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Predictors of motor complications in early Parkinson's disease: A prospective cohort study.
OBJECTIVE: The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis. METHODS: An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete-time survival analysis. A subset analysis was used to validate an online dyskinesia-risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial. RESULTS: A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11-16] <3.5 years, 16 [13-21] 3.5-5.0 years, 19 [14-26] 5-6.5 years, and 23 [16-33] >6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors. Baseline nonmotor feature severity, low mood, anxiety, and age at symptom onset were associated with motor complications among a number of previously identified predictors. Replication of the Stalevo Reduction in Dyskinesia Evaluation PD calculator was reasonable with the area under the curve for dyskinesia risk score as a predictor of dyskinesia being 0.68 (95% confidence interval, 0.55-0.81). CONCLUSIONS: This study quantifies risk of motor complications, finds consistent predictors, and demonstrates the novel finding that nonmotor features of PD, particularly low mood and anxiety, are significant risk factors for motor complications. Further validation of dyskinesia risk scores are required as well as evidence to determine if the routine use of such scores can be clinically valuable in enhancing patient care and quality of life. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Myasthenia gravis in 2025: five new things and four hopes for the future
Abstract The last 10 years has brought transformative developments in the effective treatment of myasthenia gravis (MG). Beginning with the randomized trial of thymectomy in myasthenia gravis that demonstrated efficacy of thymectomy in nonthymomatous MG, several new treatment approaches have completed successful clinical trials and regulatory launch. These modalities, including B cell depletion, complement inhibition, and blockade of the neonatal Fc receptor, are now in use, offering prospects of sustained remission and neuromuscular protection in what is a long-term disease. In this review, we update our clinico-immunological review of 2016 with these important advances, examine their role in treatment algorithms, and focus attention on key issues of biomarkers for prognostication and the growing cohort of older patients, both those with long-term disease, and late-onset MG (‘LOMG’). We close by expressing our four hopes for the next 5–10 years: improvements in laboratory medicine to facilitate rapid diagnosis, effective strategies for neuromuscular protection, more research into and better understanding of pathophysiology and treatment response in older individuals, and the potentially transformative role of therapies aimed at delivering a durable response such as chimeric antigen receptor (CAR) T cells. Our postscript summarizes some emerging themes in the field of serological and online biomarkers, which may develop greater stature in the next epoch.
Gliosarcoma associated with bilateral hippocampal sclerosis in a cat presenting complex partial seizures with orofacial involvement: A case report.
KEY CLINICAL MESSAGE: Gliosarcoma, a rare cerebral neoplasm, has not been linked to hippocampal changes in cats. We report a case of complex partial seizures with orofacial involvement, revealing gliosarcoma concurrent with bilateral hippocampal sclerosis. ABSTRACT: A 16-year-old neutered female domestic shorthair cat presented with acute inappetence, ataxia, disorientation, and vacant staring. Brain MRI revealed an ill-defined, round, intra-axial mass in the right piriform lobe, showing hyperintensity on T2W, T2-FLAIR, and T2*W, and hypointensity on T1W images. The lesion exhibited mass effect and contrast enhancement in its center. Bilateral hyperintensity on T2-FLAIR images and contrast enhancement were observed in the hippocampus. Brain histologic and immunohistochemical analysis revealed cerebral gliosarcoma with concurrent hippocampal sclerosis. Feline LGI1-antibody testing on the serum and/or CSF was not performed due to insufficient biomaterial. Although retrospective testing on brain tissue was considered, it ultimately proved unfeasible, preventing us from ruling out antibody-associated limbic encephalitis. In conclusion, cerebral gliosarcoma should be included in feline intracranial tumor differentials, warranting brain MRI and feline LGI1-antibody testing in cats showing complex partial seizures with orofacial involvement. In our case, the prognosis remained poor due to the presence of a high-grade glioma.
Established, new and future disease modifying therapies for MS
Over recent years the pace of therapeutic development in multiple sclerosis has increased, and there are now 10 disease-modifying therapies available. In this review the authors discuss the evidence supporting the use of these drugs and consider which new treatments may be available in the future.
HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis
IntroductionGenetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.MethodsWe conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.ResultsAnti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.DiscussionOur observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.
Capturing what matters: Patient‐reported LGI1‐ANTibody encephalitis outcome RatiNg scale (LANTERN)
AbstractBackgroundLGI1‐antibody encephalitis (LGI1‐Ab‐E) is a common form of autoimmune encephalitis where most patients demonstrate ‘good’ clinician‐rated outcomes. However, more targeted questionnaires reveal numerous debilitating symptoms for many years. To better quantify these persistent features, we designed the LGI1‐Antibody Encephalitis Rating (LANTERN) scale, a quantified, disease‐specific patient‐reported outcome measure (PROM), adhering to FDA guidelines.MethodsA participant‐driven mixed‐methods approach to develop a clinically valid questionnaire over three stages: (1) Item generation through semi‐structured interviews; (2) Repeated cognitive debriefing rounds to advance comprehensibility, relevance and comprehensiveness; (3) Psychometric survey to condense the most sensitive and valid questions. Analyses incorporated sensitivity testing with multiple internal and external validations.ResultsFrom 73 items across six domains (Stage 1; n = 18), a questionnaire assessing the frequency and severity of 43 symptoms (80 questions), plus nine activities of daily living (ADL), was developed through cognitive debriefing (Stage 2; n = 15). This 89‐question survey was completed (Stage 3; n = 66 patients and 32 relatives) and distilled, using exploratory factor analyses, to a three‐factor symptom‐burden questionnaire comprising 41 questions (19 symptoms and 6 ADL), separated into physical, cognitive/behavioural and ADL domains. These factors demonstrated strong internal reliability (Cronbach alpha: 0.85–0.91), correlations with relative‐completed questionnaires (R = 0.73–0.85; p < 0.001), good‐to‐excellent intraclass re‐testing correlations (0.81–0.98; n = 19) and strong associations with numerous predefined external measures.DiscussionLANTERN represents a PROM for LGI1‐Ab‐E, with initial content, structural and construct validity and test–retest reliability. It can be used as a reliable, tailored, efficient and sensitive method to establish symptom burden in people with LGI1‐Ab‐E, both in clinical practice and trials.
Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model.
BACKGROUND AND OBJECTIVE: Autoimmune encephalitis (AE) is a form of brain inflammation where pathogenic autoantibodies bind surface proteins. In humans, AE is at least as common as infective encephalitis, and seizures are a prominent manifestation. The most common adult human AE is associated with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E). AE in non-human mammals is also recognised, notably the polar bear 'Knut', diagnosed with N-methyl D-aspartate receptor antibody encephalitis. LGI1-Ab-E is an emerging cause of spontaneously-arising AE in domestic cats. Our objective was to phenotype the seizure profile of feline LGI1-Ab-E and probe parallels to its human counterpart. METHODS: We characterised seizures in naturally-occurring feline LGI1-Ab-E. Three veterinary and two human neurologists independently blind-rated 35 LGI1-antibody positive and negative feline seizure videos from 24 cats (16 LGI1-Ab-E positive, 8 negative). Data analysed included seizure frequency, semiologies and their co-occurrence, localisation, inter-rater agreement, and predictive factors. RESULTS: The mean number of daily seizures at peak was significantly higher in LGI1-antibody positive compared to LGI1-antibody-negative cats (12.6 vs. 1.9/day, pcorr = 0.011). Semiologies statistically significantly enriched in LGI1-Ab-E observations included orofacial automatisms (88/120, 73 % vs. 26/55, 47 %, pcorr = 0.024), salivation (87/120, 73 % vs. 23/55, 42 %, pcorr = 0.004); and mydriasis (79/120, 66 % vs 19/55, 35 %, pcorr = 0.004), and almost exclusively seen in LGI1-Ab-E were circling (39/120, 33 % vs. 1/55, 2 %, pcorr=<0.001) and aggression (14/120, 12 % vs. 0/55, 0 %, non significant after correction). A temporal lobe onset was proposed in 67 % (80/120) of seropositive ratings, compared to 28 % (15/55) LGI1-Ab-E negative (p
LGI1-antibody encephalitis: how to approach this highly treatable dementia mimic in memory and mental health services
Leucine-rich glioma-inactivated 1-antibody-encephalitis is a treatable and potentially reversible cause of cognitive and psychiatric presentations, and may mimic cognitive decline, rapidly progressive dementia and complex psychosis in older patients. This aetiology is of immediate relevance given the alternative treatment pathway required, compared with other conditions presenting with cognitive deficits.
Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts
Abstract Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P < 5 × 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.
HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease
Abstract Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.
Clinical data and reporting quality in NMDAR-antibody encephalitis and pregnancy: a systematic review
BackgroundN-methyl-D-aspartate receptor antibody encephalitis (NMDAR-Ab-E) can have an onset during, after or prior to a pregnancy. In animal models, transplacental NMDAR immunoglobulin G transfer can affect neurodevelopment. In contrast, clinical reports of mothers affected by NMDAR-Ab-E typically are reassuring. We systematically reviewed maternal, infant and childhood clinical data pertaining to NMDAR-Ab-E with an onset before, during or after pregnancy and compared this to our single autoimmune neurology centre experience.MethodsAfter pre-registration on PROSPERO (CRD42023408447), we searched PubMed and Scopus for NMDAR-Ab-E case reports/series with an onset before, during or after pregnancy (last search 19/10/2023). We extracted maternal, neonatal and childhood outcomes using an idealised checklist to derive summary statistics.ResultsAfter quality control, we identified 66 pregnancies in 61 women from 48 reports or series. 72% of women recovered with minimal or no neurological deficits, comparable to non-pregnancy-associated NMDAR-Ab-E. Likewise, 80% of pregnancies resulted in live births with a single neonatal death reported. Data on neonatal outcome measures were frequently unreported, and childhood follow-up was provided in only 60%. Our centre’s experience is consistent: 3/4 mothers recovered with no functional deficits and 7/8 children without evidence of compromise at a median follow-up of 2 years.ConclusionsCurrent evidence does not overall suggest unfavourable maternal, fetal or childhood outcomes after NMDAR-Ab-E. However, the available sample is small, predominantly single case reports with modest follow-up, lacks standardisation, and data are often incomplete. Future approaches should address these caveats: developing multi-centre collaboration towards an international registry.
Anatomy of the diaphragmatic crura and other paraspinal structures relevant to en-bloc spondylectomy for lumbar spine tumours
Abstract Introduction En-bloc spondylectomy in the lumbar spine is a challenging procedure mainly due to a complex prevertebral anatomy. The aim of our study is to describe the anatomy of the diaphragmatic crura and surrounding vascular and neural structures which may be iatrogenically injured during the surgical resection. Materials and methods Ten embalmed specimens were meticulously dissected. Widths of the diaphragmatic crura, abdominal aorta, cisterna chyli, thoracic duct, sympathetic trunks, and inferior vena cava as well as their distances from the midline were measured at nine levels (L1 to L4 vertebra and adjacent intervertebral discs). Results The right crus was attached to the L2–L4 vertebral bodies and L2/3 intervertebral disc, while the left crus inserted onto L1–L3 vertebrae. The thoracic duct arose commonly at the level of L2 vertebra and overlaid the right crus at the L3 vertebra and L2/3-disc levels. The cisterna chyli was present in 70% of specimens and overlapped with the left crus at the same levels. Both sympathetic trunks emerged underneath the crura at the L1/2 discs or L1 vertebra level. The aorta overlapped with the crura at all levels. Conclusion The L3 level appears to be the riskiest for spondylectomy due to the overlap of both diaphragmatic crura with the thoracic duct and cisterna chyli, respectively. Spondylectomy at the L2 level also brings the risk of lymphatic structures injury while injury to the left sympathetic trunk may be the main issue at the L1 level.
New options and techniques in reconstructing the sacrum
Abstract Purpose Sacral tumours, both benign and malignant, often necessitate surgical removal (sacrectomy) to achieve optimal outcomes. However, this procedure disrupts the pelvic ring’s stability, potentially leading to pain and limited mobility. Methods This article explores innovative approaches to reconstruct the sacrum and restore function in primary and secondary sacral tumours. Results Beyond traditional bone graft-based spino-pelvic fixation, the paper delves into minimally invasive alternatives like robotic-assisted surgery which may be used especially as a palliative procedure in destructive lumbosacral junction metastases. This technique offers enhanced precision for implant placement and often a reduced surgical exposure, potentially improving patient recovery. Additionally, the article discusses the application of 3D-printed custom implants, precisely matched the patient’s anatomy to provide immediate structural support. It also explores the use of vascularised long bone flaps for pelvic reconstruction to achieve both stability and ambulation after sacrectomy. Additionally, it is necessary to mention the crucial role of soft tissue reconstruction using local flaps or free flaps from other body regions. Conclusion By presenting these advancements in sacral reconstruction techniques, this article empowers surgeons to select an individualised approach for their patient. This personalised approach can optimise post-operative outcomes, allowing patients to regain function and improve their quality of life.
Diagnosis and management of de novo non-specific spinal infections: European Association of Neurosurgical Societies (EANS) Spine Section Delphi consensus recommendations.
INTRODUCTION: The management of de novo non-specific spinal infections (spondylodiscitis - SD) remains inconsistent due to varying clinical practices and a lack of high-level evidence, particularly regarding the indications for surgery. RESEARCH QUESTION: This study aims to develop consensus recommendations for the diagnosis and management of SD, addressing diagnostic modalities, surgical indications, and treatment strategies. MATERIAL AND METHODS: A Delphi process was conducted with 26 experts from the European Association of Neurosurgical Societies (EANS). Sixtytwo statements were developed on diagnostic workup, management decisions, surgical techniques, non-surgical treatment, and follow-up and submitted to the panel of experts. RESULTS: Consensus was reached on 38 of 62 statements. MRI was confirmed as the gold standard for diagnosis. Regarding surgical indications, the panel agreed that any new neurological deficit, even subtle, warrants surgical consideration. Motor deficits with a motor score (MRC) below 4 and bladder or bowel dysfunction were unanimously considered clear indications for surgery. For spinal deformity and instability, thresholds such as kyphosis >20°, scoliosis >10°, and vertebral body collapse >50% were established to guide surgical decision-making. Minimally invasive surgery (MIS) was endorsed whenever feasible, and a 12 week antibiotic treatment regimen was favored in cases of complicated infections. DISCUSSION AND CONCLUSION: This EANS consensus provides updated recommendations for SD management, incorporating recent evidence on improved outcomes with surgical therapy. While these guidelines offer a more structured approach to clinical decision-making, further research is required to optimize surgical timing and validate the long-term impact of these treatment strategies.