Management of psychogenic non-epileptic seizures: a multidisciplinary approach.

The International League against Epilepsy (ILAE) proposed a diagnostic scheme for psychogenic non-epileptic seizure (PNES). The debate on ethical aspects of the diagnostic procedures is ongoing, the treatment is not standardized and management might differ according to age group. The objective was to reach an expert and stakeholder consensus on PNES management. A board comprising adult and child neurologists, neuropsychologists, psychiatrists, pharmacologists, experts in forensic medicine and bioethics as well as patients' representatives was formed. The board chose five main topics regarding PNES: diagnosis; ethical issues; psychiatric comorbidities; psychological treatment; and pharmacological treatment. After a systematic review of the literature, the board met in a consensus conference in Catanzaro (Italy). Further consultations using a model of Delphi panel were held. The global level of evidence for all topics was low. Even though most questions were formulated separately for children/adolescents and adults, no major age-related differences emerged. The board established that the approach to PNES diagnosis should comply with ILAE recommendations. Seizure induction was considered ethical, preferring the least invasive techniques. The board recommended looking carefully for mood disturbances, personality disorders and psychic trauma in persons with PNES and considering cognitive-behavioural therapy as a first-line psychological approach and pharmacological treatment to manage comorbid conditions, namely anxiety and depression. Psychogenic non-epileptic seizure management should be multidisciplinary. High-quality long-term studies are needed to standardize PNES management.

Brand-to-generic levetiracetam switching: a 4-year prospective observational real-life study.

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether switching from branded levetiracetam (Keppra® ) to a levetiracetam generic equivalent product (Matever® ) in an epilepsy cohort could provide adequate results in terms of seizure control and tolerability. METHODS: To be eligible for the study, patients had to have been taking Keppra® as monotherapy or polytherapy for at least 6 months. Between March 2013 and April 2017, patients were invited to switch to Matever® as part of their follow-up. We evaluated the number of seizures per month, drug-related adverse events and electroencephalography before the switch (T0, baseline) and 6 months after switching (T1). Furthermore, we reported the long-term follow-up of patients who continued to use Matever® after the end of the study, considering the most recent visit for each patient (T2). RESULTS: A total of 55 patients refused the switch. Among the remaining 125 patients, 59 (47%) were treated using Keppra® as monotherapy and 66 (53%) were on Keppra® as polytherapy. All 125 patients were subjected to switching from Keppra® to Matever® . Comparing patients before (T0) and after (T1) switching, we found no statistically significant differences in terms of seizure frequency and occurrence of adverse effects. There were no significant differences (number of seizures/month and drug-related adverse events) between patients treated with Matever® as monotherapy and patients who refused the switch and continued to use Keppra® as monotherapy for a long-term follow-up of 48 months. Electroencephalography findings were also unchanged. CONCLUSION: In our sample, brand-to-generic levetiracetam switching was effective and safe in both monotherapy and polytherapy regardless of the epilepsy syndrome.

Kaposi's sarcoma after T-cell costimulation blockade with abatacept in rheumatoid arthritis: a case report.

WHAT IS KNOWN AND OBJECTIVE: Kaposi's sarcoma (KS) is a malignant neoplasm caused by HHV-8, a pathogen that leads to endothelial cell transformation when host defences are weakened. CASE DESCRIPTION: Here we report the first case of KS during treatment with abatacept, a biologic agent targeting T-cell costimulation. The patient was a 64-year-old female with rheumatoid arthritis who developed multiple firm, purple-reddish nodules on the dorsal aspect of the right hand. Histological examination confirmed KS. WHAT IS NEW AND CONCLUSION: Although a direct causal relationship between KS development and abatacept treatment cannot be proved, we hypothesize a role for costimulation blockade.

The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial.

OBJECTIVE: We investigated the effects of celecoxib, diclofenac, and ibuprofen on the disease-specific quality of life, synovial fluid cytokines and signal transduction pathways in symptomatic knee osteoarthritis (OA). DESIGN: Ninety patients scheduled for a total knee arthroplasty (TKA) were randomized to six groups that were treated with low and high dosages of celecoxib, diclofenac or ibuprofen. At the time of the first admission (T0) and at surgery (T1 = 14 days after beginning of the nonsteroidal anti-inflammatory drugs (NSAIDs)), samples of knee synovial fluid were obtained from each patient for analysis. During the surgery the synovial tissue was harvested from the knee of patients. The Western Ontario and McMaster universities (WOMAC) score was used to evaluate the patient disease-specific quality of life at T0 and T1. Microarray tests performed at T0 and T1 were used to evaluate the effects of NSAIDs on Tumor necrosis factor (TNF)-alpha, Interleukin-6 (IL-6), IL8 and Vascular endothelial growth factor (VEGF) concentration in the synovial fluid. Western blot assays evaluated the effects of NSAIDs on MAP kinase (MAPK) signal transduction pathway in the synovial membrane. RESULTS: NSAID treatment induced a statistically significant improvement in the WOMAC score and a statistically significant decrease in the IL-6, VEGF and TNF-alpha concentration in the synovial fluid. Higher dosages of NSAIDs provided a greater improvement in the disease-specific quality of life of patients and lower concentrations of pro-inflammatory cytokines in the synovial fluid. Inhibition of MAPKs was noted after NSAID treatment. CONCLUSION: Short-term NSAID treatment improves the patient disease-specific quality of life with a parallel decrease in pro-inflammatory synovial fluid cytokine levels in knee OA. Signal transduction pathways may be involved in regulating the anti-inflammatory effects of NSAIDs. ClinicalTrial.gov: NCT01860833.

Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis.

BACKGROUND AND OBJECTIVE: Ibuprofen is a non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitor used to treat pain conditions and inflammation. Limited data have been published concerning the pharmacokinetic profile and clinical effects of ibuprofen in patients with osteoarthritis (OA). In this paper we compared the pharmacokinetic and clinical profile of ibuprofen (at a dosage of from 800 mg/day to 1800 mg/day) administered in patients affected by severe knee OA. METHODS: Ibuprofen was administered for 7 days to patients who were scheduled to undergo knee arthroplasty due to OA. After 7 days, the ibuprofen concentration in plasma and synovial fluid was measured through both high-performance liquid chromatography (HPLC)-UV and gas chromatography-mass spectroscopy (GC/MS), while clinical effects were evaluated through both visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC) scores. The Naranjo scale and the WHO causality assessment scale were used for estimating the probability of adverse drug reactions (ADRs). The severity of ADRs was assessed by the modified Hartwig and Siegel scale. RESULTS: Ibuprofen showed a dose-dependent diffusion in both plasma and synovial fluid, which was related to the reduction of pain intensity and improvement of health status, without the development of ADRs. CONCLUSION: Ibuprofen at higher dosages can be expected to provide better control of OA symptoms as a result of higher tissue distribution.

A case of adverse drug reaction induced by dispensing error.

OBJECTIVE: To report about a case of acute renal failure due to absence of communication between physician and patient. CASE SUMMARY: A 78 year old man with human immunodeficiency virus (HIV) accessed our hospital and was brought to our attention in August 2011 for severe renal failure. Clinical history revealed that he had been taking highly active antiretroviral therapy with lamivudine/abacavir and fosamprenavir since 2006. In April 2011 due to an augmentation in creatinine plasma levels, a reduction in lamivudine dosage to 100 mg/day and the prescription of abacavir 300 mg/day became necessary. Unfortunately, the patient took both lamivudine and abacavir therefore the association of the two medications (lamivudine/abacavir) lead to asthenia and acute renal failure within a few days. CONCLUSIONS: This case emphasizes the importance about how physicians must pay very careful attention during drug prescription, most particularly, as far as elderly patients are concerned. In fact, communication improvement between physicians and patients can prevent increase of adverse drug reactions related to drug dispensing, with consequential reduction of costs in the healthcare system.

Protective activity of α-lactoalbumin (ALAC), a whey protein rich in tryptophan, in rodent models of epileptogenesis.

The aim of the present work was to evaluate the potential activity of α-lactoalbumin (ALAC), a whey protein rich in tryptophan (TRP), in two rodent models of epileptogenesis and we explored a possible mechanism of action. The effects of ALAC (oral administration) were tested in two standard epileptogenesis protocols, namely the pilocarpine post-status epilepticus model in mice and the WAG/Rij rat model of absence epileptogenesis. The mechanism of action was investigated by assessing the effects of ALAC in two seizure models (N-methyl-d-aspartate (NMDA) and pentylenetetrazol (PTZ) -induced seizures) including d-serine co-administration. ALAC showed protecting properties in both models of epileptogenesis, reducing spontaneous seizures development. In acute seizure models, ALAC possessed antiseizure properties at some of the doses tested (PTZ-seizures: >50% seizure-reduction between 250 and 375 mg/kg; NMDA-seizures: >90% reduction at 250 and 500 mg/kg). When a dose of d-serine ineffective per se was co-administered with ALAC, ALAC effects were significantly reversed in both models. ALAC is active in experimental models of seizure and epileptogenesis. Its effects are likely mediated by the inhibition of NMDA receptors at the glycine binding site, possibly secondarily to the in vivo enzymatic conversion of ALAC-generated tryptophan to kynurenic acid. However, other mechanisms of action contributing to ALAC effects cannot be excluded.

Efficacy and safety of bevacizumab in glioblastomas.

Glioblastoma multiforme (GBM) is a common and malignant primary brain tumor arising from glial precursors the survival of which is estimated to be about 14 months after diagnosis despite current standard care with radiotherapy, surgery, and chemotherapies. Therapeutic approaches were greatly improved in the last years; however, GBM still represents the most lethal subtype of glioma. Actually, it has been estimated that only about 3.4% of patients will survive at the most five years when obtaining the best outcome from treatment; however, this depends on tumor resistance, which is generally related to repairing radiation injury, and self- improving cell growth repair and survival. All GBMs recur after initial therapy, limiting patients � survival at 20-25% within 1 year after diagnosis of recurrent disease. Moreover, for recurrent GBM response rates are less than 10% (ranging from 5% to 9%), and progression free survival at 6-month (PFS-6) rates ranges between 9% and 28% (median 15%). The development of targeted therapy based on tumor vascular blockade led to the approval of bevacizumab for recurrent or progressive glioblastoma, since it was proven that this offers a new opportunity for patients suffering from this malignancy. Bevacizumab is a recombinant antivascular monoclonal antibody binding to circulating Vascular Endothelial Growth Factor (VEGF) preventing this cytokine from reaching its receptors (VEGFR1 and VEGFR2) on endothelium, resulting in an inhibition of cells proliferation and vessels sprouting. The aim of this review is to address bevacizumab mode of action in malignant gliomas and provide a summary on currently available data on efficacy and safety.

Antiepileptic drugs for central post-stroke pain management.

Antiepileptic drugs (AEDs) are commonly prescribed for a wide range of disorders other than epilepsy, including both neurological and psychiatric disorders. AEDs play also a role in pharmacological management of neuropathic pain. Central post-stroke pain (CPSP) is a disabling morbidity occurring in 35% of patients with stroke. The pathophysiology of CPSP is not well known but central disinhibition with increased neuronal excitability has been suggested. AEDs include many different drugs acting on pain through several mechanisms, such as reduction of neuronal hyperexcitability. To our knowledge conclusive evidence has not been published yet. The aim of this review is to delineate efficacy and safety of AEDs in CPSP.

Long-term immunogenicity of hepatitis B vaccination in children and adolescents in a southern Italian town.

PURPOSE: Universal anti-hepatitis B vaccination of infants and of 12-year-old children became mandatory in Italy in 1991. The purpose of this study was to evaluate the persistence of anti-hepatitis B surface (HBs) antibodies several years after a primary course of vaccination. METHODS: In 2010, anti-HBs titers were measured in all subjects aged between 5 and 25 years residing in a southern Italian town. Individuals with an anti-hepatitis B antibody concentration of 10 IU/ml or more were considered to be protected. RESULTS: Of the 671 subjects evaluated, 149 (30%) lacked protective antibodies. Fifty-three (29.4%) of the subjects had been vaccinated ≤10 years earlier and 96 (30.3%) more than 10 years earlier (P = not significant). Subjects vaccinated in infancy were more likely to lack protective anti-HBs antibodies than subjects vaccinated at 12 years of age, regardless of the years elapsed since immunization. CONCLUSIONS: Most subjects maintained protective antibodies for a considerable number of years after vaccination. Vaccination in adolescence results in more prolonged immunogenicity than vaccination in infancy.

Use of antiepileptic drugs for hyperkinetic movement disorders.

Many studies investigated the use of antiepileptic drugs (AEDs) in several neurological diseases other than epilepsy. These neurological disorders, usually, involve neuronal excitability through the modulating of ion channels, receptors and intracellular signaling pathways, and are the targets of the AEDs. This article provides a review of the clinical efficacy of both conventional and newer AEDs in hyperkinetic movement disorders. Some of these indications for AEDs have been established, while others are under investigation. The modulation of GABAergic transmission may explain the neuronal hyper-excitability that underlies some forms of hyperkinetic movement disorders. So, AEDs able to increase GABAergic neurotransmission may play a role in hyperkinetic movement disorders treatment. Therefore, AEDs could represent a useful therapeutic option in the management of hyperkinetic movement disorders where the available treatments are ineffective.

Valproate-induced delirium in a demented patient.

In this study we report a case of valproate-induced delirium in a patient affected with Alzheimer's disease (AD). A 75-year-old woman with AD presented moderate cognitive impairment associated to behavioral disorders, characterized by aggression, agitation, severe insomnia. She was treated with galantamine, promazine, acetylsalicylic acid and pantoprazole. Since behavioral disorders worsened more and more, home neurological consultation was asked. The neurologist prescribed a mood stabilizer, sodium valproate 500 mg daily for the first week and then, twice a day and stopped promazine. After an apparent initial benefit, about 16 days later, patient suddenly developed hyperactive delirium. It was characterized by worsening of insomnia and agitation, severe confusion, delusions, visual hallucinations alternated to sedation. She became progressively unable to walk and completely dependent in daily living activities. An urgent geriatric consultation was performed at patient's home; physical examination showed mild dehydration, normal blood pressure. Oxygen saturation and electrocardiogram were normal. Sodium valproate was immediately stopped and rehydration was performed. The patient was admitted to a Geriatric Unit, where organic and metabolic damages were excluded. During the hospital stay the patient was agitated, aggressive, confused; intramuscular haloperidol 5mg and saline intravenous infusion 1500 cc daily were performed, they were partly successful. Three days after she was discharged and continued treatment with oral haloperidol 5mg daily. One week later the patient recovered and she is at present healthy. This is a case report of valproate-induced delirium. The Naranjo scale scored 7, classifying this drug-related event as probable. The present case report suggests the need for minimizing the use of psychoactive drugs in elderly demented patients, whether possible; age-related changes in pharmacokinetics and pharmacodynamics suggest the opportunity of a careful evaluation and a slow titration of treatments in these patients.

Rosuvastatin-induced rhabdomyolysis probably via CYP2C9 saturation.

A 66 year-old woman with no history of renal or liver disease presented with progressive asthenia and diffuse myalgia. She cited 5 months history of mild hyperlipidemia under treatment with rosuvastatin (10 mg/day). Clinical examination documented both an increase in liver size and proximal muscle weakness, with difficulty in raising arms above the head. Blood tests showed the presence of renal, liver and muscle failure, with no evidence of virological, immunological or haematological diseases. Rosuvastatin treatment was stopped and blood values normalised within five days; but because of an increase in cholesterol plasma levels, rosuvastatin (10 mg/day) was restarted. Two days later, the patient returned to our observation due to the development of asthenia and muscle weakness, with an increase in creatine phosphokinase, 12,165 U/l. Rosuvastatin was discontinued and replaced with pravastatin (40 mg/day) with a complete resolution of clinical and laboratory findings in about six days. Our patient was taking rosuvastatin, warfarin and telmisartan, which are metabolised by CYP2C9; we therefore hypothesised that the rosuvastatin-induced rhabdomyolysis was probably by CYP2C9 enzyme saturation.

Serum transaminase elevations during pegylated interferon treatment of chronic HCV hepatitis probably induced by polyethylene glycol.

OBJECTIVE: We report elevated serum alanine aminotransferase (ALT) levels during pegylated interferon (PEG-IFN)-alpha-2a in a patient with chronic HCV without other clinical manifestations. CASE SUMMARY: A 38-year-old man presented for HCV infection evaluation. Serum aspartate aminotransferase (AST) and ALT levels were 43 and 116 U/l, respectively; RT-PCR blood analysis revealed HCV-RNA infection. PEG-IFN-alpha-2b plus ribavirin treatment induced both a rapid virologic response and a normalization of transaminase plasma levels. During follow-up, an increase in transaminase and HCV-RNA values prompted us to start a new antiviral treatment with PEG-IFN-alpha-2a plus ribavirin. Four months later, after the follow-up, a new blood test documented both a HCV-RNA titer <50 U/ml and an increase in ALT and AST plasma levels. Immunostaining of the liver biopsy showed an accumulation of PEG-IFN-alpha-2a. PEG-IFN-alpha-2a elimination and the addition of recombinant IFN-alpha-2a induced normalization of the plasma transaminase levels in about 2 months. CONCLUSION: We postulate PEG-IFN-alpha-2a treatment because both the molecular weight and the distribution volume of the PEG-IFN may accumulate in the liver resulting in an increase of plasma transaminase levels. In contrast, during PEG-IFN-alpha-2b treatment, we did not document any increase in plasma transaminase values probably because of the lower molecular weight of the PEG.

Serum prolactin levels in repetitive temporal epileptic seizures.

The primary aim of this work was: to evaluate the time course of serum prolactin (PRL) increase following repetitive seizures in epileptic patients with (Group II) and without (Group I) temporal ischemia. Epileptic patients were examined after 2 or 3 epileptic seizures in wakefulness with seizure-free intervals of 4 hours. Serum PRL levels was assessed within 3 hours of the last epileptic seizure and up to 48 hours after. The increase of serum PRL attained within baseline levels after 6 h in Group I and after 12 h in Group II. A longer increase of serum PRL levels were observed in Group II patients respect to Group I (P < 0.01). In conclusion, this different long time attenuation of serum PRL following repetitive temporal seizures with and without damage of temporal structure, may be useful in order to better analyse the synaptic transmission involved in the pathways interconnect limbic areas.

Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures.

Individual metabotropic glutamate (mGlu) receptor subtypes have been implicated in the pathophysiology of epileptic seizures, and are potential targets for novel antiepileptic drugs. Here, we examined the role of the mGlu4 receptor subtype in absence seizures using as models: (i) WAG/Rij rats, which develop spontaneous absence seizures after 2-3months of age; and (ii) mice treated with pentylentetrazole (PTZ, 30mg/kg, s.c.). Expression of mGlu4 receptors was enhanced in the reticular thalamic nucleus (RTN) of symptomatic WAG/Rij rats as compared with age-matched controls, as assessed by immunoblotting and immunohistochemistry. No changes were found in other regions of WAG/Rij rats including ventrobasal thalamic nuclei, somatosensory cortex, and hippocampus. Electron microscopy and in situ hybridization data suggested that mGlu4 receptors in the RTN are localized on excitatory cortical afferents. Systemic injection of the selective mGlu4 receptor positive allosteric modulator, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen1a-carboxamide (PHCCC, 10mg/kg, s.c.), substantially enhanced the number of spike-and-wave discharges (SWDs) in WAG/Rij rats. Injection of PHCCC also enhanced absence-like seizures in PTZ-treated mice, whereas it was totally inactive in mGlu4 receptor knockout mice, which were intrinsically resistant to PTZ-induced seizures, as expected. This data supports the hypothesis that activation of mGlu4 receptors participates in the generation of absence seizures which can be exacerbated with the use of a positive allosteric modulator.

Effectiveness and safety of hypnotic drugs in the treatment of insomnia in over 70-year old people.

Good sleep is an important index of the quality of life in people and above all in old subjects. Among all the symptoms reported to general practitioner, insomnia is at the 3(rd) place and this is present in particular in the elderly. In elderly people high comorbidity and polytreatment are often present. We have studied 60 elderly people with history of insomnia and concomitant diseases: depression, dementia and behavioral disturbances. All the patients of the present study were visited in our outpatients' department. Three hypnotic drugs were used for the treatment of insomnia: zolpidem, or triazolam, or oxazepam, respectively at doses of 10mg/day, 0.125-0.25mg/day and 15.0mg/day. All the three drugs showed to be effective and safe; no paradoxical effects were observed.

Anticholinergic drug-induced delirium in an elderly Alzheimer's dementia patient.

Drug-induced delirium is a common matter in the elderly and anticholinergics, together with a number of different drugs, may significantly contribute to the delirium onset, especially in demented people. We report a case of a probable anticholinergic drug-induced delirium in an elderly patient. An 80-year-old man with Alzheimer's dementia presented with wandering, depressed mood with crying, somatic worries, anedonism and suicide recurrent ideas. A first external psychiatric assessment led to the diagnosis of melancholic depression and therapy with haloperidol 2mg/day, orphenadrine 100mg daily, amitriptyline 40 mg/day, lorazepam 2mg/day was started. Two weeks later patient suddenly developed delirium, characterized by nocturnal agitation, severe insomnia, daytime sedation, confusion, hallucinations and persecutory delusions. These symptoms progressively worsened, with the consequent caregiver's stress. A geriatric consultation excluded the main causes of delirium, therefore both Operative Units of Pharmacovigilance and Psychiatry were activated, for a clinical pharmacological and psychiatric assessment. Haloperidol, amitriptyline and orphenadrine were promptly dismissed. The patient began a treatment with quetiapine 25mg/day for two days, then twice a day, and infusion of saline 1000 ml/day for two days; psychiatric symptoms gradually diminished and therapy with galantamine was begun. We postulate that this clinical report is suggestive for an anticholinergic drug- induced delirium since the Naranjo probability scale indicated a probable relationship between delirium and drug therapy. In conclusion, a complete geriatric, pharmacological, and psychiatric evaluation might be necessary in order to reduce the adverse drug reactions in older patients treated with many drugs.

Retrospective evaluation of adverse drug reactions induced by nonsteroidal anti-inflammatory drugs.

BACKGROUND AND OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs, and their use can be complicated by the development of adverse drug reactions (ADRs). The aim of this study was to assess the frequency of NSAID-induced ADRs in hospitalised patients in the Clinical Divisions of the Catanzaro and Cosenza hospitals. METHODS: We retrospectively analysed NSAID-induced ADRs after evaluating all ADRs recorded by the Clinical Divisions of the Catanzaro and Cosenza hospitals over a 10-year period, from January 1995 to December 2004. RESULTS: NSAIDs were found to be responsible for 55.2% of the episodes of ADRs overall. Diclofenac and aspirin (acetylsalicylic acid) were the drugs most frequently involved in the development of ADRs, while the skin was the body system most susceptible to NSAID-induced ADRs (43%). We determined that the drug-ADR relationship was probable in 62% of the reports; withdrawal of NSAID therapy led to a resolution of the clinical features of ADRs in 86% of episodes. CONCLUSION: NSAID therapy represents a common cause of ADRs in hospitalised patients. Their use should be carefully considered, especially in the presence of polydrug therapy.