Scales for Antipsychotic-Associated Movement Disorders: Systematic Review, Critique, and Recommendations.

BACKGROUND: Antipsychotic-associated movement disorders remain common and disabling. Their screening and assessment are challenging due to clinical heterogeneity and different use of nomenclature between psychiatrists and neurologists. OBJECTIVE: An International Parkinson and Movement Disorder Society subcommittee aimed to rate psychometric quality of severity and screening instruments for antipsychotic-associated movement disorders. METHODS: Following the methodology adopted by previous International Parkinson and Movement Disorders Society subcommittee papers, instruments for antipsychotic-associated movement disorders were reviewed, applying a classification as "recommended," "recommended with caveats," "suggested," or "listed." RESULTS: Our review identified 23 instruments. The highest grade of recommendation reached is "recommended with caveats," assigned to seven severity rating instruments (Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, Abnormal Involuntary Movements Scale, Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre involuntary movements scale, Simpson Angus Scale, and Matson Evaluation of Drug Side effects). Only three of these seven (Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre, Matson Evaluation of Drug Side effects) were also screening instruments. Their main caveats are insufficient demonstration of psychometric properties (internal consistency, skewing, responsiveness to change) and long duration of administration. Eight "suggested" instruments did not meet requirements for the "recommended" grade also because of insufficient psychometric validation. Other limitations shared by several instruments are lack of comprehensiveness in assessing the spectrum of antipsychotic-associated movement disorders and ambiguous nomenclature. CONCLUSIONS: The high number of instruments "recommended with caveats" does not support the need for developing new instruments for antipsychotic-associated movement disorders. However, addressing the caveats with new psychometric studies and revising existing instruments to improve the clarity of their nomenclature are recommended next steps. © 2023 International Parkinson and Movement Disorder Society.

Current Status of Pain Management in Parkinson's Disease.

BACKGROUND: Pain is a non-motor symptom in Parkinson's disease (PD) which commonly goes underreported. Adequate treatment for pain in PD remains challenging, and to date, no clear guidelines for management are available. METHODS: With the goal of understanding and organizing the current status of pain management in PD, we conducted a review of pharmacological and non-pharmacological treatments for pain in patients with PD. Suitable studies cataloged in PubMed and the Cochrane database up to October 31, 2019, were included prioritizing randomized controlled trials. Post-hoc analyses and open-label studies were also included. RESULTS: Treatment with levodopa increases pain thresholds in patients with PD. Apomorphine did not have similar efficacy. Duloxetine provided benefit in an open-label trial. Oxycodone-naloxone PR did not have a significant improvement in pain, but per-protocol analysis showed a reduction in pain when adherence was strong. Rotigotine patch had numerical improvement on pain scales with no statistical significance. Safinamide significantly improved the "bodily discomfort" domain in the PDQ-39 questionnaire. Botulinum toxin A had a non-significant signal toward improving dystonic limb pain in PD. DBS to the subthalamic nucleus may modulate central pain thresholds, and a pilot study of cranioelectric therapy warrants future research in the area. CONCLUSION: After optimizing dopaminergic therapy, understanding the type of pain a patient is experiencing is essential to optimizing pain control in PD. While recommendations can be made regarding the treatment options in each domain, evidence remains weak and future randomized controlled studies are needed.

Cannabis use is both independently associated with and mediates worse psychosocial health in patients with epilepsy.

OBJECTIVE: To examine whether cannabis use is associated with or mediates psychosocial health in people with epilepsy. METHODS: Consecutive adult epilepsy patients visiting the Calgary Comprehensive Epilepsy Programme clinic were administered validated patient-reported outcome measures (PROMs) including the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), Quality of Life in Epilepsy (QOLIE-10-P), EuroQOL five dimensions five level scale (EQ-5D-5L), Global Assessment of Severity of Epilepsy Scale, Global Assessment of Disability Associated with Seizures Scale and the Treatment Satisfaction Questionnaire for Medication scale. We used multiple regression analyses to investigate associations between cannabis use and PROMs. Mediation analyses were performed to determine the degree to which cannabis modulated the associations between current or past psychiatric disorders, monthly seizure frequency, and 1-year seizure freedom on psychosocial health. RESULTS: Of 337 consecutive patients, 71 (21%) reported cannabis use. Cannabis use was independently associated with depression (NDDI-E score≥14; OR 3.90; 95% CI 2.01 to 7.59; p<0.001), lower quality of life (ß=-16.73, 95% CI - 26.26 to - 7.20; p=0.001), worse epilepsy-related disability (OR 2.23, 95% CI 1.19 to 4.17; p=0.01) and lower satisfaction with antiepileptic medication (OR 0.41, 95% CI 0.23 to 0.72; p=0.002). Cannabis use mediates 7%-12% of the effect of a psychiatric history on depression, worse quality of life and worse health valuation. CONCLUSIONS: There is a strong and independent association between cannabis use and poor psychosocial health, and it partially mediates the deleterious effect of a psychiatric history on these same outcomes. Inclusion of PROMs in future cannabis trials is warranted.

Movement Disorders Associated With Antipsychotic Medication in People With Schizophrenia: An Overview of Cochrane Reviews and Meta-Analysis.

Movement disorders associated with antipsychotic medications are relatively common, stigmatising, and potentially disabling. Their prevalence in people with psychosis who are prescribed second-generation antipsychotics (SGAs) is uncertain, as is their level of recognition by clinicinas. We conducted meta-analyses of randomised controlled trials included in the Cochrane Database of Systematic Reviews on schizophrenia and schizophrenia-like psychoses to estimate the prevalence of new-onset dystonia, akathisia, parkinsonism, and tremor with SGAs (amisulpride, asenapine, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, L-sulpiride, and ziprasidone) approved in Canada and the UK, comparing them with haloperidol and chlorpromazine. We used a random effects model because of the heterogeneity between-studies in drug dosage and method of ascertainment of movement disorders. Our systematic search yielded 37 Cochrane systematic reviews (28 for SGAs), which generated 316 informative randomised controlled trials (243 for SGAs). With respect to SGAs, prevalence estimates ranged from 1.4% (quetiapine) to 15.3% (L-sulpiride) for dystonia, 3.3% (paliperidone) to 16.4% (L-sulpiride) for akathisia, 2.4% (asenapine) to 29.3% (L-sulpiride) for parkinsonism, and 0.2% (clozapine) to 28.2% (L-sulpiride) for tremor. Prevalence estimates were not influenced by treatment duration, the use of a flexible or fixed dosing scheme, or whether studies used validated instruments for the screening/rating of movement disorders. Overall, we found high overlap on the prevalence of new-onset movement disorders across different SGAs precribed for established psychoses. Variations in prevalence figures across antipsychotic medications were observed for the different movement disorders. Differences in pharmacological properties, such as for the dopamine D2 R association rate and serotonin 5-HT2A antagonism, could contribute to this variation.

Differences in neuronal activity explain differences in memory forming abilities of different populations of Lymnaea stagnalis.

The ability to learn and form long-term memory (LTM) can enhance an animal's fitness, for example, by allowing them to remember predators, food sources or conspecific interactions. Here we use the pond snail, Lymnaea stagnalis, to assess whether variability between natural populations (i.e., strains) in memory forming capabilities correlates with electrophysiological properties at the level of a single neuron, RPeD1. RPeD1 is a necessary site of LTM formation of aerial respiratory behaviour following operant conditioning. We used strains from two small, separate permanent ponds (TC1 and TC2). A comparison of the two populations showed that the TC1 strain had enhanced memory forming capabilities. Further, the behavioural phenotype of enhanced memory strain was explained, in part, by differences in the electrophysiology of RPeD1. Compared to RPeD1 from the naive TC2 strain, RPeD1 from the TC1 strain has both a decreased resistance and decreased excitability. Moreover, 24h after a single 0.5h training session, those membrane properties, as well as the firing and bursting rate, decrease further in the TC1 strain but not in the TC2 strain. The initial differences in RPeD1 properties in the TC1 strain coupled with their ability to further change these properties with a single training session suggests that RPeD1 neurons from the TC1 strain are "primed" to rapidly form memory.

Sensory input from the osphradium modulates the response to memory-enhancing stressors in Lymnaea stagnalis.

In the freshwater environment species often rely on chemosensory information to modulate behavior. The pond snail, Lymnaea stagnalis, is a model species used to characterize the causal mechanisms of long-term memory (LTM) formation. Chemical stressors including crayfish kairomones and KCl enhance LTM formation (≥24 h) in Lymnaea; however, how these stressors are sensed and the mechanism by which they affect the electrophysiological properties of neurons necessary for memory formation are poorly understood. Here, we assessed whether the osphradium, a primary chemosensory organ in Lymnaea, modulates LTM enhancement. To test this we severed the osphradial nerve proximal to the osphradium, using sham-operated animals as controls, and assessed the behavioral and electrophysiological response to crayfish kairomones and KCl. We operantly conditioned aerial respiratory behavior in intact, sham and osphradially cut animals, and tested for enhanced memory formation after exposure to the chemical stressors. Sham-operated animals displayed the same memory enhancement as intact animals but snails with a severed osphradial nerve did not show LTM enhancement. Extracellular recordings made from the osphradial nerve demonstrate that these stressors evoked afferent sensory activity. Intracellular recordings from right pedal dorsal 1 (RPeD1), a neuron necessary for LTM formation, demonstrate that its electrophysiological activity is altered by input from the osphradium following exposure to crayfish kairomones or KCl in sham and intact animals but no response is seen in RPeD1 in osphradially cut animals. Therefore, sensory input from the osphradium is necessary for LTM enhancement following exposure to these chemical stressors.

Acute combined exposure to heavy metals (Zn, Cd) blocks memory formation in a freshwater snail.

The effect of heavy metals on species survival is well documented; however, sublethal effects on behaviour and physiology are receiving growing attention. Measurements of changes in activity and respiration are more sensitive to pollutants, and therefore a better early indicator of potentially harmful ecological impacts. We assessed the effect of acute exposure (48 h) to two heavy metals at concentrations below those allowable in municipal drinking water (Zn: 1,100 µg/l; Cd: 3 µg/l) on locomotion and respiration using the freshwater snail, Lymnaea stagnalis. In addition we used a novel assessment method, testing the ability of the snail to form memory in the presence of heavy metals in both intact snails, and also snails that had the osphradial nerve severed which connects a chemosensory organ, the osphradium, to the central nervous system. Aerial respiration and locomotion remained unchanged by acute exposure to heavy metals. There was also no effect on memory formation of these metals when administered alone. However, when snails were exposed to these metals in combination memory formation was blocked. Severing the osphradial nerve prevented the memory blocking effect of Zn and Cd, indicating that the snails are sensing these metals in their environment via the osphradium and responding to them as a stressor. Therefore, assessing the ability of this species to form memory is a more sensitive measure of heavy metal pollution than measures of activity, and indicates that the snails' ability to demonstrate behavioural plasticity may be compromised by the presence of these pollutants.

Sensory mediation of memory blocking stressors in the pond snail Lymnaea stagnalis.

The great pond snail, Lymnaea stagnalis, is commonly used as a model species to study how stress affects the ability to form long-term memory (LTM); however, we still have little information about how the snail senses stressful stimuli. The osphradium is an external sensory organ that demonstrates electrophysiological responses to a variety of external chemical stimuli. We examined the role, if any, played by the osphradium in sensing two environmental stressors, crowding and low environmental calcium, both known to block LTM in intact animals. We severed the osphradial nerve, blocking external sensory input from this organ to the central nervous system, and then exposed the snails to low environmental calcium or crowding stress to assess whether these stressors continued to block LTM formation. When exposed to low environmental calcium, snails with their osphradial nerve severed responded as if they were maintained in our standard calcium environment. That is, they did not respond to low calcium as a stressor blocking LTM; therefore, the osphradium plays a crucial role in mediating how snails respond to this stressor. However, following crowding, LTM formation was blocked in both control groups and snails that had the osphradial nerve severed, indicating that sensory information from the osphradium is not required to sense crowded conditions. Together these data show that two stressors that result in the same behavioural phenotype, blocking LTM formation, do so via two distinct sensory pathways.

Low external environmental calcium levels prevent forgetting in Lymnaea.

Forgetting may allow an animal to react more appropriately to current conditions, rather than continuing to exhibit a previously learned, possibly maladaptive behaviour based on previous experience. One theory is that forgetting is an active process, whereby the previously learnt response is replaced by new learning that interferes with the older memory. Hence, we hypothesized that an appropriately timed environmental stressor that blocks long-term memory (LTM) formation would also block forgetting. Lymnaea stagnalis (L.) is a freshwater snail, which requires environmental calcium of at least 20 mg l(-1) to meet its requirements. Low environmental Ca(2+) (i.e. 20 mg l(-1)) in their environment acts as a stressor, and prevents LTM formation. Here, we asked whether a low Ca(2+) environment would also prevent forgetting, concordant with the retrograde interference model of Jenkins and Dallenbach. Snails were operantly conditioned to reduce aerial respiration in hypoxia. When maintained in standard conditions (80 mg l(-1) Ca(2+)), snails demonstrated LTM following training lasting 24 h, but not 72 h; however, when trained in standard conditions then exposed to a low Ca(2+) environment (20 mg l(-1)) immediately following training, they retained memory for at least 96 h, indicating that forgetting had been blocked. Thus, when exposed to low environmental Ca(2+), Lymnaea will fail to form new memories, but will also continue to retain information previously learned and remembered as the low calcium blocks forgetting.

Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial.

BACKGROUND: Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death. METHODS: This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR] viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data. RESULTS: Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety. INTERPRETATION: There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04329611.

Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism.

BACKGROUND: Autism is a behaviourally defined neurodevelopmental disorder with unknown etiology. Recent studies in autistic children consistently point to neuropathological and functional abnormalities in the temporal association cortex (TeA) and its associated structures. It has been proposed that the trajectory of postnatal development in these regions may undergo accelerated maturational alterations that predominantly affect sensory recognition and social interaction. Indeed, the temporal association regions that are important for sensory recognition and social interaction are one of the last regions to mature suggesting a potential vulnerability to early maturation. However, direct evaluation of the emerging hypothesis that an altered time course of early postnatal development can lead to an ASD phenotype remains lacking. RESULTS: We used electrophysiological, histological, and behavioural techniques to investigate if the known neuronal maturational promoter valproate, similar to that in culture systems, can influence the normal developmental trajectory of TeA in vivo. Brain sections obtained from postnatal rat pups treated with VPA in vivo revealed that almost 40% of cortical cells in TeA prematurely exhibited adult-like intrinsic electrophysiological properties and that this was often associated with gross cortical hypertrophy and a reduced predisposition for social play behaviour. CONCLUSIONS: The co-manifestation of these functional, structural and behavioural features suggests that alteration of the developmental time course in certain high-order cortical networks may play an important role in the neurophysiological basis of autism.

Cervical Dystonia Following Injury to the Cerebellar Pontine Angle: An Instructive Case.

A 38-year-old woman presented with cervical dystonia in the context of a recent surgery to remove a vestibular schwannoma. She initially presented to neurology with pain in the right arm, and MRI of the brain showed an incidental right-sided vestibular schwannoma (Video 1, Segment 1). An elective gamma-knife procedure was performed, which failed. Hydrocephalus requiring ventriculoperitoneal shunt insertion developed, and 3 years following the initial procedure the lesion was surgically excised. Surgery was further complicated by right middle cerebellar peduncle injury, extending to the cerebellopontine angle and marginally to the right pontine tegmentum, with subsequent mass effect on cerebellum displayed on follow-up MRI (Video 1, Segment 2). Six months later, the patient experienced forced head deviation to the right, with difficulty moving from this position. Examination revealed clear right-sided torticollis, with hypertrophy of the left sternocleidomastoid muscle. Cervical dystonia worsened with action and nearly resolved with the patient lying down. A clear geste antagoniste, where symptoms improved with the patient touching the side of her head, was present (Video 1, Segment 3). Findings consistent with injury to the cerebellar pathways were additionally exhibited. She demonstrated clear dysarthria, bilateral dysmetria, dysdiadochokinesia (worse on the right), and prominent gait ataxia (Video 1, Segment 4). Although a possible role of the schwannoma itself in the cervical dystonia pathogenesis cannot be entirely ruled out, the timing of signs, occurring soon after the postsurgical injury, suggest a prominent involvement of structures lying within the cerebellar pontine angle.

Safety and Dosing Study of Glucagon-Like Peptide 2 in Children With Intestinal Failure.

BACKGROUND AND AIMS: A glucagon-like peptide 2 (GLP-2) analogue is approved for adults with intestinal failure, but no studies of GLP-2 have included children. This study examined the pharmacokinetics, safety, and nutritional effects of GLP-2 in children with intestinal failure. METHODS: Native human GLP-2(1-33) was synthesized following good manufacturing practices. In an open-label trial, with parental consent, 7 parenteral nutrition-dependent pediatric patients were treated with subcutaneous GLP-2 (20 µg/kg/d) for 3 days (phase 1) and, if tolerated, continued for 42 days (phase 2). Nutritional treatment was directed by the primary caregivers. Patients were followed to 1 year. RESULTS: Seven patients were enrolled (age: 4.0 ± 0.8 years; bowel length, mean ± SEM: 24% ± 4% of predicted). All were parenteral nutrition dependent since birth, receiving 44% ± 5% of calories by parenteral nutrition. GLP-2 treatment had no effect on vital signs (blood pressure, heart rate, and temperature) and caused no significant adverse events. Peak GLP-2 levels were 380 pM (day 3) and 295 pM (day 42), with no change in half-life or endogenous GLP-2 levels. Nutritional indices showed a numeric improvement in z scores and citrulline levels; the z score was maintained while citrulline levels returned to baseline once GLP-2 was discontinued. CONCLUSIONS: GLP-2 was well tolerated in children, with a pharmacokinetic profile similar to that of adults. There were no changes in endogenous GLP-2 release or metabolism. These results suggest that GLP-2 ligands may be safely used in pediatric patients; larger trials are suggested to investigate nutritional effects.