Krzysztof Sadowski

Role of mTOR inhibitors in epilepsy treatment

In spite of the fact, that subsequent new antiepileptic drugs (AEDs) are being introduced into clinical practice, the percentage of drug-resistant epilepsy cases remains stable. Although a substantial progress has been made in safety profile of antiepileptic drugs, currently available substances have not been unambiguously proven to display disease-modifying effect in epilepsy and their mechanisms of action influence mainly on the end-stage phase of epileptogenesis, namely seizures. Prevention of epileptogenesis requires new generation of drugs modulating molecular pathways engaged in epileptogenesis processes. The mammalian target of rapamycin (mTOR) pathway is involved in highly epileptogenic conditions, such as tuberous sclerosis complex (TSC) and represents a reasonable target for antiepileptogenic interventions. In animal models of TSC mTOR inhibitors turned out to prevent the development of epilepsy and reduce underlying brain abnormalities. Accumulating evidence from animal studies suggest the role of mTOR pathway in acquired forms of epilepsy. Preliminary clinical studies with patients affected by TSC demonstrated seizure reduction and potential disease-modifying effect of mTOR inhibitors. Further studies will determine the place for mTOR inhibitors in the treatment of patients with TSC as well as its potential antiepileptogenic effect in other types of genetic and acquired epilepsies. This review presents current knowledge of mTOR pathway physiology and pathology in the brain, as well as potential clinical use of its inhibitors.

Management of side effects of mTOR inhibitors in tuberous sclerosis patients

mTOR inhibitors represent a relatively new therapeutic option in the management of patients affected by tuberous sclerosis complex (TSC). Randomized clinical trials support the use of everolimus in the treatment of subependymal giant cell astrocytomas (SEGA) and renal angiomyolipomas (AML) related to TSC. Accumulating data suggest also systemic disease-modifying potential of mTOR inhibitors. Given that increasing number of patients with TSC receive mTOR inhibitors, the issue of adverse events associated with this therapy becomes practically important. In the present study we provide the overview of clinical manifestations and therapeutic options for the most common adverse events related to mTOR inhibitors in TSC patients.

Topical Use of Mammalian Target of Rapamycin (mTOR) Inhibitors in Tuberous Sclerosis Complex—A Comprehensive Review of the Literature

BACKGROUND Tuberous sclerosis complex is a genetically determined multisystem disorder that may affect almost any human organ. The discovery of the mammalian target of rapamycin (mTOR) pathway and its involvement in tuberous sclerosis complex-related pathology has led to the introduction of mTOR inhibitors into clinical practice. Topical administration of mTOR inhibitors for skin lesions related to tuberous sclerosis complex may represent a reasonable alternative for more invasive procedures. A growing number of patients have been described exhibiting positive therapeutic effects from the topical administration of these agents. The aim of this review was to systematically analyze available literature on the use of topical mTOR inhibitors to treat dermatologic lesions related to tuberous sclerosis complex. RESULTS A comprehensive review of PubMed, Medscape, and Cochrane databases between 1995 and 2015 was performed to identify available studies describing topical use of mTOR inhibitors in individuals with tuberous sclerosis complex. In most studies, topical mTOR inhibitor application proved to be effective in the treatment of skin lesions related to tuberous sclerosis complex. Facial angiofibromas were the target lesions in most instances. Few studies reported clinical improvement of hypomelanotic macules. These drugs directly address the molecular defect related to tuberous sclerosis complex manifestations. CONCLUSIONS Currently available clinical data suggest that topical application of mTOR inhibitors may be effective in the treatment of facial angiofibromas associated with tuberous sclerosis complex. Ongoing randomized clinical trials of topical mTOR inhibitors for TSC-related cutaneous lesions should add clarity to the role of these agents.

Brain tissue echogenicity—implications for substantia nigra studies in parkinsonian patients

The aim of the present study was to assess the origin of the substantia nigra hyperechogenicity in Parkinson disease patients. The cause of hyperechogenicity was tested on an animal model. Fresh porcine brains were injected consecutively with ferritin, apoferritin and water. Then, glioma samples were inserted into animal model. The echogenicity of the region of interest was assessed before and after experimental procedures. We observed the same echogenicity of porcine brain before and after injections of iron-loaded ferritin, apoferritin and water. Increased echogenicity of glioma samples compared to surrounding porcine brain tissue could be clearly seen. We postulate that the relative gliosis might be, at least partially, responsible for the increased echogenicity of the substantia nigra in Parkinson disease patients. Keeping in mind all limitations and inaccuracies of animal model used, it seems that hyperechogenicity of substantia nigra is caused rather by structural changes within the brain tissue than by increased iron concentration.

Neurological manifestations of Proteus syndrome – review of the literature.

Introduction. Proteus syndrome is a rare disorder associated with a mutation in the AKT1 gene. Its various clinical features have been broadly reviewed. However, no review on neurological complications has been provided since the MRI imaging became a routine and the cause of the disease has been discovered. Considering that roughly 40% of patients with Proteus syndrome develop neurological symptoms, it is essential to increase the awareness among pediatric neurologists. Aim, material and methods. The aim of this review is to present the most common neurological complications in patients with Proteus syndrome, emphasize the role of neuroimaging as well as assess the literature regarding available treatment. Articles available through PubMed and Medscape have been reviewed and those containing neurological complications have been collected for further analysis. Results. The most common clinical manifestation is cognitive impairment, followed by epilepsy. Other symptoms such as gait disturbance, hand tremor, headache, and abnormal muscle tone seem to occur sporadically. As regards seizures, the early-childhood onset was present in all cases and they were poorly controlled on antiepileptic drugs. The large number of brain lesions in CT and MRI scans have been documented, out of which the most common was hemimegalencephaly. Other CNS abnormalities were: meningiomas, lipomas, vascular malformations, lissencephaly, cortical dysplasias, cysts, hydrocephalus and cerebellar malformations. It was noted that Proteus syndrome patients can suffer from spinal cord compromise due to tumors’ infiltrations, scoliosis or bone abnormalities causing spinal stenosis. Conclusions. The neurological manifestations of Proteus syndrome are frequent and important hallmark of the disease. The awareness of them among neurologists may increase efficacy of the syndrome management.