Rising mortality from motor neurone disease: an explanation.

There is considerable debate about the increasing mortality from motor neurone disease (MND). However, examination of the relationship between increased life expectancy (through decreased general mortality) and increased mortality in both England and Wales and the United States indicates a close association between the two variables. Using a statistical model, defined sub-populations susceptible to MND can be identified in both countries. The size of such a sub-population has been estimated from the 1989 mortality data to be approximately 160,000 people in England and Wales. The proportion of this sub-population dying from MND has increased over the last 30 years, rather than, as previously, dying at an earlier age from other conditions. On this basis, deaths from MND are expected to increase by a further 20% in this sub-population between 1991-2021 because of continuing changes in life expectancy. MND is a condition made increasingly visible in mortality statistics through decreased general mortality, rather than one in which the underlying population at risk has substantially changed. Aetiological extrapolations from the data indicate that susceptibility to the disease is acquired early in life, and that it is unlikely, given the relative stability of the underlying sub-population, that either changed environmental circumstances or artifactual factors can account in themselves for the rise in mortality.

Migraine and heredity.

Since the time of Liveing and Gowers in the nineteenth century, migraine has been thought to be inherited, although family history has been widely studied, nearly all the reports are not scientifically based and studies on twins have never shown 100% concordance in monozygotic (MZ) pairs, indicating that migraine cannot be inherited by a single gene. Furthermore, the criteria for a polygenic trait are not fulfilled by migraine patients. The only two syndromes with a strong genetic basis of inheritance are familial hemiplegic migraine and migraine occurring in Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes (MELAS). It is the predisposition to headache that is likely to be inherited; this is supported by the induction of migraine-like headaches with either m-chlorophenyl-piperazine (m-CPP) or nitroglycerin in normal subjects with a positive family history for migraine.

Some clinical comparisons between common and classical migraine: a questionnaire-based study.

In a questionnaire-based study we compared the clinical features of migraine with aura (classical migraine) and migraine without aura (common migraine) in 354 and 397 patients, respectively, attending The Princess Margaret Migraine Clinic. Other than those related to the aura, no significant differences were seen in any clinical features of the attack (e.g. frequency or duration of attacks, time of day at onset, location of headache at onset, severity of headache, or nausea and vomiting). Common migraine attacks were significantly more likely to occur at weekends (p = 0.002). Dietary triggers tended to be more troublesome in classical migraineurs while pregnancy and the menstrual cycle affected both migraine types equally. Classical migraine patients were twice as likely to have a history of hypertension (p less than 0.05) and showed a slightly but not significantly greater tendency to depression. Family histories of migraine were similar in each migraine type. We conclude that classical and common migraine are fundamentally similar in their clinical characteristics and that the occurrence of focal neurological symptoms during a migraine attack has little influence on the rest of the attack.

Kinetics of platelet 5-hydroxytryptamine uptake in headache patients.

Platelet 5-hydroxytryptamine (5-HT) uptake was measured in asymptomatic headache patients attending a specialist migraine clinic, and in hospital staff who did not suffer from regular or severe headache. Current levels of anxiety and depression were assessed in all subjects using the Hospital Anxiety and Depression (HAD) scale and their possible influence on the uptake kinetics taken into account during the analysis of results. The Michaelis-Menten constant (Km) was significantly raised in common migraine and tension headache compared with controls (p less than 0.001 and p less than 0.01, respectively), but not in classical migraine or cluster headache. The increase remained significant after adjusting for differences in age, sex, presence of anxiety or depression (HAD sub-scale score greater than or equal to 8), drug intake during the week before testing, time elapsed since last attack and time of assay (am or pm). No differences were observed between patients and controls in the maximal rate of uptake (Vmax) or platelet count, and previous reports of a reduction in Vmax in patients experiencing attack within 5 days prior to testing could not be confirmed. The cause and significance of an increased Km are not clear, but plasma factors acting as competitive inhibitors for the uptake site or an alteration in the configuration of the uptake site are possible explanations. If confirmed, the shared biochemical abnormality may suggest that common migraine and tension headache have a common pathogenesis.

Chocolate is a migraine-provoking agent.

Patients with migraine who believed that chocolate could provoke their attacks were challenged with either chocolate or a closely matching placebo. In a double-blind parallel group study, chocolate ingestion was followed by a typical migraine episode in 5 out of 12 patients, while none of the 8 patients challenged with placebo had an attack (p = 0.051). The median time to the onset of the attack was 22 h. This brief study provides some objective evidence that chocolate is able to provoke a migraine attack in certain patients who believe themselves sensitive to it.

First clinical study of the selective 5-HT3 antagonist, granisetron (BRL 43694), in the acute treatment of migraine headache.

Granisetron (BRL 43694), a selective 5-HT3 receptor antagonist, was assessed as acute therapy for the first time in migraine patients. In an open pilot study 7 migraine attacks were treated in 6 patients. All but 1 patient experienced marked and rapid relief from the headache, and nausea and vomiting were rapidly resolved in the 6 cases where these symptoms accompanied the attack. No side effects were recorded. Development of granisetron for migraine was suspended during the study for extraneous reasons.

Anticardiolipin antibodies in migraine.

Antiphospholipid antibodies have occasionally been observed in small series of migraine patients, possibly signalling an immunological pathogenesis in a subgroup. We have measured anticardiolipin antibody levels in a series of 94 migraine patients (35 patients having migraine with aura, 59 without aura), during acute attacks and between attacks. Platelet counts were normal and VDRL was negative in all patients. A low positive anticardiolipin antibody level was found in only one patient, which was negative six months later. There appears to be no association between the presence of anticardiolipin antibodies and migraine. Antiphospholipid antibodies are unlikely to have a material pathogenetic role. Statistically, the incidence of significantly raised anticardiolipin antibody levels in this group of patients does not exceed 4% at a 95% probability level.

Platelet activity and selective beta-blockade in migraine prophylaxis.

Migraine is associated with increased platelet activity and an incidence of cerebrovascular ischemic events. Because cerebrovascular events might result from platelet aggregation, enhancing platelet activity further in the treatment of migraine is not desirable. beta-Adrenoceptor blockers effective in migraine prophylaxis include propranolol (nonselective) and metoprolol (beta 1-selective), but it is uncertain how beta-receptor subtype selectivity might influence platelet behavior in migraine. In 29 patients, comparable clinical responses were obtained with therapeutic doses during 1 month of treatment with propranolol, metoprolol, and the beta 2-selective Li 32-468. Propranolol increased and metoprolol decreased platelet aggregation and ATP release, and the effect of Li 32-468 could be related to that of propranolol. These actions can be largely explained in terms of what is known of platelet beta-receptors and therefore can be generalized to other effective beta-blockers. Since altered platelet activity does not account for the efficacy of these agents in migraine, the actions of beta-blockers on platelets should be considered as side effects. Those beta-blockers inhibiting platelet activity should be preferred in migraine treatment, assuming equal efficacy, which implies the use of beta 1-selective blockers.

Cryptococcal meningitis presenting as uveitis.

A patient presented with a posterior uveitis. An inferior plaque of retinal exudation was seen. Full investigation failed to establish a cause until six weeks later, when cryptococcal meningitis developed. The patient was immunocompetent. Exudation in relation to retinal vessels is unusual in idiopathic posterior uveitis, and cryptococcosis should be considered in the differential. Diagnosis is by lumbar puncture or vitreous aspiration.

Laterality of pain in migraine distinguished by interictal rates of habituation of electrodermal responses to visual and auditory stimuli.

Support is provided for a primary neural factor in migraine by studies in autonomic responsiveness to sensory stimuli in relation to the laterality of pain. Migraineurs with consistently lateralised headaches were found in two studies to exhibit extremes of autonomic responsiveness to sensory stimuli during the interictal phase. The direction of responsiveness was predictive of the laterality of pain; left-sided pain was associated with under-responsiveness and fast habituation, right-sided pain with over-responsiveness and slow habituation. Bipolarity in rate of habituation is consistent with a defect in a regulatory mechanism that controls regional cerebral activation such as the diffuse thalamic projection system.

Towards a model stroke trial. The single-centre naftidrofuryl study.

It has been questionable whether the lack of proven pharmacological treatments in acute cerebral infarction (ACI) reflects ineffective drugs or only inadequacies in their assessment. The difficulties in developing a rationale for drug therapy in this condition favoured the former, although the latter possibility was supported by re-evaluation of most published trials. In this paper, a plausible rationale, in terms of our current understanding of both the drug and the condition, is expounded for treatment of ACI with naftidrofuryl. Guidelines for the design and conduct of clinical trials in acute stroke are discussed in relation to the particular problems posed: need for early initiation of treatment; need for, and difficulties of, diagnostic confirmation; matching of treatment groups by prognostic indicators of uncertain significance, and requirements for large numbers of patients and long-term follow-up. The practical application of these guidelines is tested in a clinical trial of naftidrofuryl conducted in a single centre on 100 patients with proven diagnoses. Rigorous attention to all aspects of selection, treatment and follow-up, with an explanatory approach to the trial design, was predicted to produce a positive result if the drug was effective. The findings were that naftidrofuryl treatment was associated with no change in death rate but with clinically and statistically significant improvements in neurological recovery and bed-occupancy. Better functional recovery was also noted, so that the trial result was coherent. It was concluded that a beneficial effect had been recorded, and consistency of this outcome with those of previous studies is demonstrated. A case is made for further studies to define exactly the role of this drug in the management of ACI.

Cultured rat spinal cord neurons: interaction with motor neuron disease immunoglobulins.

Conditions have been developed for the culture of rat spinal cord neurons in serum-free media supplemented with hormones and growth factors. Neurons were identified by immunofluorescence-labeled anti-neurofilament antibody, and their growth was monitored by assay of choline acetyltransferase and cholinesterase activities. Activities of these enzymes were considerably higher than those of comparable cultures in serum supplemented media in which there were visibly many more nonneuronal cells. Serum immunoglobulins from patients with motor neuron disease showed enhanced binding to rat spinal cord cells maintained in both serum-supplemented and serum-free media, as compared with those from normal healthy individuals. Enhanced binding was more marked with the latter cells, presumably because of the higher proportion of neuronal cells in these cultures. Serum immunoglobulins from patients with other neurologic disorders showed a similar binding to that of the normal controls. The results demonstrate the presence of an immune response to spinal cord cell membrane components in patients with motor neuron disease, although whether the response is primary or secondary in the disease process remains unclear.

The classification of headache.

The definition of headache syndromes in the past have lacked precision, not only because different terms have been used for the same condition, but also because there is no general agreement on the essential characteristics of each. Since even minor variations will produce marked differences in case series purporting to be of the same disorder, it is important to get general agreement and to improve on previous classifications of headache.