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Objectives: Neuromyelitis optica (NMO) has a complex pathology. Clinical symptoms, derived from damage to optic nerves and spinal cord, cause optic neuritis and/or longitudinally extensive myelitis. Treatment options are limited. We assessed adrenocorticotropic hormone (ACTH) use in patients developing exacerbations on systemic steroid treatment and declining other treatments., Methods: Patients with NMO who initiated intravenous methylprednisolone (IVMP) for exacerbations and experienced a subsequent exacerbation on monthly IVMP or had inadequate response to IVMP received ACTH 80 U/d intramuscularly for 7 days (for acute relapse), followed by 80 U every 2 weeks (for long taper down/maintenance). Every 1 to 3 months, relapse, Expanded Disability Status Scale, laboratory, and adverse event assessments were performed., Results: Six patients (mean age: 48.6 years; NMO-suggestive clinical/imaging presentations; cerebral spinal fluid revealing no oligoclonal bands; aquaporin-4 positive [n = 5]) were identified: 5 experiencing subsequent exacerbations with monthly IVMP and 1 with inadequate response to IVMP. No relapses occurred during ACTH treatment or taper-down period, laboratory values indicated no safety concerns, and annual follow-up magnetic resonance imagings were stable. Adverse events were generally characterized as improved or unchanged versus with IVMP, although 1 patient reported transient edema (lower extremities) only during ACTH treatment. Potential treatment-related AEs included edema, acne, urinary tract infection, and insomnia and were reportedly less severe with ACTH treatment than IVMP., Conclusions: Adrenocorticotropic hormone treatment for acute NMO was associated with clinical improvement, suggesting that ACTH could have a role in treating acute NMO patients failing IVMP and declining other treatments. Fewer/less severe AEs were observed with ACTH versus IVMP. Larger, controlled clinical studies are needed.

Background: Prolonged use of corticosteroids continues to be the mainstay in the management of most proteinuric glomerulopathies, but is limited by extensive side effects. Alternative medications such as adrenocorticotropic hormone (ACTH) have been recently used to treat refractory glomerulopathies and have shown superior outcomes when compared with steroids. However, the clinical responsiveness to ACTH therapy varies considerably with a number of patients exhibiting de novo or acquired resistance. The underlying mechanism remains unknown., Methods: A patient with steroid-dependent focal segmental glomerulosclerosis (FSGS) developed severe steroid side effects impacting quality of life and was converted to repository porcine ACTH therapy. Immediate response in the form of remission of nephrotic syndrome was noted followed by relapse in 10 weeks. Suspecting the role of some ACTH-antagonizing factors, the patient's serum was examined., Results: Immunoblot-based antibody assay revealed high titers of de novo IgG antibodies in the patient's serum that were reactive to the porcine corticotropin with negligible cross-reactivity to human corticotropin. In vitro, in cultured B16 melanoma cells that express abundant melanocortin receptors, addition of the patient's serum substantially abrogated the porcine corticotropin triggered signaling activity of the melanocortinergic pathway, marked by phosphorylation of glycogen synthase kinase 3β, thus suggesting a mitigating effect on the biological functionality of porcine corticotropin., Conclusion: ACTH is a useful alternative therapeutic modality for refractory proteinuric glomerulopathies like FSGS. However, as quintessential therapeutic biologics, natural ACTH, regardless of purity and origin, is inevitably antigenic and may cause the formation of neutralizing antibodies in some sensitive patients, followed by resistance to ACTH therapy. It is imperative to develop ACTH analogues with less immunogenicity for improving its responsiveness in patients with glomerular diseases., (© 2020 S. Karger AG, Basel.)

Background: Current treatments after an episode of optic neuritis have limited success protecting the retinal nerves and restoring visual function., Objective: To assess the effectiveness of Repository Corticotropin Injection (RCI) after the onset of optic neuritis., Methods: Twenty-four adults were treated with RCI within 2 weeks of symptom onset. Seven exams over 400 days measured low- and high-contrast visual acuity (LCVA and HCVA) and spectral domain optical coherence tomography of the retinal structures. Differences between and among affected and contralateral eyes were assessed using linear mixed models., Results: HCVA improved in the affected eye over the study (36.2 letters to 52.5), and LCVA improved in both the affected eye (1.8 letters to 6.8) and the contralateral eye (8.3 letters to 11.7). These functional improvements occurred concurrent to a thinning in the papillomacular bundle and the ganglion cell, inner plexiform, and retinal nerve fiber layers, while the inner nuclear, outer plexiform, outer nuclear, and photoreceptor layers thickened., Conclusion: The eyes affected by the ON and treated with RCI improved in both LCVA and HCVA, and unexpectedly LCVA improved in the contralateral eye as well. This functional improvement was mirrored by structural changes in the retina. This study lays the groundwork for future studies to explore potential neuro-protective and neuro-restorative effects of RCI., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To compare the therapeutic effectiveness of oral corticosteroids with that of adrenocorticotrophic hormone for infantile spasms., Methods: PubMed, Embase, Scopus, and the Cochrane library were searched to retrieve studies published before December 2018 to identify pediatric patients with a diagnosis of infantile spasms. The interventions of oral corticosteroids and adrenocorticotrophic hormone were compared. We included only randomized controlled trials that reported the cessation of spasms as treatment response. The primary outcome was clinical spasm cessation on day 13 or 14. The secondary outcomes were the resolution of hypsarrhythmia, side effects, continued spasm control, spasm relapse rate, and subsequent epilepsy rate. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, the study-level quality assessment was conducted using the Cochrane risk-of-bias tool., Results: After extensive review, 39 articles were included for meticulous evaluation. Five randomized controlled trials with a total of 239 individuals were eligible for further analysis. No significant difference was detected between the corticosteroids and adrenocorticotrophic hormone in the cessation of clinical spasms (odds ratio [OR]: 0.54; 95% confidence interval [CI]: 0.16 to 1.81; P = 0.32). The subgroups of high-dose prednisolone versus adrenocorticotrophic hormone and low-dose prednisone versus adrenocorticotrophic hormone also exhibited no significant difference. Furthermore, the two subgroups did not differ in terms of hypsarrhythmia resolution, side effects, relapse rate, or subsequent epilepsy rate., Interpretation: This meta-analysis suggests that high-dose prednisolone is not inferior to adrenocorticotrophic hormone and that it be considered a safe and effective alternative treatment., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Background: There is ongoing debate regarding the comparative effectiveness of adrenocorticotropic hormone and prednisolone in the treatment of infantile spasms. With a large cohort and extended follow-up, we set out to evaluate a protocol in which adrenocorticotropic hormone is reserved for prednisolone nonresponders., Methods: The following standardized hormonal therapy protocol was adopted. Patients initially receive prednisolone (8 mg/kg/day [maximum 60 mg/day], divided in three daily doses for 14 days). Prednisolone responders taper it over 14 days, whereas prednisolone nonresponders immediately transition to natural adrenocorticotropic hormone (150 U/m 2 /day, divided in two daily doses for 14 days). We evaluated short-term response, defined as video-electroenecphaloagraphy-confirmed resolution of both epileptic spasms and hypsarrhythmia on day 14, without relapse for 28 additional days. We then evaluated long-term relapse and calculated the rates of sustained response at six, 12, and 18 months., Results: We identified 102 children with infantile spasms who were treated with prednisolone. Prior exposure to hormonal therapy and vigabatrin was observed among 12% and 35% of patients, respectively. Sixty (59%) patients responded to prednisolone, and 13 (33%) prednisolone nonresponders then responded to adrenocorticotropic hormone. Cumulative response to prednisolone and adrenocorticotropic hormone (if needed) was higher among treatment-naive patients (84%) than among patients with prior exposure to first-line treatment (51%), with P < 0.001. Relapse was relatively common among all subgroups., Conclusion: Short-term response to prednisolone was favorable and higher among treatment-naive patients. These data suggest that prednisolone is a reasonable approach to initial therapy and that adrenocorticotropic hormone exhibits substantial efficacy after prednisolone failure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To investigate the factors in first-time adrenocorticotropic hormone (ACTH) therapy and their influence on spasm control time in infants with infantile spasms., Methods: A total of 72 infants with infantile spasms who were admitted from January 2008 to October 2013 were enrolled. Their clinical data were collected, and the exposure factors for infantile spasms were selected. A Cox proportional-hazards regression model analysis was performed for these factors to analyze their influence on spasm control time., Results: Clarification of the etiology (known or unexplained etiology), frequency of spasms before treatment, and presence or absence of combination therapy (ACTH used alone or in combination with magnesium sulfate) had a significant influence on spasm control time in infants with infantile spasms. The infants with a known etiology had a significantly shorter spasm control time than those with unexplained etiology, and the infants with a low frequency of spasms before treatment and receiving ACTH combined with magnesium sulfate early had a significantly longer spasm control time than their counterparts (P<0.05)., Conclusions: For infants with infantile spasms at initial diagnosis, etiology should be clarified, which may helpful for evaluating prognosis. A combination of ACTH and magnesium sulfate should be given as soon as possible, which may improve their prognosis.

Despite little evidence supporting its superiority to glucocorticoid therapy, use and expenditures for repository corticotropin (rACTH) injection (H.P. Acthar Gel; Mallinckrodt) have increased dramatically in the last 5 years, particularly among a small number of nephrologists, rheumatologists, and neurologists. Recently, the manufacturer justified the extremely high and rapidly increasing cost of rACTH by citing the ongoing need to generate clinical data to support its use. We test this assertion by investigating the quality and provenance of the evidence likely to emerge in the foreseeable future. We identified all completed, in-progress, and proposed studies of rACTH registered at ClinicalTrials.gov. 75 studies representing 2,953 participants met inclusion criteria. Studies addressed primarily nephrologic (n = 23), rheumatologic (n = 28), and neurologic (n =22) indications. Of the 23 studies proposed for renal indications (enrollment, 33 ± 49 [mean ± SD]), 11 were not randomized, 8 compared only different rACTH treatment regimens, and 4 compared rACTH to placebo. No studies of rACTH proposed for renal indications included an rACTH-free arm receiving active treatment (ie, another form of immunosuppression). We conclude that evidence emerging in the foreseeable future is unlikely to broadly support rACTH use over lower-cost glucocorticoid-based alternatives for renal indications., (Published by Elsevier Inc.)

Epileptic spasms during infancy (infantile spasms) represent a serious treatment and social problem despite their rare occurrence. Current treatments include hormonal therapy (adrenocorticotropin-ACTH or corticosteroids) or vigabatrin (per se or in the combination). These treatments are partially effective and with potentially significant adverse effects. Thus, the search for new effective drugs is warranted. We tested efficacy of a novel fusion peptide AQB-565 developed by Aequus Biopharma in a model of infantile spasms consisting of prenatal exposure to betamethasone and repeated postnatal trigger of spasms with N-methyl-d-aspartic acid (NMDA). AQB-565 molecule includes the first 24 amino acids of ACTH, a ten amino acid linker and a modified melanocyte-stimulating hormone molecule. In contrast to ACTH with almost uniform activity over all peripheral and central melanocortin receptor isoforms, AQB is preferentially active on central melanocortin receptors MC3 and MC4. Here, we used equivalent doses of rat ACTH (full molecule) and AQB-565 and compared their efficacy in a prospective randomized test against of repeated bouts of spasms on postnatal days (P)12, P13 and P15 in the rat model. All doses of ACTH (range 0.02-1.0 mg/kg s.c.) and all doses but one of AQB-565 in the same range suppressed spasms in P15 rats (treatment stopped on P14). There was no dose-dependent effect and both compounds had all-or-none effect that is similar to clinical outcome of hormonal treatment of infantile spasms in children. Thus, AQB-565 may represent a novel treatment of infantile spasms similarly effective as ACTH but with potentially limited side effects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Repository corticotropin injection (RCI) has immune-modulatory and anti-inflammatory effects and is approved for multiple indications, including severe and acute chronic allergic and inflammatory processes involving the eye and adnexa. This study describes patient characteristics, treatment patterns, and physicians' assessments of patients with uveitis treated with RCI., Methods: This was a retrospective medical record review of US patients. Eligible patients had a diagnosis of uveitis, received RCI in the past 12 months, and had completed or were receiving RCI treatment at the time of data collection. Baseline characteristics and after-treatment clinical data are descriptively reported., Results: The study included 91 patients (mean age 41 years, 62% female, and mean time since diagnosis 3.98 years). Most patients had moderate (n = 48, 53%) to severe (n = 21, 23%) visual impairment, and none was blind before RCI therapy. Patients used an average of 2.5 medications before RCI. Initial RCI dosing regimens, dose adjustments, and treatment durations were different for each patient. Concomitant medication use and dosages were reduced during RCI; 76 patients (84%) improved, 15 patients (16%) stayed the same, and none worsened; 86% of patients had improvements in vision., Conclusions: Physicians individualized RCI therapy among patients who suffered uveitis for several years and when previous therapies were inadequate. Most patients improved after initiating RCI, most commonly in vision. The findings support use of RCI for uveitis and provide a better understanding of patient characteristics and practice patterns to guide appropriate use.

Objective: To compare the efficacy and safety of the ketogenic diet (KD) with standard adrenocorticotropic hormone (ACTH) treatment in infants with West syndrome., Methods: In this parallel-cohort (PC) randomized controlled trial (RCT), infants were randomly allocated to KD or high-dose ACTH. Those who could not be randomized were followed in a PC. Primary end point was electroclinical remission at day 28. Secondary end points were time to electroclinical remission, relapse after initial response, seizure freedom at last follow-up, adverse effects, and developmental progress., Results: One hundred one infants were included: 32 in the RCT (16 KD; 16 ACTH) and 69 in the PC (37 KD; 32 ACTH). Electroclinical remission at day 28 was similar between KD and ACTH (RCT: 62% vs 69%; PC: 41% vs 38%; combined cohort: 47% vs 48%; KD vs ACTH, respectively). In the combined cohort, time to electroclinical remission was similar between both treatments (14 days for KD, 16 days for ACTH). However, relapse rates were 16% (KD) and 43% (ACTH, P = 0.09), and seizure freedom at last follow-up was 40% (KD) and 27% (ACTH, P = 0.18). Adverse effects needing acute medical intervention occurred more often with ACTH (30% with KD, 94% with ACTH, P < 0.001). Age-appropriate psychomotor development and adaptive behavior were similar. Without prior vigabatrin (VGB) treatment, remission at day 28 was 47% (KD) and 80% (ACTH, P = 0.02); relapse rates were 29% (KD) and 56% (ACTH, P = 0.13). Consequently, seizure freedom at last follow-up was similar. In infants with prior VGB, seizure freedom at last follow-up was 48% (KD) and 21% (ACTH, P = 0.05)., Significance: The study is underpowered; therefore, its results should be interpreted with caution. KD is as effective as ACTH in the long term but is better tolerated. Without prior VGB treatment, ACTH remains the first choice to achieve short-term remission. However, with prior VGB, KD was at least as effective as ACTH in the short term and was associated with lower relapse rates in the long term; therefore, it represents an appropriate second-line treatment after VGB., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: To compare the outcomes of adrenocorticotrophic hormone (ACTH) and Prednisolone therapy in children with West syndrome., Methods: The study was done at a tertiary health centre for children. The pediatric neurologist at the centre enrolled children into the study based on the inclusion and exclusion criteria. They were evaluated in detail, classified according to etiologic type and then, randomly assigned into two treatment groups, either ACTH or Prednisolone. They were followed at regular intervals till 6 mo., Results: There was no difference between ACTH and Prednisolone groups with respect to all the outcomes measured. Cessation of spasms was achieved in 6/15 (40%) in Prednisolone group and 9/18 (50%) in ACTH group (p = 0.3906). The average time for achieving cessation was 6.9 and 8 d in ACTH and Prednisolone groups respectively (p = 0.7902). The relapse rates were 18.18 and 50% in ACTH and Prednisolone groups respectively (p = 0.28). The side-effects profile, subsequent epilepsy rates and improvement in milestones were similar in both the treatment groups., Conclusions: There is no significant difference in children treated with ACTH and Prednisolone. Study results cannot be generalized due to small sample size. However, Prednisolone can be a suitable alternative to ACTH in resource poor settings.

Objectives: Acute gout is traditionally treated with NSAIDs, corticosteroids, and colchicine. However, the presence of comorbid conditions and advancing age, often seen in hospitalised patients, may prevent their use. We reviewed the published data on the use of ACTH in the treatment of acute gouty arthritis., Methods: A search was performed up to June 2017. We included clinical trials or case studies/series where ACTH had been administered in human subjects as a treatment for acute gout or pseudogout., Results: Data consistently demonstrated ACTH to be fast-acting, typically relieving the painful symptoms of acute gout within 24 h of treatment. Furthermore, the average number of days needed to achieve 100% resolution of gout symptoms in patients treated with ACTH was similar to those of the corticosteroid triamcinolone. Retrospective data confirm the efficacy of ACTH or the synthetic analogue Synacthen in the treatment of acute gout in patients with comorbidities such as cardiovascular disease, chronic kidney disease, and hypertension, including those who were hospitalised, with all patients responding after 1-3 doses. ACTH appears to be well-tolerated with side effects being minor and transient in nature. Importantly, ACTH/Synacthen has no clinically significant effect on glucose and potassium levels or blood pressure. Clinical evidence from available case studies supports these findings., Conclusions: ACTH is a fast acting, efficacious and well-tolerated option for patients with acute gout when traditional therapies have failed or are contraindicated. However, large, carefully designed, randomised controlled trials are required to confirm these findings.

Background: Treatment of focal segmental glomerular sclerosis (FSGS) after kidney transplantation is challenging with unpredictable outcomes. The objective was to investigate the use of adrenocorticotropic hormone (ACTH) analogue gel in kidney transplant recipients with de novo or recurrent FSGS resistant to therapeutic plasma exchange (TPE) and/or rituximab., Methods: We performed a retrospective review of cases of de novo or recurrent resistant FSGS at 2 large US transplant centers between April 2012 and December 2016. Proteinuria was measured by urine protein to creatinine ratio., Results: We identified 20 cases of posttransplant recurrent and de novo FSGS resistant to conventional therapy with TPE and rituximab. Mean ± SD age was 49 ± 15.5 years, 14 (70%) were male, 13 (65%) were whites, and 8 (38%) had previous kidney transplants. Median (interquartile range) of recurrent and de novo FSGS was 3 (0.75-7.5) months posttransplant. The majority of patients, 15 (75%), received TPE as a treatment at the time of diagnosis and 10 (50%) received rituximab, which was started before the use of ACTH gel. There was a significant improvement of urine protein to creatinine ratio from a mean ± SD of 8.6 ± 7.6 g/g before ACTH gel to 3.3 ± 2.3 g/g after the use of ACTH gel (P = 0.004). Ten (50%) patients achieved complete or partial remission., Conclusions: Although, the response varied among the recipients, ACTH gel might be an effective therapy for posttransplant resistant FSGS cases that fail to respond to TPE and rituximab.

Purpose: Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) is a leading cause of childhood-onset encephalopathy in Japan. Children with AESD frequently develop intractable epilepsy, whereas their treatment options remain to be determined., Method: We present 2 unrelated girls, who developed AESD at 25 months (case 1) and 12 months of age (case 2). Both cases underwent intensive cares from the first day of illness, whereas severe neurological impairments were left on discharge. They showed repeated signs of epileptic spasms at 2 months (case 1) and 8 months (case 2) after the onset of AESD. Video-monitoring electroencephalograms (EEG) detected the recurrent attacks accompanying slow-wave bursts and transient suppressions of the precedent epileptiform discharges, as typically observed in epileptic spasms., Results: Intramuscular injection of adrenocorticotropic hormone (ACTH, 0.0125 mg/kg/d) was introduced within 1 month from the onset of epileptic spasms and continued for 2 weeks. The ACTH treatment disrupted the paroxysmal activity in EEG, and it has relieved these patients from epileptic seizures for more than 1 year., Conclusion: This report illustrates the potential efficacy of ACTH for a group of children with epileptic spasms after AESD.

Background and Objectives: There is renewed interest in adrenocorticotropic hormone (ACTH) for the treatment of nephrotic syndrome. We evaluated the efficacy and safety of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome in a randomized trial., Design, Setting, Participants, & Measurements: Participants aged 2-20 years old with frequently relapsing or steroid-dependent nephrotic syndrome were enrolled from 16 sites in the United States and randomized 1:1 to ACTH (repository corticotropin injection) or no relapse-preventing treatment. ACTH treatment regimen was 80 U/1.73 m 2 administered twice weekly for 6 months, followed by 40 U/1.73 m 2 administered twice weekly for 6 months. The primary outcome was disease relapse during the first 6 months. Participants in the control group were offered crossover to ACTH treatment if they relapsed within 6 months. Secondary outcomes were relapse after ACTH dose reduction and treatment side effects., Results: The trial was stopped at a preplanned interim analysis after enrollment of 31 participants because of a lack of discernible treatment efficacy. Fourteen out of 15 (93%) participants in the ACTH arm experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range, 9-32), compared with 15 out of 16 (94%) participants and at a median of 21 days (interquartile range, 14-51) in the control group. There was no difference in the proportion of relapsed patients (odds ratio, 0.93; 95% confidence interval, 0.05 to 16.40; P >0.99) or time to first relapse (hazard ratio, 1.03; 95% confidence interval, 0.50 to 2.15; P =0.93). Thirteen out of 16 participants in the control group crossed over to ACTH treatment. Three out of 28 participants completed 12 months of ACTH treatment; the others exited the trial because of frequent relapses or side effects. There were no disease relapses after ACTH dose reduction among the three participants. Most side effects were mild and similar to side effects of corticosteroids., Conclusions: ACTH at 80 U/1.73 m 2 administered twice weekly was ineffective at preventing disease relapses in pediatric nephrotic syndrome., (Copyright © 2018 by the American Society of Nephrology.)

Objective: To investigate the knowledge, attitude, and practice of Infantile Spasms among pediatricians., Methods: A survey was carried out among pediatricians serving in Punjab, Haryana, Chandigarh, Himachal Pradesh and Delhi. The survey was done by Survey Monkey Software through emails by using a structured questionnaire between July 2016 and December 2017., Results: A total of 236 pediatricians responded to the survey. Most of the respondents (95.5%) correctly considered Infantile Spasms as a seizure type. The most preferred investigation was Electroencephalogram by 91.8% pediatricians; however, only 57.7% considered it to decide the treatment. Perinatal asphyxia was the most recognized etiology (60.7% pediatricians). For treatment of Infantile Spasms, 66.8% follow Nelson textbook of Pediatrics. Adrenocorticotropic hormone was the most preferred first choice drug by 40% pediatricians. Alternate anti-epileptic drug was considered by 60.9% pediatricians when there is no clinical response. Only 24% pediatricians considered treatment response as a complete cessation of spasms. Majority (90%) of pediatricians felt that there is a necessity for increased awareness and 62% pediatricians felt that available information was insufficient., Conclusions: A substantial number of pediatricians lack precise knowledge on evidence-based practice of Infantile Spasms. In developing countries, where pediatricians provide the initial management of Infantile Spasms, there is need to empower them and develop simplified national guidelines/consensus statement for management of Infantile Spasms.

Objective: Epileptic spasms (ES) are associated with pathological neuronal networks, which may underlie characteristic EEG patterns such as hypsarrhythmia. Here we evaluate EEG functional connectivity as a quantitative marker of treatment response, in comparison to classic visual EEG features., Methods: We retrospectively identified 21 ES patients and 21 healthy controls. EEG data recorded before treatment and after ≥10 days of treatment underwent blinded visual assessment, and functional connectivity was measured using cross-correlation techniques. Short-term treatment response and long-term outcome data were collected., Results: Subjects with ES had stronger, more stable functional networks than controls. After treatment initiation, all responders (defined by cessation of spasms) exhibited decreases in functional connectivity strength, while an increase in connectivity strength occurred only in non-responders. There were six subjects with unusually strong pre-treatment functional connectivity, and all were responders. Visually assessed EEG features were not predictive of treatment response., Conclusions: Changes in network connectivity and stability correlate to treatment response for ES, and high pre-treatment connectivity may predict favorable short-term treatment response. Quantitative measures outperform visual analysis of the EEG., Significance: Functional networks may have value as objective markers of treatment response in ES, with potential to facilitate rapid identification of personalized, effective treatments., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

In the last 10 years, basic science and clinical research have made important contributions to the understanding and management of primary membranous nephropathy (MN). The identification of antibodies directed against the M-type phospholipase A 2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A protein have added a new perspective on diagnosis, monitoring the immunological activity, predicting prognosis and guiding therapy in patients with primary MN. Mounting evidence suggests that quantification and follow-up of antiPLA2R Abs levels can help in assessing prognosis and evaluate the response to treatment. The kidney disease improving global outcomes guidelines published in 2012 have not been updated. New data on the use of rituximab suggest it should be considered as a potential initial therapy in the treatment of patients with primary MN.

Adrenocorticotropic hormone (ACTH) therapy is effective for West syndrome; however, the underlying mechanism of action remains unknown. This study explored this mechanism in 5 Japanese patients with West syndrome, injected with ACTH for 28 days. Serum samples were obtained before and 30, 120, and 720 minutes after ACTH injection divided into an "early" (1-4 days) and a "late" (10-28 days) group. Responses to ACTH over time were analyzed by measuring the levels of 27 cytokines. In the early group, serum levels of interleukins-5, -9, and -17, basic fibroblast growth factor, interferon (IFN-γ), IFN-γ-inducible protein 10, chemokine ligand (CCL) 3 and 4, and platelet-derived growth factor were higher in all patients before ACTH administration than in the 720-minute time point. In the late group, no definite trend was observed except for decreased CCL2 levels after ACTH administration. These changes may correlate with mechanisms underlying the anticonvulsant effects of ACTH.

Measurement of the cortisol concentration in hair has been used as an index of chronic stress in several species including humans, wildlife and domestic animals. However, how accurately the cortisol concentration in hair reflects the changes in circulating cortisol concentrations has not been well documented. The objective of the present study was to examine the effect of repeated adrenocorticotropic hormone (ACTH) administration on the reproductive function during the estrous cycle and hair cortisol concentrations in goats. In experiment 1, goats were administered ACTH (0.625 IU/10 kg of body weight, n = 6) or saline (n = 6) intramuscularly once a day for 7 days on Day 11-17 of the estrous cycle (day 0 was the day of ovulation). In experiment 2, goats were administered ACTH (0.625 IU/10 kg of body weight, n = 6) or saline (n = 6) intramuscularly twice a day on Day 11-24 of the estrous cycle. Blood samples were collected 0, 0.5, and 6 h after first administration to determine the circulating cortisol concentrations. Hair was clipped at 0, 1, and 2 months after the start of administration. In both experiments, the plasma cortisol concentration increased at 0.5 h and returned to baseline at 6 h after ACTH administration. During the experiments, estrus was observed in most animals in ACTH and saline groups (6/6 and 4/6 in experiment 1 and 5/6 and 6/6 in experiment 2, respectively) and ovulation was observed in all goats examined. However, the number of ovulatory follicles was significantly different between the ACTH and saline groups, and the maximal diameter of ovulatory follicles tended to be different (P = .07) between the ACTH and saline groups. In experiment 1, the hair cortisol concentration was not influenced by the ACTH administration throughout the sampling period. In experiment 2, the hair cortisol concentration in the ACTH group was greater at 1 month after administration than the pre-administration value, but was not significantly different at 2 months. These results suggest that repeated ACTH administration affects the development and ovulatory process of ovarian follicles and analysis of the hair cortisol concentration can be used for assessing relatively long-term changes in cortisol concentration in the circulation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Immunomodulatory therapy has shown some therapeutic benefits in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. In this report, we describe the use of adrenocorticotropic hormone (ACTH) immunotherapy with good outcome in a patient with anti-NMDAR encephalitis., Subject and Methods: A 4-year-old girl developed convulsions in her right arm and leg without impaired consciousness. These convulsions occurred frequently in clusters of 10-20 events of 10-20 s duration. She was admitted to our hospital on the 6th day following her initial series of convulsions. Flaccid paralysis of the right hand and leg was also found. Interictal electroencephalography showed high-amplitude slow waves. No abnormal findings were shown on MRI. 99m Tc-ECD brain SPECT on the 14th day showed hyperperfusion in the left hemisphere, including the left basal ganglia. The convulsions ceased following the oral administration of valproic acid on the 10th day; however, paralysis associated with choreic dyskinesia of the right arm and leg remained. ACTH immunotherapy was then performed on the 15th day. We identified the presence of N-methyl-D-aspartate receptor antibody in CSF samples taken on the 6th day. After ACTH therapy, the patient fully recovered from the paralysis associated with choreic dyskinesia of the right arm and leg. She has not had a relapse and has not required medication for over a year., Conclusion: ACTH immunotherapy may be a useful treatment option for patients with anti-NMDAR encephalitis, although further evaluation is required., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

West syndrome (WS), also known as infantile spasms, occurs in infancy with a peak between 4 and 7 months. Spasms, neurodevelopmental regression and hypsarrhythmia on electroencephalogram (EEG) basically define WS. The International League Against Epilepsy commission classifies the aetiologies of WS into genetic, structural, metabolic and unknown. Early diagnosis and a shorter lag time to treatment are essential for the overall outcome of WS patients. These goals are feasible with the addition of brain magnetic resonance imaging (MRI) and genetic and metabolic testing. The present work analysed the medical literature on WS and reports the principal therapeutic protocols of its management. Adrenocorticotropic hormone (ACTH), vigabatrin (VGB) and corticosteroids are the first-line treatments for WS. There is no unique therapeutic protocol for ACTH, but most of the evidence suggests that low doses are as effective as high doses for short-term treatment, which is generally 2 weeks followed by dose tapering. VGB is generally administered at doses from 50 to 150 mg/kg/day, but its related retinal toxicity, which occurs in 21-34% of infants, is most frequently observed when treatment periods last longer than 6 months. Among corticosteroids, a treatment of 14 days of oral prednisolone (40-60 mg/day) has been considered effective and well tolerated. Considering that an early diagnosis and a shorter lag time to treatment are essential for successful outcomes in these patients, further studies on efficacy of the different therapeutic approaches with evaluation of final outcome after cessation of therapy are needed.

Objective: To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years)., Methods: Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study-level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or ≥50% seizure reduction., Results: We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies., Significance: This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Aim: To evaluate the efficacy of semax and timing of rehabilitation on the dynamics of plasma BDNF levels, motor performance, and Barthel index score in patients after ischemic stroke (IS)., Material and Methods: One hundred and ten patients after IS (43 men, 67 women, mean age 58.0±9.7, Ме 63 years) were examined. All patients were divided into early (89±9 days) and late (214±22 days) rehabilitation groups. Each group was subdivided into semax+ and semax- subgroups. Standard regimen of semax included 2 courses (6000 mcg/day) for 10 days with 20 day interval. Plasma BDNF levels, motor performance on the British Medical Research Council scale and Barthel index were assessed in all groups., Results: Administration of semax, regardless of the timing of rehabilitation, increased BDNF plasma levels which remained high during the whole study period. In semax- subgroups high BDNF plasma levels were positively correlated with early rehabilitation. Administration of semax and high BDNF levels accelerated the improvement and ameliorated the final outcome of Barthel score index. There was a positive correlation between BDNF plasma levels and Barthel score, as well as a correlation between early rehabilitation and motor performance improvement. The correlation between BDNF plasma levels and Barthel score was modified by the timing of rehabilitation., Conclusion: Early rehabilitation and administration of semax increase BDNF plasma level, speed functional recovery, and improve motor performance.

Vigabatrin was approved for the treatment of infantile spasms by the US Food and Drug Administration, but not in Japan at the time of initiating this clinical study because of concerns about irreversible peripheral visual field defects (VFDs). This study evaluated the efficacy and safety of vigabatrin for Japanese patients with infantile spasms. Of 15 patients (aged ≥4weeks and <2years) enrolled, with the exception of two patients who did not receive vigabatrin, 13 were treated with a titrated dosage of vigabatrin (50-150mg/kg/day; limited to 3000mg/day). Twelve out of 13 patients receiving vigabatrin had spasms that were treatment refractory; these patients were concurrently treated with at least one other antiepileptic drug. One patient received vigabatrin monotherapy. Eight of the 13 patients (61.5% [95% CI: 31.6-86.1%]) had a ≥50% reduction during the dose-adjustment phase compared with baseline in the frequency of spasms, with efficacy maintained through a 2-week maintenance phase. Spasms disappeared in six out of nine patients (66.7% [95% CI: 29.9-92.5%]) who transitioned to the maintenance phase and hypsarrhythmia on electroencephalography also resolved in four patients. Hypsarrhythmia was improved in another two patients. Six out of seven patients who continued treatment through Week 32 of an extension study reported ongoing efficacy for vigabatrin. The most common adverse events (AEs) were psychiatric disorders and nervous system disorders (n=8; 61.5%) that were generally mild in severity. No treatment-related peripheral VFDs were observed. No severe AEs or AEs resulting in discontinuation of vigabatrin therapy were reported. An abnormality in magnetic resonance images was observed in one patient during the extension period. Vigabatrin was deemed to be clinically effective and well tolerated in Japanese patients with infantile spasms., (Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.)

Objective: The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia., Methods: Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation., Results: Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) ., Significance: First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Objectives: To characterize and quantify diagnostic and treatment delay among children with infantile spasms, and to estimate the developmental impact of this delay., Study Design: In this cohort study, we surveyed the parents of 100 patients with infantile spasms about their experiences with diagnosis and treatment, and ascertained medical and sociodemographic factors potentially related to care of these infants. We specifically determined the latency to first visit an "effective provider," defined as a provider who identified infantile spasms, and prescribed an appropriate first-line treatment, namely adrenocorticotropic hormone, corticosteroids, or vigabatrin. Time to the first visit to an effective provider was evaluated using Cox proportional hazards regression., Results: The median time from the onset of infantile spasms to first visit with an effective provider was 24.5 days. Only 29% of patients were evaluated by an effective provider within 1 week of infantile spasms onset. The time to first effective provider visit was associated with parental language preference, but with no other sociodemographic characteristics. Parents' suspicions that "something is wrong" were often discounted by healthcare providers, and survey respondents frequently reported that pediatricians and neurologists were unfamiliar with infantile spasms., Conclusion: This study demonstrates that substantial delay (ie, >1 week) in appropriate care is common, and suggests that the poor awareness of infantile spasms among healthcare providers is at least partly responsible for preventable and potentially significant delays in treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To evaluate healthcare resource utilization (HRU) and costs among patients who initiated repository corticotropin injection (RCI; H.P. Acthar Gel) treatment for rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE)., Methods: Patients aged ≥18 years with ≥2 diagnoses for either RA or SLE between July 1, 2006 and April 30, 2015 were identified in the HealthCore Integrated Research Database. Index RCI date was the earliest date of a medical or pharmacy claim for RCI after diagnosis. Baseline characteristics, pre- and post-initiation HRU and costs were assessed using descriptive statistics., Results: This study identified 180 RA patients (mean age = 60 years, 56% female) and 29 SLE patients (mean age = 45 years, 90% female) who initiated RCI. First RCI use averaged 7.1 and 22.6 months after the initial RA and SLE diagnosis, respectively. After RCI initiation, RA patients incurred significantly lower per-patient-per-month (PPPM) all-cause medical costs ($1,881 vs $682, p < .01) vs the pre-initiation period, driven by lower PPPM hospitalizations costs ($1,579 vs $503, p < .01). Overall PPPM healthcare costs were higher ($2,751 vs $5,487, p < .01) due to higher PPPM prescription costs ($869 vs $4,805, p < .01). Similarly, SLE patients had decreased PPPM hospitalization costs ($3,192 vs $799, p = .04) and increased PPPM prescription costs ($905 vs $7,443, p < .01) after initiating RCI; the difference in overall PPPM healthcare costs was not statistically significant likely, due to small sample size., Conclusion: This study, across a heterogeneous population of variable disease duration, described clinical and healthcare utilization and costs of RA and SLE patients initiating RCI in a real-world setting. We observed that patients receiving RCI had lower utilization and costs for medical services in both disease populations, which partially offset the increased prescription costs by 30% and 37%. Future research is needed to explore factors associated with RCI initiation and its impact on long-term outcomes.

This study tested the hypothesis that adrenocortical function would be altered in horses with equine gastric ulcer syndrome (EGUS). Twenty-six sport horses competing at national or international levels in eventing (n=15) or endurance (n=11) were subjected to a gastroscopic examination and an adrenocorticotropic hormone (ACTH) stimulation test. Salivary cortisol concentrations were measured before (baseline) and after (30, 60, 90, 120 and 150min) IV ACTH injection (1μg/kg bodyweight). Within EGUS, two distinct diseases, equine squamous gastric disease (ESGD) and equine glandular gastric disease (EGGD), can be distinguished. ESGD was diagnosed in 8/11 (73%; 95% confidence intervals [95%CI], 43-92%) endurance horses and 5/15 (33%; 95% CI, 14-58%) eventing horses. EGGD was observed in 9/11 (82%; 95% CI, 53-96%) endurance horses and 9/15 (60%; 95% CI, 35-81%) eventing horses. The presence or severity of ESGD was unrelated to the presence or severity of EGGD. ACTH stimulation induced a larger increase in cortisol concentration in horses with moderate EGGD than in horses with mild EGGD. Cortisol concentration during the entire sampling period (total increase in cortisol concentration during the entire sampling period [dAUC], 31.1±6.4ng/mL) and the highest measured concentration at a single time point (maximal increase in cortisol concentration [dMAX], 10.3±2.3ng/mL) were increased (P=0.005 and P=0.038, respectively), indicating that horses with glandular gastric disease exhibited increased adrenocortical responses to ACTH stimulation. These results suggest that EGGD might be associated with an enhanced adrenocortical sensitivity. Further investigations are warranted to confirm the association between adrenocortical sensitivity and EGGD and to elucidate the pathophysiological mechanisms involved., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The membranous nephropathy (MN) is the major cause of nephrotic syndrome in in the adult, account for 20% of cases with annual incidence is 1 in 100.000. In the past 10 years, the role of podocytes has been identified; environmental triggers in genetically predisposed patients can activate podocytes to exhibit antigenic epitopes (receptor of phospholipase A2, thrombospondin type 1) that become targets of specific autoantibodies with subsequent complement activation. The discovery of this mechanisms has opened new horizons in the therapy of MN and novel drugs are available with more specific mechanism of action. Rituximab, a monoclonal antibody directed against CD20 expressed by lymphocytes B, has been used in several trials and appears able to induce remission of nephrotic syndrome in 60% of patients (GEMRITUX trial) with similar risk profile. Nowadays it remains to define the most effective therapeutic pattern. In MN, the concept of targeting disease control, has permit novel therapies with specific blocking mechanisms (belimumab) and non-specific (ACTH) and new therapeutic options, such as ofatumumab, bortezomib and eculizumab, that have allowed to recognize pathological processes involved in the glomerular diseases., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Introduction: Encephalopathy with electrical status epilepticus in sleep (ESES) syndrome is a rare epilepsy syndrome of childhood that is characterized by sleep-induced epileptiform discharges and problems with cognition or behavior. The neuropsychiatric symptoms in ESES syndrome, among which the ADHD-like symptoms are prominent, bear a close resemblance to symptoms in various developmental disorders. Positive response to adrenocorticotropic hormone (ACTH) is associated with the normalization of the EEG and improvement of neuropsychiatric function. This study aimed to determine the improvement in ADHD-like symptoms in response to ACTH and establish a relationship between improvement in clinical symptoms and EEG parameters., Methods: Seventy-five patients with ESES syndrome, who had clinically displayed ADHD-like symptoms, had been treated with ACTH for ESES, and their medical records were retrospectively reviewed. Sleep EEGs were recorded at referral and follow-up visits, and short courses of ACTH were administered when spike-wave index (SWI) was ≥15%. The assessment of treatment effectiveness was based on reduction in SWI and the clinician-reported improvement in ADHD-like symptoms. Statistical analyses were conducted in order to investigate the relationship between the clinical and EEG parameters., Results: Following treatment with ACTH, a reduction in SWI in all the patients was accompanied by a mean improvement of 67% in ADHD-like symptoms. Disappearance/reduction of foci and cessation/reduction of seizures were achieved in patients with formerly antiepileptic-resistant seizures. Multiple linear regressions established that pretreatment SWI and treatment delay predicted posttreatment SWI, while reduction in SWI, treatment delay, and the presence of foci predicted improvement in ADHD-like symptoms., Discussion: Improvement in ADHD-like symptoms showed high correlation and was timely with the resolution of ESES. It is suggested that ESES and ADHD may be the two different expressions of a common neurobiological abnormality. With enhanced interpretation of sleep EEG, a more thorough assessment and treatment of neurodevelopmental disorders is possible., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We studied the dependence of post-rest positive inotropic response of isolated rat papillary muscles subjected to rhythmic stimulation on severity of postinfarction cardiosclerosis developed during 6 weeks after occlusion of the left descending coronary artery. The isolated papillary muscles were perfused with oxygenated Krebs-Henseleit solution and electrically stimulated at a rate of 0.5 Hz. In all rats, coronary occlusion provoked postinfarction cardiosclerosis with the formation of a scar occupying 20-50% (min-max of the sample) of the left ventricular wall. Despite the presence of large postinfarction scar in all rats, the positive post-rest inotropic responses greatly varied. The post-rest response in rats with scar occupying <37% left ventricular wall was similar to that in intact animals, but rats with scar area >44% demonstrated dramatically decreased inotropic response to rest periods.

The effect of peptide Semax on remodeling of cardiac sympathetic innervation was examined in rats with experimental myocardial infarction. In 28 days after ischemia/reperfusion injury, Semax diminished the growth of sympathetic innervation of ventricular septum, although it produced no effect on the density of β 1 and β 2 adrenoceptors.

There is increasing evidence supporting the use of corticotropin as an alternative treatment of refractory proteinuric glomerulopathies. The efficacy of short-acting corticotropin, however, remains unknown and was tested here in an adolescent with steroid-dependent nephrotic syndrome caused by minimal change disease. After developing Cushing syndrome and recently being afflicted with severe cellulitis, the patient was weaned off all immunosuppressants, including corticosteroids. This resulted in a relapse of generalized anasarca, associated with massive proteinuria and hypoalbuminemia. Subsequently, mono-therapy with short-acting animal-derived natural corticotropin was initiated and resulted in a rapid response, marked by substantial diuresis, reduction in body weight, and partial remission of proteinuria. Ten days later, the patient developed mild skin rash and subcutaneous nodules at injection sites. A relapse followed despite doubling the dose of corticotropin, consistent with delayed-onset resistance to treatment. Immunoblot-based antibody assay revealed de novo formation of antibodies in the patient's serum that were reactive to the natural corticotropin. In cultured melanoma cells known to express abundant melanocortin receptors, addition of the patient's serum strikingly mitigated dendritogenesis and cell signaling triggered by natural corticotropin, denoting neutralizing properties of the newly formed antibodies. Collectively, short-acting natural corticotropin seems effective in steroid-dependent nephrotic syndrome. De novo formation of neutralizing antibodies is likely responsible for acquired resistance to corticotropin therapy. The proof of concept protocols established in this study to examine the anticorticotropin neutralizing antibodies may aid in determining the cause of resistance to corticotropin therapy in future studies., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Brain stroke continues to claim the lives of million people every year. To build the effective strategies for stroke treatment it is necessary to understand the neuroprotective mechanisms that are able to prevent the ischemic injury. Consisting of the ACTH (4-7) fragment and the tripeptide Pro-Gly-Pro (PGP), the synthetic peptide Semax effectively protects brain against ischemic stroke. However, the molecular mechanisms underlying its neuroprotection and participation of PGP in them are still needed to be clarified. To reveal biological processes and signaling pathways, which are affected by Semax and PGP, we performed the transcriptome analysis of cerebral cortex of rats with focal cerebral ischemia treated by these peptides. The genome-wide biochip data analysis detected the differentially expressed genes (DEGs) and bioinformatic web-tool Ingenuity iReport found DEGs associations with several biological processes and signaling pathways. The immune response is the process most markedly affected by the peptide: Semax enhances antigen presentation signaling pathway, intensifies the effect of ischemia on the interferon signaling pathways and affects the processes for synthesizing immunoglobulins. Semax significantly increased expression of the gene encoding the immunoglobulin heavy chain, highly affects on cytokine, stress response and ribosomal protein-encoding genes after occlusion. PGP treatment of rats with ischemia attenuates the immune activity and suppresses neurotransmission in the CNS. We suppose that neuroprotective mechanism of Semax is realized via the neuroimmune crosstalk, and the new properties of PGP were found under ischemia. Our results provided the basis for further proteomic investigations in the field of searching Semax neuroprotection mechanism.

Steroid-resistant nephrotic syndrome remains a challenge to treat, but various efforts are underway to better understand the pathogenesis and improve patient outcomes. This review provides an update on the newer advances in understanding the molecular etiologies for a variety of podocyte abnormalities, potential circulating factors that may initiate and sustain the steroid-resistant state, genetic mutations, and precision medicine treatment modalities in this continuously perplexing disorder.

Introduction: Resistance to treatments is a common feature of Ohtahara, Aicardi, West and Dravet syndromes, as well as malignant migrating epilepsy in infancy., Aims: To update the therapeutic management and to analyse whether the aetiology somehow determines the treatment., Development: Convulsive seizures in the first year of life may be due to a potentially treatable aetiology, which makes it essential to carry out a complete evaluation so as to be able to begin, as early as possible, the most suitable and the non-specific symptomatic treatments to control the seizures, which prevents or minimises their deleterious effects. Metabolic disease must be ruled out and it is also essential to try a therapeutic regimen of vitamins and cofactors, as well as antiepileptic drugs. In Ohtahara and Aicardi syndromes, the first-order treatment is phenobarbital and phenytoin, and the most commonly used second-order drugs are midazolam, levetiracetam, lidocaine and valproate. In West's syndrome, the first-order treatment consists of adrenocorticotropic hormone and vigabatrine for the case of tuberous sclerosis; if there is no response, other pharmaceuticals, a ketogenic diet and surgery must be considered. For Dravet's syndrome, the main treatment consists in valproate with clobazam and stiripentol, and as the second order, other drugs and a ketogenic diet should be considered. In epilepsy with migrating seizures, the most effective treatment is with bromides, stiripentol, clonazepam and levetiracetam., Conclusions: Today there is little consensus on the therapeutic approach to be able to establish specific indications. The aetiology has an influence on the treatment, both in cases in which a curative treatment exists (metabolic diseases) and in the symptomatic management with antiepileptic drugs or other treatments (ketogenic diet or surgery).

Fournier's gangrene is an infectious necrotizing fasciitis of the perineal, genital, or perianal regions and is uncommon in children. Adrenocorticotropic hormone (ACTH) is effective for the treatment of infantile spasms; however, suppression of immune function is one of the major adverse effects of this approach. We encountered a 2-month-old boy with infantile spasms that had been treated with ACTH and had developed complicating Fournier's gangrene. Strangulation of a right inguinal hernia was observed after ACTH treatment. Although surgical repair was successful and no intestinal injuries were detected, swelling and discoloration of the right scrotum developed in association with pyrexia and a severe inflammatory response. A scrotal incision revealed pus with a putrid smell. The patient was subsequently diagnosed with Fournier's gangrene complicated by septic shock and disseminated intravascular coagulation. Extensive debridement and intensive care was performed. Enterobactor aerogenes, methicillin-resistant Staphylococcus aureus, and Enterococcus faecalis were isolated from the pus. Meropenem, teicoplanin, and clindamycin were administered to control the bacterial infection. The patient was discharged from the intensive care unit without any obvious neurological sequelae. Suppression of immune function associated with ACTH therapy may have been related to the development of Fournier's gangrene in this case., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is the second most common severe neurodegenerative disorder that is characterized by progressive degeneration of dopaminergic neurons (DA neurons) in the substantia nigra pars compacta (SNpc) region of the brain. In the present study, we investigated the effects of the synthetic regulatory peptides Semax (analog of an ACTH 4-10 fragment (ACTH4-10)) and Selank (analog of immunomodulatory taftsin) on behavior of rats with 6-hydroxidopamine (6-OHDA) induced PD-like parkinsonism. It was showed that both peptides did not affect motor activity of rats in elevated cross shaped maze and passive defensive behavior of the animals. At the same time, Selank decreased level of anxiety of rats with toxic damage of DA neurons in elevated cross shaped maze. Previously such effects of Selank were revealed in healthy rodents (rats and mice) with different models of psycho-emotional stress. Therefore, toxic damage of substantia nigra does not affect the response of the rat organism on this peptide.

ACTH, a member of the melanocortin family of peptides, is often used in the treatment of the developmental epileptic encephalopathy spectrum disorders including, Ohtahara, West, Lennox Gastaut and Landau-Kleffner Syndromes and electrical status epilepticus of sleep. In these disorders, although ACTH is often successful in controlling the seizures and/or inter-ictal EEG abnormalities, it is unknown whether ACTH possesses other beneficial effects independent of seizure control. We tested whether ACTH can ameliorate the intrinsic impairment of hippocampal-based learning and memory in epileptic Kcna1-null (KO) mice. We found that ACTH - administered in the form of Acthar Gel given i.p. four times daily at a dose of 4 IU/kg (16 IU/kg/day) for 7days - prevented impairment of long-term potentiation (LTP) evoked with high-frequency stimulation in CA1 hippocampus and also restored spatial learning and memory on the Barnes maze test. However, with this treatment regimen, ACTH did not exert a significant effect on the frequency of spontaneous recurrent seizures. Together, our findings indicate that ACTH can ameliorate memory impairment in epileptic Kcna1-null mice separate from seizure control, and suggest that this widely used peptide may exert direct nootropic effects in the epileptic brain., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: West syndrome (also known as infantile spasm because of its main seizure type) is a rare form of epilepsy that begins during early infancy. Recent guidelines and reviews on West syndrome recommend the use of adrenocorticotropic hormone steroids, or vigabatrin, as the first-line treatment. However, West syndrome remains to be one of the most challenging epilepsies to treat. Here, we systematically reviewed the current literature obtained during the previous decade. This article provides an overview of the current treatment of infantile spasms., Methods: PubMed and EMBASE were searched to retrieve studies on human published during 2005-2015 and to identify patients with clinical diagnosis of infantile spasms. Drug or diet treatments were used as interventions and comparators., Results: We included 55 studies, of which 1 study was a meta-analysis, 9 were randomized controlled trials, 21 were prospective studies, and 24 were retrospective studies. Topiramate, levetiracetam, zonisamide, and sodium valproate with benzodiazepine (clonazepam or nitrazepam) were found to be potential drugs for treating West syndrome besides adrenocorticotropic hormone, steroids, and vigabatrin. Ketogenic diet and modified Atkins diet were also found to be effective., Conclusions: To date, data regarding the efficacy of treatments of West syndrome still remain limited. Some treatments, including topiramate and ketogenic diet, seem promising besides adrenocorticotropic hormone, steroids, and vigabatrin. Well-designed trials are warranted to validate the findings.

Introduction: Etiology of stuttering remains unknown and no pharmacologic intervention has been approved for treatment. We aimed to evaluate EEG parameters and the effect of adrenocorticotropic hormone (ACTH) therapy in stuttering., Methods: In this retrospective study, 25 patients with attention deficit and hyperactivity (ADHD) or autism spectrum disorder (ASD), and comorbid stuttering were followed and treated with ACTH for electrical status epilepticus in sleep (ESES). Sleep EEGs were recorded at referral and follow-up visits and short courses of ACTH were administered when spike-wave index (SWI) was ⩾15%. The assessment of treatment effectiveness was based on reduction in SWI, and the clinician-reported improvement in stuttering, and ADHD or ASD. Statistical analyses were conducted in order to investigate the relationship between the clinical and EEG parameters., Results: Following treatment with ACTH, a reduction in SWI in all the patients was accompanied by a 72% improvement in ADHD or ASD, and 83.8% improvement in stuttering. Twelve of the 25 patients with stuttering showed complete treatment response. Linear regressions established that SWI at final visit significantly predicted improvement in ADHD or ASD, and in stuttering. If symptoms had recurred, improvement was once again achieved with repeated ACTH therapies. Stuttering always improved prior to, and recurred following ADHD or ASD., Conclusion: The underlying etiology leading to ESES may play a significant role in the pathophysiology of stuttering and connect stuttering to other developmental disorders. ACTH therapy has beneficial effects on stuttering and improves EEG parameters., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Adrenocorticotropic hormone (ACTH) as a treatment for proteinuria due to nephrotic syndrome (NS) has re-emerged over the last decade. Current clinical data are primarily limited to adults with treatment-resistant NS. Largely unknown to today's clinicians is the existence of early clinical studies, following ACTH's introduction in the late 1940s, showing sustained proteinuria response in idiopathic NS in predominantly pediatric, treatment-naïve patients. Before ACTH, patients suffered severe edema and high mortality rates with no reliable or safe treatment. ACTH dramatically altered NS management, initially through recognition of diuresis effects and then through sustained proteinuria remission. This review synthesizes early clinical literature to inform current NS patient management. We undertook a MEDLINE search using MeSH terms "adrenocorticotropic hormone" and "nephrotic syndrome," with limits 1945-1965 and English. Sixty papers totaling 1137 patients were found; 14 studies (9 short-term, five long-term, N = 419 patients) met inclusion criteria. Studies were divided into two groups: short-term (≤28 days) and long-term (>5 weeks; short-term initial daily treatment followed by long-term intermittent)ACTH therapy and results were aggregated. An initial response, defined as a diuresis, occurred in 74 % of patients/treatment courses across nine short-term ACTH studies. Analyzed in eight of these studies, proteinuria response occurred in 56 % of patients/treatment courses. Across five long-term ACTH studies, proteinuria response was shown in 71 % of patients and was sustained up to 4.7 years following treatment. The inventory and re-evaluation of early clinical data broadens the evidence base of clinical experiences with ACTH for implementation of current treatment strategies and aiding the design of future studies.

The diagnostic steps for primary aldosteronism (PA) include case screening tests, confirmatory tests, and localization. The aim of this study was to identify useful confirmatory tests and their cut-off values for differentiating the subtype of primary aldosteronism, especially in unilateral PA, such as aldosterone-producing adenoma, and bilateral PA, such as idiopathic hyperaldosteronism. Seventy-six patients who underwent all four confirmatory tests, the captopril-challenge test (CCT), furosemide upright test (FUT), saline infusion test (SIT), and ACTH stimulation test (AST), and who were confirmed to have an aldosterone excess by adrenal venous sampling (AVS) were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n=17) or bilateral aldosterone excess (n=59) by AVS. The SIT-positive rate was significantly higher in the unilateral group (94.1%) than in the bilateral group (57.6%). Multivariable logistic regression analysis showed that tumor on computed tomography (CT) and plasma aldosterone concentration (PAC) max /cortisol on the AST were useful for differentiating the subtype of PA. Receiver operating characteristic (ROC) curve analysis for distinguishing the subtype of PA showed that a cut-off value of 18.3 PAC max /cortisol on the AST had a sensitivity of 83% and a specificity of 88%. The area under the ROC curve was 0.918 (95% confidence interval 0.7916-0.9708). These data suggest that abdominal CT and AST are useful for differentiating the subtype of PA and the indication for AVS.

Background: Gout is a common type of inflammatory arthritis in patients seen by primary care physicians., Purpose: To review evidence about treatment of acute gout attacks, management of hyperuricemia to prevent attacks, and discontinuation of medications for chronic gout in adults., Data Sources: Multiple electronic databases from January 2010 to March 2016, reference mining, and pharmaceutical manufacturers., Study Selection: Studies of drugs approved by the U.S. Food and Drug Administration and commonly prescribed by primary care physicians, randomized trials for effectiveness, and trials and observational studies for adverse events., Data Extraction: Data extraction was performed by one reviewer and checked by a second reviewer. Study quality was assessed by 2 independent reviewers. Strength-of-evidence assessment was done by group discussion., Data Synthesis: High-strength evidence from 28 trials (only 3 of which were placebo-controlled) shows that colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids reduce pain in patients with acute gout. Moderate-strength evidence suggests that low-dose colchicine is as effective as high-dose colchicine and causes fewer gastrointestinal adverse events. Moderate-strength evidence suggests that urate-lowering therapy (allopurinol or febuxostat) reduces long-term risk for acute gout attacks after 1 year or more. High-strength evidence shows that prophylaxis with daily colchicine or NSAIDs reduces the risk for acute gout attacks by at least half in patients starting urate-lowering therapy, and moderate-strength evidence indicates that duration of prophylaxis should be longer than 8 weeks. Although lower urate levels reduce risk for recurrent acute attacks, treatment to a specific target level has not been tested., Limitation: Few studies of acute gout treatments, no placebo-controlled trials of management of hyperuricemia lasting longer than 6 months, and few studies in primary care populations., Conclusion: Colchicine, NSAIDs, and corticosteroids relieve pain in adults with acute gout. Urate-lowering therapy decreases serum urate levels and reduces risk for acute gout attacks., Primary Funding Source: Agency for Healthcare Research and Quality. (Protocol registration: http://effectivehealth-care.ahrq.gov/ehc/products/564/1992/Gout-managment-protocol-141103.pdf).