[A case suspected of dystonia with marked cerebellar atrophy with torsion dystonia of the neck and cerebellar ataxia that developed during pharmacologic schizophrenia treatment].

A 46 year-old man with schizophrenia had taken several anti-psychotic drugs since 25 years of age. From ~35 years of age, he noticed occasional neck torsion to the left, and later an ataxic gait; both symptoms gradually worsened. On admission, the patient was taking olanzapine (5 mg/day) and biperiden hydrochloride (1 mg/day) because his schizophrenia was well controlled. His parents were not consanguineous, and there was no family history of neuropsychiatric diseases. On neurological examination, he showed mild cognitive impairment, saccadic eye pursuit with horizontal gaze nystagmus, mild dysarthria, dystonic posture and movement of the neck, incoordination of both hands, and an ataxic gait. Deep tendon reflexes were normal except for the patellar tendon reflex, which was exaggerated bilaterally. Pathological reflexes were negative and there was no sign of rigidity, sensory disturbance or autonomic dysfunction. Ophthalmological examinations detected thinning of the outer macula lutea in both eyes, indicative of macular dystrophy. After admission, all anti-psychotic drugs were ceased, but his dystonia was unchanged. Levodopa and trihexyphenidyl hydrochloride were not effective. General blood, urine and cerebrospinal fluid examinations showed no abnormalities. Brain MRI showed cerebellar atrophy and bilateral symmetrical thalamic lesions without brainstem atrophy or abnormal signals in the basal ganglia. I123-IMP SPECT also revealed a decreased blood flow in the cerebellum. Genetic screening, including whole exome sequencing conducted by the Initiative on Rare and Undiagnosed Disease identified no possible disease-causing variants. The patient's dystonia worsened and choreic movements manifested on his right hand and foot. We suspected dystonia with marked cerebellar atrophy (DYTCA), but could not exclude drug-induced dystonia. Macular dystrophy and bilateral thalamic lesions on brain MRI have not been previously described in DYTCA. Whether these features might be primarily associated with dystonia or cerebellar ataxia now remains to be determined.

Anti-Cholinergic Derangement of Cortical Metabolism on 18F-FDG PET in a Patient with Frontotemporal Lobar Degeneration Dementia: A Case of the TREDEM Registry.

We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old patient, followed by psychiatrists for depression and behavioral disorders, received a diagnosis of dementia with Lewy bodies (DLB) at another Center due to auditory hallucinations, gait impairment, and tendency to fall. He was then admitted to our Memory Clinic Unit for behavioral disturbances, such as delusional thinking, auditory hallucinations, and memory complaints. At that time, the patient's therapy included Lorazepam, Quetiapine, Promazine, and Biperiden. The latter was immediately suspended for the absence of extrapyramidal signs and to avoid the anticholinergic cognitive side effects. A 18F-FDG PET showed a derangement of cortical metabolism with diffusely reduced activity, and limited areas of hyperactivity involving lateral frontal and lateral temporal inferior regions bilaterally. The patient underwent a series of exams, including neuropsychological tests, 123I-MIBG scintigraphy, cerebrospinal fluid examination, and genetic analysis. A second 18F-FDG PET showed an extensive remodulation of metabolic activity: relative higher concentration of the tracer in the prefrontal and inferior temporal cortex was no more detectable. Similarly, the diffuse reduced metabolic activity could not be traced anymore. Nonetheless, the metabolic activity still appeared reduced in the frontal lobe, in the anterior cingulate bilaterally, and in the anterior part of the hemispheric fissure. Taken together, clinical and neuroimaging features would point to a FTLD-like form. Furthermore, the diagnostic work-up was likely confounded by the anticholinergic drug on 18F-FDG PET, highlighting the importance of carefully checking the patient's pharmacology during the diagnostic process.

Biperiden Selectively Impairs Verbal Episodic Memory in a Dose- and Time-Dependent Manner in Healthy Subjects.

PURPOSE/BACKGROUND: Biperiden is a muscarinic antagonist that produces memory impairments without impairing attention or motor functions in healthy subjects. It has been suggested that a biperiden-induced memory deficit could model age- and dementia-related memory impairments. The goal of the current study was to determine the dose- and time-dependent effects of biperiden on cognition in healthy volunteers. METHODS/PROCEDURES: Twenty-one healthy volunteers participated in a placebo-controlled, 3-way, crossover study. After a baseline test, cognitive performance was tested at 3 time points after a single dose of biperiden 2 or 4 mg, or placebo. Episodic memory was measured using a 15-word verbal learning task (VLT). Furthermore, n-back tasks, a sustained attention to response task and a reaction time task were used, as well as subjective alertness and a side effects questionnaire. In addition, blood serum values and physiological measures were taken. FINDINGS/RESULTS: Biperiden decreased the number of words recalled in immediate and delayed recall of the VLT 90 minutes after drug intake. A dose-dependent impairment was found for the delayed recall, whereas the immediate recall was equally impaired by the 2 doses. Biperiden did not affect the performance on the VLT 4 hours after administration. Performance in the n-back task and the sustained attention to response task were not affected by biperiden at any time point. Both doses were well tolerated as reported side effects were mild at Tmax and were minimal at the other time points. IMPLICATIONS/CONCLUSIONS: Biperiden exerts effects on episodic memory without negatively affecting other cognitive performance and behavioral measures that were assessed in this study. The data provide further evidence that biperiden has selective effects on cognition, even after a high dose.

Biperiden-Induced Delirium In A Five-Years Old Child.

OBJECTIVE: Extrapyramidal adverse effects of antipsychotic drugs are more reported in children. Biperiden is an anticholinergic agent to treat the adverse effects of antipsychotic drugs. The drug has the potential to induce delirium at toxic doses. However, data are scarce about delirium associated with biperiden in children. Thus far, a case of delirium has been associated with biperiden in an adolescent patient. We report the first case of delirium associated with the use of biperiden in a preadolescent patient. CASE REPORT: A boy aged five years and weighing 20 kilograms had been diagnosed as having oppositional defiant disorder and separation anxiety disorder in the previous treatment center. Ten milligrams fluoxetine and 0.25 milligrams risperidone had been initiated. On the third day of treatment, dystonia developed and he was administered with biperiden. An hour later, he was brought to our emergency clinic due to disorganized speech and behavior. His vital signs were stable. There were no findings in blood and urine tests. No electrolyte imbalance, liver, kidney, and thyroid dysfunction have been observed. His neurologic examination was unremarkable and no abnormal findings were shown on cranial magnetic resonance imaging. No other system findings or findings pointing out to infectious diseases have been observed. One milligram physostigmine was administered with intravenous infusion. However, symptoms did not resolve and he was diagnosed with delirium. Naranjo Adverse Drug Reaction Probability Scale score was seven, indicating a "Probable" Adverse Drug Reaction. Half milligram haloperidol was administered bid for three days and he was discharged with complete recovery. CONCLUSION: Clinicians must be aware of the risk of delirium when using non-toxic doses of biperiden in young children.

Anticholinergic medication for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with serious mental illnesses. However, it is associated with a wide range of adverse effects, including movement disorders. Because of this, many people treated with antipsychotic medication also receive anticholinergic drugs in order to reduce some of the associated movement side-effects. However, there is also a suggestion from animal experiments that the chronic administration of anticholinergics could cause tardive dyskinesia. OBJECTIVES: To determine whether the use or the withdrawal of anticholinergic drugs (benzhexol, benztropine, biperiden, orphenadrine, procyclidine, scopolamine, or trihexylphenidyl) are clinically effective for the treatment of people with both antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illnesses. SEARCH METHODS: We retrieved 712 references from searching the Cochrane Schizophrenia Group's Study-Based Register of Trials including the registries of clinical trials (16 July 2015 and 26 April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included reports identified in the search if they were controlled trials dealing with people with antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illness who had been randomly allocated to (a) anticholinergic medication versus placebo (or no intervention), (b) anticholinergic medication versus any other intervention for the treatment of tardive dyskinesia, or (c) withdrawal of anticholinergic medication versus continuation of anticholinergic medication. DATA COLLECTION AND ANALYSIS: We independently extracted data from included trials and we estimated risk ratios (RR) with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The previous version of this review included no trials. We identified two trials that could be included from the 2015 and 2017 searches. They randomised 30 in- and outpatients with schizophrenia in the USA and Germany. Overall, the risk of bias was unclear, mainly due to poor reporting: allocation concealment was not described; generation of the sequence was not explicit; studies were not clearly blinded; and outcome data were not fully reported.Findings were sparse. One study reported on the primary outcomes and found that significantly more participants allocated to procyclidine (anticholinergic) had not improved to a clinically important extent compared with those allocated to isocarboxazid (MAO-inhibitor) after 40 weeks' treatment (1 RCT, n = 20; RR 4.20, 95% CI 1.40 to 12.58; very low quality evidence); that there was no evidence of a difference in the incidence of any adverse effects (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence); or acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence). The other trial compared anticholinergic withdrawal with anticholinergic continuation and found no evidence of a difference in the incidence of acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 10; RR 2.14, 95% CI 0.11 to 42.52; very low quality evidence).No trials reported on social confidence, social inclusion, social networks, or personalised quality of life - outcomes designated important to patients. No studies comparing either i. anticholinergics with placebo or no treatment, or ii. studies of anticholinergic withdrawal, were found that reported on the primary outcome 'no clinically important improvement in TD symptoms and adverse events'. AUTHORS' CONCLUSIONS: Based on currently available evidence, no confident statement can be made about the effectiveness of anticholinergics to treat people with antipsychotic-induced tardive dyskinesia. The same applies for the withdrawal of such medications. Whether the withdrawal of anticholinergics may benefit people with antipsychotic-induced TD should be evaluated in a parallel-group, placebo-controlled randomised trial, with adequate sample size and at least 6 weeks of follow-up.

Actualización en enfermedad con cuerpos de Lewy / Update in Lewy body disease

La enfermedad con cuerpos de Lewy incluye 2 entidades que podrían ser consideradas variantes clínicas de una misma patología: la demencia con cuerpos de Lewy y la demencia en enfermedad de Parkinson. Con la finalidad de describir correctamente lo que sucede en la evolución de la enfermedad se divide el cuadro en etapa prodrómica y de demencia propiamente dicha. La primera está clínicamente representada por aquel período en el cual, si bien el paciente exhibe algunos signos y síntomas propios de la enfermedad, no reúne criterios de demencia. A pesar de ser difícil de definir y por carecerse todavía de contundentes datos clínicos y biomarcadores, se caracteriza principalmente por deterioro leve selectivo en función atencional ­ visuoespacial, trastorno del sueño REM y disautonomía‒. La segunda etapa está claramente caracterizada en los criterios de consenso del año 2005. Recientemente hemos publicado la validación de un instrumento llamado ALBA Screening Instrument, que permite diagnosticar con alta sensibilidad y especificidad la enfermedad aun en etapas tempranas y diferenciarla de otras patologías semejantes. La tomografía por emisión de positrones (PET) para transportador de dopamina es el procedimiento de referencia (gold standard) del diagnóstico. El tratamiento sintomático con anticolinesterásicos y neurolépticos atípicos favorece una buena evolución de la enfermedad y es fundamental tener en cuenta evitar medicamentos que pueden dañar gravemente a los pacientes como los anticolinérgicos y antipsicóticos típicos. Los avances en el diagnóstico y la difusión del impacto de esta enfermedad en la población contribuirán a generar mayores esfuerzos de investigación para hallar un tratamiento eficaz, preventivo o curativo o de ambas características. (AU)

Lewy body disease includes 2 entities that could be considered clinical variants of the same pathology: Dementia with Lewy bodies and Parkinson's disease Dementia. Two stages of the disease are described in this review, a prodromal stage and one of explicit dementia. The first one is clinically represented by that period in which, the patient exhibits some typical features of the disease, but not dementia criteria. Despite being difficult to define the prodromal stage and that strong clinical data and biomarkers are still lacking, there is evidence to characterize it mainly by mild selective impairment in attention and visuo-spatial function, REM sleep disorder and dysautonomia. The second stage is clearly characterized in the known consensus criteria of 2005. We have recently published the validation of an instrument called ALBA Screening Instrument which showed a high sensitivity and specificity for diagnosis of the disease even in the early stages. It´s useful to differentiate the disease from other similar pathologies. Positron Emission Tomography for dopamine transporter is the gold standard of diagnosis in life. Symptomatic treatment with anticholinesterases and atypical neuroleptics help patients in their evolution of the disease. Anticholinergics and typical antipsychotics are agents to avoid in the treatmen of the disease because can severely damage patients. Future advances in the diagnosis and dissemination of the knowledge of the disease will contribute to generate greater research efforts to find an effective preventive and / or curative treatment. (AU)

Flatulencia: una enfermedad inocua, ¿un tratamiento inocuo? / Flatulence: an innocuous condition, an innocuous treatment?

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Potential drug-drug interaction in Mexican patients with schizophrenia.

OBJECTIVE: The aim of this study was to observe potential drug-drug interactions in the medication of Mexican schizophrenic patients. METHODS: We performed a retrospective and cross-sectional study that was carried out in a psychiatric clinic. Only the prescriptions of patients with schizophrenia whose diagnoses were based on the DSM-IV instrument were included in this study. The Drug Interactions Checker software ( http://www.drugs.com/drug_interactions.html ) was used in this study to analyse potential drug-drug interactions. RESULTS: In total, 86 of 126 patients were at risk of potential drug-drug interactions. Haloperidol and biperiden was the most common drug pair of 232 pairs evaluated. In our study, 13.8% of drug-drug interaction showed a major level of severity, whereas in 83.2%, the interaction was moderate. Finally, central nervous system (CNS) depression and anticholinergic effect were the main possible effects of drug-drug interaction. CONCLUSIONS: Our results revealed a high number of patients with schizophrenia receiving two or more drugs. The potential drug-drug interactions observed in the Mexican population are consistent with the concomitant use of antipsychotics, benzodiazepines, and antidepressants prescribed in schizophrenia that could cause central nervous system (CNS) depression and anticholinergic effect. Drug-drug interaction must be considered when the patient with schizophrenia is medicated.

Stercoral perforation of the sigmoid colon. A case report and brief review of the literature.

Stercoral perforation of the colon due to fecaloma is a rare disease and less than 100 cases have been described in the literature. The disease mainly involves the rectosigmoid colon. The condition is correlated with longstanding decubitus, chronic constipation, abuse of laxatives and/or constipating agents (anticholinergics, neuroleptics, etc). We report a case of 82-year old woman who presented a covered colonic perforation due to fecaloma, related with a history of longstanding decubitus because of senile dementia, chronic constipation and use of anticholinergic drugs.

Adicción a biperideno y síndrome anticolinérgico: a propósito de un caso / Biperiden addiction and anticholinergic syndrome: a case report

Se reporta el caso de un paciente de 46 años de edad, con diagnóstico de esquizofrenia, en tratamiento desde los 26 años, con trifluoperazina y decanoato de flufenazina y uso concomitante de biperideno por los efectos adversos, que desarrolló dependencia al biperideno llegando a tomar, en la última semana antes de su hospitalización 14 mg diarios. El día de su ingreso tomó 20 mg, desarrollando un cuadro compatible con síndrome anticolinérgico, que se complicó con hiponatremia severa, acidosis metabólica con alcalosis respiratoria, leucocitosis, fiebre y elevación de la creatinfosfoquinasa, por lo que la impresión diagnóstica inicial fue de síndrome neuroléptico maligno. Su evolución fue favorable, saliendo de alta a la semana.

We report the case of a 46-year-old man diagnosed with schizophrenia, treated with trifluoperazine and fluphenazine decanoate since he was 26 years old, with concomitant use of biperiden for adverse effects. He developed dependence to biperiden, taking in the last week, prior to his hospitalization, 14 mg daily. The day of his admission he took 20 mg, developing an anticholinergic syndrome, complicated with severe hyponatremia, metabolic acidosis with respiratory alkalosis, leukocytosis, fever and creatine phosphokinase elevation, due to this he was initially focused as a neuroleptic malignant syndrome. He had a favorable outcome; being discharged one week later.

Comparison of the efficacy and impact on cognition of glycopyrrolate and biperiden for clozapine-induced sialorrhea in schizophrenic patients: a randomized, double-blind, crossover study.

BACKGROUND: Clozapine-induced sialorrhea (CIS) is a subjective distressing adverse effect and occurs in 31%-57% of schizophrenic patients receiving clozapine therapy. Current pharmacotherapy on CIS has focused on anticholinergic agents, even though they may impair cognitive function. Previous case reports have suggested the benefit of glycopyrrolate or biperiden in treating this condition, but no randomized controlled trial has provided evidence. The objective of our study was to evaluate the efficacy and impact on cognition of glycopyrrolate and biperiden treatments for schizophrenic patients suffering from CIS. METHODS: Patients who satisfied the inclusion criteria entered a 12-week, randomized, double-blind, crossover, fixed-dose trial. The study consisted of two 4-week crossover phases, which were separated by a 4-week washout period. Sialorrhea and global cognitive function were assessed by using a Drooling Rating Scale (DRS) and the Mini Mental State Examination (MMSE), respectively. RESULTS: Throughout the study, patients treated with glycopyrrolate or biperiden had significantly reduced DRS scores. Moreover, the DRS scores were significantly lower with glycopyrrolate treatment than with biperiden. In other respects, there were no significant differences in MMSE scores in patients treated with glycopyrrolate. However, we found a significant reduction in MMSE scores in patients treated with biperiden. CONCLUSION: We provide evidence, for the first time, of the efficacy of glycopyrrolate and biperiden in the treatment of CIS. Furthermore, glycopyrrolate displays less impact on cognitive function. Consequently, glycopyrrolate can become a valid option for treating CIS. Observations from our study serve as a springboard for additional large-scale prospective trials.

The antidepressant effects of anticholinergic drugs.

Acetylcholine is a neurotransmitter that is important for communication between neurons and muscle, is involved in direct neurotransmission in the autonomic parasympathetic nervous system, and has been implicated in cognitive processing, arousal, and attention in the brain. The cholinergic-adrenergic hypothesis of mood disorders states that a given affective state might represent a balance between central cholinergic and adrenergic neurotransmitter activity in those areas of the brain regulating moods. According to this hypothesis, depression would be the clinical manifestation of a state of cholinergic dominance, whereas mania would reflect adrenergic dominance. On the basis of this hypothesis, anticholinergic drugs have been investigated as potential treatments for depression, but study results have not shown consistent antidepressant effects. However, the dosage dependency of scopolamine's effect across different studies and the lack of antidepressant effects with other anticholinergic drugs suggest that a specific muscarinic receptor subtype might be most relevant to the potential antidepressant mechanism of action of anticholinergic drugs.