Shaun A. Hussain

Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox–Gastaut syndrome

There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their childrens epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patients seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.

Treatment of infantile spasms with very high dose prednisolone before high dose adrenocorticotropic hormone

This study investigated the short‐term response to a standardized hormonal therapy protocol for treatment of infantile spasms.

A randomized placebo‐controlled lovastatin trial for neurobehavioral function in neurofibromatosis I

Lovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras‐MAPK pathway and associated with learning disabilities. We conducted a randomized double‐blind placebo‐controlled trial to assess lovastatins effects on cognition and behavior in patients with NF1.

Hypsarrhythmia assessment exhibits poor interrater reliability: A threat to clinical trial validity

Hypsarrhythmia is the classic interictal electroencephalographic pattern associated with infantile spasms, and characterized by high voltage, disorganization, and multifocal independent epileptiform discharges. Given this seemingly simple definition, one might expect excellent interrater reliability (IRR) in the identification of this pattern. Alternatively, it may be argued that assessments of voltage and disorganization are fairly subjective, and thus quite challenging in borderline cases. We sought to test the IRR of hypsarrhythmia assessment in a systematic fashion.

Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent.

Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB‐associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible—and largely asymptomatic—signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena.

Pharmacologic Treatment of Intractable Epilepsy in Children: A Syndrome-Based Approach

The successful pharmacologic treatment of intractable childhood epilepsy is predicated upon an accurate classification of the epilepsy syndrome. The selection of an antiepileptic drug is facilitated by the knowledge of syndrome-specific efficacy, the anticipation of potential side effects, and a careful risk-benefit assessment tailored to each patient. As such, the identification of comorbidities and careful monitoring for treatment-emergent adverse events, especially cognitive and behavioral effects, is of utmost importance. Especially in refractory cases, polypharmacy may increase the likelihood of side effects, but carefully chosen combinations can result in synergistic benefit. For most epilepsy syndromes, newer antiepileptic drugs typically yield equivalent efficacy and superior tolerability. Nevertheless, continued research is needed to further contrast the syndrome-specific efficacy and tolerability of available drugs and to foster the development of new agents with superior efficacy and side effect profiles.

Intraoperative fast ripples independently predict postsurgical epilepsy outcome: Comparison with other electrocorticographic phenomena

In the surgical management of epilepsy, the resection of cortex exhibiting interictal fast ripples (250-500Hz) on electrocorticography has been linked to postoperative seizure-freedom. Although fast ripples appear to accurately identify the epileptogenic zone-the minimum tissue that must be removed at surgery to achieve seizure-freedom-it has not been established that fast ripples are a superior biomarker in comparison with multimodal presurgical neuroimaging and other electrocorticography abnormalities. Hence, in the prediction of postoperative seizure-freedom, we compared the value of fast ripples with other intraoperative electocorticography abnormalities including focal slowing, paroxysmal fast activity, intermittent spike discharges, continuous epileptiform discharges, focal attenuation, and intraoperative seizures, as well as complete resection of the lesion defined by MRI and other neuroimaging. In a cohort of 60 children with lesional epilepsy and median postsurgical follow-up exceeding 4 years, who underwent resective epilepsy surgery with intraoperative electrocorticography, we evaluated the extent to which removal of each intraoperative electrocorticography abnormality impacts time to first postoperative seizure using the Kaplan-Meier method and Cox proportional hazards regression. Secondly, we contrasted the predictive value of resection of each competing electrocorticography abnormality using standard test metrics (sensitivity, specificity, positive predictive value, and negative predictive value). In contrast with all other intraoperative electrocorticography abnormalities, fast ripples demonstrated the most favorable combination of positive predictive value (100%) and negative predictive value (76%) in the prediction of postoperative seizures. Among all candidate electrocorticography features, time to first postoperative seizure was most strongly associated with incomplete resection of fast ripples (hazard ratio=19.8, p<0.001). In multivariate survival analyses, postoperative seizures were independently predicted by incomplete resection of cortex generating fast ripples (hazard ratio=25.4, 95%CI 6.71-96.0, p<0.001) and focal slowing (hazard ratio=5.79, 95%CI 1.76-19.0, p=0.004), even after adjustment for the impact of an otherwise complete resection. All children with incomplete resection of interictal FR-generating cortex exhibited postoperative seizures within six months. Notably, this cohort included many patients with large resections and thus limited opportunity to exhibit unresected fast ripples. Future study in a cohort with small resection volume, or a clinical trial in which resection margins are guided by fast ripple distribution, would likely yield a more precise estimate of the risk posed by unresected fast ripples. With a high detection rate during brief intraoperative electrocorticography and favorable positive and negative predictive value, interictal fast ripple characterization during surgery is a feasible and useful adjunct to standard methods for epilepsy surgery planning, and represents a valuable spatially-localizing biomarker of the epileptogenic zone, without the need for prolonged extraoperative electrocorticography.

Limited efficacy of the ketogenic diet in the treatment of highly refractory epileptic spasms

PURPOSE Numerous studies have suggested that the ketogenic diet is effective in the treatment of epileptic spasms, even in refractory cases. However, there has been very limited demonstration of prompt and complete (video-EEG confirmed) response. We set out to describe our centers experience with the ketogenic diet in the treatment of children with highly refractory epileptic spasms, with rigorous seizure outcome assessment. METHOD Children treated with the ketogenic diet for epileptic spasms between April, 2010 and June, 2014 were retrospectively identified. Seizure burden was tabulated at baseline and after 1, 3, 6, and 12-months of ketogenic diet exposure. Adverse events were similarly ascertained. RESULTS We identified a cohort of 22 consecutive patients who received ketogenic diet therapy, with median age of onset of epileptic spasms of 5.2 (IQR 2.0-9.0) months, with diet initiation beginning a median of 26.4 (12.5-38.7) months after onset, and following a median of 7 (IQR 5-7) treatment failures. Only 2 patients exhibited a complete response during ketogenic diet exposure, and response was more reasonably attributed to alternative therapies in both cases. A modest early reduction in seizure frequency was not sustained beyond 1 month of diet exposure. The diet was well tolerated, and continued in 6 patients with subjective and/or partial response. CONCLUSION In contrast to prior studies reporting substantial efficacy of the ketogenic diet, our findings suggest limited efficacy, albeit in a highly refractory cohort. Prospective studies in both refractory and new-onset populations, with both video-EEG confirmation of response and rigorous cognitive outcome assessment, would be of great value to more clearly define the utility of the ketogenic diet in the treatment of epileptic spasms.

A lack of clinically apparent vision loss among patients treated with vigabatrin with infantile spasms: The UCLA experience.

BACKGROUND Vigabatrin (VGB) is one of two FDA-approved medications for treatment of infantile spasms. Despite demonstrated efficacy, its use has been curtailed by reports indicating a substantial risk of VGB-associated visual field loss (VAVFL). As these reports have conflicted with our clinical observations in routine practice, we systematically reviewed the experiences of patients treated with VGB at UCLA to estimate the prevalence of clinically apparent VAVFL. METHODS Patients with video-EEG-confirmed infantile spasms evaluated at our center between February 2007 and February 2014 were retrospectively identified. Among patients with VGB exposure, we documented relevant clinical factors and determined the duration of therapy, peak dosage, and cumulative dosage. Based on a review of serial neurologic and ophthalmologic reports and aided by electroretinography (ERG) assessments when available, we ascertained whether each patient had evidence of clinically apparent vision impairment (i.e., recognized by a neurologist or ophthalmologist during any follow-up visit) and whether or not the vision loss was attributed to VGB exposure (i.e., evidence of bilateral, symmetric, and peripheral visual field loss), either by the treating physician or on retrospective review by the study team. RESULTS During the study period, 257 patients with video-EEG-confirmed infantile spasms were identified. One hundred and forty-three (56%) patients received VGB. Although visual loss of any cause was common among patients with (31%) and without (32%) VGB exposure, there were no cases in which visual field defects were plausibly linked to VGB. We estimate that the risk of clinically significant VAVFL does not exceed 3.2% (95% CI upper bound). Vision loss was never characterized as exclusively peripheral and was always better explained by other causes (e.g., hemianopsia following hemispherectomy and cortical vision impairment after hypoxic ischemic encephalopathy). Precise quantitative exposure data were available for 104 (73%) patients treated with VGB, among whom the median duration of treatment was 8.6 (IQR: 3.7-16.2) months, the median peak dosage was 141.5 (IQR: 104.8-166.0) mg/kg/day, and the median cumulative dosage was 314 (IQR: 140.8-645.7) grams. CONCLUSIONS We found that the risk of clinically apparent vision loss is quite low among young children treated for infantile spasms. Our estimate of risk contrasts with prior studies and likely reflects our ascertainment of vision loss without the aid of perimetry or serial ERG, the short treatment duration, and the relatively young age of our patients. In the treatment of infantile spasms, risk-benefit assessment should consider both the low prevalence of ERG-identified VAVFL among patients with brief (<6-9months) exposure and the very low prevalence of clinically apparent VAVFL in this population.

Prevention of infantile spasms relapse: Zonisamide and topiramate provide no benefit.

There is scant evidence to guide the management of infantile spasms after successful response to initial therapies. There is significant risk of relapse, largely because effective pharmacologic treatments cannot be continued long term because of concern for significant adverse events. Zonisamide (ZNS) and topiramate (TPM) are commonly used to prevent relapse, and the purpose of this study was to specifically evaluate the efficacy of ZNS and TPM as agents for secondary prevention of infantile spasms.