Decreased abundance of Akkermansia after adrenocorticotropic hormone therapy in patients with West syndrome

Background Infants suffer from a severe epileptic encephalopathy known as West syndrome (WS). Treatment with adrenocorticotropic hormone (ACTH) indicates the involvement of the gut-brain axis in WS. Several pieces of evidence show the communication of the gut microbiota (GM) with the brain via the hypothalamic–pituitary–adrenal axis (HPA axis) and blood cytokines. This study aimed at (1) determining the GM diversity in infants having WS and (2) comparing the results of infants having WS with those of the healthy infants and also in the patients with WS before and after the ACTH therapy. Results In this study, 29 infants with WS and 29 healthy infants aged 3–13 months were recruited. Fecal samples were collected, and DNA was extracted and sequenced on the Illumina MiSeq platform. Kruskal-Wallis rank-sum test was used to analyze the between-group differences in the Chao1 index, Shannon index, and the abundances of GM at different taxonomy levels. R software was used to plot the graphs. The top five dominant GM genera between patients with WS and healthy infants showed no significant differences. However, the relative abundance of genus Akkermansia was observed to be significantly (P = 0.011) higher in the BT group than in the HC group and AT group. After 2 weeks of ACTH therapy, the relative abundance of Akkermansia significantly (P = 0.003) decreased. Conclusion The relative abundance of Akkermansia was observed to be significantly higher in patients with WS than that in healthy infants. However, the relationship between Akkermansia and WS pathogenesis needs to be clarified in further studies.

Adrenocorticotropic Hormone Therapy Improved Spasms and Sleep Disturbance in Smith–Magenis Syndrome: A Case Report

Smith–Magenis syndrome (SMS) is a complex disorder characterized by variable mental retardation, sleep disturbances, craniofacial and skeletal anomalies, self-injurious and attention-seeking behaviors, and speech and motor delays. The case of a 14-month-old girl with SMS who was experiencing spasm clusters and sleep disturbances with sleep–wake intervals of 1.5 to 2 h persisting from the neonatal period was examined. The patient’s spasms stopped and interictal electroencephalography did not show epileptic discharges after undergoing a high-dose adrenocorticotropic hormone (ACTH) therapy. Moreover, the patient’s sleep cycle stabilized 1 month after receiving the ACTH therapy. Dramatic reductions in the patient’s self-injurious behaviors were also noted. At 1 year following ACTH treatment, the patient’s improved sleep was maintained. High-dose ACTH treatment was considered to contribute to the normal adaptation of the hypothalamic–pituitary–adrenal axis by regulating the release of corticotropin-releasing hormone, resulting in improvement of the patient’s infantile spasms and sleep disturbances.

Automated Detection of Ripple Oscillations in Long-Term Scalp EEG from Patients with Infantile Spasms

ObjectiveScalp high frequency oscillations (HFOs) are a promising biomarker of epileptogenicity in infantile spasms (IS) and many other epilepsy syndromes, but prior studies have relied on visual analysis of short segments of data due to the prevalence of artifacts in EEG. Therefore, we set out to develop a fully automated method of HFO detection that can be applied to large datasets, and we sought to robustly characterize the rate and spatial distribution of HFOs in IS.MethodsWe prospectively collected long-term scalp EEG data from 13 subjects with IS and 18 healthy controls. For patients with IS, recording began prior to diagnosis and continued through initiation of treatment with adenocorticotropic hormone (ACTH). The median analyzable EEG duration was 18.2 hours for controls and 83.9 hours for IS subjects (∼1300 hours total). Ripples (80-250 Hz) were detected in all EEG data using an automated algorithm.ResultsHFO rates were substantially higher in patients with IS compared to controls. In IS patients, HFO rates were higher during sleep compared to wakefulness (median 5.5/min and 2.9/min, respectively; p =0.002); controls did not exhibit a difference in HFO rate between sleep and wakefulness (median 0.98/min and 0.82/min, respectively). Spatially, the difference between IS patients and controls was most salient in the central/posterior parasaggital region, where very few HFOs were detected in controls. In IS subjects, ACTH therapy significantly decreased the rate of HFOs.DiscussionHere we show for the first time that a fully automated algorithm can be used to detect HFOs in long-term scalp EEG, and the results are accurate enough to clearly discriminate healthy subjects from those with IS. We also provide a detailed characterization of the spatial distribution and rates of HFOs associated with infantile spasms, which may have relevance for diagnosis and assessment of treatment response.

ACTH Treatment for Management of Nephrotic Syndrome: A Systematic Review and Reappraisal

Background. In recent years, the use of adrenocorticotropic hormone (ACTH) therapy for treatment of proteinuria due to nephrotic syndrome (NS) has been heavily explored. ACTH therapy, which comes in the natural (H. P. Acthar Gel) or synthetic (tetracosactide) form, has resulted in remission in patients with immunosuppressive and steroid-resistant NS. However, the exact efficacy of ACTH therapy in the NS etiologies, such as membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), lupus nephritis (LN), IgA nephropathy (IgAN), and membranoproliferative glomerulonephritis (MPGN), has not been determined. Objective. This systematic review analyzed the published literature on ACTH therapy in various NS etiologies to determine its efficacy. Methods. A comprehensive search of MEDLINE, EMBASE, and Cochrane databases was conducted for articles through June 2019. An additional search was performed on clinicaltrials.gov to search for additional trials and cross reference the results of our database search. The literature which studied synthetic or natural ACTH treatment in patients with known etiologies of NS was included. Studies were excluded when they consisted of a single case report or did not analyze the lone effect of ACTH in NS. Results. The initial search yielded a total of 411 papers, and 22 papers were included. In 214 MN patients, there was an overall remission of 40% (85/214) and an overall remission of 43% (42/98) in FSGS patients. In other etiologies, there were overall remissions of 78% (11/14), 31% (5/16), 40% (16/40), and 62% (8/13) in MCD, LN, IgAN, and MPGN patients, respectively. Conclusion. ACTH showed benefits in proteinuria reduction across all etiologies of NS. However, more randomized controlled studies with larger population sets and longer follow-ups are imperative to establish causal benefits. New studies into its efficacy in children are also necessary.

Novel ARX mutation identified in infantile spasm syndrome patient

We report a 7-year-old boy with infantile spasms caused by a novel mutation in the Aristaless-related homeobox (ARX) gene. He showed infantile spasms and hypsarrhythmia on electroencephalogram from early infancy. Brain MRI did not reveal severe malformation of the brain except mild hypoplasia of the corpus callosum. Two-fold adrenocorticotropic hormone (ACTH) therapy failed to control the seizures, and ketogenic diet therapy and multi-antiepileptic drug therapy were required as he showed intractable daily tonic-clonic seizures. Exome sequencing identified a hemizygous mutation in the ARX gene, NG_008281.1(ARX_v001):c.1448 + 1 G > A, chrX: 25025227 C > T (GRCh37). To our knowledge, this mutation has not been reported previously.

Experience With Acth In Membranous Nephropathy In Older Patients

Background The most common cause of nephrotic syndrome in the older population is probably memranous nephropathy (MN). Treatment of patients with nephrotic syndrome caused by MN with adrenocorticotrophic hormon (ACTH) is shown to be efficient as primary and secondary therapy. We present our experience using ACTH in older patients with MN.Methods Between 2016 and 2019 six older patients with MN were treated with ACTH gel. We have used tetracosactide, a synthetic analog of ACTH, in intramuscular doses of 1 mg twice a week for 6-9 months. Estimated glomerular filtration rate, levels of albumin, glucose and proteinuria were studied both before and monthly during the follow-up period. Response in proteinuria was assessed as percent reduction from baseline level and as percent of patients with complete or partial remission or no response. Safety and tolerability were evaluated using the reported adverse event frequency either by the patients or the treating nephrologist and using the frequency of discontinuation due to adverse events.Results Three patients achieved total and another two partial remission with ACTH therapy for 6 months. One of the patients did not meet partial remission criteria but had a decrease in proteinuria level. None of the patients experienced cardiovascular or infectious events or a decrease in renal function.Conclusions ACTH is a good therapeutic alternative in older patients with MN with preserved renal function. Further controlled studies are needed to clarify the benefits of ACTH as a first line treatment option in older patients with MN and compare its use with other currently available therapies.