[Fatal ecstasy intoxication in a 22-year-old man]. / Ecstasy-intoxicatie met fatale afloop bij een 22-jarige man.

A 22-year-old man was admitted to the hospital with an ecstasy (MDMA) intoxication which was accompanied by hyperthermia. The patient developed rhabdomyolysis with hyperkalaemia, hypoglycaemia and acidosis, followed by multiple organ failure with disseminated intravascular coagulation and cerebral oedema. Despite maximal symptomatic treatment, the patient died after 4 days. MDMA is a serotonin agonist but also has noradrenergic and dopaminergic effects. It is a popular drug in the Netherlands among young people and is often wrongly considered to be safe. The occurrence of serious side effects is unpredictable and can have fatal consequences. Especially hyperthermia as a side effect of MDMA is a potentially life-threatening complication. The treatment is mainly symptomatic and consists of cooling, fluids, treatment of electrolyte disturbances, and support for respiration and circulation. The usefulness of dantrolene in the treatment of MDMA-induced hyperthermia is controversial, but for now it is still recommended.

Status epilepticus caused by a myxoedema coma.

The case of a 63-year-old woman who presented with status epilepticus, coma and hypoventilation is reported. A primary neurological cause was considered. Hypothermia led to further investigations and a diagnosis of severe hypothyroidism. The neurological complications of hyperthyriodism include alteration in mental status with slowness, decreased concentration and lethargy, headache, cranial nerve palsies, dysarthria, hoarseness, myopathy, neuropathy, reflex changes, ataxia, and psychotic episodes. Our patient suffered from a rare consequence of severe hypothyroidism presenting with status epilepticus and she died despite treatment. To our knowledge this is the second patient to be reported with myxoedema coma with this kind of presentation. Despite therapeutic options, there is a high mortality rate.

Temporary occlusion of middle cerebral artery by macroembolism in carotid surgery.

Two patients are presented who during carotid endarterectomy (CEA) temporarily showed an obstruction of the middle cerebral artery (MCA) mainstem by a macroembolus resulting in cerebral ischaemia. Both cases are unusual examples of CEA and selected from a cohort of more than 1,500 operations. During surgery with general anaesthesia, brain function was monitored with computerized electroencephalography (EEG) and transcranial Doppler (TCD) ultrasonography. The simultaneous use of EEG and TCD monitoring allowed us to witness the development of intraoperative cerebral ischaemia and to relate these events to a temporary occlusion of the MCA mainstem by a macroembolus. This is the first life report that describes obstruction of a cerebral artery by arterial embolism resulting in cerebral ischaemia.

Amyotrophic lateral sclerosis: mortality risk during the course of the disease and prognostic factors. The Netherlands ALS Consortium.

We performed a historical cohort study of 307 untreated patients with probable or definite amyotrophic lateral sclerosis in order to investigate whether the mortality risk changed during the disease course and to identify prognostic factors at diagnosis. Patients were diagnosed in one of the academic hospitals in The Netherlands and followed-up for at least 6 years after diagnosis. The median survival from diagnosis was 1.4 years (95% confidence interval, 1.3-1.6 years) with an estimated 5- and 10-year survival of 20 and 8%, respectively. Mortality was at its maximum in the second year after diagnosis and declined considerably thereafter. Observed mortality approached the expected mortality in patients who survived diagnosis 6 or more years. In univariate and multivariate analyses, young age, limb onset, and a long delay between initial weakness and diagnosis were associated with lower mortality. The better prognosis of limb-onset patients was not observed in females. Patients with initial respiratory muscle weakness, had the worst prognosis with a median survival of only 2 months. The significantly greater mortality of older patients proved not to result from a rise in expected mortality only. In conclusion, the annual mortality risk in ALS does not remain constant throughout the disease and depends on age at diagnosis, site of onset, diagnostic delay, but also on the time since diagnosis. These findings may have consequences for the planning of symptomatic care and the design and analysis of therapeutic trials.

Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants.

Between 1983 and 1988 we treated 36 patients with sporadic amyotrophic lateral sclerosis (ALS) by an array of antioxidants and added other drugs to the regimen whenever a patient reported deterioration. Our customary prescription sequence was N-acetylcysteine (NAC); vitamins C and E; N-acetylmethionine (NAM); and dithiothreitol (DTT) or its isomer dithioerythritol (DTE). Patients with a history of heavy exposure to metal were also given meso 2,3-dimercaptosuccinic acid (DMSA). NAC, NAM, DTT, and DTE were administered by subcutaneous injection or by mouth or by both routes, the other vitamins and DMSA by mouth alone. The hospital pharmacy supplied NAC and NAM injections fluid as 100 ml bottles of 5.0 and 5.85% solutions, respectively. DTT was delivered in special double-walled capsules of 200 mg. DTT/DTE injection fluid was added to the NAC and NAM bottles, the final DTT/DTE concentrations never exceeding 0.5%. DMSA was provided in 250 mg capsules. All of the 36 patients used NAC and DTT/DTE; 29 also used vitamins C and E; 21 also used NAM; and 7 also used DMSA, DMSA, NAM, vitamins C and E were tolerated well. In many patients, DTT, DTE, NAC and NAM induced pain, redness and swelling at the injection sites in that order of decreasing frequency. DTT and DTE did often and NAC did sometimes cause gastric pain, nausea and other abdominal discomfort. Comparison of survival in the treated group and in a cohort of untreated historical controls, disclosed a median survival of 3.4 years (95% confidence interval: 3.0-4.2) in the treated and of 2.8 (95% confidence interval 2.2-3.1) years in the control patients. This difference may be explained by self-selection of our highly motivated treated group and by its initial survival of diagnosis for an average of 8.5 months before onset of treatment. We conclude that antioxidants neither seem to harm ALS patients, nor do they seem to prolong survival.

Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis.

BACKGROUND: Free radicals may play a role in the pathogenesis of amyotrophic lateral sclerosis. OBJECTIVE: To investigate the efficacy of the free radical scavenging agent acetylcysteine in patients with amyotrophic lateral sclerosis. DESIGN: Randomized, double-blind, placebo-controlled clinical trial to assess the effect of treatment with acetylcysteine on survival and disease progression. SETTING: A university hospital referral setting. PATIENTS: One hundred ten consecutive patients who fulfilled the diagnostic criteria for amyotrophic lateral sclerosis, followed up at monthly intervals for 12 months. INTERVENTION: Acetylcysteine or placebo in a dose of 50 mg/kg per day subcutaneously for 12 months. MAIN OUTCOME MEASURE: Survival. RESULTS: After 12 months, 35 patients (65%) treated with acetylcysteine and 30 (54%) given placebo were still alive (hazard ratio, 0.74 in the acetylcysteine group relative to the placebo group; 95% confidence interval, 0.41 to 1.33; log-rank test, P = .31). Rates of disease progression, as expressed by decline in muscle strength, pulmonary function, disability, and bulbar function were similar in both groups. In the subgroup of 81 patients with limb onset of the disease, 28 patients (74%) in the acetylcysteine group and 22 (51%) in the placebo group survived 12 months (hazard ratio, 0.50; 95% confidence interval, 0.24 to 1.04; P = .06). In the bulbar subgroup of 29 patients, seven patients (44%) receiving acetylcysteine and eight (62%) receiving placebo were alive at the end of the study (hazard ratio, 1.66; 95% confidence interval, 0.56 to 4.99; P = .36). CONCLUSION: In this trial, treatment with the free radical scavenger acetylcysteine did not result in a major increase in 12-month survival or a reduction in disease progression in patients with amyotrophic lateral sclerosis.

Differential diagnosis in spinal and bulbar muscular atrophy clinical and molecular aspects.

Kennedy disease is caused by an enlarged trinucleotide repeat sequence within the androgen receptor gene. We report here seven male patients with a benign motor neuron syndrome highly analogous to Kennedy disease but with a normal trinucleotide repeat.

Urinary excretion of lead and mercury after oral administration of meso-2,3-dimercaptosuccinic acid in patients with motor neurone disease.

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are progressive neurodegenerative disorders involving motor neurones. The aetiology of the non-familiar forms is still unknown but it has been suggested that long-term exposure to heavy metals such as lead and mercury may play a role in the pathogenesis of these diseases. In 53 patients suffering from ALS (n = 42) and SMA (n = 9) the oral administration of dimercaptosuccinic acid (DMSA, 20 mg/kg) did not result in a greater mobilization of lead and mercury from peripheral depots than in control subjects. Although it cannot be excluded that the amount of lead or mercury excreted after DMSA administration may not be a reflection of the amount accumulated in the motor neurons, this study does not provide support for the hypothesis that heavy metals play a significant role in the occurrence of motor neurone diseases.

Temporal lobe pathology in amyotrophic lateral sclerosis. Do amyotrophic lateral sclerosis and Alzheimer's disease share a common etiological factor?

An autopsy study was performed on temporal lobe samples from 20 non-demented patients with amyotrophic lateral sclerosis (ALS), 17 age-matched non-demented controls and 4 Alzheimer's disease (AD) patients. Formalin fixed, paraffin embedded sections from the hippocampus with adjacent parahippocampal gyrus and from the superior temporal gyrus were stained with conventional and immunohistochemical stains. Immunohistochemical staining for the A4 protein was enhanced by pretreatment with 0.25% pepsin before 100% formic acid. The incidence and severity of AD-like pathological changes were similar in ALS patients and non-demented controls. In both groups, pathological changes increased with age. This study does not support the hypothesis that ALS and AD share an etiopathogenetic background.

Inflammatory cells in the peripheral nervous system in motor neuron disease.

We examined post-mortem material of the peripheral nervous system of 26 cases of motor neuron disease (MND) for the presence of lymphocyte subsets and macrophages. Findings were quantified and compared with those in control nerves. Lymphocytes in chronic and acute axonal degeneration were studied in sural nerve biopsy and animal material. Signs of demyelination were studied in MND and controls with infiltrates of T cells. A few T lymphocytes were scattered diffusely within the fascicles. The numbers did not differ between MND and controls. About half of the T cells was positive for CD45RA, the other half being positive for CD45RO. T cells were negative for CD25, CD54 and major histocompatibility complex (MHC)-class II. There were hardly any B lymphocytes. The numbers of lymphocytes in nerves with and without axonal degeneration did not differ. Increased MHC class II expression was present on denervated Schwann cells and macrophages in MND and in sural nerves with axonal degeneration. Macrophages were increased in number and in size, both in MND and in control material with axonal degeneration. No signs of demyelination were present either in MND or in controls. It is concluded that a T cell-mediated process in peripheral nerves in MND is very unlikely.

Increased metallothionein in the liver and kidney of patients with amyotrophic lateral sclerosis.

To evaluate the putative role of metals and trace elements in the pathogenesis of classic amyotrophic lateral sclerosis, we studied the metallothionein levels in liver and kidney samples obtained at autopsy from 24 patients with amyotrophic lateral sclerosis and 18 controls. To assay metallothioneins and copper, cadmium, and zinc bound to metallothioneins, we used high-performance liquid chromatography directly coupled to flame atomic absorption spectrometry. Total cadmium, zinc, and copper concentrations were determined separately with the use of graphite furnace atomic absorption spectrometry with Zeeman background correction. The median liver metallothionein level was 60.3 mg/kg (range, 9 to 318 mg/kg) in the patients with amyotrophic lateral sclerosis and 12.6 mg/kg (range, 0 to 104.5 mg/kg) in the controls. In the kidney, median metallothionein levels were 126.9 mg/kg (range, 44 to 387 mg/kg) in the patients with amyotrophic lateral sclerosis and 64 mg/kg (range, 13.1 to 187 mg/kg) in the controls. Total zinc, cadmium, and copper concentrations, as measured by atomic absorption spectrometry, were not significantly different in patients vs controls. Our finding of elevated metallothionein levels in organs from patients with amyotrophic lateral sclerosis may indicate an increased exposure to metals.

Immunohistological alterations in muscle of patients with amyotrophic lateral sclerosis: mononuclear cell phenotypes and expression of MHC products.

Muscle biopsy specimens from 15 autopsied patients with the isolated form of amyotrophic lateral sclerosis were examined by routine histological and immunocytochemical methods using a panel of monoclonal antibodies directed against differentiation and activation markers of immunocompetent cells. In 12 cases, cellular infiltrates consisting mainly of T-cells and macrophages were seen. Both CD8+ and CD3+ cells, in juxtaposition with OKM1+ macrophages, were particularly seen in the atrophied parts of muscle. The majority of the T-cells appeared to be of the CD4+ T-helper/inducer type, whereas the CD8+ T-suppressor/cytotoxic cells were only rarely and focally present. On the other hand, B-, NK- and K-cells were infrequently seen. Most of the T-cells and macrophages surrounding the atrophied muscle fibers were in an activated state, as indicated by their intense HLA DR expression. In addition, some angulated degenerated fibers showed strong endomysial positivity for HLA DR in the regions where T-cells and macrophages were present in clusters. The immunoreactive changes in ALS-associated muscle atrophy are very similar to those reported for exercise-induced damage and some forms of myositis. The present study shows that the expression of major histocompatibility complex products and the relative numbers of infiltrating immunocompetent cells are closely associated with the extent of destruction of muscle fibers in ALS.

Circadian and circatrigintan rhythms of biogenic amines in premenstrual syndrome (PMS).

Circadian and circatrigintan (menstrual) rhythms in biogenic amines were studied in premenstrual syndrome (PMS). Selection of patients and controls was based on assessment of Menstrual Distress Questionnaires (MDQs). Patients showed a clear increase in menstral tension symptoms in the week before menstruation, both during selection and during the study. In the group of control subjects, there was hardly any increase in average MDQ symptoms during the late luteal phase. Diurnal urine and nocturnal urine were collected on days 5, 11, 17, 21, and 25 of the cycle. Blood was sampled from subjects in supine position through an intravenous (iv) catheter the morning after urine collection. Patients showed a higher tryptophan (Trp) and epinephrine (Epi) level in plasma, higher excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine and a larger volume of 24-hr urine. Excretion of norepinephrine (NE) in 24-hr urine showed a linear increase during the cycle, while excretion of dopamine (DA) showed a quadratic pattern, being lowest at day 17. Homovanillic acid (HVA) and MHPG gave cubic patterns, i.e., an increase during the follicular phase, followed by a decrease after ovulation and a subsequent increase in the late luteal phase. Plasma Epi showed a linear decline during the cycle in patients, but not in control subjects. Excretion of NE, Epi, vanilmandelic acid (VMA), and HVA in urine was higher during the day than at night. The results of this study suggest that the metabolism of biogenic amines in patients suffering from PMS differs from that in control subjects, but that, except for plasma Epi, changes do not parallel the actual presence of PMS symptoms.

Aberrant myelinated neurites in the anterior horns of a patient with amyotrophic lateral sclerosis.

A case of amyotrophic lateral sclerosis revealed the classical pathologic features of ALS, i.e. neuronal loss in the anterior horns and pyramidal tract degeneration. In addition to the pathological hallmarks of Alzheimer's disease, senile plaques, neurofibrillary tangles and granulovacuolar changes of neurons were also present. Clinically the 67-year-old patient exhibited ALS of the upper extremity and a mild forgetfulness. Two striking pathological features were noted in the spinal cord: first, at several levels in the spinal cord excessive amounts of myelinated neurites were found; second, the microglial proliferation in the anterior horns was very intense and positive for leukocyte common antigen.