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Background: The leaves of Origanum majorana ( O. majorana ) are traditionally renowned for treating diarrhea and gut spasms. This study was therefore planned to evaluate its methanolic extract., Methods: Gas chromatography-mass spectrometry (GC-MS) was used to identify the phytochemicals, and Swiss albino mice were used for an in vivo antidiarrheal assay. Isolated rat ileum was used as an ex vivo assay model to study the possible antispasmodic effect and its mechanism(s)., Results: The GC-MS analysis of O. majorana detected the presence of 21 compounds, of which alpha-terpineol was a major constituent. In the antidiarrheal experiment, O. majorana showed a substantial inhibitory effect on diarrheal episodes in mice at an oral dosage of 200 mg/kg, resulting in 40% protection. Furthermore, an oral dosage of 400 mg/kg provided even greater protection, with 80% effectiveness. Similarly, loperamide showed 100% protection at oral doses of 10 mg/kg. O. majorana caused complete inhibition of carbachol (CCh, 1 µM) and high K+ (80 mM)-evoked spasms in isolated ileal tissues by expressing significantly higher potency ( p < 0.05) against high K+ compared to CCh, similar to verapamil, a Ca++ antagonist. The verapamil-like predominant Ca++ ion inhibitory action of O. majorana was further confirmed in the ileal tissues that were made Ca++-free by incubating the tissues in a physiological salt solution having ethylenediaminetetraacetic acid (EDTA) as a chelating agent. The preincubation of O. majorana at increasing concentrations (0.3 and 1 mg/mL) shifted towards the right of the CaCl2-mediated concentration-response curves (CRCs) with suppression of the maximum contraction. Similarly, verapamil also caused non-specific suppression of Ca++ CRCs towards the right, as expected., Conclusions: Thus, this study conducted an analysis to determine the chemical constituents of the leaf extract of O. majorana and provided a detailed mechanistic basis for the medicinal use of O. majorana in hyperactive gut motility disorders., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Objective: The aim of this study was to assess efficacy, safety, and tolerability of highly purified cannabidiol oil (CBD) as add-on therapy for the treatment of a series of patients with infantile epileptic spasms syndrome (IESS) who were resistant to antiseizure medications and ketogenic dietary therapy., Material and Methods: We conducted a retrospective analysis of the medical records of 28 infants with treatment-resistant IESS aged 6 to 21 months who received highly purified CBD between July 2021 and June 2023. Data were collected on neurological examinations, EEG, Video-EEG and polygraphic recordings, imaging studies, laboratory testing, and seizure frequency, type, and duration, and adverse effects. As the primary outcome, a reduction of frequency of epileptic spasms (ES) was assessed. ES freedom was considered after a minimal time of 1 month without ES., Results: Sixteen male and 12 female patients, aged 6-21 months, who received CBD for treatment-resistant IESS were included. The etiology was structural in 10, Down syndrome in seven, genetic in nine, and unknown in two. Initial CBD dose was 2 mg/kg/day, which was uptitrated to a median dose of 25 mg/kg/day (range, 2-50). Prior to CBD initiation, patients had a median of 69 ES in clusters per day (range, 41-75) and of 10 focal seizures per week (range, 7-13). After a mean and median follow-up of 15 and 12.5 months (range, 6-26 months), seven patients were ES free and 12 had a >50 % ES reduction. Five of seven patients (71 %) with Down syndrome and 3/5 (60 %) with cerebral palsy responded well. Adverse effects were mild. EEG improvements correlated with ES reductions., Conclusion: In this study evaluating the use of CBD in children with IESS, 19/28 (67.8 %) had a more than 50 % ES reduction with good tolerability., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest regarding this study., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Infantile spasms, newly classified as infantile epileptic spasm syndrome (IESS), occur in children under 2 years of age and present as an occur as brief, symmetrical, contractions of the musculature of the neck, trunk, and extremities. When infantile spasms occur with a concomitant hypsarrhythmia on electroencephalogram (EEG) and developmental regression, it is known as West Syndrome. There is no universally accepted mainstay of treatment for this condition, but some options include synthetic adrenocorticotropic hormone (ACTH), repository corticotropin injection (RCI/Acthar Gel), corticosteroids, valproic acid, vigabatrin, and surgery. Without effective treatment, infantile spasms can cause an impairment of psychomotor development and/or cognitive and behavioral functions. The first-line treatment in the USA is ACTH related to high efficacy for cessation of infantile spasms long-term and low-cost profile. Acthar Gel is a repository corticotropin intramuscular injection that became FDA-approved for the treatment of IESS in 2010. Though it is believed that ACTH, Acthar Gel, and corticosteroids all work via a negative feedback pathway to decrease corticotropin-releasing hormone (CRH) release, their safety and efficacy profiles all vary. Vigabatrin and valproic acid are both anti-seizure medications that work by increasing GABA concentrations in the CNS and decreasing excitatory activity. Acthar Gel has been shown to have superior efficacy and a diminished side effect profile when compared with other treatment modalities., (© 2023. Fondazione Società Italiana di Neurologia.)

Objective: This study was undertaken to evaluate our treatment algorithm for infantile epileptic spasms syndrome (IESS) used between 2000 and 2018. We initiated vigabatrin (VGB), and steroids were added if the electroclinical response (spasms and electroencephalogram [EEG]) to VGB was not obtained or incomplete., Methods: Individuals with IESS treated with VGB were recruited from our hospital clinical data warehouse based on electronic health records (EHRs) generated since 2009 and containing relevant keywords. We confirmed the diagnosis of IESS. Clinical, EEG, imaging, and biological data were extracted from the EHRs. We analyzed factors associated with short-term response, time to response, relapse, time to relapse of spasms, and the presence of spasms at last follow-up., Results: We collected data from 198 individuals (female: 46.5%, IESS onset: 6 [4.5-10.3] months, follow-up: 4.6 [2.5-7.6] years, median [Q1-Q3]) including 129 (65.2%) with identifiable etiology. VGB was started 17 (5-57.5) days after IESS diagnosis. A total of 113 individuals were responders (57.1% of the cohort), 64 with VGB alone and 38 with VGB further combined with steroids (56.6% and 33.6% of responders, respectively). Among responders, 33 (29%) experienced relapses of spasms, mostly those with later onset of spasms (p = .002) and those who received VGB for <24 months after spasms cessation compared to a longer duration on VGB (45% vs. 12.8%, p = .003). At follow-up, 92 individuals were seizure-free (46.5% of the whole cohort), including 26 free of therapy (13.1%). One hundred twelve individuals (56.6%) were still receiving VGB, with a duration of 3.2 (1.75-5.7) years., Significance: Our sequential protocol introducing VGB then adding steroids is an effective alternative to a combined VGB-steroids approach in IESS. It avoids steroid-related adverse events, as well as those from VGB-steroid combination. According to our data, a period of 7 days seems sufficient to assess VGB response and enables the addition of steroids rapidly if needed. Continuing VGB for 2 years may balance the risk of relapse and treatment-induced adverse events., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

This was a prospective, randomized, double-blind, single-center placebo-controlled trial to assess the efficacy and safety of melatonin as an add-on treatment for infantile epileptic spasms syndrome (IESS). Participants aged 3 months to 2 years with a primary diagnosis of IESS were recruited and assigned to two groups in a 1:1 ratio. Both treatment groups received a combination of adrenocorticotrophic hormone (ACTH) and magnesium sulfate (MgSO 4 ) for 2 weeks, and the treatment group also received melatonin (3 mg) between 20:00 and 21:00 daily, 0.5-1 h before bedtime. The study's primary endpoint was the average reduction rate in spasm frequency assessed by seizure diaries. Secondary endpoints included assessment of the response rate, EEG hypsarrhythmia (Kramer score), and psychomotor development (Denver Developmental Screening Test, DDST). Sleep quality was assessed by using the Brief Infant Sleep Questionnaire (BISQ), the Infant Sleep Assessment Scale (ISAS), and actigraphy. Safety parameters were also evaluated. Statistical analyses were conducted on intention-to-treat and per-protocol populations. The trial is registered at Clinicaltrials.gov (ChiCTR2000036208). Out of 119 screened patients, 70 were randomized and 66 completed treatments. In the intention-to-treat population, there were no significant differences in the average percentage reduction of spasm frequency (median [interquartile range, IQR: Q3-Q1], 100% [46.7%] vs. 66.7% [55.3%], p = .288), the 3-day response rate (51.4% vs. 37.1%, p = .229), the 28-day response rate (42.9% vs. 28.6%, p = .212), EEG Kramer scores (2 [3.5] vs. 2 [3], p = .853), or DDST comprehensive months (5 [2.5] vs. 6 [6], p = .239) between the melatonin (n = 35) and placebo (n = 35) groups. However, caregivers reported improved sleep quality after melatonin treatment, with 85.7% reporting regular sleep compared to 42.9% with placebo (42.9%, p < .001). The melatonin group had lower ISAS scores in 4-11-month-old patients compared to the placebo (mean ± SD, 29.3 ± 4.4 vs. 35.2 ± 5.9, p < .001). Moreover, the median (IQR) value of sleep-onset latency was shortened by 6.0 (24.5) min after melatonin treatment, while that in the placebo group was extended by 3.0 (22.0) min (p = .030). The serum melatonin (6:00 h) level (pg/mL) of the children in the melatonin group after treatment was significantly higher than in the placebo group (median [IQR], 84.8 [142] vs. 17.5 [37.6], p < .001). No adverse effects related to melatonin were observed in the study, and there were no significant differences in adverse effects between the melatonin and placebo groups. Although not statistically significant, the results of this randomized clinical trial proved that melatonin supplementation, as an add-on treatment, can improve spasm control rate in the treatment of IESS. For IESS children treated with ACTH, the addition of melatonin was found to improve sleep quality, shorten sleep onset latency, and increase blood melatonin levels. Moreover, it was observed to be a safe treatment option., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This ambispective, observational study evaluated the impact of the COVID-19 pandemic on managing children with Infantile epileptic spasms syndrome (IESS) and the feasibility of telemedicine-based management for IESS. Caregivers of children with IESS were telephonically interviewed using a structured questionnaire and various relevant indices were compared between the study population and a pre-pandemic cohort from the same center. There was a significant increase in diagnostic lag during the pandemic (p = 0.04). Adrenocorticotropic hormone was the first-line antiseizure medication of choice in both cohorts and the response to treatment was also similar. Telemedicine was utilized by around 80% of caregivers and satisfaction rates with telemedicine were high. However, caregivers continued to rate physical consultations higher in preference., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

To describe a new phenotype and the diagnostic workup of a vitamin-B 6 -dependent epilepsy due to pyridoxal 5'-phosphate-binding protein (PLPBP) deficiency in an infant with early-onset epilepsy at the age of 5 years 6 months. Following immediate and impressive clinical response to treatment with pyridoxine, metabolic screening for vitamin-B 6 -dependent epilepsies and targeted next-generation sequencing (NGS)-based gene panel analysis were performed. Potentially pathogenic variants were confirmed by Sanger sequencing in the patient, and variants were analyzed in both parents to confirm biallelic inheritance. The clinical phenotype and course of disease were compared to the 44 cases reported in the literature, harboring variants in pyridoxal phosphate homeostasis protein ( PLPHP ) and with cases of vitamin-B 6 -dependent epilepsy due to other known causative genes. Levels of alpha-aminoadipic semialdehyde in urine and amino acids were normal. Two inherited pathogenic variations in PLPHP were found in compound heterozygosity, including one novel deletion. We here describe a previously unreported individual harboring biallelic pathogenic PLPHP variants presenting with paroxysmal eye-head movements followed by epileptic spasms and an almost normal interictal electroencephalogram, thus expanding the clinical spectrum of PLPBP deficiency. This warrants consideration of vitamin-B 6 -dependent epilepsies in patients with early-onset epilepsy, including epileptic spasms, and eye movement disorders also beyond the neonatal period even when metabolic screening for vitamin-B 6 -dependent epilepsies is negative. PLPHP should be included systematically in NGS epilepsy gene panels., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Little is known about the risks and benefits of cannabis use in the context of cancer care. This study characterized the prevalence, reasons for use, and perceived benefits of cannabis and compared symptoms and perceived risks between those who reported past 30-day cannabis use and those who did not., Methods: Adults undergoing cancer treatment at a National Cancer Institute-designated cancer center completed measures of sociodemographic characteristics, cannabis use, use modalities, reasons for use, perceived harms/benefits of use, physical and psychological symptoms, and other substance/medication use. Analyses compared patients who used or did not use cannabis in the past 30 days., Results: Participants (N = 267) were 58 years old on average, primarily female (70%), and predominantly White (88%). Over a quarter of respondents (26%) reported past 30-day cannabis use, and among those, 4.5% screened positive for cannabis use disorder. Participants who used cannabis most often used edibles (65%) or smoked cannabis (51%), and they were younger and more likely to be male, Black, and disabled, and to have lower income and Medicaid insurance than participants who did not use cannabis. Those who used cannabis reported more severe symptoms and perceived cannabis as less harmful than those who did not use cannabis. The most common medical reasons for cannabis use were pain, cancer, sleep problems, anxiety, nausea/vomiting, and poor appetite. Participants reported the greatest cannabis-related symptom relief from sleep problems, nausea/vomiting, headaches, pain, muscle spasms, and anxiety., Conclusions: Patients with cancer who used cannabis perceived benefits for many symptoms, although they showed worse overall symptomatology., Plain Language Summary: Among adults undergoing cancer treatment, 26% reported cannabis use in the past 30 days. Those who used cannabis were more likely to be male and disabled and to have lower income and Medicaid insurance than those who did not use cannabis. Participants most commonly reported using cannabis for pain, cancer, sleep, anxiety, and nausea/vomiting and reported the greatest perceived benefits for sleep, nausea/vomiting, headaches, pain, muscle spasms, and anxiety, yet participants who used cannabis also reported feeling worse physically and psychologically compared to those who did not use cannabis. Participants who used cannabis were more likely to report that cannabis was less risky to their health than alcohol, smoking, and opioids than those who did not use cannabis., (© 2023 American Cancer Society.)

Background: Infantile epileptic spasms syndrome (IESS) is a rare but severe condition affecting children early and is usually secondary to an identifiable brain disorder. It is related to psychomotor deterioration in childhood and epilepsy in adult life. Treatment is challenging as infantile spasms may not respond to most antiseizure medication, and relapse is frequent., Objective: To evaluate the literature regarding treatment of IESS and provide a practical guidance to a healthcare system with limited resources., Methods: An expert committee from the Brazilian Society of Child Neurology reviewed and discussed relevant scientific evidence in the treatment of IESS regarding the drugs available in Brazil., Results: Oral prednisolone and vigabatrin are the most common drugs used as first-line therapy; they are efficient and affordable therapy as both are available in the Brazilian unified health system (SUS, in the Portuguese acronym). Intramuscular adrenocorticotropic hormone (ACTH) presents similar efficacy as oral prednisolone but has a higher cost and is not available in Brazil. Other antiseizure medications such as topiramate, levetiracetam, or benzodiazepines have limited response and are prescribed as adjuvant therapy. If the health service has nutritionists, a ketogenic diet should be implemented for those not responding to hormonal and vigabatrin treatment. Epilepsy surgery is mainly indicated for patients with focal lesions that do not respond to pharmacological therapy., Conclusion: Early treatment of IESS with efficient drugs is feasible in our country. Using standard protocols increases the odds of achieving complete cessation in a shorter time and decreases relapse., Competing Interests: The authors have no conflict of interest to declare., (Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Background: The purpose of this study was to evaluate the accuracy of parental reporting of epileptic spasms (ES) after 14 days of appropriate medical therapy for new-onset ES by comparison with extended video electroencephalography (vEEG) monitoring results., Methods: Fifty-eight patients were identified from August 2019 to February 2021 with new-onset ES, confirmed on vEEG. Patients were initiated on appropriate treatment (high-dose steroids or vigabatrin). After two weeks of therapy, patients underwent overnight (18 to 24 hours) vEEG monitoring in the epilepsy monitoring unit. Parental reporting of presence or absence of ES on admission was compared with results of vEEG monitoring., Results: The 58 patients ranged in age from three to 20 months (average 7.8 months). An underlying etiology was identified in 78%, whereas 22% patients had unknown etiology. The overall accuracy of parental reporting was 74% (43 of 58) when compared with results of vEEG within 14 to 18 days of starting therapy. Of these, 65% (28 of 43) reported ES resolution and 35% (15 of 43) reported continued ES. Of the 26% (15 of 58) families who were incorrect at two-week follow-up, 67% (10 of 15) reported resolution of ES. However, a minority of families, 33% (five of 15), who continued to report spasms clinically, were inaccurate., Conclusions: Although a majority of inaccurate parental reports at two weeks of treatment were due to unrecognized ES (a widely known phenomenon), a minority were conversely inaccurate due to persistent over-reporting of ES. This fact highlights the importance of correlating parental history with objective vEEG monitoring, to prevent inappropriate escalation of medication therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Satoyoshi syndrome is a rare multisystem disease of presumed autoimmune aetiology. We carried out a systematic review to evaluate the available evidence to support that autoimmune hypothesis., Methods: We searched for Satoyoshi syndrome cases in PubMed, the Web of Science and Scopus up to January 2022, using keywords 'Satoyoshi syndrome' or 'Komuragaeri disease'. Data on symptoms, associated autoimmune diseases, presence of autoantibodies and response to treatment were collected., Results: A total of 77 patients from 57 articles published between 1967 and 2021 were included; 59 patients were women. The mean age at diagnosis was 21.2 years. All cases had painful muscular spasms and alopecia. Frequent manifestations included: diarrhoea, malabsorption, growth retardation, amenorrhoea and bone deformity. Satoyoshi syndrome was associated with other autoimmune diseases: myasthenia gravis, autoimmune thyroiditis, idiopathic thrombocytopenic purpura, atopic dermatitis, bronchial and lupus erythematosus. Autoantibody determinations were performed in 39 patients, of which 27 had positive results. The most frequently detected autoantibodies were ANAs. Other less frequently found autoantibodies were: anti-acetylcholine receptor antibodies, anti-DNA antibodies, antithyroid antibodies, anti-glutamic acid decarboxylase (anti-GAD) and anti-gliadin antibodies. Pharmacological treatment was reported in 50 patients. Most of them improved with CS, immunosuppressants and immunoglobulins, or a combination of these medications., Conclusion: Satoyoshi syndrome is associated with other autoimmune diseases and a variety of autoantibodies. Improvement after CS or other immunosuppressant treatment was observed in 90% of cases. These data support an autoimmune aetiology for Satoyoshi syndrome. More studies including systematic determination of autoantibodies in all patients with Satoyoshi syndrome will help us advance in our understanding of this disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess whether access to smartphone video capture of infantile spasms at initial presentation is associated with improved time to diagnosis and treatment., Methods: We conducted a collaborative retrospective cohort study of 80 consecutive infants with confirmed infantile epileptic spasms syndrome initially presenting from 2015 to 2021 at 2 US pediatric centers. Statistical methods used included Mann-Whitney U test to assess the difference in lead times to electroencephalogram (EEG), diagnosis, and treatment between groups with and without video capture. A χ 2 analysis was used to assess differences in demographics, clinical characteristics, and treatment outcomes between groups. Multivariate regression analysis was used to account for etiology types and infantile spasms capture on EEG., Results: Patients with smartphone video infantile spasms capture initially presented a median of 9 days earlier (P = .02), had their first EEG 16 days earlier (P = .007), and were diagnosed and started treatment 17 days earlier (P = .006 and P = .008, respectively) compared with the nonvideo group. The video group had a 25% greater response to initial standard treatment (P = .02) and a 21% greater freedom from infantile spasms at long-term follow-up (P = .03), although this long-term outcome lost statistical significance after adjustment for etiology type (P = .07) and EEG capture of infantile spasms (P = .059)., Conclusion: Our findings suggest a benefit of smartphone video capture of infantile spasms in reduced time to diagnosis and initial standard treatment, which are associated with improved treatment response rates. Substantial differences in lead times and treatment response highlight the clinical importance of pediatricians recommending caregivers to obtain smartphone video of events concerning for infantile spasms., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Infantile epileptic spasms syndrome (IESS) with periventricular leukomalacia (PVL) has a poor neurological prognosis. Adrenocorticotropic hormone (ACTH) and vigabatrin therapies are the recommended first-line treatments for IESS. However, ACTH monotherapy for IESS with PVL has not been studied in detail. We analysed long-term outcomes of ACTH monotherapy for IESS with PVL., Methods: We retrospectively examined 12 patients with IESS and PVL at Saitama Children's Medical Center between January 1993 and September 2022. We evaluated seizure outcomes 3 months post-ACTH therapy and at the last visit. We also assessed electroencephalography findings and developmental outcomes. A positive response was defined as complete remission of epileptic spasms, no other seizure types, and hypsarrhythmia resolution post-ACTH therapy., Results: The median onset age of epileptic spasms was 7 (range: 3-14) months. The median age at initiation of ACTH therapy was 9 (7-17) months. Seven of 12 patients (58.3%) showed a positive response. The median age at the last visit was 5 years and 6 months (1 year and 5 months-22 years and 2 months). At the last visit, only 2 of 7 initial responders remained seizure-free who demonstrated normal electroencephalography findings within 1-month post-ACTH therapy. Patients with epileptic discharge in the parieto-occipital region within 1-month post-ACTH therapy showed relapse of epileptic spasms or other seizure types., Conclusion: Patients having epileptic discharge in the parietal or occipital regions on electroencephalography within 1-month post-ACTH therapy may be at a high risk of epileptic spasm recurrence or other seizure types in the long term., Competing Interests: Declaration of Competing Interest Shin-ichiro Hamano has received research funding from Syneos Health Clinical Co. Ltd for the clinical trial of Zogenix and has received funds for speaker honoraria and travel from UCB Japan Co. Ltd., Daiichi Sankyo Co. Ltd., and Eisai Co. Ltd. Kenjiro Kikuchi has received research funding from Janssen Pharmaceutical K.K. and Syneos Health Clinical Co. Ltd. for clinical trial of Zogenix. The other authors have nothing to disclose in terms of conflict of interest., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: To provide a comprehensive assessment of the treatment effects of nabiximols oromucosal spray on multiple sclerosis spasticity in two clinical trials, GWSP0604 and SAVANT., Methods: Both studies enriched for responders before randomization, defined by a ≥20% improvement in Spasticity 0-10 numeric rating scale (NRS) score. Additionally, SAVANT used randomized re-titration following washout. Spasticity NRS outcomes, spasm count, and modified Ashworth scale (MAS) scores were analyzed., Results: Mean change from baseline in average daily Spasticity NRS scores was significantly larger for nabiximols than placebo at all postbaseline timepoints, ranging from -0.36 to -0.89 in GWSP0604 and -0.52 to -1.96 in SAVANT. Percent reduction in geometric mean change from baseline in average daily spasm count for nabiximols ranged from 19-35% versus placebo. A treatment difference favoring nabiximols was observed in overall MAS scores during the randomized part of each study. Treatment effect was larger for combinations of lower limb muscle groups (ranging between -0.16 and -0.37)., Conclusions: Nabiximols leads to improvement in spasticity that was sustained over the 12-week treatment period as measured by average daily Spasticity NRS scores, daily spasm counts, and MAS scores for combinations of muscle groups, especially the combination of the 6 key muscle groups in the lower limbs in NRS responders to nabiximols treatment., Competing Interests: Declaration of Competing Interest Jacqueline Nicholas has received research grants from ADAMAS, Biogen Idec, Genentech, Novartis, and PCORI and consulting and/or speaking fees from Alexion, Bristol Myers Squib, EMD Serono, Genetech, Jazz Pharmaceuticals, Inc., Novartis, and Viela Bio. Fred Lublin has consulted for, conducted studies funded by, or received honraria for services provided to Jazz Pharmaceuticals, Inc. Sylvia Klineova has consulted for, conducted studies funded by, or received honraria for services provided to Biogen Idec, Alexion and Jazz pharmaceuticals, Inc. Joris Berwaerts is an employee of Jazz Pharmaceuticals, Inc. Robert Chinnapongse is an employee of Jazz Pharmaceuticals, Inc. Daniel Checketts is an employee of Jazz Pharmaceuticals, Inc. Joshua R. Steinerman is an employee of Jazz Pharmaceuticals, Inc. Sajida Javaid has consulted for, conducted studies funded by, or received honraria for services provided to Jazz Pharmaceuticals, Inc., (Copyright © 2023. Published by Elsevier B.V.)

Objective: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies., Methods: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months., Results: We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p < .0001). Fourteen-day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p = .0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p < .0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD., Significance: Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed., (© 2023 International League Against Epilepsy.)

This systematic review and meta-analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta-analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR = 0.37, 95% CI = 0.20-0.67) for patients with new-onset IESS. Meta-analysis of the nine OSs agrees with the result from RCTs (OR = 0.61, 95% CI = 0.43-0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR = 5.59, 95% CI = 2.17-14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR = 0.75, 95% CI = 0.09-6.45). Hormonal monotherapy is better than VGB monotherapy for non-TSC-associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Aim: To better understand the aetiologies of epileptic spasms in infants, as well as the safety and efficacy of high dose corticosteroids in tuberculosis and human immunodeficiency virus (HIV) endemic resource-limited settings., Method: This was a retrospective analysis of infants with epileptic spasms managed at the tertiary referral centres in the Western Cape, South Africa., Results: Of 175 children with epileptic spasms, the median age at onset was 6 months (interquartile range 4-8 months). Structural aetiologies were most common (115 out of 175 [66%]), with two-thirds related to perinatal insults. A lead time to treatment (LTTT) of less than 1 month was more likely in the epileptic encephalopathy/developmental and epileptic encephalopathy (DEE) group: 58 out of 92 (63%), compared to 28 out of 76 (37%) of those with developmental encephalopathy (p = 0.001). Failure to recognize preceding developmental delay was common. Ninety-nine children (57%) received first line hormonal therapy such as adrenocorticotropic hormone. A total of 111 out of 172 children (65%) from the developmental encephalopathy and epileptic encephalopathy/DEE groups had clinical and/or electroencephalogram resolution of spasms within 14 days. In our population, children in whom an aetiology could not be identified were statistically more likely to have moderate to profound developmental delay at 1 year of age: 33 out of 44 (p = 0.001). Based on reported incidence of epileptic spasms, 23 to 58 cases per annum would be expected but a far smaller proportion presented to our centres., Interpretation: Whilst this is the largest cohort of infants with epileptic spasms from sub-Saharan Africa, the study size is less than expected; this may reflect misdiagnosis and failure of referral pathways. Despite a reported shorter LTTT, infants with DEE had worse developmental outcomes compared to international studies. Hormonal therapy was safe and effective in our setting, despite exposure to high levels of tuberculosis and HIV., What This Paper Adds: The number of unreferred cases of epileptic spasms in South Africa remains high. Caregivers and health care workers in primary care facilities often fail to recognize developmental delay. The burden of disease from hypoxic-ischaemic encephalopathy remains high in our resource-limited setting. Hormonal treatment (e.g. adrenocorticotropic hormone) was safe and effective despite the high prevalence of human immunodeficiency virus and tuberculosis., (© 2022 Mac Keith Press.)

Objective: The purpose of this study was to find the most and least commonly prescribed medications for treating secondary health complications associated with spinal cord injury (SCI); and determine overall polypharmacy rates and risk factors associated with it., Design: Observational design, cross-sectional analysis., Setting: Community; Canada., Participants: Individuals with spinal cord injury ( n  = 108)., Results: A total of 515 prescriptions were issued to the sample comprising 213 different medications to treat 10 SCI-related complications. Forty-five (45%) participants were prescribed >5 medications concurrently. No associations were found between the number of drugs taken and age, sex, level of injury, completeness of injury, time since injury, or cause of injury. The most commonly treated complications included pain (56.5%), muscle spasms (54%) and urinary tract infections (43%). Anti-convulsants (pregabalin, gabapentin), anti-spasmodics (baclofen, diazepam) and nitrofurantoins (Macrobid) were the most commonly prescribed medications to treat each of the three conditions, respectively. Thirty five percent of the total sample received a combination of two or more analgesics including fourth-line agents in the opiate class (hydromorphone, hydrocodone and morphine). Similarly, some participants were prescribed general muscle relaxants and cephalosporins for treatment of muscle spasms and urinary tract infections, respectively, that are generally not recommended in SCI patients. We compare these prescribing patterns with the available clinical practice guidelines and highlight areas where the prescriptions fall outside the recommended clinical practice while considering the complexity of medication management in SCI., Conclusion: Medication management in SCI is complex. Tools are required that enable prescribers to choose evidence-based medical regimens and deprescribe potentially inappropriate medications for their patients with SCI.

Objective: To describe the temporal trends in the cost and use of adrenocorticotropic hormone (ACTH), oral prednisolone, and vigabatrin, the first-line treatments for infantile epileptic spasms syndrome (IESS)., Methods: Retrospective observational study using the MarketScan Commercial database from 2006 to 2020. We identified patients with IESS diagnosed between birth and 18 months of age who received at least one of the first-line treatments within 60 days of diagnosis. Costs were adjusted for inflation using the Gross Domestic Product Implicit Price Deflator., Results: A total of 1131 patients received at least one first-line treatment (median [p 25 -p 75 ] age: 6.3 [4.5-8.3] months, 55% male), of whom 592 patients received ACTH, 363 patients received oral prednisolone, and 355 patients received vigabatrin. After adjusting for inflation, the median average wholesale price of a 14-day course of treatment increased for ACTH from $3718 in 2006 to $100 457 in 2020, ~2700% (by a factor of 27), whereas it decreased for oral prednisolone from $169 in 2006 to $89 in 2020, ~50% (by a factor of 0.5), and increased for vigabatrin from $1206 in 2009 (first year with data on vigabatrin used for IESS) to $4102 in 2020, ~340% (by a factor of 3.4). During the first 60 days after diagnosis, inpatient admission days and costs where higher for ACTH than for oral prednisolone and vigabatrin-5.0 (3.0-8.3) days vs 2.0 (0.0-5.0) days vs 2.0 (0.0-6.0) days, p < .0001; and $32 828 ($14 711-$67 216) vs $16 227 ($0-$35 829) vs $17 844 ($0-$47 642), p < .0001. ACTH use decreased from representing 78% of first-line treatments in 2006 to 18% in 2020 (p < .0001). Sensitivity analyses confirmed the robustness of the results., Significance: The gap between the cost of ACTH and the cost of oral prednisolone or vigabatrin has widened markedly from 2006 to 2020, whereas the relative proportion of ACTH use has decreased., (© 2023 International League Against Epilepsy.)

The molecular mechanisms leading to infantile epileptic spasm syndrome (IESS) remain obscure. The only common factor seems to be that the spasms are restricted to a limited period of infancy, during a certain maturational state. Here the current literature regarding the biochemical mechanisms of brain maturation in IESS is reviewed, and various hypotheses of the pathophysiology are put together. They include: (1) imbalance of inhibitory (NGF, IGF-1, ACTH, GABA) and excitatory factors (glutamate, nitrites) which distinguishes the different etiological subgroups, (2) abnormality of the hypothalamic pituitary adrenal (HPA) axis linking insults and early life stress, (3) inflammation (4) yet poorly known genetic and epigenetic factors, and (5) glucocorticoid and vigabatrin action on brain development, pinpointing at molecular targets of the pathophysiology from another angle. An altered maturational process may explain why so many, seemingly independent etiological factors lead to the same clinical syndrome and frequently to developmental delay. Understanding these factors can provide ideas for novel therapies., Competing Interests: Declaration of Competing Interest I have no conflict of interest to disclose., (Copyright © 2023 The Author. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Pain and spasms of urinary and biliary tracts are conditions causing poor quality of life. Treatment with analgesic drugs such as non-steroidal anti-inflammatory drugs and modulators of the parasympathetic system are not always tolerated, and often additional therapeutic options are necessary. The present analysis aimed to evaluate the pharmacokinetics and effectiveness of oral and parenteral preparations based on phloroglucinol in reducing pain and spasms associated with renal or biliary colic in phase 3, multicentre, open-label, randomized, comparative studies on clinical effectiveness and safety., Methods: Pharmacokinetic and pharmacodynamic studies were carried out. Four phase 3 multicentre, open-label, randomized, comparative studies were conducted to evaluate the clinical effectiveness and safety in patients with pain and spasms of urinary or biliary tracts. Eligible patients randomly received either phloroglucinol orally or via intramuscular (IM)/intravenous (IV) administration and reference drug, dexketoprofen for urinary spasms and pain, the non-steroidal anti-inflammatory drug metamizole or scopolamine-based reference drug for biliary colic. The primary outcomes were symptoms and observed frequency of spasms, while the secondary outcome was the duration of improvement or the time between the drug administration and the recurrence of symptoms. Comparison of groups by quantitative characteristics was performed using the T-test for independent samples or the Mann-Whitney test. Intragroup comparisons were performed using the Wilcoxon test, or the T-test for linked samples. Qualitative signs were analysed using the Pearson's χ 2 test and Fisher's exact test., Results: The pharmacokinetic studies showed that (i) most of the phloroglucinol (> 80% for IV and per os formulations) was eliminated in the first 6 h after dosing, (ii) the drug was eliminated in urine as unchanged phloroglucinol (1,3,5-trihydroxybenzene) in a small proportion (< 3% of the dose) and (iii) a considerable amount of the drug was detected after enzymatic deconjugation with β-glucoronidase/arylsulfatase from Helix pomatia. As for the pharmacokinetic study, a total of 364 patients were enrolled, divided in four studies: two designed to test the effectiveness of oral and IM/IV preparations in biliary colic and two in urinary colic. Baseline characteristics between groups were similar. Phloroglucinol oral or IV/IM showed an effectiveness comparable to the reference drug in reducing pain and spasms associated with both urinary and biliary colic. There was no difference between all groups by survival analysis., Conclusion: Oral and parenteral preparations based on phloroglucinol are as effective in reducing pain and spasms associated with renal or biliary colic as current therapeutic options. Therefore, phloroglucinol may be considered as useful to treat pain and spasms associated with urinary and biliary colic., (© 2022. The Author(s).)

Objectives: To study the factors influencing the short-term (28 days) efficacy of initial adrenocorticotropic hormone (ACTH) therapy for infantile epileptic spasms syndrome (IESS), as well as the factors influencing recurrence and prognosis., Methods: The clinical data were collected from the children with IESS who received ACTH therapy for the first time in the Department of Pediatric Neurology, Xiangya Hospital of Central South University, from April 2008 to January 2018 and were followed up for ≥2 years. The multivariate logistic regression analysis was used to evaluate the factors influencing the short-term efficacy of ACTH therapy, recurrence, and long-term prognosis., Results: ACTH therapy achieved a control rate of seizures of 55.5% (111/200) on day 28 of treatment. Of the 111 children, 75 (67.6%) had no recurrence of seizures within 12 months of follow-up. The possibility of seizure control on day 28 of ACTH therapy in the children without focal seizures was 2.463 times that in those with focal seizures ( P <0.05). The possibility of seizure control on day 28 of ACTH therapy in the children without hypsarrhythmia on electroencephalography on day 14 of ACTH therapy was 2.415 times that in those with hypsarrhythmia ( P <0.05). The possibility of recurrence within 12 months after treatment was increased by 11.8% for every 1-month increase in the course of the disease ( P <0.05). The possibility of moderate or severe developmental retardation or death in the children without seizure control after 28 days of ACTH therapy was 8.314 times that in those with seizure control ( P <0.05). The possibility of moderate or severe developmental retardation or death in the children with structural etiology was 14.448 times that in those with unknown etiology ( P <0.05)., Conclusions: Presence or absence of focal seizures and whether hypsarrhythmia disappears after 14 days of treatment can be used as predictors for the short-term efficacy of ACTH therapy, while the course of disease before treatment can be used as the predictor for recurrence after seizure control by ACTH therapy. The prognosis of IESS children is associated with etiology, and early control of seizures after ACTH therapy can improve long-term prognosis.

Objective: To examine the efficacy, dosing, and safety profiles of intrathecal and oral baclofen in treating spasticity after spinal cord injury (SCI)., Data Sources: PubMed and Cochrane Databases were searched from 1970-2018 with keywords baclofen, spinal cord injury, and efficacy., Study Selection: The database search yielded 588 sources and 10 additional relevant publications. After removal of duplicates, 398 publications were screened., Data Extraction: Data were extracted using the following population, intervention, comparator, outcomes, and study designs criteria: studies including adult patients with SCI with spasticity; the intervention could be oral or intrathecal administration of baclofen; selection was inclusive for control groups, surgical management, rehabilitation, and alternative pharmaceutical agents; outcomes were efficacy, dosing, and adverse events. Randomized controlled trials, observational studies, and case reports were included. Meta-analyses and systematic reviews were excluded., Data Synthesis: A total of 98 studies were included with 1943 patients. Only 4 randomized, double-blinded, and placebo-controlled trials were reported. Thirty-nine studies examined changes in the Modified Ashworth Scale (MAS; 34 studies) and Penn Spasm scores (Penn Spasm Frequency; 19 studies), with average reductions of 1.7±1.3 and 1.6±1.4 in individuals with SCI, respectively. Of these data, a total of 6 of the 34 studies (MAS) and 2 of the 19 studies (Penn Spasm Frequency) analyzed oral baclofen. Forty-three studies addressed adverse events with muscle weakness and fatigue frequently reported., Conclusions: Baclofen is the most commonly-prescribed antispasmodic after SCI. Surprisingly, there remains a significant lack of large, placebo-controlled, double-blinded clinical trials, with most efficacy data arising from small studies examining treatment across different etiologies. In the studies reviewed, baclofen effectively improved spasticity outcome measures, with increased efficacy through intrathecal administration. Few studies assessed how reduced neural excitability affected residual motor function and activities of daily living. A host of adverse events were reported that may negatively affect quality of life. Comparative randomized controlled trials of baclofen and alternative treatments are warranted because these have demonstrated promise in relieving spasticity with reduced adverse events and without negatively affecting residual motor function., (Copyright © 2022 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Platanus orientalis is traditionally used to treat diarrhea and spasm. However, studies are lacking on its mechanism of action in diarrhea and spasm. Pharmacological in-vivo activities were performed. In-vitro activities were carried out to explore the underlying mechanism(s) of action in isolated tissue preparations of mice jejunum and ileum. Crude extract of Platanus orientalis, loperamide and verapamil were used. The crude extract provided dose-dependent protection in castor oil diarrhea like verapamil and reduced the intestinal fluid accumulation and charcoal meal transit distance. In-vitro studies produced spasmolytic effect on the spontaneous (EC 50 value=0.21mg/mL), high K + (EC 50 value=0.37mg/mL) and carbachol (CCh)-induced contractions 5.35mg/mL (3.88-6.85) respectively. The quiescent ileum responded well to the high K + and carbachol (CCh)-induced contractions when tested against crude extract. It caused inhibition of the induced contraction with EC 50 values of 0.20mg/mL (0.10-0.30) and 3.25mg/mL (2-4.5) respectively and showed potent effect against CCh-induced contractions. Calcium response curves produced a similar effect to verapamil. The crude extract of Platanus orientalis remained safe up to 5g/kg dose.

Aim: To report response to first treatment in infants with infantile spasms (IS), including incremental benefit of prednisolone 60 mg/day and vigabatrin following prednisolone 40 mg/day failure in infants commenced on the United Kingdom Infantile Spasms Study (UKISS) treatment sequence., Methods: In this retrospective analysis, we compared effectiveness of prednisolone, vigabatrin and nonstandard treatments as first treatment for IS. In infants who commenced the UKISS treatment sequence, we evaluated response to each step. Primary outcome was spasm cessation after 42 days. Secondary outcomes were severe side effects and spasm relapse after 42 days., Results: Treatment response data were available for 151 infants. First treatment was prednisolone in 99 infants, vigabatrin in 18 and nonstandard treatment in 34. The rate of spasm cessation with first treatment was significantly higher with prednisolone (62/99, 63%) than vigabatrin (5/18, 28%, P = 0.01) or nonstandard treatment (2/34, 5.9%, P < 0.01). Of 112 infants who commenced the UKISS treatment sequence, 71/112 (63%) responded to prednisolone 40 mg/day. Among non-responders, 12/29 (41%) subsequently responded to prednisolone 60 mg/day, and 10/22 (45%) to vigabatrin. Severe side effects and spasm relapse were not significantly different between each treatment., Conclusion: We confirm higher rates of spasm cessation with initial treatment with prednisolone than vigabatrin and nonstandard therapy. Non-use of prednisolone as first treatment in over one third of infants highlights a concerning treatment gap. The UKISS treatment sequence has high overall treatment response (total 93/112; 83%), with similar benefit of subsequent prednisolone 60 mg/day and vigabatrin in prednisolone 40 mg/day non-responders., (© 2022 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

BACKGROUND Serotonin toxicity, often referred to as 'serotonin syndrome,' is a drug-induced condition due to excess serotonin released from brain synapses, resulting in symptoms that may be autonomic, neuromuscular, and/or cognitive in nature. Most cases involve more than 1 of the following drug regimens: monoamine oxidase inhibitors (MAOIs), serotonin releasers, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs). This report is of a 70-year-old woman who presented with confusion and muscle spasms due to serotonin toxicity associated with paroxetine and quetiapine treatment. CASE REPORT An elderly woman with dementia presented to the Emergency Department with fever, altered mental status, labile blood pressures, and inducible clonus. No known medication dosage increases had been made, nor had any new serotonergic agents been added to the patient's drug regimen. She underwent a thorough workup in the Emergency Department and later during her hospitalization. A presumptive diagnosis of serotonin toxicity was made early on during her stay, with the etiology attributed to use of paroxetine and quetiapine. Clinical improvement was observed after benzodiazepine administration, discontinuation of offending agents, and a brief cyproheptadine course. The patient survived her hospital stay and was ultimately discharged to hospice care with a return to her baseline level of functioning. CONCLUSIONS Diagnosing serotonin toxicity requires a high degree of clinical suspicion and can occur in the absence of increased dosage of existing, or initiation of new, serotonergic agents.

The aim of this study was to investigate the frequency of hemorrhagic side effects of botulinum neurotoxin A injections (BoNT/A) for the treatment of benign essential blepharospasm (BEB) and hemifacial spasm (HFS) in patients taking antithrombotic drugs (ATD). A total of 140 patients were included (female: 65%; BEB: 75%; mean age: 70 ± 12 years). According to their current antithrombotic medication, participants were either assigned to the ATD group (41%), or to the control group (59%). The ATD group was further divided into subgroups depending on the medication administered: acetylsalicylic acid, ADP receptor antagonists, direct oral anticoagulants, vitamin-K antagonists, or dual antiplatelet therapy. The frequency of hemorrhagic side effects was recorded by retrospective analysis of past treatments as documented in the patient's file set in relation to the number of past treatments (hematoma frequency of past treatments, HF retro ) as well as by a prospective survey capturing the side effects of one single treatment (hematoma frequency of actual treatment, HF actual ). There was no significant difference in hematoma frequency between the ATD group and the control group, neither for past (HF retro : ATD: 2%; 45/2554; control: 4%; 109/2744) nor for the current BoNT/A treatments (HF actual : ATD: 30%; 16/53; control: 31%; 22/72). Even between ATD subgroups, hematoma frequency did not differ significantly. Overall, hemorrhagic side effects of the BoNT/A treatment for BEB and HFS were mild and non-disabling.

Summary: The infantile spasms (IS) syndrome is a catastrophic developmental epileptic encephalopathy syndrome characterized by an age-specific expression of epileptic spasms that are associated with extremely abnormal, oftentimes described as chaotic, interictal EEG pattern known as hypsarrhythmia. Patients with IS generally have poor neurodevelopmental outcomes, in large part because of the frequent epileptic spasms and interictal EEG abnormalities. Current first-line treatments such as adrenocorticotropic hormone or vigabatrin are often ineffective and are associated with major toxic side effects. There is therefore a need for better and safer treatments for patients with IS, especially for the intractable population. Hope is on the horizon as, over the past 10 years, there has been robust progress in the development of etiology-specific animal models of IS. These models have been used to identify potential new treatments for IS and are beginning to provide some important insights into the pathophysiological substrates for this disease. In this review, we will highlight strengths and weaknesses of the currently available animal models of IS in addition to new insights into the pathophysiology and treatment options derived from these models., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 by the American Clinical Neurophysiology Society.)

Summary: The initial description of infantile spasms and its association to developmental abnormalities was attributed to Dr. Williams J. West in 1841 but the clinical scenario at the time had also been seen by other physicians. French physician Henry Gastaut proposed the eponym of West syndrome in the 9th Colloquium de Marseille in 1960. The description of hypsarrhythmia in 1952 by Gibbs and Gibbs added the EEG component to the triad of infantile spasms. The hypsarrhythmia discovery led to a sudden interest in understanding the etiology and developing treatments for this devastating disease affecting infants and young children. It was in the 1950s when cases of infantile spasms with absence of hypsarrhythmia were initially observed. Also, the treatment with adrenocorticotrophic hormone was initially reported as efficacious for treating infantile spasms and hypsarrhythmia in the late 1950s. Adrenocorticotrophic hormone remains the best treatment option for these epilepsy types. This article will provide a historical review of knowledge developments about hypsarrhythmia and infantile spasms, emphasizing the period 1952 to 1982. The goal of the article was to highlight clinical elements that were discovered then and remain clinically relevant today., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 by the American Clinical Neurophysiology Society.)

Programmed cell death protein 1 (PD-1) inhibitors open a new era of cancer immunotherapy, but they are associated with immune-related adverse events (irAEs) involving multiple endocrine organs of which thyroid dysfunction is the most common An uncommon condition of coronary artery spasm and ventricular tachycardia associated with thyrotoxicosis, induced by a PD-1 inhibitor, is discussed in this case. A 60-year-old male patient with a 1-week history of chest tightness and palpitation at rest was referred to us in July 2021. No obvious abnormalities were noted on physical examination and electrocardiography. He was being treated with a PD-1 inhibitor (camrelizumab, 200 mg) for lung metastasis of liver cancer; treatment stopped because he was found to have hyperthyroidism. Holter recorded intermittent STsegment arch back raised 0.5-14 mm upward lasting for 1-5 min, accompanied by ventricular tachycardia. He was treated with antivasospasm drugs (isosorbide mononitrate and diltiazem). Thyroid function was reexamined and revealed elevated FT3 and FT4 levels, decreased TSH levels, and negative thyroid-associated antibodies. After antivasospasm treatment and iodine taboo diet, his symptoms were relieved, and ST-segment elevation and ventricular tachycardia were disappeared. This case adds to our knowledge of the association between coronary artery spasms and thyrotoxicosis, which is an irAE induced by a PD-1 inhibitor. Patients treated with PD-1 inhibitors need regular follow-ups for cardiac complications, especially those with a history of heart disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Even though adrenocorticotropic hormone (ACTH) demonstrated powerful efficacy in the initially successful treatment of infantile spasms (IS), nearly half of patients have experienced a relapse. We sought to investigate whether features of electroencephalogram (EEG) predict relapse in those IS patients without structural brain abnormalities., Methods: We retrospectively reviewed data from children with IS who achieved initial response after ACTH treatment, along with EEG recorded within the last two days of treatment. The recurrence of epileptic spasms following treatment was tracked for 12 months. Subjects were categorized as either non-relapse or relapse groups. General clinical and EEG recordings were collected, burden of amplitudes and epileptiform discharges (BASED) score and multiscale entropy (MSE) were carefully explored for cross-group comparisons., Results: Forty-one patients were enrolled in the study, of which 26 (63.4%) experienced a relapse. The BASED score was significantly higher in the relapse group. MSE in the non-relapse group was significantly lower than the relapse group in the γ band but higher in the lower frequency range (δ, θ, α). Sensitivity and specificity were 85.71% and 92.31%, respectively, when combining MSE in the δ/γ frequency of the occipital region, plus BASED score were used to distinguish relapse from non-relapse groups., Conclusions: BASED score and MSE of EEG after ACTH treatment could be used to predict relapse for IS patients without brain structural abnormalities. Patients with BASED score ≥ 3, MSE increased in higher frequency, and decreased in lower frequency had a high risk of relapse., (© 2022. Children's Hospital, Zhejiang University School of Medicine.)

Recent animal experiments suggested that centrally transported botulinum toxin type A (BoNT-A) might reduce an abnormal muscle tone, though with an unknown contribution to the dominant peripheral muscular effect observed clinically. Herein, we examined if late BoNT-A antispastic actions persist due to possible central toxin actions in rats. The early effect of intramuscular (i.m.) BoNT-A (5, 2 and 1 U/kg) on a reversible tetanus toxin (TeNT)-induced calf muscle spasm was examined 7 d post-TeNT and later during recovery from flaccid paralysis (TeNT reinjected on day 49 post-BoNT-A). Lumbar intrathecal (i.t.) BoNT-A-neutralizing antiserum was used to discriminate the transcytosis-dependent central toxin action of 5 U/kg BoNT-A. BoNT-A-truncated synaptosomal-associated protein 25 immunoreactivity was examined in the muscles and spinal cord at day 71 post-BoNT-A. All doses (5, 2 and 1 U/kg) induced similar antispastic actions in the early period (days 1-14) post-BoNT-A. After repeated TeNT, only the higher two doses prevented the muscle spasm and associated locomotor deficit. Central trans-synaptic activity contributed to the late antispastic effect of 5 U/kg BoNT-A. Ongoing BoNT-A enzymatic activity was present in both injected muscle and the spinal cord. These observations suggest that the treatment duration in sustained or intermittent muscular hyperactivity might be maintained by higher doses and combined peripheral and central BoNT-A action.

The leaves of Clerodendrum polycephalum Baker (Labiatae) are used as a dietary legume supplement and applied ethnomedicinally for the management of epilepsy, convulsion, and spasms. This study is aimed at evaluating the effects of Clerodendrum polycephalum (CP) leaf extract on chemical-induced seizures in mice and the possible mechanisms of action. Swiss albino mice were pretreated with CP (50, 100, or 500 mg/kg, p.o.) prior to intraperitoneal injection of picrotoxin (PTX) or pentylenetetrazole (PTZ). However, the most effective dose was used to elucidate the role of GABAergic and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling mechanisms in mice brains. Accordingly, we evaluated the preventive and reversal effects of CP on kainic acid (KA)-induced temporal lobe epilepsy (TLE), oxidative stress, and neuroinflammatory in mice. The pretreatment of mice with CP delayed the latencies to PTX and PTZ-induced seizures and decrement in the period of tonic-clonic attacks. Interestingly, CP (100 mg/kg) completely prevented PTZ-induced tonic-clonic seizures. Contrastingly, flumazenil (benzodiazepine receptor antagonist), N G -nitro-L-Arginine (L-NNA) (10 mg/kg., neuronal nitric oxide synthase inhibitor), and methylene blue (MB) (2 mg/kg, a soluble guanylyl cyclase inhibitor) but not L-arginine (150 mg/kg., nitric oxide precursor) reversed CP-induced anticonvulsant-like effect in PTZ model. Furthermore, KA-elicited TLE was prevented by CP treatment. CP also attenuated KA-induced oxidative stress, cyooxygenase-2 (COX-2), and nuclear factor kappa-B (NF-κB) elevated expressions in the hippocampus. The study revealed that the ethanolic leaf extract of CP produced anticonvulsant actions through enhancement of antioxidant defense, GABAergic, and NO-cGMP signaling pathways as well as attenuation of inflammatory processes. PRACTICAL APPLICATIONS: The leaves of Clerodendrum polycephalum Baker (Labiatae) are used as a dietary legume supplement and applied ethnomedicinally for the management of epilepsy, convulsion, and spasms. For this reason, we believe that supplementation of the Clerodendrum polycephalum leaf extract would prevent epileptic-related disorders in mice induced with epileptic conditions using kainic acid and other behavioral phenotypic models. Here, our findings clearly revealed that Clerodendrum polycephalum leaf extract protects against conditions of epileptic-related disorders and thus might be relevant as a dietary supplement in the prevention or delay of the onset of seizures and epileptic behavior., (© 2022 Wiley Periodicals LLC.)

Background: Infantile epileptic spasms syndrome (IESS) is the most common type of severe epilepsy in infants. However, etiological frequency and optimized therapy, particularly corticosteroid regimen and dose, remain unknown., Methods: An ambispective study of an IESS-diagnosed cohort was conducted. Etiologies were evaluated based on the 2017 International League Against Epilepsy classification system. Patients received intravenous dexamethasone or methylprednisolone for 3-5 consecutive days, followed by usual-dose (2 mg/kg/d) oral prednisone for 60-90 days with tapering doses for 1-2 months or high-dose (4 mg/kg/d) oral prednisone for 9-11 days with tapering doses for 2-4 weeks. Treatment responses were compared between the usual and high-dose prednisone groups after propensity score matching. Correlation analysis between treatment responses and underlying etiology was performed., Results: Of the 441 included participants, 218 (49.4%) cases had proven etiologies. The most common etiology of IESS was acquired-structural (23.6%), followed by genetic (15.4%) and congenital-structural (7.0%). Hypoxic-ischemic encephalopathy (55, 52.8%) was the most common acquired-structural etiology. Among the 242 patients administered corticosteroids, 95 received usual-dose oral prednisone and 147 received high-dose oral prednisone. After propensity score matching, 54 patients were included in the usual-dose and high-dose groups, respectively, and treatment effectiveness was compared. There were no significant differences in seizure freedom at days 13-14 (55.6% vs. 51.9%, p = 0.700) and continued seizure freedom between days 14-42 (29.6% vs. 38.9%, p = 0.311) post corticosteroid administration between the usual- and high-dose prednisone groups. The proportion of children achieving seizure cessation at days 13-14 (χ 2  = 1.470, p = 0.698) and days 14-42 (χ 2  = 0.928, p = 0.836) was similar in the different etiological subgroups. Unknown etiological group showed significantly higher resolution of hypsarrhythmia than other etiological groups (χ 2  = 10.761, p = 0.009). Both usual-dose and high-dose group showed tolerance to full-dose corticosteroids and similar adverse events over the observation period., Conclusion: IESS etiology was primarily related to structural causes. Clinical response in short-term follow-up was independent of prednisone dosage and underlying etiology. Better EEG responses may occur in patients with unknown etiology., Competing Interests: Conflicts of interest The authors declare that they have no potential conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

A 65-year-old man was admitted to our hospital with a 6-year history of painful muscle stiffness in his trunk and lower limbs, preventing him from walking. Stiff-person syndrome (SPS) was diagnosed because the patient had symptoms of painful muscle spasms elicited by tactile stimulation without joint contracture. Although SPS- related autoantibodies in the serum, including anti-glycine R, anti-amphiphysin, anti-glutamic acid decarboxylase (GAD), anti-dipeptidyl peptidase-like protein (DPPX) and anti-γ-aminobutyric acid-A (GABA A ) R, were negative, the ACTH and cortisol levels were low. On the basis of additional loading tests for anterior pituitary function and ACTH, isolated ACTH deficiency (IAD) was diagnosed. Hormonal replacement therapy with hydrocortisone at 15 mg/day ameliorated the condition quickly, and the patient became asymptomatic after three months. Flexion contractures have been reported as musculoskeletal symptoms of IAD, but are not usually evident in patients with SPS. The present case illustrates that the painful muscle spasms elicited by tactile stimulation without joint contracture characteristic of SPS can also be symptoms of IAD.

Dystonia and muscle spasms are a group of common and unfavorable clinical neurological symptoms. The use of botulinum toxin (BTX-A) abroad has achieved good results in the treatment of various movement disorders characterized by involuntary or abnormal muscle contractions. It is expected to open up a new field for the treatment of myelodysplastic syndromes (MDs) such as focal dystonia and muscle spasm. There are theoretical and practical implications for the diagnosis and development of some effective neurological treatments. The efficacy of BTX-A in the treatment of various focal dystonia and muscle spasm disorders is as follows: symptoms were improved to varying degrees after injection of Botox or botulinum toxin type A (CBTX-A), but Botox or CBTx. There was no significant difference in the efficacy of A. 30.4% of patients had complete remission, 57.8% had significant remission, and 8.9% had partial remission. Among them, HFS and BS had the best curative effect, and the symptoms were significantly improved by 95.3% and 89.4%, respectively. The efficacy of CD was also satisfactory, with 75.5% of the patients showing significant improvement in symptoms, followed by Meg/OMD (OMD) with 73.3% and SD with 3.3%. The efficacy of WC is poor, and functional improvement is uncertain. Other forms of focal dystonia and spasticity also showed significant functional improvement in 60% of patients. Most patients start to see effects within 1 week after BTX-A injection, symptoms gradually improve, and the bridge of curative effect is reached in 2-4 weeks, and the healing effect lasts for about 3-5 months on average. The overall severity of adverse effects was not severe and resolved spontaneously within a few days to ten weeks, with the most concerning complications being ptosis and dysphagia., Competing Interests: The author declares no competing interests., (Copyright © 2022 Zhen Zhang.)

Purpose: The hemodynamic effects of intra-arterial vasodilator administration for the prevention of radial artery spasm during transradial access have not been well characterized. This study evaluates the effect of intra-arterial Verapamil and Nitroglycerine administration on systemic blood pressure and its correlation with timing of moderate sedation administration., Materials and Methods: Institutional review board approval was granted. Patients who underwent transradial access from 4/2018 to 4/2019 and received both intra-arterial vasodilators and moderate sedation were identified and their electronic medical records reviewed. Patients were divided into three cohorts based on the timing of sedation and intra-arterial vasodilator administration. Decrease in systolic blood pressure (SBP) was expressed as means with standard deviation which were then compared using Student's t -test., Results: A total of 84 patients who met inclusion criteria demonstrated an overall mean decrease in SBP of 16.45 mmHg ± 15.45 mmHg. Patients receiving sedation and intra-arterial vasodilators within their expected peak SBP effect times had similar SBP change following the intra-arterial vasodilators as those in whom the interval was greater than 10 min (4.2 mmHg; 95% CI (-4.11 to 12.52), p  = 0.3171). Two patients experienced asymptomatic hypotension., Conclusions: Patients undergoing transradial access for procedures utilizing moderate sedation can safely receive intra-arterial Verapamil and Nitroglycerine for prevention of radial artery spasm.

Objective: To determine epilepsy and neurodevelopmental outcomes beyond 2 y of age and their putative prognostic factors in children with West syndrome (WS)., Methods: This cross-sectional study was initiated after approval from Institutional Ethics Committee. A follow-up cohort of 114 children (aged ≥ 2 y) diagnosed and treated for WS at the authors' center were assessed in-person for epilepsy and neurodevelopmental outcomes using Vineland Social Maturity Scale - Malin's adaptation for Indian children. Subsequently, age at onset, lead-time-to-treatment, etiology, and response to any of the standard therapies were analyzed as possible predictors of these outcomes., Results: Of 114 children (mean age: 55 ± 32 mo, 91 boys), structural etiology was the predominant underlying etiology (79.8%) for WS. At 2 y of age, 64% had ongoing seizures. At the last follow-up, 76% had social quotient < 55, and 39% had cerebral palsy (spastic quadriparesis in 21%). An underlying structural etiology was associated with ongoing seizures [OR (95% CI) 3.5 (1.4-9); p = 0.008] at 2 y of age and poor developmental outcomes [OR (95% CI): 3.3 (1.3-8.9); p = 0.016]. Complete cessation of spasms with the standard therapy was significantly associated with better seizure control [OR (95% CI): 5.4 (2.3-13); p < 0.001] and neurodevelopmental outcome [OR (95% CI): 5.2 (1.8-14.9); p < 0.001]., Conclusion: The majority of children with WS have a poor neurodevelopmental outcome and epilepsy control on follow-up. The underlying etiology and response to initial standard therapy for epileptic spasms have a prognostic role in predicting the neurological outcome in these patients on follow-up., (© 2021. Dr. K C Chaudhuri Foundation.)

Six mutations in the salt-inducible kinase 1 (SIK1) have been identified in developmental and epileptic encephalopathy (DEE-30) patients, and two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. In a previous study, we generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing and found an increase in excitatory synaptic transmission and enhancement of neural excitability in neocortical neurons in SIK1-MT mice. NMDA was injected into SIK1-MT males to induce epileptic seizures in the mice. The severity of the NMDA-induced seizures was estimated by the latency and the number of tail flickering and hyperflexion. Activated brain regions were evaluated by immunohistochemistry against c-fos, Iba1, and GFAP. As another epilepsy model, pentylenetetrazol was injected into the adult SIK1 mutant mice. Seizure susceptibility induced by both NMDA and PTZ was enhanced in SIK1-MT mice. Brain regions including the thalamus and hypothalamus were strongly activated in NMDA-induced seizures. The epilepsy-associated mutation of SIK1 canceled the pharmacological effects of the ACTH treatment on NMDA-induced seizures. These results suggest that SIK1 may be involved in the neuropathological mechanisms of NMDA-induced spasms and the pharmacological mechanism of ACTH treatment.

Spasm of accommodation refers to constant contraction of the ciliary muscles of the eye, which fail to relax. Neurological issues, head injury, and psychogenic factors can lead to spasm of accommodation, which is generally bilateral. This case report describes the clinical presentation of traumatic, unilateral accommodative spasm in an army person. A 26-year-old male presented with complaints of diminution of near vision in the left eye noticed accidentally. History revealed a blunt injury in the eyebrow region of the left eye two months back. His best corrected visual acuity was 6/6, 0.8 M (N6) in the right eye and 6/9, 2.5 M (N18) in the left eye. Accommodative response was documented using an open-field autorefractometer that showed asymmetry in the accommodation response and pupillary diameter between the two eyes. One percent Atropine sulfate eye ointment - twice a day for 3 days - was prescribed. On the fourth day, the spasm was resolved in the left eye. Pre- and post-Atropine administration, lens thickness measurements were documented, which showed significant changes. Accommodative facility exercise was initiated after the pharmacological management. Unilateral accommodative spasm is rare and needs careful investigations. Objective assessment of accommodative response and lens thickness measurement play a vital role in confirming the diagnosis.

Purpose: The purpose of this meta-analysis was to assess the effect of statins on major adverse cardiovascular events (MACE) related to coronary artery spasm (CAS) and to evaluate the effectiveness of statins in patients with CAS., Methods: A systematic search of electronic databases, including Google Scholar, the Cochrane Central Register of Controlled Trials, and PubMed, was conducted. These studies were all published in English, and the databases were searched from inception to July 2021. All articles were evaluated independently by 2 researchers on the basis of inclusion and exclusion criteria. In the research, data about the incidence of major adverse cardiovascular events in CAS patients undergoing statin therapy was included and divided into different subgroups. A random effects model was conducted to synthesize the data., Findings: Five cohort studies were included in the analysis. These results indicated that statins failed to reduce the incidence of stroke in patients with CAS in general. However, subgroup analysis revealed that statins were more effective in improving outcomes for CAS patients without severe coronary stenosis compared with those with severe coronary stenosis., Implications: Statins may have a potential benefit in patients with CAS who do not have coronary stenosis. To investigate these findings further, future prospective, randomized controlled research will be required., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Elsevier Inc. All rights reserved.)