Categories
Myasthenia gravis

How effective is rituximab in refractory myasthenia gravis?

Rituximab in AChR subtype of myasthenia gravis: systematic review.

Di Stefano V, Lupica A, Rispoli MG, Di Muzio A, Brighina F, Rodolico C.

JNNP 2020; 91:392-395.

Abstract

Background:

Myasthenia gravis (MG) is a chronic autoimmune disorder of the neuromuscular junction characterised by an autoantibody against acetylcholine receptor (AChR-Ab), autoantibody against muscle-specific kinase (MuSK-Ab), lipoprotein-related protein 4 or agrin in the postsynaptic membrane at the neuromuscular junction. Many patients are resistant to conventional treatment and effective therapies are needed. Rituximab (RTX) is a monoclonal antibody directed against CD20 antigen on B cells which has been successfully employed in anti-MuSK-Ab+MG, but the efficacy in anti-AChR-Ab+MG is still debated. The purpose of this systematic review was to describe the best evidence for RTX in the acetylcholine receptor subtype.

Methods:

The authors undertook a literature search during the period of 1999-2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analys methodology, employing (myasthenia)+(gravis)+(RTX) as search terms. The analysis was confined to studies that include at least five patients with confirmed anti-AChR-Ab+MG. Thirteen studies have been selected, showing a good safety. The data obtained were heterogeneous in terms of posology, administration scheme and patients’ evaluation, ranging from a minimum of two to a maximum of three cycles.

Results:

Rituximab led to a sustained clinical improvement with prolonged time to relapse, in parallel to a reduction or discontinuation of other immunosuppressive therapies. Treatment with rituximab appears to work in some but not all patients with anti-AChR-Ab+MG, but randomised controlled trials are needed.

Conclusions:

Future studies should take into account the subtype of MG and employ reliable measures of outcome and severity focusing on how to identify patients who may benefit from the treatment.

This paper is cited in the neurochecklist:

Refractory myasthenia gravis (MG): treatment

By Ib intaspharmaOwn work, CC BY-SA 3.0, Link

Abstract link

Categories
Multiple sclerosis

How does the menopause influence the course of MS?

Impact of natural menopause on multiple sclerosis: a multicentre study.

Baroncini D, Annovazzi PO, De Rossi N, et al.

JNNP 2019; pii: jnnp-2019-320587 (Epub ahead of print).

Abstract

OBJECTIVE:

To study the effect of natural menopause on multiple sclerosis clinical course.

METHODS:

This was an observational, retrospective, multicentre, cohort study. Menopause onset was defined by the final menstrual period (FMP) beyond which no menses occurred for 12 months. We included multiple sclerosis (MS) patients with FMP occurred after 2005 and a recorded follow-up of at least 2 years pre-FMP and post-FMP. We excluded patients with primary progressive course, iatrogenic menopause and with other confounders that could mask menopause onset. We compared relapse-rate and expanded disability status scale (EDSS) scores pre-FMP and post-FMP, searching for possible interactions with age, disease duration, cigarette smoking and nulliparity status.

RESULTS:

148 patients were included (mean observation: 3.5 years pre-FMP and post-FMP). Most patients (92%) received disease-modifying therapies, mainly first-lines. After menopause the annualised relapse rate (ARR) significantly decreased (from 0.21±0.31 to 0.13± 0.24; p=0.005), while disability worsened (increase of mean 0.4 vs 0.2 points after menopause; p<0.001). Older age and long-lasting disease were associated with ARR reduction (p=0.013), but not with disability worsening. Cigarette smokers showed a trend to a higher disability accumulation after menopause (p=0.059).

CONCLUSION:

Natural menopause seems to be a turning point to a more progressive phase of MS. Relapse rate is also reduced after menopause, but this effect could be driven most by ageing and shifting to progressive phase in patients with long-lasting disease. Cigarette smoking could speed up disability progression after menopause.

For a contrary finding, see:

Ladeira F, Salavisa M, Caetano A, Barbosa R, Sá F, Correia AS. The influence of menopause in multiple sclerosis course: a longitudinal cohort study. Eur Neurol 2018; 80:223-227.

Both abstracts are cited in  the neurochecklist:

Multiple sclerosis (MS): prognostic features

Abstract link 1

Abstract link 2

Menopausal tulips. Sue Richards on Flickr. https://www.flickr.com/photos/suerichards/147015369
Categories
Multiple sclerosis Peripheral neuropathy Uncategorized

Is CMT-X a risk factor for MS?

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association

Koutsis G, Breza M, Velonakis G, et al.

JNNP 2019; 90:187-194.

Abstract

OBJECTIVE:

X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes. Four patients with CMTX developing central nervous system (CNS) demyelination compatible with multiple sclerosis (MS) have been individually published. We presently sought to systematically investigate the relationship between CMTX and MS.

METHODS:

Over 20 years, 70 consecutive patients (36 men) with GJB1 mutations were identified at our Neurogenetics Unit, Athens, Greece, and assessed for clinical features suggestive of MS. Additionally, 18 patients with CMTX without CNS symptoms and 18 matched controls underwent brain MRI to investigate incidental findings. Serum from patients with CMTX and MS was tested for CNS immunoreactivity.

RESULTS:

We identified three patients with CMTX who developed clinical features suggestive of inflammatory CNS demyelination fulfilling MS diagnostic criteria. The resulting 20-year MS incidence (4.3%) differed significantly from the highest background 20-year MS incidence ever reported from Greece (p=0.00039). The search for incidental brain MRI findings identified two CMTX cases (11%) with lesions suggestive of focal demyelination compared with 0 control. Moreover, 10 cases in the CMTX cohort had hyperintensity in the splenium of the corpus callosum compared with 0 control (p=0.0002). No specific CNS-reactive humoral factors were identified in patients with CMTX and MS.

CONCLUSIONS:

We have demonstrated a higher than expected frequency of MS in patients with CMTX and identified incidental focal demyelinating lesions on brain MRI in patients with CMTX without CNS symptoms. This provides circumstantial evidence for GJB1 mutations acting as a possible MS risk factor.

This paper is now cited in the neurochecklist:

Multiple sclerosis (MS): unusual presentations and associations

Abstract link

By Benefros at English WikipediaOwn work (Original text: Own work, originally from en.wikipedia; description page is/was here.), CC BY-SA 3.0, Link
Categories
Dementia Motor neurone disease

Do pre-symptomatic c9orf72 carriers have a brain MRI signature?

Gyrification abnormalities in presymptomatic c9orf72 expansion carriers

Caverzasi E, Battistella G, Chu SA, et al.

JNNP 2019; 90:1005-1010.

Abstract

OBJECTIVE:

To investigate in-vivo cortical gyrification patterns measured by the local gyrification index (lGI) in presymptomatic c9orf72 expansion carriers compared with healthy controls, and investigate relationships between lGI and cortical thickness, an established morphometric measure of neurodegeneration.

METHODS:

We assessed cortical gyrification and thickness patterns in a cohort of 15 presymptomatic c9orf72 expansion carriers (age 43.7 ± 10.2 years, 9 females) compared with 67 (age 42.4 ± 12.4 years, 36 females) age and sex matched healthy controls using the dedicated Freesurfer pipeline.

RESULTS:

Compared with controls, presymptomatic carriers showed significantly lower lGI in left frontal and right parieto-occipital regions. Interestingly, those areas with abnormal gyrification in presymptomatic carriers showed no concomitant cortical thickness abnormality. Overall, for both presymptomatic carriers and healthy controls, gyrification and cortical thickness measures were not correlated, suggesting that gyrification captures a feature distinct from cortical thickness.

CONCLUSIONS:

Presymptomatic c9orf72 expansion carriers show regions of abnormally low gyrification as early as their 30s, decades before expected symptom onset. Cortical gyrification represents a novel grey matter metric distinctive from grey matter thickness or volume and detects differences in presymptomatic carriers at an early age.

This paper is now cited in the neurochecklist:

Motor neurone disease (MND): C9orf72 variant

Abstract link

By U.S. National Library of Medicine – http://ghr.nlm.nih.gov/gene/C9orf72, Public Domain, Link
Categories
Stroke

Do statins increase the risk of intracerebral haemorrhage following stroke?

Statins and the risk of intracerebral haemorrhage in patients with stroke: systematic review and meta-analysis.

Ziff OJ, Banerjee G, Ambler G, Werring DJ.

JNNP 2019; 90:75-83.

Abstract

OBJECTIVE:

Whether statins increase the risk of intracerebral haemorrhage (ICH) in patients with a previous stroke remains uncertain. This study addresses the evidence of statin therapy on ICH and other clinical outcomes in patients with previous ischaemic stroke (IS) or ICH.

METHODS:

A systematic literature review and meta-analysis was performed in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assess observational and randomised studies comparing statin therapy with control (placebo or no treatment) in patients with a previous ICH or IS. The risk ratios (RR) for the primary outcome (ICH) and secondary outcomes (IS, any stroke, mortality and function) were pooled using random effects meta-analysis according to stroke subtype.

RESULTS:

Forty-three studies with a combined total of 317 291 patient-years of follow-up were included. In patients with previous ICH, statins had no significant impact on the pooled RR for recurrent ICH (1.04, 95% CI 0.86 to 1.25; n=23 695); however, statins were associated with significant reductions in mortality (RR 0.49, 95% CI 0.36 to 0.67; n=89 976) and poor functional outcome (RR 0.71, 95% CI 0.67 to 0.75; n=9113). In patients with previous IS, statins were associated with a non-significant increase in ICH (RR 1.36, 95% CI 0.96 to 1.91; n=103 525), but significantly lower risks of recurrent IS (RR 0.74, 95% CI 0.66 to 0.83; n=53 162), any stroke (RR 0.82, 95% CI 0.67 to 0.99; n=55 260), mortality (RR 0.68, 95% CI 0.50 to 0.92; n=74 648) and poor functional outcome (RR 0.83, 95% CI 0.76 to 0.91; n=34 700).

CONCLUSIONS:

Irrespective of stroke subtype, there were non-significant trends towards future ICH with statins. However, this risk was overshadowed by substantial and significant improvements in mortality and functional outcome among statin users.

This paper is cited in the neurochecklist:

Intracerebral haemorrhage (ICH): causes and risk factors

Abstract link

By Solidach – With software of which I am the product manager, CC BY-SA 3.0, Link
Categories
Autoimmune

What are the HLA risk factors for NMDAR autoimmune encephalitis?

HLA class II allele DRB1*16:02is associated with anti-NMDAR encephalitis.

Shu Y, Qiu W, Zheng J, et al.

JNNP 2019; 90:652-658.

Abstract

BACKGROUND:

Aetiology and pathogenesis of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most common autoimmune encephalitis, is largely unknown. Since an association of the disease with the human leucocyte antigen (HLA) has not been shown so far, we here investigated whether anti-NMDAR encephalitis is associated with the HLA locus.

METHODS:

HLA loci of 61 patients with anti-NMDAR encephalitis and 571 healthy controls from the Chinese Han population were genotyped and analysed for this study.

RESULTS:

Our results show that the DRB1*16:02 allele is associated with anti-NMDAR encephalitis (OR 3.416, 95% CI 1.817 to 6.174, p=8.9×10-5, padj=0.021), with a higher allele frequency in patients (14.75%) than in controls (4.82%). This association was found to be independent of tumour formation. Besides disease susceptibility, DRB1*16:02 is also related to the clinical outcome of patients during treatment, where patients with DRB1*16:02 showed a lower therapeutic response to the treatment than patients with other HLA alleles (p=0.033). Bioinformatic analysis using HLA peptide-binding prediction algorithms and computational docking suggested a close relationship between the NR1 subunit of NMDAR and the DRB1*16:02.

CONCLUSIONS:

This study for the first time demonstrates an association between specific HLA class II alleles and anti-NMDAR encephalitis, providing novel insights into the pathomechanism of the disease.

This paper is cited in the neurochecklist:

Anti NMDAR autoimmune encephalitis: clinical features

Abstract link

By Ryan TJ, Emes RD, Grant SG, Komiyama NH. – Evolution of NMDA receptor cytoplasmic interaction domains: implications for organisation of synaptic signalling complexes, CC BY 2.0, Link
Categories
Motor neurone disease

Is alcohol a risk factor for motor neurone disease?

Association between alcohol exposure and the risk of amyotrophic lateral sclerosis in the Euro-MOTOR study.

D’Ovidio F, Rooney JPK, Visser AE, et al; Euro-MOTOR consortium.

JNNP 2019; 90:11-19.

Abstract

OBJECTIVES:

Several studies focused on the association between alcohol consumption and amyotrophic lateral sclerosis (ALS), although with inconsistent findings. Antioxidants may play a role since lyophilised red wine was found to prolong SOD1 mice lifespan. The aim of this international population-based case-control study performed in Ireland, The Netherlands and Italy was to assess the role of alcohol, and red wine in particular, in developing ALS.

METHODS:

Euro-MOTOR is a case-control study where patients with incident ALS and controls matched for gender, age and area of residency were recruited in a population-based design. Logistic regression models adjusted for sex, age, cohort, education, leisure time physical activity, smoking, heart problems, hypertension, stroke, cholesterol and diabetes were performed.

RESULTS:

1557 patients with ALS and 2922 controls were enrolled in the studyExposure to alcohol drinking was not significantly associated with ALS risk. A stratified analysis of exposure to alcohol by cohort revealed significant ORs in The Netherlands and in Apulia, with opposite directions (respectively 0.68 and 2.38). With regard to red wine consumption, only in Apulia the double-fold increased risk (OR 2.53) remained significant. A decreased risk was found for current alcohol drinkers (OR 0.83), while a significantly increased risk was detected among former drinkers (OR 1.63). Analysis of cumulative exposure to alcohol revealed no significant associations with ALS risk.

CONCLUSION:

With few exceptions, no significant association was found between alcohol consumption and ALS.  The study of the association between alcohol and ALS requires a thorough exploration, especially considering the role of different types of alcoholic beverages.

This paper is cited in the neurochecklist:

Motor neurone disease (MND): protective and neutral risk factors

Abstract link

By Nik Frey (niksan) – stock.xchng: http://www.sxc.hu/browse.phtml?f=view&id=207042 [dead link], CC BY 2.5, Link
Categories
Neuropsychiatry Parkinson's disease

Are people with PD prone to functional neurological disorders?

Functional neurological disorders in Parkinson disease.

Wissel BD, Dwivedi AK, Merola A, et al.

JNNP 2018; 89:566-571.

Abstract

OBJECTIVE:

To ascertain demographic and clinical features of Parkinson disease (PD) associated with functional neurological features.

METHODS:

A standardised form was used to extract data from electronic records of 53 PD patients with associated functional neurological disorders (PD-FND) across eight movement disorders centres in the USA, Canada and Europe. These subjects were matched for age, gender and disease duration to PD patients without functional features (PD-only). Logistic regression analysis was used to compare both groups after adjusting for clustering effect.

RESULTS:

Functional symptoms preceded or co-occurred with PD onset in 34% of cases, nearly always in the most affected body side. Compared with PD-only subjects, PD-FND were predominantly female (68%), had longer delay to PD diagnosis, greater prevalence of dyskinesia (42% vs 18%; P=0.023), worse depression and anxiety (P=0.033 and 0.025, respectively), higher levodopa-equivalent daily dose (972±701 vs 741±559 mg; P=0.029) and lower motor severity (P=0.019). These patients also exhibited greater healthcare resource utilisation, higher use of [(123)I]FP-CIT SPECT and were more likely to have had a pre-existing psychiatric disorder (P=0.008) and family history of PD (P=0.036).

CONCLUSIONS:

A subtype of PD with functional neurological features is familial in one-fourth of cases and associated with more psychiatric than motor disability and greater use of diagnostic and healthcare resources than those without functional features. Functional manifestations may be prodromal to PD in one-third of patients.

This article is cited in the neurochecklist:

Parkinson’s disease (PD): neuropsychiatric features

Abstract link

Child brain. Isaac Mao on Flikr. https://www.flickr.com/photos/isaacmao/544928/
Categories
CMT Multiple sclerosis

Is there any association between multiple sclerosis and X-linked CMT?

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association.

Koutsis G, Breza M, Velonakis G, et al.

JNNP 2018 (Epub ahead of print).

Abstract

OBJECTIVE:

X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes. Four patients with CMTX developing central nervous system (CNS) demyelination compatible with multiple sclerosis (MS) have been individually published. We presently sought to systematically investigate the relationship between CMTX and MS.

METHODS:

Over 20 years, 70 consecutive patients (36 men) with GJB1 mutations were identified at our Neurogenetics Unit, Athens, Greece, and assessed for clinical features suggestive of MS. Additionally, 18 patients with CMTX without CNS symptoms and 18 matched controls underwent brain MRI to investigate incidental findings. Serum from patients with CMTX and MS was tested for CNS immunoreactivity.

RESULTS:

We identified three patients with CMTX who developed clinical features suggestive of inflammatory CNS demyelination fulfilling MS diagnostic criteria. The resulting 20-year MS incidence (4.3%) differed significantly from the highest background 20-year MS incidence ever reported from Greece (p=0.00039). The search for incidental brain MRI findings identified two CMTX cases (11%) with lesions suggestive of focal demyelination compared with 0 control. Moreover, 10 cases in the CMTX cohort had hyperintensity in the splenium of the corpus callosum compared with 0 control (p=0.0002). No specific CNS-reactive humoral factors were identified in patients with CMTX and MS.

CONCLUSIONS:

We have demonstrated a higher than expected frequency of MS in patients with CMTX and identified incidental focal demyelinating lesions on brain MRI in patients with CMTX without CNS symptoms. This provides circumstantial evidence for GJB1 mutations acting as a possible MS risk factor.

This paper is cited in the neurochecklists:

Multiple sclerosis (MS): unusual presentations

Charcot Marie Tooth disease type X (CMTX): clinical features

Abstract link 

MRI scan. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/30754695411