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PubMed1999

[Prognostic value of SPECT in newly diagnosed symptomatic West syndrome].

In 19 cases with newly diagnosed symptomatic West syndrome, we assessed interictal regional cerebral blood flow (rCBF) before ACTH therapy with single photon emission computed tomography (SPECT). Based on the SPECT findings, we divided these cases into 3 groups: normal rCBF (Group A, 7 cases), abnormal rCBF corresponding to cerebral lesions on MRI and CT (Group B, 6 cases), and abnormal rCBF in areas different from lesions on MRI and CT (Group C, 6 cases). We compared clinical features, response to initial treatment, and short-term outcome among these 3 groups. No significant differences were found in clinical characteristics (sex, age of onset, prior seizures before onset of spasms, EEG findings). Four cases in Group B (67%) and 5 in Group C (83%) showed complete cessation of spasms after initial treatment (high dose vitamin B6-->zonisamide-->ACTH therapy), while in Group A only 2 patients (29%, p > 0.05; compared to Group B or Group C) responded. Although not statistically significant, short-term prognosis (both seizures and development) after a mean follow-up of 2 years and 8 months was also worst in Group A. Our results suggest that normal SPECT findings may be predictive of unfavorable prognosis in infants with symptomatic West syndrome.

Female↗
PubMed1999

Preclinical evaluation of newly approved and potential antiepileptic drugs against cocaine-induced seizures.

Seizures and status epilepticus are among the neurological complications of cocaine overdose in humans. The aim of the present study was to evaluate the protective effectiveness and therapeutic index (separation between anticonvulsive and side effect profiles) of 14 newly approved and potential antiepileptic drugs using a murine model of acute cocaine toxicity and the inverted-screen test for behavioral side effect testing. Cocaine (75 mg/kg i.p.) produces clonic seizures (approximately 90% of mice), and conventional antiepileptic drugs have been reported to be either ineffective or only effective at doses producing significant sedative/ataxic effects. Clobazam, flunarizine, lamotrigine, topiramate, and zonisamide were ineffective against seizures up to doses producing significant motor impairment. In contrast, felbamate, gabapentin, loreclezole, losigamone, progabide, remacemide, stiripentol, tiagabine, and vigabatrin produced dose-dependent protection against cocaine-induced convulsions with varied separations between their anticonvulsant and side effect profiles: the protective index values (toxic TD(50)/anticonvulsive ED(50)) ranged from 1.26 (felbamate) to 7.67 (loreclezole), and gabapentin had the highest (protective index >152). Thus, several drugs were identified with greater protective efficacy and reduced motor impairment compared with classic antiepileptic drugs. Based on the proposed mechanism of action of these new anticonvulsants, it is noteworthy that 1) drugs that enhance gamma-aminobutyric acid-mediated neuronal inhibition in a manner distinct from barbiturates and benzodiazepines offer the best protective/behavioral side effect profiles, and 2) functional antagonists of Na(+) and Ca(2+) channels are generally ineffective. Overall, this study provides the first description of the effectiveness of new antiepileptic drugs against experimentally induced cocaine seizures and points to several drugs that deserve clinical scrutiny for this indication.

Animals↗
PubMed2000

Clinical pharmacology of new antiepileptic drugs.

Advances in neurobiology, molecular biology, and pharmaceutical science have led to the development of a number of new antiepileptic drugs (AEDs). The investigational AEDs described in this review include ganaxolone, levetiracetam, losigamone, pregabalin, remacemide, rufinamide, stiripentol, and zonisamide. They have shown efficacy in a variety of seizure types and offer hope for improved therapeutic efficacy, beneficial pharmacokinetics, and a decrease in the incidence of drug interactions and adverse events. As the results of ongoing clinical trials of these drugs become available, these medications may be considered for rational drug therapy of epilepsy, either singly or in combination with currently available AEDs.

Anticonvulsants↗
PubMed2000

Expanding first-line therapy options for children with partial seizures.

Carbamazepine and phenytoin are considered first-line therapies for children with partial seizures on the basis of the adult Veterans Administration studies, open-label controlled and uncontrolled pediatric studies, and clinical experience. Although many new antiepileptic drugs (AEDs) have demonstrated efficacy in controlled trials in adults with partial seizures, additional issues must be examined before these new AEDs are considered as first-line therapy for children with partial seizures. This article proposes three criteria for assessing the suitability of a new AED as first-line therapy for pediatric partial seizures: (a) demonstrated efficacy against pediatric partial seizures in two or more randomized, double-blind controlled trials involving patients less than 12 years old (with at least one of the trials utilizing a monotherapy design); (b) a favorable safety profile in monotherapy trials and no severe idiosyncratic reactions; and (c) ease of use in children across a wide range of ages. On the basis of these criteria, two new AEDs, oxcarbazepine (OXC) and topiramate (TPM), are suitable for consideration. OXC has demonstrated efficacy in monotherapy and adjunctive therapy in pediatric partial seizures, along with good tolerability and the ability to be titrated rapidly. TPM has also demonstrated efficacy and tolerability in pediatric partial seizures but should be titrated slowly. In addition, gabapentin (GBP) can be considered as first-line therapy for pediatric partial seizures if the preliminary analysis of a monotherapy trial is confirmed. There are not yet enough data on efficacy to support consideration of lamotrigine, tiagabine, felbamate, levetiracetam, or zonisamide as first-line therapy for pediatric partial seizures.

Anticonvulsants↗
PubMed2001

Advances in the treatment of epilepsy.

Significant advances have been made in the diagnosis and treatment of epilepsy over the past decade. With the advent of electroencephalographic video monitoring, physicians are now able to reliably differentiate epilepsy from other conditions that can mimic it, such as pseudoseizures. In addition, neuroimaging has changed the way treatment for difficult epilepsy is approached. As a result, the classification systems that have been in use since the early 1980s are currently being revised. A broader range of treatment options for epilepsy is now available. Many new antiepileptic drugs have become available in recent years, including felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine and zonisamide. These medications offer options for patients with epilepsy whose seizures cannot be controlled using the classic agents. Several classic antiepileptic drugs have been modified and reformulated. The ketogenic diet has resurfaced as a treatment option in certain types of epilepsy. The vagus nerve stimulator, approved in 1997, represents a completely new treatment modality for patients with seizures not controlled by medications. Epilepsy surgery is now a well-documented and effective treatment for some patients with intractable epilepsy.

Anticonvulsants↗
PubMed2001

[Efficacy of anticonvulsants on acute encephalitis with refractory, repetitive partial seizures (AERRPS)].

The first purpose of this study is to propose a new clinical entity, acute encephalitis with refractory, repetitive partial seizures (AERRPS), which satisfy the following five criteria: 1. a prolonged acute phase of more than 2 weeks; 2. partial seizures of the same seminology persisting from the acute phase to the convalescence; 3. seizures frequently evolving into convulsive status especially during the acute phase; 4. marked intractableness of seizures; 5. exclusion of related disorders such as known viral encephalitis or metabolic disorders. The second purpose is to evaluate the efficacy of therapeutic agents on AERRPS. We reviewed 21 cases reported previously, as well as one patient seen by us. Based on the data, we recommend that patients with AERRPS should be under a high dose intravenous barbiturate during the acute phase, followed by a high dose of phenobarbital or phenytoin in the convalescence. Clonazepam, zonisamide, and potassium bromide were sometimes effective during the recovery phase.

Acute Disease↗
PubMed2000

Pharmacotherapy of epilepsy.

Epilepsy represents the most common serious neurologic complications affecting approximately 1% of the world's populations. Although standard therapy permits control of seizures in about 80% of affected individuals, millions of global population have uncontrolled epilepsy. In the United States alone, the uncontrolled epilepsy represents more than 500,000 people. In the past decade, we have witnessed an array of new generations of antiepileptic drugs (AEDs) with more favorable pharmacokinetics and pharmacodynamic parameters, providing wider option to neurologists/epileptologists for more clinically effective and safer treatment. This was in part due to our better understanding of neural and molecular mechanisms in recurrent seizures. The new generations of AEDs currently include tiagabine, vigabatrin, lamotrigine, zonisamide, felbamate, oxacarbazine, topiramate, and gabapentine. There will be newer generations of AEDs being developed by pharmaceutical companies in United States, Japan, and European countries and will enter into global market sometimes during this decade. Although more clinical trails concerning the existing new generations of AEDs are needed, the available data suggest that in principal, these agents offer advantageous in terms of seizure control, fewer side effects and drug-drug interactions compared to traditional agents phenytoin, carbamazepine, phenobarbital, and valproate. The new generations of AEDs are significantly more expensive than the traditional agents. The two most clinical concerns over the use of traditional AEDs include (i) deleterious adverse effects and (ii) drug interactions, however, these agents are widely used in the third world countries. A thorough understanding of clinical pharmacology of both traditional and new antiepileptic agents will enable clinicians to have better appreciation of their clinical use and the treatment outcome, especially when the traditional agents are pharmacoeconomically preferred. Clinical pharmacology of AEDs is a vast science in medicine consisted of two principal arms, (i) pharmacokinetics and (ii) pharmacodynamics. This article briefly describes the pros and cons of common AEDs in practice, with more emphasis on new AEDs.

Anticonvulsants↗
PubMed2002

Gateways to Clinical Trials. June 2002.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, alicaforsen sodium, almotriptan, alteplase, amlodipine, amoxicillin trihydrate, amprenavir, argatroban monohydrate, aspirin, atorvastatin calcium, azathioprine; Baclofen, benidipine hydrochloride, benserazide, BMS-214662, bosentan, botulinum toxin type B; Candesartan cilexetil, carbamazepine, carbidopa, carboplatin, ceftriaxone sodium, celecoxib, cetirizine hydrochloride, clarithromycin, clavulanate potassium, clopidogrel hydrogensulfate, clozapine, CPI-1189, cyclophosphamide, cytarabine; Darbepoetin alfa, denileukin diftitox, dexamethasone, dipyridamole, droperidol, DW-166HC; Ebastine, efalizumab, efavirenz, eletriptan, enalapril maleate, enfuvirtide, enoxaparin sodium, enrasentan, entacapone, epoetin, eprosartan mesilate, etanercept, etoricoxib; Fenofibratefexofenadine hydrochloride, filgrastim, fludarabine phosphate, fluoxetine hydrochloride fluvoxamine maleate, frovatriptan, furosemide; Gabapentin, galantamine hydrobromide, gatifloxacin, gefitinib, ghrelin (human), glatiramer acetate; Haloperidol; Ibuprofen, ibuprofen, guaiacol ester, idarubicin hydrochloride, imipramine hydrochloride, imiquimod, interferon beta, interferon beta-1a, interferon beta-1b, interferon omega, irbesartan, itraconazole; Ketorolac, ketorolac tromethamine; Lamifiban, lamotrigine, lanoteplase, lansoprazole, leflunomide, leuprorelin acetate, levetiracetam, levocetirizine, levodopa, lisinopril, loratadine; Manidipine, methylprednisolone, metronidazole, mirtazapine, mizolastine, modafinil, morphine sulfate; Naproxen sodium, naratriptan hydrochloride, nifedipine, NSC-683864; Ofloxacin, olanzapine, omalizumab, omapatrilat, ondansetron hydrochloride, oxcarbazepine; Paclitaxel, parecoxib sodium, paroxetine hydrochloride, phenytoin sodium, pimecrolimus, pramipexole hydrochloride, pravastatin, prednisone, pregabalin; Quetiapine fumarate; Ranitidine hydrochloride, rasburicase, ritonavir, rivastigmine tartrate, rizatriptan benzoate, rofecoxib; Saquinavir mesilate, sertraline, sildenafil citrate, simvastatin, sumatriptan succinate; Tacrolimus, tiagabine hydrochloride, ticlopidine hydrochloride, tirofiban hydrochloride, tolvaptan, topiramate, tretinoin; Valproic acid, valsartan, venlafaxine hydrochloride, verapamil; Warfarin sodium; Ximelagatran; Zanamivir, ziconotide, zolmitriptan, zonisamide.

Drug Therapy↗
PubMed2002

[Monitoring serum levels of new antiepileptics].

AIM: Therapeutic monitoring of old antiepileptic drugs has been useful in improving their use in clinical practice. The new antiepileptic drugs have been developed with the idea that monitoring their serum levels was going to be unnecessary. We review the characteristics of the new antiepileptic drugs that can be relevant to their being monitored and their possible uses. DEVELOPMENT: After discussion of the evolution of the therapeutic monitoring of antiepileptic drugs in general, we take a more detailed look at the requirements needed for it to be useful, such as the indications, the procedure and a correct interpretation of the results. We point out the reasons why monitoring the new antiepileptic drugs can be worthwhile and we examine the characteristics of felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide which may be relevant in their monitoring. These include the type of kinetics, the factors that have an influence on the relationship between dosage and serum levels, the concentration/dose ratio, data on the relationship between serum levels and effects, the factors that can influence this relationship, as well as the characteristics of sampling. CONCLUSION: The new antiepileptic drugs present a wide interindividual and intraindividual variability which leads us to believe that some of they may be suitable candidates for therapeutic monitoring, but at present no target ranges have been clearly defined for any of them. Therefore, routine monitoring cannot be recommended, but it may be useful to establish an individual reference level that allows control over compliance and dosage readjustment in the presence of factors that alter their pharmacokinetics. Specific prospective studies are needed to establish target ranges that allow to individualize dosage in the absence of clinical criteria and to resolve doubts about the efficacy and toxicity of these drugs. Quicker and simpler assays that make monitoring easier are also needed.

Anticonvulsants↗
PubMed2002

Pharmacokinetics of mood stabilizers and new anticonvulsants.

Mechanisms of action, efficacy spectra, pharmacokinetics, and adverse effects differentiate the mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA). Lithium, which has a low therapeutic index, is excreted through the kidneys, resulting in renally mediated, but not hepatically mediated, drug-drug interactions. CBZ also has a low therapeutic index and is metabolized primarily by a single isoform (CYP3A3/4). It has an active epoxide metabolite, is susceptible to CYP3A3/4 or epoxide hydrolase inhibitors, and is able to induce drug metabolism (both via cytochrome P450 oxidation and conjugation). CBZ thus has multiple problematic drug-drug interactions. In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, and it is less susceptible to pharmacokinetic drug interactions. Still, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of certain medications by displacing them from plasma proteins. The newer anticonvulsants lamotrigine, topiramate, and tiagabine have different, generally less problematic, hepatically mediated drug-drug interactions. Gabapentin, which is renally excreted, lacks hepatic drug-drug interactions, though bioavailability may be reduced at higher doses. Recently approved anticonvulsants, including oxcarbazepine, zonisamide, and levetiracetam, may have improved pharmacokinetic profiles compared to older agents. Novel psychotropic effects of these drugs may also be demonstrated, based on their mechanisms of action and preliminary clinical data.

Affect↗
PubMed2003

Review of the newer antiepileptic drugs.

This review article discusses the newer anti-epileptic drugs gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, and zonisamide. Emphasis is given to FDA-approved indications and place in therapy. The mechanisms of action and pharmacokinetics of each drug is provided and the most common adverse effects are reviewed. Clinical studies leading to FDA approval are discussed. Practical points on proper dosing and monitoring are stressed, and drug interactions are also included.

Anticonvulsants↗
PubMed2002

[A case of bilateral perisylvian polymicrogyria with epileptic attacks of focal inhibitory seizure followed by complex partial seizure].

A 20 year-old woman began to have epileptic attacks of focal inhibitory seizure with paralysis and hypesthesia of her left or right upper limb followed by complex partial seizure several times a week since age 19. She was born by breech presentation and umbilical cord was coiling around her neck at birth. EEG showed spike foci on P 3, O1 and T5. Cerebral MRI with 4 mm-section inversion recovery image revealed bilaterally symmetrical polymicrogyria involving the posterior portion of sylvian fissure extending posteriorly to the inner cortex of the postcentral gyrus and the supramarginal gyrus, and she was diagnosed as bilateral perisylvian polymicrogyria. 99mTc-ECD SPECT showed increased cerebral blood flow over the bilateral polymicrogyric lesion. On cerebral MRA, bilateral middle cerebral arteries were narrow all way through. Epileptic attacks were controlled with zonisamide and carbamazepin. This is a rare case of bilateral perisylvian polymicrogyria because epileptic attacks were the only manifestation and the patient showed neither mental retardation nor neurological abnormality.

Adult↗
PubMed2003

Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation.

Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Most antiepileptic drugs (AEDs) have been associated with such risk. Valproate and carbamazepine have been associated specifically with the development of neural tube defects (NTDs), especially spina bifida. Other factors may contribute to the risk, including concomitant diseases such as diabetes mellitus, occupational exposure to teratogens, excessive prepregnancy weight, and various nutrient deficiencies. In the general population, maternal folate deficiency, in particular, has been linked with the development of NTDs, and periconceptional folate supplementation with a reduction of risk. It is unclear whether folate supplementation has a comparable protective effect for WWE. Data concerning the risk for congenital malformations associated with the newer AEDs (gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) are still limited. Several pregnancy registries for women taking AEDs have been established. Comprehensive postmarketing surveillance, regionally or nationally, might be the ideal method of monitoring medication safety, but government support for such an undertaking has for the most part been lacking. Despite uncertainty about the efficacy of periconceptional folate supplementation in WWE, these women should receive such supplementation at dosage levels recommended for the general population of women of childbearing age. Seizure control must not be neglected in a pregnant woman with epilepsy since seizures are associated with harm to the fetus as well as the mother. Risk may be minimized by using a single AED at the lowest effective dosage.

Abnormalities, Drug-Induced↗
PubMed2003

[An autopsy case of encephalopathy associated with small cell carcinoma of the stomach with nonconvulsive status epilepticus resembling Creutzfeldt-Jakob disease].

A 64-year-old man developed progressive dementia and altered consciousness with myoclonus over 2 months. Neurological examination revealed mild dysphagia and negative myoclonus of both hands. Electroencephalography (EEG) showed continuous periodic synchronous discharge (PSD) of 1 Hz, although his EEG abnormality was not similar to that usually observed in Creutzfeldt-Jakob disease (CJD). Magnetic resonance imaging (MRI) of the brain revealed only few lacunes. Laboratory data were also normal. Since his consciousness level fluctuated and the PSD were spiky, we came to a diagnosis of nonconvulsive status epilepticus (NCSE). After administering the valproic acid, his symptoms and EEG finding improved. Nine months after the onset, despite his continued valproic acid, the patient had recurrent NCSE and PSD of 1 Hz. Diffusion-weighted MRI showed a T2-hyperintense lesion in the right parietal lobe, where SPECT scans showed hyperperfusion. After adding zonisamide, he improved slowly. The follow-up MRI and SPECT showed a disappearance of the previous lesion. Now CT scans of the abdomen showed enlarged periaortic lymph node and endoscopic ultrasonography disclosed a submucosal tumor of the stomach. Biopsy of the periaortic lymph node by laparotomy revealed undifferentiated adenocarcinoma with its origin being unclear. Chemotherapy didn't work well for the tumor and the patient underwent a downhill course, although his mental and neurological manifestation were mostly unremarkable. Two years and four months after the onset, he died in emaciation. Autopsy confirmed small cell carcinoma originating in the stomach and metastases in the liver and lungs. Neuropathological examination revealed only mild scattered gliosis. This case was unique in the prolonged CJD-like manifestations, which turned out to be due to NCSE. Despite anti-neuronal antibodies were not detected, we suspect yet another paraneoplastic brain syndrome in this patient.

Aged↗
PubMed2003

Mechanism of action of newer anticonvulsants.

Bipolar disorder, like epilepsy, is episodic in nature. It should not be surprising, then, that anticonvulsants such as carbamazepine and valproate have proven efficacy as mood stabilizers. The newer anticonvulsants-agents like lamotrigine, gabapentin, topiramate, oxcarbazepine, and zonisamide-may also be effective treatments for bipolar disorder. Identifying an anticonvulsant for use in bipolar disorder should take into account not only the pathophysiology of bipolar disorder but also the mechanism of action of the anticonvulsant. This article will explore the mechanisms of action of the newer anticonvulsants and their relationship to the pathophysiology of bipolar disorder in an attempt to determine which of these agents might make effective mood stabilizers.

Animals↗
PubMed2003

[A case of intractable epilepsy showing frequent gelastic seizures by administration of clobazam].

A 13-year-old boy patient had severe mental retardation and spastic quadriplegia due to fetal distress and hypoxic-ischemic brain damage in the perinatal period. He suffered from West syndrome at the age of 7 months, and subsequently was diagnosed as having symptomatic localization-related epilepsy. His intractable epileptic seizures were not controlled by combination of various antiepileptic drugs. After prescribing nitrazepam and zonisamide for more than 1 year, we added clobazam (CLB), which has been marketed in Japan since 2000, to this combination therapy. After the introduction of CLB, tonic seizures disappeared. However, gelastic seizures laughing with a stiff face and a wry mouth appeared frequently before falling asleep, and sleep disturbance worsened subsequently. It has not been reported previously that gelastic seizures are a side effect of CLB, although irritability and sleep disturbance have been described.

Adolescent↗
PubMedDate not supplied

[West's syndrome. Analysis, aetiological factors and therapeutic options].

West's syndrome (WS), which is also known as infantile myoclonic encephalopathy with hypsarrhythmia, is one of the generalized epileptic syndromes with a cryptogenic or symptomatic origin. It is an age-dependent epileptic syndrome. The latest neuroimaging techniques have enabled us to gain a better understanding of its physiopathology and to identify new aetiological factors responsible for the clinical symptoms. WS can be due to a number of aetiologies, the most notable of which are congenital errors of metabolism. The incidence of cases due to phenylketonuria or hypoglycaemia is currently diminishing, yet, there is a rise in the number of new metabolic diseases that are responsible for the symptoms of WS. These include the carbohydrate-deficient glycoprotein syndromes or biotinidase deficiency. In all cases, and especially so in those that are idiopathic, it is wise to conduct exhaustive aetiological studies, since on some occasions metabolic diseases will be shown to be responsible, and this will then modify the prognosis, therapy and genetic counselling. It is important to have a protocol for both study and therapy available for this syndrome. The therapeutic options available can be implemented after ruling out a neurometabolic disease as being responsible for the syndrome and quickly beginning treatment with vigabatrine, sodium valproate plus pyridoxine, ACTH or hydrocortisone. If there is no response then topiramate can be used. Other therapeutic options, such as the use of zonisamide, a ketogenic diet or even surgical treatment, are also analyzed.

Clinical Protocols↗
PubMed1992

[Choroid plexus papilloma of the third ventricle in infancy: a case report].

The incidence of choroid plexus papilloma is about 0.5% of all intracranial tumors, but they are only infrequently found in the third ventricle. This is a case report of choroid plexus papilloma of the third ventricle in an infant. A make child in his 7th month of age was admitted because of large head circumference, on the 28th February, 1989. CT scan demonstrated hydrocephalus caused by a tumor in the third ventricle. Total removal of the tumor was performed on the 8th of March. Histologically the tumor was found to be choroid plexus papilloma. The patient suffered from postoperative subdural effusion and convulsions, so we performed ventriculoperitoneal shunt on the 14th April, and convulsions were controlled by zonisamid.

Age Factors↗