The role of angiotensin receptor blockers in treating epilepsy: a review.

Epilepsy is a chronic brain disease with a global prevalence of 70 million people. According to the World Health Organization, roughly 5 million new cases are diagnosed every year. Anti-seizure drugs are the treatment of choice. However, in roughly one third of the patients, these drugs fail to produce the desired effect. As a result, finding novel treatments for epilepsy becomes inevitable. Recently, angiotensin receptor blockers have been proposed as a treatment to reduce the over-excitation of neurons in epilepsy. For this purpose, we conducted a review using Medline/PubMed and Google Scholar using the relevant search terms and extracted the relevant data in a table. Our review suggests that this novel approach has a very high potential to treat epilepsy, especially in those patients who fail to respond to conventional treatment options. However, more extensive and human-based trials should be conducted to reach a decisive conclusion. Nevertheless, the use of ARBs in patients with epilepsy should be carefully monitored keeping the adverse effects in mind.

Neuroprotective effect of Arthrospira (Spirulina) platensis against kainic acid-neuronal death.

Context Arthrospira (Spirulina) platensis (SP) is a cyanobacterium which has attracted attention because of its nutritional value and pharmacological properties. It was previously reported that SP reduces oxidative stress in the hippocampus and protects against damaging neurobehavioural effects of systemic kainic acid (KA). It is widely known that the systemic administration of KA induces neuronal damage, specifically in the CA3 hippocampal region. Objective The present study determines if the SP sub-chronic treatment has neuroprotective properties against KA. Materials and methods Male SW mice were treated with SP during 24 d, at doses of 0, 200, and 800 mg/kg, once daily, and with KA (35 mg/kg, ip) as a single dose on day 14. After the treatment, a histological analysis was performed and the number of atrophic neuronal cells in CA3 hippocampal region was quantified. Results Pretreatment with SP does not protect against seizures induced by KA. However, mortality in the SP 200 and the SP 800 groups was of 20%, while for the KA group, it was of 60%. A single KA ip administration produced a considerable neuronal damage, whereas both doses of SP sub-chronic treatment reduced the number of atrophic neurons in CA3 hippocampal region with respect to the KA group. Discussion The SP neurobehaviour improvement after KA systemic administration correlates with the capacity of SP to reduce KA-neuronal death in CA3 hippocampal cells. This neuroprotection may be related to the antioxidant properties of SP. Conclusion SP reduces KA-neuronal death in CA3 hippocampal cells.

The anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1ß and TNF-α expression in rat hippocampus.

In the present study, the effects of the two classical anti-epileptic drugs, carbamazepine and valproic acid, and the non-classical anti-seizure drug vinpocetine were investigated on the expression of the pro-inflammatory cytokines IL-1ß and TNF-α in the hippocampus of rats by PCR or western blot after the administration of one or seven doses. Next, the effects of the anti-seizure drugs were investigated on the rise in cytokine expression induced by lipopolysaccharides (LPS) inoculation in vivo. To validate our methods, the changes induced by the pro-convulsive agents 4-aminopyridine, pentylenetetrazole and pilocarpine were also tested. Finally, the effect of the anti-seizure drugs on seizures and on the concomitant rise in pro-inflammatory cytokine expression induced by 4-aminopyridine was explored. Results show that vinpocetine and carbamazepine reduced the expression of IL-1ß and TNF-α from basal conditions, and the increase in both pro-inflammatory cytokines induced by LPS. In contrast, valproic acid failed to reduce both the expression of the cytokines from basal conditions and the rise in IL-1ß and TNF-α expression induced by LPS. Tonic-clonic seizures induced either by 4-aminopyridine, pentylenetetrazole or pilocarpine increased the expression of IL-1ß and TNF-α markedly. 4-aminopyridine-induced changes were reduced by all the tested anti-seizure drugs, although valproic acid was less effective. We conclude that the anti-seizure drugs, vinpocetine and carbamazepine, whose mechanisms of action involve a decrease in ion channels permeability, also reduce cerebral inflammation. The mechanism of action of anti-seizure drugs like vinpocetine and carbamazepine involves a decrease in Na(+) channels permeability. We here propose that this mechanism of action also involves a decrease in cerebral inflammation.

First European case of convulsions related to analytically confirmed use of the synthetic cannabinoid receptor agonist AM-2201.

PURPOSE: There is increasing reported use of synthetic cannabinoid receptor agonists (SCRA) across Europe. To date, there is limited information on the acute toxicity (harm) related to the use of these products. We describe here a case in which an individual developed convulsions related to the use of the SCRA AM-2201. CASE REPORT: A 20 year old male smoked a "Spice" (SCRA-containing) product called "Black Mamba," and rapidly after smoking, he had a generalised self-terminating tonic-clonic convulsion. After a 2 h observation period in the Emergency Department (ED), he self-discharged against medical advice. Subsequent analysis of urine collected at the time of presentation to the ED detected metabolites of AM-2201; no other drugs were detected on extensive analytic screening. DISCUSSION: This is the first case of convulsions related to the use of SCRA described in Europe, and the first case of convulsions related to the use the SCRA AM-2201 confirmed by analysis of biological samples. It is important for emergency physicians, clinical toxicologists and clinical pharmacologists managing those presenting with acute toxicity related to the use of SCRA to analytically confirm the exact compound(s) involved, to enable accurate description of the acute toxicity associated with individual SCRA.

Generalized tonic-clonic seizures in adult patients following intravenous administration of desmopressin.

Desmopressin is a synthetic replacement for vasopressin, which is used to reduce perioperative blood loss. However, seizure attacks were observed in patients after administration of desmopressin. Here, we reported two cases of adult Chinese patients experienced generalized tonic-clonic seizures associated with severe hyponatremia caused by intravenously administered desmopressin after surgery. The patients' neurological conditions returned to baseline quickly and completely following discontinuation of desmopressin, control of the seizures, and fluid intake restriction. These cases illustrate the importance of periodic monitoring of electrolyte concentrations and fluid intake during use of desmopressin.

Methohexital-induced seizures during electroconvulsive therapy.

Methohexital is a common anesthetic agent used for electroconvulsive therapy. In the adult literature, there are a few case reports of tonic-clonic seizures occurring immediately after the administration of methohexital. However, to date, there are no reports of this occurrence in children or adolescents. This case documents a generalized tonic-clonic seizure in a 15-year-old girl after receiving 60 mg of methohexital and numerous prior episodes of bitemporal electroconvulsive therapy.

Voluntary exercise protects hippocampal neurons from trimethyltin injury: possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity.

In the periphery, exercise induces interleukin (IL)-6 to downregulate tumor necrosis factor (TNF), elevate interleukin-1 receptor antagonist (IL-1RA), decreasing inflammation. Exercise also offers neuroprotection and facilitates brain repair. IL-6 production in the hippocampus following exercise suggests the potential of a similar protective role as in the periphery to down-regulate TNFα and inflammation. Using a chemical-induced model of hippocampal dentate granule cell death (trimethyltin, TMT 2.4 mg/kg, ip) dependent upon TNF receptor signaling, we demonstrate neuroprotection in mice with 2 weeks access to running wheel. Exercise attenuated neuronal death and diminished elevations in TNFα, TNF receptor 1, myeloid differentiation primary response gene (MyD) 88, transforming growth factor ß, chemokine (C-C motif) ligand 2 (CCL2), and CCL3. Elevated mRNA levels for IL-1α, IL-1RA, occurred with injury and protection. mRNA and protein levels of IL-6 and neuronal expression of IL-6 receptor α, were elevated with injury and protection. Microarray pathway analysis supported an up-regulation of TNFα cell death signaling pathways with TMT and inhibition by exercise. IL-6 pathway recruitment occurred in both conditions. IL-6 downstream signal events differed in the level of STAT3 activation. Exercise did not increase mRNA levels of brain derived neurotrophic factor, nerve growth factor, or glial derived neurotrophic factor. In IL-6 deficient mice, exercise did not attenuate TMT-induced tremor and a diminished level of neuroprotection was observed. These data suggest a contributory role for IL-6 induced by exercise for neuroprotection in the CNS similar to that seen in the periphery.

Acetylcholine-mediated neurotransmission within the nucleus raphe magnus exerts a key role in the organization of both interictal and postictal antinociception.

The role of the acetylcholine-mediated system in the organization of postictal antinociception was investigated. For this purpose, nicotinic and muscarinic cholinergic receptor antagonists were microinjected into the nucleus raphe magnus (NRM), a key structure of the endogenous pain inhibitory system. After the tail-flick test baseline recording, male Wistar rats (N=8 per group) were submitted to stereotaxic surgery for the introduction of a guide cannula aiming at the NRM. Five days after surgery, atropine or mecamylamine (1 µg/0.2 µL, 3 µg/0.2 µL, or 5 µg/0.2 µL) was microinjected into the NRM. The tail-flick withdrawal latency was recorded immediately after peripheral treatment with pentylenetetrazole (PTZ) (64 mg/kg), in two different interictal time windows, and for 130 minutes after the last seizure evoked by intraperitoneal injection of PTZ. The blockade of GABA-mediated Cl(-) influx caused tonic-clonic convulsions in all animals followed by sustained postictal antinociception lasting 110 minutes after seizures; the nociceptive threshold was also found to be high in interictal periods. Pretreatment of the NRM with either atropine or mecamylamine antagonized both interictal and postictal antinociception, suggesting the involvement of cholinergic mechanisms recruiting muscarinic and nicotinic cholinergic receptors of the NRM in the organization of tonic-clonic seizure-induced antinociception.

Epileptic seizure induced by fennel essential oil.

An epileptic seizure is reported in a 38-year-old woman, known to be an epileptic patient. Although she was under antiepileptic treatment and had well-controlled epilepsy, she developed a typical generalised tonic-clonic seizure and remained unconscious for 45 minutes following ingestion of a number of cakes containing an unknown quantity of fennel essential oil. Involuntary diarrhoea accompanied her epileptic seizure. This reported case recalls the fact that fennel essential oil can induce seizures and that this oil should probably be avoided by patients with epilepsy. Labelling of products with fennel essential oil should refer to the risk of seizures, particularly for patients with epilepsy. An awareness programme should involve all stakeholders affected by this issue.

Possible long-acting risperidone-induced hypothermia precipitating phenytoin toxicity in an elderly patient.

WHAT IS KNOWN AND OBJECTIVE: Thermodysregulation, including hypothermia, is recognized as a potential adverse effect secondary to atypical antipsychotics. We report the first known case of hypothermia possibly associated with long-acting risperidone depot injection, precipitating further adverse events secondary to supratherapeutic phenytoin concentrations. CASE SUMMARY: A 75-year-old African-American female presented as a transfer from an outpatient psychiatric center with hypothermia (35·1 °C), bradycardia, altered mental status and a series of witnessed tonic-clonic seizures. The patient was discovered to be profoundly neutropenic (absolute neutrophil count = 266 × 10(9) /L) and a corrected phenytoin concentration was 147·708 µm. During the 3 months preceding admission, phenytoin dosing was stable and consecutive therapeutic concentrations were documented. The only recent change in medication regimen was a switch from oral risperidone to the long-acting injectable formulation. Upon discontinuation of the risperidone and phenytoin, the patient's mental status and laboratory abnormalities returned to baseline. The patient did not experience additional seizure activity. WHAT IS NEW AND CONCLUSION: This unintentional significant drop in core body temperature may have resulted in altered metabolism of phenytoin leading to supratherapeutic concentrations and subsequent tonic-clonic seizures, bradycardia and neutropenia. Low core body temperatures can alter the pharmacokinetic profiles of hepatically metabolized medications, prompting careful patient assessment especially in those receiving medications with a narrow-therapeutic index. Hypothermia should be recognized as a potential adverse event with the long-acting injectable formulation of risperidone.

Overdose of propafenone surreptitiously sold as "Percocet".

BACKGROUND: Drug abuse is a common problem in the United States. Drugs can be acquired in many ways, and can be knowingly or mistakenly misrepresented when sold. Propafenone is an uncommonly encountered class IC antidysrhythmic that is a look-alike for the opioid, oxycodone/acetaminophen 5/325. OBJECTIVE: We report a case of propafenone overdose presenting with generalized tonic-clonic seizure and a widened QRS complex, occurring after the patient had reported ingesting "Percocet®" (Endo Pharmaceuticals, Chadds Ford, PA). CASE REPORT: A 17-year-old boy presented to the emergency department (ED) after a witnessed seizure lasting 2 min. The patient reported having ingested 6 "Percocet®" tablets that he purchased from a classmate. He noted feeling weak and dizzy approximately 3 h after the ingestion, just before the seizure. On arrival in the ED, the patient was awake and alert with a QRS length of 168 ms. A sodium bicarbonate bolus and infusion shortened the QRS length to 90 ms. The patient was discharged the following day with no further complications. The pills were identified as propafenone hydrochloride (HCl) 225-mg tablets. The classmate surreptitiously sold the pills as "Percocet®" due to their similar "512" imprint. CONCLUSIONS: Pharmaceutical drugs are often sold on the street, and often misrepresented. Propafenone HCl 225-mg is an uncommonly encountered pharmaceutical, but is a look-alike for oxycodone/acetaminophen 5/325. An overdose due to propafenone ingestion may present with seizures and a widened QRS complex.

Zolpidem dependence and withdrawal seizure--report of two cases.

Zolpidem is a non-benzodiazepine property which binds selectively to the ?1-GABAA receptors, and has been widely prescribed to patients suffering from insomnia. We report two cases of zolpidem dependence with withdrawal seizure in the Asian population. The first case is a 43-year-old woman who took zolpidem up to the dosage of 200 to 400 mg per night. The second case is a 35-year-old woman who even began to take zolpidem every 15 to 30 minutes to get euphoric and relaxed, and she gradually increased the dosage to 400 to 500mg per day. After abrupt discontinuation of zolpidem, both cases immediately developed anxiety, global insomnia, restlessness, and tonic seizure. The purpose of this case report is to suggest that clinicians should pay close attention to the potential of zolpidem tolerance, abuse and dependence. The possibility of withdrawal seizure cannot be excluded especially at high doses.

Vigabatrin but not valproate prevents development of age-specific flexion seizures induced by N-methyl-D-aspartate (NMDA) in immature rats.

In immature rats, N-methyl-D-aspartate (NMDA) induces several seizure types: flexion seizures (FS; in rats younger than 3 weeks), clonic seizures (in animals older than 3 weeks), and clonic-tonic seizures (CTS; in rats of all ages). FS represent a model of human infantile spasms. Effects of vigabatrin and valproate against all types of NMDA-induced seizures were studied in rats at postnatal days 12 (P12) and 25 (P25). NMDA (60 or 300 mg/kg) was injected to animals pretreated with vigabatrin (300-1,200 mg/kg; 24 h before NMDA) or valproate (100-400 mg/kg; 15 min before NMDA). Vigabatrin suppressed FS in P12 rats, but was ineffective against CTS in both age groups. Valproate suppressed CTS in P12, but not in P25 rats. Clonic seizures were rare in NMDA-treated P25 rats, but valproate pretreatment increased their incidence significantly. Neither drug decreased NMDA-induced mortality, which occurred within approximately 15 min after NMDA administration and reached almost 100% in all groups.

Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model.

Some studies suggest a higher risk of hypertension in people with epilepsy. Captopril, a potent and selective angiotensin-converting enzyme (ACE) inhibitor, is a well known antihypertensive drug. Besides the peripheral renin-angiotensin system (RAS), ACE inhibitors are also suggested to affect the brain RAS which might participate in the regulation of seizure susceptibility. The purpose of the current study was to evaluate the effect of captopril on the protective action of numerous antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], valproate [VPA], phenobarbital [PB], oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) against maximal electroshock-induced seizures in mice. This study was accompanied by an evaluation of adverse effects of combined treatment with captopril and antiepileptic drugs in the passive avoidance task and chimney test. Captopril (25 and 50 mg/kg i.p.) did not influence the threshold for electroconvulsions. Among the tested antiepileptics, captopril (25 and 50 mg/kg i.p.) potentiated the antiseizure action of CBZ, decreasing its ED(50) value from 12.1 to 8.9 and 8.7 mg/kg, respectively. Moreover, captopril (50 mg/kg i.p.) enhanced the anticonvulsant activity of LTG. ED(50) value for LTG was lowered from 5.1 to 3.5 mg/kg. The observed interactions between captopril and CBZ or LTG were pharmacodynamic in nature as captopril did not alter plasma and total brain concentrations of these antiepileptics. The combinations of captopril with antiepileptic drugs did not lead to retention deficits in the passive avoidance task or motor impairment in the chimney test. Based on the current preclinical data, it is suggested that captopril may positively interact with CBZ and LTG in epileptic patients. The combinations of captopril with the remaining antiepileptics (PHT, VPA, PB, OXC and TPM) seem neutral.

Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome.

Posterior reversible encephalopathy syndrome (PRES) is known to occur after solid organ transplantation, and is caused by immunosuppressive agents such as tacrolimus. PRES onset usually occurs within the first 2months after liver transplantation. Clinical findings include seizures, headache, focal neurological deficits, visual disturbances, and altered mental status. These are associated with characteristic imaging features of subcortical white matter lesions on brain MRI. Atypical localizations of this posterior leukoencephalopathy have been reported. Expeditious recognition of the syndrome may lead to a complete recovery. Abnormalities of EEG during follow-up might be associated with unfavorable seizure outcome, even when neuroimaging changes resolve. We report a case of late-onset PRES with atypical localization following liver transplantation. The patient developed epilepsy despite resolution of MRI lesions at 8 months of follow-up. EEG was a prognostic factor of seizure persistence, suggesting an incomplete recovery of brain lesions in contrast to neuroimaging findings.

Levetiracetam-induced seizure aggravation associated with continuous spikes and waves during slow sleep in children with refractory epilepsies.

We present a patient with cryptogenic focal epilepsy and another with Dravet syndrome, who experienced seizure aggravation and negative myoclonus, associated with continuous spikes and waves during slow sleep, induced by levetiracetam. For both patients levetiracetam was discontinued, and there was significant improvement of this particular electroclinical picture.

Subacute methotrexate neurotoxicity and cerebral venous sinus thrombosis in a 12-year-old with acute lymphoblastic leukemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: homocysteine-mediated methotrexate neurotoxicity via direct endothelial injury.

From as early as the 1970s methotrexate has been associated with disseminated necrotizing leukoencephalopathy and other neurotoxic sequelae. Yet, a clear mechanism for methotrexate-induced neurotoxicity has not been established. The authors describe the case of a 12-year-old male with acute lymphoblastic leukemia and a homozygous methylenetetrahydrofolate reductase C677T mutation, who developed subacute methotrexate-induced toxicity and cerebral venous thrombosis after receiving intrathecal methotrexate. The role of homocysteine as a possible mediator in methotrexate-induced neurotoxicity via direct endothelial injury is discussed.

[Propofol-induced generalized tonic-clonic seizure: a case report].

A 23-year-old man with no history of convulsion underwent removal of the nails in his upper arm. He received propofol infusion after axillary brachial plexus block. Ten minutes after propofol infusion (15 minutes after axillary block), generalized tonic-clonic seizure occurred. The rate of propofol infusion was increased, and midazolam was given intravenously ; however, the seizure continued. Propofol infusion was withheld, and anesthesia was maintained with sevoflurane. The seizure gradually decreased in 15 minutes after termination of propofol infusion, and it finally stopped 30 minutes after termination of propofol infusion.

An Adult Case of Generalized Convulsions Caused by the Ingestion of Ginkgo biloba Seeds with Alcohol.

A 64-year-old woman developed symptoms of vomiting and tonic-clonic convulsions 9.5 h after eating 50 roasted Ginkgo biloba seeds with 100 g of alcohol. The intravenous administration of pyridoxal phosphate effectively improved the symptoms. Blood samples were collected and stored over 35 h. The assessment of 4'-O-methylpyridoxine and vitamin B6 vitamers indicated high levels of both, but the pyridoxal phosphate levels were low during the acute stage. These results suggest that 4'-O-methylpyridoxine inhibits the transformation of vitamin B6 analogues to the active form, pyridoxal phosphate. In our case, alcohol may have extended the period until ginkgo intoxication appeared.

Ondansetron and seizures.

Experimental studies suggest that 5-hydroxytryptamine (5-HT) receptors play a role in epileptogenesis and seizure propagation. Ondansetron, a 5-HT(3) receptor antagonist, has been reported to have proconvulsant and anticonvulsant effects in animals. We describe three patients who developed seizures after receiving ondansetron. There were two females and one male. Ages ranged from 38-56 years. None had a previous or family history of seizures. Four milligrams (mg) of ondansetron was given intravenously for severe nausea and vomiting in association with migraine, gastritis, and diabetic ketoacidosis. A generalized tonic-clonic seizure occurred in each patient--12, 15, and 22 min after injection. Brain magnetic resonance imaging (MRI) and electroencephalography (EEG) were normal in all patients. Although no antiepileptic drugs were given, none had seizure recurrence subsequently. The temporal relationship between ondansetron administration and seizures, lack of EEG or MRI abnormalities, and absence of seizure recurrence suggest that the seizures were causally related to ondansetron in our patients.