A clinical trial of dextromethorphan in amyotrophic lateral sclerosis.

INTRODUCTION: Although the cause of amyotrophic lateral sclerosis (ALS) is unknown, excitotoxicity mediated by glutamate has been implicated. Dextromethorphan is a NMDA-glutamate receptor antagonist with neuroprotective properties. MATERIAL AND METHODS: The effect of treatment with dextromethorphan (150 mg daily) in ALS patients was evaluated in a randomized, double-blind, placebo-controlled study. Forty-five patients were included in the analysis. RESULTS: At the end of the treatment period, 12 months after randomization, 15 patients (65%) in the placebo group and 12 patients (55 %) in the dextromethorphan group were still alive (log rank test, P=0.49). Rates of disease progression, as expressed by rates of decline in pulmonary function and in functional disability, were similar in both groups except for a significantly less pronounced rate of decline in the ability scores for the lower extremities in the dextromethorphan group. CONCLUSION: Treatment with a relatively low dose of dextromethorphan did not result in an improvement in 12-month survival in ALS.

Serum cobalamin and methylmalonic acid in Alzheimer dementia.

The cobalamin status was evaluated in Alzheimer dementia (n = 26), other dementias (n = 24), various gerontopsychiatric disorders (n = 25), and in neuro-psychiatrically healthy controls (n = 20). Supplementing serum cobalamin we measured methylmalonic acid (MMA), a metabolite accumulating early in cobalamin deficiency. Subnormal cobalamin and/or clearly elevated MMA concentrations were found in 11 cases: 7 Alzheimer patients (27%), 2 with other dementias (8%), one psychiatric patient (4%), and one control (5%). None presented the typical neurologic features of cobalamin deficiency and macrocytosis was found in only one. The mean cobalamin concentration was significantly lower in Alzheimer patients (179 +/- 18 pmol/l) than in the age-matched controls (256 +/- 23 pmol/l) (p = 0.013) and the other patient groups. Correspondingly, the mean MMA level was higher in the Alzheimer group (0.480 +/- 0.062 mumol/l) than in any other diagnostic group (controls: 0.347 +/- 0.040 mumol/l). Comparing the Alzheimer group to the other groups as a whole, the elevation was significant (p = 0.0097). Our findings indicate that Alzheimer patients are particularly prone to cobalamin deficiency, and even subtle biochemical signs of deficiency seem to justify treatment.

Methylmalonic acid concentrations in serum of normal subjects: biological variability and effect of oral L-isoleucine loads before and after intramuscular administration of cobalamin.

The clinical value of measuring concentrations of methylmalonic acid in serum (S-MMA) as an aid in the diagnosis of cobalamin deficiency has recently aroused interest. In 58 healthy subjects, ages 40-68 years, we found a 0.95 reference interval of 0.05-0.37 mumol/L (mean 0.21, SD 0.094). In 33 of the subjects, who were studied further, day-to-day variation (SD) was 0.031 mumol/L. Intake of food had no effect. Weekly and three-monthly intra-individual variations were both 0.038 mumol/L. In all seven subjects with S-MMA greater than 0.30 mumol/L, the concentrations declined significantly after intramuscular administration of cobalamin. No significant difference was found between mean serum cobalamin concentrations in these seven and in the remaining subjects. We have also established the normal response of S-MMA to standardized oral loading of L-isoleucine: 100 mmol caused a significant average S-MMA increase of 0.072 mumol/L before cobalamin administration vs 0.013 mumol/L after cobalamin, without significant relation to initial S-MMA values. Our results provide a necessary background for interpretation of S-MMA measurements in clinical studies.

[Neurotransmitters in Alzheimer's disease]. / Neurotransmittere ved Alzheimer-demens.

Alzheimer's disease is characterized by markedly reduced concentration of acetylcholine in hippocampus and neocortex, caused by degeneration of cholinergic neurons. Acetylcholine is essential in learning and memory. However, despite correlation between cholinergic defect and intellectual impairment in Alzheimer's disease, the effect of substitution therapy with cholinergics is very limited. Especially in younger Alzheimer patients, the degenerative process also affects other transmitter systems. Particularly the concentrations of serotonin, somatostatin and glutamate are significantly reduced. It is not elucidated how these transmitter defects contribute to symptomatology. The serotonin defect is thought to underlie the emotional and behavioural symptoms. The somatostatin defect is correlated to the reduced cerebral metabolism and thus might be a central phenomenon. The glutamate defect has been suggested to represent the neurochemical correlate to clinical dementia, because the activity in the hippocampal glutamatergic synapses is normally increased during learning. Therapeutically, the multiple transmitter defects imply that simple transmitter substitution can be expected to be of only limited value in Alzheimer's disease.

[Complaints following treatment of common acute eye diseases]. / Gener efter behandling af almindeligt forekommende akutte øjenlidelser.

The aim of the study was to determine the duration of symptoms in patients treated in the emergency room at Glostrup Hospital for acute eye-trouble. Nine common diagnoses were selected for the study. All patients seen during a 2 1/2 month period were asked to complete a questionnaire one week after the consultation. Those who did not return the questionnaire, and cases where the diagnosis was changed by a doctor in the days following the consultation, were excluded. The final material comprised 422 patients. 28% did not have any complaints after the consultation. 50% were free of symptoms within 24 hours and 75% within 48 hours. 10% had symptoms for more than a week. Cases of infectious conjunctivitis and trauma to the eye (without intrabulbar lesion) had the highest risk of developing symptoms after the consultation. The lowest incidence of complaints was seen among patients in whom a foreign body was removed from the cornea or conjunctiva. The longest duration of symptoms was seen among patients with infectious conjunctivitis. Cases with a foreign body on the cornea or conjunctiva or trauma to the eye (without intrabulbar lesion) had a slightly longer duration of the symptoms when a corneal tear was present. Patients with photoelectric conjunctivitis and conjunctivitis caused by chemical products had the shortest durations of symptoms. Patients with pain should be treated with analgesic tablets as the pain-relief after application of local anaesthetics was brief. Only half of those who had a prescription for chloramphenicol used this for as long as it had been recommended. Compliance was better to ointment than to eye-drops.

Progressive supranuclear palsy--20 years later.

Reviewing the literature since recognition of progressive supranuclear palsy (PSP) as a clinicopathological entity 20 years ago, the present state of knowledge is delineated. The etiology of PSP is still unknown. The clinical hallmarks are supranuclear palsy of vertical gaze, axial dystonia in extension and pseudobulbar palsy with marked dysarthria and dysphagia. Accessory features include subcortical dementia, mental, extrapyramidal, pyramidal and cerebellar symptoms. PSP is a disease of the presenium (average age at onset, 59.6 years) with a male preponderance (60% men). The onset is insidious with vague complaints of dysequilibrium (60%), mental changes (46%) and disturbed vision (21%), often preceding abnormal neurological findings. The important borderland and main differential diagnosis is parkinsonism. However, in PSP, responsiveness to antiparkinsonian agents is poor and progression is rapid and fatal within few years (average survival time, 5.7 years). Promising diagnostic tools at present include CT-scanning and neuro-otologic and -ophthalmologic examination. Neuropathological findings, confined to specific diencephalic, brainstem and cerebellar nuclei, include neurofibrillary tangles (ultrastructurally different from those seen in other CNS disorders), neuron loss and gliosis. The importance of research on neurocytochemistry, brain ultrastructure and immunology in the current investigation of PSP is outlined.