Amyotrophic lateral sclerosis with ophthalmoplegia and multisystem degeneration in patients on long-term use of respirators

Summary We describe two patients with sporadic amyotrophic lateral sclerosis (ALS), who had developed progressive external ophthalmoplegia of a predominantly supranuclear type while they survived on respirators, and displayed histopathological abnormalities both typical and atypical of ALS. Patient 1 was a 43-year-old man with ALS of 5-year duration, who had initially exhibited fulminant ALS, and remained on a respirator for 4 years. Patient 2 was a 51-year-old man with ALS of 13-year duration, who remained on a respirator for 8 years. Both patients died in a totally locked-in state. Autopsy of both patients revealed not only histopathological abnormalities consistent with ALS, but also multisystem degeneration which involved the pontine tegmentum, substantia nigra, Clarke's dorsal nuclei and spinocerebellar tracts. In addition, Patient 2 displayed intracyto-plasmic neuronal basophilic inclusion bodies which exhibited marked immunoreactivity to anti-ubiquitin antibodies. Our case reports indicate that the longer survival which is possible through the use of respirators may make one subgroup of ALS patients prone to develop atypical clinical and neuropathological features which are not observed during the natural cours of ALS.Supported by a Grant-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health and Welfare of Japan, and by a Grant from Nihon University School of Medicine, Tokyo     

MRI predictors of long-term evolution in amyotrophic lateral sclerosis

We investigated whether conventional and diffusion tensor (DT) magnetic resonance imaging (MRI) features of the corticospinal tract (CST) contribute to the prediction of the long-term clinical evolution in patients with amyotrophic lateral sclerosis (ALS). Brain conventional and DT MRI were obtained from 18 healthy subjects and 24 patients with sporadic ALS. Mean diffusivity (MD) and fractional anisotropy (FA) of the CST were obtained. Patients were scanned at baseline, then entered a longitudinal clinical follow-up. The ALS Functional Rating scale (ALSFRS) progression rate during follow-up was estimated. Patients were followed up prospectively for a median period of 3.4 years. Two patients were lost at follow-up and eight died during the observation period. The mean ALSFRS progression rate was 0.7/month (range = 0.0–2.0/month). At baseline, ALS patients showed significantly increased MD and decreased FA of the CST compared with controls. CST FA was associated with ALSFRS progression rate. ALSFRS deterioration rate and CST FA were independent predictors of survival in ALS patients. Survival at year 3 was 42% in patients with CST FA ≤ 0.56 compared with 90% in patients with CST FA > 0.56. This study shows that more severe CST DT MRI abnormalities predict a poorer long-term clinical outcome in ALS patients. DT MRI of the brain has the potential to offer in vivo markers of disease severity.     

Central fatigue during isometric exercise in amyotrophic lateral sclerosis

While both upper and lower motor neuron dysfunction may contribute to impaired muscle function in amyotrophic lateral sclerosis (ALS), the precise mechanisms of muscle fatigue have not been clarified in this disease. Therefore, the central and peripheral factors in muscle fatigue were investigated during intermittent submaximal isometric ankle dorsiflexion in 7 patients with ALS and 6 healthy control subjects. Voluntary and electrically stimulated force, central and peripheral indices of muscle activation, and intramuscular energy metabolism were measured before and during exercise. At the end of exercise, only the ALS group had an increase in the "added force" in response to a stimulus train imposed during maximal voluntary contraction, indicating significant central fatigue in ALS. In support of this conclusion, patients with ALS had less intramuscular phosphocreatine depletion and less fatigue of stimulated tetanic force during exercise compared to control. Thus, due to the central failure, there was decreased muscle activation resulting in a smaller metabolic demand and less fatigue within the muscle itself. These data demonstrate a major contribution of central factors to muscle fatigue in ALS.     

Hereditary amyotrophic lateral sclerosis

A Spanish family transmits, as an autosomal dominant trait, a form of amyotrophic lateral sclerosis characterized by an unusually prolonged evolution of the disease in all affected members. Precocity and persistence of muscle cramps, presence of unilateral proximal segmental myoclonus and early abolition of ankle jerks are other clinical features conspicuous in this family. This type of hereditary ALS of non-Chamorro origin and prolonged evolution is rare.     

Juvenile amyotrophic lateral sclerosis

This paper presents two juvenile cases of familial amyotrophic lateral sclerosis. They are the first and fourth child in a family with seven children from the eastern part of Finland. All seven children, as well as the parents, were examined by our group. In the first case the disease showed a rather mild course, while in the second a noticeable progression was observed even during a period of 10 months. The patients come from a rural area with a stable population and low immigration, which may favor an enrichment of certain genes and therefore support the possible hereditary basis for the disease.     

Familial amyotrophic lateral sclerosis

Familial occurrence of neuromuscular disease similar to sporadic amyotrophic lateral sclerosis has been reported from several countries.
A Norwegian family with muscular wasting in men and women of three generations is described. The propositus and his father's sister were examined, as well as a second cousin of the propositus. The disease was characterized by late onset, predominantly upper limb peripheral pareses, and "pyramidal" signs in the lower extremities. Although peripheral neuromuscular affection in the lower limbs tended to be subclinical, chonchotome biopsies from the tibialis anterior muscle showed neurogenic atrophy in all three cases.     

Familial amyotrophic lateral sclerosis

The increasing complexity of the pathways implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) has stimulated intensive research in many directions. Genetic analysis of familial ALS has yielded six loci and one disease gene (SOD1), initially suggesting a role for free radicals in the disease process, although the mechanisms through which the mutant exerts toxicity and results in selective motor neuron death remain uncertain. Numerous studies have focused on structural elements of the affected cell, emphasizing the role of neurofilaments and peripherin and their functional disruption in disease. Other topics examined include cellular homeostasis of copper and calcium, particularly in the context of oxidative stress and the processes of protein aggregation, glutamate excitotoxicity, and apoptosis. It has become evident that there is considerable interplay between these mechanisms and, as the role of each is established, a common picture may emerge, enabling the development of more targeted therapies. This study discusses the main areas of investigation and reviews the findings.     

Ceftriaxone in amyotrophic lateral sclerosis

One hundred and eight patients with amyotrophic lateral sclerosis (ALS) received ceftriaxone 2 g daily i.v. (62) or i.m. (34) or by both routes (12), for 21-day cycles on an open basis. Baseline MRC and Norris scores were similar to those at the end of the first 21-day cycle of therapy. Seven patients showed remarkable clinical improvement, mostly segmental, which started during the first week of treatment and lasted up to 2 months after its completion. Improvement was also noted in seven out of 21 cases given a subsequent cycle of treatment. Based on these findings, the drug is supposed to act by altering the neurochemical transmission at the neuromuscular junction and/or by facilitating the presynaptic uptake of glutamate at the synaptic junction. This hypothesis positively correlates with the results of in vitro experiments showing that ceftriaxone increases ³H-glutamate uptake in rat spinal cord synaptosomes.     

Microglia in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disorder that results in the selective death of motor neurons in the central nervous system. This progressive motor neuron degeneration leads to death of the patient on average three to five years after onset of the disease. To date, no therapy is available. Many hypotheses have been formulated to explain the selective degeneration of motor neurons. One of the most studied hypotheses is the putative role of the inflammatory response that accompanies motor neuron death. The proliferation of microglia and astrocytes has been considered to be a secondary phenomenon, but recently, evidence is accumulating in favour of a contributory role of the non-neuronal cell populations to the pathogenesis of the disease. In this review, we will introduce the characteristics of microglial cells in the central nervous system. We will summarize the evidence of the expansion and the activation of the microglial cell population that accompanies motor neuron degeneration. Finally, an overview will be given of the different therapeutic strategies that targeted the inflammatory process in amyotrophic lateral sclerosis.