Treatment failure in persistent tic disorders: an expert clinicians' consensus-based definition.

A standardized definition of treatment failure in the management of tics is currently lacking. Such definition would prevent persistent use of unnecessary interventions and help clinicians to determine when to offer less established treatments (e.g., deep brain stimulation surgery). To achieve an expert consensus-based definition of failure of medical treatments for tics, we used a multi-step, multi-round, web-based Delphi approach involving international specialist clinicians with specific expertise in tic disorders. These experts were identified through professional networks or consortia related to chronic tic disorders. We created a survey and reviewed the questions with stakeholders prior to two rounds of Delphi surveys, followed by a final review and discussion among research team members. Both survey rounds were completed using a sample of 36 expert stakeholders from 14 countries, including neurologists, psychiatrists, and clinical psychologists. The Delphi process led to consensus on 10 statements which formed the final definition of treatment failure. The definition was structured and operationalized according to two separate sections, one for behavioral and one for pharmacological treatments. Core components of the definition and its operationalization included lack of efficacy, adherence, and tolerability, as well as a definition of failure of behavioral therapies as a whole, and of pharmacological therapies as a whole. The group concluded that the components of this specific definition reflect the range and complexity of characteristics to consider in establishing tic-related treatment failure. Future research should assess the feasibility of this operational definition and whether it will change clinical decision-making and improve management outcomes.

Distinct movement disorders in contactin-associated-protein-like-2 antibody-associated autoimmune encephalitis.

Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan's syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P < 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, 'mixed movement disorders', Morvan's syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.

Effectiveness and Tolerability of Natural Herbal Formulations in the Prevention of Radiation-Induced Skin Toxicity in Patients Undergoing Radiotherapy.

The aim of this study is to investigate the preventive role of 3 herbal formulation products on reducing the incidence of radiation-induced dermatitis in patients undergoing radiotherapy for either breast or head and neck cancer. A total of 59 patients participated in the study. The novel herbal products, a combination of beeswax, olive oil, Calendula and Hypericum oils and Aloe gel, were daily and regularly being used by the patients during radiotherapy and 2 weeks after treatment end. Acute skin toxicity was scored weekly during radiotherapy and after treatment for a further 4-week follow-up period. Demographic data were analyzed by descriptive statistics. Statistical analyses of the study objectives were based on an intent-to-treat principle. Most of the patients presented with grade I (RTOG/EORTC) toxicity in the first weeks of radiotherapy, progressed to grade II but reverted to grade I toxicity up until the study end. A total of 94.9% of the patients had Dermatology Life Quality Index up to 1, and 66.1% remained in this scale. The application of the novel natural product combinations proved to be statistically significantly effective in reducing the intensity of radiation dermatitis, positively affecting the quality of life of the patients.

Chemical Profile and Screening of Bioactive Metabolites of Rindera graeca (A. DC.) Bois. & Heldr. (Boraginaceae) In Vitro Cultures.

Rindera graeca is a rare endemic plant where in vitro culture has been used in order to investigate bioactive metabolites. Phytochemical study of the in vitro shoots and hairy roots led to the isolation of seven phenolic derivatives and the unusual furano-naphthoquinone rinderol. R. graeca was also analyzed for its pyrrolizidine alkaloids content by LC-MS, and it was found to contain echinatine together with echinatine and rinderine N-oxides. Rinderol, isolated only from in vitro hairy root culture for the first time in the genus, revealed promising bioactivities. It was evaluated in vitro against a panel of microorganisms, showing very strong activity specifically against Gram-positive bacteria (MIC values 0.98 × 10-2-1.18 µg/mL) as well as very interesting antiproliferative effect against the human non-small-cell bronchopulmonary carcinoma cell line NSCLC-N6-L16 and the epidermoid lung cancer cell line A549. These findings were compared with the chemical profile of the plant from nature, while this study is the first to report on the effects of R. graeca extracts obtained from in vitro culture, providing a valuable contribution to the scientific community towards this sustainable method of production of potential bioactive molecules.

The 5 Pillars in Tourette Syndrome Deep Brain Stimulation Patient Selection: Present and Future.

The selection of patients with Tourette syndrome (TS) for deep brain stimulation (DBS) surgery rests on 5 fundamental pillars. However, the operationalization of the multidisciplinary screening process to evaluate these pillars remains highly diverse, especially across sites. High tic severity and tic-related impact on quality of life (first 2 pillars) require confirmation from objective, validated measures, but malignant features of TS should per se suffice to fulfill this pillar. Failure of behavioral and pharmacologic therapies (third pillar) should be assessed taking into account refractoriness through objective and subjective measures supporting lack of efficacy of all interventions of proven efficacy, as well as true lack of tolerability, adherence, or access. Educational interventions and use of remote delivery formats (for behavioral therapies) play a role in preventing misjudgment of treatment failure. Stability of comorbid psychiatric disorders for 6 months (fourth pillar) is needed to confirm the predominant impact of tics on quality of life, to prevent pseudo-refractoriness, and to maximize the future DBS response. The 18-year age limit (fifth pillar) is currently under reappraisal, considering the potential impact of severe tics in adolescence and the predictive effect of tic severity in childhood on tic severity when transitioning into adulthood. Future advances should aim at a consensus-based definition of failure of specific, noninvasive treatment strategies for tics and of the minimum clinical observation period before considering DBS treatment, the stability of behavioral comorbidities, and the use of a prospective international registry data to identify predictors of positive response to DBS, especially in younger patients.

Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.

Pimpinella anisum seeds essential oil from Lesvos island: Effect of hydrodistillation time, comparison of its aromatic profile with other samples of the Greek market. Safe use.

The essential oil of Pimpinella anisum L. (Apiaceae) seeds from Lesvos Island (Greece), famous as flavor for the production of the aperitif "ouzo", has been analyzed by GC-MS for the first time. Additionally, three samples of the Greek market originated from North and Central Greece (Thessaly, Viotia) and Turkey, were also analyzed and all of them were compared to the quality limits given in European Pharmacopoeia for medicinal purposes. The effect of hydrodistillation time found to be very important as the results showed differentiations of the oil yield and the chemical content. The most abundant identified metabolites were trans-anethole, γ-himachalene, estragole and pseudoisoeugenyl 2-methylbutyrate. It is noteworthy, that Lesvos anise oil showed the best quality according to European Pharmacopoeia's standards, while it had the highest yield and the richest chemical composition (28 identified compounds) among all studied samples, contributing to the well known quality of "ouzo" from Plomari. Furthermore, two major secondary metabolites from Lesvos' anise oil: trans-anethole and a mixture of himachalenes have been isolated and structurally determined. Moreover, the safe use of anise oil is discussed due to potential toxic effects of estragole.

Tics in the Pediatric Population: Pragmatic Management.

BACKGROUND: Primary tic disorders, notably Tourette syndrome, are very common movement disorders in childhood. However, the management of such patients still poses great therapeutic challenges to medical professionals. METHODS: Based on a synthesis of the available guidelines published in Europe, Canada, and the United States, coupled with more recent therapeutic developments, the authors provide a pragmatic guide to aid clinicians in deciding when and how to treat patients who have primary tic disorders. RESULTS: After a systematic assessment of tics and common neuropsychiatric comorbidities (primarily attention-deficit hyperactivity disorder [ADHD] and obsessive-compulsive disorder [OCD]), the first step in treatment is a comprehensive psychoeducation of patients and families that addresses the protean phenomenology of tics and associated behaviors, coping mechanisms, prognosis, and treatment options. When more active intervention beyond watchful monitoring is indicated, hierarchical evaluation of treatment targets (i.e., tics vs. comorbid behavioral symptoms) is crucial. Behavioral treatments for tics are restricted to older children and are not readily available to all centers, mainly due to the paucity of well-trained therapists. Pharmacological treatments, such as antipsychotics for tics, stimulants and atomoxetine for ADHD, and α2A-agonists for children with tics plus ADHD, represent widely available and effective treatment options, but safety monitoring must be provided. Combined polypharmacological and behavioral/pharmacological approaches, as well as neuromodulation strategies, remain under-investigated in this population of patients. CONCLUSIONS: The treatment of children with tics and Tourette syndrome is multifaceted. Multidisciplinary teams with expertise in neurology, psychiatry, psychology, and pediatrics may be helpful to address the complex needs of these children.

The long-term outcome of orthostatic tremor.

OBJECTIVES: Orthostatic tremor is a rare condition characterised by high-frequency tremor that appears on standing. Although the essential clinical features of orthostatic tremor are well established, little is known about the natural progression of the disorder. We report the long-term outcome based on the largest multicentre cohort of patients with orthostatic tremor. METHODS: Clinical information of 68 patients with clinical and electrophysiological diagnosis of orthostatic tremor and a minimum follow-up of 5 years is presented. RESULTS: There was a clear female preponderance (76.5%) with a mean age of onset at 54 years. Median follow-up was 6 years (range 5-25). On diagnosis, 86.8% of patients presented with isolated orthostatic tremor and 13.2% had additional neurological features. At follow-up, seven patients who initially had isolated orthostatic tremor later developed further neurological signs. A total 79.4% of patients reported worsening of orthostatic tremor symptoms. These patients had significantly longer symptom duration than those without reported worsening (median 15.5 vs 10.5 years, respectively; p=0.005). There was no change in orthostatic tremor frequency over time. Structural imaging was largely unremarkable and dopaminergic neuroimaging (DaTSCAN) was normal in 18/19 cases. Pharmacological treatments were disappointing. Two patients were treated surgically and showed improvement. CONCLUSIONS: Orthostatic tremor is a progressive disorder with increased disability although tremor frequency is unchanged over time. In most cases, orthostatic tremor represents an isolated syndrome. Drug treatments are unsatisfactory but surgery may hold promise.

A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease.

Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes.