Amyotrophic lateral sclerosis a population study

Summary A country-wide study of the frequency of amyotrophic lateral sclerosis (ALS) was undertaken in Israel for the period 1960–1970. Israel was chosen for this study because of its excellent medical facilities and detailed demographic information. Moreover, the population includes representative groups from all parts of the world for comparison of frequency. A wide variety of motor system disease was screened in all hospitals, clinics, and chronic care facilities in the country, death certificates were reviewed and physicians with a neurological practice were contacted to derive a tentative list of cases. Only those who fit strict clinical diagnostic criteria or had autopsy confirmation were included in estimates of prevalence and incidence.On January 1, 1965, the mid-point of the study, 62 patients with ALS were living in Israel. The age-adjusted prevalence of ALS on that date was 3 per 100000 population. The average annual age-adjusted incidence for the period 1960–1970 was 0.78 per 100000 population (0.86 in males, 0.46 in females; ratio 1.9:1). There was no appreciable change in trend of incidence over the study interval. Age-specific incidence rates were similar in native-born inhabitants of Israel, immigrants from Europe and immigrants from Afro-Asian countries. The range in age-adjusted incidence among subgroups of immigrants to Israel from various countries was 0.25 to 1.20 per 100000 population but small numbers precluded testing the statistical significance of these rather narrow differences.Mean age at onset was 55.4 years for males and 52.4 years for females. The mean age at death was 60.2 for males and 58.0 for females. The average annual mortality from ALS was 0.58 per 100000 population. There were no familial aggregates of ALS in Israel and autopsy data showed no neurofibrillary changes, granulovacuolar or inclusion bodies.There are only a few other population studies of ALS in different regions of the world. The average annual incidence in these other studies ranged from 0.4 to 1.4 per 100000 population. Thus, the incidence in Israel falls within this narrow range. The present study lends further support to the impression that ALS has a remarkably uniform geographic distribution with Guam and the Kii peninsula of Japan being the only known areas with significantly high rates. If an environmental factor contributes to the pathogenesis of ALS, the factor must also have a uniform geographic distribution.Supported in part by the Minneapolis Veterans Administration Hospital.     

Amyotrophic lateral sclerosis with neuronal intranuclear protein inclusions

A 46-year-old patient developed amyotrophic lateral sclerosis (ALS) characterized by rapid progression. She needed respiratory assistance after a course of 9 months. She died 4.5 years after onset. Autopsy showed dramatic atrophy of the spinal cord, sparing only the posterior tracts, associated with neuronal loss and astrogliosis in various areas including the anterior horns, motor cortex, striatum, thalamus, and substantia nigra. Ubiquitin immunohistochemistry showed rare skein-like inclusions in the surviving spinal and medullary motor neurons. Eosinophilic inclusions were found in the nuclei of pyramidal neurons in the hippocampus. These inclusions were immunoreactive to antibodies against ubiquitin, promyelocytic leukemia gene product, proteasome, and ataxin-3. They were not immunoreactive to antibodies against tau, cystatin C, neurofilament, alpha-synuclein, SOD-1, and polyglutamine (1C2), and were not stained by ethidium bromide. Similar inclusions were found in the motor cortex. The immunoreactivity of the inclusions was similar to that encountered in diseases associated with CAG repeats, except for the negativity of the immunolabelling with 1C2. At the ultrastructural level, the nuclear inclusions were made of straight filaments (10–12 nm in diameter) arranged at random, reminiscent of the polyglutamine intranuclear hyaline inclusions.     

Amyotrophic lateral sclerosis with supranuclear ophthalmoplegia and rigidity

Abstract

Ophthalmoplegia is rarely reported in patients with amyotrophic lateral sclerosis (ALS). We describe a patient with sporadic ALS, who had developed progressive external ophthalmoplegia of supranuclear origin and rigidity in the neck. Autopsy findings showed histopathological abnormalities consistent with ALS. In addition to these findings, there was neuronal loss and gliosis in the putamina and globi pallidi, and gliosis in the periaqueductal gray matter. Our case appears to raise the possibility that ALS comprises a heterogenous group of disorders. [Neurol Res 1999; 21: 661-664]     

Pathogenic Lrrk2 substitutions and Amyotrophic lateral sclerosis

Summary. Pathogenic Lrrk2 Y1699C substitution observed in a large German-Canadian kindred presents a neurodegenerative disorder that is reminiscent of amyotrophic lateral sclerosis and Parkinsonism-Dementia Complex. We screened 54 patients with ALS for seven known Lrrk2 pathogenic substitutions in the Roc, COR and kinase domains. No mutations were observed suggesting that this locus does not have a major influence on the ALS phenotype. However we can not rule out other genetic variation at the LRRK2 locus may play a role in parkinsonian disorders with amyotrophic lateral sclerosis and may be considered candidates for genetic screening.     

Amyotrophic lateral sclerosis. A study of its presentation and prognosis

Summary All identified Israeli patients with amyotrophic lateral sclerosis (ALS) with onset of the disease from 1959 through 1975 (n=318) were evaluated clinically. Most of our patients (63%) presented with weakness; only 10% presented with atrophy and 3% with fasciculations. In 31% of the cases, the onset of the disease was focal and 22% of the patients presented with bulbar signs, but only 6 patients presented with emotional lability (pseudo-bulbar). Twelve per cent of the patients presented with muscle cramps, pain or paraesthesia. Atypical signs such as motor cranial nerve lesion, dementia, sphincter disturbance and deep sensation loss are discussed. A relatively high proportion of our patients suffered from malignant tumour, but with no association with any specific tumour. The median survival time was 3 years. Patients with onset of their disease with bulbar signs had a shorter life expectancy (2.2 years): Twenty nine per cent of our patients survived for more than 5 years and 16% for more than 10 years.Supported in part by grants from the Amyotrophic Lateral Sclerosis Society of America, and Yad Avi-Hayishuv, Israel     

Amyotrophic lateral sclerosis patients and ocular ptosis

Ptosis is not a feature observed in amyotrophic lateral sclerosis (ALS). We describe two old women with bulbar-onset ALS and rapid progression, in whom ptosis and diplopia were noted. They did not improve on pyridostigmine or steroids. Antibodies against acetylcholine receptor were negative, thymoma was excluded, but neurophysiological showed marked neuromuscular transmission failure in orbicularis oculi. We discuss the association between ALS and ocular myasthenia gravis in these cases.     

Amyotrophic lateral sclerosis in Middle-Finland: an epidemiological study

ABSTRACT- Amyotrophic lateral sclerosis (ALS) was diagnosed in 36 patients in Middle-Finland Central Hospital District during 1976–1981. The annual incidence of ALS was 2.4 per 100,000 population and the prevalence rate was 6.4 per 100,000 population. The age-specific incidences of ALS were similar for men and women with a maximum of 14/100,000/year in the age group 60–69 years. The initial symptoms originated in 37% of the patients from bulbar and in 63% from spinal levels. Bulbar onset was more common in patients aged 60 years or more compared with younger patients. Patients with bulbar onset had a significantly poorer prognosis than those with spinal onset, which explained the poorer prognosis of older patients.
4 matched controls were chosen for each ALS patient from the files of the Central Hospital. There was no difference between the patients and the controls with respect to previous injuries, surgical operations, malignant neoplasms, or exposure to domestic animals. An earlier observation that evacuees from Karelia ceded to USSR after World War II should have a prevalence twice that of the remaining population was not substantiated.     

Amyotrophic lateral sclerosis in Finland: Birthplaces of patients, parents and grandparents

Amyotrophic lateral sclerosis (ALS) appears to be more prevalent in the southeastern part of Finland and among the war evacuees displaced from this area after the World War II than elsewhere in the country. A random sample of 31 ALS patients was chosen and the birthplaces of their ancestors traced back in two generations to find out whether there would be any tendency of clustering in certain regions of the country. No such trend was found. This finding speaks against a genetically determined tendency for the disease.     

Amyotrophic lateral sclerosis among the migrant population to Piemonte, northwestern Italy

Recent surveys indicate a decreasing north-to-south gradient in the mortality and incidence rates of amyotrophic lateral sclerosis (ALS) in Italy, possibly indicating a different susceptibility to ALS in these populations. Piemonte, a region of northwestern Italy, experienced a considerable migration from other regions in Italy between 1940 and 1975; we therefore analyzed the effects of place of birth and migration upon the risk of developing ALS. Data on all ALS cases occurring in Piemonte during the period 1971–1990 were collected. Standardized incidence ratios (SIRs) for patients born outside Piemonte were calculated, using the Piemonte-born population as reference. A total of 962 ALS cases were identified during the study period, corresponding to a mean annual crude incidence rate of 1.37/100,000 population (95% confidence interval, 1.29–1.46). The SIRs of patients born in three southern Italian regions and of foreign-born persons were significantly higher than those of persons born in Piemonte and or other regions in Italy, and increased with age. This observation may be explained by an interaction between environmental and genetic factors or by selective migration. Received: 3 April 1998 Received in revised form: 3 July 1998 Accepted: 17 July 1998     

Nerve growth factor receptor immunostaining in the spinal cord and peripheral nerves in amyotrophic lateral sclerosis

Summary In animal experiments, nerve transection is followed by expression of nerve growth factor receptors (NGFR) on Schwann cells of both motor and sensory nerve fibres distally to the site of the lesion. To determine whether denervated Schwann cells in amyotrophic lateral sclerosis (ALS) similarly express NGFR, a study was made of post-mortem material of peripheral nerves and ventral roots from ALS cases and age-matched controls, using immunolabelling methods. Dorsal roots and spinal cords were also examined for the presence of NGFR. In all the ALS cases and controls, NGFR immunostaining was seen in the outer layer of vessel walls, perineurial sheaths, connective tissue surrounding fascicles in nerve roots and in the substantia gelatinosa of the spinal cord. In ALS, NGFR staining was also present in the Schwann cells of degenerated nerve fibres in mixed peripheral nerves, in ventral roots and, to a lesser extent, in dorsal roots. NGFR immunoreactivity was also seen in elongated cells extending from the perifascicular connective tissue into the nerve fascicles. It is concluded that denervated Schwann cells in ALS express NGFR and that NGFR immunostaining on Schwann cells may be used as an indicator of axonal degeneration. The NGFR labelling in the dorsal roots supports the notion that ALS is not a pure motor syndrome.Supported by a grant from the Foundation for Research of ALS and Spinal Muscular Atrophy     

Persistent inward currents in spinal motoneurons: Important for normal function but potentially harmful after spinal cord injury and in amyotrophic lateral sclerosis

Meaningful body movements depend on the interplay between synaptic inputs to motoneurons and their intrinsic properties. Injury and disease often alter either or both of these factors and cause motoneuron and movement dysfunction. The ability of the motoneuronal membrane to generate persistent inward currents (PICs) is especially potent in setting the intrinsic excitability of motoneurons and can drastically change the motoneuron output to a given input. In this article, we review the role of PICs in modulating the excitability of spinal motoneurons during health, and their contribution to motoneuron excitability after spinal cord injury (SCI) and in amyotrophic lateral sclerosis (ALS) leading to exaggerated long-lasting reflexes and muscle spasms, and contributing to neuronal degeneration, respectively.     

Amyotrophic lateral sclerosis,frontotemporal dementia and beyond: the TDP-43 diseases

Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to α-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.     

Amyotrophic lateral sclerosis of Guam: the nature of the neuropathological findings

To elucidate the fundamental differences and similarities of the neuropathological features and etiopathogenesis of the amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) of Guam, we conducted a topographic, quantitative and histological investigation of tau-containing neurons, neurofibrillary tangles (NFTs), Bunina bodies and ubiquitinated inclusion bodies in 27 non-ALS non-PDC Guamanian subjects, as well as 10 Guam ALS patients, 28 PDC patients, and 5 patients with combined ALS and PDC (ALS-PDC). The topographic distribution of NFTs was basically the same in each disease and also in the non-ALS non-PDC group. There were relatively few, if any, NFTs in non-ALS non-PDC subjects and ALS patients, but there were many, especially in the frontal and temporal cortex, in Guam PDC and ALS-PDC patients. The histological and ultrastructural features of Bunina bodies in Guam ALS and ALS-PDC patients were similar to those reported in classic ALS. The ratio of occurrence of the inclusion in Guam ALS and ALS-PDC patients was similar to that reported so far in classic ALS. Ubiquitinated skein-like inclusion bodies were observed in the spinal anterior horn cells in Guam ALS and ALS-PDC patients. These findings indicate that classic ALS does exist on Guam, that NFTs in Guam ALS patients are merely a background feature widely dispersed in the population, that the mechanism of neuronal degeneration of Guam ALS is basically different from that of PDC, and that Guam ALS occurs initially as classic ALS.Supported in part by a Grant-in-Aid for Scientific Research (c) 05680653 from the Ministry of Education, Science and Culture and a research grant for CNS degenerative diseases from the Ministry of Health and Welfare, JapanMedical student of Leiden University, Holland, in 1981. He stayed on Guam and accomplished his thesis on part of this study under the guidance of Drs. K.-M. Chen and K. Oyanagi.     

Amyotrophic lateral sclerosis with marked neurological asymmetry: clinicopathological study

We attempted to correlate the marked neurological asymmetry observed in two amyotrophic lateral sclerosis patients with their histopathological lesions. Patient 1, a 52-year-old man, developed dysarthria and dysphagia, followed by muscle weakness in the left arm and then of the left leg. Patient 2, a 44-year-old man, developed muscle weakness in the left hand, left leg, tongue with left-sided predominance, right hand and right leg in that order of progression. Both patients exhibited moderate to marked left-sided predominant involvement of the lower motor neuron system, accompanied by retained or hyperactive deep tendon reflexes on the left side in the early stage of their illness. Most of the asymmetry in the lower motor neuron system involvement persisted until the death of the patients. Histopathological examinations, including semiquantitative analysis, revealed that both patients exhibited left-sided predominant degeneration of the lower motor neuron system at those spinal cord levels where the neurological asymmetry was of a moderate to marked degree. In addition left-sided predominant degeneration of the lateral corticospinal tracts was seen in both patients and right-sided predominant involvement of Betz cells in the leg area of the motor cortex of patient 1. This pattern of both the neurological and histopathological asymmetry suggested the probable existence of an intimate somatotopically related linkage between the upper motor neuron system degeneration and lower motor neuron system degeneration in both patients.     

Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. The author initially summarizes the principal features of human ALS neuropathology, and subsequently describes in detail ALS animal models mainly from the viewpoint of pathological similarities and differences. ALS animal models in this review include strains of rodents that are transgenic for superoxide dismutase 1 (SOD1), ALS2 knockout mice, and mice that are transgenic for cytoskeletal abnormalities. Although the neuropathological results obtained from human ALS autopsy cases are valuable and important, almost all of such cases represent only the terminal stage. This makes it difficult to clarify how and why ALS motor neurons are impaired at each clinical stage from disease onset to death, and as a consequence, human autopsy cases alone yield little insight into potential therapies for ALS. Although ALS animal models cannot replicate human ALS, in order to compensate for the shortcomings of studies using human ALS autopsy samples, researchers must inevitably rely on ALS animal models that can yield very important information for clarifying the pathogenesis of ALS in humans and for the establishment of reliable therapy. Of course, human ALS and all ALS animal models share one most important similarity in that both exhibit motor neuron degeneration/death. This important point of similarity has shed much light on the pathomechanisms of the motor neuron degeneration/death at the cellular and molecular levels that would not have been appreciated if only human ALS autopsy samples had been available. On the basis of the aspects covered in this review, it can be concluded that ALS animal models can yield very important information for clarifying the pathogenesis of ALS in humans and for the establishment of reliable therapy only in combination with detailed neuropathological data obtained from human ALS autopsy cases.     

Amyotrophic lateral sclerosis: Thyroid and prolactin hormone changes in thyrotropin-releasing hormone therapy

13 patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous infusion of thyrotropin-releasing hormone (TRH). In 6 patients 2 mg/day of TRH was i. v. given over 2 hours for 10 days. In 7 others 2 mg/day of TRH was continuously infused by means of a pump. An increase of thyroid hormones related to the duration of the treatment was observed. A surprising finding was the onset of prolactin (PRL) response to growth hormone releasing hormone (GHRH), previously absent.

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Sommario 13 pazienti con sclerosi laterale amiotrofica furono trattati con TRH endovena. In 6 pazienti TRH, alla dose di 2 mg al dì, fu somministrato in 2 ore per 10 giorni. In 7 altri pazienti 2 mg di TRH furono continuativamente infusi, per mezzo di una pompa, per 15 giorni. Un aumento degli ormoni tiroidei T3 e T4 fu osservato. Fu anche osservata la comparsa di una risposta, normalmente assente, della prolattina alla stimolazione con GHRH.

     

Respiratory function in amyotrophic lateral sclerosis

Abstract. The aim of this study was to examine the vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1) in relation to the site of amyotrophic lateral sclerosis (ALS) onset and the duration of the disease. Respiratory involvement is the principal cause of death in ALS patients. The study was conducted at the Department of Neurology, University School of Medicine in Lublin. The study comprised 18 ALS patients. The average duration of ALS was 12 months. The patients were divided into two groups according to the site of ALS onset and into two groups according to the duration of the disease. FVC was significantly higher in the group of patients with a limb onset than in the group of patients with a bulbar onset of the disease. The study has shown respiratory function disturbances in ALS patients. FVC significantly depends on the site of ALS onset but not on the duration of the disease.     

Amyotrophic lateral sclerosis associated with IgG anti-GalNAc-GD1a antibodies

A variety of immunological abnormalities have been reported in some patients with amyotrophic lateral sclerosis (ALS). It has been postulated that a disturbance of immunoregulation may play a role in the degeneration of motor neurons in ALS. We describe a 62-year-old man with a 9-month history of slowly progressive muscular weakness and atrophy of the upper and lower extremities and dysarthria. Neurological examinations revealed weakness and atrophy with fasciculation in the skeletal muscles including the face and tongue. In the limbs, distal muscles were affected predominantly. Electromyography showed chronic neurogenic changes with denervation potentials. Serum antibody testing demonstrated an increased titer of anti-N-acetylgalactosaminyl GD1a (GalNAc-GD1a) antibodies (IgGx160; normal, less than x40). The patient was treated with intravenous immunoglobulin (IVIg) therapy which was repeated two times at an interval of 2 months. However, the response to IVIg was negligible. To the authors' knowledge, this is the first report on ALS, in which the patient had anti-GalNAc-GD1a IgG antibody.     

Arabic adaptation of the Edinburgh cognitive and behavioural Amyotrophic lateral sclerosis screen (ECAS-AR)

Current screening batteries for assessing neuropsychological function are not specific for Amyotrophic Lateral Sclerosis (ALS) and are considered as limited tools due to the physical disabilities associated with ALS. The Edinburgh Cognitive and Behavioural ALS screen (ECAS) was developed to detect the specific cognitive and behavioral changes that may occur among ALS patients. This study presents the ECAS developed for Arabic-speaking ALS patients (ECAS-AR) for use by healthcare professionals. ECAS was translated and modified to refined variety of Arabic language. Eighty-five ALS patients were included. Normative data were collected from 200 healthy controls (among them 97 were matched). Subjects were administered the ECAS-AR and two conventional cognitive screening batteries, Frontal Assessment Battery (FAB) and Mini-Mental State Examination (MMSE). ECAS-AR discriminated well between healthy controls and ALS patients. Significant differences were noted in language, executive functions, memory, and visuospatial domains between the two groups. The most prevalent deficit occurred in language and executive functions in ALS-specific functions. Whereas memory was more readily impaired in the lower and middle education groups concerning ALS non-specific functions. Verbal fluency tended to be preserved. Positive correlations were found between ECAS-AR and the standard cognitive tests supporting its full validity. The ECAS-AR version proposed will provide rapid, efficient and sensitive tools for healthcare professional to determine the cognitive-behavioural profile in Arabic-speaking ALS patients.     

Prevalence of depression in amyotrophic lateral sclerosis and other motor disorders

Background: Research suggests the prevalence of severe depression in ALS is <20%. In contrast, studies have reported that severe depression affects 40–50% of patients with other neurodegenerative motor conditions (e.g. multiple sclerosis, Parkinson’s disease and Huntington’s disease). The comparison with such disorders has generated a clinical impression that patients with ALS have surprisingly low rates of depression. However, comparisons with such disorders do not take into account the markedly different pathological, physical and behavioural profiles associated with these disorders. To assess further the extent to which ALS is associated with a low prevalence of depression, we compared the prevalence of depression in patients with ALS to that in patients with neuromuscular disorders with more comparable disease profiles. Methods: The Beck Depression Inventory‐II (BDI‐II), the Major Depression Inventory (MDI), the Hospital Anxiety and Depression Scale (HADS) and the ALS Functional Rating Scale‐Revised were sent to 212 patients from a tertiary referral Motor Nerve Clinic in London, UK. Results: Data were obtained from 51 people with ALS and 39 with other neuromuscular disorders. The non‐ALS group included patients diagnosed with disorders that are characterized by motor neurone dysfunction and/or a decline in everyday function. Analyses revealed no between‐group differences on severity and prevalence rates of depression according to the BDI‐II, HADS Depression Subscale and MDI. Conclusions: Our findings do not support the impression that patients with ALS have lower rates of depression than patients with other varied neuromuscular disorders.