Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders

OBJECT: The object of this study was to assess the long-term safety of deep brain stimulation (DBS) in a large population of patients with a variety of movement disorders. METHODS: All patients treated with DBS at the authors' center between 1995 and 2005 were assessed for intraoperative, perioperative, and long-term adverse events (AEs). A total of 319 patients underwent DBS device implantation. Of these 319, 182 suffered from medically refractory Parkinson disease; the other patients had essential tremor (112 patients), dystonia (19 patients), and other hyperkinetic movement disorders (six patients). Intraoperative AEs were rare and included vasovagal response in eight patients (2.5%), syncope in four (1.2%), severe cough in three (0.9%), transient ischemic attack in one (0.3%), arrhythmia in one (0.3%), and confusion in one (0.3%). Perioperative AEs included headache in 48 patients (15.0%), confusion in 16 (5.0%), and hallucinations in nine (2.8%). Serious intraoperative/perioperative AEs included isolated seizure in four patients (1.2%), intracerebral hemorrhage in two patients (0.6%), intraventricular hemorrhage in two patients (0.6%), and a large subdural hematoma in one patient (0.3%). Persistent long-term complications of DBS surgery included dysarthria (4.0%), worsening gait (3.8%), cognitive dysfunction (4.0%), and infection (4.4%). Revisions were completed in 25 patients (7.8%) for the following reasons: loss of effect, lack of efficacy, infection, lead fracture, and lead migration. Hardware-related complications included 12 lead fractures and 10 lead migrations. CONCLUSIONS: The authors conclude that in their 10-year experience, DBS has proven to be safe for the treatment of medically refractory movement disorders.     

Hyperhidrosis due to deep brain stimulation in a patient with essential tremor. Case report

The authors present a unique case of hyperhidrosis as a side effect of a misplaced deep brain stimulation (DBS) electrode near the ventrointermedius (Vim) nucleus in a patient with essential tremor. Magnetic resonance imaging of the brain showed electrode placement in the left anterior thalamus traversing the hypothalamus. High-frequency electrical stimulation possibly resulted in unilateral activation of the efferent sympathetic pathways in the zona incerta. Although a rare complication, hypothalamic dysfunction may occur as a stimulation-related side effect of Vim-DBS.     

GIGYF2 Asn56Ser and Asn457Thr mutations in Parkinson disease patients

Parkinson disease (PD) is one of the most common neurodegenerative disorders with major clinical features of bradykinesia, rigidity, resting tremor, and postural instability. At least thirteen gene loci responsible for PD or parkinsonism have been found and nine causative genes have been identified. Recently, Asn56Ser or Asn457Thr mutations in the Grb10-Interacting GYF Protein-2 gene (GIGYF2) were found to occur in about 2.4% familial PD Italian and French patients. We conducted genetic examination of Asn56Ser or Asn457Thr mutations, but none was found in 310 PD patients from North America. We did identify a non-disease-associated polymorphism Pro460Thr. Our results suggest that the GIGYF2 Asn56Ser and Asn457Thr mutations are a rare cause of PD in North American Caucasian population.     

Rapamycin protects against rotenone-induced apoptosis through autophagy induction

Ubiquitin proteasome system (UPS) and autophagy lysosome pathway (ALP) are the two most important routes for degradation of aggregated/misfolded proteins. Additionally, ALP is so far the only known route to clear entire organelles, such as mitochondria. We proposed that enhancement of ALP may be beneficial for some neurodegenerative disorders, such as Parkinson's disease (PD), in which the accumulation of aggregated/misfolded proteins and the dysfunction of mitochondria are the two major pathogenesis. Mitochondrial complex I inhibitor rotenone, which causes dysfunction mitochondria and UPS, has been considered as one of the neurotoxins related to PD. In this study, rotenone-exposed human neuronal SH-SY5Y cells were used as an in vitro model for us to determine whether autophagy enhancer rapamycin could protect against rotenone-induced injury and its underlying mechanisms. The observed results showed that rapamycin alleviated rotenone-induced apoptosis, whose effects were partially blocked when autophagy related gene 5 (Atg5) was suppressed by Atg5 small interference RNA (siRNA) transfection. Additionally, the results showed that rapamycin pretreatment diminished rotenone-induced accumulation of high molecular weight ubiquitinated bands, and reduced rotenone-induced increase of cytochrome c in cytosolic fraction and decreased mitochondrial marker cytochrome oxidase subunit IV (COX IV) in mitochondrial fraction. The changes in cytochrome c and COX IV indicated that the decreased translocation of cytochrome c from mitochondria to cytosol was probably due to the turn over of entire injured mitochondria. The results that lysosome and mitochondria were colocolized within the cells pretreated with rapamycin and that the mitochondria could be found within autophagy double membrane structures further supported that the damaged mitochondria might be cleared through autophagy, which process has been termed as “mitophagy.” Our studies suggested that autophagy enhancer rapamycin is neuroprotective against rotenone-induced apoptosis through autophagy enhancement. We concluded that pharmacologically induction of autophagy by rapamycin may represent a useful therapeutic strategy as disease-modifiers in PD.     

Osteolytic lesions marker in multiple myeloma

The degradation product of collagen type I carboxy terminal telopeptide (ICTP) represents a new biochemical parameter that reflects the changes in the resorption properties of skeletal system. Affection of the skeleton is one of the most important characteristics of multiple myeloma (MM). We estimated significance of ICTP as osteolysis predictor and overall survival in comparison with standard prognostic parameters β₂-microglobulin and C-reactive protein (CRP), in patients with MM. With our results, we have shown significant difference in serum level of ICTP (P = 0.009) between patients with and without osteolysis on conventional radiography. It was proved that ICTP is the most significant predictor of osteolysis (P = 0.09), while CRP is the most significant risk factor for overall survival (P < 0.01). Being highly significant predictor of osteolysis, ICTP can be used for identification of patients with MM who had increased risk for developing osteolytic lesions.     

Divergent Squamous Differentiation in Upper Urothelial Carcinoma—Comparative Clinicopathological and Molecular Study

Upper urothelial carcinoma (UUC) has a plasticity to demonstrate divergent differentiation with squamous metaplastic elements. There was no previous study exploring profiling of molecular markers in metaplastic squamous upper urothelial carcinoma (SUUC) and conventional upper urothelial carcinoma (CUUC). The aims of this study was to compare expression of the phenotypic characteristics of tumors and molecular markers (p53, p16, cyclin D1, E-cadherin, HER-2, Ki-67, Bcl-2, Bax) in SUUC and CUUC. SUUC was detected in 20% of 44 patients. There was significant difference between SUUC and CUUC in the pathological stage, grade, growth and presence of lymphovasular invasion (p < 0.05; 0.05; 0.05; 0.01 respectively). The mean Ki-67 and p53 labeling index was significantly higher in SUUC than in CUUC (p < 0.05; 0.05). There was no significant difference in the expression of p16, cyclin D1, E-cadherin, HER-2, Bcl-2 and Bax between SUUC and CUUC. Univariant model showed that SUUC was significantly associated with lymphovascular invasion (p = 0.007), Ki-67 activity (p = 0.016) and growth (p = 0.026). Exploration of UUC with squamous divergent differentiation showed changes in phenotypic characteristics and Ki-67, as well as similar molecular profile with CUUC.     

Removal of tracheobronchial foreign bodies in adults using flexible bronchoscopy: experience 1995–2006

Background  Tracheobronchial foreign body (TFB) removal in adult patients using the combined technique of flexible bronchoscopy (FBSC) through the endotracheal tube as well as using the simple FBSC has not often been described. This study reports our experience with FBSC for removal of TFBs and describes diagnosis, techniques of removal, and types of TFBs. Methods  We retrospectively examined bronchoscopic records of adult patients performed between 1995 and 2006 and collection of foreign bodies in Clinical Department for Respiratory Diseases, University Hospital Split, Croatia. Results  TFBs were found in 86 (0.33%) out of 26,124 patients who were submitted to bronchoscopy. The majority of the patients (90%) had some risk factor for aspiration, among which stroke (30%) was the most frequent. Patients with different neurologic and neuromuscular diseases together accounted for 58% of all patients with TFB aspiration. Medical history was suggestive of foreign body aspiration in 38.4% of the patients, while chest X-ray was indicative in 7% of the patients. TFBs were most often found in the right bronchial tree (75.6%). The most common TFBs were animal and fish bones (39.5%). In 90.7% of the patients they were successfully removed under FBSC, whereas in 8.1% of the patients a TFB was extracted with flexible bronchoscope through endotracheal tube. Surgery was needed in only one case. Conclusions  Although foreign bodies in the tracheobronchial tree are rare in adults, the clinician must be aware of their likelihood. Foreign body aspiration should be considered especially in the etiology of recurrent lung diseases and in the presence of risk factors for aspiration, in particular with different neurologic and neuromuscular diseases. They can be successfully and safely removed in the majority of patients under local anesthesia by using FBSC. In cases when repeated procedure is needed, endotracheal tube is recommended.     

High-dose calcitriol therapy and progression of cardiac vascular calcifications

BACKGROUND: Dialysis patients show a very high prevalence of cardiovascular complications, affected as they are with abnormal and accelerated vascular calcifications and, eventually, calcium and phosphorous metabolism disorders. Multislice computed tomography (MSCT) provides a reproducible, high-resolution imaging of calcium contained in cardiac arteries, measured by Agatston score. The aim of the present study was to evaluate the influence of high-dose and low-dose calcitriol therapy on the progression of cardiac vascular calcifications in dialyzed patients. METHODS: We enrolled 36 dialyzed patients in a prospective study, including an interventional period of 12 months and a follow-up period of 12 months. Eighteen protocol patients received intravenous pulses of high-doses calcitriol at the end of dialytic treatment and sevelamer hydrochloride therapy. Control patients received low-dose calcitriol and sevelamer hydrochloride as well. Two MSCT scans were performed: 1 at the start of the study and 1 at the end of follow-up, and Agatston score was calculated at both examinations. RESULTS: At first examination, protocol patients showed almost the same level of cardiac vascular calcification as control patients. At the second MSCT, statistically significantly higher values of Agatston score were recorded for all patients. Indeed, patients who showed higher baseline values developed worse calcifications as recorded at the end of follow-up, both in the protocol and control group. CONCLUSIONS: Our data show that baseline level is strongly predictive of vascular calcification progression, and, moreover, there is no association between calcitriol administered doses and the progression of cardiac vascular calcification.