Levetiracetam in clinical practice: efficacy and tolerability in epilepsy.

BACKGROUND: The aim of this study was to evaluate efficacy and tolerability of levetiracetam (LEV) in patients with different epilepsy syndromes. METHODS: We evaluated epileptic patients seen in the previous 18 months, including all patients with present or past exposure to LEV. Tolerability of LEV therapy was evaluated in all patients; efficacy was evaluated only in patients who had received LEV for at least six months. Two hundred and two patients were included in the study. Patients were considered responsive when showing a > 50% reduction in seizures frequency and non-responders when seizure frequency was unchanged, worsened or showed a reduction < 50%. RESULTS: Thirty patients did not complete six months of LEV treatment and dropped out. 57.4% of the patients with uncontrolled seizures treated for at least six months were responders, with 27.7% seizure free. Adverse effects were observed in 46 patients (23%) and were responsible for early drop out in 26. Adverse effects occurred significantly more often in females than in males (30.6% vs 13.2%); moreover, nearly 30% of women with adverse effects complained of more than one adverse effect, while this was never observed in male patients. CONCLUSIONS: Our study shows LEV as a well tolerated and effective treatment, both in monotherapy and as an add-on. Further investigations on larges samples are needed to investigate the issue of gender-related tolerability

Transient epileptic amnesia: an emerging late-onset epileptic syndrome.

Transient epileptic amnesia (TEA) is a distinct neurologic condition occurring in late-middle/old age and presenting with amnesic attacks of epileptic nature and interictal memory disturbances. For many years this condition has been associated with the nonepileptic condition of transient global amnesia (TGA) and still today is poorly recognized by clinicians. Despite the clinical and laboratory findings that distinguish TEA from TGA, differential diagnosis may be difficult in the individual patient. Every effort must be employed for an early diagnosis, since antiepileptic treatment may readily control both ictal episodes and memory disturbances

Cranial neuralgias: from physiopathology to pharmacological treatment

Cranial neuralgias are paroxysmal painful disorders of the head characterised by some shared features such as unilaterality of symptoms, transience and recurrence of attacks, superficial and "shock-like" quality of pain and the presence of triggering factors. Although rare, these disorders must be promptly recognised as they harbour a relatively high risk for underlying compressive or inflammatory disease. Nevertheless, misdiagnosis is frequent. Trigeminal and glossopharyngeal neuralgias are sustained in most cases by a neurovascular conflict in the posterior fossa resulting in a hyperexcitability state of the trigeminal circuitry. If the aetiology of trigeminal neuralgia (TN) and other typical neuralgias must be brought back to the peripheral injury, their pathogenesis could involve central allodynic mechanisms, which, in patients with inter-critical pain, also engage the nociceptive neurons at the thalamic-cortical level. Currently available medical treatments for TN and other cranial neuralgias are reviewed

Differential neuropsychological profiles in Parkinsonian patients with or without vascular lesions.

The purpose of this study is to compare the neuropsychological profile of patients affected by parkinsonism and vascular lesions to that in patients with PD alone (PD) and to evaluate whether the brain vascular lesion load is associated with neuropsychological variables. Thirty-six nondemented patients with parkinsonism were divided into 3 groups of 12 patients each, according to both clinical history and the presence of brain vascular lesions and/or dopaminergic denervation as revealed by magnetic resonance and dopamine transporter imaging, respectively. The first group had vascular lesions without dopaminergic denervation (VP group); the second group had vascular lesions and dopaminergic denervation (DD) (VP+DD group); and the third group consisted of patients with dopaminergic denervation (PD group) without vascular lesions. All patients underwent neurological and neuropsychological assessments. The groups differed in disease duration, age at onset, and cerebrovascular risk factors. The VP and VP+DD groups performed worse than the PD group on frontal/executive tasks. Regardless of the presence of dopaminergic denervation, cerebrovascular lesions in hemispheric white matter, basal ganglia, and cerebellum have an important effect in determining early onset and severity of cognitive impairment in patients with parkinsonism

Abnormal sensorimotor cortex and thalamo-cortical networks in familial adult myoclonic epilepsy type 2: pathophysiology and diagnostic implications

: Familial adult myoclonic epilepsy type 2 is a hereditary condition characterized by cortical tremor, myoclonus and epilepsy. It belongs to the spectrum of cortical myoclonus and the sensorimotor cortex hyperexcitability represents an important pathogenic mechanism underlying this condition. Besides pericentral cortical structures, the impairment of subcortical networks seems also to play a pathogenetic role, mainly via the thalamo-cortical pathway. However, the mechanisms underlying cortical-subcortical circuits dysfunction, as well as their impact on clinical manifestations, are still unknown. Therefore, the main aims of our study were to systematically study with an extensive electrophysiological battery, the cortical sensorimotor, as well as thalamo-cortical networks in genetically confirmed familial adult myoclonic epilepsy patients and to establish reliable neurophysiological biomarkers for the diagnosis. In 26 familial myoclonic epilepsy subjects, harbouring the intronic ATTTC repeat expansion in the StAR-related lipid transfer domain-containing 7 gene, 17 juvenile myoclonic epilepsy patients and 22 healthy controls, we evaluated the facilitatory and inhibitory circuits within the primary motor cortex using single and paired-pulse transcranial magnetic stimulation paradigms. We also probed the excitability of the somatosensory, as well as the thalamo-somatosensory cortex connection by using ad hoc somatosensory evoked potential protocols. The sensitivity and specificity of transcranial magnetic stimulation and somatosensory evoked potential metrics were derived from receiver operating curve analysis. Familial adult myoclonic epilepsy patients displayed increased facilitation and decreased inhibition within the sensorimotor cortex compared with juvenile myoclonic epilepsy patients (all P  0.05). Patients with a longer disease duration had more severe myoclonus (r = 0.467, P = 0.02) associated with a lower frequency (r = -0.607, P = 0.001) and higher power of tremor (r = 0.479, P = 0.02). Finally, familial adult myoclonic epilepsy was reliably diagnosed using transcranial magnetic stimulation, demonstrating its superiority as a diagnostic factor compared to somatosensory evoked potential measures. In conclusion, deficits of sensorimotor cortical and thalamo-cortical circuits are involved in the pathophysiology of familial adult myoclonic epilepsy even if these alterations are not associated with clinical severity. Transcranial magnetic stimulation-based measurements display an overall higher accuracy than somatosensory evoked potential parameters to reliably distinguish familial adult myoclonic epilepsy from juvenile myoclonic epilepsy and healthy controls

Complex phenotype in an Italian family with a novel mutation in SPG3A.

Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations

Levetiracetam in patients with epilepsy and chronic liver disease: observations in a case series.

OBJECTIVES: To evaluate levetiracetam (LEV) tolerability in patients with epilepsy and liver disease. METHODS: Fourteen patients with epilepsy and concomitant liver disease were treated with LEV in an open prospective investigation mimicking the daily clinical practice. All patients were stabilized (ie, for at least 1 year) on traditional antiepileptic drugs with complete or partial control of seizures. In the 6-month pre-LEV baseline period, seizure frequency ranged from 3 to 300. Levetiracetam was added on to the basal treatment at a starting daily dose of 250 mg, and the dose was adjusted according to the tolerability and the therapeutic response. Four patients discontinued the drug within the first 3 months because of intolerable side effects. The remaining 10 continued LEV treatment, and the present follow-up is 12 to 38 months. RESULTS: In the last 6 months of observation, none of the patients showed worsening of liver function on the basis of blood chemistry, and in 4 patients, a complete normalization or a trend toward physiological values of transaminase and/or gamma-glutamyltransferase activity was observed. A greater than 50% reduction in seizure frequency occurred in all uncontrolled patients, 2 of whom achieved seizure freedom during LEV treatment. CONCLUSIONS: Based on these observations, LEV seems to be an attractive therapeutic option in epileptic patients with chronic liver diseases

Connectivity and circuitry in a dish versus in a brain

In order to understand and find therapeutic strategies for neurological disorders, disease models that recapitulate the connectivity and circuitry of patients’ brain are needed. Owing to many limitations of animal disease models, in vitro neuronal models using patient-derived stem cells are currently being developed. However, prior to employing neurons as a model in a dish, they need to be evaluated for their electrophysiological properties, including both passive and active membrane properties, dynamics of neurotransmitter release, and capacity to undergo synaptic plasticity. In this review, we survey recent attempts to study these issues in human induced pluripotent stem cell-derived neurons. Although progress has been made, there are still many hurdles to overcome before human induced pluripotent stem cell-derived neurons can fully recapitulate all of the above physiological properties of adult mature neurons. Moreover, proper integration of neurons into pre-existing circuitry still needs to be achieved. Nevertheless, in vitro neuronal stem cell-derived models hold great promise for clinical application in neurological diseases in the future

Ionic homeostasis in brain conditioning

Most of the current focus on developing neuroprotective therapies is aimed at preventing neuronal death. However, these approaches have not been successful despite many years of clinical trials mainly because the numerous side effects observed in humans and absent in animals used at preclinical level. Recently, the research in this field aims to overcome this problem by developing strategies which induce, mimic, or boost endogenous protective responses and thus do not interfere with physiological neurotransmission. Preconditioning is a protective strategy in which a subliminal stimulus is applied before a subsequent harmful stimulus, thus inducing a state of tolerance in which the injury inflicted by the challenge is mitigated. Tolerance may be observed in ischemia, seizure, and infection. Since it requires protein synthesis, it confers delayed and temporary neuroprotection, taking hours to develop, with a pick at 1-3 days. A new promising approach for neuroprotection derives from post-conditioning, in which neuroprotection is achieved by a modified reperfusion subsequent to a prolonged ischemic episode. Many pathways have been proposed as plausible mechanisms to explain the neuroprotection offered by preconditioning and post-conditioning. Although the mechanisms through which these two endogenous protective strategies exert their effects are not yet fully understood, recent evidence highlights that the maintenance of ionic homeostasis plays a key role in propagating these neuroprotective phenomena. The present article will review the role of protein transporters and ionic channels involved in the control of ionic homeostasis in the neuroprotective effect of ischemic preconditioning and post-conditioning in adult brain, with particular regards to the Na(+)/Ca2(+) exchangers (NCX), the plasma membrane Ca2(+)-ATPase (PMCA), the Na(+)/H(+) exchange (NHE), the Na(+)/K(+)/2Cl(-) cotransport (NKCC) and the acid-sensing cation channels (ASIC). Ischemic stroke is the third leading cause of death and disability. Up until now, all clinical trials testing potential stroke neuroprotectants failed. For this reason attention of researchers has been focusing on the identification of brain endogenous neuroprotective mechanisms activated after cerebral ischemia. In this context, ischemic preconditioning and ischemic post-conditioning represent two neuroprotecive strategies to investigate in order to identify new molecular target to reduce the ischemic damage