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Reversible Valproate Induced Pisa Syndrome and Parkinsonism in a Neuro-Oncology Patient with Depression and Epilepsy

Authors:
  • North West Tuscany Local Health Unit Company - IRCCS Ca' Granda Foundation, Maggiore Policlinico Hospital, Psychiatric Clinic University of Milan

Abstract

Neurological and psychiatric conditions frequently overlap in neuro-oncology. This overlapping negatively affects patients’ quality of life and decreases the ability of providers to manage specific symptoms by therapy modulation, especially when psychopharmacotherapy needs to be prescribed. We describe here a patient with recurrent brain tumor, symptomatic epilepsy and depression who developed Pisa syndrome and parkinsonism after several months of valproic acid use. An accurate recognition of symptoms and treatment side effect allowed an appropriate clinical approach so as to rapidly improve both movement disorder and depression without increasing the risk of developing seizure. This has improved the autonomy and quality of life in a patient with poor prognosis.
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New-onset movement disorders have been frequently reported in association with the use of antiseizure medications (ASMs). The frequency of specific motor manifestations and the spectrum of their semiology for various ASMs have not been well characterized. We carried out a systematic review of literature and conducted a search on CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and Scopus from inception to April 2021. We compiled the data for all currently available ASMs using the conventional terminology of movement disorders. Among 5123 manuscripts identified by the search, 437 met the inclusion criteria. The largest number of reports of abnormal movements were in association with phenobarbital, valproic acid, lacosamide, and perampanel, and predominantly included tremor and ataxia. The majority of attempted interventions for all agents were discontinuation of the offending drug or dose reduction which led to the resolution of symptoms in most patients. Familiarity with the movement disorder phenomenology previously encountered in relation with specific ASMs facilitates early recognition of adverse effects and timely institution of targeted interventions.
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Valproate (VPA) was first synthesized in 1882, but it was only in the early 1960s that its anticonvulsant properties were discovered. The aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of VPA-associated movement disorder (MD). Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 138 reports containing 362 cases of subjects who developed a MD secondary to VPA were reported. The MD identified were parkinsonism (PKN) (252), myoclonus (MCL) (54), dystonia (DTN) (17), dyskinesia (DKN) (16), stutters (4), tics (3), akathisia (AKT) (1). In the not clearly defined group, 15 extrapyramidal symptoms, 3 AKT, 2 DTN, 1 rigidity, 1 unstable gait were assessed. The mean and median age was 55.8 (SD: 16.58) and 61 years (range: 4–87 years). The most common VPA-indication was epilepsy, and 51.36% were males. The mean and median time from the VPA start to the MD onset was 32.75 (SD: 30.05) and 21.15 months (range: 1 day – 20 years). The mean and median time from the VPA withdrawal until the MD recovery was 2.89 (SD: 2.79) and 3 months (1 day – 12 months). The most common management was drug withdrawal. A complete recovery was obtained in 80.61%. VPA-associated MD was extensively reported in the literature. PKN was the most well-described. Future studies need to clearly report the clinical history of the patient, considering the full investigation of other adverse events during their entire life.
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Background: Depressive disorders are the most common psychiatric comorbidity in patients with epilepsy, affecting around one-third, with a significant negative impact on quality of life. There is concern that patients may not be receiving appropriate treatment for their depression because of uncertainty regarding which antidepressant or class works best and the perceived risk of exacerbating seizures. This review aims to address these issues and inform clinical practice and future research. Objectives: We aimed to review and synthesise evidence from randomised controlled trials of antidepressants and prospective non-randomised studies of antidepressants used for treating depression in patients with epilepsy. The primary objectives were to evaluate the efficacy and safety of antidepressants in treating depressive symptoms and the effect on seizure recurrence. Search methods: We conducted a search of the following databases: the Cochrane Epilepsy Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 5), MEDLINE (Ovid), SCOPUS, PsycINFO, www.clinicaltrials.gov and conference proceedings, including studies published up to 31 May 2014. There were no language restrictions. Selection criteria: We included randomised controlled trials (RCTs) and prospective non-randomised cohort controlled and uncontrolled studies investigating children or adults with epilepsy treated with an antidepressant for depressive symptoms. The intervention group consisted of patients receiving an antidepressant drug in addition to an existing antiepileptic drug regimen. The control group(s) consisted of patients receiving a placebo, comparative antidepressant, psychotherapy or no treatment in addition to an existing antiepileptic drug regimen. Data collection and analysis: We extracted data on trial design factors, patient demographics and outcomes for each study. The primary outcomes were changes in depression scores (proportion with a greater than 50% improvement or mean difference) and change in seizure frequency (mean difference or proportion with a seizure recurrence or episode of status epilepticus, or both). Secondary outcomes included the number of patients withdrawing from the study and reasons for withdrawal, as well as any adverse events. Two authors undertook data extraction separately for each included study. We then cross-checked the data extraction. We assessed risk of bias using a version of the extended Cochrane Collaboration tool for assessing risk of bias in both randomised and non-randomised studies. We presented binary outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). We presented continuous outcomes as standardised mean differences (SMDs) with 95% CIs, and mean differences (MDs) with 95% CIs. If possible we intended to use meta-regression techniques to investigate possible sources of heterogeneity however this was not possible due to lack of data. Main results: We included in the review eight studies (three RCTs and five prospective cohort studies) including 471 patients with epilepsy treated with an antidepressant. The RCTs were all single-centre studies comparing an antidepressant versus active control, placebo or no treatment. The five non-randomised prospective cohort studies reported on outcomes mainly in patients with partial epilepsy treated for depression with a selective serotonin reuptake inhibitor (SSRI). We rated all the RCTs and one prospective cohort study as having unclear risk of bias. We rated the four other prospective cohort studies as having high risk of bias. We were unable to perform any meta-analysis for the proportion with a greater than 50% improvement in depression scores because the studies reported on different treatment comparisons. The results are presented descriptively and show a varied responder rate of between 24% and 97%, depending on the antidepressant given. For the mean difference in depression score we were able to perform a limited meta-analysis of two prospective cohort studies of citalopram, including a total of 88 patients. This gave low quality evidence for the effect estimate of 1.17 (95% CI 0.96 to 1.38) in depression scores. Seizure frequency data were not reported in any RCTs and we were unable to perform any meta-analysis for prospective cohort studies due to the different treatment comparisons. The results are presented descriptively and show that treatment in three studies with a selective serotonin reuptake inhibitor did not significantly increase seizure frequency. Patients given an antidepressant were more likely to withdraw due to adverse events than inefficacy. Reported adverse events for SSRIs included nausea, dizziness, sedation, gastrointestinal disturbance and sexual dysfunction. Across three comparisons we rated the evidence as moderate quality due to the small sizes of the contributing studies and only one study each contributing to the comparisons. We rated the evidence for the final comparison as low quality as there was concern over the study methods in the two contributing studies. Authors' conclusions: Existing evidence on the effectiveness of antidepressants in treating depressive symptoms associated with epilepsy is very limited. Only one small RCT demonstrated a statistically significant effect of venlafaxine on depressive symptoms. We have no high quality evidence to inform the choice of antidepressant drug or class of drug in treating depression in people with epilepsy. This review provides low quality evidence of safety in terms of seizure exacerbation with SSRIs, but there are no available comparative data on antidepressant classes and safety in relation to seizures. There are currently no comparative data on antidepressants and psychotherapy in treating depression in epilepsy, although psychotherapy could be considered in patients unwilling to take antidepressants or where there are unacceptable side effects. Further comparative clinical trials of antidepressants and psychotherapy in large cohorts of patients with epilepsy and depression are required to better inform treatment policy in the future.
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