Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate

Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.     

Seizures and EEG pattern in the 22q13.3 deletion syndrome: Clinical report of six Italian cases

PurposeThe 22q13.3 deletion syndrome, also known as Phelan–McDermid syndrome, is a rare genetic disorder characterized by hypotonia, severely impaired development of speech and language, autistic-like behaviour, and minor dysmorphic features. Neurologic problems may include seizures of different types, such as febrile, generalized tonic–clonic, focal, and absence seizures. No peculiar EEG features have been associated with 22q13 deletion syndrome to date. In order to verify if a peculiar clinical and EEG pattern is present in 22q13.3 deletion syndrome, we studied six Italian patients with this chromosome abnormality.MethodArray CGH analysis was carried out in the six subjects (1 male, 5 females, age range 11–30 years, median 19.5). They underwent a complete general and neurologic examinations. The EEG study consisted of at least one awake and one nap–sleep video-EEG recordings and evaluation of other EEGs performed elsewhere.ResultsThree subjects suffered from myoclonic or generalized tonic–clonic seizures with a rather benign course; all showed multifocal paroxysmal abnormalities on EEG recording, predominant over the frontal–temporal regions, activated during sleep.Conclusion22q13.3 deletion syndrome seems to be associated, at least in a subgroup of patients, with a peculiar clinical and EEG pattern, characterized by a childhood epilepsy with a rather benign evolution and with multifocal paroxysmal EEG abnormalities activated by sleep.     

Multinodular and Vacuolating Neuronal Tumor of the Cerebrum (MVNT): A case series and review of the literature

Background and purposeMultinodular and Vacuolating Neuronal Tumor of the cerebrum (MVNT) is a benign –seizure associated– lesion affecting mostly adults. This new entity has been included in the 2016 World Health Organization classification of tumors of the central nervous system.Its pathologic hallmark consist of a subcortical cluster of nodular lesions located on the subcortical white matter.We aim to report a series of cases of presumed MVNT observed in our institution and review the literature.Materials and methodsIn this retrospective study, a search was performed on our hospital information system. Sixteen cases were included. Demographic, clinical and radiological features were detailed in a table.All patients had an MRI acquired either on a 1.5 or a 3 Tesla scanner. Sequences performed included T1, T2, GRE/SWI, T2 FLAIR and DWI. Gadolinium enhanced T1-WI wer available in 11 patients and follow-up MRI were available in 7 patients.ResultsPatient ages ranged from 16 to 77 years (mean 42 years). Seizure and non-focal headache were by far the most common neurological complaints for which MRI was requested. All lesions consisted of clusters of multiple, discrete, round or ovoid, intra-axial, FLAIR and T2-WI hyperintense nodules. Follow-up MRI scans showed no changes between studies.ConclusionsMVNT is a benign, stable lesion that exhibits a typical radiological pattern that most of the times sufficed to arrive to a diagnosis, without the need of pathological confirmation. We confirm that our demographic, clinical and radiological findings are in accordance with those published in international literature.     

Neuropeptides in epilepsy

Neuropeptides play an important role in modulating seizures and epilepsy. Unlike neurotransmitters which operate on a millisecond time-scale, neuropeptides have longer half lives; this leads to modulation of neuronal and network activity over prolonged periods, so contributing to setting the seizure threshold. Most neuropeptides are stored in large dense vesicles and co-localize with inhibitory interneurons. They are released upon high frequency stimulation making them attractive targets for modulation of seizures, during which high frequency discharges occur. Numerous neuropeptides have been implicated in epilepsy; one, ACTH, is already used in clinical practice to suppress seizures. Here, we concentrate on neuropeptides that have a direct effect on seizures, and for which therapeutic interventions are being developed. We have thus reviewed the abundant reports that support a role for neuropeptide Y (NPY), galanin, ghrelin, somatostatin and dynorphin in suppressing seizures and epileptogenesis, and for tachykinins having pro-epileptic effects. Most in vitro and in vivo studies are performed in hippocampal tissue in which receptor expression is usually high, making translation to other brain areas less clear. We highlight recent therapeutic strategies to treat epilepsy with neuropeptides, which are based on viral vector technology, and outline how such interventions need to be refined in order to address human disease.     

Sex Differences in Rats in the Development of and Recovery From Ethanol Dependence Assessed by Changes in Seizure Susceptibility

BACKGROUND: Previous investigations have found sex differences in rats in response to chronic ethanol exposure. The most dramatic differences were observed with anticonvulsant treatment during ethanol withdrawal, when seizure susceptibility is significantly increased. Sex differences in this response were found for both GABAergic and glutamatergic compounds. This study was aimed at exploring whether sex also influences the timing for the development of and recovery from ethanol dependence. METHODS: Ethanol was administered in a liquid diet, with pair-fed animals receiving dextrose, substituted isocalorically for the ethanol. Ethanol dependence and withdrawal were assessed by measurement of seizure thresholds after abrupt removal of the ethanol diet. Seizure thresholds were determined by slow, tail vein infusion of the gamma-aminobutyric acidA-receptor antagonist bicuculline. RESULTS: Male and female rats displayed differences in timing for both onset and recovery from ethanol dependence, as determined by changes in ethanol withdrawal seizure susceptibility. Female rats were slower to develop dependence and quicker to recover compared with male rats. Furthermore, acute ethanol administration did not alter seizure susceptibility in pair-fed control animals, but it was anticonvulsant in ethanol-withdrawn rats. Ethanol-withdrawn female rats showed a greater response to acute ethanol administration than did male rats. CONCLUSIONS: This set of experiments uncovered additional sex differences in one measure of ethanol dependence and withdrawal. Proposed mechanisms for the development of ethanol dependence involve alterations in subunit assembly of gamma-aminobutyric acidA and NMDA receptors or various posttranslational modifications. In consideration of these findings, whatever mechanisms underlie the development of ethanol dependence, there is a different sequence of events in male compared with female rats. Studies are ongoing to determine associations between behavioral measures of ethanol dependence/withdrawal and selective neuronal adaptations.