Vagus nerve stimulation for treatment-resistant depression: is this therapy distinct from other antidepressant treatments?

BACKGROUND: The treatment-resistant depression (TRD) is a very disabling disease. OBJECTIVE: The aim of this article is to provide an overview of the therapeutic activity of vagus nerve stimulation (VNS) therapy system in TRD. We summarised the progress made during the last decade in this area. METHODS: We conducted a non-systematic review on the efficacy and safety of the VNS therapy for this disease. We analysed the results from acute and long-term studies that utilised this technique. Major electronic databases were searched. RESULTS: The patients with TRD may show acute and long-term benefit when treated with this technique. There are promising results for VNS therapy for these patients. The level of evidence as an acute treatment option is only 3, but as chronic treatment is 2. This therapy should be offered as an added long-term treatment option for patients with chronic and recurrent difficult to treat depression. CONCLUSIONS: The antidepressant effects of this procedure remain controversial. The clinical trials have produced mixed results, but VNS therapy for TRD has two distinct features that differentiate it from other antidepressant treatments: a sustained therapeutic response obtained in highly resistant depressive disorders, a favourable safety profile and guaranteed compliance.

New neuromodulation techniques for treatment resistant depression.

In the treatment of depression, when pharmacotherapy, psychotherapy and the oldest brain stimulation techniques are deadlocked, the emergence of new therapies is a necessary development. The field of neuromodulation is very broad and controversial. This article provides an overview of current progress in the technological advances in neuromodulation and neurostimulation treatments for treatment-resistant depression: magnetic seizure therapy; focal electrically administered seizure therapy; low field magnetic stimulation; transcranial pulsed electromagnetic fields; transcranial direct current stimulation; epidural cortical stimulation; trigeminal nerve stimulation; transcutaneous vagus nerve stimulation; transcranial focussed ultrasound; near infra-red transcranial radiation; closed loop stimulation. The role of new interventions is expanding, probably with more efficacy. Nowadays, still under experimentation, neuromodulation will probably revolutionise the field of neuroscience. At present, major efforts are still necessary before that these therapies are likely to become widespread.Key pointsThere is a critical need for new therapies for treatment resistant depression.Newer therapies are expanding. In the future, these therapies, as an evidence-based adjunctive treatments, could offer a good therapeutic choice for the patients with a TRD.The current trend in the new neuromodulation therapies is to apply a personalised treatment.These news therapies can be complementary.That treatment approaches can provide clinically significant benefits.

Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.

OBJECTIVE: The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs). METHODS: Seven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA. RESULTS: All patients had drug-resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI-negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure-free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation. INTERPRETATION: Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a "2-hit" mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable.

Deep brain stimulation in multiple sclerosis-associated tremor. A large, retrospective, longitudinal open label study, with long-term follow-up.

BACKGROUND: Tremor affects up to 25%-58% in multiple sclerosis (MS) population. Deep-brain stimulation (DBS) of the ventral-intermediate nucleus (VIM) of the thalamus is considered as a potential option following medical treatments. Long term DBS efficacy is not well known in these patients with a poor outcome mostly related to disease progression. OBJECTIVE: To report a large and retrospective study of thalamic DBS in MS tremor. METHODS: We conducted a large and retrospective study of patients with MS disabling and pharmacologically resistant upper limb tremor, who underwent thalamic DBS procedure from January 1992 to January 2015 in University Hospital of Henri Mondor, France. Demographic data, clinical assessment and activity daily living were collected. A three-month and twelve-month post-operative assessment with clinical and functional rating scales have been achieved, as well as long term follow-up for most patients. RESULTS: One hundred and four patients underwent DBS procedure. There were 71 female (68%) and 33 male (32%). At three-month post-operative assessment, 64% patients were improved clinically and functionally. Among these, 93% of patients kept a good efficacy at one-year post-operative assessment. Mean duration of follow-up for these patients was 6 years. CONCLUSION: We described a long-term sustained clinical and functional improvement in this large and retrospective report of thalamic DBS. This neuromodulation approach could be a therapeutic option for all severe upper extremity refractory tremor in MS patients.

Epilepsy in multiple sclerosis as a network disease.

This is a review paper, essentially a commentary with summary of literature that actualizes the problem of epilepsy in patients with multiple sclerosis. There is a bidirectional relation between multiple sclerosis and epilepsy. A possible associate pathophysiological pathway is considered. In multiple sclerosis, a combination of gray matter involvement and inflammation could influence epileptogenesis. Patients with multiple sclerosis have individual profiles and an inter-individual variability of epileptogenicity. No treatment guidelines have been specified for these patients. We postulate that an epileptic manifestation means a relapse or an aggravation of the inflammatory process. In this condition, over time, this symptom could integrate into the Expanded Disability Status Scale. Epileptogenesis is an active process and an interesting question is if disease-modifying therapy in multiple sclerosis can prevent, or mitigate, epilepsy. In light of the latest knowledge of the inflammatory process in epilepsy, the possibility of preventing epileptogenesis with actual treatment of MS is emphasized. We would argue that it is a strong argument for starting treatment quicker for both diseases. Over the last few years, the concepts of epilepsy have completely changed. The model of epilepsy in multiple sclerosis can currently be regarded as a network disease and this new concept can have a highly significant clinical impact.

Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes.

To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12-week maintenance period. Primary outcomes were incidence of treatment-emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure-free. Flexible lacosamide dosing in this open-label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.

DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.

OBJECTIVE: To study the prevalence of DEPDC5 mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). METHODS: Thirty unrelated families referred with ADNFLE were recruited in France, Italy, Germany, Belgium, and Norway. Whole-exome sequencing was performed in 10 probands and direct sequencing of the DEPDC5 coding sequence in 20 probands. Testing for nonsense-mediated messenger RNA decay (NMD) was performed in lymphoblastic cells. RESULTS: Exome sequencing revealed a splice acceptor mutation (c.2355-2A>G) in DEPDC5 in the proband of a German family. In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family. The nonsense mutations p.Arg487* and p.Arg1087* were targeted by NMD, leading to the degradation of the mutated transcripts. At the clinical level, 78% of the patients with DEPDC5 mutations were drug resistant. CONCLUSIONS: DEPDC5 loss-of-function mutations were found in 13% of the families with a presentation of ADNFLE. The rate of drug resistance was high in patients with DEPDC5 mutations. Small ADNFLE pedigrees with DEPDC5 mutations might actually represent a part of the broader familial focal epilepsy with variable foci phenotype.