David Bearden

Targeted treatment of migrating partial seizures of infancy with quinidine

Migrating partial seizures of infancy is an early onset epileptic encephalopathy syndrome that is typically resistant to treatment. The most common cause is a gain of function mutation in the potassium channel KCNT1. The antiarrhythmic drug quinidine is a partial antagonist of KCNT1 and hence may be a candidate drug for treatment of this condition. We report the case of a child with migrating partial seizures of infancy secondary to an activating mutation in KCNT1 treated with quinidine. Treatment with quinidine was correlated with a marked reduction in seizure frequency and improved psychomotor development. Ann Neurol 2014;76:457–461

Pediatric Cerebral Palsy in Africa: A Systematic Review

Cerebral palsy is a common neurologic problem in children and is reported as occurring in approximately 2-2.5 of 1000 live births globally. As is the case with many pediatric neurologic conditions, very little has been reported on this condition in the African context. Resource-limited settings such as those found across the continent are likely to result in a different spectrum of etiologies, prevalence, severity as well as management approaches. This review aims to establish what has been reported on this condition from the African continent so as to better define key clinical and research questions.

Pediatric Cerebral Palsy in Africa: Where Are We?

Cerebral palsy is the most common cause of physical disability in children worldwide. However, little is reported on this condition in the African context. Doctors from 22 countries in Africa, and representatives from a further 5 countries outside Africa, met to discuss the challenges in the evaluation and management of children with cerebral palsy in Africa and to propose service needs and further research. Basic care is limited by the poor availability of diagnostic facilities or medical personnel with experience and expertise in managing cerebral palsy, exacerbated by lack of available interventions such as medications, surgical procedures, or even regular therapy input. Relevant guidelines are lacking. In order to guide services for children with existing disabilities, to effectively target the main etiologies and to develop preventive strategies for the continent, research priorities must include multicenter collaborative studies looking at the prevalence, risk factors, and treatment of cerebral palsy.

Enteroviruses in X-Linked Agammaglobulinemia: Update on Epidemiology and Therapy.

X-linked agammaglobulinemia (XLA) has been associated with a broad range of infections, but enteroviral disease represents one of the most damaging infections. The risk of enteroviral infection in XLA is lower now than in the setting of intramuscular immunoglobulin or in patients without immunoglobulin replacement, but the rate of infection has not declined significantly in the era of intravenous immunoglobulin replacement. Enteroviruses can cause inflammation of nearly every organ, but in XLA, infections often manifest as dermatomyositis or chronic meningoencephalitis. Difficulty and delay in recognizing symptoms and lack of specific therapy contribute to the poor outcomes. Furthermore, cerebrospinal fluid detection of enteroviruses is not very sensitive. Reluctance to perform brain biopsies can lead to significant delays. The other feature compromising outcomes is the lack of specific therapy. High-dose peripheral and intraventricular immunoglobulin have been used, but failure is still common. New antienteroviral drugs are in development and show promise for immunodeficient patients with life-threatening infections with enterovirus.

Treatment of Chronic Enterovirus Encephalitis With Fluoxetine in a Patient With X-Linked Agammaglobulinemia.

INTRODUCTION Enterovirus may result in a devastating chronic encephalitis in immunocompromised patients, particularly in patients with X-linked agammaglobulinemia. Prognosis for patients with chronic enterovirus encephalitis is poor, almost invariably resulting in mortality without specific treatment. There are currently no approved antiviral agents for enterovirus, but the antidepressant drug fluoxetine has been identified through library-based compound screening as a potential anti-enteroviral agent in vitro. However, use of fluoxetine has not previously been studied in humans with enteroviral disease. PATIENT DESCRIPTION A five year old boy with X-linked agammaglobulinemia presented with progressive neurological deterioration and was found to have chronic enterovirus encephalitis by brain biopsy. He failed to respond to standard treatment with high dose intravenous immunoglobulin, but showed stabilization and improvement following treatment with fluoxetine. CONCLUSIONS This is the first report to describe the use of fluoxetine as a potential therapy for chronic enterovirus infection. Further investigation of fluoxetine as a treatment option for chronic enterovirus encephalitis is necessary.

Early antiretroviral therapy is protective against epilepsy in children with human immunodeficiency virus infection in botswana.

Background: Seizures are common among patients with HIV/AIDS in the developing world and are associated with significant morbidity and mortality. Early treatment with combination antiretroviral therapy (cART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. Methods: A case–control study of new-onset epilepsy among children aged 0–18 years with perinatally acquired HIV/AIDS followed in Gaborone, Botswana, during the period 2003–2009 was conducted. Children with epilepsy were identified and compared with age- and sex-matched controls without epilepsy with respect to timing of cART initiation. Early treatment was defined as treatment with cART before the age of 12 months, at a CD4% of greater than 25 in children aged 1–5 years, or at an absolute CD4 count of >350 cell per cubic millimeter in children aged 5 years and older. Results: We identified 29 cases of new-onset epilepsy and 58 age- and sex-matched controls. The most common identified etiologies for epilepsy were central nervous system infections and direct HIV neurotoxicity. Only 8 (28%) of the children who developed epilepsy received early treatment compared with 31 (53%) controls (odds ratio: 0.36, 95% confidence interval: 0.14 to 0.92, P = 0.03). This effect was primarily driven by differences in rates of epilepsy among children who initiated treatment with cART between the ages of 1 and 5 years (11% vs. 53%, odds ratio: 0.11, 95% confidence interval: 0.01 to 1.1, P = 0.06). Conclusions: Earlier initiation of cART may be protective against epilepsy in children with HIV.

Should the Frascati criteria for HIV-associated neurocognitive disorders be used in children?

Cognitive impairment is likely common in children and adolescents with HIV infection in low-resource settings.1 While early treatment with highly active antiretroviral therapy has greatly reduced the most severe form of cognitive impairment in children,2 milder forms of cognitive impairment may be increasing in prevalence due to longer survival.3–5 Before 2007, marked heterogeneity in definitions of HIV-associated neurocognitive disorders (HAND) made it challenging to interpret different rates of cognitive impairment among regions or populations. The Frascati criteria, developed in 2007, created a uniform approach to the diagnosis of HAND in adults and vastly improved the ability of researchers to understand these disorders and their consequences. Application of the Frascati criteria requires neuropsychological testing in at least 5 cognitive domains, assessment of impairment of activities of daily living, and exclusion of other causes of cognitive impairment.6 Recently, several analyses suggest that the Frascati criteria have a high false-positive rate for milder forms of HAND in adults, which may limit the utility of these criteria.5,7,8 False-positive rates may be affected by incomplete exclusion of confounding disorders such as subclinical depression, drug use, educational deprivation, and effects of socioeconomic status.

Neurologic complications of rotavirus in neonates More common than we thought

Rotavirus is the most common cause of gastroenteritis in children worldwide, with near universal exposure to rotavirus by age 5.1 Rotaviruses belong to the family Reoviridae and are nonenveloped double-stranded RNA viruses.2 Neurologic complications are not uncommon in older children, occurring in approximately 2%–3% of all children with rotavirus gastroenteritis, with the most common manifestations being febrile or afebrile seizures.3 Less commonly, rotavirus can cause an acute encephalopathy or frank encephalitis. The mechanism by which rotavirus causes neurologic complications is unknown, although various hypotheses include direct viral invasion causing neuronal injury, viral toxin production, and excitotoxicity.3 Until recently, the conventional wisdom has been that while rotavirus is relatively common in neonates, neurologic complications are rare in this population.4

Response to Chong et al Letter to the Editor

We thank Dr Chong and colleagues for their comments regarding our paper on quinidine for migrating partial seizures of infancy (MPSI), also known as epilepsy of infancy with migrating focal seizures. In their letter, they describe a 6-year-old child with a history of intractable epilepsy secondary to a KCNT1 mutation. The child did not have an MPSI phenotype, and did not respond to treatment with quinidine. Although quinidine (or another, more selective, KCNT1 antagonist) remains a promising potential therapy for MPSI secondary to KCNT1 mutations, we agree that further study is required both to assess efficacy and to identify the appropriate population for treatment. We agree with Dr Chong and colleagues that possible contributing factors to the lack of effect of quinidine were the older age of their patient and lack of an MPSI phenotype. As we suggested in our initial report, for a variety of reasons older patients may not respond as well as younger patients. We also note that the recent study by Mikati et al found a significant effect of quinidine in a patient with an MPSI phenotype, but not in a second patient with a nocturnal frontal lobe epilepsy phenotype. Efficacy of quinidine for MPSI may depend on the underlying genetic mutation as well as the age of the patient and the epilepsy phenotype, although as of yet there appears to be no clear correlation between genotype and disease severity. Other factors influencing the effect of quinidine might include the dose, serum drug level, and background genetic effects. We note that in our published case report, seizure freedom occurred when the serum drug level was maintained at 2 to 5 mg/ml, which is higher than the level reported by Chong et al. Although at this point there is no evidence that higher levels are superior to lower levels, a dose-finding study would be necessary to clarify optimal dosing and levels. In addition, further studies are necessary to identify other factors that might contribute to treatment efficacy of quinidine. To this end, we have created a registry of patients with MPSI and other KCNT1-related epilepsy that will attempt to answer some of these questions. Since the initial patient described in our report, we have presented data on 14 additional patients with MPSI secondary to KCNT1 mutations treated with quinidine at the American Academy of Neurology meeting in 2015. In that case series, we noted that 7 of 14 patients with KCNT1-related MPSI treated with quinidine had a significant decrease in seizure frequency or became seizure free, whereas quinidine had little or no effect in the other 7 patients. It should be noted that case reports or series of this sort are likely to provide an unreliable estimate of actual efficacy due to placebo effect and reporting bias, and randomized controlled trials are still necessary to evaluate the efficacy of quinidine before it should be widely used clinically outside of a study. One of the challenges of developing treatments for rare diseases such as KCNT1-related epilepsy is the recruitment of enough patients to conduct studies to definitively assess efficacy. Although we suggest that a definitive randomized controlled trial of quinidine is necessary and are working to develop this, in the absence of such a trial we would strongly encourage neurologists working with patients with MPSI or other KCNT1-related epilepsy to contact the authors at Children’s Hospital of Philadelphia for enrollment in our registry. Utilizing this registry, we will be able to characterize the natural history of KCNT1-related epilepsy in preparation for a planned trial, and collect preliminary data on efficacy, side effects, and likely effective dose of quinidine.

Retinopathy in cerebral malaria New answers, new puzzles

Cerebral malaria is one of the most common neurologic diseases in the world. According to WHO estimates, in 2010 alone there were over 216 million cases of malaria, and over 650,000 deaths, with 90% of deaths occurring in children.1 Among survivors of cerebral malaria, neurologic sequelae are common, with almost a third of patients developing epilepsy or other neurodevelopmental disabilities.2 Despite this, we know surprisingly little about the pathophysiology of cerebral malaria. Presumably sequestration of the parasite in the central circulation, with parasitized red blood cells interrupting normal cerebral blood flow, plays an important role. However, recent evidence suggests that the pathophysiology may be modulated by downstream effectors including nitric oxide, immune activation, excitotoxicity, and disruption of the blood–brain barrier leading to increased intracranial pressure.3 Complicating any discussion of pathophysiology, however, is the difficulty in describing exactly what we mean when we talk about cerebral malaria. Cerebral malaria is defined by the …