Phenotypical differences of C9ORF72 gene-positive and negative amyotrophic lateral sclerosis: a comparative case series.

BACKGROUND: Hexanucleotide repeat expansions of C9ORF72 account for a significant proportion of autosomal dominant neurodegenerative diseases in the amyotrophic lateral sclerosis (ALS)-frontotemporal dementia spectrum. In the absence of a family history, clinical identification of such patients remains difficult. We aimed to identify differences in demographics and clinical presentation between patients with C9ORF72 gene-positive ALS (C9pALS) versus C9ORF72 gene-negative ALS (C9nALS), to aid identification of these patients in the clinic and examine differences in outcomes including survival. METHODS: We retrospectively reviewed the clinical presentations of 32 patients with C9pALS and compared their characteristics with a cohort of 46 patients with C9nALS from the same tertiary neurosciences centre. RESULTS: Patients with C9pALS more commonly presented with mixed upper and lower motor signs (C9pALS 87.5%, C9nALS 65.2%; p=0.0352), but less frequently presented with purely upper motor neuron signs (C9pALS 3.1%, C9nALS 21.7%; p=0.0226). The C9pALS cohort had a higher frequency of cognitive impairment (C9pALS 31.3%, C9nALS 10.9%; p=0.0394) and bulbar disease (C9pALS 56.3%, C9nALS 28.3%; p=0.0186). There were no differences between cohorts in age at diagnosis, gender, limb weakness, respiratory symptoms, presentation with predominantly lower motor neuron signs or overall survival. DISCUSSION: Analysis of this ALS clinic cohort at a UK tertiary neurosciences centre adds to the small but growing understanding of the unique clinical features of patients with C9pALS. In the age of precision medicine with expanding opportunities to manage genetic diseases with disease-modifying therapies, clinical identification of such patients is increasingly important as focused therapeutic strategies become available.

Cognition and behaviour in frontotemporal dementia with and without amyotrophic lateral sclerosis.

OBJECTIVE: The precise relationship between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is incompletely understood. The association has been described as a continuum, yet data suggest that this may be an oversimplification. Direct comparisons between patients who have behavioural variant FTD (bvFTD) with and without ALS are rare. This prospective comparative study aimed to determine whether there are phenotypic differences in cognition and behaviour between patients with FTD-ALS and bvFTD alone. METHODS: Patients with bvFTD or FTD-ALS and healthy controls underwent neuropsychological testing, focusing on language, executive functions and social cognition. Behavioural change was measured through caregiver interview. Blood samples were screened for known FTD genes. RESULTS: 23 bvFTD, 20 FTD-ALS and 30 controls participated. On cognitive tests, highly significant differences were elicited between patients and controls, confirming the tests' sensitivities to FTD. bvFTD and FTD-ALS groups performed similarly, although with slightly greater difficulty in patients with ALS-FTD on category fluency and a sentence-ordering task that assesses grammar production. Patients with bvFTD demonstrated more widespread behavioural change, with more frequent disinhibition, impulsivity, loss of empathy and repetitive behaviours. Behaviour in FTD-ALS was dominated by apathy. The C9ORF72 repeat expansion was associated with poorer performance on language-related tasks. CONCLUSIONS: Differences were elicited in cognition and behaviour between bvFTD and FTD-ALS, and patients carrying the C9ORF72 repeat expansion. The findings, which raise the possibility of phenotypic variation between bvFTD and FTD-ALS, have clinical implications for early detection of FTD-ALS and theoretical implications for the nature of the relationship between FTD and ALS.

Relapsing cerebral amyloid angiopathy-related inflammation: the wax and the wane.

Cerebral amyloid angiopathy-related inflammation (CAA-I) is a rare variant of cerebral amyloid angiopathy (CAA). Its precise pathophysiology remains uncertain and we currently have limited evidence on which immunosuppressive agents are the most effective in its treatment. The disease course of CAA-I disorders can vary from an isolated clinical event to recurrent episodes. We present a case of biopsy-confirmed CAA-I that gives insight into its potential relapsing nature and the challenges of its long-term management.

Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective.

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.

The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) in frontotemporal dementia.

OBJECTIVES: To examine the usefulness of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS) as a cognitive screening tool for the detection of behavioral variant frontotemporal dementia (bvFTD). A secondary aim was to determine whether people with FTD combined with ALS (ALS-FTD) exhibit a similar ECAS profile to that of people with bvFTD alone. Methods: Patients with ALS-FTD and bvFTD and healthy controls were recruited. Participants were administered the ECAS, which comprises tests of language, verbal fluency, executive functions, memory, and visual-spatial functions. They also carried out analogous, full-length cognitive tests that examine naming, spelling, sentence completion, and social cognition skills. Results: The study cohort comprised 20 ALS-FTD patients, 23 with bvFTD, and 30 controls. Highly significant group differences were elicited for all cognitive domains, reflecting poorer performance in patients compared to controls. No significant differences in overall test scores were found between ALS-FTD and bvFTD patients, although ALS-FTD patients showed a higher frequency of impairment on verbal fluency. Correlative analyses revealed inter-relationships in patients (but not controls) between scores in different domains, most marked in bvFTD. There were strong correlations between performance on ECAS subtests and analogous cognitive tasks. Conclusion: The ECAS is a sensitive and valuable tool for the assessment of FTD. Executive, language and behavioral breakdown may, however, compromise performance in other cognitive domains, reducing the specificity of the 'frontotemporal' cognitive profile. Subtle differences observed between ALS-FTD and bvFTD raise questions regarding the precise relationship between bvFTD with and without ALS.

FUS-ALS presenting with myoclonic jerks in a 17-year-old man.

Fused in sarcoma-related amyotrophic lateral sclerosis (FUS-ALS) accounts for 4% of all familial motor neurone disease, but has a much higher incidence in juvenile ALS. We present a case of a 17-year-old British man with rapidly progressive bulbar and respiratory failure. On examination he had weak periocular muscles, neck flexion weakness, and a wasted, fasciculating and weak tongue. There were no sensory, cerebellar, or extrapyramidal features but he had frequent myoclonic jerks of the limbs. Routine bloods were normal and an MRI of the neuroaxis as well as CT chest, abdomen and pelvis were unremarkable. NCS/EMG was consistent with anterior horn cell disorder and EEG showed multiple paroxysmal generalized spike-wave discharges. DNA sequencing demonstrated that he was heterozygous for the c.1483C>T pathogenic nonsense mutation in exon 14 of the FUS gene, consistent with ALS6. This is the first reported case of FUS-ALS presenting with prominent myoclonus.

Pathological tau deposition in Motor Neurone Disease and frontotemporal lobar degeneration associated with TDP-43 proteinopathy.

It has been suggested that patients with motor neurone disease (MND) and those with MND combined with behavioural variant frontotemporal dementia (bvFTD) (ie FTD + MND) or with FTD alone might exist on a continuum based on commonalities of neuropathology and/or genetic risk. Moreover, it has been reported that both a neuronal and a glial cell tauopathy can accompany the TDP-43 proteinopathy in patients with motor neurone disease (MND) with cognitive changes, and that the tauopathy may be fundamental to disease pathogenesis and clinical phenotype. In the present study, we sought to substantiate these latter findings, and test this concept of a pathological continuum, in a consecutive series of 41 patients with MND, 16 with FTD + MND and 23 with FTD without MND. Paraffin sections of frontal, entorhinal, temporal and occipital cortex and hippocampus were immunostained for tau pathology using anti-tau antibodies, AT8, pThr(175) and pThr(217), and for amyloid ß protein (Aß) using 4G8 antibody. Twenty four (59 %) patients with MND, 7 (44 %) patients with FTD + MND and 10 (43 %) patients with FTD showed 'significant' tau pathology (ie more than just an isolated neurofibrillary tangle or a few neuropil threads in one or more brain regions examined). In most instances, this bore the histological characteristics of an Alzheimer's disease process involving entorhinal cortex, hippocampus, temporal cortex, frontal cortex and occipital cortex in decreasing frequency, accompanied by a deposition of Aß up to Thal phase 3, though 2 patients with MND, and 1 with FTD did show tau pathology beyond Braak stage III. Four other patients with MND showed novel neuronal tau pathology, within the frontal cortex alone, specifically detected by pThr(175) antibody, which was characterised by a fine granular or more clumped aggregation of tau without neurofibrillary tangles or neuropil threads. However, none of these 4 patients had clinically evident cognitive disorder, and this type of tau pathology was not seen in any of the FTD + MND or FTD patients. Finally, two patients, one with MND and one with FTD, showed a tau pathology consistent with Argyrophilic Grain Disease (AGD). Western blotting and use of 3- and 4-repeat tau antibodies confirmed the histological interpretation of Alzheimer's disease type pathology in all instances except for those patients with accompanying AGD where a banding pattern on western blot, and immunohistochemistry, confirmed 4-repeat tauopathy. In all 3 patient groups, amyloid pathology was more likely to be present in patients dying after 65 years of age, and in the presence of APOE ε4 allele. We conclude that tau pathological changes are equally common amongst patients with MND, FTD + MND and FTD though, in most instances, these are limited in extent. In patients with MND, when cognitive impairment is present this is most likely due to an accompanying/evolving (coincidental) Alzheimer's disease process or, as in a single case, Dementia with Lewy bodies, within the cerebral cortex rather than as a result of TDP-43 proteinopathy. Conversely, in FTD and FTD + MND dementia is more likely to be associated with TDP-43 proteinopathy than tau. Hence, present study shows no progression in severity of (tau) pathology from MND through FTD + MND to FTD, and does not support the concept of these conditions forming a continuum of clinical or pathological change.

DiPALS: Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis - a randomised controlled trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2-3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4(®) diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure. OBJECTIVE: The Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure. DESIGN: The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy. PARTICIPANTS: Eligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged ≥ 18 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1 : 1 non-deterministic minimisation. INTERVENTIONS: Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS. MAIN OUTCOME MEASURES: The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost-utility analysis and health-care resource use; tolerability and adverse events. Acceptability and attitudes to DP were assessed in a qualitative substudy. RESULTS: In total, 74 participants were randomised into the trial and analysed, 37 participants to NIV plus pacing and 37 to standard care, before the Data Monitoring and Ethics Committee advised initial suspension of recruitment (December 2013) and subsequent discontinuation of pacing (on safety grounds) in all patients (June 2014). Follow-up assessments continued until the planned end of the study in December 2014. The median survival (interquartile range) was 22.5 months (lower quartile 11.8 months; upper quartile not reached) in the NIV arm and 11.0 months (6.7 to 17.0 months) in the NIV plus pacing arm, with an adjusted hazard ratio of 2.27 (95% confidence interval 1.22 to 4.25; p = 0.01). CONCLUSIONS: Diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure. FUTURE WORK: It may be that certain population subgroups benefit from DP. We are unable to explain the mechanism behind the excess mortality in the pacing arm, something the small trial size cannot help address. Future research should investigate the mechanism by which harm or benefit occurs further. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53817913. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 45. See the HTA programme website for further project information. Additional funding was provided by the Motor Neurone Disease Association of England, Wales and Northern Ireland.

Acute disc prolapse secondary to seizure.

A 37-year-old female presented following a witnessed generalised tonic clonic seizure while washing her car. Witnesses reported the patient hit her head on the car bumper upon falling. She was investigated for a cause of a second seizure with blood tests, CT and MR brain which were normal. On day 3 of her admission she was still unable to walk since the seizure and a neurological examination was performed which revealed signs consistent with a cervical myelopathy. A cervical MRI scan revealed a disc prolapse with cord compression at C5/6. This was successfully operated and the patient made a good recovery. Given that many of our medical assessment units and emergency department frequently assess patient with seizures, there was an important lesson for us to be more aware of the consequences as well as the cause of seizures.