Rapid versus slow withdrawal of antiepileptic monotherapy in 2-year seizure-free adult patients with epilepsy (RASLOW) study: a pragmatic multicentre, prospective, randomized, controlled study.

Antiepileptic drug withdrawal may be an option for patients who have been seizure free for some years. The best withdrawal rate is questionable; in particular, it is unknown whether "rapid" withdrawal is associated with a higher risk of relapse as compared to "slow" withdrawal. We aim to establish if a slow or a rapid withdrawal schedule of antiepileptic monotherapy influences relapse rate in adult patients with focal or generalized epilepsy who have been seizure free for at least 2 years. This multicentre, prospective, randomized controlled study will enroll adult patients with focal or generalized epilepsy, who are seizure free on monotherapy. Patients will be randomized to a slow (160 days) or a rapid (60 days) schedule. Follow-up will last 1 year after randomization. The primary endpoint is the time to seizure relapse; secondary endpoints are compliance to the assigned schedule, occurrence of status epilepticus, of seizure-related injuries and mortality. A sample size of 350 patients has been planned. Univariate and multivariate analysis by Kaplan-Meier curves and Cox regression (primary endpoint) and by logistic regression (secondary endpoint) will be performed. The present study should contribute to better define the best withdrawal period for AED treatment in adult patients with epilepsy.

Effectiveness of risk minimization measures for cabergoline-induced cardiac valve fibrosis in clinical practice in Italy.

On June 2008, the European Medicines Agency (EMA) introduced changes to the Summary of Product Characteristics (SPC) for cabergoline and pergolide, to reduce the risk of cardiac valvulopathy in users of these drugs. To assess the effectiveness of EMA recommendations in Italian clinical practice, we retrospectively reviewed medical charts of patients with degenerative Parkinsonism treated with cabergoline in three large Italian clinics between January 2006 and June 2012. The prevalence and the severity of cardiac valve regurgitation were assessed in patients who stopped cabergoline therapy prior to June 2008 or continued therapy after that date. In addition, the proportion of patients undergoing echocardiographic examination in each cohort was evaluated. A total of 61 patients were available for evaluation. The proportion of patients who underwent a baseline echocardiographic examination increased from 64 % in the period before the 2008 SPC changes to 71 % among those who continued treatment after that date. However, only 18 and 29 % of patients underwent at least two echocardiographic examinations during the pre-SPC and cross-SPC change period, respectively. No severe cardiac valve regurgitation was documented in any of the study patients using cabergoline either prior or after 26th June 2008. Our findings show that the 2008 changes to the SPC resulted in an increase in physicians' awareness of cabergoline-induced valvulopathy risk in Italy. However, only a small percentage of patients underwent serial echocardiography. Further efforts are needed to achieve better compliance with the prescribing guidelines for cabergoline treated patients in clinical practice.

Indications of newer and older anti-epileptic drug use: findings from a southern Italian general practice setting from 2005-2011.

AIMS: The aim of the study was to analyze the prescribing pattern of both newer and older AEDs. METHODS: A population of almost 150 000 individuals registered with 123 general practitioners was included in this study. Patients who received at least one AED prescription over 2005-2011 were identified. The 1 year prevalence and cumulative incidence of AED use, by drug class and individual drug, were calculated over the study period. Potential predictors of starting therapy with newer AEDs were also investigated. RESULTS: The prevalence of use per 1000 inhabitants of older AEDs increased from 10.7 (95% CI10.1, 11.2) in 2005 to 13.0 (95% CI12.4, 13.6) in 2011, while the incidence remained stable. Newer AED incidence decreased from 9.4 (95% CI 8.9, 9.9) in 2005 to 7.0 (95% CI 6.6, 7.5) in 2011, with a peak of 15.5 (95% CI 14.8, 16.1) in 2006. Phenobarbital and valproic acid were the most commonly prescribed AEDs as starting therapy for epilepsy. Gabapentin and pregabalin accounted for most new pain-related prescriptions, while valproic acid and lamotrigine were increasingly used for mood disorders. Female gender (OR 1.36, 95% CI 1.20, 1.53), age ranging between 45-54 years (OR 1.39, 95% CI 1.16, 1.66) and pain as an indication (OR 16.7, 95% CI, 13.1, 21.2) were associated with newer AEDs starting therapy. CONCLUSIONS: Older AEDs were mainly used for epileptic and mood disorders, while newer drugs were preferred for neuropathic pain. Gender, age, indication of use and year of starting therapy influenced the choice of AED type. The decrease of newer AED use during 2007 is probably related to the restricted reimbursement criteria for gabapentin and pregabalin.

Generic Olanzapine Substitution in Patients With Schizophrenia: Assessment of Serum Concentrations and Therapeutic Response After Switching.

BACKGROUND: Several reports of loss of efficacy or adverse effects have been described after generic substitution of antipsychotics. To date, studies comparing serum drug levels in patients switched to generic antipsychotics in a standard clinical setting are lacking. The aim of this study was to investigate if switching to generic olanzapine in patients affected by schizophrenia is associated with differences in its serum concentrations and therapeutic response. METHODS: Preswitching and postswitching serum olanzapine concentrations were compared in schizophrenic outpatients who were switched from a chronic treatment with branded olanzapine to the same dose of its generic alternative. The Positive and Negative Syndrome Scale was concurrently administered to assess modifications in schizophrenia symptom control. RESULTS: A total of 25 patients (13 women and 12 men, mean age 41.2 ± 12.8 years) concluded the study. Mean olanzapine dose was 12.2 ± 5.4 mg/d. The mean olanzapine serum concentrations decreased from 27.7 ± 14.4 ng/mL during treatment with the branded formulation to 22.6 ± 12.3 ng/mL after switching to the generic formulation (P < 0.01). The log-transformed ratio of generic/brand-name olanzapine serum concentration at steady state was 0.81 (90% confidence interval: 0.72-0.91). The total Positive and Negative Syndrome Scale scores did not significantly change after switching from branded to generic formulation (49.6 ± 8.3 versus 48.6 ± 9.5, P = 0.777). No patient exhibited disease relapse or required dose adjustment after switching. CONCLUSIONS: Significantly lower serum olanzapine concentrations were found after switching from branded to generic olanzapine. Although these modifications did not significantly impair schizophrenia symptoms control, it cannot be excluded that a longer exposure to lower olanzapine serum concentrations may result in relapse of schizophrenic symptoms. Generic substitution should be considered as an indication for therapeutic drug monitoring in psychiatry.

Minor and repetitive head injury.

Traumatic brain injury (TBI) is the leading cause of death and disability in the young, active population and expected to be the third leading cause of death in the whole world until 2020. The disease is frequently referred to as the silent epidemic, and many authors highlight the "unmet medical need" associated with TBI.The term traumatically evoked brain injury covers a heterogeneous group ranging from mild/minor/minimal to severe/non-salvageable damages. Severe TBI has long been recognized to be a major socioeconomical health-care issue as saving young lives and sometimes entirely restituting health with a timely intervention can indeed be extremely cost efficient.Recently it has been recognized that mild or minor TBI should be considered similarly important because of the magnitude of the patient population affected. Other reasons behind this recognition are the association of mild head injury with transient cognitive disturbances as well as long-term sequelae primarily linked to repeat (sport-related) injuries.The incidence of TBI in developed countries can be as high as 2-300/100,000 inhabitants; however, if we consider the injury pyramid, it turns out that severe and moderate TBI represents only 25-30 % of all cases, while the overwhelming majority of TBI cases consists of mild head injury. On top of that, or at the base of the pyramid, are the cases that never show up at the ER - the unreported injuries.Special attention is turned to mild TBI as in recent military conflicts it is recognized as "signature injury."This chapter aims to summarize the most important features of mild and repetitive traumatic brain injury providing definitions, stratifications, and triage options while also focusing on contemporary knowledge gathered by imaging and biomarker research.Mild traumatic brain injury is an enigmatic lesion; the classification, significance, and its consequences are all far less defined and explored than in more severe forms of brain injury.Understanding the pathobiology and pathomechanisms may aid a more targeted approach in triage as well as selection of cases with possible late complications while also identifying the target patient population where preventive measures and therapeutic tools should be applied in an attempt to avoid secondary brain injury and late complications.

The challenge of mild traumatic brain injury: role of biochemical markers in diagnosis of brain damage.

During the past decade there has been an increasing recognition of the incidence of mild traumatic brain injury (mTBI) and a better understanding of the subtle neurological and cognitive deficits that may result from it. A substantial, albeit suboptimal, effort has been made to define diagnostic criteria for mTBI and improve diagnostic accuracy. Thus, biomarkers that can accurately and objectively detect brain injury after mTBI and, ideally, aid in clinical management are needed. In this review, we discuss the current research on serum biomarkers for mTBI including their rationale and diagnostic performances. Sensitive and specific biomarkers reflecting brain injury can provide important information regarding TBI pathophysiology and serve as candidate markers for predicting abnormal computed tomography findings and/or the development of residual deficits in patients who sustain an mTBI. We also outline the roles of biomarkers in settings of specific interest including pediatric TBI, sports concussions and military injuries, and provide perspectives on the validation of such markers for use in the clinic. Finally, emerging proteomics-based strategies for identifying novel markers will be discussed.

Changes in the prescribing pattern of antidepressant drugs in elderly patients: an Italian, nationwide, population-based study.

BACKGROUND: Despite the high use of antidepressants (ADs) among the elderly, there is limited information about the prescribing pattern of these drugs in the Italian elderly population. The aim of this study was to analyze the trend in the use of ADs in the Italian elderly patients in the years 2003-2009, and specifically, to evaluate rates and predictors of AD treatment discontinuation in depressed older patients. METHODS: The nationwide general practice Health Search Database (HSD) was used to identify AD users aged 65 years old and over from 2003 to 2009. ADs were categorized as (1) selective serotonin reuptake inhibitors (SSRIs); (2) serotonin-norepinephrine reuptake inhibitors (SNRIs); (3) tricyclic antidepressants (TCAs); (4) noradrenergic and specific serotonergic antidepressants (NaSSAs); and (5) other ADs. Incidence and prevalence of AD use per 1,000 inhabitants was calculated by drug class and single compound. We also measured rates and predictors of AD discontinuation (i.e., treatment gap ≥ 60 days) during the first year of therapy. RESULTS: Overall, 39,557 AD users ≥65 years (17 % of the total HSD elderly population) were included in the study. SSRIs were increasingly and most frequently prescribed ADs (102.7-195.3 per 1,000 over seven years). The most common indications for AD use were depression and anxiety. Overall, 14 % of AD users continued their AD medication without treatment gaps, 27 % were intermittent AD users and 58 % discontinued their ADs during the first year of follow-up. Specific AD classes such as TCAs and 'other ADs were found to be predictors of discontinuation. In depressed patients, the use of NaSSas, TCAs and 'other ADs as well the concomitant use of >5 drugs (other than ADs) and living in Southern Italy were more likely to predict discontinuation. CONCLUSION: ADs, especially SSRIs, are widely and increasingly prescribed in elderly Italian patients in recent years. The observed high AD discontinuation rates are likely to impact the achievement of a therapeutic endpoint in depressed patients. Patients who are at high risk of AD discontinuation such as those receiving multi-drug therapy or living in Southern Italy should be monitored more closely to improve benefits of AD treatments.

Ketotifen-induced nocturnal bruxism.

UNLABELLED: Nocturnal bruxism is a common oromandibular movement disorder highly prevalent in children, but its pathophysiological mechanism has not been fully explained. Iatrogenic sleep bruxism has been described following treatment with several psychotropic medications. However, no case of antihistamine-induced bruxism has been reported to date. Herein, we describe a 4-year-old child who experienced nocturnal bruxism during treatment for bronchospasm and rhinitis with the antihistamine ketotifen. Drug rechallenge was also performed. CONCLUSION: The present case adds useful information to our knowledge of bruxism. Complex and poorly understood interactions between multiple central nervous system neurotransmitters, such as histamine, serotonin, and dopamine, are involved.

Levetiracetam-associated loss of libido and anhedonia.

The relationship between the older antiepileptic drugs (AEDs) and sexual dysfunction has long been known and it is likely to be related to sexual hormonal changes. Instead, rare reports on sexual disorders related to new AEDs suggest the possibility of complex and poorly understood mechanisms, mainly involving central nervous system neurotransmitters such as glutamate, serotonin, and dopamine. Herein, we describe two young men with epilepsy who experienced severe loss of libido and anhedonia after levetiracetam intake.

Single tonic-clonic seizure after energy drink abuse.

Energy drinks are soft beverages especially marketed for adolescents in order to obtain a heightened sense of awareness. Concerns about the safety of these drinks are raised based on our observation of potentially serious adverse effects. Caffeine and taurine are psychoactive agents highly present in energy drinks, which may lead to modification of neurotransmission. We herein report the case of a 20-year-old man presenting with a generalized epileptic seizure after energy drink consumption.

A pilot open-label trial of zonisamide in Unverricht-Lundborg disease.

Action myoclonus frequently remains the primary cause of disability in Unverricht-Lundborg disease (EPM1) patients. Pharmacological treatment of myoclonus in these patients continues to be challenging; indeed conventional AEDs may be poorly effective in monotherapy or even in combination. We carried out a pilot, open-label trial of add-on zonisamide (ZNS) in patients with EPM1. Twelve EPM1 patients with epilepsy and action myoclonus were included in the study. Oral ZNS was gradually titrated until the target dose of 6 mg/Kg/day. Unified Myoclonus Rating Scale was obtained in each subject before and after ZNS add-on. A significant reduction of myoclonus severity was reached after ZNS introduction. ZNS was generally well tolerated and only two patients withdrew due to mild adverse effects. Our trial suggests that ZNS may be a valuable therapeutic option in EPM1 patients.

Recurrent occipital seizures misdiagnosed as status migrainosus.

Periictal headache is commonly reported in patients with epilepsy and often exhibits migraine features. Misdiagnosis is frequent since visual seizures may often be misinterpreted as visual aura of migraine. We herein describe a 35-year-old woman with recurrent occipital seizures, clinically presenting with intractable headache. EEG monitoring was crucial in order to reach the correct diagnosis.

Artificial intelligence for reduced dose 18F-FDG PET examinations: a real-world deployment through a standardized framework and business case assessment.

BACKGROUND: To determine whether artificial intelligence (AI) processed PET/CT images of reduced by one-third of 18-F-FDG activity compared to the standard injected dose, were non-inferior to native scans and if so to assess the potential impact of commercialization. MATERIALS AND METHODS: SubtlePET™ AI was introduced in a PET/CT center in Italy. Eligible patients referred for 18F-FDG PET/CT were prospectively enrolled. Administered 18F-FDG was reduced to two-thirds of standard dose. Patients underwent one low-dose CT and two sequential PET scans; "PET-processed" with reduced dose and standard acquisition time, and "PET-native" with an elapsed time to simulate standard acquisition time and dose. PET-processed images were reconstructed using SubtlePET™. PET-native images were defined as the standard of reference. The datasets were anonymized and independently evaluated in random order by four blinded readers. The evaluation included subjective image quality (IQ) assessment, lesion detectability, and assessment of business benefits. RESULTS: From February to April 2020, 61 patients were prospectively enrolled. Subjective IQ was not significantly different between datasets (4.62±0.23, p=0.237) for all scanner models, with "almost perfect" inter-reader agreement. There was no significant difference between datasets in lesions' detectability, target lesion mean SUVmax value, and liver mean SUVmean value (182.75/181.75 [SD:0.71], 9.8/11.4 [SD:1.13], 2.1/1.9 [SD:0.14] respectively). No false-positive lesions were reported in PET-processed examinations. Agreed SubtlePET™ price per examination was 15-20% of FDG savings. CONCLUSION: This is the first real-world study to demonstrate the non-inferiority of AI processed 18F-FDG PET/CT examinations obtained with 66% standard dose and a methodology to define the AI solution price.

Does lacosamide aggravate Lennox-Gastaut syndrome? Report on three consecutive cases.

Lennox-Gastaut syndrome is an intractable epileptic encephalopathy, with most patients experiencing daily seizures despite therapy with multiple antiepileptic drugs. New treatments need to be tested to define their efficacy in this syndrome. Lacosamide is a new antiepileptic drug recently approved for the treatment of partial-onset seizures. We describe three patients with Lennox-Gastaut syndrome resistant to conventional antiepileptic drugs whose seizures were aggravated by lacosamide.

Description of a family with a novel progressive myoclonus epilepsy and cognitive impairment.

We report a family of Algerian origin presenting an unusual, severe form of progressive myoclonus epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment, with probable autosomal recessive inheritance. Disease onset was between 6 and 16 years of age. The diagnosis of Unverricht-Lundborg disease and all other known causes of progressive myoclonus epilepsies were excluded by specific laboratory tests and molecular analysis.

Topiramate-induced erectile dysfunction.

Described here is a case of topiramate-induced reversible erectile dysfunction in which possible pathogenetic mechanisms were excluded by use of appropriate psychological, neurophysiological, ultrasound, and laboratory tests.

Neuropsychological findings in patients with Unverricht-Lundborg disease.

The aims of this study were to clarify if patients with Unverricht-Lundborg disease (ULD) have adequate cognitive functioning and to delineate their neuropsychological profile. We evaluated 20 patients with ULD and 20 healthy, matched controls. Mean age of the patients was 35 years, and mean duration of disease, 22 years. Patients underwent a neuropsychological battery exploring intelligence, executive functions, visuospatial and verbal memory, depression, and anxiety. Eleven of 20 subjects with ULD had mild to moderate cognitive impairment. Compared with controls, patients with ULD had lower scores on all short-term memory and executive function tasks. Linear regression analysis disclosed significant associations between impaired performance on some memory tests and duration of disease and between severity of myoclonus and performance on most executive function tests. In conclusion, most patients with ULD seem to be impaired with respect to cognitive abilities. Longitudinal prospective studies are needed to confirm and further expand our findings.