The treatment of hydrocephalus has changed in recent years with better imaging and introduction of endoscopic procedures as well as enhanced shunts. Indications of endoscopic third ventriculostomy (ETV) are now more refined with better quantification of outcome. This article reviews the current state of neuroendoscopy for infective hydrocephalus in children. The roles of third ventriculostomy as a primary procedure or after shunt malfunction, endoscopic interventions in multiloculated hydrocephalus and introduction of intraventricular lavage to salvage severely infected children are evaluated.
Granulomatous amoebic encephalitis due to Acanthamoeba is a chronic disease that almost always results in death. Hematogenous spread is a pre-requisite followed by amoebae invasion of the blood-brain barrier to enter the central nervous system. Given the systemic nature of this infection, a significant latent period of several months before the appearance of clinical manifestations is puzzling. Based on reported cases, here we propose pathogenetic mechanisms that explain the above described latency of the disease.
For the past several decades, there has been little improvement in the morbidity and mortality associated with Acanthamoeba keratitis and Acanthamoeba encephalitis, respectively. The discovery of a plethora of antiacanthamoebic compounds has not yielded effective marketed chemotherapeutics. The rate of development of novel antiacanthamoebic chemotherapies of translational value and the lack of interest of the pharmaceutical industry in developing such chemotherapies have been disappointing. On the other hand, the market for contact lenses/contact lens disinfectants is a multi-billion-dollar industry and has been successful and profitable. A better understanding of drugs, their targets, and mechanisms of action will facilitate the development of more-effective chemotherapies. Here, we review the progress toward phenotypic drug discovery, emphasizing the shortcomings of useable therapies.
Balamuthia mandrillaris and Naegleria fowleri are free-living amoebae that cause infection of the central nervous system, granulomatous amoebic encephalitis (GAE) and primary amoebic meningoencephalitis (PAM), respectively. The fact that mortality rates for cases of GAE and PAM are more than 95% indicates the need for new therapeutic agents against those amoebae. Considering that curcumin exhibits a wide range of biological properties and has shown efficacy against Acanthamoeba castellanii, we evaluated the amoebicidal properties of curcumin against N. fowleri and B. mandrillaris. Curcumin showed significant amoebicidal activities with an AC50 of 172 and 74 μM against B. mandrillaris and N. fowleri, respectively. Moreover, these compounds were also conjugated with gold nanoparticles to further increase their amoebicidal activities. After conjugation with gold nanoparticles, amoebicidal activities of the drugs were increased by up to 56 and 37% against B. mandrillaris and N. fowleri, respectively. These findings are remarkable and suggest that clinically available curcumin and our gold-conjugated curcumin nanoparticles hold promise in the improved treatment of fatal infections caused by brain-eating amoebae and should serve as a model in the rationale development of therapeutic interventions against other infections.
Acanthamoeba castellanii is an opportunistic protozoan responsible for serious human infections including Acanthamoeba keratitis and granulomatous amoebic encephalitis. Despite advances in antimicrobial therapy and supportive care, infections due to Acanthamoeba are a major public concern. Current methods of treatment are not fully effective against both the trophozoite and cyst forms of A. castellanii and are often associated with severe adverse effects, host cell cytotoxicity and recurrence of infection. Therefore, there is an urgent need to develop new therapeutic approaches for the treatment and management of Acanthamoebic infections. Repurposing of clinically approved drugs is a viable avenue for exploration and is particularly useful for neglected and rare diseases where there is limited interest by pharmaceutical companies. Nanotechnology-based drug delivery systems offer promising approaches in the biomedical field, particularly in diagnosis and drug delivery. Herein, we conjugated an antihyperglycemic drug, metformin with silver nanoparticles and assessed its anti-acanthamoebic properties. Characterization by ultraviolet-visible spectrophotometry and atomic force microscopy showed successful formation of metformin-coated silver nanoparticles. Amoebicidal and amoebistatic assays revealed that metformin-coated silver nanoparticles reduced the viability and inhibited the growth of A. castellanii significantly more than metformin and silver nanoparticles alone at both 5 and 10 μM after 24 h incubation. Metformin-coated silver nanoparticles also blocked encystation and inhibited the excystation in Acanthamoeba after 72 h incubation. Overall, the conjugation of metformin with silver nanoparticles was found to enhance its antiamoebic effects against A. castellanii. Furthermore, the pretreatment of A. castellanii with metformin and metformin-coated silver nanoparticles for 2 h also reduced the amoebae-mediated host cell cytotoxicity after 24 h incubation from 73% to 10% at 10 μM, indicating that the drug-conjugated silver nanoparticles confer protection to human cells. These findings suggest that metformin-coated silver nanoparticles hold promise in the improved treatment and management of Acanthamoeba infections.
Naegleria fowleri and Balamuthia mandrillaris are protist pathogens that infect the central nervous system, causing primary amoebic meningoencephalitis and granulomatous amoebic encephalitis with mortality rates of over 95%. Quinazolinones and their derivatives possess a wide spectrum of biological properties, but their antiamoebic effects against brain-eating amoebae have never been tested before. In this study, we synthesized a variety of 34 novel arylquinazolinones derivatives (Q1-Q34) by altering both quinazolinone core and aryl substituents. To study the antiamoebic activity of these synthetic arylquinazolinones, amoebicidal and amoebistatic assays were performed against N. fowleri and B. mandrillaris. Moreover, amoebae-mediated host cells cytotopathogenicity and cytotoxicity assays were performed against human keratinocytes cells in vitro. The results revealed that selected arylquinazolinones derivatives decreased the viability of B. mandrillaris and N. fowleri significantly (P < 0.05) and reduced cytopathogenicity of both parasites. Furthermore, these compounds were also found to be least cytotoxic against HaCat cells. Considering that nanoparticle-based materials possess potent in vitro activity against brain-eating amoebae, we conjugated quinazolinones derivatives with silver nanoparticles and showed that activities of the drugs were enhanced successfully after conjugation. The current study suggests that quinazolinones alone as well as conjugated with silver nanoparticles may serve as potent therapeutics against brain-eating amoebae.