Patients carrying the mutation p.R406W in MAPT present with non-conforming phenotypic spectrum.

The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.R406W patients. Over 18 years follow-up, we extended the family with 10 p.R406W carriers and provided an in-depth clinical description of the patients. Additionally, genetic screening was used to identify p.R406W carriers in Belgian cohorts of frontotemporal dementia and Alzheimer's disease patients and to calculate p.R406W frequency. In the frontotemporal dementia cohort, we found four p.R406W carriers (n = 647, 0.62%) and three in the Alzheimer's disease cohort (n = 1134, 0.26%). Haplotype sharing analysis showed evidence of a shared haplotype suggesting that they are descendants of a common ancestor. Of the p.R406W patients, we describe characteristics of neuropsychological, imaging and fluid biomarkers as well as neuropathologic examination. Intriguingly, the phenotypic spectrum among the p.R406W patients ranged from typical behavioural variant frontotemporal dementia to clinical Alzheimer's disease, based on CSF biomarker analysis and amyloid PET scan. Heterogeneous overlap syndromes existed in between, with highly common neuropsychiatric symptoms like disinhibition and aggressiveness, which occurred in 100% of frontotemporal dementia and 58% of clinical Alzheimer's disease patients. This was also the case for memory problems, 89% in frontotemporal dementia and 100% in clinical Alzheimer's disease patients. Median age at death was significantly lower in patients with frontotemporal dementia (68 years) compared to clinical Alzheimer's disease patients (79 years), although the sizes of the sub-cohorts are limited and do not allow prognostic predictions. Post-mortem brain analysis of one p.R406W patient with behavioural variant frontotemporal dementia revealed frontotemporal lobar degeneration with tau pathology. Notably, neuropathological investigation showed only 3R tau isoforms in the absence of 4R tau reactivity, an unusual finding in microtubule-associated protein tau-related frontotemporal lobar degeneration. No traces of amyloid pathology were present. Prevalence of the p.R406W mutation was relatively high in both frontotemporal dementia and Alzheimer's disease Belgian patient cohorts. These findings grant new insights into genotype-phenotype correlations of p.R406W carriers. They may help in further unravelling of the pathophysiology of this tauopathy and in facilitating the identification of patients with p.R406W-related frontotemporal lobar degeneration, both in clinical diagnostic and research settings.

Deep brain stimulation in patients with refractory temporal lobe epilepsy.

PURPOSE: This pilot study prospectively evaluated the efficacy of long-term deep brain stimulation (DBS) in medial temporal lobe (MTL) structures in patients with MTL epilepsy. METHODS: Twelve consecutive patients with refractory MTL epilepsy were included in this study. The protocol included invasive video-EEG monitoring for ictal-onset localization and evaluation for subsequent stimulation of the ictal-onset zone. Side effects and changes in seizure frequency were carefully monitored. RESULTS: Ten of 12 patients underwent long-term MTL DBS. Two of 12 patients underwent selective amygdalohippocampectomy. After mean follow-up of 31 months (range, 12-52 months), one of 10 stimulated patients are seizure free (>1 year), one of 10 patients had a >90% reduction in seizure frequency; five of 10 patients had a seizure-frequency reduction of > or =50%; two of 10 patients had a seizure-frequency reduction of 30-49%; and one of 10 patients was a nonresponder. None of the patients reported side effects. In one patient, MRI showed asymptomatic intracranial hemorrhages along the trajectory of the DBS electrodes. None of the patients showed changes in clinical neurological testing. Patients who underwent selective amygdalohippocampectomy are seizure-free (>1 year), AEDs are unchanged, and no side effects have occurred. CONCLUSIONS: This open pilot study demonstrates the potential efficacy of long-term DBS in MTL structures that should now be further confirmed by multicenter randomized controlled trials.

Effect of repetitive transcranial magnetic stimulation on saccades in depression: a pilot study.

Therapeutic repetitive transcranial magnetic stimulation (rTMS) in depression is applied over the prefrontal cortex. This brain region is known to play an important role in the control of saccades. We wanted to investigate whether the fast rTMS procedure affected saccadic activity in depression. Reflexive saccades (RS) and voluntary saccades were studied in 11 patients before and after therapeutic rTMS for depression. Two types of voluntary saccade tasks were used: a voluntary prosaccade (VpS) task and an antisaccade (AS) task. Eye movements were registered by infrared oculography. Latency and directional error rate were analyzed. rTMS was applied over the left dorsolateral prefrontal cortex (DLPFC). RS and VpS parameters were unchanged after 10 sessions of rTMS. However, the latency of antisaccades (AS) was significantly shorter after rTMS than before rTMS. It can be concluded that rTMS over the left DLPFC cortex in depression seems to have no important effect on reflexive saccades, while antisaccade activity is clearly favored by shortening of latency. As voluntary prosaccades were not significantly influenced, our findings may indicate that not merely the voluntary triggering of saccades but the inhibition of unwanted reflexive saccades is influenced by fast rTMS delivered over the DLPFC. These results suggest the intriguing possibility that rTMS might differentially affect specific aspects of saccade behavior.

Latanoprost in hemifacial spasm.

An empirical observation that the prostaglandin derivate latanoprost quited facial spasms in patients with glaucoma prompted us to study latanoprost in non-glaucomatous patients with hemifacial spasms [HFS]. This explorative trial followed an open-label, prospective treatment design. At short term, most patients showed no or only mild improvement and subsequently needed therapy with Botulinum toxin A. Although these results are not impressive, latanoprost could be considered as an interesting alternative in the treatment of patients with HFS and with concomitant glaucoma. A role for prostaglandins in the trigeminofacial reflex is hypothesised.