of alcoholics without the syndrome. These abnormalities improved following thiamine treatment and abstinence from alcohol. The presence of prolonged I-III interval in an alcoholic should raise the possibility of Wernicke's encephalopathy.     

Effects of exercise on muscle activation and metabolism in multiple sclerosis

We investigated the role of metabolism in muscle fatigue during voluntary exercise in persons with mild multiple sclerosis (MS). Six MS and 8 healthy control subjects performed intermittent, progressive, isometric contractions of the ankle dorsiflexors, during which we measured maximum voluntary force (MVC), inorganic phosphate (Pi), phosphocreatine (PCr), and pH. During exercise. MVC fell sooner in MS, but by the end of exercise the relative decrease in MVC was similar in both groups. In contrast, at the end of exercise Pi/PCr increased to 1.86 ± 0.22 in controls but to only 0.66 ± 0.04 in MS (P < 0.01); likewise, pH was 6.75±0.04 in controls and unchanged (7.06 ± 0.04) in MS (P <0.01). The smaller metabolic change at the same relative exercise intensity suggests a failure of muscle activation that is present even in mild MS. Neurophsyiologic measures of activation indicated some central activation failure and no neuromuscular junction impairment in MS, and suggested that activation failure beyond the muscle membrane(excitation–contraction coupling) may be important in MS. We conclude that metabolic factors do not play a significant role in the development of muscle fatigue during voluntary exercise in mild MS. © 1994 John Wiley & Sons, Inc.     

Postexercise phosphocreatine resynthesis is slowed in multiple sclerosis

To determine whether skeletal muscle oxidative metabolism is impaired in multiple sclerosis (MS), ³¹ phosphorus magnetic resonance spectroscopy was used to measure the rate of intramuscular phosphocreatine (PCr) resynthesis following exercise in MS and controls. Thirteen MS patients underwent intermittent isometric tetanic contractions of the dorsiflexor muscles elicited by stimulation of the peroneal nerve. Eight healthy control subjects performed voluntary isometric exercise of the same muscles. During exercise, there were no differences between groups in the fall of either PCr or pH. However, the half-time (T-_1/2) of PCr recovery following exercise was significantly longer in MS (2.3 ± 0.3 min) compared to controls (1.2 ± 0.1 min, P < 0.02). These data provide evidence of slowed PCr resynthesis following exercise in MS, which indicates impaired oxidative capacity in the skeletal muscle of this group. This finding suggests that intramuscular changes consistent with deconditioning may be important in the altered muscle function of persons with MS. © 1994 John Wiley & Sons, Inc.     

Somatosensory evoked potentials in chronic alcoholics with spasticity

Somatosensory evoked potentials to median and bilateral tibial nerve stimulation were investigated in eight chronic alcoholics with spasticity, 12 patients with alcoholic polyneuropathy, and 11 normal subjects. Central conduction velocities from the third lumbar vertebra to the fifth cervical vertebra and from the 12th thoracic vertebra to the fifth cervical vertebra were significantly lower in the chronic alcoholics with spasticity than in the alcoholic polyneuropathy group and in the healthy nonalcoholic group. The result indicates that chronic alcoholics with spasticity have conduction disturbance in the posterior column and/or the medial lemniscus, which is considered to be due to alcoholic myelopathy and/or a brainstem lesion.