Christos Sidiropoulos

Bilateral pallidal stimulation in cervical dystonia: blinded evidence of benefit beyond 5 years

The local injection of botulinum toxin is accepted as the first-line treatment of primary cervical dystonia. This approach provides adequate symptomatic relief for most patients, but up to one-third will have an unsatisfactory response. Deep brain stimulation of the globus pallidus internus has been increasingly used in dystonic syndromes that are refractory to best pharmacological approaches. Although cervical dystonia is the most common idiopathic focal dystonia, evidence for long-term responsiveness to pallidal stimulation is limited. The primary objective of this study was to prospectively collect outcome data from baseline to last clinical follow-up on patients with idiopathic cervical dystonia treated with bilateral pallidal stimulation. Blinded video assessment of examinations performed preoperatively and at last video assessment were performed. Ten patients had complete prospective clinical follow-up. Baseline total Toronto Western Spasmodic Torticollis Rating Scale score (±standard deviation) was 54.5 ± 12.4 (range, 35.0-70.3). Comparison of the blinded severity sub-score on baseline video and at last video assessment at a mean of 7.7 years postoperatively demonstrated a mean improvement of 47.6% (P = 0.002) and strong inter-observer correlation between blinded raters (Spearman r = 0.78, 95% confidence interval 0.49-0.92, P = 0.0001). All 10 patients had 5 years of open prospective follow-up, documenting a 47.4 ± 26.4% (P < 0.01) mean improvement with respect to baseline. This was maintained at a mean of 7.8 years at last follow-up after surgery (range, 4.9-10.7 years) with a 54.4 ± 27.4% mean improvement (P < 0.01). Deep brain stimulation of the globus pallidus is an effective and long-lasting second-line treatment of cervical dystonia, with benefit in some of our patients extending to >10 years. More data are needed to explain variations in individual responses and to guide individual programming parameters.

Hippocampal volume differences between healthy young apolipoprotein E ε2 and ε4 carriers.

The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for the development of late-onset Alzheimers disease (AD), whereas the presence of the APOE ε2 allele seems to confer protection. Here, we report that healthy young APOE ε4 carriers have statistically significantly smaller hippocampal volumes than APOE ε2 carriers, while no differences were detected between the two groups in memory performance. The difference in hippocampal morphology is cognitively/clinically silent in young adulthood, but could render APOE ε4 carriers more prone to the later development of AD possibly due to lower reserve cognitive capacity.

Bilateral Pallidal Stimulation for Wilson's Disease

To report on the clinical efficacy of bilateral globus pallidus internus deep brain stimulation in a 29‐year‐old patient with severe generalized dystonia secondary to Wilsons disease.

Long-term double-blinded unilateral pedunculopontine area stimulation in Parkinson's disease

Gait‐related symptoms are often refractory to current available treatment options with a significant reduction in quality of life in Parkinsons disease.

Extensive intracranial calcifications in a patient with a novel polymerase gamma-1 mutation

A 55-year-old woman presented to our center with an almost lifelong action tremor, associated with peripheral neuropathy, progressive sensorineural hearing loss, and a strong family history of tremor. CT of the brain was notable for extensive intracranial calcifications, much more prominent in the dentate nucleus, cerebellar hemispheres, and midpons, compared to the globus pallidus (figure 1). T1-weighted MRI demonstrated hypointense signal in the aforementioned areas (figure 2). Polymerase gamma-1 (POLG1) gene analysis revealed a novel heterozygous sequence variant at c3239G > c; p.Ser1080Thr. Similar diffuse intracranial calcification can be seen in a variety of disorders including idiopathic basal ganglia calcifications and spinocerebellar ataxia 20.1 Mitochondrial disorders2 are a well-recognized cause; however, to our knowledge this is the first time that such extensive intracranial calcium deposits have been described in a patient with a POLG1 mutation.

Surgical Treatment of Parkinson’s Disease

Opinion statementDeep brain stimulation is now an established therapy for Parkinson’s disease, and DBS continues to be refined. Well-established targets, such as the STN and GPi, have shown clear benefit in reducing motor complications in PD, and other more novel targets, such as PPN are being explored. Furthermore, there have been advances in imaging which allow for improved lead placement and also can reduce patient discomfort. The way electrical current is delivered through the DBS lead is also undergoing a transformation, allowing for more options regarding current shaping, steering, and new stimulation paradigms. The future holds promise for novel methodologies of neuromodulation including closed-loop devices and more focused lesion therapies that alter CNS circuitry.

Influence of brain-derived neurotrophic factor and apolipoprotein E genetic variants on hemispheric and lateral ventricular volume of young healthy adults.

Objective: Brain-derived neurotrophic factor (BDNF) and apolipoprotein E (ApoE) are thought to be implicated in a variety of neuronal processes, including cell growth, resilience to noxious stimuli and synaptic plasticity. A Val to Met substitution at codon 66 in the BDNF protein has been associated with a variety of neuropsychiatric conditions. The ApoE4 allele is considered a risk factor for late-onset Alzheimers disease, but its effects on young adults are less clear. We sought to investigate the effects of those two polymorphisms on hemispheric and lateral ventricular volumes of young healthy adults. Methods: Hemispheric and lateral ventricular volumes of 144 healthy individuals, aged 19–35 years, were measured using high resolution magnetic resonance imaging and data were correlated with BDNF and ApoE genotypes. Results: There were no correlations between BDNF or ApoE genotype and hemispheric or lateral ventricular volumes. Conclusion: These findings indicate that it is unlikely that either the BDNF Val66Met or ApoE polymorphisms exert any significant effect on hemispheric or lateral ventricular volume. However, confounding epistatic genetic effects as well as relative insensitivity of the volumetric methods used cannot be ruled out. Further imaging analyses are warranted to better define any genetic influence of the BDNF Val6Met and ApoE polymorphism on brain structure of young healthy adults.

Bilateral pallidal stimulation for sargoglycan epsilon negative myoclonus

We report on the clinical efficacy of bilateral globus pallidus internus deep brain stimulation in two patients with myoclonus dystonia/essential myoclonus who lack mutations in the epsilon sarcoglycan gene. The primary outcome measures were the Burke-Fahn-Marsden Dystonia Scale motor severity and the Unified Myoclonus Rating Scale scores, and the secondary outcome measure was the 36-item Short Form Health Survey score at the last postoperative follow up. Neuronal firing rates were also calculated from microelectrode recordings. At the last postoperative follow-up (16 weeks for Patient 1 and 18 weeks for Patient 2), there was 57.1% (Patient 1) improvement in the Burke-Fahn-Marsden Dystonia Scale motor severity score and 31.3% (Patient 1) and 69% (Patient 2) in the Unified Myoclonus Rating Scale score while individual SF-36 scores showed improvement in most subdomains. Bilateral globus pallidus internus deep brain stimulation can be effective in ameliorating epsilon sarcoglycan negative myoclonus with or without concurrent dystonia. Whether an epsilon sarcoglycan negative status represents a less favorable prognostic factor for pallidal deep brain stimulation remains to be elucidated.

Low-frequency subthalamic nucleus stimulation in Parkinson's disease

It is with great interest that we read the study by Khoo et al. using low frequency stimulation of the subthalamic nucleus (LFS-STN) to treat axial symptoms in advanced Parkinson’s disease (PD). Despite its elegant design, we have some concerns as to interpreting their results and thus translating them into daily clinical practice. The foremost important issue is the duration of clinical benefit. Current evidence indicates that LFS-STN can improve axial signs in some but not all PD patients, and mostly in the short term. In the study by Moreau et al., 85% of patients still had some improvement in axial symptomatology at the 8-month follow-up, whereas in the case series by Brozova et al., 3 of 12 patients could not tolerate LFS-STN at all, and 2 of 9 remaining lost the initial benefit on the axial signs after 8 to 12 weeks. Ricchi et al., using 80 Hz stimulation, found an improvement in the Stand-Walk-Sit test 3 hours after switching from highfrequency stimulation (HFS) to LFS-STN, but this effect was lost as soon as 1 month later. We recently published the largest series of patients (N 5 45) tested with LFS-STN stimulation. Although our study was not randomized or blinded, most of our patients experienced loss of LFS-STN efficacy. The common denominator in the four prior studies is a remarkable loss of initial axial benefit relatively soon after switching from HFS to LFS-STN. As such, the report of the clinical effectiveness of an immediate improvement in balance and posture with LFS, without confirmation of its long-term duration, is likely to be very limited. One interesting aspect of the study by Khoo et al., however, was the change to more ventral contacts with LFS-STN. This has not been systematically studied previously and merits further investigation. Moreover, none of their patients experienced freezing of gait (FOG) before undergoing LFS. This is odd, because FOG resistant to HFS-STN is one of the common reasons that may prompt a trial of LFS. Based on their provided material, the authors may have adjusted the stimulation voltage when using LFS to achieve the same amount of total electrical energy delivered. However, they did not clearly indicate in their paper whether they actually did so. In our experience, LFS-STN can be used when conventional HFS-STN fails to control various axial signs, including FOG (ON or OFF), imbalance, falls, hypophonia, and eyelid-opening apraxia. The reason why LFS should not be used in the initial programming phase has been clearly reported in earlier studies, because it can actually worsen bradykinesia. We have also tested LFS on one patient with globus pallidus internus stimulation (unpublished data). This patient had severe and unpredictable start hesitation and FOG, and had an almost immediate and remarkable benefit. Unfortunately, within a few days, she lost this initial improvement. Strategies to bypass this tolerance phenomenon to LFS may have to be developed, such as periodically discontinuing stimulation (cycling mode), or periodically switching from high to low frequency.

Unilateral thalamic infarction presenting as vertical gaze palsy: a case report

IntroductionVertical gaze palsy is a recognized manifestation of midbrain lesions. It rarely is a consequence of unilateral thalamic infarction.Case presentationWe report the case of a 48-year-old African-American woman who presented to our facility with vertical gaze palsy and evidence of left medial thalamic infarct on diffusion-weighted imaging without coexisting midbrain ischemia. The etiology of infarct was determined to be small vessel disease after extensive investigation.ConclusionsThis report suggests a possible role of the thalamus as a vertical gaze control center. Clinicoradiological studies are needed to further define the role of the thalamus in vertical gaze control.