Current trends in the treatment of infantile spasms

Infantile spasms are an epilepsy syndrome with distinctive features, including age onset during infancy, characteristic epileptic spasms, and specific electroencephalographic patterns (interictal hypsarrhythmia and ictal voltage suppression). Adrenocorticotropic hormone (ACTH) was first employed to treat infantile spasms in 1958, and since then it has been tried in prospective and retrospective studies for infantile spasms. Oral corticosteroids were also used in a few studies for infantile spasms. Variable success in cessation of infantile spasms and normalization of electroencephalograms was demonstrated. However, frequent significant adverse effects are associated with ACTH and oral corticosteroids. Vigabatrin has been used since the 1990s, and shown to be successful in resolution of infantile spasms, especially for infantile spasms associated with tuberous sclerosis. It is associated with visual field constriction, which is often asymptomatic and requires perimetric visual field study to identify. When ACTH, oral corticosteroids, and vigabatrin fail to induce cessation of infantile spasms, other alternative treatments include valproic acid, nitrazepam, pyridoxine, topiramate, zonisamide, lamotrigine, levetiracetam, felbamate, ganaxolone, liposteroid, thyrotropin-releasing hormone, intravenous immunoglobulin and a ketogenic diet. Rarely, infantile spasms in association with biotinidase deficiency, phenylketonuria, and pyridoxine-dependent seizures are successfully treated with biotin, a low phenylalanine diet, and pyridoxine, respectively. For medically intractable infantile spasms, some properly selected patients may have complete cessation of infantile spasms with appropriate surgical treatments

Treatment of infantile spasms: emerging insights from clinical and basic science perspectives.

Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s) of action is unknown. This review describes the emerging candidate mechanisms that can underlie the therapeutic effects of ACTH in infantile spasms. These mechanisms can ultimately help to improve understanding and treatment of the disease. An overview of current treatments of infantile spasms, novel conceptual and experimental approaches to infantile spasms treatment, and a perspective on remaining clinical challenges and current research questions are presented here. This summary derives from a meeting of specialists in infantile spasms clinical care and research held in New York City on June 14, 2010

Infantile Spasms Treated with Intravenous Methypredinsolone Pulse

How to Cite This Article: Hassanzadeh Rad A, Aminzadeh V. Infantile Spasms Treated with Intravenous Methypredinsolone Pulse. Iran J Child Neurol. Spring 2017; 11(2):8-12.AbstractObjectiveInfantile spasms is diagnosed late even by expert pediatricians. Late diagnosis (later than 3 weeks) can have a negative effect on the long-term prognosis. We aimed to investigate infantile spasms treated with intravenous methylprednisolone pulse.Materials & MethodsIn this case series study, 20 infants with infantile spasms in 17-Shahrivar Hospital, Rasht, Iran were enrolled. Drugs were administered based on Mytinger protocol that included 3 days of methylprednisolone pulse and 56 days of oral prednisolone. The control of spasms and the omission of hypsarrhythmia in infants follow-up were the primary and secondary outcomes, respectively. Remission was indicated if the caregivers mentioned no spasms or >50% decrease regarding drug initiation for at least 5 consecutive days and the electroencephalography during sleep period noted the omission of hypsarrhythmia.Results Eleven female (55%) and 9 male (45%) patients with the mean age of 4.95±1.39 months were enrolled. Mean rapid remission was noted as 4.41±1.50 days. Twelve patients (60%) noted early remission. seizure was controlled in 3(15%) patients completely after 24 months. Five (25%) occasional seizures were noted controlled by routine anticonvulsant drugs after 24 months and 12 (60%) no response was mentioned. Most of the patients (65%) had cryptogenic etiology for infantile spasms. Uncontrolled seizure was mentioned after initial remission.Conclusion Methyl prednisolone is an appropriate drug based on easy administering, low cost, and its accessibility. References1.Widjaja E, Go C, McCoy B, Snead OC. Neurodevelopmental outcome of infantile spasms: a systematic review and meta-analysis. Epilepsy Res 2015;109:155-62.2. Mackay M, Weiss S, Adams-Webber T, Ashwal S, Stephens D, Ballaban-Gill K, et al. Practice Parameter: Medical Treatment of Infantile Spasms Report of the American Academy of Neurology and the Child Neurology Society. Neurology 2004;62(10):1668-81.3. Abbas A, Elseed M, Hamed A, Mohamed IN. The role of oral prednisolone in the management of infantile spasms in resource-limited countries: experience from Sudan. Khartoum Med J 2016 Apr 5;7(3): 1012-18.4. Riikonen R. A long-term follow-up study of 214 children with the syndrome of infantile spasms. Neuropediatrics 1982;13(1):14-23.5. O’Callaghan FJ, Edwards SW, Alber FD, Hancock E, Johnson AL, Kennedy CR, et al. Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial. The Lancet Neurol 2017;16:33-42.6. Pellock JM, Hrachovy R, Shinnar S, Baram TZ, Bettis D, Dlugos DJ, et al. Infantile spasms: a US consensus report. Epilepsia 2010;51(10):2175-89.7. Hrachovy RA, Frost JD, Kellaway P, Zion TE. Double-blind study of ACTH vs. prednisone therapy in infantile spasms. J Pediatr 1983;103(4):641-5.8. Delesalle F, Staumont D, Houmany MA, Breviere GM, Piette F. Pulse methylprednisolone therapy for threatening periocular haemangiomas of infancy. Acta Derm Venereol 2006;86(5):429-32.9. Nguyen J, Fay A. Pharmacologic therapy for periocular infantile hemangiomas: a review of the literature. Semin Ophthalmol 2009: 24(3):178-184.10. Mytinger JR, Quigg M, Taft WC, Buck ML, Rust RS. Outcomes in treatment of infantile spasms with pulse methylprednisolone. J Child Neurol 2010: 25(8): 948-53.11. Azam M, Bhatti N, Krishin J. Use of ACTH and prednisolone in infantile spasms: experience from a developing country. Seizure 2005;14(8):552-6.12. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. The Lancet 2004;364(9447):1773-8.13. Kossoff EH, Hartman AL, Rubenstein JE, Vining EP. High-dose oral prednisolone for infantile spasms: an effective and less expensive alternative to ACTH. Epilepsy Behav 2009;14(4):674-6

Cerebrospinal fluid corticotropin and cortisol are reduced in infantile spasms.

Infantile spasms respond to ACTH, and levels of the hormone in cerebrospinal fluid of untreated infants with this disorder were found to be lower than in age-matched controls. In this study we analyzed cerebrospinal fluid cortisol and ACTH using improved immunoassays in a larger cohort of infants with infantile spasms. Analysis of 20 patients and 15 age-matched controls revealed significantly lower levels of both ACTH and cortisol in the cerebrospinal fluid. These data, combined with the efficacy of ACTH and glucocorticoids for infantile spasms, support an involvement of the brain-adrenal-axis in this disorder

Clinical profile and treatment of infantile spasms using vigabatrin and ACTH - a developing country perspective

Background: Infantile spasms represent a serious epileptic syndrome that occurs in the early infantile age. ACTH and Vigabatrin are actively investigated drugs in its treatment. This study describes the comparison of their efficacy in a large series of Patients with infantile spasms from Pakistan. Methods: All Patients with infantile spasms who presented to Aga Khan University Hospital, Karachi, Pakistan from January, 2006 to April, 2008 were included in this study. Inclusion criteria were clinical symptoms of infantile spasms, hypsarrythmia or modified hyparrythmia on electroencephalography, at least six months of follow-up period and receipt of any of the two drugs mentioned above. The type of drug distribution was random according to the availability, cost and ease of administration. Results: Fifty six cases fulfilled the inclusion criteria. 62.5% were males. Mean age at onset of seizures was 5 +/- 1.4 months. Fifty two (92.8%) Patients demonstrated hypsarrythmia on electroencephalography. 64.3% cases were identified as symptomatic while 19.6% were cryptogenic and 16.1% were idiopathic. Eighteen Patients received ACTH while 38 Patients received Vigabatrin as first line therapy. Initial response to first line therapy was similar (50% for ACTH and 55.3% for Vigabatrin). Overall, the symptomatic and idiopathic groups responded better to Vigabatrin. The relapse rate was higher for ACTH as compared to Vigabatrin (55.5% vs. 33.3%) when considering the first line therapy. Four Patients evolved to Lennox-Gastaut variant, all of these Patients had initially received Vigabatrin and then ACTH. Conclusion: Vigabatrin and ACTH showed no significant difference in the initial treatment of infantile spasms. However, Patients receiving ACTH were 1.2 times more likely to relapse as compared to the Patients receiving Vigabatrin when considering monotherapy. We suggest that Vigabatrin should be the initial drug of choice in Patients presenting with infantile spasms. However, larger studies from developing countries are required to validate the therapeutic trends observed in this study

Efficacy and tolerability of the Galanin Analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms

Infantile spasms are seizures manifesting in infantile epileptic encephalopathies that are associated with poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. Early cessation of spasms has been proposed to improve long-term outcomes. To identify new therapies for infantile spasms with rapid suppression of spasms, we are using the multiple-hit rat model of infantile spasms, which is a model of refractory infantile spasms. Here, we are testing the efficacy and tolerability of a single dose of the galanin receptor 1 preferring analog, NAX 5055, in the multiple-hit model of spasms. To induce the model, postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide; p-chlorophenylalanine was then injected intraperitoneally (i.p.) at PN5. After the onset of spasms at PN4, 11-14 rats/group were injected i.p. with either NAX 5055 (0.5, 1, 2, or 4mg/kg) or vehicle. Video monitoring for spasms included a 1h pre-injection period, followed by 5h of recording post-injection, and two 2h sessions on PN5. The study was conducted in a randomized, blinded manner. Neurodevelopmental reflexes were assessed daily as well as at 2h after injection. Respiratory function, heart rate, pulse distension, oximetry and blood glucose were measured 4h after injection. The relative expression of GalR1 and GalR2 mRNA over β-actin in the cerebral cortex and hippocampus was determined with real time reverse transcription polymerase chain reaction. There was no acute effect of NAX 5055 on spasm frequency after the single dose of NAX 5055 (n=11-13 rats/group, following exclusions). Neurodevelopmental reflexes, vital signs, blood glucose measured 4h post-injection, and survival were not affected. A reduction in pulse and breath distention of unclear clinical significance was observed with the 7mg/kg NAX 5055 dose. GalR1 mRNA was present in the cerebral cortex and hippocampus of PN4 and adult rats. The hippocampal - but not the cortical - GalR1 mRNA expression was significantly lower in PN4 pups than in adults. GalR1 mRNA was also at least 20 times less abundant in the PN4 cortex than GalR2 mRNA. In conclusion, a single dose of NAX 5055 has no acute efficacy on spasms or toxicity in the multiple hit rat model of medically refractory infantile spasms. Our findings cannot exclude the possibility that repetitive NAX 5055 administration may show efficacy on spasms. The higher expression of GalR2 in the PN4 cortex suggests that GalR2-preferring analogs may be of interest to test for efficacy on spasms

Infantile Spasms

Infantile Spams is an epilepsy syndrome that usually appears in children between the ages of four and eight months. The spasms generally occur upon waking or right after feeding, and can occur in clusters of a hundred or more at a time (Go et al., 2012). Children with infantile spasms present with a classic, abnormal electroencephalogram. The pattern that determines if it is indeed infantile spasms is called hypsarrythmia, which is a disorganized pattern (Iype et al., 2016). Children with infantile spams will also regress in milestones and can have mental retardation. Many studies have been done to determine the best treatment options for infantile spams. The standard treatment consists of either high dose oral steroids, vigabatrin, or adrenocorticotropin hormone (ACTH). The quicker the initiation of treatment, the better the outcome for the child (Beatty, Wrede, & Blume, 2017). This project presents research that support the most effective treatment for infantile spams

The mystery of the Doctor's son, or the riddle of West syndrome.

Although the eponym "West syndrome" is used widely for infantile spasms, the originators of the term and the time frame of its initial use are not well known. This article provides historical details about Dr. West, about his son who had infantile spasms, and about the circumstances leading to the coining of the term West syndrome

Infantile Spasm: A Review Article

How to Cite This Article: Taghdiri MM, Nemati H. Infantile Spasm: A Review Article. Iran J Child Neurol. 2014 Summer;8(3): 1-5.AbstractObjectiveInfantile spasm (IS) is a convulsive disease characterized by brief, symmetric axial muscle contraction (neck, trunk, and/or extremities). IS is a type of seizure that was first described by West in 1841, who witnessed the seizure in his own son. West’s syndrome refers to the classic triad of spasms, characteristic EEG, and neurodevelopmental regression. Most cases involve flexors and extensors,but either of the types may be involved independently.IS, as its name implies, most often occurs during the first year of life with an incidence of approximately 1 per 2000-4000 live births. Most, but not all, patients with this disorder have severe EEG abnormalities; this pattern was originallyreferred to as hypsarrhythmia by Gibbs and Gibbs. Cases with known etiology or signs of brain damage are considered as symptomatic. The Overall prognosis of the disease is poor. Peak onset age of the epileptic syndrome is 3 to 7 months, which mainly occurs before 2 years of age in 93% of patients. Hypsarrhythmia is the EEG hallmark of IS, which comprised a chaotic, bilaterally asynchronous high-voltage polyspike, and slow wave discharges interspersed with multifocal spikes and slow waves.Etiological classification is as follows: 1) Symptomatic: with identifiable prenatal, perinatal, and postnatal causes with developmental delay at the presentation time; 2) Cryptogenic: unknown underlying cause, normal development at the onset of spasms, normal neurological exam and neuroimaging, and no abnormality in the metabolic evaluation; 3) Idiopathic: pure functional cerebral dysfunction with complete recovery, no residual dysfunction, normal neuroimaging and normal etiologic evaluation, and normal neurodevelopment.ReferencesInfantile Spasms. In: Jean Aicardi: Disease of Nervous system in childhood. 3th ed. Mac Keith pres; 2009. p. 593-7.Fujii, Oquni H, Hirano Y, Shioda M, Osawa M. A longterm, clinical study on symptomatic infantile spasm with focal features. Brain Dev 2013;35(5):379-85.SankarR, Koh S, Wu J. Menkes JH. Paroxysmal disorders. In: Menkes JH, Sarnat HB,. MariaBL, editors Child neurology. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 857-942.Kendall Nash and Joseph Sullivan. Myoclonic seizures and infantile spasms. InSwaiman KF, Ashwal S, Ferriero DM, Schor NF, editors.. Swaiman’s pediatric Neurology: principles and practice. 5th ed. Edinburgh: Elsevier Saunders; 2012. p. 774-89.Paroxysmal Disorders. In: Piña-Garza J. Fenichel’s Clinical Pediatric Neurology. 7th ed. Elsevier Saunders; 2013. p. 1-46.Paciorkowski AR, Thio LL, Dobyns WB. Genetic and biologic classification of infantile spasms. Pediatr Neurol 2011;45(6):355-67.Manqanno S, Nardello R, Tripi G, Giordano G, Spitaleri C, Manfano GR. West Syndrome Followed by juvenile myoclonic epilepsy: a coincidental occurrence. BMC Neural 2013;13:48.LUX AL. Latest American and European update on infantile spasms. Curr Neural Neurosci Rep 2013;13(3):334.Hrachovy RA, Frost JD Jr. Infantile spasms. Handb Clin Neuro. 2013;111:611-8.Shumiloff NA, Lam WM, Manasco KB. Adrenocorticotropic hormone for the treatment of west syndrome in children. Ann Pharmacother 2013 47(5):744- 54.Wheless JW, Gibson PA, Rosbeck KL, Hardin M, O’Dell C, Whiltemore V. Infantile Spasms (west syndrome):  Update and resources for pediatricians and providers to share with parents. BMC Pediatr. 2012;12:108.Watemberg N. Infantile Spasms: treatment challenges. Curr Treat Options Neural. 2012;14(4): 322-31.Fukui M, Shimakawa S, Tanabe T, Nomura S, Kashiwagi M, Azumakawa K. Partial seizures during ACTH therapy in a cryptogenic West syndrome patient. Brain Dev 2013;Pii:s0387-7604(13)00003-x.Friedman D, Boqner M, Parker-Menzer K, Dviskyo. Vigabatin for partial- onset seizure treatment in patients with tuberous sclerosis complex. Epilepsy Behav 2013;27(1):118-20.Bilton JY, Sauerwein HC, Wiss SK, Donner EJ, Whiting S, Dooley JM, et al. A randomized controlled trial of flunarizine as add-on therapy and effect on cognitive outcome in children with infantile Spasms. Epilepsia 2012;53(9):1570-6.Pires ME, IIea A, Bourel E, Bellaroine V, Merdariv D, Berquin P. Ketogenic diet for infantile spasms refractory to first-line treatment: An open prospective study. Epilepsy Res 2013; 105(1-2): 189-94.Vykuntaragu KN, Bhat S, Sangay KS, Govindaagu M. Symptomatic West syndrome Secondary to Glucose transporter-1 (GluT1) Deficiency with complete response to 4:1 Ketogenic Diet. Indian J Pediatr 2013. [Epub ahead of print]Taghdiri MM, Comparative effects of Nitrazepam and ACTH on the treatment of infantile Spasms. Iran J Child Neurol 2007;1(4):25-30.Taghdiri MM, Presentation of 60 cases of infantile spasms based on etiology, clinical manifestation, EEG and brain CT scan in Mofid Children’s Hospital. JRehab 2002;3(8- 9);39-42.Taghdiri MM. Report of 40 cases of Tuberous sclerosis in Tehran. Scientific Journal of Hamadan University of Medical sciences 2002;9(1):63-7.Mytinger JR, Joshi S; Pediatric Epilepsy Research Consortium, Section on Infantile Spasms. The current evaluation and treatment of infantile spasms among members of the child Neurology Society. J child Neural 2012;227(10):1289-94.Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev 2013;6:CD001770

Pathophysiology of massive infantile spasms: perspective on the putative role of the brain adrenal axis.

Massive infantile spasms are an age-specific seizure syndrome of infancy. Uniquely, the spasms respond to hormonal manipulation using adrenocorticotropic hormone (ACTH) or glucocorticoids. A hypothesis explaining the efficacy of hormonal therapy, age-specificity, multiple causative factors, and spontaneous resolution of infantile spasms is presented. Corticotropin-releasing hormone (CRH), an excitant neuropeptide suppressed by ACTH/steroids, is implicated. Evidence for the age-specific convulsant properties of CRH is presented, and a putative scenario in which a stress-induced enhancement of endogenous CRH-mediated seizures is discussed. Clinical testing of the CRH-excess theory and its therapeutic implications are suggested