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  • Myelin imaging in amyotrophic and primary lateral sclerosis.

    24 October 2018

    Primary lateral sclerosis (PLS) has been regarded as a rare, extreme form of amyotrophic lateral sclerosis (ALS). Like ALS, it is a clinical diagnosis without established biomarkers. We sought to explore loss of cerebral myelin in relation to clinical features, including cognitive impairment, in cases of both ALS and PLS. A novel MRI sequence (mcDESPOT) sensitive to water pools within myelin and intra- and extra-cellular spaces was applied to 23 ALS patients, seven PLS patients and 12 healthy controls, with interval follow-up in 15 ALS and four PLS patients. Results demonstrated that PLS patients were distinguished by widespread cerebral myelin water fraction reductions, independent of disease duration and clinical upper motor neuron burden. ALS patients showed a significant increase in intra- and extra-cellular water, indirectly linked to neuroinflammatory activity. Limited measures of cognitive impairment in the ALS group were associated with myelin changes within the anterior corpus callosum and frontal lobe projections. Longitudinal changes were only significant in the PLS group. In conclusion, in this exploratory study, myelin imaging has potential to distinguish PLS from ALS, and may have value as a marker of extramotor involvement. PLS may be a more active cerebral pathological process than its rate of clinical deterioration suggests.

  • The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis.

    24 October 2018

    BACKGROUND: Despite the inevitability of disease progression in amyotrophic lateral sclerosis, there is a high degree of prognostic heterogeneity in all subtypes. Some bulbar-onset (BO) patients may develop rapid anarthria yet remain ambulant for a prolonged period, whereas others progress rapidly, with early generalisation of motor weakness to the limbs and respiratory muscles. Diagnostic delay is a common occurrence in ALS, and many BO patients report having attended other specialist clinics prior to diagnosis. METHODS: A retrospective descriptive study of BO ALS patients seen in a tertiary clinic over a six year period. RESULTS: Forty-nine BO ALS patients were studied. Median survival from symptom onset was 27 months (range 6-84). 63% of subjects were female and the mean age at symptom onset was 68 years. Half had been referred to another speciality prior to diagnosis, either otolaryngology or stroke clinics, but this did not influence diagnostic latency or survival. Emotionality was reported in 45% of patients. Neurophysiological assessment was performed in 80%, brain imaging recorded in 69%, and antibody testing for myasthenia gravis in 22%. The median time to symptomatic progression beyond the bulbar region was approximately 1 year, with equal proportions progressing to the upper or lower limbs. The median interval from onset to anarthria was 18 months, and to loss of ambulation 22 months. There was a close correlation between the two (r(2)=0.6) and median survival from loss of ambulation was only 3 months. Gastrostomy was carried out in 78% of patients with a median time of 13 months from symptom onset, and 3 months from diagnosis. Median survival from gastrostomy was 10 months. CONCLUSIONS: Survival in bulbar-onset ALS is highly variable. Half of the patients were referred to an inappropriate clinic prior to diagnosis. The time interval to the development of anarthria predicted the timing of subsequent loss of ambulation accurately from which survival may then be only a few months.

  • Head and other physical trauma requiring hospitalisation is not a significant risk factor in the development of ALS.

    24 October 2018

    The pathogenesis of ALS is not fully understood but, as an overwhelmingly sporadic disorder, it is likely to result from a complex mixture of polygenic and environmental risk factors operating in the context of an ageing nervous system. Physical trauma, in particular head injury, has been variably associated with both Alzheimer's and Parkinson's disease, and largely discounted in relation to multiple sclerosis. Several case-control studies in ALS have reported an association with physical trauma or head injury, but such studies are greatly limited by recall bias. The Oxford Record Linkage Study (ORLS) includes brief statistical abstracts of records of all hospital admissions, including day cases, and all deaths for a defined region of UK National Health Service hospitals. We used ORLS spanning a 36year period to study the relationship between recorded head, upper and lower limb trauma both before and after a diagnosis of ALS. Overall the adjusted rate ratio for ALS after head injury, compared with a control group, was 1.5 (95% confidence interval 1.1-2.1); but this elevation of risk was only found within the first year after injury, and we speculate that this is most likely to be a consequence of incipient ALS causing a tendency to fall. We conclude that there is no association between antecedent injury requiring hospitalisation, and the later development of ALS. The high risk of head injury observed in the immediate post-diagnosis period may be amenable to primary prevention.

  • Amyotrophic lateral sclerosis.

    24 October 2018

    Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.

  • Whole-brain magnetic resonance spectroscopic imaging measures are related to disability in ALS.

    24 October 2018

    OBJECTIVE: To demonstrate the sensitivity of a recently developed whole-brain magnetic resonance spectroscopic imaging (MRSI) sequence to cerebral pathology and disability in amyotrophic lateral sclerosis (ALS), and compare with measures derived from diffusion tensor imaging. METHODS: Whole-brain MRSI and diffusion tensor imaging were undertaken in 13 patients and 14 age-similar healthy controls. Mean N-acetylaspartate (NAA), fractional anisotropy, and mean diffusivity were extracted from the corticospinal tract, compared between groups, and then in relation to disability in the patient group. RESULTS: Significant reductions in NAA were found along the course of the corticospinal tracts on whole-brain MRSI. There were also significant changes in fractional anisotropy (decreased) and mean diffusivity (increased) in the patient group, but only NAA showed a significant relationship with disability (r = 0.65, p = 0.01). CONCLUSION: Whole-brain MRSI has potential as a quantifiable neuroimaging marker of disability in ALS. It offers renewed hope for a neuroimaging outcome measure with the potential for harmonization across multiple sites in the context of a therapeutic trial.