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.     

Motor neuron disease and multiple sclerosis mortality in Australia, New Zealand and South Africa compared with England and Wales.

There has been a marked increase in the reported mortality from motor neuron disease (MND) but not multiple sclerosis (MS) in England and Wales and in a number of other countries. A comparison has been made of the mortality from MND and from MS for two time periods in Australia, New Zealand and South Africa. An increase in MND mortality occurred in Australia and New Zealand between 1968-77 and 1978-87, greater than that which occurred in England and Wales, but there was no increase in MS mortality. Among the white population of South Africa, the MND mortality was half of that in England and Wales, Australia and New Zealand in both time periods. Both MND and MS mortality is higher in the English-speaking than in the Afrikaans-speaking white South African-born. The marked increase in MND mortality which has now been reported from many countries, is good evidence that an environmental factor is important in causing this disease. The large differences in MND mortality in different populations may be important clues to the environment factors causing the disease.     

The mortality of motor neuron disease in Sweden

The age-standardized mortality from motor neuron disease in Sweden doubled from 1961 to 1985. The average annual rate during the period was 1.9 per 100,000 population. The male to female ratio was 1.2:1. The age-specific mortality rates had a peak at 70 to 79 years of age. When each birth cohort was followed up separately over time, the peak was less clear and in some cohorts the mortality rates increased continuously with advancing age. A significant increase of motor neuron disease among men was found in one Swedish county.     

Adult onset motor neuron disease: worldwide mortality, incidence and distribution since 1950.

This review examines the commonly held premise that, apart from the Western Pacific forms, motor neuron disease (MND), has a uniform worldwide distribution in space and time; the methodological problems in studies of MND incidence; and directions for future epidemiological research. MND is more common in men at all ages. Age-specific incidence rises steeply into the seventh decade but the incidence in the very elderly is uncertain. A rise in mortality from MND over recent decades has been demonstrated wherever this has been examined and may be real rather than due to improved case ascertainment. Comparison of incidence studies in different places is complicated by non-standardised methods of case ascertainment and diagnosis but there appear to be differences between well studied populations. In developed countries in the northern hemisphere there is a weak positive correlation between standardised, age-specific incidence and distance from the equator. There is now strong evidence for an environmental factor as the cause of the Western Pacific forms of MND. A number of clusters of sporadic MND have been reported from developed countries, but no single agent identified as responsible.     

British motor neuron disease twin study.

OBJECTIVES: To investigate the cause of sporadic motor neuron disease (MND) by twin study, so allowing (1) estimation of the genetic contribution, and (2) collection of matched pairs for a case-control study of possible environmental factors. METHODS: 10872 death certificates bearing the diagnosis MND were collected from 1979 to 1989 inclusive. Inspection of individual birth entries allowed identification of potential twins. The status of each co-twin was determined and contact made through the National Health Service Central Register (NHS-CR) and their general practitioner (GP). The diagnosis of MND was verified via the co-twin and relatives, and medical records where available. Zygosity was assessed using a recognised questionnaire. Details concerning environmental exposures and health were gathered by interview of cotwin and relatives using a semistructured questionnaire. Heritability (h2) of MND was estimated, and the environmental information was analysed by conditional logistic regression modelling. RESULTS: Seventy seven probands were identified, of whom 26 were monozygotic and 51 dizygotic. Four monozygotic probands were concordant, but two probands came from a family known to have familial MND. The estimated heritability was between 0.38 and 0.85. Most environmental risk factors were not significant. Regular vehicle maintenance (odds ratio (OR) = 7.0; 95% confidence interval (95% CI) 1.3-89.9) and occupational paint usage (OR = 3.75; 95% CI 1.0-17.1), however, occurred significantly more often in the affected cases. CONCLUSIONS: This "death discordant" method for twin collection has proved to be viable, and has allowed the ascertainment of a large population sample in a rare disease. The genetic role in sporadic MND is substantial, and higher than expected. Exposure to industrial chemicals, particularly constituents of petrochemicals and paints, may contribute to the aetiology of MND.     

Ecological correlates of motor neuron disease mortality: a hypothesis concerning an epidemiological association with radon gas and gamma exposure

This study investigates variations in motor neuron disease (MND) mortality rates between the counties of England and Wales from 1981 to 1989, and their relationship with gamma-ray dose rates, indoor radon gas concentrations and enhanced general life expectancy. A stong correlation was confirmed between age-adjusted rates of MND mortality and life expectancy. Weaker, but statistically significant, associations were observed between indoor radon gas concentrations, terrestrial gamma radiation and marginal variations in MND mortality. Life expectancy and radon gas concentrations were positively associated with MND mortality rates whilst gamma radiation was negatively associated. The negative correlation of gamma radiation with MND mortality may be understood with reference to its negative effects on overall population life expectancy. Radon gas concentrations seemingly account for a small elevation in MND mortality, amounting to at most 4% of total deaths. Further research is required to investigate this association.     

Geographical epidemiology of residence of patients with motor neuron disease in Lancashire and south Cumbria

OBJECTIVES—To seek objective evidence forgeographical clustering of places of residence of patients with motorneuron disease (MND).
METHODS—A complete residential history frombirth to onset of disease was obtained from a cohort of 130 patients with MND from Lancashire and south Cumbria presenting to theDepartment of Neurology in Preston between 1 January 1989 and 31 December 1993. These data were compared with population basedreference data from the 1991UK Census.
RESULTS—Some areal units showed a greater, othersa lesser, number of MND patient residences than expected. The resultssuggest that the background population incidence of MND is relativelylow and that the overall incidence figures previously quoted have been skewed upwards by areas in which the incidence of MND is relatively increased. These findings were further tested by Poisson modelling. ThePoisson model provided a poor fit for the data at postcode district andsector levels confirming that patients with MND were significantly morelikely to have lived in some areas than others after allowing forvariation in population of the different areal units and for variationin duration of residence.
CONCLUSIONS—These findings reinforce the resultsof previous work, much of which has been qualitative rather thanquantitative. The results presented here suggest a low backgroundincidence of MND in the context of generally quoted overall incidencefigures. This low background incidence is, however, skewed upwards bysome areal units with a relatively high incidence, thus achievingoverall incidence rates comparable with generally quoted figures. Weconclude that there is prima facie evidence of spatial patterns in the distribution of places of residence of patients with MND. Further examination of occupational and environmental factors in the lives ofthe patients with MND is required to obtain a better understanding ofthe importance of these findings.

     

The contribution of mortality statistics to the study of multiple sclerosis in Australia.

Mortality statistics provided a valuable source of support for data obtained from prevalence surveys of multiple sclerosis in Australia. Firstly, multiple sclerosis mortality data for the decade 1971-80 in the States of Australia confirmed the relationship between increasing disease frequency and increasing south latitude shown by State and regional point prevalence surveys based on the national census day 30 June 1981. Secondly, a comparison with mortality data from the decade 1950-59 showed that in most States there had been a substantial fall in multiple sclerosis mortality in the more recent decade and this was clearly an important contributing factor to the rise in prevalence noted between the morbidity surveys of 1961 and 1981. Thirdly, multiple sclerosis mortality in the UK-born migrant population dying in Australia was found to be similar to that of the Australian-born population and very much lower than that found in the UK. This observation corroborated evidence from the 1981 morbidity surveys and suggested that migration from the UK to Australia may lower the risk of developing multiple sclerosis either through a reduction in disease incidence or the operation of environmental factors curbing disease expression.     

The changing mortality from motor neurone disease and multiple sclerosis in England and Wales and the Republic of Ireland.

A study has been undertaken to ascertain the changes in mortality from motor neurone disease (MND) and from multiple sclerosis (MS) in England and Wales and in the Republic of Ireland. During the 20 years 1968-1987, 16,077 deaths were reported as being primarily due to MND in England and Wales with a male/female ratio of 1.22. There has been an increase in MND deaths from 3,185 in 1968-1972 to 5,241 in 1983-1987. The increase occurred in the death rates in both sexes and in all age groups, but particularly over the age of 65. In contrast, there was no increase in MS deaths and the MS death rates fell below the age of 55 but increased over this age, evidence that MS patients are living longer. A similar but more marked increase in MND mortality, and a considerable fall in MS mortality, occurred in the Republic of Ireland. The increase in MND mortality is not due to an increase in the number of neurologists, as there has been little increase in their numbers. The highest MND mortality was in Social Class IIIN males - skilled non-manual workers.     

Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS)

A motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/motor neurone disease (MND). FTD is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex. The motor neuronopathy comprises bulbar palsy and limb amyotrophy. The major histological change is typically of microvacuolation of the cerebral cortex, with atrophy of the bulbar neurones and anterior horn cells of the spinal cord. Ubiquitinated inclusion bodies occur in large pyramidal cortical neurones and in surviving cranial nerve nuclei and anterior horn cells. Evidence is emerging that some patients with classical MND/amyotrophic lateral sclerosis (ALS), who are thought not to be demented, develop cognitive deficits in the realm of frontal executive functions. Moreover, frontal lobe abnormalities have been demonstrated by neuroimaging. The findings point to a link between FTD/MND and cMND/ALS and suggest that a proportion of patients with cMND/ALS go on to develop FTD. Patients with cMND/ALS may not be equally vulnerable. The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD.     

Phenotypic variation in ALS]

Making a diagnosis of typical amyotrophic lateral sclerosis (ALS) is not a tough job, but when it comes to atypical forms of motor neuron disease (MND) which are not uncommon in clinical setting, we may have some difficulty to diagnose ALS/MND. There is striking phenotypic variation in sporadic ALS/MND, such as frail arm syndrome (brachial amyotrophic diplegia), pseudopolyneuritic form, hemiplegic type, ALS/MND with markedly extended involvement beyond the motor system, and MND with basophilic inclusion bodies. These variations must be recognized if physicians are to tailor advice on disease progression, prognosis, drug therapy, and care to the needs of the individual. Clinical trials of new therapeutic agents have been performed, on the assumption that patients with ALS/MND have the same underlying etiology, addressing the heterogeneous population of the patients under a single diagnostic category. This can be detrimental to the well-being of the individual, because clinical heterogeneity may mask drug effects in clinical trials. The attempt to categorize subgroups based on the clinical and pathological backgrounds within the spectrum of ALS/MND may be a critical step in facilitating clinical research in ALS/MND. Definition of clinicopathologic syndromes in patients with ALS/MND is an important challenging task that cannot be ignored.     

Manganese-containing superoxide dismutase signal sequence polymorphism associated with sporadic motor neuron disease

An alanin-9valin (Ala-9Val) polymorphism in the mitochondrial targeting sequence of manganese-containing superoxide dismutase (Mn-SOD) has recently been described. We studied this polymorphism in 72 Swedish patients with sporadic motor neuron diseases (MND) and controls using an oligonucleotide ligation assay. There were significant differences in genotype between MND patients and controls (P = 0.025), and between male and female MND patients (P = 0.009). Individuals homozygous for the Ala allele had a higher risk for MND [odds ratio, 2.9; 95% confidence interval (CI), 1.3-6.6], which was increased when including only females in the analysis (odds ratio, 5.0; 95% CI, 1.8-14.0). In classical amyotrophic lateral sclerosis, the odds ratio was 3.8 (95% CI, 1.3-10.0), and 5. 5 (95% CI, 1.5-19.9) when including only females. The results suggest that mutations influencing the cellular allocation of Mn-SOD may be a risk factor in MND, especially in females, and that MND may be a disease of misdistribution of the superoxide dismutase enzymes.     

Olfactory Disorder in Motor Neuron Disease

In Parkinson's disease and Alzheimer's disease there is profound disorder of olfaction. The extent to which this modality is involved in motor neuron disease (MND) has been studied little. To address this further we assessed olfaction by three methods—a smell identification test (“UPSIT”) in 58 patients and 135 controls; olfactory-evoked response (OEP) to H₂S in 15 patients, and pathological examination of olfactory bulbs obtained from 8 cadavers. It was found that smell identification compared with the controls was slightly worse overall in the MND group as a whole, but only the bulbar patients scored significantly less on the UPSIT. Patients displayed a subtle defect in cheese odor recognition. OEPs were normal in 9 subjects and delayed in 1 subject. The remaining 5 OEPs were unsuccessful. Histopathological studies of olfactory bulbs showed excess lipofuscin deposition in all 8 cases examined, indicating subclinical neuronal damage. Olfactory neurons with a degree of antioxidant defect may be more susceptible to cellular damage than other neuronal groups because of their direct relationship to environmental agents. Overall we found the degree of olfactory dysfunction in MND to be mild and in contrast with the marked changes described by others.     

Motor neuron disease and multiple sclerosis among immigrants to England from the Indian subcontinent, the Caribbean, and east and west Africa.

The mortality from motor neuron disease (MND) and multiple sclerosis (MS) was studied among immigrants to England and Wales from the Indian subcontinent, the Caribbean, and East and West Africa during the 10 years 1979-88. The MND mortality among ethnic Asian males was only half and for females one fifth of that expected at English rates. MND mortality in Caribbean immigrants was somewhat lower than expected. White immigrants from the Indian subcontinent had the expected MND mortality. MS mortality was low among Asian, West Indian, and African immigrants. This study is evidence that MND mortality is not the same in all ethnic groups.     

The ALS/MND prevalence in Sweden estimated by riluzole sales statistics

OBJECTIVES: To determine whether sales statistics for riluzole can be used as a marker for the prevalence of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) in Sweden. MATERIALS AND METHODS: A questionnaire was sent to all neurological units in Sweden asking about the numbers of patients with ALS/MND and whether these patients were treated with riluzole. Sales statistics for riluzole were obtained from the 906 public pharmacies and 89 hospital pharmacies in Sweden. RESULTS: Eighty percent of the neurological units answered the questionnaire. The estimated prevalence in September 2003 from the questionnaire was 5.4/100,000 inhabitants. The sales expressed in defined daily dose/100,000 inhabitants/day was 3.8. For the counties the correlation between these two parameters was 0.83. CONCLUSION: Estimated prevalence is highly correlated with sales statistics for riluzole. Riluzole sales statistics could be used as a crude marker for the prevalence of ALS/MND in Sweden.     

Affective disorders in motor neuron disease: a population-based study

Several studies have suggested that there may be an increased prevalence of affective disorders in people with motor neuron disease (MND). However, the literature is inconsistent, possibly because of small sample sizes in the existing studies. The Canadian province of Alberta has a universal health care system in which physician contacts are recorded along with ICD-9-CM diagnostic codes. In this analysis, diagnostic codes indicative of MND and affective disorders were used. Stratified analysis and logistic regression were used in the analysis. There were 336 cases of MND leading to a prevalence of 14.5 per 100,000 in provincial residents > or =20 years old. Affective disorders were identified in 8.6% of the total population during the same year. The crude odds ratio for affective disorders in MND was 2.3 (95% CI = 1.7-3.0). However, the prevalence of affective disorders declined with increasing illness duration.     

Induction of endogenous neural precursors in mouse models of spinal cord injury and disease

Adult neural precursor cells (NPCs) in the mammalian central nervous system (CNS) have been demonstrated to be responsive to conditions of injury and disease. Here we investigated the response of NPCs in mouse models of spinal cord disease [motor neuron disease (MND)] with and without sciatic nerve axotomy, and spinal cord injury (SCI). We found that neither axotomy, nor MND alone brought about a response by Nestin-positive NPCs. However, the combination of the two resulted in mobilization of NPCs in the spinal cord. We also found that there was an increase in the number of NPCs following SCI which was further enhanced by systemic administration of the neuregulatory cytokine, leukaemia inhibitory factor (LIF). NPCs were demonstrated to differentiate into astrocytes in axotomized MND mice. However, significant differentiation into the various neural cell phenotypes was not demonstrated at 1 or 2 weeks following SCI. These data suggest that factors inherent to injury mechanisms are required for induction of an NPC response in the mammalian spinal cord.     

The relationship between extramotor ubiquitin-immunoreactive neuronal inclusions and dementia in motor neuron disease

Dementia is thought to be an uncommon complication of motor neuron disease (MND). In addition to the characteristic motor system degeneration, pathological studies of MND patients with dementia have demonstrated changes in extramotor cortex; ubiquitin-immunoreactive inclusions are present in neocortical layer II neurons and hippocampal dentate granule cells. To examine how specifically this pathology is associated with dementia in MND, we performed ubiquitin immunohistochemistry on sections of hippocampus, prefrontal and temporal neocortex from 29 cases of MND, 10 with dementia and 19 with no clinical history of cognitive impairment. All cases with dementia had numerous ubiquitin-positive inclusions in dentate granule cells, whereas involvement of the neocortex was more variable. Six (32%) of the nondemented cases had ubiquitin pathology, which was similar to the demented cases in its morphology and distribution but of slightly less severe degree. These findings demonstrate that, although ubiquitinated inclusions in extramotor cortex are a consistent finding in MND with dementia, they are also common in MND in the absence of documented cognitive abnormalities. Such cases may either represent a subclinical stage of pathology or indicate that cognitive dysfunction is an underrecognized complication of MND.     

Motor neuron disease and polio in Scotland.

An analysis of mortality and morbidity rates for motor neuron disease (MND) in Scotland has confirmed earlier observations that the disease is more common in men and older age groups. The geographical distribution is non-uniform and related to discharge rates for all neurological diseases. Discharge and mortality rates are increasing but there has been no decline in populations who would have been vaccinated against polio.