Preclinical to Clinical Translation of Studies of Transcranial Direct-Current Stimulation in the Treatment of Epilepsy: A Systematic Review

Abstract

Epilepsy is a chronic brain syndrome characterized by recurrent seizures resulting from excessive neuronal discharges. Despite the development of various new antiepileptic drugs, many patients are refractory to treatment and report side effects. Non-invasive methods of brain stimulation, such as transcranial direct current stimulation (tDCS), have been tested as alternative approaches to directly modulate the excitability of epileptogenic neural circuits. Although some pilot and initial clinical studies have shown positive results, there is still uncertainty regarding the next steps of investigation in this field. Therefore, we reviewed preclinical and clinical studies using the following framework: (1) preclinical studies that have been successfully translated to clinical studies, (2) preclinical studies that have failed to be translated to clinical studies, and (3) clinical findings that were not previously tested in preclinical studies. We searched PubMed, Web of Science, Embase, and SciELO (2002–2017) using the keywords “tDCS,” “epilepsy,” “clinical trials,” and “animal models.” Our initial search resulted in 64 articles. After applying inclusion and exclusion criteria, we screened 17 full-text articles to extract findings about the efficacy of tDCS, with respect to the therapeutic framework used and the resulting reduction in seizures and epileptiform patterns. We found that few preclinical findings have been translated into clinical research (number of sessions and effects on seizure frequency) and that most findings have not been tested clinically (effects of tDCS on status epilepticus and absence epilepsy, neuroprotective effects in the hippocampus, and combined use with specific medications). Finally, considering that clinical studies on tDCS have been conducted for several epileptic syndromes, most were not previously tested in preclinical studies (Rasmussen's encephalitis, drug resistant epilepsy, and hippocampal sclerosis-induced epilepsy). Overall, most studies report positive findings. However, it is important to underscore that a successful preclinical study may not indicate success in a clinical study, considering the differences highlighted herein. Although most studies report significant findings, there are still important insights from preclinical work that must be tested clinically. Understanding these factors may improve the evidence for the potential use of this technique as a clinical tool in the treatment of epilepsy.

Glutamate Chemical Exchange Saturation Transfer (GluCEST) Magnetic Resonance Imaging in Pre-clinical and Clinical Applications for Encephalitis

“…Currently, up to 85% of encephalitis is unexplained. Although the International Encephalitis Consortium (IEC) defined the diagnostic criteria of encephalitis (Venkatesan et al, 2013), some challenging problems still remain in their clinical application (Granerod et al, 2011;Regner et al, 2018;Bewersdorf et al, 2019), as follows: (i) biopsy represents the "gold standard" for encephalitis; owing to its invasive nature and high false positive rate, it is rarely performed in the clinic; (ii) symptoms are atypical and disease progression is rapid, it is easily confused with other brain disorders, and sometimes a definitive treatment is lacking; and (iii) significant cerebrospinal fluid (CSF) pleocytosis or demonstrable neuroimaging abnormalities are often regarded as surrogate markers of brain inflammation in the absence of pathologic evidence; however, there is a high false-negative rate. In addition to the consensus reached by the IEC, other consensus statements or guidelines have also proposed that imaging technology will play an important role in the early diagnosis of the disease.…”

The (in)adequacy of translational research in dentistry

“…The translational research process passes several important steps on the way to support and justify the routine use of new drugs or techniques in the treatment of patients. The typical approach is first to test the efficacy and safety of the new drug or technique at a basic level, in other words, using in vitro and/or animal model studies (). Hence, by virtue of these non‐human models, a better understanding is obtained of the behaviour of these new therapies.…”

Novel therapies for epilepsy in the pipeline

“…Three studies evaluated the effect of a single 20-minute session of cathodal tDCS. While 2 studies found a significant reduction in the number of interictal epileptiform discharges in patients with malformations of cortical development and in children with focal epilepsy, only Assenza and colleagues found a statistically significant and clinically relevant 71% reduction in seizure frequency compared with sham stimulation (+25%) in patients with TLE in the week following tDCS [47][48][49]. Three studies evaluated the effect of 3 to 5 sessions of cathodal tDCS.…”