Therapeutic use of medical Cannabis in neurological diseases: a clinical update.

The use of medical Cannabis has increased in recent years due to changing legal circumstances in many countries. Approval exists only for a few neurological conditions such as rare forms of epilepsy or spasticity in multiple sclerosis. Beyond that, however, medical Cannabis is used for a wide range of neurological conditions and symptoms. In Germany, in parallel with new legislation that has simplified the prescription of medical Cannabis, an accompanying survey has been implemented for which initial data are now available. In this context, our review provides an overview of the evidence for the therapeutic use of medical Cannabis in neurology, the potential benefits, and side effects.

Compulsive sexual behavior and paraphilic interests in adults with chronic tic disorders and Tourette syndrome: a survey-based study.

Early research suggested that compulsive sexual behavior (CSB) and paraphilic interests (PI) are more prevalent in adults with primary tic disorders compared to the general population. However, recent data on this topic remain scarce. We conducted an anonymous online survey capturing data on CSB and PI in adult patients with primary tic disorders. We also explored the role of antipsychotic tic medication and the impact of neuropsychiatric comorbidities like attention-deficit hyperactivity disorder and depression. In total, 62 participants (26 females/36 males) completed the survey. The prevalence of CSB and PI were 12.9% and 19.4%, respectively. There was no association with antipsychotic medication nor with symptoms of depression. However, the presence of attention-deficit hyperactivity disorder was associated with a higher prevalence of both CSB and PI. The current results contrast with earlier reports and show that in adults with primary tic disorders, the prevalence of CSB and PI is not overly prominent.

Prospective controlled study on the effects of deep brain stimulation on driving in Parkinson's disease.

To explore the influence of bilateral subthalamic deep brain stimulation (STN-DBS) on car driving ability in patients with Parkinson's disease (PD), we prospectively examined two age-matched, actively driving PD patient groups: one group undergone DBS-surgery (PD-DBS, n = 23) and one group that was eligible for DBS but did not undergo surgery (PD-nDBS, n = 29). In PD-DBS patients, investigation at Baseline was done just prior and at Follow-up 6-12 month after DBS-surgery. In PD-nDBS patients, time interval between Baseline and Follow-up was aimed to be comparable. To assess the general PD driving level, driving was assessed once in 33 age-matched healthy controls at Baseline. As results, clinical and driving characteristics of PD-DBS, PD-nDBS and controls did not differ at Baseline. At Follow-up, PD-DBS patients drove unsafer than PD-nDBS patients. This effect was strongly driven by two single PD-DBS participants (9%) with poor Baseline and disastrous Follow-up driving performance. Retrospectively, we could not identify any of the assessed motor and non-motor clinical Baseline characteristics as predictive for this driving-deterioration at Follow-up. Excluding these two outliers, comparable driving performance between PD-DBS and PD-nDBS patients not only at Baseline but also at Follow-up was demonstrated. Age, disease duration and severity as well as Baseline driving insecurity were associated with poorer driving performance at Follow-up. This first prospective study on driving safety in PD after DBS surgery indicates that DBS usually does not alter driving safety but might increase the risk for driving deterioration, especially in single subjects with already unsafe driving prior to DBS surgery.

Distinguishing functional from primary tics: a study of expert video assessments.

BACKGROUND: Reliably applied criteria to differentiate functional from primary tics are lacking. In the absence of biological markers, the development of new diagnostic criteria to assist clinicians is predicated on expert judgement and consensus. This study examines the level of diagnostic agreement of experts in tic disorders using video footage and clinical descriptions. METHODS: Using a two-part survey, eight experts in the diagnosis and management of tics were first asked to study 24 case videos of adults with primary tics, functional tics or both and to select a corresponding diagnosis. In the second part of the survey, additional clinical information was provided, and the diagnosis was then reconsidered. Inter-rater agreement was measured using Fleiss' kappa. In both study parts, the factors which influenced diagnostic decision-making and overall diagnostic confidence were reviewed. RESULTS: Based on phenomenology alone, the diagnostic agreement among the expert raters was only fair for the pooled diagnoses (κ=0.21) as well as specifically for functional (κ=0.26) and primary tics (κ=0.24). Additional clinical information increased overall diagnostic agreement to moderate (κ=0.51) for both functional (κ=0.6) and primary tics (κ=0.57). The main factors informing diagnosis were tic semiology, age at tic onset, presence of premonitory urges, tic suppressibility, the temporal latency between tic onset and peak severity, precipitants and tic triggers and changes in the overall phenotypic presentation. CONCLUSIONS: This study confirmed that in the absence of clinical information, the diagnostic distinction between primary and functional tics is often difficult, even for expert clinicians.

Characterisation and differential diagnosis of neurological complications in adults with phenylketonuria: literature review and expert opinion.

OBJECTIVE: Phenylketonuria (PKU) is a rare inherited metabolic disorder characterised by elevated phenylalanine (Phe) concentrations that can exert neurotoxic effects if untreated or upon treatment discontinuation. This systematic review supported by expert opinion aims to raise awareness among the neurological community on neurological complications experienced by adults with PKU (AwPKU). METHODS: The PubMed database was searched for articles on neurological signs and symptoms in AwPKU published before March 2022. In addition, two virtual advisory boards were held with a panel of seven neurologists and two metabolic physicians from Germany and Austria. Findings are supported by three illustrative patient cases. RESULTS: Thirty-nine articles were included. Despite early diagnosis and treatment, neurological signs and symptoms (e.g. ataxia, brisk tendon reflexes, tremor, visual impairment) can emerge in adulthood, especially if treatment has been discontinued after childhood. In PKU, late-onset neurological deficits often co-occur with cognitive impairment and psychiatric symptoms, all of which can be completely or partially reversed through resumption of treatment. CONCLUSION: Ideally, neurologists should be part of the PKU multidisciplinary team, either to bring lost to follow-up patients back to clinic or to manage symptoms in referred patients, considering that symptoms are often reversible upon regaining metabolic control. The current findings have been combined in a leaflet that will be disseminated among neurologists in Germany and Austria to create awareness.

Skin stretch modulates tactile distance perception without central correction mechanisms.

Tactile distance perception is influenced by stimulus orientation. On the hands or face, effects of orientation may originate from the mostly oval shape of receptive fields (RF) of which the long axis aligns with the proximodistal body axis. As tactile distance estimation relies on the number of RFs between stimuli, their alignment leads to a distortion of perception with distances being perceived as shorter in the proximodistal than the mediolateral body axis. It is however unknown, how physical manipulations such as skin stretch affect distance perception. Participants judged which of two distances aligned with the mediolateral or proximodistal axis on their dorsal dominant hand felt larger in two conditions: without physical manipulation and with proximodistal skin stretch. Distances were perceived shorter in proximodistal direction in both the nonstretch and the stretch condition, which was significantly pronounced in the stretch condition. Skin stretch led to perception of tactile distances as smaller, possibly related to the removal of afferent nerve endings and corresponding somatosensory RFs in the same external reference frame between the two touches. Though skin stretch is represented centrally, our results likely show that no correctional top-down mechanism corrects for skin stretch when estimating tactile distances. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Backward leaning during gait: An underrecognized sign in Niemann-Pick type C.

Niemann-Pick type C (NPC) is a rare but treatable lysosomal disorder with heterogeneous clinical presentations including cognitive impairment, movement disorders and vertical gaze palsy. We illustrate five cases of genetically confirmed NPC and highlight backward leaning during gait as a relevant clinical sign and a useful diagnostic clue.

The neurological and neuropsychiatric spectrum of adults with late-treated phenylketonuria.

INTRODUCTION: Phenylketonuria (PKU) is a rare, treatable inborn error of metabolism with frequent neurological and neuropsychiatric complications, especially in undiagnosed or insufficiently treated individuals. Given the wide range of clinical presentations and the importance of treatment implications, we here delineate the neurological and neuropsychiatric symptom spectrum in a large cohort of previously unreported adults with late-treated PKU. METHODS: We consecutively evaluated late-treated PKU cases and pooled clinical and paraclinical data, including video-material, from three centers with expertise in complex movement disorders, inborn errors of metabolism and pediatrics. RESULTS: 26 individuals were included (10 females, median age 52 years). Developmental delay and intellectual disability were omnipresent with severe impairment of expressive communication noted in 50% of cases. Movement disorders were prevalent (77%), including tremor (38%, mostly postural), stereotypies (38%), and tics (19%). One case had neurodegenerative levodopa-responsive parkinsonism. Mild ataxia was noted in 54% of cases and 31% had a history of seizures. Neuropsychiatric characteristics included obsessive-compulsive (35%) and self-injurious behaviors (31%), anxiety (27%), depression (19%) and features compatible with those observed in individuals with autism spectrum disorder (19%). Neuroimaging revealed mild white matter changes. Adherence to dietary treatment was inconsistent in the majority of cases, particularly throughout adolescence. CONCLUSION: A history of movement disorders, particularly tremor, stereotypies and tics, in the presence of developmental delay, intellectual disability and neuropsychiatric features, such as obsessive-compulsive and self-injurious behaviors in adults should prompt the diagnostic consideration of PKU. Initiation and adherence to (dietary) treatment can ameliorate the severity of these symptoms.

Aggression Toward Others Misdiagnosed as Primary Tics.

BACKGROUND: 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. CASES: 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. CONCLUSIONS: 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.

Intact Organization of Tactile Space Perception in Isolated Focal Dystonia.

BACKGROUND: Systematic perceptual distortions of tactile space have been documented in healthy adults. In isolated focal dystonia impaired spatial somatosensory processing is suggested to be a central pathophysiological finding, but the structure of tactile space for different body parts has not been previously explored. OBJECTIVES: The objective of this study was to assess tactile space organization with a novel behavioral paradigm of tactile distance perception in patients with isolated focal dystonia and controls. METHODS: Three groups of isolated focal dystonia patients (cervical dystonia, blepharospasm/Meige syndrome, focal hand dystonia) and controls estimated perceived distances between 2 touches across 8 orientations on the back of both hands and the forehead. RESULTS: Stimulus size judgments differed significantly across orientations in all groups replicating distortions of tactile space known for healthy individuals. There were no differences between groups in the behavioral parameters we assessed on the hands and forehead. CONCLUSIONS: Tactile space organization is comparable between patients with isolated focal dystonia and healthy controls in dystonic and unaffected body parts. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Functional pain disorders - more than nociplastic pain.

BACKGROUND: Nociplastic pain has been recently introduced as a third mechanistic descriptor of pain arising primarily from alterations of neural processing, in contrast to pain due to tissue damage leading to nociceptor activation (nociceptive) or due to lesion or disease of the somatosensory nervous system (neuropathic). It is characterized by hyperalgesia and allodynia, inconsistency and reversibility, as well as dynamic cross-system interactions with biological and psychobehavioral factors. Along with this renewed understanding, functional pain disorders, also classified as chronic primary pain, are being reframed as biopsychosocial conditions that benefit from multimodal treatment. OBJECTIVE: To summarize the current understanding of nociplastic pain and functional pain disorders, with a focus on conditions that are common in neurology practice. METHODS: This was a narrative literature review. RESULTS: Chronic back pain, fibromyalgia syndrome and complex regional pain syndrome are best understood within a biopsychosocial framework of pain perception that considers structural factors (predispositions and sequelae) and psychobehavioral mechanisms. Although pain is often the primary complaint, it should not be the only focus of treatment, as accompanying symptoms such as sleep or mood problems can significantly impact quality of life and offer useful leverage points for multimodal treatment. Analgesic pharmacotherapy is rarely helpful on its own, and should always be imbedded in a multidisciplinary setting.

Deep brain stimulation reduces (nocturnal) dyskinetic exacerbations in patients with ADCY5 mutation: a case series.

Mutations in the ADCY5 gene can cause a complex hyperkinetic movement disorder. Episodic exacerbations of dyskinesia are a particularly disturbing symptom as they occur predominantly during night and interrupt sleep. We present the clinical short- and long-term effects of pallidal deep brain stimulation (DBS) in three patients with a confirmed pathogenic ADCY5 mutation. Patients were implanted with bilateral pallidal DBS at the age of 34, 20 and 13 years. Medical records were reviewed for clinical history. Pre- and postoperative video files were assessed using the "Abnormal Involuntary Movement Scale" (AIMS) as well as the motor part of the "Burke Fahn Marsden Dystonia Rating Scale" (BFMDRS). All patients reported subjective general improvement ranging from 40 to 60%, especially the reduction of nocturnal episodic dyskinesias (80-90%). Objective scales revealed only a mild decrease of involuntary movements in all and reduced dystonia in one patient. DBS-induced effects were sustained up to 13 years after implantation. We demonstrate that treatment with pallidal DBS was effective in reducing nocturnal dyskinetic exacerbations in patients with ADCY5-related movement disorder, which was sustained over the long term.

Dopamine boosts intention and action awareness in Parkinson's disease.

Dopaminergic deficiency in Parkinson's disease (PD) has been associated with underactivation of the supplementary motor area and a reduction of voluntary actions. In these patients, awareness of intention to act has been shown to be delayed. However, delayed awareness of intention to act has also been shown in patients with hyperdopaminergic states and an excess of unwilled movements, as in Tourette's, and in patients with functional movement disorders. Hence, the role of dopamine in the awareness of intention and action remains unclear. 36 PD patients were tested ON and OFF dopaminergic medication and compared with 35 healthy age-matched controls. In addition, 17 PD patients with subthalamic deep brain stimulation (DBS) were tested ON medication and ON and OFF stimulation. Participants judged either the moment a self-generated action was performed, or the moment the urge to perform the action was felt, using the "Libet method". Temporal judgments of intention and action awareness were comparable between unmedicated PD patients and controls. Dopaminergic medication boosted anticipatory awareness of both intentions and actions in PD patients, relative to an unmedicated condition. The difference between ON/OFF DBS was not statistically reliable. Functional improvement of motor ability in PD through dopaminergic supplementation leads to earlier awareness of both intention, and of voluntary action.

Learning volition: A longitudinal study of developing intentional awareness in Tourette syndrome.

Tourette syndrome (TS) is characterized by the presence of involuntary movements (tics) which are, at least partly, generated within 'voluntary' motor pathways. Here we reassess 16 TS patients (age 19 ± 2.3 years) who participated in a mental chronometry study of volition 5.5 years previously (Ganos C et al. Cortex. 2015 Mar.; 64:47-54), and 16 age-matched controls. Participants estimated the time of their own voluntary movements (Libet's M judgement), or of conscious intention to make voluntary movements (Libet's W judgement), in separate blocks. We considered M judgement as a control condition. Therefore, the experience of an intention to move occurring prior to actual movement onset, as measured by the W-M gap, was taken as the cardinal feature of volition. Time estimates of the TS group did not differ significantly from controls, for either M or W judgement. Further, M and W time estimates in the TS group had not changed significantly between the two assessments. However, exploratory analyses revealed a strong relation between disease duration and the development of M- and W-judgements: the longer was the disease duration, the less was the developmental increase in the W-M gap (linear regression, p = .003). In conclusion, our results suggest compromised development of experience of volition in developing TS patients. The developmental difficulty in processing internal premotor signals for voluntary actions could reflect the chronic persistence of tics from adolescence to adulthood.

Self-injurious behaviour in movement disorders: systematic review.

Self-injurious behaviours (SIBs) are defined as deliberate, repetitive and persistent behaviours that are directed towards the body and lead to physical injury and are not associated with sexual arousal and without suicidal intent. In movement disorders, SIBs are typically associated with tic disorders, most commonly Tourette syndrome, and neurometabolic conditions, such as classic Lesch-Nyhan syndrome. However, beyond these well-known aetiologies, a range of other movement disorder syndromes may also present with SIBs, even though this clinical association remains less well-known. Given the scarcity of comprehensive works on this topic, here we performed a systematic review of the literature to delineate the spectrum of movement disorder aetiologies associated with SIBs. We report distinct aetiologies, which are clustered in five different categorical domains, namely, neurodevelopmental, neurometabolic and neurodegenerative disorders, as well as disorders with characteristic structural brain changes and heterogeneous aetiologies (eg, autoimmune and drug-induced). We also provide insights in the pathophysiology of SIBs in these patients and discuss neurobiological key risk factors, which may facilitate their manifestation. Finally, we provide a list of treatments, including practical measures, such as protective devices, as well as behavioural interventions and pharmacological and neurosurgical therapies.

C-Fiber Loss as a Possible Cause of Neuropathic Pain in Schwannomatosis.

Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis.

The spectrum of involuntary vocalizations in humans: A video atlas.

In clinical practice, involuntary vocalizing behaviors are typically associated with Tourette syndrome and other tic disorders. However, they may also be encountered throughout the entire tenor of neuropsychiatry, movement disorders, and neurodevelopmental syndromes. Importantly, involuntary vocalizing behaviors may often constitute a predominant clinical sign, and, therefore, their early recognition and appropriate classification are necessary to guide diagnosis and treatment. Clinical literature and video-documented cases on the topic are surprisingly scarce. Here, we pooled data from 5 expert centers of movement disorders, with instructive video material to cover the entire range of involuntary vocalizations in humans. Medical literature was also reviewed to document the range of possible etiologies associated with the different types of vocalizing behaviors and to explore treatment options. We propose a phenomenological classification of involuntary vocalizations within different categorical domains, including (1) tics and tic-like vocalizations, (2) vocalizations as part of stereotypies, (3) vocalizations as part of dystonia or chorea, (4) continuous vocalizing behaviors such as groaning or grunting, (5) pathological laughter and crying, (6) vocalizations resembling physiological reflexes, and (7) other vocalizations, for example, those associated with exaggerated startle responses, as part of epilepsy and sleep-related phenomena. We provide comprehensive lists of their associated etiologies, including neurodevelopmental, neurodegenerative, neuroimmunological, and structural causes and clinical clues. We then expand on the pathophysiology of the different vocalizing behaviors and comment on available treatment options. Finally, we present an algorithmic approach that covers the wide range of involuntary vocalizations in humans, with the ultimate goal of improving diagnostic accuracy and guiding appropriate treatment. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.