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Peripheral blood helper T cell profiles and their clinical relevance in MOG-IgG-associated and AQP4-IgG-associated disorders and MS

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (2)

Objective To investigate the immunological characteristics and their clinical relevance in anti-myelin oligodendrocyte glycoprotein (MOG)-IgG-associated and anti-aquaporin-4 (AQP4)-IgG-associated disorders (MOGAD and AQPAD) and multiple sclerosis (MS). Methods We measured peripheral blood helper T cell subsets (Th1, Th2, Th17 and regulatory T cell (Treg)) in patients with MOGAD (n=26), AQPAD (n=32) and MS (n=28) in the attack and remission phases by flow cytometry with intracellular cytokine staining. We also studied their correlation with clinical parameters. Ten normal subjects served as healthy controls. Results In all the three disorders, Th17 significantly increased at attack, and downregulated in the remission phases, although still elevated compare with healthy controls. MOGAD and AQPAD patients shared the common T cell profiles, while the extent of Th17 shift was more prominent in AQPAD. Patients with MS showed decreased Th2 than ones with MOGAD and AQPAD at attack. In terms of clinical correlation, MS patients showed that higher Th1 and Th17 proportion was associated with more frequent relapse and more severe clinical disability, whereas in MOGAD, higher Treg was associated with milder clinical severity. In AQPAD, no obvious correlation of Th profiles with clinical manifestation was found. Conclusions The present study first investigated intracellular cytokine levels among MOGAD, AQPAD and MS. The different patterns and extent of helper T cell profiles could reflect the pathogenesis of each disorders, and may affect disease severity and activity.

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (2)

Objective Sudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy-related mortality in young adults. It has been suggested that SUDEP may kill over 20 000 people with epilepsy in China yearly. The aetiology of SUDEP is unclear. Little is known about candidate genes for SUDEP in people of Chinese origin as most studies have ascertained this in Caucasians. No candidate genes for SUDEP in Chinese people have been identified. Methods We performed whole exome sequencing (WES) in DNA samples collected from five incident cases of SUDEP identified in a large epilepsy cohort in rural China. We filtered rare variants identified from these cases as well as screened for SUDEP, epilepsy, heart disease or respiratory disease-related genes from previous published reports and compared them with publicly available data, living epilepsy controls and ethnicity-match non-epilepsy controls, to identify potential candidate genes for SUDEP. Results After the filtering process, the five cases carried 168 qualified mutations in 167 genes. Among these genetic anomalies, we identified rare variants in SCN5A (1/5:20% in our cases), KIF6 (1/5:20% in our cases) and TBX18 (1/5:20% in our cases) which were absent in 330 living epilepsy control alleles from the same original cohort and 320 ethnicity-match non-epilepsy control alleles. Conclusions These three genes were previously related to heart disease, providing support to the hypothesis that underlying heart disorder may be a driver of SUDEP risk.

Pallidal deep brain stimulation in primary Meige syndrome: clinical outcomes and psychiatric features

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (12)

Objectives To study the efficacy and safety of bilateral globus pallidus internus deep brain stimulation (GPi-DBS) in refractory Meige syndrome (MS) and evaluate the psychiatric disorders before and after surgery. Methods Twenty-two patients with MS treated with bilateral GPi-DBS were retrospectively analysed before surgery and after continuous neurostimulation. Before surgery, patients were assessed by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Self-Rating Depression Scale, Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) and Pittsburgh Sleep Quality Index (PQSI), which corresponded to motor symptoms, depressive state, quality of life and sleep quality, respectively. The implantable pulse generator of each patient was activated at 1 month after surgery. At 1 month, 3 months, 6 months and 12 months after continuous neurostimulation, all patients were evaluated by the same scales above. Results The BFMDRS movement scores decreased from 15.0 +/- 5.3 before surgery to 3.5 +/- 4.5 at 12 months after neurostimulation, with a mean improvement of 78% (p<0.001). The BFMDRS disability scores improved from 7.4 +/- 4.9 before surgery to 4.0 +/- 4.6 at 12 months after neurostimulation, with a mean improvement of 56% (p<0.001). The postoperative SF-36 scores had the remarkable improvement compared with baseline scores. Impaired sleep quality was found in 82% of patients and depression in 64% before surgery, which didn't neither obtained amelioration after continuous neurostimulation. Conclusions Bilateral pallidal neurostimulation is a beneficial therapeutic option for refractory MS, which could improve the motor symptoms except for depression and sleep quality.

Anti-A beta agents for mild to moderate Alzheimer's disease: systematic review and meta-analysis

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (12)

Objective To assess the efficacy and safety of A beta-targeting agents for mild to moderate Alzheimer's disease Methods The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform search portal were searched from their inception to April 2020. We generated pooled estimates using random effects meta-analyses. Results Nineteen randomised controlled trials, of which 17 had a low risk of bias, included 12 903 participants. The meta-analysis showed no difference in the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog) between anti-A beta drugs and placebo (mean difference (MD): 0.20, 95% CI -0.40 to 0.81; I-2=99.8%; minimal important difference 3.1-3.8 points, moderate-certainty evidence). For ADAS-Cog, results suggested that one drug that increases A beta clearance may differ in effect (MD: -0.96, 95% CI -0.99 to -0.92) from drugs that reduce A beta production (MD: 0.78, 95% CI 0.25 to 1.32) (interaction p<0.000001); this difference also existed in the outcome of MMSE and CDR-SOB. Compared with placebo, anti-A beta drug-related adverse events were as follows: anxiety, depression, diarrhoea, fatigue, rash, syncope and vomit. Discussion From current evidence, anti-A beta interventions are unlikely to have an important impact on slowing cognitive or functional decline. Although the subgroup analysis suggested possible benefits from A beta clearance drugs, the analysis has limited credibility, and a benefit from drugs that increase clearance, if real, is very small.

Brain imaging abnormalities and outcome after acute ischaemic stroke: the ENCHANTED trial

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (12)

Objective To test the hypothesis that imaging signs of 'brain frailty' and acute ischaemia predict clinical outcomes and symptomatic intracranial haemorrhage (sICH) after thrombolysis for acute ischaemic stroke (AIS) in the alteplase dose arm of ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED). Methods Blinded assessors coded baseline images for acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions; and hyperattenuated arteries) and pre-existing changes (atrophy, leucoaraiosis and old ischaemic lesions). Logistic regression models assessed associations between imaging features and death at 7 and 90 days; good recovery (modified Rankin Scale scores 0-2 at 90 days) and sICH. Data are reported with adjusted ORs and 95% CIs. Results 2916 patients (67 +/- 13 years, National Institutes of Health Stroke Scale 8 (5-14)) were included. Visible ischaemic lesions, severe hypoattenuation, large ischaemic lesion, swelling and hyperattenuated arteries were associated with 7-day death (OR (95% CI): 1.52 (1.06 to 2.18); 1.51 (1.01 to 2.18); 2.67 (1.52 to 4.71); 1.49 (1.03 to 2.14) and 2.17 (1.48 to 3.18)) and inversely with good outcome. Severe atrophy was inversely associated with 7-day death (0.52 (0.29 to 0.96)). Atrophy (1.52 (1.08 to 2.15)) and severe leucoaraiosis (1.74 (1.20 to 2.54)) were associated with 90-day death. Hyperattenuated arteries were associated with sICH (1.71 (1.01 to 2.89)). No imaging features modified the effect of alteplase dose. Conclusions Non-expert-defined brain imaging signs of brain frailty and acute ischaemia contribute to the prognosis of thrombolysis-treated AIS patients for sICH and mortality. However, these imaging features showed no interaction with alteplase dose.

Sleep problems and risk of all-cause cognitive decline or dementia: an updated systematic review and meta-analysis

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (3)

Objectives To conduct an updated systematic review and meta-analysis of association between sleep and all-cause cognitive disorders. Methods PubMed and EMBASE were searched from inception to 18 February 2019. Cohort studies exploring longitudinal associations of sleep with cognitive decline or dementia were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment. The robusterror meta-regression model was used to conduct the dose-response meta-analysis for sleep duration. Results 11 155 reports were searched and 51 eligible cohorts with 15 sleep problems were included for our meta-analyses. Ten types of sleep conditions or parameters, including six (insomnia, fragmentation, daytime dysfunction, prolonged latency, rapid eye movement sleep behaviour disorder and excessive time in bed) with moderate-to-high levels of evidence, were linked to higher risk of all-cause cognitive disorders. Furthermore, a U-shaped relationship was revealed for the associations with sleep duration. Conclusions Sleep management might serve as a promising target for dementia prevention.

Incidence and prevalence of amyotrophic lateral sclerosis in urban China: a national population-based study

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (5)

Objective Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease and information on disease burden of ALS in mainland China was limited. We aimed to estimate the prevalence and incidence of ALS in China. Methods We used 2012-2016 data from China's Urban Employee Basic Medical Insurance and Urban Residence Basic Medical Insurance, covering approximately 0.43 billion individuals. ALS cases were identified by the primary diagnosis (International Classification of Diseases code or text of diagnosis) in the insurance database. Results The crude prevalence and incidence in 2016 were 2.91 per 100 000 person-years (95% CI 2.31 to 3.58) and 1.65 (95% CI 1.33 to 2.01), respectively. The standardised prevalence and incidence based on 2010 Chinese census data were 2.97 (95% CI 2.91 to 3.03) and 1.62 (95% CI 1.58 to 1.67), respectively. The annual prevalence between 2013 and 2016 remained relatively constant, ranging from 2.91 (95% CI 2.31 to 3.58) in 2016 to 3.29 (95% CI 2.51 to 4.17) in 2014 (linear regression: beta=-0.129, p=0.104). Both rates peaked in the group aged 75-79 years. Conclusions The prevalence and incidence of ALS in mainland China were lower than those in developed countries, and maintained a relatively stable trend. The age at onset and age at diagnosis for ALS patients were younger than those in developed countries. Further research is expected to clarify the potential pathophysiological mechanism of ALS.

Clinical prognosis of FLAIR hyperintense arteries in ischaemic stroke patients: a systematic review and meta-analysis

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (5)

Objective We performed a systematic review and meta-analysis to determine the association of fluid-attenuated inversion recovery (FLAIR) hyperintense arteries (FLAIR-HAs) on brain MRI and prognosis after acute ischaemic stroke (AIS). Methods We searched Medline, Embase and Cochrane Central Register of Controlled Trials for studies reporting clinical or imaging outcomes with presence of FLAIR-HAs after AIS. Two researchers independently assessed eligibility of retrieved studies and extracted data, including from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Outcomes were unfavourable functional outcome (primary, modified Rankin scale scores 3-6 or 2-6), death, intermediate clinical and imaging outcomes. We performed subgroup analyses by treatment or types of FLAIR-HAs defined by location (at proximal/distal middle cerebral artery (MCA), within/beyond diffusion-weighted imaging (DWI) lesion) or extent. Results We included 36 cohort studies (33 prospectively collected) involving 3577 patients. FLAIR-HAs were not associated with functional outcome overall (pooled risk ratio 0.87, 95% CI 0.71 to 1.06), but were significantly associated with better outcome in those receiving endovascular therapy (0.56, 95% CI 0.41 to 0.75). Contrary to FLAIR-HAs at proximal MCA or within DWI lesions, FLAIR-HAs beyond DWI lesions were associated with better outcome (0.67, 95% CI 0.57 to 0.79). FLAIR-HAs favoured recanalisation (1.21, 95% CI 1.06 to 1.38) with increased risk of intracerebral haemorrhage (2.07, 95% CI 1.37 to 3.13) and early neurological deterioration (1.93, 95% CI 1.30 to 2.85). Conclusions FLAIR-HAs were not associated with functional outcome overall but were associated with outcome after endovascular therapy for AIS. FLAIR-HAs were also associated with early recanalisation or haemorrhagic complications, and early neurologic deterioration. PROSPERO registration number CRD42019131168.

Pain and the immune system: emerging concepts of IgG-mediated autoimmune pain and immunotherapies

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (2)

The immune system has long been recognised important in pain regulation through inflammatory cytokine modulation of peripheral nociceptive fibres. Recently, cytokine interactions in brain and spinal cord glia as well as dorsal root ganglia satellite glia have been identified important- in pain modulation. The result of these interactions is central and peripheral sensitisation of nociceptive processing. Additionally, new insights and the term 'autoimmune pain' have emerged through discovery of specific IgGs targeting the extracellular domains of antigens at nodal and synaptic structures, causing pain directly without inflammation by enhancing neuronal excitability. Other discovered IgGs heighten pain indirectly by T-cell-mediated inflammation or destruction of targets within the nociceptive pathways. Notable identified IgGs in pain include those against the components of channels and receptors involved in inhibitory or excitatory somatosensory synapses or their pathways: nodal and paranodal proteins (LGI1, CASPR1, CASPR2); glutamate detection (AMPA-R); GABA regulation and release (GAD65, amphiphysin); glycine receptors (GLY-R); water channels (AQP4). These disorders have other neurological manifestations of central/peripheral hyperexcitabability including seizures, encephalopathy, myoclonus, tremor and spasticity, with immunotherapy responsiveness. Other pain disorders, like complex regional pain disorder, have been associated with IgGs against beta 2-adrenergic receptor, muscarinic-2 receptors, AChR-nicotinic ganglionic alpha-3 receptors and calcium channels (N and P/Q types), but less consistently with immune treatment response. Here, we outline how the immune system contributes to development and regulation of pain, review specific IgG-mediated pain disorders and summarise recent development in therapy approaches. Biological agents to treat pain (anti-calcitonin gene-related peptide and anti-nerve growth factor) are also discussed.

Impact of GBA1 variants on long-term clinical progression and mortality in incident Parkinson's disease

期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2020; 91 (7)

Introduction Variants in theGBA1gene have been identified as a common risk factor for Parkinson's disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of 'non-pathogenic' variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of 'non-pathogenic'GBA1variants on PD course is less clear. In this study, we report the effect ofGBA1variants in incident PD patients with long-term follow-up. Methods The study population consisted of patients in the Cambridgeshire Incidence of Parkinson's disease from General Practice to Neurologist and Parkinsonism: Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire cohorts. Patients were grouped into non-carriers, carriers of 'non-pathogenic'GBA1variants and carriers of pathogenicGBA1mutations. Survival analyses for time to development of dementia, postural instability and death were carried out. Cox regression analysis controlling for potential confounders were used to determine the impact ofGBA1variants on these outcome measures. Results GBA1variants were identified in 14.4% of patients. Pathogenic and 'non-pathogenic'GBA1variants were associated with the accelerated development of dementia and a more aggressive motor course. PathogenicGBA1variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia. Discussion GBA1variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course.

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