First-line Treatment For Infantile Spasms Research Articles

Acthar Gel (RCI): A Narrative Literature Review of Clinical and Economic Evidence.

Acthar® Gel (repository corticotropin injection [RCI]) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides used to treat patients with serious and rare inflammatory and autoimmune conditions. This narrative review summarizes the key clinical and economic findings among 9 indications: infantile spasms (IS), multiple sclerosis (MS) relapses, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis and polymyositis (DM/PM), ocular inflammatory diseases (primarily uveitis and severe keratitis), symptomatic sarcoidosis, and proteinuria in nephrotic syndrome (NS). Key studies of clinical efficacy and healthcare resource utilization and cost from 1956 to 2022 are discussed. Evidence supports the efficacy of RCI across all 9 indications. RCI is recommended as first-line treatment for IS and is associated with improved outcomes for the other 8 indications, including increased recovery rates in MS relapse; improved disease control in RA, SLE, and DM/PM; real-world effectiveness in patients with uveitis and severe keratitis; improved lung function and reduced corticosteroid use in symptomatic sarcoidosis; and increased rates of partial remission of proteinuria in NS. For many indications, RCI may improve clinical outcomes during exacerbations or when conventional treatments have failed to show a benefit. RCI is also associated with a reduction in the use of biologics, corticosteroids, and disease-modifying antirheumatic drugs. Economic data suggest RCI is a cost-effective, value-based treatment option for MS relapse, RA, and SLE. Other economic benefits have been demonstrated for IS, MS relapses, RA, SLE, and DM/PM, including reduced hospitalizations, lengths of stay, inpatient and outpatient services, and emergency department visits. RCI is considered safe and effective and features economic benefits for numerous indications. Its ability to control relapse and disease activity makes RCI an important nonsteroid treatment option that could help preserve functioning and well-being among patients with inflammatory and autoimmune conditions.

Blood coagulation dynamics during adrenocorticotropic hormone therapy in pediatric patients with infantile spasms

IntroductionAdrenocorticotropic hormone (ACTH) therapy is a first-line treatment for infantile spasms, which may rarely cause intracranial hemorrhage. However, the changes in blood coagulation during ACTH therapy are poorly understood, with little description in the management guidelines. ObjectiveTo assess the changes in blood coagulation during ACTH therapy. Patients/MethodsThis retrospective study reviewed the medical records of 10 patients diagnosed with infantile spasms and treated with ACTH therapy, between January 2015 and March 2021. The underlying diseases included intracranial hemorrhage, hypoxic-ischemic encephalopathy, tuberous sclerosis, and cerebral infarction. Antiepileptic drugs administered were valproic acid (VPA), vitamin B6, zonisamide, topiramate, clobazam, clonazepam, and phenobarbital. ResultsThe 10 patients had a median age of 8 months (4–17 months) and included eight males. The median fibrinogen (Fbg) level before ACTH therapy was 202 mg/dL (125–392 mg/dL); however, this significantly decreased to 108.5 mg/dL (65–135 mg/dL) during treatment at a median of 12 days after (days 8–17) (p < 0.01). Decreased Fbg levels were observed with and without VPA. This suggests the possible influence of ACTH therapy on Fbg levels, irrespective of the VPA combination. Additionally, prothrombin time and activated partial thromboplastin time were significantly shortened when compared to those before ACTH therapy and at the lowest of Fbg levels. ConclusionsCareful coagulation monitoring, especially during the second week of treatment, is necessary for the safe completion of ACTH therapy, with or without concomitant VPA.

Risk of vigabatrin-associated brain abnormalities on MRI: A retrospective and controlled study.

Vigabatrin (VGB) is the first-line treatment for infantile spasms (IS). Previous studies have shown that VGB exposure may cause vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM). Based on previous studies, this study aimed to go further to explore the possible risk factors and the incidence of VABAM. In addition, diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) were compared to explore whether DWI should be used as a routine examination sequence when MRI is performed in children receiving VGB. Children with IS receiving VGB were selected as the study subjects. Whether VABAM occurred or not was categorized as the VABAM group and the non-VABAM group, respectively. Their general clinical data and medication exposure were collected. The possible risk factors of VABAM and different MRI sequences were compared and statistically analyzed. A total of 77 children with IS were enrolled in the study, of which 25 (32.5%) developed VABAM. Twenty-three of the 25VABAM cases have a peak dosage of VGB between 50 and 150mg/kg/day. The earliest observation time of VABAM was 30days. Regression analysis of relevant risk factors showed that the peak dosage of VGB was the risk factor for VABAM. Comparison between different MRI sequences showed that DWI is more sensitive than T2WI to the evaluation of VABAM. In our study, the occurrence of VABAM was 32.5%, indicating a higher incidence than in most previous reports. In addition, we once again verified that the peak dosage of VGB was the risk factor of VABAM. Caution should be exercised that our data also suggest that VABAM may occur even using the conventional dosage of VGB (ie, 50-150mg/kg/day). Therefore, even when using the conventional dosage of VGB, regular MRI examination should be required. Furthermore, DWI sequence should be used as a routine examination sequence when MRI is performed in children with IS who are receiving VGB.

Combined melatonin and adrenocorticotropic hormone treatment attenuates N-methyl-d-aspartate-induced infantile spasms in a rat model by regulating activation of the HPA axis

Infantile spasms (IS) is a serious epileptic syndrome that frequently occurs in infancy. Adrenocorticotropic hormone (ACTH) is generally the first-line treatment for IS; however, side effects limit its application. Melatonin (MT) has been used in clinical treatment for sleep disorders with only minor side effects. Further, MT was shown to be a powerful anticonvulsant in an animal model of epilepsy. In this research, we aimed to compare the anticonvulsant efficacy of ACTH and/or MT for treatment of IS and explore the mechanisms underlying the anticonvulsant activity of MT, using an N-methyl-d-aspartate (NMDA)-induced IS model in neonatal rats following exposure to prenatal stress. Latency to the onset of spasms and the total number of spasms were recorded to assess spasm severity. Treatment with ACTH and/or MT significantly reduced the number of spasms and prolonged the latency period. Additionally, expression of GR-α, HDAC2, BNDF, TrkB, and C-Cbl were significantly increased by induction with NMDA, and this effect was reversed by ACTH and/or MT treatment. Hence, our data suggest that combined ACTH and MT treatment is effective for reducing the number of spasms and increasing the latency period in NMDA rats, by restoring dysregulation of the HPA axis. These findings have the potential to provide a new strategy for the treatment of IS.

Outcomes among patients with infantile spasms treated with hormonal therapy and adjuvant topiramate versus hormonal therapy alone.

Hormonal therapy is the first-line treatment for infantile spasms and is sometimes used in combination with topiramate for better seizure control and potentially improved developmental outcomes. Retrospective review of pediatric patients with infantile spasms, with data compiled on patient sex, age at onset, etiology, electroencephalographic and imaging findings, topiramate use, spasm resolution (at one, six, and 12 months), and developmental outcome (at 12 months). Of 105 patients screened, 55 (28 female) met inclusion criteria (28 [51%] had spasms with known etiology and 27 [49%] had spasms with unknown etiology). Forty-six patients were followed for 12 months or longer to determine seizure outcome; a 12-month developmental assessment was documented for 49 patients. Thirty-seven patients (67%) received combination therapy; 18 (33%) received hormonal therapy alone. Resolution of spasms was comparable among treatment groups, with no difference relative to spasm etiology (p>0.18 for all). No difference was found in developmental outcomes with and without adjunct topiramate (p=0.38). Combination therapy was the most common treatment at our institution. However, combination therapy was not found to be beneficial for the treatment of spasms or developmental outcomes when compared to hormonal therapy alone.

Vigabatrin for Epileptic Spasms and Tonic Seizures in Tuberous Sclerosis Complex.

Vigabatrin is recommended as first-line treatment for infantile spasms in tuberous sclerosis complex (TSC), but other indications in children with tuberous sclerosis complex are less known. We retrospectively reviewed 201 children with tuberous sclerosis complex, and identified 21 children older than 1 year started on vigabatrin for any indication and with sufficient follow-up data. The indication for vigabatrin was epileptic spasms (n = 13), tonic seizures (n = 5), both (n = 2), and status epilepticus (n = 1). Mean age of treatment onset was 4.0 years (range 1.1-18.3). All but 1 patient had a reduction in seizures. Ten patients became seizure free and 4 had an improvement of >90%. In 9 patients, vigabatrin was tapered successfully after 8 to 33 months. Side effects reported included rash (n = 1) and behavioral decline (n = 1). No retinal toxicity was detected in 14 of 21 patients with adequate ophthalmologic surveillance data. In conclusion, vigabatrin may be an effective treatment for epileptic spasms and tonic seizures beyond the infantile age.

ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms

We profiled the gene expression in the hypothalamic arcuate nuclei (ARC) of 20 male and 20 female rats to determine the infantile spasms (IS) related transcriptomic alteration of neurotransmission and recovery following two treatments. Rats were prenatally exposed to betamethasone or saline followed by repeated postnatal subjection to NMDA-triggered IS. Rats with spasms were treated with ACTH, PMX53 or saline. Since ACTH, the first line treatment for IS, has inconsistent efficacy and potential harsh side effects, PMX53, a potent complement C5ar1 antagonist, was suggested as a therapeutic alternative given its effects in other epilepsy models. Novel measures that consider all genes and are not affected by arbitrary cut-offs were used, in addition to standard statistical tests, to quantify regulation and recovery of glutamatergic, GABAergic, cholinergic, dopaminergic and serotonergic pathways. Although IS alters expression of ~30% of the ARC genes in both sexes the transcriptomic effects are 3× more severe in males than their female counterparts, as indicated by the Weighted Pathway Regulation measure. Both treatments significantly restored the ARC neurotransmission transcriptome to the non-IS condition with PMX53 performing slightly better, as measured by the Pathway Restoration Efficiency, suggesting these treatments may reduce autistic traits often associated with IS.

Effectiveness and Safety of Different Once-Daily Doses of Adrenocorticotropic Hormone for Infantile Spasms.

Adrenocorticotropic hormone (ACTH) has been commonly used as a first-line treatment for infantile spasms (IS), but its optimal dose and duration are still unclear. This study is the largest retrospective cohort to document the therapeutic efficacy and tolerability for three gradient doses of ACTH in IU/kg/day units in Chinese patients. The aim of our study was to elucidate the effectiveness and safety of three different low doses and duration of ACTH treatment for IS in China. We conducted a retrospective, chart review of IS cases that were treated with biologic short-acting ACTH and followed up for at least 6months at a single center in China between June 2010 and June 2016. In total, 200 children met the inclusion criteria. Cases were divided into three groups according to dosage (1, 1.1-1.9, and 2-4IU/kg/day). Furthermore, we divided the 2-4IU/kg/day group into 2-3 and 3.1-4IU/kg/day subgroups. All groups were evaluated for response rates, relapse rates, and adverse effects. Electroclinical remission by day 14 occurred in 41.4% of infants given 2-4IU/kg/day and 36.4% of infants given 1.1-1.9IU/kg/day, compared with only 14.7% of patients given 1IU/kg/day (p=0.004 and 0.03, respectively). Prolonging ACTH treatment for up to 28days improved response by 24% in all 200 infants. Overall, 73.9% of infants receiving 2-4IU/kg/day responded, significantly higher than the 52.7% responding to 1.1-1.9IU/kg/day and the 23.5% responding to 1IU/kg/day (p<0.01). There was no significant difference in the number of relapses or adverse effects in the three groups. Moreover, in the 2-4IU/kg/day group, 74.7% of children receiving 2-3IU/kg/day of ACTH responded, compared with 70% who responded to 3.1-4IU/kg/day (p=0.78). ACTH at a dosage of 2-3IU/kg/day is superior to 1.1-1.9 and 1IU/kg/day dosages, is as good as a 3.1-4IU/kg/day dosage in terms of response rate, and causes no more adverse effects or relapses than other dosages. In addition, prolonging the duration of ACTH treatment can improve response.

Vigabatrin as First-Line Treatment for Infantile Spasms Not Related to Tuberous Sclerosis Complex

BackgroundInfantile spasms are a rare, catastrophic, age-specific seizure disorder of infancy. Adrenocorticotropic hormone or vigabatrin have been recommended for the short-term treatment of infantile spasms by the Child Neurology Society/American Academy of Neurology practice parameter. ObjectiveThis retrospective study reviewed the Hospital for Sick Children's experience with the short-term efficacy of vigabatrin as first-line treatment for infantile spasms not related to tuberous sclerosis complex. MethodWe performed a single-center, retrospective analysis of all cases of newly diagnosed infantile spasms between January 2010 and September 2013. Duration of follow-up was at least 6 months from treatment initiation. ResultsEighteen of the 61 infants (30%) had a clinical and electrographic response to vigabatrin therapy within 4 weeks of treatment. Of the vigabatrin responders, 2/18 (11%) relapsed. At final follow-up after initiation of vigabatrin therapy, 17/61 (27%) of the vigabatrin responders were free of all clinical seizure types. Normal development at the time of infantile spasms diagnosis was statistically associated with vigabatrin response. ConclusionThese findings do not support our hypothesis that vigabatrin is effective as first-line, short-term treatment of infantile spasms in non-tuberous sclerosis complex patients. However, when used in this setting, vigabatrin is most effective in children with normal development at the time of diagnosis. These findings may assist clinicians in the optimal treatment choice for children at the first presentation of infantile spasms not related to tuberous sclerosis complex.

The Current Evaluation and Treatment of Infantile Spasms Among Members of the Child Neurology Society

The optimal evaluation and treatment of children with infantile spasms is unknown. To aid in the development of a standardized approach to infantile spasms, members of the Child Neurology Society were surveyed to determine common practice. The survey had 222 responders with a responder rate of 18.5%. We found that the diagnostic evaluation and the use of first-line treatments varied among responders. For example, although adrenocorticotropic hormone continues to be the most commonly used first-line treatment for infantile spasms not due to tuberous sclerosis, some clinicians use corticosteroids, vigabatrin, and topiramate as first-line treatments for this group. Seventy percent of our responders reported seeing fewer than 10 new-onset cases of infantile spasms per year. Thus, future clinical trials will require multicenter collaboration. An important first step in such collaboration is to standardize the evaluation and treatment of infantile spasms within and between participating centers.

Topiramate and Adrenocorticotropic Hormone (ACTH) as Initial Treatment for Infantile Spasms

Historically, adrenocorticotropic hormone was used as a first-line treatment for infantile spasms; however, there has been increasing use of topiramate as initial therapy. Here, we report a retrospective study of adrenocorticotropic hormone (ACTH) and topiramate as initial treatment for infantile spasms. The neurology patient database at the Children's Hospital of Philadelphia was searched using the International Classification of Diseases, Ninth Revision code for infantile spasms, and 50 patients were randomly chosen for chart review. We identified 31 patients receiving either adrenocorticotropic hormone or topiramate monotherapy (adrenocorticotropic hormone n = 12, topiramate n = 19) as a first-line treatment for infantile spasms. A total of 26 patients were symptomatic and 5 cryptogenic. Six patients treated with adrenocorticotropic hormone had resolution of clinical spasms and hypsarrhythmia within a month, but 3 relapsed. Of the 19 patients treated with topiramate, 4 patients eventually, though over a period of 0, 1, 8, or 69 months, had resolution of spasms and hypsarrhythmia.

Steroids in childhood epilepsy

Treatment of epileptic encephalopathies can be very challenging as most anticonvulsant drugs fail to achieve good seizure control. Steroids are disease modifying as well as anticonvulsant in these conditions. Though steroids are accepted as the first-line treatment for infantile spasms, there are many unanswered questions with regard to the preparation, dose and duration of treatment. In this review a re-exploration of the literature is attempted. Putative mechanism of action of steroids in infantile spasms is also discussed. As steroids are being increasingly used in other epileptic encephalopathies and Rasmussen's encephalitis, a brief discussion on the role of steroids in these conditions is attempted. The review ends with the discussion on newer neuroactive steroids in the management of epilepsy.