Lokesh Wijesekera

Natural history and clinical features of the flail arm and flail leg ALS variants

Objective: We sought to define the significance of brachial amyotrophic diplegia (flail arm syndrome [FA]) and the pseudopolyneuritic variant (flail leg syndrome [FL]) of amyotrophic lateral sclerosis (ALS; motor neuron disease). Methods: We analyzed survival in clinic cohorts in London, UK (1,188 cases), and Melbourne, Australia (432 cases). Survival from disease onset was analyzed using the Kaplan- Meier method and Cox proportional hazards model. Results: In the London cohort, the FA syndrome represented 11% and the FL syndrome 6% of the sample. Median survival was 35 months for limb onset and 27 months for bulbar onset ALS, whereas this was 61 months for FA syndrome (p < 0.001) and 69 months for FL syndrome (p < 0.001). Five-year survival in this cohort was 8.8% for bulbar onset, 20% for limb onset, 52% for FA syndrome, and 64% for FL syndrome. The ratio of men to women was 4:1 in the FA group compared to 2:1 in other limb onset cases. Excluding lower motor neuron FA and FL cases, progressive muscular atrophy comprised 4% of the sample and had a prognosis similar to typical limb onset ALS. In the Melbourne cohort, median survival for limb onset ALS was 31 months, bulbar onset 27 months, FA syndrome 66 months (p < 0.001), and FL syndrome 71 months (p = 0.001). Conclusions: The flail arm (FA) and flail leg (FL) syndromes had significantly better survival than typical amyotrophic lateral sclerosis (ALS) or progressive muscular atrophy cases that were not classified as FA or FL. Our findings underline the clinical and prognostic importance of the FA and FL variants of ALS.

A proposed staging system for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, with a median survival of 2–3 years. Although various phenotypic and research diagnostic classification systems exist and several prognostic models have been generated, there is no staging system. Staging criteria for amyotrophic lateral sclerosis would help to provide a universal and objective measure of disease progression with benefits for patient care, resource allocation, research classifications and clinical trial design. We therefore sought to define easily identified clinical milestones that could be shown to occur at specific points in the disease course, reflect disease progression and impact prognosis and treatment. A tertiary referral centre clinical database was analysed, consisting of 1471 patients with amyotrophic lateral sclerosis seen between 1993 and 2007. Milestones were defined as symptom onset (functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, needing gastrostomy and non-invasive ventilation. Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration. Milestones occurred at predictable proportions of the disease course. Diagnosis occurred at 35% through the disease course, involvement of a second region at 38%, a third region at 61%, need for gastrostomy at 77% and need for non-invasive ventilation at 80%. We therefore propose a simple staging system for amyotrophic lateral sclerosis. Stage 1: symptom onset (involvement of first region); Stage 2A: diagnosis; Stage 2B: involvement of second region; Stage 3: involvement of third region; Stage 4A: need for gastrostomy; and Stage 4B: need for non-invasive ventilation. Validation of this staging system will require further studies in other populations, in population registers and in other clinic databases. The standardized times to milestones may well vary between different studies and populations, although the stages themselves and their meanings are likely to remain unchanged.

An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline

The transactive response DNA binding protein (TDP‐43) proteinopathies describe a clinico‐pathological spectrum of multi‐system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP‐43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP‐43‐positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star‐shaped p62‐immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP‐43‐positive inclusions were sparse. This pattern was also seen in the cerebellum where p62‐positive, TDP‐43‐negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD‐TDP, showed high p62 levels and low TDP‐43 levels with no high molecular weight smearing. MND/ALS‐associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9‐linked MND/ALS and FTLD. We conclude that these chromosome 9‐linked MND/ALS cases represent a pathological sub‐group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.

Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial

Summary Background Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. Methods The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. Findings Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ2 on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40–1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. Interpretation We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. Funding The Motor Neurone Disease Association of Great Britain and Northern Ireland.

The sex ratio in amyotrophic lateral sclerosis: A population based study

Abstract Replicable risk factors for ALS include increasing age, family history and being male. The male: female ratio has been reported as being between 1 and 3. We tested the hypothesis that the sex ratio changes with age in a population register covering the south-east of England. The sex ratio before and after the age of 51 years was compared using a Z-test for proportions. Kendalls tau was used to assess the relationship between age group and sex ratio using incidence and prevalence data. Publicly available data from Italian and Irish population registers were compared with results. There was a significant difference in the proportion of females with ALS between those in the younger group (30.11%) and those in the older group (43.66%) (p = 0.013). The adjusted male: female ratio dropped from 2.5 in the younger group to 1.4 in the older group using prevalence data (Kendalls tau = −0.73, p = 0.039). Similar ratios were found in the Italian but not the Irish registry. We concluded that sex ratios in ALS may change with age. Over-representation of younger patients in clinic registers may explain the variation in sex ratios between studies. Menopause may also play a role.

Latent Cluster Analysis of ALS Phenotypes Identifies Prognostically Differing Groups

Background Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. Methods Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. Results The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). Conclusion The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research.

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.

Nutritional factors associated with survival following enteral tube feeding in patients with motor neurone disease.

BACKGROUND Motor neurone disease (MND) is a progressive neurodegenerative disease leading to limb weakness, wasting and respiratory failure. Prolonged poor nutritional intake causes fatigue, weight loss and malnutrition. Consequently, disease progression requires decisions to be made regarding enteral tube feeding. The present study aimed to investigate the survival, nutritional status and complications in patients with MND treated with enteral tube feeding. METHODS A retrospective case note review was performed to identify patients diagnosed with MND who were treated with enteral tube feeding. A total of 159 consecutive cases were identified suitable for analysis. Patients were treated with percutaneous endoscopic gastrostomy (PEG), radiologically inserted gastrostomy (RIG) or nasogastric feeding tube (NGT). Nutritional status was assessed by body mass index (BMI) and % weight loss (% WL). Serious complications arising from tube insertion and prescribed daily energy intake were both recorded. RESULTS Median survival from disease onset was 842 days [interquartile range (IQR) 573-1263]. Median time from disease onset to feeding tube was PEG 521 days (IQR 443-1032), RIG 633 days (IQR 496-1039) and NGT 427 days (IQR 77-781) (P = 0.28). Median survival from tube placement was PEG 200 (IQR 106-546) days, RIG 216 (IQR 83-383) days and NGT 28 (IQR 14-107) days. Survival between gastrostomy and NGT treated patients was significant (P < or = 0.001). Analysis of serious complications by nutritional status was BMI (P = 0.347) and % WL (P = 0.489). CONCLUSIONS Nutritional factors associated with reduced survival were weight loss, malnutrition and severe dysphagia. Serious complications were not related to nutritional status but to method of tube insertion. There was no difference in survival between PEG and RIG treated patients.

Prognostic categories for amyotrophic lateral sclerosis.

Our objective was to generate a prognostic classification method for amyotrophic lateral sclerosis (ALS) from a prognostic model built using clinical variables from a population register. We carried out a retrospective multivariate analysis of 713 patients with ALS over a 20-year period from the South-East England Amyotrophic Lateral Sclerosis (SEALS) population register. Patients were randomly allocated to ‘discovery’ or ‘test’ cohorts. A prognostic score was calculated using the discovery cohort and then used to predict survival in the test cohort. The score was used as a predictor variable to split the test cohort in four prognostic categories (good, moderate, average, poor). The accuracy of the score in predicting survival was tested by checking whether the predicted survival fell within the actual survival tertile which that patient was in. A prognostic score generated from one cohort of patients predicted survival for a second cohort of patients (r2 = 0.72). Six variables were included in the survival model: age at onset, diagnostic delay, El Escorial category, use of riluzole, gender and site of onset. Cox regression demonstrated a strong relationship between these variables and survival (χ2 80.8, df 1, p < 0.0001, n = 343) in the test cohort. Kaplan-Meier analysis demonstrated a significant difference in survival between clinical categories (log rank 161.932, df 3, p < 0.001), and the prognostic score generated for the test cohort accurately predicted survival in 64% of the patients. In conclusion, it is possible to correctly classify patients into prognostic categories using clinical data easily available at time of diagnosis.

The association between ALS and population density: A population based study

Abstract We aimed to assess whether rural residence is associated with amyotrophic lateral sclerosis in the south-east of England using a population based register. Previous studies in different populations have produced contradictory findings. Residence defined by London borough or non-metropolitan district at time of diagnosis was recorded for each incident case in the South-East England ALS Register between 1995 and 2005. Each of the 26 boroughs or districts of the catchment area of the register was classified according to population density. Age- and sex-adjusted incidence of ALS was calculated for each region and the relationship with population density tested by linear regression, thereby controlling for the underlying population structure. We found that population density in region of residence at diagnosis explained 25% of the variance in ALS rates (r = 0.5, p < 0.01). Thus, in this cohort in the south-east of England, people with ALS were more likely to be resident in areas of high population density at diagnosis.