History Of Amyotrophic Lateral Sclerosis Research Articles

Scientific plurality and amyotrophic lateral sclerosis (ALS): A philosophical and historical perspective on Charcot’s texts

ABSTRACT The history of amyotrophic lateral sclerosis (ALS)—also known as Charcot’s disease, Lou Gehrig’s disease, and motor neuron disease (MND)—freezes the texts of the scientist and physician Jean-Martin Charcot in a hagiographic narrative describing a brilliant discovery, based on the anatomo-clinical method. This narrative is often used by biologists and physicians as a reference point. This article shows that the use of the hagiographic register faces limitations. In particular, it obscures points of interest from Charcot’s texts on ALS, such as the epistemological and ontological implications of scientific plurality in medicine. Although Charcot recognized the importance of scientific plurality in medicine, he prioritized the approaches and conferred the most important epistemic authority on clinical and pathological observations. In his view, animal modeling remains secondary to the understanding of disease. The concept of ALS and its diagnostic operability are the result of symptoms and lesions. By studying the past, we can highlight the specific features of the present. Today, although the ALS concept retains its diagnostic and clinical relevance, it is increasingly called into question in etiological and mechanistic research. Despite these differences, Charcot’s reflections are a reminder of the importance of theoretical thinking on scientific plurality, all the more so today in the context of ALS research, in which combining different approaches is increasingly valued to understand the phenotypic and genetic heterogeneity of ALS.

Real-time ultrasound-guided sacral plexus block combined with mild sedation for hemorrhoidectomy and hemorrhoidal artery ligation in a patient with amyotrophic lateral sclerosis: a case report

BackgroundPatients with amyotrophic lateral sclerosis present perioperative challenges for clinical anesthesiologists for anesthesia-associated complications.Case presentationA 54-year-old Han woman with a 2-year history of amyotrophic lateral sclerosis was scheduled for hemorrhoidectomy and hemorrhoidal artery ligation. We performed real-time ultrasound-guided sacral plexus block with dexmedetomidine under standard monitoring. The anesthesia method met the surgical demands and avoided respiratory complications during the procedures. There was no neurological deterioration after the surgery and 3 months after, the patient was discharged.ConclusionsReal-time ultrasound-guided sacral plexus block combined with mild sedation may be an effective and safe technique in patients with amyotrophic lateral sclerosis undergoing hemorrhoidectomy and hemorrhoidal artery ligation.

Clinical spectrum of frontotemporal dementia: schizophrenia-like symptoms and amyotrophic lateral sclerosis (family case study)

Frontotemporal dementia is a heterogeneous pathology with various clinical, histological, and genetic variants. The behavioral variant of frontotemporal dementia (bvFTD) in some cases presents differential diagnostic difficulties when distinguishing from primary mental disorders. The article provides an observation of patient K., who was observed at the initial stage of the disease with a diagnosis of schizophrenia. The comparison of psychopathological and behavioral symptoms with the presence of a family history of amyotrophic lateral sclerosis (ALS) served as a turning point to a different interpretation of the pathology and recognition and confirmation of the “definite diagnosis” — bvFTD.

Chronic respiratory failure negatively affects speech function in patients with bulbar and spinal onset amyotrophic lateral sclerosis: retrospective data from a tertiary referral center

Background: Although dysarthria and respiratory failure are widely described in literature as part of the natural history of Amyotrophic lateral sclerosis (ALS), the specific interaction between them has been little explored. Aim: To investigate the relationship between chronic respiratory failure and the speech of ALS patients. Materials and methods: In this cross-sectional retrospective study we reviewed the medical records of all patients diagnosed with ALS that were accompanied by a tertiary referral center. In order to determine the presence and degree of speech impairment, the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) speech sub-scale was used. Respiratory function was assessed through spirometry and through venous blood gasometry obtained from a morning peripheral venous sample. To determine whether differences among groups classified by speech function were significant, maximum and mean spirometry values of participants were compared using multivariate analysis of variance (MANOVA) with Tukey’s post hoc test. Results: Seventy-five cases were selected, of which 73.3% presented speech impairment and 70.7% respiratory impairment. Respiratory and speech functions were moderately correlated (seated FVC r = 0.64; supine FVC r = 0.60; seated FEV1 r = 0.59 and supine FEV1 r = 0.54, p < .001). Multivariable logistic regression revealed that the following variables were significantly associated with the presence of speech impairment after adjusting for other risk factors: seated FVC (odds ratio [OR] = 0.862) and seated FEV1 (OR = 1.106). The final model was 81.1% predictive of speech impairment. The presence of daytime hypercapnia was not correlated to increasing speech impairment. Conclusion: The restrictive pattern developed by ALS patients negatively influences speech function. Speech is a complex and multifactorial process, and lung volume presents a pivotal role in its function. Thus, we were able to find that lung volumes presented a significant correlation to speech function, especially in those with bulbar onset and respiratory impairment. Neurobiological and physiological aspects of this relationship should be explored in further studies with the ALS population.

A Barium Swallow Study Leading to an Incidental Finding on a Screening Colonoscopy

Barolith is a mixture of firm feces with barium sulfate, and a frequent cause of obstruction of the appendiceal lumen that can result in appendicitis. Nonetheless, some other complications like aspiration, allergic reaction, and bowel obstruction have also been reported. We present the case of a 71-year-old man with a history of amyotrophic lateral sclerosis (ALS), who came to the gastroenterology clinic complaining of intermittent loose stools and dysphagia to solids for the past months. The patient underwent a barium swallow study six days prior and was completely normal. A colonoscopy was done showing normal appearing mucosa, with a whitish foreign object found on the appendiceal orifice. Removal of the barolith was done by means of a biopsy forceps.Our patient did not have any signs or symptoms of appendicitis prior to the procedure, and the successful removal of the barolith was achieved. Elderly patients, and patients with decreased gastrointestinal (GI) transit, could be a population at risk for barium retention/appendicitis; for this reason, more research studies should be done to assess possible preventive treatments.

Stratification of ALS patients' survival: a population-based study.

The natural history of amyotrophic lateral sclerosis (ALS) and patient risk stratification are areas of considerable research interest. We aimed (1) to describe the survival of a representative cohort of French ALS patients, and (2) to identify covariates associated with various patterns of survival using a risk classification analysis. ALS patients recruited in the FRALim register (2000-2013) were included. Time-to-death analyses were performed using Kaplan-Meier method and Cox model. A recursive partitioning and amalgamation (RECPAM) algorithm analysis identified subgroups of patients with different patterns of survival. Among 322 patients, median survival times were 26.2 and 15.6 months from time of onset and of diagnosis, respectively. Four groups of patients were identified, depending on their baseline characteristics and survival (1) ALSFRS-R slope >0.46/month and definite or probable ALS (median survival time (MST) 10.6 months); (2) ALSFRS-R slope >0.46/month and possible or probable laboratory-supported ALS (MST: 18.1 months); (3) ALSFRS-R slope ≤0.46/month and definite or probable ALS (MST: 22.5 months), and (4) ALSFRS-R slope ≤0.46/month and possible or probable laboratory-supported ALS (MST: 37.6 months). Median survival time is among the shortest ever reported by a worldwide population-based study. This is probably related to the age structure of the patients (the oldest identified to date), driven by the underlying population (30 % of subjects older than 60 years). Further research in the field of risk stratification could help physicians better anticipate prognosis of ALS patients, and help improve the design of randomized controlled trials.

Brain morphologic changes in asymptomatic C9orf72 repeat expansion carriers.

To investigate possible effects of the C9orf72 repeat expansion before disease onset, we assessed brain morphology in asymptomatic carriers. Aiming to diminish the effects of genetic variation between subjects, apart from the C9orf72 repeat expansion, 16 carriers of the repeat expansion were compared with 23 noncarriers from the same large family with a history of amyotrophic lateral sclerosis (ALS). Cortical thickness, subcortical volumes, and white matter connectivity, as assessed from high-resolution T1-weighted and diffusion-weighted MRIs, were evaluated. For comparison, we included 14 C9orf72 carriers with ALS and 28 healthy, unrelated controls. We found temporal, parietal, and occipital regions to be thinner (p < 0.05) and the left caudate and putamen to be smaller (p < 0.05) in asymptomatic carriers compared with noncarriers. Cortical thinning of the primary motor cortex and decreased connectivity of white matter pathways (global, corticospinal tract, and corpus callosum) were observed in patients with C9orf72-associated ALS, but not in asymptomatic carriers. Asymptomatic C9orf72 carriers show cortical and subcortical differences compared with noncarriers from the same family, possibly effects of the C9orf72 repeat expansion on the brain. Of note, changes in the primary motor regions and motor-related tracts were found exclusively in patients with ALS, indicating that such motor changes may be a disease phenomenon.

Galactorrhea Associated with Sertraline: a Case Report and Literature Review

Introduction Even though the most common cause of galactorrhea in adults is medication-induced, SSRIs are very rarely incriminated. Among SSRIs, sertraline appears to be one of the least reported drugs, whereas escitalopram and paroxetine appear to be the most. Objective To outline the occurrence of sertraline-induced (and more generally SSRI-induced) galactorrhea and to discuss the possible underlying mechanisms and the subsequent therapeutic implications. Methods Case report and review Results We report the case of a female patient aged 40, with a family history of amyotrophic lateral sclerosis and with a personal history of fibromyalgia on pregabalin. The patient presented with anhedonia, asthenia, panic attacks, restlessness as well as decreased appetite and insomnia. The diagnosis of a major depressive disorder, single episode, moderate with anxious distress was made (DSM-5 criteria). The patient was started on sertraline 50mg qd and lorazepam 1 mg qd. In the absence of adequate improvement, sertraline dosage was increased to 100mg qd. About two months later, the patient started to complain of galactorrhea. Prolactin level was not obtained. MRI examination of the brain and the pituitary gland was normal. Sertraline was, then, withdrawn and galactorrhea ceased a few days later. The patient was switched to venlafaxine, which was well tolerated. Conclusions Although SSRI-induced galactorrhea seems very rare, the high number of patients on SSRIs makes the prevalence of this side effect probably significant and thus worth monitoring. A patient who develops galactorrhea on one SSRI might tolerate (and can thus be switched to) other SSRIs or SNRIs.

Widespread grey matter pathology dominates the longitudinal cerebral MRI and clinical landscape of amyotrophic lateral sclerosis.

Diagnosis, stratification and monitoring of disease progression in amyotrophic lateral sclerosis currently rely on clinical history and examination. The phenotypic heterogeneity of amyotrophic lateral sclerosis, including extramotor cognitive impairments is now well recognized. Candidate biomarkers have shown variable sensitivity and specificity, and studies have been mainly undertaken only cross-sectionally. Sixty patients with sporadic amyotrophic lateral sclerosis (without a family history of amyotrophic lateral sclerosis or dementia) underwent baseline multimodal magnetic resonance imaging at 3 T. Grey matter pathology was identified through analysis of T1-weighted images using voxel-based morphometry. White matter pathology was assessed using tract-based spatial statistics analysis of indices derived from diffusion tensor imaging. Cross-sectional analyses included group comparison with a group of healthy controls (n = 36) and correlations with clinical features, including regional disability, clinical upper motor neuron signs and cognitive impairment. Patients were offered 6-monthly follow-up MRI, and the last available scan was used for a separate longitudinal analysis (n = 27). In cross-sectional study, the core signature of white matter pathology was confirmed within the corticospinal tract and callosal body, and linked strongly to clinical upper motor neuron burden, but also to limb disability subscore and progression rate. Localized grey matter abnormalities were detected in a topographically appropriate region of the left motor cortex in relation to bulbar disability, and in Broca's area and its homologue in relation to verbal fluency. Longitudinal analysis revealed progressive and widespread changes in the grey matter, notably including the basal ganglia. In contrast there was limited white matter pathology progression, in keeping with a previously unrecognized limited change in individual clinical upper motor neuron scores, despite advancing disability. Although a consistent core white matter pathology was found cross-sectionally, grey matter pathology was dominant longitudinally, and included progression in clinically silent areas such as the basal ganglia, believed to reflect their wider cortical connectivity. Such changes were significant across a range of apparently sporadic patients rather than being a genotype-specific effect. It is also suggested that the upper motor neuron lesion in amyotrophic lateral sclerosis may be relatively constant during the established symptomatic period. These findings have implications for the development of effective diagnostic versus therapeutic monitoring magnetic resonance imaging biomarkers. Amyotrophic lateral sclerosis may be characterized initially by a predominantly white matter tract pathological signature, evolving as a widespread cortical network degeneration.

Cardiac failure as an unusual presentation in a patient with history of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most well-known form of motor neuron diseases in which both upper and lower motor neurons are involved in this disease. We presented an unusual case of ALS whom had presented with chief complaint of dyspnea. Cardiac failure was diagnosed at the final stage of the ALS disease. The pathogenetic mechanism leading to an elevated occurrence of cardiomyopathy in ALS is not comprehensible. Dilated cardiomyopathy has been explained in some previous studies. Based on the collected data, it was hypothesized that cardiomyopathy is underdiagnosed in the ALS population, probably because symptoms are masqueraded as a result of the patients' disability. It was suggested that in all motor neuron diseases a serial cardiological evaluation should be executed, including annual echocardiography.

Carnitine deficiency presenting with a decreased mental state in a patient with amyotrophic lateral sclerosis receiving long-term tube feeding: a case report

IntroductionL-carnitine is an important metabolic mediator involved in fatty acid transport. It is obtained from the diet, particularly from animal products, such as red meat. Previous reports have revealed that long-term tube feeding with a commercial product containing no or low levels of carnitine can lead to an altered mental state caused by hyperammonemia.Case presentationA 72-year-old Japanese man had a 12-year history of amyotrophic lateral sclerosis. He was bedridden and had required mechanical ventilation and enteral tube feeding for 10 years at home. His main enteral solution was a commercial product that contained low carnitine levels, and he sometimes received coffee and homemade products such as miso soup. Our patient’s ability to communicate gradually deteriorated over a period of one year. His serum total carnitine level was abnormally low, at 26.7μmol/L (normal range, 45 to 91μmol/L), but his ammonium level was normal. His mental state improved dramatically after starting L-carnitine supplementation (600mg twice daily).ConclusionThis case highlights the importance of avoiding carnitine deficiency in patients with amyotrophic lateral sclerosis undergoing long-term tube feeding. These patients experience progressive muscle atrophy that might cause impaired carnitine storage and might manifest as communication difficulties. Carnitine deficiency can be misdiagnosed as a progression of systemic muscle atrophy. Clinicians should be aware of this disorder and should consider periodically measuring carnitine levels, regardless of the patient’s serum ammonium levels.

Activity of the Novel T137A Sod1 Mutation In Amyotrophic Lateral Sclerosis Patients

Aim: More than 160 mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene are known and identifiable in approximately 20% of patients with familial history of amyotrophic lateral sclerosis (ALS) and in the 1–2% of the sporadic cases. A new SOD1 variant, the T137A missense mutation, was recently discovered. The aim of this study was to better clarify the activity of T137A-SOD1 in ALS patients. Methods: The activity of erythrocyte SOD enzyme and the plasma total antioxidant capacity were measured in 20 ALS patients with wild-type SOD1, in five ALS-patients harboring mutated SOD1 and in seven healthy controls. Results: Erythrocyte Cu/Zn-SOD activity was significantly lower in mutated patients than in wild-type participants and in controls, regardless of the type of mutation. Our data demonstrate that the SOD1 enzyme harboring the novel T137A mutation presents typical features of other known SOD1 variants. Conclusion: These results provide further evidence of the possible pathogenic role of the T137A mutation in ALS.

Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72

Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.

The risk to relatives of patients with sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons with a median survival of 2 years. Most patients have no family history of amyotrophic lateral sclerosis, but current understanding of such diseases suggests there should be an increased risk to relatives. Furthermore, it is a common question to be asked by patients and relatives in clinic. We therefore set out to determine the risk of amyotrophic lateral sclerosis to first degree relatives of patients with sporadic amyotrophic lateral sclerosis attending a specialist clinic. Case records of patients with sporadic amyotrophic lateral sclerosis seen at a tertiary referral centre over a 16-year period were reviewed, and pedigree structures extracted. All individuals who had originally presented with sporadic amyotrophic lateral sclerosis, but who subsequently had an affected first degree relative, were identified. Calculations were age-adjusted using clinic population demographics. Probands (n = 1502), full siblings (n = 1622) and full offspring (n = 1545) were identified. Eight of the siblings and 18 offspring had developed amyotrophic lateral sclerosis. The unadjusted risk of amyotrophic lateral sclerosis over the observation period was 0.5% for siblings and 1.0% for offspring. Age information was available for 476 siblings and 824 offspring. For this subset, the crude incidence of amyotrophic lateral sclerosis was 0.11% per year (0.05–0.21%) in siblings and 0.11% per year (0.06–0.19%) in offspring, and the clinic age-adjusted incidence rate was 0.12% per year (0.04–0.21%) in siblings. By age 85, siblings were found to have an 8-fold increased risk of amyotrophic lateral sclerosis, in comparison to the background population. In practice, this means the risk of remaining unaffected by age 85 dropped from 99.7% to 97.6%. Relatives of people with sporadic amyotrophic lateral sclerosis have a small but definite increased risk of being affected.

Robotic Roux-en-Y Duodenojejunostomy for Superior Mesenteric Artery Syndrome: Operative Technique

Superior mesenteric artery (SMA) syndrome, also known as Wilkie's syndrome, is a rare condition characterized by vascular compression of the duodenum that leads to intestinal obstruction. While there have been a few recent case reports of laparoscopic duodenojejunostomy performed as an option for surgical treatment, the role of the da Vinci(®) robot in superior mesenteric syndrome has been underestimated. The authors report a robotic Roux-en-Y duodenojejunostomy for the treatment of SMA syndrome. A 39-year-old man with a history of Amyotrophic lateral sclerosis presented with an upper gastrointestinal obstruction with distended abdomen. A computed tomography scan showed a transition in the third portion of the duodenum where the SMA vessels crossed over, with a decompressed jejunum. He was identified as a candidate for a duodenojejunostomy. The da Vinci Surgical System was used to mobilize the colon and duodenum, and a Roux-en-Y duodenojejunostomy was performed with hand-sewn anastomosis. There were no intraoperative complications. The blood loss was minimal and operative time was 120 minutes. The postoperative course was uneventful with resolution of intestinal obstruction. Robotic Roux-en-Y duodenojejunostomy as a surgical option for treatment of SMA syndrome is safe, feasible, and a valid alternative to open surgery with the added benefits of a minimally invasive approach.

Changes in the Spinal Cord Proteome of an Amyotrophic Lateral Sclerosis Murine Model Determined by Differential In-gel Electrophoresis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons resulting in progressive paralysis. To date, more than 140 different mutations in the gene encoding CuZn-superoxide dismutase (SOD1) have been associated with ALS. Several transgenic murine models exist in which various mutant SOD1s are expressed. We used DIGE to analyze the changes in the spinal cord proteome induced by expression of the unstable SOD1 truncation mutant G127insTGGG (G127X) in mice. Unlike mutants used in most other models, G127X lacks SOD activity and is present at low levels, thus reducing the risk of overexpression artifacts. The mice were analyzed at their peak body weights just before onset of symptoms. Variable importance plot analysis showed that 420 of 1,800 detected protein spots contributed significantly to the differences between the groups. By MALDI-TOF MS analysis, 54 differentially regulated proteins were identified. One spot was found to be a covalently linked mutant SOD1 dimer, apparently analogous to SOD1-immunoreactive bands migrating at double the molecular weight of SOD1 monomers previously detected in humans and mice carrying mutant SOD1s and in sporadic ALS cases. Analyses of affected functional pathways and the subcellular representation of alterations suggest that the toxicity exerted by mutant SODs induces oxidative stress and affects mitochondria, cellular assembly/organization, and protein degradation.

March 13 Highlight and Commentary

Spina et al. provide the results of a multidisciplinary study of three individuals with frontotemporal dementia (FTD) associated with a progranulin ( PGRN ) sequence variation. Two cases had a PGRN truncating mutation, a family history of FTD, and ubiquitin-positive neuronal intranuclear inclusions (NII). The third case had a PGRN missense mutation, a strong family history of amyotrophic lateral sclerosis, and absence of NII. see page 820 Commentary by Paul G. Ince, MD, FRCPath Disparate threads of clinical, pathologic, and genetic evidence weave a tapestry supporting a hypothesis …

Clinicopathological phenotype of ALS with a novel G72C SOD1 gene mutation mimicking a myopathy

A 71-year-old woman with a family history of amyotrophic lateral sclerosis (ALS) was investigated for symmetrical, proximal limb and abdominal muscle weakness. Initial examination showed mild proximal muscle weakness in the arms and legs, slightly elevated serum creatine kinase (CK) level, and normal electromyographic (EMG) findings. A myopathy was the presumed diagnosis. Over the next year, weakness became severe and tendon reflexes became unelicitable; no upper motor signs were present. EMG then showed acute and chronic denervation and a muscle biopsy showed target fibers and grouped atrophy. DNA analysis revealed a G72C CuZn-superoxide dismutase (SOD1) mutation. Fasciculations were absent throughout the disease. The patient died 53 months after symptom onset and autopsy revealed loss of lower motor neurons (LMN) and SOD1-positive inclusions. This case expands the phenotypic spectrum of ALS associated with SOD1 mutations to include presenting features that mimic a myopathy.

Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction.

Over 1200 patients with motor neuron disease have been carefully diagnosed, followed, and included in a detailed database delineating characteristics of the disease. Of these patients, 831 were identified as exhibiting typical, sporadic amyotrophic lateral sclerosis (ALS). The progression of the disease in these patients has been followed with our scoring system, and the ALS score was verified as a significant covariate of survival. Age at first symptom, delay from first symptom to entering ALS clinic, and rate of change of respiratory function were also identified as significant covariates of survival. These measures, applied to the Cox proportional hazards model, were used to develop a mathematical model for prediction of survival time in ALS, which proved highly accurate for the 80% of patients at intermediate risk. For those patients, a second model was developed which accurately predicts, after an initial period of observation, the time over which ALS patients will decline a set number of points in total ALS score. Such validation permits initial trials for drug therapies in ALS by comparison of relatively small groups of treated patients to this historical control group, based on the model of predicted time to a particular decrement in total ALS score.

The natural history of amyotrophic lateral sclerosis.

Using 42 strength and functional assessments recorded monthly, the natural history of amyotrophic lateral sclerosis (ALS) is described in 167 patients (98 men, 67 women) followed in five medical centers in the western United States. The mean age at onset was 57.4 years, and symptoms were present for 2.64 years before study entry. Although there was a highly variable rate of decline within the group of patients, there were no differences in rate of decline by age or gender. Older patients and women were weaker on entry. Forty-eight patients died during the study. The median survival was 4.0 years for the study cohort but 2.1 years for newly diagnosed cases. Decline in pulmonary function most closely correlated with death. Our results emphasize the importance of considering clinical variability in planning clinical trials. One possible strategy is to identify and stratify patients by rate of decline in pulmonary function since prospectively identifying homogeneous subgroups allows investigators to substantially reduce sample size in therapeutic trials.