Treatment of Infantile Spasms

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

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De Novo KCNQ2 Mutation in One Case of Epilepsy of Infancy With Migrating Focal Seizures That Evolved to Infantile Spasms

Child Neurology Open ◽

10.1177/2329048x18767738 ◽

2018 ◽

Vol 5 ◽

pp. 2329048X1876773 ◽

Cited By ~ 2

Author(s):

Haolin Duan ◽

Jing Peng ◽

Miriam Kessi ◽

Fei Yin

Keyword(s):

Adrenocorticotropic Hormone ◽

De Novo ◽

Epileptic Encephalopathy ◽

Infantile Spasms ◽

Heterozygous Mutation ◽

Interictal Spikes ◽

Rare Type ◽

Focal Seizures ◽

First Case ◽

New Association

Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare type of early-onset epileptic encephalopathy that is characterized by refractory migratory multifocal seizures that migrate between hemispheres. Its etiology is not well known although it is postulated to occur due to channelopathy. The authors report the first case of EIMFS due to a de novo heterozygous mutation in exon 4(c.881C>T missense mutation, p.Ala294Val, NM_172107.2) in KCNQ2 gene which later evolved into infantile spasms. However, it is the second case of EIMFS with KCNQ2 mutation. He presented with multifocal migratory partial seizures which started at the age of 8 days. Electroencephalogram examination revealed multifocal interictal spikes that migrated from one hemisphere to the other within a seizure. It was intractable with antiepileptic drugs and adrenocorticotropic hormone. He later developed spasms from the age of 8 months. Consequently, our case supports the new association between EIMFS and KCNQ2 mutations. Moreover, it enriches the disease phenotype because of transformation.

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Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms

Children ◽

10.3390/children7010005 ◽

2020 ◽

Vol 7 (1) ◽

pp. 5 ◽

Cited By ~ 1

Author(s):

Remi Janicot ◽

Li-Rong Shao ◽

Carl E. Stafstrom

Keyword(s):

Treatment Options ◽

Epileptic Encephalopathy ◽

Infantile Spasms ◽

First Year ◽

Cellular Mechanisms ◽

Novel Treatments ◽

Clinical Models ◽

Eeg Changes ◽

Preclinical Animal Models ◽

First Year Of Life

Infantile spasms (IS) is an epileptic encephalopathy with unique clinical and electrographic features, which affects children in the middle of the first year of life. The pathophysiology of IS remains incompletely understood, despite the heterogeneity of IS etiologies, more than 200 of which are known. In particular, the neurobiological basis of why multiple etiologies converge to a relatively similar clinical presentation has defied explanation. Treatment options for this form of epilepsy, which has been described as “catastrophic” because of the poor cognitive, developmental, and epileptic prognosis, are limited and not fully effective. Until the pathophysiology of IS is better clarified, novel treatments will not be forthcoming, and preclinical (animal) models are essential for advancing this knowledge. Here, we review preclinical IS models, update information regarding already existing models, describe some novel models, and discuss exciting new data that promises to advance understanding of the cellular mechanisms underlying the specific EEG changes seen in IS—interictal hypsarrhythmia and ictal electrodecrement.

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The Collaborative Network Approach: a model for advancing patient-centric research for Castleman disease and other rare diseases

Emerging Topics in Life Sciences ◽

10.1042/etls20180178 ◽

2019 ◽

Vol 3 (1) ◽

pp. 97-105

Author(s):

Mary Zuccato ◽

Dustin Shilling ◽

David C. Fajgenbaum

Keyword(s):

Rare Diseases ◽

Treatment Options ◽

Castleman Disease ◽

High Impact ◽

Collaborative Network ◽

Network Approach ◽

Grant Applications ◽

Research Questions ◽

Novel Strategy ◽

Patient Centric

Abstract There are ∼7000 rare diseases affecting 30 000 000 individuals in the U.S.A. 95% of these rare diseases do not have a single Food and Drug Administration-approved therapy. Relatively, limited progress has been made to develop new or repurpose existing therapies for these disorders, in part because traditional funding models are not as effective when applied to rare diseases. Due to the suboptimal research infrastructure and treatment options for Castleman disease, the Castleman Disease Collaborative Network (CDCN), founded in 2012, spearheaded a novel strategy for advancing biomedical research, the ‘Collaborative Network Approach’. At its heart, the Collaborative Network Approach leverages and integrates the entire community of stakeholders — patients, physicians and researchers — to identify and prioritize high-impact research questions. It then recruits the most qualified researchers to conduct these studies. In parallel, patients are empowered to fight back by supporting research through fundraising and providing their biospecimens and clinical data. This approach democratizes research, allowing the entire community to identify the most clinically relevant and pressing questions; any idea can be translated into a study rather than limiting research to the ideas proposed by researchers in grant applications. Preliminary results from the CDCN and other organizations that have followed its Collaborative Network Approach suggest that this model is generalizable across rare diseases.

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Response to Steroids in IQSEC2-Related Encephalopathy Presenting with Rett-Like Phenotype and Infantile Spasms

Journal of Pediatric Genetics ◽

10.1055/s-0040-1721371 ◽

2020 ◽

Author(s):

Divya Nagabushana ◽

Aparajita Chatterjee ◽

Raghavendra Kenchaiah ◽

Ajay Asranna ◽

Gautham Arunachal ◽

...

Keyword(s):

Late Onset ◽

Neurodevelopmental Disorder ◽

Epileptic Encephalopathy ◽

Infantile Spasms ◽

The Past ◽

Resource Limited ◽

The Central Nervous System ◽

Motor Milestone ◽

Behavior And Cognition ◽

Atypical Rett Syndrome

Abstract Introduction IQSEC2-related encephalopathy is an X-linked childhood neurodevelopmental disorder with intellectual disability, epilepsy, and autism. This disorder is caused by a mutation in the IQSEC2 gene, the product of which plays an important role in the development of the central nervous system. Case Report We describe the symptomatology, clinical course, and management of a 17-month-old male child with a novel IQSEC2 mutation. He presented with an atypical Rett syndrome phenotype with developmental delay, autistic features, midline stereotypies, microcephaly, hypotonia and epilepsy with multiple seizure types including late-onset infantile spasms. Spasms were followed by worsening of behavior and cognition, and regression of acquired milestones. Treatment with steroids led to control of spasms and improved attention, behavior and recovery of lost motor milestone. In the past 10 months following steroid therapy, child lags in development, remains autistic with no further seizure recurrence. Conclusion IQSEC2-related encephalopathy may present with atypical Rett phenotype and childhood spasms. In resource-limited settings, steroids may be considered for spasm remission in IQSEC2-related epileptic encephalopathy.

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Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

Journal of Clinical Medicine ◽

10.3390/jcm10132803 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2803

Author(s):

Carolin Czauderna ◽

Martha M. Kirstein ◽

Hauke C. Tews ◽

Arndt Vogel ◽

Jens U. Marquardt

Keyword(s):

Clinical Care ◽

Treatment Options ◽

Treatment Strategies ◽

Specific Treatment ◽

Growth Factor Receptor ◽

Treatment Modalities ◽

Precision Oncology ◽

Recurrence Rates ◽

Isocitrate Dehydrogenase 1 ◽

Liver Cancers

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.

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Estimation of Damage Induced by Single-Hole Rock Blasting: A Review on Analytical, Numerical, and Experimental Solutions

Energies ◽

10.3390/en14010029 ◽

2020 ◽

Vol 14 (1) ◽

pp. 29

Author(s):

Mahdi Shadabfar ◽

Cagri Gokdemir ◽

Mingliang Zhou ◽

Hadi Kordestani ◽

Edmond V. Muho

Keyword(s):

Structural Reliability ◽

Numerical Models ◽

Experimental Models ◽

Rock Blasting ◽

Discussion Section ◽

Reliability Models ◽

Fine Grain ◽

Experimental Approaches ◽

Engineering Projects

This paper presents a review of the existing models for the estimation of explosion-induced crushed and cracked zones. The control of these zones is of utmost importance in the rock explosion design, since it aims at optimizing the fragmentation and, as a result, minimizing the fine grain production and recovery cycle. Moreover, this optimization can reduce the damage beyond the set border and align the excavation plan with the geometric design. The models are categorized into three groups based on the approach, i.e., analytical, numerical, and experimental approaches, and for each group, the relevant studies are classified and presented in a comprehensive manner. More specifically, in the analytical methods, the assumptions and results are described and discussed in order to provide a useful reference to judge the applicability of each model. Considering the numerical models, all commonly-used algorithms along with the simulation details and the influential parameters are reported and discussed. Finally, considering the experimental models, the emphasis is given here on presenting the most practical and widely employed laboratory models. The empirical equations derived from the models and their applications are examined in detail. In the Discussion section, the most common methods are selected and used to estimate the damage size of 13 case study problems. The results are then utilized to compare the accuracy and applicability of each selected method. Furthermore, the probabilistic analysis of the explosion-induced failure is reviewed using several structural reliability models. The selection, classification, and discussion of the models presented in this paper can be used as a reference in real engineering projects.

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Ultrasound-Guided Injection of Dextrose Versus Corticosteroid in Chronic Plantar Fasciitis Management: A Randomized, Double-Blind Clinical Trial

Foot & Ankle Specialist ◽

10.1177/1938640020980924 ◽

2021 ◽

pp. 193864002098092

Author(s):

Gholamreza Raissi ◽

Amin Arbabi ◽

Maryam Rafiei ◽

Bijan Forogh ◽

Arash Babaei-Ghazani ◽

...

Keyword(s):

Clinical Trial ◽

Plantar Fasciitis ◽

Rating Scale ◽

Corticosteroid Injection ◽

Treatment Options ◽

Plantar Fascia ◽

Numeric Rating Scale ◽

Therapeutic Effects ◽

Ultrasound Guided ◽

Double Blind

Design Chronic plantar fasciitis (PF) is a common cause of chronic heel pain, with different conventional treatment options. In this randomized clinical trial, the effect of ultrasound-guided injection of dextrose versus corticosteroid in chronic PF was evaluated and compared. Methods A total of 44 patients suffering from chronic PF who visited the physical medicine and rehabilitation clinic were enrolled in the study. Two table-randomized groups were formed. They received an ultrasonography-guided, single injection of either 40 mg methylprednisolone or 20% dextrose. Numeric Rating Scale (NRS), Foot and Ankle Ability Measure questionnaire with 2 subscales, Activities of Daily Living (FAAM-A) and Sports (FAAM-S), along with ultrasonographic parameters were evaluated before and at 2 and 12 weeks after the injection. Results. A total of 40 participants completed the study. Both interventions significantly improved pain and function at 2 and 12 weeks postinjection. After 2 weeks, compared with the dextrose prolotherapy, the corticosteroid group had significantly lower daytime and morning NRS scores (2.55 vs 4.1, P = .012, and 2.75 vs 4.65, P = .004), higher FAAM-S (66.84 vs 54.19; P = .047), and lower plantar fascia thickness at insertion and 1 cm distal to the insertion zone (3.89 vs 4.29 mm, P = .004, and 3.13 vs 3.48 mm, P = .002), whereas FAAM-A was similar in both groups ( P = .219). After 12 weeks, all study variables were statistically similar between corticosteroid and dextrose prolotherapy groups. No injection-related side effects were recorded in either group. Conclusion Both methods are effective. Compared with dextrose prolotherapy, our results show that corticosteroid injection may have superior therapeutic effects early after injection, accompanied by a similar outcome at 12 weeks postinjection. Levels of Evidence: Level II

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Therapeutic Features and Updated Clinical Trials of Mesenchymal Stem Cell (MSC)-Derived Exosomes

Journal of Clinical Medicine ◽

10.3390/jcm10040711 ◽

2021 ◽

Vol 10 (4) ◽

pp. 711

Author(s):

Byung-Chul Lee ◽

Insung Kang ◽

Kyung-Rok Yu

Keyword(s):

Clinical Trials ◽

Therapeutic Agent ◽

Therapeutic Potential ◽

Therapeutic Option ◽

Treatment Options ◽

Genetic Material ◽

Experimental Models ◽

Attractive Alternative ◽

Cell Based Therapy ◽

Cellular Rejection

Identification of the immunomodulatory and regenerative properties of mesenchymal stem cells (MSCs) have made them an attractive alternative therapeutic option for diseases with no effective treatment options. Numerous clinical trials have followed; however, issues such as infusional toxicity and cellular rejection have been reported. To address these problems associated with cell-based therapy, MSC exosome therapy was developed and has shown promising clinical outcomes. MSC exosomes are nanosized vesicles secreted from MSCs and represent a non-cellular therapeutic agent. MSC exosomes retain therapeutic features of the cells from which they originated including genetic material, lipids, and proteins. Similar to MSCs, exosomes can induce cell differentiation, immunoregulation, angiogenesis, and tumor suppression. MSC exosomes have therefore been employed in several experimental models and clinical studies. Here, we review the therapeutic potential of MSC-derived exosomes and summarize currently ongoing clinical trials according to disease type. In addition, we propose several functional enhancement strategies for the effective clinical application of MSC exosome therapy.

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Optimizing cisplatin delivery to triple-negative breast cancer through novel EGFR aptamer-conjugated polymeric nanovectors

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02039-w ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Lisa Agnello ◽

Silvia Tortorella ◽

Annachiara d’Argenio ◽

Clarissa Carbone ◽

Simona Camorani ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Tumor Targeting ◽

Triple Negative ◽

Ex Vivo ◽

Treatment Options ◽

Negative Control ◽

Therapeutic Effects ◽

Metastatic Setting

Abstract Background Management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC. Methods Nanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses. Results We demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs. Conclusions Our study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.

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Perspectives and experiences of patients and healthcare professionals with geriatric assessment in chronic kidney disease: a qualitative study

BMC Nephrology ◽

10.1186/s12882-020-02206-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Carlijn G. N. Voorend ◽

Noeleen C. Berkhout-Byrne ◽

Yvette Meuleman ◽

Simon P. Mooijaart ◽

Willem Jan W. Bos ◽

...

Keyword(s):

Kidney Disease ◽

Qualitative Study ◽

Clinical Outcomes ◽

Geriatric Assessment ◽

Clinical Care ◽

Treatment Options ◽

Routine Care ◽

Treatment Team ◽

Dutch Hospital ◽

Additional Support

Abstract Background Older patients with end-stage kidney disease (ESKD) often live with unidentified frailty and multimorbidity. Despite guideline recommendations, geriatric assessment is not part of standard clinical care, resulting in a missed opportunity to enhance (clinical) outcomes including quality of life in these patients. To develop routine geriatric assessment programs for patients approaching ESKD, it is crucial to understand patients’ and professionals’ experiences with and perspectives about the benefits, facilitators and barriers for geriatric assessment. Methods In this qualitative study, semi-structured focus group discussions were conducted with ESKD patients, caregivers and professionals. Participants were purposively sampled from three Dutch hospital-based study- and routine care initiatives involving geriatric assessment for (pre-)ESKD care. Transcripts were analysed inductively using thematic analysis. Results In six focus-groups, participants (n = 47) demonstrated four major themes: (1) Perceived characteristics of the older (pre)ESKD patient group. Patients and professionals recognized increased vulnerability and (cognitive) comorbidity, which is often unrelated to calendar age. Both believed that often patients are in need of additional support in various geriatric domains. (2) Experiences with geriatric assessment. Patients regarded the content and the time spent on the geriatric assessment predominantly positive. Professionals emphasized that assessment creates awareness among the whole treatment team for cognitive and social problems, shifting the focus from mainly somatic to multidimensional problems. Outcomes of geriatric assessment were observed to enhance a dialogue on suitability of treatment options, (re)adjust treatment and provide/seek additional (social) support. (3) Barriers and facilitators for implementation of geriatric assessment in routine care. Discussed barriers included lack of communication about goals and interpretation of geriatric assessment, burden for patients, illiteracy, and organizational aspects. Major facilitators are good multidisciplinary cooperation, involvement of geriatrics and multidisciplinary team meetings. (4) Desired characteristics of a suitable geriatric assessment concerned the scope and use of tests and timing of assessment. Conclusions Patients and professionals were positive about using geriatric assessment in routine nephrology care. Implementation seems achievable, once barriers are overcome and facilitators are endorsed. Geriatric assessment in routine care appears promising to improve (clinical) outcomes in patients approaching ESKD.

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