Domenico Italiano

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.

Relationship between serum mono-hydroxy-carbazepine concentrations and adverse effects in patients with epilepsy on high-dose oxcarbazepine therapy

PURPOSE To investigate the relationship between the serum concentration of the mono-hydroxy-derivative (MHD) of oxcarbazepine (OXC) and adverse effects (AEs) in epileptic patients on high-dose OXC therapy. PATIENTS AND METHODS Forty-four consecutive patients, aged 18-65 years, with refractory epilepsy receiving OXC dosages > or = 1500 mg/day (range 1500-3300 mg/day) were assessed at an outpatient clinic. Serum MHD concentrations were determined by a specific HPLC assay in samples collected before the morning dose and 2 h after drug intake. An independent observer assessed AEs at each sampling time. RESULTS AEs were reported in five patients at the first sampling time, and in 26 patients at the second sampling time. Nystagmus, sedation, blurred vision, and dizziness were the most frequent AEs. MHD concentrations (means +/- S.D.) associated with AEs were 29.6 +/- 5.58 compared with 21.7 +/- 5.0 mg/L when no AEs were detected (p = 0.0001). AEs were minimized in most patients by reducing OXC dose, increasing the number of daily administrations, or both. CONCLUSION Patients with serum MHD concentrations > or = 30 mg/L are at greater risk of developing AEs. In many patients, AEs occur intermittently in relation to fluctuations in serum MHD. Monitoring MHD concentrations could help in the management of patients on high-dose OXC therapy.

Protective effect of apocynin, a NADPH-oxidase inhibitor, against contrast-induced nephropathy in the diabetic rats: A comparison with n-acetylcysteine

The aim of this study was to investigate the effects of apocynin, a NADPH (nicotinamide adenine dinucleotide phosphate)-oxidase inhibitor, in diabetic rats with nephropathy induced by contrast medium (CIN). Diabetes was induced in male Wistar rats by a single dose of streptozotocin (60 mg/kg i.v.). Animals were then divided into the following groups: 1) control group (diabetic rats treated i.v. with saline solution); 2) iomeprol group (iomeprol at 10 ml/kg was injected i.v. 30 min after saline administration); 3) apocynin group (identical to the iomeprol group, except for pre-treatment with apocynin 5mg/kg i.v., 30 min before iomeprol injection) and 4) N-acetylcysteine group (NAC) (same as iomeprol group, except for the treatment with NAC 20 mg/kg i.v. 30 min before iomeprol injection). CIN in animals were assessed 24h after administration of iomeprol. Apocynin significantly attenuates the impaired glomerular function, concentration of Na(+), K(+), alpha glutathione S-transferase levels in urine and neutrophil gelatinase-associated lipocalin levels in plasma caused by iomeprol. In kidney, immunohistochemical analysis of some inflammatory mediators, such as nitrotyrosine, poly-ADP-ribosyl polymerase, tumor necrosis factor-α, interleukin-1β as well as apoptosis (evaluated as terminal deoxynucleotidyltransferase-mediated UTP end labeling assay) revealed positive staining in tissue obtained from iomeprol group. These parameters were markedly reduced in animals treated with apocynin. Similarly, these parameters were also markedly modified by NAC pre-treatment. Here, we have shown that apocynin attenuates the degree of iomeprol-induced nephropathy in diabetic rats.

Lennox—Gastaut syndrome in adulthood: Clinical and EEG features

PURPOSE We performed a retrospective study to investigate seizure, EEG, social and cognitive outcome in adult LGS subjects. METHODS We retrospectively evaluated 27 LGS patients aged 40-59 years. We assessed in particular the evolution of different seizure types and EEG findings, as well as cognitive and social outcome. RESULTS During the early stages of the disease, all patients presented tonic seizures (TS) during wakefulness and sleep, 20/27 had atypical absences (AA), more rarely other seizure types. EEG showed slow background activity in 21/27 patients, diffuse slow spike-wave discharges (DSSW) during wakefulness in 22/27, and bursts of diffuse fast rhythms (DFR) in sleep in all patients. At last observation, 11 patients only had TS during wakefulness, but all still presented TS during sleep; AA persisted in 6 patients. EEG showed normal BA in 12/27 patients; only 7/27 still presented DSSW. On the contrary, sleep EEG showed the persistence of DFR in all. A moderate to severe cognitive impairment was observed in 26/27 patients. CONCLUSIONS In adult LGS patients TS during sleep remain the major seizure type; moreover, a standard waking EEG may be normal. Thus, polysomnography represents the most important mean of investigation also in adult LGS patients.

Antiepileptic drugs and MTHFR polymorphisms influence hyper-homocysteinemia recurrence in epileptic patients

Summary:  The influence of antiepileptic drugs (AEDs) and/or common polymorphisms (677C → T, 1298A → C) of the methylene‐tetrahydrofolate‐reductase (MTHFR) gene on the recurrence time of hyper‐total‐homocysteinemia (tHcy > 13 μmol/L) was investigated in 59 hyper‐homocysteinemic patients (34M/25F, 20–49 years). Plasma tHcy and folate were assayed before and after 1‐month folate supplementation (5mg/day), and after 2, 4, and 6 months. Four MTHFR polymorphism groups were identified with the following tHcy (μmol/L) and folate (nmol/L) levels (mean ± SD): (a) MTHFR677TT/1298AA, 24 patients, 36.0 ± 4.8, 4.1 ± 0.7; (b) MTHFR677CT/1298AC 27.1 ± 2.7, 5.3 ± 1.0 (n = 15); (c) MTHFR677CT/1298AA 16.6 ± 3.6, 6.8 ± 1.0 (n = 11), all taking enzyme‐inducing AEDs; and (d) MTHFR677TT/1298AA 24.5 ± 3.2, 5.6 ± 1.1 (n = 9), treated with new AEDs. After folate therapy, plasma t‐Hcy and folate were normal in all patients. At 6 months, 43 patients (72.9%) exhibited hyper‐tHcy, the greater proportion belonging to the EI‐AED‐MTHFR677TT/1298AA (39%). Knowledge of the hyper‐tHcy recurrence time after folate therapy discontinuation may help in optimizing folate supplementation pulses.

α-Synuclein in CSF of patients with severe traumatic brain injury

Objective: The study aims to examine α-synuclein in the CSF of patients with severe traumatic brain injury (TBI) and its relationship with clinical characteristics and long-term outcomes. Methods: This prospective case-control study enrolled patients with severe TBI (Glasgow Coma Score ≤8) who underwent ventriculostomy. CSF samples were taken from each TBI patient at admission and daily for up to 8 days after injury and successively assessed by ELISA. Control CSF was collected for analysis from subjects receiving lumbar puncture for other medical reasons. We used trajectory analysis to identify distinct temporal profiles of CSF α-synuclein that were compared with clinical outcomes. Results: CSF α-synuclein was elevated in TBI patients after injury as compared to controls (p = 0.0008). Overall, patients who died had higher concentrations (area under the curve) over 8 days of observation compared to those who survived at 6 months postinjury (p = 0.002). Two distinct temporal α-synuclein profiles were recognized over time. Subjects who died had consistently elevated α-synuclein levels compared to those who survived with α-synuclein levels near controls. High-risk trajectory was a strong and accurate predictor of death with 100% specificity and a very high sensitivity (83%). Conclusions: Taken together, these data support the hypothesis that in severe TBI patients, substantial increase of CSF α-synuclein may indicate widespread neurodegeneration and reflect secondary neuropathologic events occurring after injury. The determination of CSF α-synuclein may be a valuable prognostic marker, adding to the clinical assessment and creating opportunities for medical intervention.

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.

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.

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.

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.