An Evidence-Based Update on Anticholinergic Use for Drug-Induced Movement Disorders.

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually.

Acute Dystonic Reaction After Propofol Administration: A Pediatric Case Report.

We present a case of a 12-year-old female with a history of infantile spasms who developed a propofol-associated acute dystonic reaction after emergence from general anesthesia for foot surgery. Uniquely, the patient's postoperative symptoms of an acute dystonic reaction were refractory to standard treatment with anticholinergics but were successfully treated with corticosteroids. The absence of any dystonic symptoms following subsequent foot surgery under general anesthesia without propofol supported a propofol-associated etiology. This case may contribute to a better understanding of the underlying mechanisms of propofol-associated acute dystonic reactions and adds a possible new treatment option.

Assessment of Patients Receiving Short-Interval Botulinum Toxin Chemodenervation Treatment for Laryngeal Dystonia and Essential Tremor of the Vocal Tract.

Importance: The gold-standard treatment for laryngeal dystonia (LD) and essential tremor of the vocal tract (ETVT) is botulinum toxin (BoNT) chemodenervation. Although safe and effective, it is not curative, and periodic injections are required. Some medical insurance companies only cover injections at a 3-month interval, though some patients benefit from injections more frequently. Objective: To determine the proportion and characteristics of patients who receive BoNT chemodenervation treatment in intervals shorter than 90 days. Design, Setting, and Participants: This retrospective cohort study across 3 quaternary care neurolaryngology specialty practices in Washington and California recruited patients who underwent at least 4 consecutive laryngeal BoNT injections for LD and/or ETVT in the past 5 years. Data were collected from March through June 2022 and analyzed from June through December 2022. Exposure: Laryngeal BoNT treatment. Main Outcomes and Measures: Biodemographic and clinical variables, injection characteristics, evolution during the 3 interinjection intervals, and lifetime laryngeal BoNT treatment data were collected from patient medical records. Logistic regression was used to assess association to the short-interval outcome, defined as an average injection interval shorter than 90 days. Results: Of 255 patients included from the 3 institutions, 189 (74.1%) were female, and the mean (SD) age was 62.7 (14.3) years. The predominant diagnosis was adductor LD (n = 199 [78.0%]), followed by adductor dystonic voice tremor (n = 26 [10.2%]) and ETVT (n = 13 [5.1%]). Seventy patients (27.5%) received short-interval injections (<90 days). The short-interval group was younger than the long-interval group (≥90 days), with a mean (SD) age of 58.6 (15.5) years and 64.2 (13.5) years, respectively, and a mean difference of -5.7 years (95% CI, -9.6 to -1.8 years). There were no patient-related differences between the short- and long-interval groups in terms of sex, employment status, or diagnosis. Conclusions and Relevance: This cohort study demonstrated that while insurance companies often mandate a 3-month or greater interval for BoNT chemodenervation financial coverage, there is a considerable subset of patients with LD and ETVT who receive short-interval treatment to optimize their vocal function. Short-interval chemodenervation injections demonstrate a similar adverse effect profile and do not appear to predispose to resistance through antibody formation.

Striatal Synaptic Dysfunction in Dystonia and Levodopa-Induced Dyskinesia.

This review provides an overview of the synaptic dysfunctions of neuronal circuits and underlying neurochemical alterations observed in the hyperkinetic movement disorders, dystonia and dyskinesia. These disorders exhibit similar changes in expression of synaptic plasticity and neuromodulation. This includes alterations in physical attributes of synapses, synaptic protein expression, and neurotransmitter systems, such as glutamate and gamma-aminobutyric acid (GABA), and neuromodulators, such as dopamine, acetylcholine, serotonin, adenosine, and endocannabinoids. A full understanding of the mechanisms and consequences of disruptions in synaptic function and plasticity will lend insight into the development of these disorders and new ways to combat maladaptive changes.

A Threat to Military Combat Power: Dietary Supplements.

BACKGROUND: The use of dietary supplements by young warfighters is pervasive and comes with a readiness cost, especially in the deployed setting. Predatory targeting and marketing by various unscrupulous companies put this population at risk for a higher than baseline risk for adverse events. METHODS: We report on 6 serious adverse events experienced by warfighters while deployed in Kuwait and Afghanistan. Presented is a discussion of current practice gaps and solutions, as well as details regarding how polypharmacy contributes to the seriousness of the threat posed by problematic supplements. RESULTS: The morbidity associated with the 6 cases of dietary supplement adverse events compromised mission readiness and was costly in terms of health and health care expenditures. CONCLUSION: The military dietary supplement issue needs exposure, review, and action at the highest levels of government.

Combined treatment with C16 peptide and angiopoietin-1 confers neuroprotection and reduces inflammation in 3-nitropropionic acid-induced dystonia mice.

Dystonia is a disorder associated with abnormalities in many brain regions including the basal ganglia and cerebellum. The toxin 3-Nitropropionic acid (3-NP) can induce neuropathologies in the mice striatum and nigra substance, including excitotoxicity, neuroinflammation, and extensive neuronal atrophy, characterized by progressive motor dysfunction, dystonia, and memory loss, mimicking those observed in humans. We established a mouse model of dystonia by administering 3-NP. Given the reported neuroprotective effects of the endothelial growth factor angiopoietin-1 (Ang-1) and the anti-inflammatory integrin αvß3 binding peptide C16, we performed this study to evaluate their combined effects on 3-NP striatal toxicity and their therapeutic potential with multiple methods using an in vivo mouse model. Sixty mice were equally and randomly divided into three groups: control, 3-NP treatment, and 3-NP+C16+Ang-1 treatment. Behavioral and electrophysiological tests were conducted and the effect of the combined C16+Ang-1 treatment on neural function recovery was determined. We found that C16+Ang-1 treatment alleviated 3-NP-induced behavioral, biochemical, and cellular alterations in the central nervous system and promoted function recovery by restoring vascular permeability and reducing inflammation in the micro-environment. In conclusion, our results confirmed the neuroprotective effect of combined C16+Ang-1 treatment and suggest their potential as a complementary therapeutic against 3-NP-induced dystonia.

Acute dystonia following epileptic seizure after bupropion intoxication.

Bupropion is an effective treatment for major depressive disorder and smoking cessation. In this paper, we present a case report about dystonia in the head and the neck after epileptic seizures due to 4200 mg of extended-release bupropion intake, and we aim to take attention to the rare neuropsychiatric side effects that may occur after the use of high doses of bupropion.

Atraumatic trismus induced by duloxetine: an uncommon presentation of acute dystonia.

Atraumatic trismus can be one of the presentations of medication-induced acute dystonia, particularly by antipsychotics and less commonly antidepressants. A case of an unusual emergency presentation of atraumatic trismus on initiation of duloxetine is reported. The patient was a 40-year-old woman experiencing sudden difficulty in mouth opening and speaking due to a stiffened jaw after taking 5 days of duloxetine prescribed for her fibromyalgia-related chest pain. Assessment of vital signs is prudent to ensure there is no laryngeal involvement. Other physical examinations and her recent investigations were unremarkable. She was treated for acute dystonia and intravenous procyclidine was given together with oral diazepam. Her symptoms improved immediately and her duloxetine was suggested to be stopped. To our knowledge, this is the first case of isolated trismus induced by duloxetine. Clinicians should be aware of this risk, especially considering the limitation of important physiological functions (such as swallowing, eating, etc) associated with this condition.

Striatal Dopamine Induced ERK Phosphorylation Is Altered in Mouse Models of Monogenic Dystonia.

BACKGROUND: Similar to some monogenic forms of dystonia, levodopa-induced dyskinesia is a hyperkinetic movement disorder with abnormal nigrostriatal dopaminergic neurotransmission. Molecularly, it is characterized by hyper-induction of phosphorylation of extracellular signal-related kinase in response to dopamine in medium spiny neurons of the direct pathway. OBJECTIVES: The objective of this study was to determine if mouse models of monogenic dystonia exhibit molecular features of levodopa-induced dyskinesia. METHODS: Western blotting and quantitative immunofluorescence was used to assay baseline and/or dopamine-induced levels of the phosphorylated kinase in the striatum in mouse models of DYT1, DYT6, and DYT25 expressing a reporter in dopamine D1 receptor-expressing projection neurons. Cyclic adenosine monophosphate (cAMP) immunoassay and adenylyl cyclase activity assays were also performed. RESULTS: In DYT1 and DYT6 models, blocking dopamine reuptake with cocaine leads to enhanced extracellular signal-related kinase phosphorylation in dorsomedial striatal medium spiny neurons in the direct pathway, which is abolished by pretreatment with the N-methyl-d-aspartate antagonist MK-801. Phosphorylation is decreased in a model of DYT25. Levels of basal and stimulated cAMP and adenylyl cyclase activity were normal in the DYT1 and DYT6 mice and decreased in the DYT25 mice. Oxotremorine induced increased abnormal movements in the DYT1 knock-in mice. CONCLUSIONS: The increased dopamine induction of extracellular signal-related kinase phosphorylation in 2 genetic types of dystonia, similar to what occurs in levodopa-induced dyskinesia, and its decrease in a third, suggests that abnormal signal transduction in response to dopamine in the postsynaptic nigrostriatal pathway might be a point of convergence for dystonia and other hyperkinetic movement disorders, potentially offering common therapeutic targets. © 2021 International Parkinson and Movement Disorder Society.

Clinical Spectrum of Drug-Induced Movement Disorders: A Study of 97 Patients.

Background: Drug-induced movement disorders (DIMDs) are commonly encountered, but an often-under-reported subgroup of movement disorders. Objectives: We aimed to highlight the spectrum of DIMDs in patients taking different groups of drugs at our movement disorder center. Methods: It is a cross-sectional descriptive study including 97 consecutive DIMDs patients diagnosed over the past two years (2017-2019). Results: The mean ± standard deviation (SD) age of our study population was 35.89 ± 17.8 years (Range-2-80 years). There were 51 males and 46 females. Different DIMDs observed included tardive dystonia (n = 41; 42.2%), postural tremor (n = 38; 39.2%), parkinsonism (n = 32; 33%), tardive dyskinesia (n = 21; 21.6%), acute dystonia (n = 10; 10.3%), neuroleptic malignant syndrome (NMS) (n = 2; 2.1%), and others [(n = 10; 10.30%) including chorea and stereotypy each in 3; acute dyskinesia in 2; and myoclonic jerks and acute akathisia each in 1 patient]. Of these 97 patients, 49 had more than one type of DIMDs while 48 had a single type of DIMDs. In our study 37 (38%) patients had received non-dopamine receptor blocking agents (non-DRBA), 30 (31%) patients had received dopamine receptor blocking agents (DRBA), and 30 (31%) patients had received both DRBA and non-DRBA. Conclusions: Tardive dystonia was the most common DIMDs observed in our study. Our DIMDs patients were younger than other reported studies. We observed a significant number of non-DRBA drugs causing DIMD in our study as compared to previous studies. Drug-induced parkinsonism (DIP) was the most common DIMDs in the DRBA group. Tardive dystonia was the most common DIMDs seen in DRBA + non-DRBA group and the second most common in the DRBA and non-DRBA group. The postural tremor was the most common DIMDs in the non-DRBA group.

Acute, severe dystonia after strabismus surgery in a patient on propofol, ondansetron, and bupropion.

Acute, severe dystonia is a frightening and potentially life-threatening surgical complication. We describe the case of a 41-year-old woman who experienced postoperative drug-induced dystonia after elective strabismus surgery. In this case, the medications likely responsible were propofol, ondansetron, and, possibly, bupropion.

Frequency and Correlates of Acute Dystonic Reactions After Antipsychotic Initiation in 441 Children and Adolescents.

Objective: To determine the incidence of acute dystonic reactions (ADRs) and risk factors for ADRs in children and adolescents treated with antipsychotics. Methods: This was a retrospective chart review-based cohort study of consecutive patients who attended a university hospital's child and adolescent psychiatry department between 2015 and 2017 and who were treated with antipsychotics and had at least two follow-up visits. Results: Thirty of 441 patients (6.8%) 4-19 years of age who were treated with antipsychotics for conduct disorders (21.5%), attention-deficit/hyperactivity disorder (13.2%) and, irritability and aggression that accompanied intellectual disability (12.9%) and followed for 99.5 ± 223.3 (median: 34) days developed ADRs. ADRs developed in 11/391 patients (2.8%) treated with one antipsychotic and 19/50 patients (38.0%) treated with two antipsychotics (p < 0.001). In patients treated with one antipsychotic that developed ADRs, the time to ADRs was 4.0 ± 4.0 days after antipsychotic initiation and 2.7 ± 2.4 days after an increase in the antipsychotic dose. The time to ADRs in those treated with two antipsychotics was 3.0 ± 2.3 days after the addition of the second antipsychotic and 1.6 ± 0.8 days after a dose increase in the second antipsychotic. The incidence of ADRs during antipsychotic monotherapy was 10.5% with first-generation antipsychotics (FGAs) and 2.2% with second-generation antipsychotics (SGAs; p = 0.037). The antipsychotic was changed due to ADRs in 12/30 (40.0%) of ADR cases. Independent factors associated with ADRs were antipsychotic polypharmacy (p < 0.0001), inpatient treatment (p = 0.013), FGA use (p = 0.015), and diagnoses of schizophrenia (p = 0.039) or bipolar disorder (p < 0.0001). Conclusion: SGAs and low-potency FGA monotherapy in children and adolescents were associated with a relatively low ADR risk, whereas high- and mid-potency FGAs were associated with a high risk. Independent predictors of ADRs were antipsychotic polypharmacy, inpatient treatment, FGAs, and schizophrenia or bipolar disorder diagnoses, which may be related to more aggressive antipsychotic dosing.

Spastic quadriplegia following intradermal use of hydrogen peroxide in the tardive curettage procedure for the treatment of a giant congenital nevus.

The possible transformation of a giant congenital melanocytic nevi (GCMN) in malignant melanoma estimated from 0.05% to 40% depend on the size of the lesions. Many are the surgical procedures proposed, including: full or partial-thickness excisions, dermabrasion, curettage in the first weeks of life and laser treatment. The curettage technique has been proposed in the literature for the treatment of GCMN in the first few weeks of life and defined as a relatively atraumatic surgery procedure without general complications. The authors report the first case in the literature of embolization due to use of subcutaneous peroxide infiltration before a tardive curettage procedure in a newborn case of GCMN resulting in spastic quadriplegia with dystonic reaction. Consequently, a lawsuit, due to this medical malpractice, has been opened.

Characteristics of Patients Experiencing Extrapyramidal Symptoms or Other Movement Disorders Related to Dopamine Receptor Blocking Agent Therapy.

PURPOSE/BACKGROUND: Dopamine receptor blocking agents (DRBAs), also known as antipsychotics, are medications widely used to treat a growing number of mental health diagnoses. However, their utility is limited by the potential to cause serious adverse movement reactions. Akathisia, dystonia, parkinsonism, and tardive dyskinesia (collectively known as extrapyramidal symptoms or EPSs) are associated with reduced social and occupational functioning, negative patient attitudes toward treatment, and nonadherence to pharmacotherapy. Neuroleptic malignant syndrome is a life-threatening reaction that can result from DRBA use and cause musculoskeletal dysfunction. The aim of this study is to profile patients who have developed DRBA-related movement adverse effects and identify risk factors significantly associated with each subtype of EPSs or other movement disorders (OMDs) such as neuroleptic malignant syndrome. METHODS/PROCEDURES: A report of all potential DRBA-related EPSs or OMDs occurrences within a large community hospital network was generated using International Classification of Diseases, Ninth Revision (ICD-9) and 10th Revision (ICD-10) billing codes. Each patient encounter was manually reviewed to confirm that a documented case of DRBA-related EPSs or OMDs had indeed occurred and subsequently determine the likely causative agent(s). FINDINGS/RESULTS: The resultant cohort of 148 patients experiencing unique DRBA-related EPS or OMD events was analyzed. The average patient was female, middle-aged, and overweight. The most common DRBAs precipitating EPSs or OMDs were haloperidol and quetiapine. In the population studied, age was significantly associated with the subtype of EPSs experienced such that those patients with akathisia and dystonia tended to be younger, whereas those with tardive dyskinesia tended to be older. Body mass index (BMI) category was also negatively correlated with the incidence of dystonia. In addition, it was observed that exposure to specific DRBAs, classes, and routes of administration significantly affected the risk of developing different subtypes of EPSs or OMDs in the study population. IMPLICATIONS/CONCLUSIONS: To our knowledge, this is the first study to describe an association between age and BMI with the risk of akathisia and dystonia, respectively, in patients taking DRBAs. Other trends observed with age and BMI in patients developing DRBA-related EPSs support previously reported findings. Expanding the knowledge base of individual characteristics associated with the risk of developing different subtypes of EPSs or OMDs can help providers and patients anticipate and attempt to mitigate these reactions, and may ultimately improve adherence to DRBA therapy.

Movement side effects of antipsychotic drugs in adults with and without intellectual disability: UK population-based cohort study.

OBJECTIVES: To measure the incidence of movement side effects of antipsychotic drugs in adults with intellectual disability and compare rates with adults without intellectual disability. DESIGN: Cohort study using data from The Health Improvement Network. SETTING: UK primary care. PARTICIPANTS: Adults with intellectual disability prescribed antipsychotic drugs matched to a control group of adults without intellectual disability prescribed antipsychotic drugs. OUTCOME MEASURES: New records of movement side effect including acute dystonias, akathisia, parkinsonism, tardive dyskinaesia and neuroleptic malignant syndrome. RESULTS: 9013 adults with intellectual disability and a control cohort of 34 242 adults without intellectual disability together contributed 148 709 person-years data. The overall incidence of recorded movement side effects was 275 per 10 000 person-years (95% CI 256 to 296) in the intellectual disability group and 248 per 10 000 person-years (95% CI 237 to 260) in the control group. The incidence of any recorded movement side effect was significantly greater in people with intellectual disability compared with those without (incidence rate ratio 1.30, 95% CI 1.18 to 1.42, p<0.001, after adjustment for potential confounders), with parkinsonism and akathisia showing the greatest difference between the groups. Neuroleptic malignant syndrome, although occurring infrequently, was three times more common in people with intellectual disability-prescribed antipsychotic drugs (incidence rate ratio 3.03, 95% CI 1.26 to 7.30, p=0.013). Differences in rates of movement side effects between the groups were not due to differences in the proportions prescribed first and second-generation antipsychotic drugs. CONCLUSIONS: This study provides evidence to substantiate the long-held assumption that people with intellectual disability are more susceptible to movement side effects of antipsychotic drugs. Assessment for movement side effects should be integral to antipsychotic drug monitoring in people with intellectual disability. Regular medication review is essential to ensure optimal prescribing in this group.

Acute Dystonia Versus Neuroleptic Malignant Syndrome Without Fever in an Eight-Year-Old Child.

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication of the use of certain medications. It is being seen more often in the pediatric population because of the increasing use of both typical and atypical antipsychotics in children. Rapid recognition of NMS is important to emergency physicians because timely treatment can be life saving. Acute dystonia is also a well-known and more common adverse effect of certain types of antipsychotics, more commonly seen with the typical antipsychotics versus the atypical antipsychotics. We describe a case of a pediatric patient who developed an acute dystonic reaction versus NMS soon after starting aripiprazole. We compare this case with the other documented cases of acute dystonia and NMS after initiating aripiprazole in the pediatric population.

Acute laryngeal dystonia: a persisting psychiatric emergency.

OBJECTIVE: Acute laryngeal dystonia is one of the most life-threatening medication side effects in psychiatry. It is rare and predominately caused by the use of antipsychotics in at-risk individuals. Within days of a patient's initial presentation, several antipsychotics can be administered for the purposes of acute sedation and ongoing pharmacotherapy. In this case report, we describe a 27-year-old at-risk male, who developed acute laryngeal dystonia in the context of antipsychotic polypharmacy. CONCLUSION: Clinicians should take into account recent sedation and ongoing antipsychotic use in patients at risk of developing acute laryngeal dystonia. Awareness of this condition and prompt treatment with parenteral anticholinergic medication can be lifesaving.

Dystonia not dystopia: effects of the legal high, 'Clockwork Orange'.

A 27-year-old man presented to hospital after smoking a legal high named 'Clockwork Orange'. He suffered dystonia, acute kidney injury, rhabdomyolysis, lactic acidosis and a troponin rise. He was treated with procyclidine and intravenous fluids.

Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder: Part 1.

This series of columns has 2 main goals: (1) to explain the use of class warnings by the US Food and Drug Administration and (2) to increase clinicians' awareness of movement disorders that may occur in patients being treated with antipsychotic medications and why it is appropriate and good practice to refrain from immediately assuming the diagnosis is tardive dyskinesia/dystonia (TD). This first column in the series will focus on the second goal, which will then serve as a case example for the first goal. Clinicians should refrain from jumping to a diagnosis of TD because a host of other causes need to be ruled out first before inferring iatrogenic causation. The causal relationship between chronic treatment with dopamine antagonists and TD is based on pharmacoepidemiology (ie, the prevalence of such movement disorders is higher in individuals receiving chronic treatment with such agents than in a control group). There is nothing pathognomonic about movement disorders, nor is there any test that can currently prove a drug caused a movement disorder in a specific individual. Another goal of this series is to describe the types of research that would be needed to establish whether a specific agent has a meaningful risk of causing TD. In this first column of the series, we present the case of a patient who developed orofacial dyskinesia while being treated with aripiprazole. In this case, the movement disorder was prematurely called TD, which led to a malpractice lawsuit. This case highlights a number of key questions clinicians are likely to encounter in day-to-day practice. We then review data concerning the historical background, incidence, prevalence, and risk factors for 2 movement disorders, TD and spontaneous dyskinesia. Subsequent columns in this series will review: (1) unique aspects of the psychopharmacology of aripiprazole, (2) the limited and inconsistent data in the literature concerning the causal relationship between aripiprazole and TD, (3) the use of class warnings by the US Food and Drug Administration, which are automatically applied to a drug if it belongs to a specific therapeutic or pharmacological class unless the manufacturer provides convincing data that it does not warrant such a class label, and (4) the types of prohibitively expensive studies that would be needed to determine whether a meaningful causal relationship between aripiprazole and TD exists.