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Article ; Online: Motor neuron disease: focusing the mind on ALS: updated practice parameters.

Leigh, P Nigel / Wijesekera, Lokesh C

2010 Volume 6, Issue 4, Page(s) 191–192

MeSH term(s)	Amyotrophic Lateral Sclerosis/therapy ; Humans ; Practice Guidelines as Topic
Language	English
Publishing date	2010-04-08
Publishing country	England
Document type	News
ZDB-ID	2491514-2
ISSN	1759-4766 ; 1759-4758
ISSN (online)	1759-4766
ISSN	1759-4758
DOI	10.1038/nrneurol.2010.33
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Article ; Online: Amyotrophic lateral sclerosis.

Wijesekera, Lokesh C / Leigh, P Nigel

Orphanet journal of rare diseases

2009 Volume 4, Page(s) 3

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per 100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio approximately 1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases. Most ALS cases are sporadic but 5-10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2-5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of upper motor neurone and lower motor neurone damage not explained by any other disease process are suggestive of ALS. The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.
MeSH term(s)	Adult ; Aged ; Amyotrophic Lateral Sclerosis/diagnosis ; Amyotrophic Lateral Sclerosis/epidemiology ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/pathology ; Mutation ; Prognosis ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Young Adult
Chemical Substances	DNA-Binding Proteins ; SOD1 protein, human ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1)
Language	English
Publishing date	2009-02-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2225857-7
ISSN	1750-1172 ; 1750-1172
ISSN (online)	1750-1172
ISSN	1750-1172
DOI	10.1186/1750-1172-4-3
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Article ; Online: Multisystem pathology in McLeod syndrome.

Schon, Katherine R / O'Donovan, Dominic G / Briggs, Mayen / Rowe, James B / Wijesekera, Lokesh / Chinnery, Patrick F / van den Ameele, Jelle

Neuropathology : official journal of the Japanese Society of Neuropathology

2023 Volume 44, Issue 2, Page(s) 109–114

Abstract: ... in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died ...

Abstract	We present a comprehensive characterization of clinical, neuropathological, and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioral change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes, and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum creatinine kinase (CK) was first noted in his thirties, but investigations, including muscle biopsy at that time, were inconclusive. Brain magnetic resonance imaging showed white matter volume loss, atrophic basal ganglia, and chronic small vessel ischemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis revealed a hemizygous pathogenic variant in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen, and mild Alzheimer's pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When a clinical diagnosis is suspected, candidate genes should be interrogated rather than solely relying on exome panels.
MeSH term(s)	Male ; Humans ; Middle Aged ; Neuroacanthocytosis/genetics ; Neuroacanthocytosis/diagnosis ; Neuroacanthocytosis/pathology ; Muscular Diseases/pathology ; Basal Ganglia/pathology ; Atrophy/pathology
Language	English
Publishing date	2023-07-12
Publishing country	Australia
Document type	Case Reports
ZDB-ID	1483794-8
ISSN	1440-1789 ; 0919-6544
ISSN (online)	1440-1789
ISSN	0919-6544
DOI	10.1111/neup.12935
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Article ; Online: Amyotrophic lateral sclerosis

Leigh P Nigel / Wijesekera Lokesh C

Orphanet Journal of Rare Diseases, Vol 4, Iss 1, p

2009 Volume 3

Abstract: Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence ( ...

Abstract	Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio~1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1–2 years. Paralysis is progressive and leads to death due to respiratory failure within 2–3 years for bulbar onset cases and 3–5 years for limb onset ALS cases. Most ALS cases are sporadic but 5–10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2–5% have mutations of the TARDBP ( TDP-43 ) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' ( e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of ...
Keywords	Medicine ; R
Subject code	616 ; 610
Language	English
Publishing date	2009-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Prognostic categories for amyotrophic lateral sclerosis.

Scotton, William J / Scott, Kirsten M / Moore, Dan H / Almedom, Leeza / Wijesekera, Lokesh C / Janssen, Anna / Nigro, Catherine / Sakel, Mohammed / Leigh, Peter N / Shaw, Chris / Al-Chalabi, Ammar

Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases

2012 Volume 13, Issue 6, Page(s) 502–508

Abstract: 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 ... ...

Abstract	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 (r(2) = 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 (χ(2) 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.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/diagnosis ; Amyotrophic Lateral Sclerosis/epidemiology ; Amyotrophic Lateral Sclerosis/mortality ; Cohort Studies ; Community Health Planning ; England ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Registries ; Regression Analysis ; Retrospective Studies ; Survival Analysis ; Young Adult
Language	English
Publishing date	2012-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2264792-2
ISSN	1471-180X ; 1743-4483 ; 1466-0822 ; 1748-2968 ; 1743-4475
ISSN (online)	1471-180X ; 1743-4483
ISSN	1466-0822 ; 1748-2968 ; 1743-4475
DOI	10.3109/17482968.2012.679281
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Article ; Online: A proposed staging system for amyotrophic lateral sclerosis.

Roche, Jose C / Rojas-Garcia, Ricardo / Scott, Kirsten M / Scotton, William / Ellis, Catherine E / Burman, Rachel / Wijesekera, Lokesh / Turner, Martin R / Leigh, P Nigel / Shaw, Christopher E / Al-Chalabi, Ammar

Brain : a journal of neurology

2012 Volume 135, Issue Pt 3, Page(s) 847–852

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/classification ; Amyotrophic Lateral Sclerosis/diagnosis ; Amyotrophic Lateral Sclerosis/pathology ; Cohort Studies ; Disease Progression ; Female ; Follow-Up Studies ; Gastrostomy ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Models, Statistical ; Patient Selection ; Prognosis ; Reproducibility of Results ; Respiration, Artificial ; Sex Factors ; Survival Analysis
Language	English
Publishing date	2012-01-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awr351
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Article ; Online: 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.

Troakes, Claire / Maekawa, Satomi / Wijesekera, Lokesh / Rogelj, Boris / Siklós, László / Bell, Christopher / Smith, Bradley / Newhouse, Stephen / Vance, Caroline / Johnson, Lauren / Hortobágyi, Tibor / Shatunov, Aleksey / Al-Chalabi, Ammar / Leigh, Nigel / Shaw, Christopher E / King, Andrew / Al-Sarraj, Safa

Neuropathology : official journal of the Japanese Society of Neuropathology

2011 Volume 32, Issue 5, Page(s) 505–514

Abstract: 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 ...

Abstract	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.
MeSH term(s)	Age of Onset ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/psychology ; Blotting, Western ; Brain/pathology ; C9orf72 Protein ; Cerebellum/pathology ; Cerebral Cortex/pathology ; Cognition Disorders/genetics ; Cognition Disorders/pathology ; DNA/genetics ; DNA-Binding Proteins/genetics ; Female ; Fluorescent Antibody Technique ; Hippocampus/pathology ; Humans ; Immunohistochemistry ; Inclusion Bodies/pathology ; Male ; Microscopy, Electron ; Middle Aged ; Motor Neuron Disease/genetics ; Motor Neuron Disease/psychology ; Proteins/genetics ; Proto-Oncogene Proteins c-myc/genetics ; Spinal Cord/pathology ; Tissue Banks ; Trinucleotide Repeat Expansion
Chemical Substances	C9orf72 Protein ; C9orf72 protein, human ; DNA-Binding Proteins ; Proteins ; Proto-Oncogene Proteins c-myc ; DNA (9007-49-2)
Language	English
Publishing date	2011-12-19
Publishing country	Australia
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1483794-8
ISSN	1440-1789 ; 0919-6544
ISSN (online)	1440-1789
ISSN	0919-6544
DOI	10.1111/j.1440-1789.2011.01286.x
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Article ; Online: Latent cluster analysis of ALS phenotypes identifies prognostically differing groups.

Ganesalingam, Jeban / Stahl, Daniel / Wijesekera, Lokesh / Galtrey, Clare / Shaw, Christopher E / Leigh, P Nigel / Al-Chalabi, Ammar

PloS one

2009 Volume 4, Issue 9, Page(s) e7107

Abstract: 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 ...

Abstract	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.
MeSH term(s)	Adult ; Age of Onset ; Aged ; Amyotrophic Lateral Sclerosis/classification ; Amyotrophic Lateral Sclerosis/diagnosis ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/mortality ; Cluster Analysis ; Female ; Humans ; Male ; Middle Aged ; Motor Neurons/metabolism ; Phenotype ; Prognosis ; Regression Analysis ; Survival Analysis
Language	English
Publishing date	2009-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0007107
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Article: Healthcare professionals' views on the provision of gastrostomy and noninvasive ventilation to amyotrophic lateral sclerosis patients in England, Wales, and Northern Ireland.

Ruffell, Tamatha O / Martin, Naomi H / Janssen, Anna / Wijesekera, Lokesh / Knights, Catherine / Burman, Rachel / Oliver, David J / Al-Chalabi, Ammar / Goldstein, Laura H

Journal of palliative care

2013 Volume 29, Issue 4, Page(s) 225–231

Abstract: Gastrostomy and noninvasive ventilation (NIV) are recommended interventions for the management of symptoms associated with amyotrophic lateral sclerosis (ALS). This study aimed to quantify the views of a range of healthcare professionals (HCPs) on the ... ...

Abstract	Gastrostomy and noninvasive ventilation (NIV) are recommended interventions for the management of symptoms associated with amyotrophic lateral sclerosis (ALS). This study aimed to quantify the views of a range of healthcare professionals (HCPs) on the provision of these interventions in the United Kingdom. A total of 177 HCPs participated in an online survey. Significant differences were found between medical and allied HCPs' views on: whether HCPs adhere to policy and accept legal constraints when it comes to making gastrostomy available to people with ALS; the impressions that HCPs receive of the way patients and caregivers understand the effects of gastrostomy and NIV on symptoms and quality of life; and the challenges HCPs face when caring for patients who have refused gastrostomy. More widely available guidelines for the provision of gastrostomy and advice on the best way to impart information to patients and caregivers about gastrostomy and NIV appear to be needed.
MeSH term(s)	Adult ; Allied Health Personnel/psychology ; Amyotrophic Lateral Sclerosis/complications ; Attitude of Health Personnel ; England ; Female ; Gastrostomy/utilization ; Humans ; Male ; Noninvasive Ventilation/utilization ; Northern Ireland ; Palliative Care ; Practice Patterns, Physicians'/statistics & numerical data ; Quality of Life ; Surveys and Questionnaires ; Wales
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639326-3
ISSN	0825-8597
ISSN	0825-8597
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