Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterised by brief attacks of chorea, dystonia, or mixed forms precipitated by sudden movement.Observational study with a cohort of 14 PKD patients and genetic testing for PRRT2 mutations.In a series of 14 PKD patients seen in our clinic at the National Hospital of Neurology, Queen Square, from 2012-2017, we noted tics in 11 patients (79%), which stand in stark contrast to the estimated lifetime prevalence of tics estimated to reach 1%.The two reasons to point out this possible association are the clinical implications and the potential opportunity of a better understanding of shared pathophysiological mechanisms of neuronal hyperexcitability.
Gilles de la Tourette Syndrome (GTS) is the most severe form of chronic tic disorders, characterized by uncontrollable motor actions and vocalizations. While brain stimulation techniques show promise in reducing tic severity, optimal target networks are not well-defined. Here, we leveraged datasets from two independent deep brain stimulation (DBS) cohorts and a cohort of tic-inducing lesions to infer critical networks for treatment and occurrence of tics by mapping stimulation sites and lesions to a functional connectome derived from 1,000 healthy participants. We found that greater tic reduction is linked to higher connectivity of DBS sites (N = 37) with action-related functional resting-state networks, i.e., the cingulo-opercular (R = 0.62; p < 0.001) and somato-cognitive action networks (R = 0.47; p = 0.002). Hubs within the cingulo-opercular network best matched the optimal connectivity profiles of thalamic DBS. We replicated the significance of targeting cingulo-opercular and somato-cognitive action network connectivity in an independent DBS cohort (N = 10). Finally, we demonstrate that tic-inducing brain lesions (N = 22) exhibit similar connectivity to these networks. Collectively, these results suggest a critical role for these action-related networks in the pathophysiology and treatment of GTS.
Medizinische Genetik.
Anatomie.
Histologie.
Neurologie.
Introduction: The family of orphan nuclear receptors comprises ligand-independent intracellular and/or intranuclear transcription factors, which play several roles in basic physiological functions including cell metabolism, differentiation and growth. The last orphan nuclear receptor identified was the estrogen-related receptor (ERR) gamma. Its role in determining morphological and phenotypical properties was examined in the present study using knockout mice.
Materials & Methods: Tissues of ERR gamma -/- mice generated from embryonic stages to adulthood were histologically analysed after genotypic analysis. Immunohistochemistry was also used. Morphometric analysis was employed to quantify the total and regional brain size of the phenotypes.
Results: We found that ERR gamma -/- were underrepresented in the postnatal phase indicating to an increased lethality of the phenotype allowing only <1% of the mice to reach adult age. A significant reduction in body weight (41.2% for adult mice) beginning from P1 was observed and a reduction in vertex-breech length (12.7% for adult mice) was noted in the surviving mice. The mice demonstrated dystonic hind-limb reactions leading to tremorous circling body movements (waltzing) and retropulsion. On gross morphological organ examination, the brain and the stomach were altered. The telencephalic region of the ERR gamma -/- brain was dorsally shortened, with the lamina quadrigemina protruding to a greater extend between the telencephalon and the cerebellum. The mesencephalic tegmentum of the ERR gamma -/- mice was significantly larger and the cerebellum smaller (normalized values to the absolute brain size of each genotype) compared to their wildtype and heterozygous littermates. The wall of the stomach of the ERR gamma -/- mice was thickened with protruding bulgy masses, representing glandular hypertrophy with mononuclear cell infiltration.
Conclusions: These results support the hypothesis that the ERR gamma receptor plays a key role in neurogenesis and neuronal migration, leading to regional brain disproportionality causing a morphological and functional disruption between the cerebellum and the basal ganglia. They also highlight the suppressive effect of ERR gamma -/- on cell proliferation in the stomach leading to glandular hyperplasia if absent.
Tics describe a wide range of sudden and repetitive behaviors. Their multifaceted clinical features may resemble other explosive behaviors, including repetitive episodes of aggression toward others (allo-aggression) reported by subjects without tics. Here, we document 3 exemplary cases that help disentangle allo-aggressive behaviors from tics.We report 3 cases who presented with an array of complex repetitive behaviors, most notably allo-aggression (eg, sudden kicking, hitting, slapping and biting others, or pushing someone off a bike), which were misdiagnosed as primary tics. In all cases, additional symptoms, such as blackouts, feeling of being controlled by different personalities, or being empowered by repetitive behaviors, and examination pointed toward different neuropsychiatric diagnoses.Repetitive allo-aggressive behaviors are not part of the range of motor manifestations of tics. This observation not only has important medico-legal implications but is also relevant for the overall perception of Tourette syndrome and other primary tic disorders.
A 42-year-old man, born of consanguineous parents, presented with long-standing severe, nonepileptic jerky movements of the upper body, pronounced during the second half of the day and improving after sleep (video, A and B). There was a history of neurodevelopmental disorder with axial hypotonia, delayed milestones, intellectual disability, and poor speech production. The combination of a neurodevelopmental syndrome and a movement disorder with diurnal fluctuations1 led to targeted exome sequencing for monoamine metabolism disorders. A homozygous nonsense variant in the SPR gene was identified (figure), confirmed by Sanger sequencing (figure). Treatment with levodopa led to marked improvement of abnormal movements (video, C).
The choice to become a neurologist may be driven by many factors. Most often, however, one is compelled to explore that last bastion that holds the secrets to human behavior. The thrilling possibility of recognizing signs and formulating syndromes, which allow drawing diagnostic conclusions on the putative topology of neural dysfunction with observation alone is a motivating force for young doctors. It also provides satisfaction even in the more advanced stages of a neurologist's career. The advent of many novel therapies during the past few decades in nearly every domain of neurology further reinforces the exciting possibilities the field has to offer. Among the many different manifestations of neurological disease, movement disorders constitute a most challenging domain. Not only does a large number of disorders of different aetiologies fall under the “movement disorders” rubric but also a unique vocabulary has been devised to describe and thereby discern motor phenomena and movement patterns, with often overlapping features. Indeed, young neurologists (or neurologists to be) frequently feel reluctant to confidently apply this specific language when first asked whether a patient presents, for example, with chorea or myoclonus, complex tics or stereotypies, or limb rigidity or paratonia. The question of how to scientifically approach the phenomenology of behavior, including classifying different types of movements based on observation, has a long-standing tradition in neuroscience.1, 2 To quote Jean-Martin Charcot, “Let someone say of a doctor that he really knows his physiology or anatomy, that he is dynamic—these are not real compliments; but if someone says: he is an observer, a person who knows how to see, this is perhaps the greatest compliment one can make”3 (Fig. 1). The International Parkinson's Disease and Movement Disorder Society, which counts >9000 active members, offers a wide variety of educative activities in nearly all parts of the world, with the determined goal to improve clinical movement disorders research and patient care. The annual International Parkinson and Movement Disorder Society (MDS) International Congress is one of the main pillars of the Society to achieve this purpose. Since its conceptual inauguration in 2008, the Video Challenge (VC; previously branded as Video Olympics and subsequently Video Games) is perhaps the most celebrated event of the annual International Congress. It provides the stage for some of the world's most intriguing movement disorders cases to be presented to select panelists—global experts with strong track records in the field—who in turn exercise their best skills in phenomenological analysis attempting to confidently reach a diagnosis. All this in real time and in the eyes of several thousand International Congress participants who in turn and from their own seats also feel challenged and attempt to “solve” the presented cases. Not uncommonly, lively discussions sprout on the phenomenology of individual cases, and it is often enlightening and comforting to witness how the opinions of experts may differ even on issues such as determining the basic type of abnormal movements. Indeed, disagreements are not unusual, and they are even politely encouraged, until the masters of ceremony, Drs. Anthony Lang and Kapil Sethi, provide decisive information in order to “move things forward.” Not to mention that when experts do not get to the right diagnosis, the audience may sigh in exasperation or even in relief, acknowledging that everybody can fail and its impossible to get the correct final diagnosis every time. It is the route of analytical thought leading to diagnosis that is celebrated in VC first and foremost. The VC often goes quite late into the night and is perceived by many as the established rite of passage to yet another novel exciting year for the movement disorder field. Most of the thousands of attendees leave the VC invigorated by the phenomenological richness of their field and eager to apply new knowledge back to their clinics. They are also on the lookout among their own cases whether some could make the cut to the world's best, most complex, and specifically instructive presentations for the year to come. It is an incredible achievement if one considers how brief of an exposure this is: only 2 to 3 hours spent with the experts phenomenologically dissecting movement disorders presentations is enough. Although it is true that attendees to the MDS annual International Congress are usually already strongly oriented toward a movement disorders career, we are aware of many colleagues who have made their final decision to focus on abnormal movements as a consequence of the VC. Clearly the success of the VC relies on a unique combination of many ingredients, perfectly mixed by the hosts. However, although thousands of neurologists participate live in the VC, a much higher number of colleagues are not able to take advantage of this unique once-in-a-year experience. Furthermore, as the number of presented cases has increased over the years, the rhythm of presentations during the VC may have been sometimes overwhelming. Given the tremendous educational value of the session, we believed it was important to support the publication of the presented submissions along with a clinical discussion and key learning points. After many discussions with Drs. Lang and Sethi, the editors of both Movement Disorders and Movement Disorders Clinical Practice (MDCP), and the society's Publications Oversight Committee, we agreed that the cases were best suited to publish in MDCP. Drs. Marcelo Merello and Kailash Bhatia, coeditors of MDCP, worked with the team at Wiley on a plan for an annual supplement issue of the journal at no cost to the society or authors. The availability of the cases in the online published format will now allow for global accessibility and dedicated study time; it will also complement the live discussions that arise during the event itself. Indeed, the decision to create a special supplement for MDCP every year strengthens the VC tradition and is a further step toward engaging neurologists into the fascinating world of movement disorders. This step must be interpreted also in the new scenario of a changing and interconnected world. The recent COVID-19 pandemic has forced the switch of the 2020 International Congress to a virtual format, which is a new challenge and a new opportunity. The VC will need to reinvent itself once again, but with the great advantage of new technologies that will allow for an even broader audience. For the first time neurologists and scientists from all over the world will be able to enjoy the VC show from their office or even from the couch in their living room. We are confident that this will leave a mark on many colleagues, because one look is worth a thousand words. If you got here, you have already read the 1000 words of this editorial. We now invite you to take a look at the instructive cases of this supplement and embrace this new endeavor. We would like to publicly thank all patients and their families who have accepted to be filmed and presented in the Video Challenge over the years and now published in this supplement. They provide an invaluable contribution to the field, and their altruistic participation has helped and will continue helping to spread knowledge on their respective conditions. This will hopefully translate to improving clinical care for many individuals in the world who suffer from movement disorders. Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: None. Financial Disclosures for Previous 12 Months: Christos Ganos receives academic research support from the VolkswagenStiftung (Freigeist Fellowship).
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
