Objective To foster trial‐readiness of coenzyme Q8A (COQ8A)‐ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A‐ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods Cross‐modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D‐protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results Fifty‐nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A‐ataxia presented as variable multisystemic, early‐onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss‐of‐function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross‐sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild‐to‐moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation This study provides a deeper understanding of the disease, and paves the way toward large‐scale natural history studies and treatment trials in COQ8A‐ataxia. ANN NEUROL 2020;88:251–263

Hallucinations in Parkinson’s disease (PD) are disturbing and frequent non-motor symptoms and constitute a major risk factor for psychosis and dementia. We report a robotics-based approach applying conflicting sensorimotor stimulation, enabling the induction of presence hallucinations (PHs) and the characterization of a subgroup of patients with PD with enhanced sensitivity for conflicting sensorimotor stimulation and robot-induced PH. We next identify the fronto-temporal network of PH by combining MR-compatible robotics (and sensorimotor stimulation in healthy participants) and lesion network mapping (neurological patients without PD). This PH-network was selectively disrupted in an additional and independent cohort of patients with PD, predicted the presence of symptomatic PH, and associated with cognitive decline. These robotics-neuroimaging findings extend existing sensorimotor hallucination models to PD and reveal the pathological cortical sensorimotor processes of PH in PD, potentially indicating a more severe form of PD that has been associated with psychosis and cognitive decline.

Objectives: We aim to (1) determine the frequency and distinctive features of short myelitis (SM) and longitudinally extensive transverse myelitis (LETM) in a cohort of adults with myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated myelitis and (2) determine baseline prognostic factors among MOG-Ab-positive patients whose disease started with myelitis. Material and Methods: We retrospectively analyzed clinical and paraclinical variables from a multicentric French cohort of adults with MOG-Ab-associated myelitis. At last follow-up, patients were classified into two groups according to the severity of the Expanded Disability Status Scale (EDSS) as ⩽2.5 or ⩾3.0. Results: Seventy-three patients with at least one episode of myelitis over disease course were included; among them, 28 (38.4%) presented with SM at the time of the first myelitis. Motor and sphincter involvement was less frequently observed in SM (51.9% and 48.2%, respectively) than in LETM patients (83.3% and 78.6%, respectively), p = 0.007 and p = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group, p = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%), p < 0.001. EDSS at last follow-up was higher in LETM (median 3.0 (interquartile range: 2.0–4.0)) compared to SM patients (2.0, (1.0–3.0)), p = 0.042. Finally, a higher EDSS at onset was identified as the only independent risk factor for EDSS ⩾3.0 (odds ratio, 1.40, 95% confidence interval (CI): 1.01–1.95, p = 0.046). Conclusion: SM in MOG-Ab-associated disease is not rare. The severity at onset was the only independent factor related to the final prognosis in MOG-Ab-associated myelitis.

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Vaccines have been suspected of playing a role in inducing autoimmune disease (AID) for a long time. However, apart from certain specific vaccine strains and complications (such as the swine flu vaccine and Guillain-Barré syndrome in 1976, thrombocytopenia and the Measles-Mumps-Rubella vaccine), this role has not been established. In spite of this, many isolated cases or series of cases of arthritis, vasculitis, and central or peripheral nervous system symptoms following vaccination have been reported. These cases tend to be very infrequent and usually only the shortterm outcomes are described. This paper will examine the arguments for and against the relationship between vaccines and AID, bearing in mind that no association between the two has been clearly identified up to now. The role of adjuvants in vaccines has been described by other teams and in a more general syndrome (Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants). Thus, cases of AID triggered by vaccines are highly rare and raise questions about the interaction between vaccines and/or their adjuvants and the genetic context of autoimmune disease. These observations should therefore not undermine the benefits of vaccination.

Freezing of gait (FOG) in Parkinson disease (PD) is common and disabling. It has 3 phenotypes, 1 the least common one being akinetic freezing (a lack of discernible leg movements despite an intention to walk). The other phenotypes can be characterized as freezing with attempted but ineffective stepping: one involves alternating-leg trembling with a frequency of 3 to 8 Hz, the other by small, shuffling steps. The underlying pathophysiological substrate remains insufficiently understood. In this Viewpoint, we address this fascinating but hitherto largely neglected paradox: levodopa generally reduces the severity of FOG, but 2 recent observations showed that in patients with parkinsonism who were untreated-even those with severe disease-the ineffective stepping phenotype of freezing is absent. 2,3 Such observations suggest that long-term pulsatile levodopa treatment may contribute to FOG development. Initially, it is difficult to reconcile levodopa's beneficial symptomatic outcomes with this negative development. We provide a new framework to explain this paradox as a basis for research and treatment.Several observations suggest that FOG was rare before patients were treated with levodopa. First, not long after the introduction of levodopa in the late 1960s, clinicians began to observe a new phenotype of PD. In 1971, Barbeau 4 described patients receiving levodopa treatment starting to experience a new type of walking problem-one we would now refer to as FOG with attempted stepping. In a series 5 of 80 patients, freezing typically appeared during the second year of levodopa treatment, and its cumulative prevalence gradually increased to 55% after 6 years of treatment. His observations were supported by Ambani and Van Woert, 6 who described a new gait phenotype with start hesitation and leg trembling after levodopa treatment introduction. They warned against misinterpreting gait worsening as PD progression. 6 Second, a recent structured review 3 of historical films and classic textbooks (1853-1968) from the prelevodopa era supports these observations. Specifically, FOG was not observed in any cinematographic data, and an account of what we would label freezing (in this case, of the akinetic phenotype) was described in only 1 textbook. 3 The ineffective-stepping phenotype was not seen or described. A third line of evidence comes from recently published footages of the index patients with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. 2 In 1982, 7 young adults developed severe and irreversible parkinsonism after injection with a new synthetic heroin, which consisted of almost pure MPTP. 2 Despite the severity of parkinsonism in these patients, no FOG was observed while they were still drug naive, except for a possible form of akinetic freezing in 1 patient. 2 A gait pattern resembling FOG with attempted stepping did develop in 1 patient, but only after 6 years of levodopa treatment.

Background Impact of subthalamic deep brain stimulation (DBS) on impulse control disorders (ICD) in Parkinson's disease (PD) remains controversial. Objectives The objectives of this study were to analyze the natural history of ICD between baseline and 1 year after subthalamic DBS in patients with PD and to identify predictive factors, taking into account the positions of the active contact and stimulation parameters. Methods We analyzed postoperative modifications of ICD based on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. ICD status and Ardouin Scale of Behaviour in PD were assessed at baseline and 1 year following subthalamic DBS. Location of active contacts within the 3 subthalamic nucleus functional territories was investigated. Results A total of 217 were patients included. Of the patients, 10.6% had ICD at baseline of which 95.6% improved at 1 year following subthalamic DBS; 3.6% of the patients experienced de novo ICD at 1 year following subthalamic DBS. Dopamine agonist dose reduction (from 309.8 to 109.3 mg) was the main driver of ICD regression (P = 0.05). Higher preoperative dyskinesias were associated with poorer ICD evolution (P = 0.04). Whereas baseline apathy was a risk factor of de novo ICD (P = 0.02), ICD improvement correlated with postoperative apathy (P = 0.004). Stimulation power and position of active contacts—mainly located within the sensorimotor part of the subthalamic nucleus—did not influence ICD. Conclusions This 1‐year, postoperative follow‐up study showed ICD regression and dopaminergic drug reduction with optimal position of the active contacts within the subthalamic nucleus. Whereas patients with PD with preoperative ICD were prone to postoperative apathy, we also showed that those with preoperative apathy had a higher risk to experience postoperative de novo ICD, further highlighting the meaningful influence of postoperative management of dopaminergic medication on outcome and the continuum between apathy and ICD. © 2020 International Parkinson and Movement Disorder Society

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