Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (similar to 0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO <= 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO <= 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 x 10(-34)). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 x 10(-35)). Female patients were 22% more likely to have a positive PDGT (P = 3 x 10(-4)), and for individuals with FH+ this likelihood was 55% higher (P = 1 x 10(-14)). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that similar to 15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

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.

A 21-year-old woman of south Asian origin presented with cervical dystonia which had progressed over the previous three years. Her symptoms started as writer's cramp since the age of seven years. She did not respond to medications and needed botulinum toxin injection for generalised dystonia. Subsequent whole genome sequencing revealed a likely pathogenic c.98G>A p.(Cys33Tyr) heterozygous variant in the THAP1 gene. She underwent bilateral posteroventral globus pallidus interna (GPi) deep brain stimulation (Medtronic Activa PC) implantation at the age of thirty-one years. She responded well to the deep brain stimulation even after more than 8 years post-surgery though she needs botulinum toxin injection for her cervical dystonia.

A 21-year-old patient presented with sudden-onset headache, visual disturbance and left hand incoordination. She was diagnosed with a left vertebral artery dissection of the V3 segment resulting in multiple cerebellar and cerebral infarcts. There were no risk factors for dissection other than recent COVID-19 infection. She was treated initially with antiplatelets, followed by anticoagulation, but experienced recurrent ischaemia. Although guidance suggests endovascular repair may be beneficial for patients with cerebral artery dissection (CAD) who experience recurrent strokes on medical therapy, evidence is limited. After multidisciplinary team consideration of the individual patient anatomy and risks and benefits of different endovascular techniques, the patient was treated with endovascular coiling. At 10 months follow-up, she had no further strokes and improving neurological symptoms. The case highlighted COVID-19 as a potential trigger for CAD and the use of endovascular coiling in preventing catastrophic cerebral ischaemia in CAD refractive to medical therapy.

Achieving the best outcome from STN stimulation for the treatment of Parkinson’s disease depends on ideal electrode placement and optimum stimulation settings. Motor symptoms are known to respond well to stimulation of the dorsolateral nucleus of the subthalamus and avoidance of tissue activation of the surrounding structures that may give rise to unwanted side effects including slurred speech, gait problems and neuropsychiatric symptoms. The recent development of multidirectional stimulation systems has enabled electrical current steering to activate the desired tissue areas in order to achieve effective neuromodulation.In this audit of 16 patients who underwent STN-DBS, we looked at the short-term neuropsychiatric outcomes in patients in whom current steering was deployed to achieve the best motor control to those in whom control was achieved by conventional ring mode stimulation. The patients’ symptoms were assessed at baseline and at 12 months using validated scales for anxiety, depression, apathy, and impulsivity. There was no statistical difference in the neuro-psychiatric outcomes between the two groups. However, the number of patients in this study was small and larger studies for longer periods are required to evaluate the potential benefit of this new development in minimising the neuropsychiatric complications of this treatment.

INTRODUCTION:Holmes Tremor (HT) is a unique and debilitating movement disorder. It usually results from lesions of the midbrain and its connection but can also result from posterior thalamic injury. Clinical examination can help lesion localization between these two areas. We studied the clinical features and their radiological correlations to distinguish midbrain HT (HT-m) from thalamic HT (HT-t).METHODS:Retrospective review of 17 patients with a HT-type presentation was conducted. Tremor characteristics, associated clinical signs and radiological findings were studied.RESULTS:Eleven patients had a myorythmic rest tremor, large amplitude proximal tremor with goal-directed worsening, with or without mild distal dystonic posturing, representing HT-m. Six patients had slow, large amplitude proximal tremors and distal choreathetoid movements, significant proximal/distal dystonic posturing, associated with proprioceptive sensory loss, representing HT-t. Haemorrhagic lesions were the predominant cause of HT-m; whereas, ischaemia was more commonly associated with HT-t.CONCLUSION:When assessing patients with HT, attentiveness to the presence of associated signs in the affected limb, such as a proprioceptive sensory deficits and additional movement disorders, can aid lesion localisation, which can have implications for management.

Background: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. Objective: To survey the accessible MD clinical training in these regions. Methods: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. Results: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. Conclusion: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.

When considering Deep Brain Stimulation (DBS) surgical treatment of dystonia syndromes, it is important to consider multiple aspects of the disease and its presentation. It is crucial to know if the dystonia is idiopathic, inherited or acquired as well as focal, segmental or generalised. Careful phenotyping of idiopathic as well as inherited dystonias and accurate diagnosis of acquired dystonias informs the decision-making process for patients and clinicians by providing them with useful predictors of outcomes of the proposed surgery. Here, we provided a review of the current literature, highlighted the areas where evidence is scarce and suggested future directions for research.