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.

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.

BACKGROUND: The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. METHODS: We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. RESULTS: A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). CONCLUSIONS: Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

Validation of the Hamilton Rating Scale for Depression in adults with epilepsy.

PURPOSE: Mood disorders represent a frequent psychiatric comorbidity among patients with epilepsy, having a major impact on their quality of life and contributing considerably to the global burden of the disease. The availability of standardized clinical instruments validated in populations with epilepsy has important implications in terms of diagnosis and treatment. This aimed to validate the Hamilton Rating Scale for Depression (HRSD) in adult patients with epilepsy. METHODS: A consecutive sample of 120 adult outpatients with epilepsy was assessed using the Mini International Neuropsychiatric Inventory (MINI) Plus version 5.0.0 and the HRSD. RESULTS: Cronbach's alpha coefficient was 0.824 for the 17-item version and 0.833 for the 21-item version. Receiver operating characteristic analysis showed an area under the curve of 0.896 and 0.899, respectively, for the two versions. However, the HRSD-17 demonstrated the best psychometric properties compared to the HRSD-21 and, with a cutoff score of 6, showed a sensitivity of 94%, a specificity of 80%, a positive predictive value of 46%, and a negative predictive value of 99%. CONCLUSIONS: The HRSD proved to be reliable and valid in the epilepsy setting and will stimulate further research in this area.

Novel treatment options for epilepsy: focus on perampanel.

Perampanel is a new chemical entity recently approved in the United States (US) and European Union (EU) as adjunctive treatment of partial-onset seizures with and without secondary generalization in patients with epilepsy aged 12 years and older. Pharmacological studies suggest that perampanel acts with a new mechanism of action via non-competitive antagonism of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor of glutamate, the main mediator of excitatory neurotransmission in the central nervous system. Perampanel is completely absorbed after oral administration. The drug is 95% bound to plasma proteins and is extensively metabolized by oxidation followed by glucuronidation. Perampanel has an elimination half-life of approximately 52-129h, allowing once daily dosing, with peak plasma levels observed 0.25-2h post-dose. Randomized placebo-controlled trials of adjunctive treatment have demonstrated that once-daily perampanel doses of 4-12mg/day significantly reduced partial-onset seizure frequency in patients with pharmacoresistant epilepsy along with a favorable tolerability profile. In perampanel pivotal trials, the most frequently reported treatment emergent adverse events (>10%) included dizziness, somnolence, fatigue and headache. Perampanel therapeutic response was maintained in patients included in the long term open-label extension studies for up to 4 years. Based on these data, perampanel offers a valuable option in the add-on treatment of partial-onset and secondarily generalized seizures.

Validation of the Italian version of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E).

The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) was developed for the rapid detection of a major depressive episode in people with epilepsy. It has been proven to be a user-friendly screening instrument. This study describes the development, validation, and psychometric properties of the Italian version of the NDDI-E. A consecutive sample of 120 outpatients with epilepsy has been assessed using the M.I.N.I. Plus version 5.0.0 and the NDDI-E. All patients had no major difficulties in understanding or answering the questions of the Italian version. Cronbach's alpha coefficient was 0.851. Receiver operating characteristic analysis showed an area under the curve of 0.943 (CI95%=0.902-0.985; SE 0.021; p<0.001), a cut off score of 13, a sensitivity of 86.2%, a specificity of 89%, a positive predictive value of 71.4%, and a negative predictive value of 95.3%.

Sleep disturbances in elderly subjects: an epidemiological survey in an Italian district.

OBJECTIVES: Disturbed sleep is common in elderly people and has been related to comorbidities. The aim of this study was to evaluate the prevalence of sleep problems and their relationship with chronic disease in an elderly population. MATERIALS AND METHODS: The whole population of subjects aged more than 65 years, in the municipality of Vecchiano, Pisa was considered as eligible and underwent a clinical interview and a questionnaire about insomnia, sleepiness, snoring and sleep apnea. A model of logistic regression was applied to the data. RESULTS: The participation rate was 60.3% (1427 subjects). Insomnia was observed in 44.2% of our population, while sleepiness in 31.3%, snoring in 47.2% and sleep apnea in 9.0%. The most common diseases associated with sleep symptoms were depression, cognitive decline and diabetes. CONCLUSIONS: Our results confirm that sleep problems are very common in elderly subjects and closely related to medical and psychiatric illnesses.

Mismatch negativity analysis in drug-resistant epileptic patients implanted with vagus nerve stimulator.

It is well known that some epileptic patients does not respond to conventional treatments, despite multiple combination of antiepileptic drugs, and they are therefore considered drug-resistant. For these patients, vagal nerve stimulation (VNS) represents a successful alternative to traditional therapy, and it is generally well tolerated; beside benefits on seizure frequency, VNS showed positive effects on cognition and mood. Aim of this study was to investigate short-term memory changes in a group of 12 patients implanted with VNS, through Mismatch Negativity wave (MMN). After 1 year of follow-up, MMN latencies and amplitudes did not show significant changes following VNS implantation, independently on current intensity, as compared with pre-implantation values. In two patients, MMN values, which were abnormal before VNS implantation, showed a major reduction in latency and an increase in amplitude after implantation, suggesting a likely positive effect of VNS on pre-attentive processes investigated by MMN.

A pharmacoeconomic evaluation of oral triptans in the treatment of migraine in Italy.

AIM: The goal of this economic evaluation was to compare the cost-efficacy of oral triptans currently used in the treatment of migraine in Italy. METHODS: The cost analysis of drugs was conducted through a structured decision tree, built up taking into account the National Healthcare System perspective. Data on the clinical efficacy and tolerability of oral triptans were derived from a published meta-analysis of 53 randomized, controlled trials. Drug cost-allocation included either the oral triptans price and costs related to management of treatment-associated chest and central nervous system (CNS) adverse events. Necessary resources for management of the unwanted events were identified by asking an experienced panel of experts how they would treat patients with triptan-related chest and CNS adverse events. To further improve the economic scenario and to allow a broader inference of pharmacoeconomic analysis, the number needed to treat (NNT) to attain 100 sustained pain free (SPF) patients, and 100 patients with SPF and no adverse events (SNAE) were also calculated. RESULTS: Study results show cost-effective differences among oral triptans. The best cost-efficacy ratios were attained by almotriptan 12.5 mg and rizatriptan 5 mg, with 18.47 Euro and 26.37 Euro respectively per patient successfully treated (SPF). Similarly, the NNT analysis favoured almotriptan, which requires 386 patients to attain 100 SPF patients, and 393 patients to attain 100 SNAE patients. Rizatriptan 10 mg resulted the closest competitor, requiring 395 and 457 patients, respectively. CONCLUSIONS: On the basis of published data and within the limitations of this model analysis that included several assumptions, results suggest the economical advantage of almotriptan 12.5 mg among the oral triptans approved for the treatment of migraine in Italy. This evidence could drive selection of the most appropriate oral treatment for acute migraine attacks based on both individual patient's needs and cost-effective drugs.

Rizatriptan does not change cerebral blood flow velocity during migraine attacks.

Rizatriptan represents a major advance in the treatment of migraine attack: inhibition of peripheral trigeminal nerve and constriction of intracranial extracerebral blood vessels have been proposed as its main antimigraine mechanisms of action. Although many studies may suggest that rizatriptan causes highly selective vasoconstriction within intracranial extracerebral vessels (i.e., meningeal arteries), no literature data are available to date on possible cerebral hemodynamic changes in humans after treatment with rizatriptan. The aim of this study was to evaluate the effect of rizatriptan on cerebral blood flow velocity performing transcranial Doppler during spontaneous attacks of migraine without aura. Fourteen patients suffering from migraine without aura were monitored to evaluate mean flow velocity changes on both middle cerebral arteries during migraine attack 30 min before and 120 min after oral administration of rizatriptan 10mg. Monitoring was repeated for 30 min during the pain-free period. All patients turned out to be drug responders and no significant mean flow velocity changes were observed between the pain-free period and pre-treatment phase; besides no significant difference in mean flow velocity value have been detected between the periods after the drug administration during the attack versus both pre-treatment period and pain-free phase. These findings indicate that the antimigraine action of rizatriptan is not associated with clear intracranial cerebral hemodynamic changes and may support its cerebrovascular safety.

Long-term follow-up of 106 multiple sclerosis patients undergoing interferon-beta 1a or 1b therapy: predictive factors of thyroid disease development and duration.

BACKGROUND: Conflicting data have been reported on the association between interferon (IFN)-beta therapy of multiple sclerosis (MS) patients and thyroid disease development. AIMS: The goals of this study are as follows: to assess the actual occurrence of thyroid dysfunction and autoimmunity during long-term IFN-beta therapy; to establish the possible presence of predictive factors for thyroid dysfunction development and duration; and to suggest an effective follow-up protocol for patients receiving long-term IFN-beta therapy. STUDY PROTOCOL: A total of 106 MS patients (76 women) underwent IFN-beta 1a or 1b therapy for up to 84 months (median, 42 months). Thyroid function and autoimmunity were assessed at baseline and every 3-6 months throughout the treatment course. RESULTS: Baseline thyroid autoimmunity was detected in 8.5% of patients and hypothyroidism in 2.8%. Thyroid dysfunction (80% hypothyroidism, 92% subclinical, 56% transient) developed in 24% (68% with autoimmunity) of patients and autoimmunity in 22.7% (45.5% with dysfunction), without significant differences between the two cytokines; 68% of dysfunctions occurred within the first year. Autoimmunity emerged as the only predictive factor for dysfunction development (relative risk, 8.9), whereas sustained disease was significantly associated with male gender (P < 0.003). CONCLUSIONS: Both incident thyroid autoimmunity and dysfunction frequently occur in MS patients during IFN-beta therapy, particularly within the first year of treatment. Thyroid dysfunction is generally subclinical and transient in over than half of cases; preexisting or incident autoimmunity emerged as the only significant predictive factor for thyroid dysfunction development. Thyroid function and autoimmunity assessment is mandatory within the first year of IFN-beta therapy; thereafter, serum TSH measurement only in patients with thyroid disease could be sufficient.

Effects of prolonged wakefulness combined with alcohol and hands-free cell phone divided attention tasks on simulated driving.

Simulated driving ability was assessed following administration of alcohol, at an estimated blood level of 0.05%, and combined prolonged wakefulness, while participants were undertaking divided attention tasks over a hands-free mobile phone. Divided attention tasks were structured to provide a sustained cognitive workload to the subjects. Twenty three young healthy individuals drove 10 km simulated driving under four conditions in a counterbalanced, within-subject design: alcohol, alcohol and 19 h wakefulness, alcohol and 24 h wakefulness, and while sober. Study measures were: simulated driving, self-reported sleepiness, critical flicker fusion threshold (CFFT), Stroop word-colour interference test (Stroop) and simple visual reaction times (SVRT). As expected, subjective sleepiness was highly correlated with both sleep restriction and alcohol consumption. The combination of alcohol and 24 h sustained wakefulness produced the highest driving impairment, significantly beyond the alcohol effect itself. Concurrent alcohol and 19 h wakefulness significantly affected only driving time-to-collision. No significant changes of study measures occurred following alcohol intake in unrestricted sleep conditions. CFFT, SVRT and Stroop results showed a similar trend in the four study conditions. Thus apparently 'safe' blood alcohol levels in combination with prolonged wakefulness resulted in significant driving impairments. In normal sleep conditions alcohol effects on driving were partially counteracted by the concomitant hands-free phone based psychometric tasks.

Lormetazepam effects on daytime vigilance, psychomotor performance and simulated driving in young adult healthy volunteers.

OBJECTIVE: To assess the residual effects of lormetazepam on daytime vigilance, psychomotor performance and simulated driving in adult healthy volunteers. MATERIAL: Twelve subjects (7 women, 5 men), aged 27 - 38 years (mean 31). METHOD: Subjects received lormetazepam 1 mg tablet and placebo for 3 days at nighttime in a randomized, double-blind, crossover design, with a 1-week interval between medications. On the morning following the last drug administration, the subjects completed a 15-min battery of neuropsychological tests aimed at assessing memory and attention, performed simple and choice visual reaction times, and self-rated their own level of sleepiness using the Epworth sleepiness scale. Afterwards, an interactive, computer-based driving simulator (STISIM) was used to assess the effect of the study drugs on driving ability, followed by the multiple sleep latency test (MSLT). RESULTS: The findings showed that participants had similar performance when treated with lormetazepam and placebo. Indeed, as compared with baseline, neuropsychological tests, visual reaction times, sleep latency using the MSLT and driving ability showed no deterioration following either placebo or active medication. CONCLUSIONS: The data suggest that 3-day use of lormetazepam 1 mg/day neither influences daytime vigilance nor impairs psychomotor task performance and simulated driving. Results confirm previous evidence that the intermediate-acting hypnotic benzodiazepine lormetazepam is devoid of residual effects in respect to psychomotor ability. However, caution should be exercised in the interpretation of the results due to the limited sensitivity of the study.

Second generation antihistamines in the treatment of seasonal allergic rhinitis due to Parietaria and cypress pollen.

Second generation antihistamines have been employed in the treatment of seasonal allergic rhinitis for many years. However, their effects on two distinctive Mediterranean allergic conditions, viz. Parietaria pollinosis and cypress pollinosis, have been scarcely investigated, so far. A comparative efficacy and side effect trial of astemizole and terfenadine in the treatment of seasonal allergic rhinitis due to either Parietaria or cypress pollen was carried out in 27 adult patients, according to a double-blind, double-dummy parallel-group design. Airborne pollen monitoring allowed comparison of symptom scores with pollen counts. Seven patients (26%) withdrew, due to poor symptom control. In contrast, in a subset of 15 patients who completed the trial, treatment led to a substantial and statistically significant decline in symptom severity in both the astemizole and the terfenadine study group. However, no statistically significant inter-group differences could be detected.

Asymmetric scalp distribution of pattern visual evoked potentials during interictal phases in migraine.

The N70 and P100 components of transient pattern visual evoked potentials (P-VEPs) were measured in migraine patients, with and without aura, and in normal subjects in order to evaluate their latency, amplitude and occipital scalp distribution. The aim was to find any typical electrophysiological abnormalities in migraine. P-VEP N70 and P100 were analyzed in 59 patients without any known visual field defect. Mean latency and amplitude values were within normal ranges for either N70 and P100 all over the occipital scalp; the only significant abnormality we found was related to the absolute right-left amplitude ratio either for N70 and P100 waves, providing an asymmetry in P-VEP scalp distribution; this finding was detected in 78.9% of patients with aura and 72.5% without aura. Our results show that in migraine patients, both P-VEP waves N70 and P100, have an asymmetric topographic distribution, even during interictal phases, that can be explained by a cortical disturbance in agreement with the neural hypothesis of headache.

Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports.

Parkinson's disease is a nosological entity of unknown origin for which, in some cases, a possible pathogenetic role for mitochondrial dysfunction has been postulated. Two young onset parkinsonian patients with mitochondrial DNA (mtDNA) deletions in skeletal muscle are reported on. Patient 1 also presented with increased blood creatine kinase and lactate concentrations and a family history which included a wide range of phenotypes affecting multiple systems. Patient 2 presented with multiple symmetric lipomatosis. Histopathological investigation showed ragged red fibres and COX negative fibres in muscle biopsies from both patients. The data support the hypothesis that mitochondrial DNA mutations may occur in some cases of parkinsonism, suggesting that a diagnosis of a mitochondrial disorder should be considered in the presence of consistent family history and clinical symptoms.

Impaired oxidative metabolism in exercising muscle from ALS patients.

The pathogenic mechanism of selective loss of motor neurones in amyotrophic lateral sclerosis (ALS) is still poorly understood. Recently, research evidence has suggested that mitochondrial dysfunction occurs in central nervous system as well as in peripheral tissues from ALS patients. The aim of our study was to indirectly investigate in vivo oxidative metabolism of exercising muscle in a case history of patients affected by ALS. To this purpose 11 patients, 8 male and 3 female, mean age+/-SD: 52.4+/-11.1 years, performed a bicycle incremental test for the assessment of lactate production. At rest, there was increased lactate concentration in patients: 2.77+/-0.79 vs. 1.48+/-0.49 mmol/l in normal controls (normal range: 0.67-2.47 mmol/l). Analysis of lactate curve during exercise showed a lactate production increase compared to controls. Furthermore, anaerobic lactate threshold was detected at 40-50% of the predicted normal power output, anticipated with respect to both normal subjects and non-ALS chronically denervated controls with comparable motor impairment (60-70%), suggesting that mitochondrial dysfunction can occur in exercising skeletal muscle from ALS patients.

Epidemiology of myotonic dystrophy in Italy: re-apprisal after genetic diagnosis.

Before the discovery of the myotonic dystrophy (DM) gene, the DM epidemiological rates could not be accurately estimated. The aim of this study was to calculate the DM prevalence rates in Padova (North-East Italy) and in four provinces of North-West Tuscany (Central Italy) and, as of 30 June 1999, to do so using molecular genetic testing. A minimum prevalence rate of 9.31x10(-5) inhabitants was found, consistent with epidemiological rates worldwide, and more than two times as high as those of two previous studies conducted in the same areas during the era prior to molecular genetic testing. This study, the first in Italy since the discovery of the DM gene, underlines the importance of direct genetic diagnosis of DM, especially in detecting mildly affected patients, a fundamental step in correctly estimating the risk of disease transmission in affected families.

Neurophysiological evaluation of vigilance in epileptic patients on monotherapy with lamotrigine.

OBJECTIVE: Limited research has focused to date on daytime sleepiness in epileptic patients treated with either conventional or newer antiepileptic drugs. We evaluated the level of vigilance in 15 consecutive, newly diagnosed and never medicated adult epileptic patients, receiving initial monotherapy with lamotrigine (LTG). METHODS: Patients underwent the Multiple Sleep Latency Test (MSLT), visual reaction times (VRT) and Stanford Sleepiness Scale (SSS) on two separate occasions, i.e. before and 2 months after LTG treatment. A group of 15 age-matched healthy volunteers was taken as control. RESULTS: At baseline, mean sleep latencies on the MSLT were comparable in epileptic patients and in controls. In patients, 2 months after monotherapy with LTG 200 mg/day, MSLT scores did not significantly change as compared with pre-treatment values. Accordingly, subjective evaluation of vigilance by the SSS and psychomotor performance by VRT were superimposable in controls and in untreated patients, and did not change in patients after LTG treatment. CONCLUSIONS: These results suggest that in adult, newly diagnosed epileptic patients initial monotherapy with LTG does not impair vigilance.

Circulating levels of allopregnanolone, an anticonvulsant metabolite of progesterone, in women with partial epilepsy in the postcritical phase.

PURPOSE: Several lines of evidence indicate that there exists a relation between ovarian hormones and epilepsy. Estrogens decrease seizure threshold and increase brain excitability, whereas progesterone has an inhibitory effect and reduces epileptiform activity. Recently considerable interest has turned to neuroactive steroids, a group of progesterone metabolites, as endogenous modulators of excitability of the central nervous system (CNS). Their ability to alter neuronal firing rapidly occurs through interaction with gamma-aminobutyric acid (GABA) A receptor complex. In a previous experience, serum allopregnanolone (3alpha-OH-5alpha-pregnan-20-one) levels were measured in 15 women with partial epilepsy in the intercritical phase, and no significant differences were found between patients and control subjects. METHODS: To find out if there are changes in serum allopregnanolone levels after epileptic seizure, blood samples were drawn immediately, 15 min, and 6 h after a seizure in seven fertile females with partial epilepsy. RESULTS: The most interesting finding is that allopregnanolone increases in serum during the first 15 min after partial seizures (p < 0.05) and decreases after 6 h. CONCLUSIONS: These data are consistent with a role for allopregnanolone in the control of neuronal excitability and seizures.

Pharmacological prophylaxis of post-traumatic epilepsy.

Early and late epileptic seizures are a frequent complication of severe head traumas. The administration of anticonvulsant drugs immediately after head injury is commonly implemented as a prophylactic measure; however, there is a lack of consensus on the usefulness of prophylaxis with anticonvulsants for the prevention of late post-traumatic epilepsy (PTE). The inconsistent evidence accumulated so far from clinical studies, most nonrandomised and uncontrolled in design, and the limited knowledge of the processes underlying post-traumatic epileptogenesis, do not warrant empirical pharmacological prophylaxis with long term administration of conventional anticonvulsants. Phenytoin and phenobarbital (phenobarbitone) are used to a large extent in this indication. As a general rule, a benefit/risk analysis in individual patients should drive prophylactic drug prescription in PTE as it can have potential detrimental effects on a patient's recovery. New compounds, such as free-radical scavengers and antiperoxidants, show encouraging experimental results, but their clinical use is still very limited.