Lawrence D. Morton

Prospective population-based study of intermittent and continuous convulsive status epilepticus in Richmond, Virginia.

Summary: Purpose: Previous work suggested that there is a lower mortality for convulsive status epilepticus (SE) with intermittent seizures (intermittent SE) as opposed to SE with continuous seizure activity (continuous SE). A plausible hypothesis to explain this difference is that the shorter ictal time in intermittent SE is responsible for the lower mortality in this group. This study investigates the relative contributions of total ictal time and SE duration to the differing mortalities of intermittent and continuous SE.

Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial

This is a multicenter, open-label, add-on trial, investigating the safety and efficacy of ganaxolone (GNX) in a population of children with refractory infantile spasms, or with continuing seizures after a prior history of infantile spasms. A total of 20 children aged 7 months to 7 years were enrolled in this dose-escalation study, after baseline seizure frequencies were established. Concomitant antiepilepsy drugs were maintained throughout the study period. The dose of GNX was progressively increased to 36 mg/kg/d (or to the maximally tolerated dose) over a period of 4 weeks, then maintained for 8 weeks before tapering and discontinuation. Seizure diaries were maintained by the families, and spasm frequency was compared with the baseline period. The occurrence of adverse events was clinically monitored, and global evaluations of seizure severity and response to treatment were obtained. A total of 16 of the 20 subjects completed the study, 15 of whom had refractory infantile spasms at the time of study enrollment. Spasm frequency was reduced by at least 50% in 33% of these subjects, with an additional 33% experiencing some improvement (25-50% reduction in spasm frequency). Ganaxolone was well tolerated, and adverse events attributed to GNX were generally mild. Ganaxolone was safe and effective in treating this group of refractory infantile spasms patients in an open-label, add-on trial. Further investigation with randomized, controlled study design is warranted.

NEUTROPENIA IN A PATIENT RECEIVING INTRAVENOUS IMMUNE GLOBULIN

A child with Guillain-Barre syndrome treated with intravenous immune globulin (IVIG) developed neutropenia (absolute neutrophil count = 390), which resolved 3 days after completion of the therapy. Potential mechanisms for the development of neutropenia during the use of IVIG therapy are discussed. In this case, testing of the IVIG used revealed the presence of a high concentration of anti-neutrophil antibodies compared to other samples. It is recommended that white blood cell and neutrophil counts be monitored daily during the use of such therapy.

Hemodynamic monitoring prior to and at the time of death in status epilepticus

Status epilepticus (SE) is a common neurological and medical emergency. Despite the significant mortality associated with SE, no human data have been available regarding cardiovascular changes prior to death in patients with this condition. This study was conducted to measure hemodynamic trends in the 24 h prior to death in a series of 24 prospectively evaluated SE patients. Two distinct cardiovascular patterns of mean arterial pressure (MAP) and heart rate (HR) were observed. Ten patients had a gradual decline in MAP and/or HR, and this group was designated as having gradual cardiac decompensation (GCD). The remaining 14 patients showed no significant changes in either MAP or HR up to the time of death. This group of patients was designated as having acute cardiac decompensation (ACD). The changes in MAP and HR over the last 24 h prior to death between the GCD and ACD groups were statistically significant. Ninety percent of the GCD patients had a history of multiple risk factors for arteriosclerotic cardiovascular disease (ASCVD), while only 30% of the ACD group had a history of multiple risk factors for ASCVD. The results provide the first human data of cardiovascular events immediately preceding death in SE patients. We propose that further investigation of the cardiovascular pathophysiology of SE may provide new therapeutic interventions which could decrease the significant mortality associated with SE.

Diagnosis and treatment of epilepsy in children and adolescents.

SummarySeizures have a variety of aetiologies and may have various manifestations. Some are recurrent and represent the different types of epilepsy, whereas others are isolated events. Descriptions of various epileptic seizures, as well as their corresponding electroencephalograms (EEGs), have recently led to a unifying international classification of epileptic seizures and epilepsy syndromes. These classifications are extremely important for the practitioner working with the paediatric patient, as they allow for optimal evaluation and treatment.This article reviews the epilepsies and epilepsy syndromes with special attention to age of onset and prognosis. Special circumstances such as status epilepticus, which represents a true medical emergency, are reviewed. The first step in the pharmacological management of seizures is to establish the diagnosis of epilepsy. The recurrence of seizures (or the risk), seizure type and specific syndrome help guide initial treatment choices. There is no drug of choice, but some drugs have proven more effective for certain types of seizure. Monotherapy is preferable, and combination therapy should only be used if monotherapy with first-line drugs fails. Candidates for the newer antiepileptic drugs (e.g. felbamate, gabapentin, lamotrigine and vigabatrin) include patients resistant to older agents or who are unable to tolerate them. The exact place in therapy of these newer agents is uncertain, but in many patients they provide better seizure control and are better tolerated.

Clinical Experience With Fosphenytoin in Children

Fosphenytoin, a phenytoin prodrug, can be administered in a variety of intravenous diluents and has a more neutral pH value than phenytoin. The pharmacokinetics, safety, and tolerability of fosphenytoin in children from 1 day to 16 years old have been evaluated in two multicenter studies. Data are available from 78 patients who received loading doses (62 with intravenous administration and 16 with intramuscular administration). In these studies, fosphenytoin was converted to phenytoin within 8.3 minutes (range, 2.5-18.5 minutes). In addition, no significant difference in conversion rates was noted from the youngest to the oldest patient. No deaths or serious, alarming, or unexpected adverse events occurred; most adverse events were consistent with those seen with phenytoin therapy in adults. Both intravenous and intramuscular administration were well tolerated, with mild bruising, tenderness, swelling, and/or erythema seen at infusion and injection sites in a small number of patients. (J Child Neurol 1998;13(Suppl 1):S19-S22).

New drug therapy for acute seizure management

Several new agents have recently become available for the long-term treatment of epilepsy. Until now, there has been little change for the acute management of seizures. Three new agents may alter our present practice. Fosphenytoin has recently been approved as a substitute for parenteral phenytoin. It provides similar efficacy without the risk for infusion site injury while allowing greater flexibility in intravenous solutions. Intravenous valproate adds flexibility for patients on valproate, allowing patients to be rapidly loaded. In addition, it will prevent patients from having to change seizure medications when intervening medical illness or surgery do not allow medications by mouth. Viscous diazepam solution for rectal administration will allow for safe and effective treatment for seizures at home and will potentially decrease emergency department services and hospitalization.

Ischemic Stroke and Excellent Recovery After Administration of Intravenous Tissue Plasminogen Activator

Intravenous tissue plasminogen activator has become a mainstream treatment for ischemic hyperacute stroke in the adult population. Its safety and efficacy remain undetermined in the pediatric population. We present a teenager who was hospitalized with left-sided paralysis, and with decreased sensations on the left side. Head computed tomography indicated hyperdensity in the middle cerebral artery region, which confirmed the diagnosis of acute ischemic stroke. Her score on the National Institutes of Health stroke scale was 11. She received intravenous tissue plasminogen activator without any complications. At a follow-up visit 5 months after the stroke, the patient manifested mild apraxia in her left hand and mild expressive amusia. This case underscores the need for emergency head imaging in the pediatric population to establish a diagnosis. The excellent recovery in our patient indicates the need to establish thrombolytic treatment as an option for acute stroke in pediatric populations. It also suggests that tissue plasminogen activator can be used safely and effectively, even in pediatric populations. However, further studies are needed to establish the adequate dosage and adverse-effect profile in pediatric populations.

Treatment Options for Acute Seizure Care

The advent of new anticonvulsants, the resurgence of the ketogenic diet, and the currently available surgical techniques mean that practitioners have many options for long term prophylaxis of seizure recurrence. Unfortunately, breakthrough seizures still occur. In some situations, an additional dose of the patient’s maintenance medication, or adjustment of the daily dose, is the most appropriate course of action for the management of such breakthroughs. However, in some situations, the patient may be unwilling or unable to cooperate and so oral administration of anticonvulsants is not possible. Until recently, only benzodiazepines, phenytoin and phenobarbital (phenobarbitone) have been available for parenteral administration; however, alternative treatment options have been developed: diazepam gel for rectal administration, fosphenytoin (a phenytoin prodrug) and an intravenous formulation of valproic acid (sodium valproate).An intravenous formulation of diazepam has been long used for seizure treatment and has shown good efficacy. The gel formulation showed >60% efficacy for preventing seizures over 12 to 24 hours in 2 controlled studies. No life-threatening adverse reactions were reported. Fosphenytoin is rapidly converted to phenytoin with a conversion half-life of 8 to 15 minutes following intravenous administration, and can be given in a variety of solutions. It may also be administered intramuscularly. Fosphenytoin infusion has not been associated with tissue necrosis and there have been fewer cardiac complications than are seen with intravenous infusion of phenytoin. Intravenous valproic acid shows linear pharmacokinetics, and administration by this route has been demonstrated to maintain therapeutic concentrations in patients and offers an alternative when patients cannot take the drug orally. Intravenous valproic acid has been shown to be well tolerated.