TREX-1 related Aicardi-Goutières syndrome improved by Janus kinase inhibitor.

Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy classically characterized by early onset of severe neurologic injury with basal ganglia calcifications, white matter abnormalities, and progressive cerebral atrophy, along with lymphocytosis and raised interferon alpha (INFα) in the cerebrospinal fluid (CSF). Here, we report a 31/2 year-old patient born with prenatal onset AGS, first manifesting as intra-uterine growth retardation. Cranial ultrasonography and cerebral MRI revealed ventriculomegaly and periventricular and basal ganglia calcifications, along with cerebral atrophy. Perinatal infections and known metabolic disorders were excluded. Both CSF lymphocytosis and raised INFα were present. Molecular analysis disclosed two already described compound heterozygous pathogenic variants in TREX1 (c. 309dup, p.(Thr104Hisfs*53) and c. 506G > A, p.(Arg169His)). The evolution was marked by severe global developmental delay with progressive microcephaly. Promptly, the patient developed irritability, quadri-paretic dyskinetic movements, and subsequently tonic seizures. Sensorineural hearing loss was detected as well as glaucoma. Initially, he was symptomatically treated with trihexyphenidyl followed by levetiracetam and topiramate. At age 22 months, baricitinib (0.4 mg/kg/day) was introduced, leading to normal serum INFα levels. Clinically, dyskinetic movements significantly decreased as well as irritability and sleep disturbance. We confirmed that baricitinib was a useful treatment with no major side effect.

Detecting biomarkers associated with antipsychotic-induced extrapyramidal syndromes by using machine learning techniques.

BACKGROUND: Antipsychotic-associated extrapyramidal syndromes (EPS) are a common side effect that may result in discontinuation of treatment. Although some clinical features of individuals who develop specific EPSs are well defined, no specific laboratory parameter has been identified to predict the risk of developing EPS. METHODS: Three hundred and ninety hospitalizations of patients under antipsychotic medication were evaluated. Machine learning techniques were applied to laboratory parameters routinely collected at admission. RESULTS: Random forests classifier gave the most promising results to show the importance of parameters in developing EPS. Albumin has the maximum importance in the model with 4.28% followed by folate with 4.09%. The mean albumin levels of EPS and non-EPS group was 4,06 ± 0,40 and 4,24 ± 0,37 (p = 0,027) and folate level was 6,42 ± 3,44 and 7,95 ± 4,16 (p = 0,05) respectively. Both parameters showed lower levels in EPS group. CONCLUSIONS: Our results suggest that relatively low albumin and folate levels may be associated with developing EPS. Further research is needed to determine cut-off levels for these candidate markers to predict EPS.

Driving fitness in clinically stable outpatients with chronic schizophrenia.

INTRODUCTION: Driving motorized vehicles is an integral part of individual mobility and a key parameter for employment and social integration. This naturalistic, cross-sectional study investigated the associations between driving fitness, residual symptomatology, olanzapine equivalent, and extrapyramidal symptoms (EPS) in long term stable outpatients with schizophrenia. METHODS: Beside sociodemographic data, and driving habits, residual symptoms, and EPS were assessed using the Positive and Negative Syndrome Scale (PANSS), and the Modified Simpson Angus Scale (MSAS). PANSS symptoms were analyzed using the Wallwork/Fortgang five-factor model. MSAS cut-off scores ≥3 were defined as positive for EPS. Driving skills were assessed using the Vienna Test System and an expert evaluation. RESULTS: 50 patients were included into the study. Mean PANSS total scores indicated mild residual symptomatology and EPS were not present in 48% of study participants. 44% passed the driving fitness assessment and were considered as competent to drive, 20% were judged to be partially competent and 36% to be incompetent to drive. With the exception of disorganization (r = -0·287, p = 0·048) residual symptoms of schizophrenia did not correlate with driving fitness. However, moderate negative correlations were detected between driving fitness and the severity of EPS (r = -0·554, p = 0·000), age (r = -0·413, p = 0·003) as well as olanzapine equivalent doses (r = -0·432, p = 0·002). These results were not corrected for multiple comparison. DISCUSSION: The present findings indicate that up to two thirds of clinically stable outpatients with chronic schizophrenia may be (partially) competent to drive. Both the presence of EPS as well as the dosage of antipsychotic medication seem to be of particular relevance in this regard.

Biotin-Responsive Basal Ganglia Disease: Treatable Metabolic Disorder with SLC19A3 Mutation Presenting as Rapidly Progressive Dementia.

Background and Aims: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive disorder due to mutations in the SLC19A3-gene, typically seen in early childhood. Materials and Methods: We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration. The magnetic resonance imaging (MRI) of the brain revealed T2-hyperintensities in the basal ganglia, thalamus, cortical, subcortical regions with striatal necrosis suggestive of BTBGD that was confirmed by genetic analysis. She was treated with thiamine and biotin following which there was significant clinical and MRI improvement. Conclusions: BTBGD requires a high index of suspicion in any patient presenting with unexplained rapidly progressive dementia. High doses of biotin and thiamine are the mainstay of the treatment to achieve a favorable outcome.

Basal Ganglia Disease Mimicking Acute Encephalitis Syndrome Among Infants of Bodo Tribe, Assam.

We conducted a review of hospital records of infants with acute encephalitis syndrome with bilateral symmetrical basal ganglia infarcts, between 2011-2015, at a single center in Assam. Thiamine (as part of multivitamin injection) was used in the treatment of 23 infants and not used in 27; Only 1 (3.7%) infant died in the former group and 20 infants (86.9%) died in the latter [RR (95% CI) 0.04 (0.006,0.29); P<0.001). Two infants on follow-up had normal development, both in the thiamine group. The study suggests the possibility of subclinical thiamine deficiency, mitochondrial diseases, or SLC19A3 gene mutation in this population.

Strain-specific clearance of seed-dependent tau aggregation by lithium-induced autophagy.

Different conformational strains of tau have been implicated in the clinicopathological heterogeneity of tauopathies. In this study, we hypothesized that distinct strains are degraded in a different manner. Lithium, a drug for bipolar disorder, had previously been reported to reduce aggregation-prone protein content by promoting autophagy. Here, we assessed the effects of lithium on tau aggregates using different tauopathy brain seeds. SH-SY5Y cells were transfected with C-terminal tau fragment Tau-CTF24 (residues 243-441), and Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain seeds were introduced. After 48-h lithium treatment, sarkosyl-insoluble fractions were prepared. Lithium treatment was found to reduce the amount of insoluble tau and p62, and increase LC3-II levels along with the number of autophagic vacuoles in AD-seeded cells. The effects were lower in case of CBD seeds, and comparable between PSP and AD seeds. An inhibitor of myo-inositol monophosphatase (IMPase) also demonstrated similar effects. Overall, the study suggested that aggregated tau protein is degraded by lithium-induced autophagy, influencing IMPase in a strain-specific manner.

Unusual case of biotin-thiamine responsive encephalopathy without basal ganglia involvement.

Biotin-thiamine-responsive encephalopathy, also known as biotin-responsive basal ganglia disease, is characterized by high T2 signal in the basal ganglia (caudate and putamina), which is reported as a typical feature of the disorder. Brain magnetic resonance imaging in our patient, who presented with irritability, poor feeding and prolonged seizures, found multiple areas of restricted diffusion in the cerebral cortex and thalami leading to an initial diagnosis of a mitochondrial disorder. The basal ganglia were not affected. More characteristic chronic findings of T2 prolongation and volume loss were later seen in our patient. The child improved with biotin and thiamine supplementation, a well-known feature of the condition. It is important for the radiologist and treating team to be aware of this variant and pursue further investigations to avoid delay in care and potential fatality.

A missed case of lurasidone induced laryngospasm: A case study and overview of extrapyramidal symptom identification and treatment.

OBJECTIVE: Many patients with bipolar disorder are treated exclusively in primary care settings, and the use of atypical antipsychotics as primary treatment for bipolar depression is increasing. Extrapyramidal symptoms (EPS) are common side effects of antipsychotic medications, and clinicians should actively monitor for these symptoms when prescribing antipsychotic medications. Accurate diagnosis of EPS is especially important as the symptoms can be highly distressing, and in some cases, life threatening. Our aim is to familiarize primary care providers and other clinicians prescribing antipsychotic medications with EPS and to aid in its rapid diagnosis and treatment. METHOD: We describe a case of lurasidone induced dystonia with prominent laryngospasm and oculogyric crisis which was missed for many years in the primary care setting, largely due to misdiagnosis of symptoms as being related to anxiety and panic attacks. RESULTS: In addition to summarizing this illustrative case, we present the most common forms of EPS and summarize the primary therapies for each type of EPS. CONCLUSIONS: With increased management of bipolar disorder in the primary care setting and increased use of atypical antipsychotics as the primary therapy for bipolar disorder, it is essential that all practitioners are prepared to actively monitor for EPS, followed by its rapid diagnosis and treatment.

Intravenous Migraine Treatment in Children and Adolescents.

PURPOSE OF REVIEW: Pediatric migraine is a common, chronic, and disabling neurological disorder in children and adolescents. Outpatient management is not always effective, and intravenous migraine management may be necessary for headache treatment in the pediatric emergency department. Most current treatment is based on retrospective evidence and there is a lack of well-designed randomized double-blinded controlled pediatric studies. Intravenous drug treatment agents including intravenous fluids, prochlorperazine, diphenhydramine, metoclopramide, dexamethasone, magnesium, valproate and propofol, and dihydroergotamine are reviewed in this paper. RECENT FINDINGS: Nineteen studies were reviewed including one prospective randomized double-blind; one single-blinded randomized; one prospective; and one open-label, randomized clinical trial. Most studies were retrospective and the quality of the studies was limited. No definite conclusions can be drawn from the studies, but appropriate prospective trials between major pediatric headache institutions will move pediatric intravenous migraine management forward.

Drug-Induced Extrapyramidal Symptoms at the Pediatric Emergency Department.

OBJECTIVES: Extrapyramidal symptoms (EPS) induced by pharmacologic agents can cause patient discomfort and lead to emergency department visits. Analyzing these cases at a pediatric emergency department may help to elucidate the characteristic features of extrapyramidal syndrome in children. METHODS: This retrospective study was conducted at Chang Gung Memorial Hospital in Taiwan. Pediatric patients with drug-induced extrapyramidal syndrome seeking treatment at our emergency department from January 2001 to December 2010 were enrolled. The patients' clinical features, drug history, demographic data, and treatment data were collected and analyzed. RESULTS: One hundred nineteen patients (61 females, 58 males) were enrolled. Ninety-six patients could provide their drug history; all of whom took dopamine antagonists and 90% of whom took dopamine antagonists as antiemetic agents, with only 9 patients taking them for antipsychotic purposes. Metoclopramide syrup overdose was the main cause of extrapyramidal syndrome in patients under 2 years old. The average emergency room stay of the patients who could provide their drug history was shorter than that of those who could not. CONCLUSIONS: It is not uncommon for patients with drug-induced EPS to present to a pediatric emergency room owing to the use of dopamine antagonists as antiemetic agents. Clinical symptoms with a clear drug history are helpful for the diagnosis and management. Emphasizing the correct usage of liquid medications will reduce the risk of EPS.

Progressive Supranuclear Palsy, Corticobasal Degeneration, and Multiple System Atrophy.

PURPOSE OF REVIEW: Patients who have parkinsonian features, especially without tremor, that are not responsive to levodopa, usually have one of these three major neurodegenerative disorders rather than Parkinson disease: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or corticobasal degeneration (CBD). Each of these disorders eventually develops signs and symptoms that distinguish it from idiopathic Parkinson disease, but these may not be present at disease onset. Although these conditions are not generally treatable, it is still important to correctly diagnose the condition as soon as possible. RECENT FINDINGS: In recent years, it has been increasingly recognized that the symptoms of these diseases do not accurately predict the pathology, and the pathology does not accurately predict the clinical syndrome. Despite this, interest has grown in treating these diseases by targeting misfolded tau (in the case of PSP and CBD) and misfolded α-synuclein (in the case of MSA). SUMMARY: Knowledge of the characteristic signs and symptoms of PSP, MSA, and CBD are essential in diagnosing and managing patients who have atypical parkinsonian syndromes.

Extrapyramidal motor signs in older adults with HIV disease: frequency, 1-year course, and associations with activities of daily living and quality of life.

Age and HIV disease have additive effects on neural systems that support motor functioning. The current study examined the combined impact of aging and HIV on extrapyramidal motor functions, which were hypothesized to influence on activities of daily living (ADLs) and quality of life (QoL). Participants included 336 adults classified by HIV serostatus and age. A research nurse administered the Unified Parkinson's Disease Rating Scale (UPDRS) and participants completed the modified Lawton & Brody ADL and the Short Form Survey Instrument (SF-36) questionnaires as part of a larger neuropsychological research battery. A convenience subset of 172 participants completed a 14-month follow-up evaluation. At baseline, only older age was associated with mild extrapyramidal signs; however, at 14-month follow-up, independent adverse effects of both HIV status and age group were observed on a 3-level UPDRS change variable. Among older HIV+ adults, the presence of mild UPDRS motor signs was independently associated with basic and instrumental ADL dependence, as well as lower physical (ps < .05), but not mental QoL. In the modern treatment era, older HIV+ adults show higher frequency of mild extrapyramidal signs as compared to younger individuals (but not older HIV- persons) and are at higher risk of incident extrapyramidal signs relative to HIV- persons (but not younger HIV+ persons). When present in older HIV+ adults, extrapyramidal signs are of mild severity but nevertheless increase the risk of daily functioning problems and lower health-related physical QoL.

Interplay between adenosine receptor antagonist and cyclooxygenase inhibitor in haloperidol-induced extrapyramidal effects in mice.

Antipsychotic drugs are the mainstay of psychotic disorders. The 'typical' antipsychotic agents are commonly employed for the positive symptoms of schizophrenia, though at an expense of extrapyramidal side effects (EPS). In the present study, we employed haloperidol (HP)-induced catalepsy model in mice to evaluate the role of adenosine receptor antagonist and cyclooxygenase (COX) enzyme inhibitor in the amelioration of EPS. HP produced a full blown catalepsy, akinesia and a significant impairment in locomotion and antioxidant status. Pre-treatment with COX inhibitor; naproxen (NPx) and adenosine receptor antagonist; caffeine (CAF), showed a significant impact on HP-induced cataleptic symptoms. Adenosine exerts pivotal control on dopaminergic receptors and is also involved in receptor internalization and recycling. On the other hand, prostaglandins (PGs) are implicated as neuro-inflammatory molecules released due to microglial activation in both Parkinson's disease (PD) and antipsychotics-induced EPS. The involvement of these neuroeffector molecules has led to the possibility of use of CAF and COX inhibitors as therapeutic approaches to reduce the EPS burden of antipsychotic drugs. Both these pathways seem to be interlinked to each other, where adenosine modulates the formation of PGs through transcriptional modulation of COXs. We observed an additive effect with combined treatment of NPx and CAF against HP-induced movement disorder. These effects lead us to propose that neuromodulatory pathways of dopaminergic circuitry need to be explored for further understanding and utilizing the full therapeutic potential of antipsychotic agents.

Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis.

OBJECTIVES: To determine the effectiveness of prophylactic anticholinergic medications in reducing extrapyramidal symptoms in patients taking acute antiemetics with a dopamine D2 receptor antagonist effect. METHODS: Systematic searches of all published studies through March 2017 were identified from PubMed, Cochrane library, Embase, Web of Science and Scopus. Only randomised controlled trials of patients receiving dopamine D2 antagonist antiemetic therapy for acute migraine in which an anticholinergic or placebo was compared were included. Pooled ORs were calculated for incidence of extrapyramidal symptoms and sedation. RESULTS: Four placebo-controlled randomised controlled trials consisting of 737 patients met the inclusion criteria for our meta-analysis. The effect of diphenhydramine differed depending on the method of administration of the antiemetic. When the antiemetic was delivered as a 2 min antiemetic bolus, the odds of extrapyramidal symptoms were significantly reduced in the diphenhydramine group compared with placebo (OR 0.42; 95% CI 0.22 to 0.81; P=0.01). However, when the antiemetic was given as a 15 min infusion, there was no significant difference in extrapyramidal symptoms with or without diphenhydramine (OR 1.06; 95% CI 0.58 to 1.91; P=0.85). The lowest incidence of extrapyramidal symptoms was observed in patients receiving a 15 min antiemetic infusion without diphenhydramine prophylaxis (9.8%). In two trials including 351 patients that dichotomously reported sedation scales, diphenhydramine had significantly higher rates of sedation (31.6%vs19.2%, OR 2.01, 95% CI 1.21 to 3.33; P=0.007). CONCLUSION: Prophylactic diphenhydramine reduces extrapyramidal symptoms in patients receiving bolus antiemetic therapy with a dopamine D2 antagonist effect, but not when it is given as an infusion. Because of significantly greater sedation with diphenhydramine, the most effective strategy is to administer the D2 antagonist antiemetic as a 15 min infusion without prophylaxis.

Bilateral striopallidodentate calcinosis associated with Sjögren's syndrome and IgDλ monoclonal gammopathy of undetermined significance.

We presented the first case of bilateral striopallidodentate calcinosis secondary to Sjögren's syndrome. Further consideration should be given to the association between Sjögren's syndrome and bilateral striopallidodentate calcinosis, because Sjögren's syndrome is latent, but more frequent than other autoimmune diseases.

Reducing Anticholinergic Medication Burden in Patients With Psychotic or Bipolar Disorders.

OBJECTIVE: Anticholinergic medications are prescribed to treat extrapyramidal side effects (EPS) associated with antipsychotics. Anticholinergic medications cause several side effects and can often be withdrawn during the maintenance phase of antipsychotic treatment without EPS reemergence. The purpose of this quality improvement (QI) project was to reduce anticholinergic medication burden and improve quality of life in patients with severe mental illness. METHODS: Patients with DSM-IV-TR-diagnosed schizophrenia, schizoaffective disorder, and bipolar disorders in an outpatient psychiatric clinic who were prescribed benztropine were identified, screened for anticholinergic side effects by the treating psychiatrist, and referred to an on-site clinical pharmacist for a comprehensive medication review. Anticholinergic side effects, cognitive impairment, and impact on quality of life were assessed using a Likert scale. Recommendations for potential medication changes were discussed with the prescriber. Initial and follow-up assessments were conducted over 1-8 months to identify improvements in side effects and quality of life. RESULTS: Twenty-nine patients were assessed from November 2014 to December 2015. Patients were receiving from 1 to 6 medications with anticholinergic properties (median = 3 medications). Of the 29 patients, 19 were recommended for a medication change, with 13 having 1 or more anticholinergic medications discontinued and 6 having the dose decreased. A significant reduction in anticholinergic side effects and improvements in memory and quality of life were observed for these patients (P ≤ .05). CONCLUSIONS: In this interdisciplinary, collaborative QI project, patients whose anticholinergic burden was reduced experienced a significant improvement in side effects, memory, and quality of life.