The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study ...was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS.
This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS.
The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (β = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (β = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (β = - 0.5, 95% CI -0.6 to 0.4) and 18 years (β = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (β = -1.0, 95% CI -1.1 to 0.9).
In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.
Objectives(s):
To characterise the clinical profile, aetiology and treatment responsiveness of ‘Australian Lyme’, or Debilitating Symptom Complexes Attributed to Ticks.
Methods:
Single-centre ...retrospective case analysis of patients referred to the Infectious Diseases Unit at Austin Health – a tertiary health service in Heidelberg, Australia – between 2014 and 2020 for investigation and treatment of suspected Debilitating Symptom Complexes Attributed to Ticks. Patients were included if they had debilitating symptoms suggested by either themselves or the referring clinician as being attributed to ticks.
Results:
Twenty-nine Debilitating Symptom Complexes Attributed to Ticks cases were included in the analysis. Other than Lyme disease (83%), the most common prior medical diagnoses were Epstein–Barr virus (38%), chronic fatigue syndrome (28%) and fibromyalgia (24%). Prior histories of anxiety (48%) and depression (41%) were common. The most frequently reported symptoms included fatigue (83%), headache (72%) and arthralgia (69%). National Association of Testing Authorities/Royal College of Pathologists of Australasia–accredited serology was not diagnostic of acute infective causes, including Lyme disease, in any patient. Of 25 cases with available data, 23 (92%) had previously been prescribed antimicrobials, with 53% reporting benefit from them. The most common diagnoses made by our hospital were chronic fatigue syndrome (31%), migraines (28%) and fibromyalgia (21%). Only one patient’s symptoms were not accounted for by other diagnoses.
Conclusion:
This is the first case series of patients with Debilitating Symptom Complexes Attributed to Ticks. They had high rates of other medically unexplained syndromes, and no evidence of acute Lyme disease, or any common organic disease process. Debilitating Symptom Complexes Attributed to Ticks remains medically unexplained, and may therefore be due to an as yet unidentified cause, or may be considered a medically unexplained syndrome similar to conditions such as chronic fatigue syndrome.
A missense mutation of the γ2 subunit of the γ-aminobutyric acid A (GABAA) receptor has been linked to an inherited human generalized epilepsy. As synaptic inhibition in the human brain is largely ...mediated by the GABAA receptor, we tested the hypothesis that the GABRG2(R43Q) mutation alters cortical excitability. Fourteen subjects affected by the GABRG2(R43Q) mutation (5 males, mean age: 44 ± 15 years) and 24 controls (11 males, mean age: 38 ± 11 years) were studied with transcranial magnetic stimulation (TMS). To assess the specificity of the effect of the mutation, 4 additional family members unaffected by the GABRG2(R43Q) mutation (2 males, mean age: 41 ± 16 years) were included. Subjects affected by the GABRG2(R43Q) mutation demonstrated reduced net short-interval intracortical inhibition and increased intracortical facilitation assessed with paired-pulse stimulation. Subjects with the mutation had similar motor thresholds to controls both at rest and with weak voluntary activation. No significant differences were noted between groups in the cortical silent period. Our findings provide in vivo evidence for increased intracortical excitability in subjects affected by the GABRG2(R43Q) mutation. These findings are also likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.
Introduction
In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing–remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon ...beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW.
Methods
CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed.
Results
Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a −0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a −0.10-point mean EDSS score change; 98% had stable or improved EDSS scores.
Conclusion
CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9.
Transcranial magnetic stimulation (TMS) is a technique developed to non-invasively investigate the integrity of human motor corticospinal tracts. Over the last three decades, the use of stimulation ...paradigms including single-pulse TMS, paired-pulse TMS, repetitive TMS, and integration with EEG and functional imaging have been developed to facilitate measurement of cortical excitability.Through the use of these protocols, TMS has evolved in-to an excellent tool for measuring cortical excitability.TMS has high sensitivity in detecting subtle changes in cortical excitability, and therefore it is also a good measure of disturbances associated with brain disorders. In this review, we appraise the current literature on cortical excitability studies using TMS in neurological disorders.We begin with a brief overview of current TMS measures and then show how these have added to our understand-ing of the underlying mechanisms of brain disorders.
Abstract Sakzewski L, Ziviani J, Abbott DF, Macdonell RA, Jackson GD, Boyd RN. Participation outcomes in a randomized trial of 2 models of upper-limb rehabilitation for children with congenital ...hemiplegia. Objective To determine if constraint-induced movement therapy (CIMT) is more effective than bimanual training to improve occupational performance and participation in children with congenital hemiplegia. Design Single-blind randomized comparison trial with evaluations at baseline, 3, and 26 weeks. Setting Community facilities in 2 Australian states. Participants Referred sample of children (N=64; mean age ± SD, 10.2±2.7y, 52% boys) were matched for age, sex, side of hemiplegia, and upper-limb function and were randomized to CIMT or bimanual training. After random allocation, 100% of CIMT and 94% of the bimanual training group completed the intervention. Interventions Each intervention was delivered in day camps (total 60h over 10d) using a circus theme with goal-directed training. Children receiving CIMT wore a tailor-made glove during the camp. Main Outcome Measures The primary outcome was the Canadian Occupational Performance Measure (COPM). Secondary measures included the Assessment of Life Habits (LIFE-H), Children's Assessment of Participation and Enjoyment, and School Function Assessment. Results There were no between-group differences at baseline. Both groups made significant changes for COPM performance at 3 weeks (estimated mean difference =2.9; 95% confidence interval CI, 2.3–3.6; P <.001 for CIMT; estimated mean difference=2.8; 95% CI, 2.2–3.4; P <.001 for bimanual training) that were maintained at 26 weeks. Significant gains were made in the personal care LIFE-H domain following CIMT (estimated mean difference=0.5; 95% CI, 0.1–0.9; P =.01) and bimanual training (estimated mean difference=0.6; 95% CI, 0.2–1.1; P =.006). Conclusions There were minimal differences between the 2 training approaches. Goal-directed, activity-based, upper-limb training, addressed through either CIMT or bimanual training achieved gains in occupational performance. Changes in participation on specific domains of participation assessments appear to correspond with identified goals.
Handicap, although more relevant to the patient than impairment or disability, has received little attention in people with stroke. The aim of this study was to identify, in an unselected population, ...factors determining handicap at 2 years after stroke.
All first-ever cases of stroke in a population of 306 631 over a 1-year period were assessed. Stroke severity, comorbidity, and demographic information was recorded. Among survivors, 2-year poststroke handicap was assessed with the London Handicap Scale. Disability, physical impairment, depression, anxiety, living arrangements, and recurrent stroke at 2 years were documented. If necessary, proxy assessments were obtained, except for mood. Linear regression analyses were performed to identify factors independently associated with handicap. First, all assessments (proxy and nonproxy) were examined; then, the nonproxy assessments were used to examine the effects of mood.
Of 266 patients with incident stroke who were alive at 2 years, 226 (85%) were assessed. Significant determinants of handicap on univariable analysis were age, female sex, socioeconomic status, alcohol intake, stroke subtype, initial stroke severity; 2-year physical impairment, disability, depression and anxiety scores; institutionalization; and recurrent stroke. On multivariable analysis, the independent determinants of handicap were age and 2-year physical impairment and disability. In analysis restricted to nonproxy data, depression and anxiety were also independently associated with handicap.
Age, concurrent disability, and physical impairment were more important determinants of handicap than other demographic factors or initial stroke severity. Because depression and anxiety were independently associated with handicap, their treatment may potentially reduce handicap in stroke patients.
Abstract Epilepsy encompasses a diverse group of seizure disorders caused by a variety of structural, cellular and molecular alterations of the brain primarily affecting the cerebral cortex, leading ...to recurrent unprovoked epileptic seizures. In this two-part review we examine the mechanisms underlying normal neuronal function and those predisposing to recurrent epileptic seizures starting at the most basic cellular derangements (Part 1, Volume 16, Issue 3) and working up to the highly complex epileptic networks and factors that modulate the predisposition to seizures (Part 2). We attempt to show that multiple factors can modify the epileptic process and that different mechanisms underlie different types of epilepsy, and in most situations there is an interplay between multiple genetic and environmental factors.
There are few data on the prevalence or treatment of depression from unselected populations long-term poststroke. We assessed the prevalence of depression and antidepressant use at 5-years poststroke ...in an unselected stroke population.
Five-year survivors from a prospective community-based stroke incidence study were assessed for depression with the Irritability, Depression and Anxiety Scale. Medications indicated primarily for treatment of depression were recorded.
At 5-years poststroke, 441 (45%) of 978 incident cases were alive (mean age=74+/-15 years, 49% female). Seventeen percent of those assessed were depressed. Twenty-two percent with depression were taking an antidepressant medication. Of those taking an antidepressant, 72% were not depressed.
Although nearly one-fifth of survivors were depressed, few were taking antidepressants. Further exploration of this low level of treatment is warranted.
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