Tomasz Mandat

Microlesion Effect as a Predictor of the Effectiveness of Subthalamic Deep Brain Stimulation for Parkinson’s Disease

Background: Microlesion effect (MLE) is a commonly observed phenomenon after electrode insertion into the subthalamic nucleus (STN) for deep brain stimulation (DBS). Objectives: The aim of this study was to determine the presence of the MLE in the early postoperative period and the relationship between MLE and STN DBS. Methods: 74 patients with Parkinson’s disease were included in this study. Motor symptoms were evaluated preoperatively, within 48 h after electrode implantation and at 6 months with United Parkinson’s Disease Rating Scale part III (UPDRS-III). According to the improvement level with MLE, all participants were stratified into three groups: (1) less than 20%; (2) 20–40%, and (3) more than 40% in OFF medication states. The degree of improvement in UPDRS-III with DBS ON for each MLE group was assessed at the 6-month follow-up. Regression analysis was applied for the evaluation of the relationship between MLE and improvement with DBS ON. Results: Mean results in UPDRS-III with the MLE in ON and OFF medication states were 22.1 ± 10.5 and 42.1 ± 14 points, respectively. At the 6-month follow-up, with active stimulation, results tended to further ameliorate to 14.6 (59.4%) points in ON and 20.8 (55.3%) in OFF. Mean improvement in MLE groups were: 33.6% group 1, 47.5% group 2 and 61.4% group 3. Regression analysis revealed a positive correlation between the MLE and results at 6 months with DBS ON. Conclusion: Results proved the presence of MLE in the early postoperative period. Furthermore, a positive correlation between MLE and improvement degree with active stimulation was observed.

Deep brain stimulation for refractory epilepsy.

Deep brain stimulation (DBS) is a method of treatment utilized to control medically refractory epilepsy (RE). Patients with medically refractory epilepsy who do not achieve satisfactory control of seizures with pharmacological treatment or surgical resection of the epileptic focus and those who do not qualify for surgery could benefit from DBS. The most frequently used stereotactic targets for DBS are the anterior thalamic nucleus, subthalamic nucleus, central-medial thalamic nucleus, hippocampus, amygdala and cerebellum. The DBS is believed to be an effective method of treatment for various types of epilepsy among adults and adolescents. Side effects may be associated with implantation of electrodes and with the stimulation itself. An increasing number of publications and growing interest in DBS application for RE may result in standardization of the qualification and treatment protocol for RE with DBS.

Subthalamic deep brain stimulation for the treatment of Parkinson disease

BACKGROUND AND PURPOSE The role of subthalamic nucleus deep brain stimulation (STN DBS) in the treatment of Parkinson disease (PD) is well established. The authors present a group of patients diagnosed with PD who were treated with STN DBS. MATERIAL AND METHODS Between 2008 and 2009, 32 female and 34 male patients with PD were treated with STN DBS. Mean age at implantation was 57 ± 12 years. PD lasted from 6 to 21 years (mean 10 years). Patients were qualified for the surgery according to the CAPSIT-PD criteria. The STN was identified with direct and indirect methods. Macrostimulation and microrecording for STN identification were used in all cases. A unilateral STN DBS system was implanted in two cases and bilateral implantation was performed among rest of the group. Outcome was assessed six months after implantation. Results : The mean reduction of UPDRS III score among 51 patients who underwent follow-up was 45% (5-89%). Reduction of levodopa consumption varied from 15 to 100%. Infection forced the authors to remove the DBS system in one case four months after implantation. Skin erosion above the internal pulse generator was noted in four cases. CONCLUSIONS Cardinal symptoms of Parkinsons disease can be safely and effectively treated with STN DBS in selected group of patients.

Pain perception in patients with Parkinson’s disease

Abnormalities in pain perception are a part of the clinical picture in Parkinsons disease (PD) and belong to the category of non-motor symptoms. Two groups of patients were included in this study: (i) an experimental group of 36 patients with PD who were eligible for subthalamic deep brain stimulation (the experimental group [EG]) and (ii) a control group (CG) of 34 patients with a space-occupying lesion who were admitted for a framed stereotactic biopsy. Stereotactic frame fixation was used in both groups as a nociceptive stimulus. All participants were assessed for pain perception with two kinds of visual analogue scales (VAS) (a non-color VAS [ncVAS] and a color VAS [cVAS]) immediately after the stimulus (EG - ncVAS 1 and cVAS 1; CG - ncVAS 3 and cVAS 3) and 24 hours later (EG - ncVAS 2 and cVAS 2; CG - ncVAS 4 and cVAS 4). The means for the two pain scores assessed directly after frame fixation were 3.59 (ncVAS 1) and 3.06 (cVAS 1) for patients in the EG, while the mean ncVAS was 3, and the mean cVAS 3 was 6.1 for those in the CG. The pain intensity was significantly lower for patients with PD (EG) compared to those in the CG for both ncVAS and cVAS (p<0.05 for each measure). The mean pain scores for ncVAS and cVAS measured 24 hours after the procedure were 3.18 and 2.79 for patients with PD (EG) and 6.10 and 5.77 for those in the CG, respectively. Pain intensity measured 24 hours after the procedure was significantly lower in those with PD (EG) compared to the CG. This study has demonstrated that pain perception in patients with PD is significantly lower than pain perception in non-parkinsonian patients.

Quality of life and depressive symptoms in Parkinson's disease after subthalamic deep brain stimulation: a 2-year follow-up study.

AIM To assess the correlation between quality of life (QoL), depressive symptoms and motor signs in patients with Parkinson disease after subthalamic deep brain stimulation (DBS STN). MATERIAL AND METHODS 74 patients, average age 55.6 ± 7 and duration of disease 12.3 years ± 3.8, treated with l STN DBS for PD were included in the study. All patients were evaluated with (UPDRS III), (PDQ-39) (BDI) at baseline and at 6, 12, and 24-month follow up. All patients were also stratified into three groups depending on UPDRS III improvement ( < 30%, 30-60%, > 60%). RESULTS Scores in all scales significantly decreased from baseline. The improvement in PDQ-39 was 43.3%, in BDI 25.3 %; UPDRS-III 55.5% at 6 months. At 24 months, motor results and QoL deteriorated by 15.6% and 19.6% respectively. BDI remained unchanged. Mean scores at baseline in PDQ-39 were group I 67.4 ± 29.7; II 64.8 ± 32.0; III 53.4 ± 22.0 and for BDI, group I 17.4 ± 12.04; II 14.0 ± 9.7; III- 15.1 ± 10.55. Scores decreased significantly with DBS at 6-month follow-up and mean change was: PDQ-39, group I 42.7%, II- 40.7%, III 51.6%; BDI group I 23%, II 28.1%, III 23.3 %. CONCLUSION Reduction of depressive symptoms, motor signs and improvement of QoL in PD after DBS STN are closely related. Improvement of QoL depends significantly on motor symptoms.

EGFR, PIK3CA, KRAS and BRAF mutations in meningiomas

Meningiomas are among the most frequent intracranial tumors. Treatment involves surgical resection with optional subsequent radiotherapy for high-grade meningiomas or radiosurgery following incomplete tumor removal. At present, no pharmacological agents are used as treatment. The use of targeted therapies has been considered, and specific therapies, including anti-EGFR treatment, have been clinically tested. The experience from the treatment of various types of cancers shows that patient outcome depends on the mutational status of particular molecules, including epithelial growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA). Therefore, the aim of the present study was to assess the occurrence and potential use of these markers in patients with meningioma. In total, 55 formalin-fixed, paraffin-embedded meningioma samples were subjected to genomic sequencing of EGFR (exons 18–21), KRAS (exon 1), BRAF (exon 15) and PI3K (exons 9, 20). No mutations were identified in EGFR, KRAS or BRAF. Point mutations in PIK3CA were revealed in the samples of two patients with atypical and anaplastic meningiomas. Although these mutations appear to be rare, this result, along with previously reported findings, indicates that the PI3K/protein kinase B pathway may serve as a more reasonable molecular target for meningioma than EGFR.

Subthalamic nucleus deep brain stimulation after bilateral pallidotomy in the treatment of generalized dystonia

Although it is pallidal (globus pallidus pars interna, GPi) deep brain stimulation (DBS) that has been most consistently employed in treating medically refractory dystonia, the effectiveness of the thalamus, zona incerta, or subthalamic nucleus (STN) stimulation has also been demonstrated. However, there is very little data on how DBS in the STN affects dystonia treatment. Therefore, we report a case of a patient after STN DBS and prior pallidotomy. A 27-year-old female patient complaining about disabling movements of the neck, trunk and limbswas admitted to theMovement Disorder division of the Department of Neurology (Jagiellonian University Medical College, Kraków, Poland). The patient was unable to walk, even when assisted, and was bedridden. She required constant help in basic activities of daily living. The patient had no history of birth trauma or serious neonatal illness, her family history was unremarkable. Her past medical history revealed the following: at the age of 12, she experienced clumsiness due to cramps of the right hand while writing; subsequently, over the next years, she developed sustained twisting and repetitivemovements of both upper limbs as well as of the neck, shoulder girdle and the trunk. Postural and rest tremor of both arms was also intermittently present. At the age of 19, the patient was admitted to the Department of Genetics at the Institute of Psychiatry and Neurology inWarszawa, Poland. At that time, dysarthria, torticollis with head rotation to the right and backwards, adduction of the right shoulder, dystonic movements, sometimes with postural and rest tremor of the upper limbs, and abnormal excessive lordosis in the supine position were found on neurological examination. Further clinical evaluation and laboratory testing for primary dystonia, Huntington’s disease, Wilson’s disease, other types of heredodegenerative dystonia and psychogenic dystonia yielded negative results and she was finally diagnosed with DYT1 negative primary generalized dystonia. Within the next two years, the symptoms deteriorated; moreover, progressive gait disturbances and frequent falling appeared. As the pharmacological treatment (levodopa, MAO-B inhibitor, tetrazepam, diazepam,

Thalamic deep brain stimulation in the treatment of essential tremor

BACKGROUND AND PURPOSE Quality of life can be severely impaired by essential tremor (ET) being the main cause of the patients disability. The authors present a group of ET patients treated with deep brain stimulation of the ventral intermediate nucleus of the thalamus (Vim DBS). The aim of the study was to evaluate the efficacy and safety of Vim DBS in the treatment of ET. MATERIAL AND METHODS Between 2006 and 2009, 8 female and 10 male ET patients were treated with Vim DBS. Mean age at implantation was 63 ± 15 years. ET lasted from 4 to 30 years (mean 12 years). Clinical condition of the group was evaluated before surgery and 3 months after implantation with spirography (spiral drawings), the modified Fahn (Tremor Rating Scale, TRS) scale, and the modified ADL (Activity of Daily Living) scale. The Vim was localized with CT and MRI. The procedures of implantation were performed under local and general anaesthesia. A bilateral procedure was performed in 11 cases and a unilateral procedure was performed in 7 cases. RESULTS The therapeutic effect of DBS was maintained at the follow-up in the third month following surgery. Mean contralateral limb tremor reduction was 79%. Head tremor reduction was reported by 75% of patients in the bilateral Vim DBS subgroup and 50% of patients in the unilateral Vim DBS subgroup. Mean ADL score improved by 61%. CONCLUSIONS Vim DBS is a safe and effective method of ET treatment. Vim DBS improves activities of daily living of ET patients.

Alternative splicing of iodothyronine deiodinases in pituitary adenomas. Regulation by oncoprotein SF2/ASF.

Pituitary tumors belong to the group of most common neoplasms of the sellar region. Iodothyronine deiodinase types 1 (DIO1) and 2 (DIO2) are enzymes contributing to the levels of locally synthesized T3, a hormone regulating key physiological processes in the pituitary, including its development, cellular proliferation, and hormone secretion. Previous studies revealed that the expression of deiodinases in pituitary tumors is variable and, moreover, there is no correlation between mRNA and protein products of the particular gene, suggesting the potential role of posttranscriptional regulatory mechanisms. In this work we hypothesized that one of such mechanisms could be the alternative splicing. Therefore, we analyzed expression and sequences of DIO1 and DIO2 splicing variants in 30 pituitary adenomas and 9 non-tumorous pituitary samples. DIO2 mRNA was expressed as only two mRNA isoforms. In contrast, nine splice variants of DIO1 were identified. Among them, five were devoid of exon 3. In silico sequence analysis of DIO1 revealed multiple putative binding sites for splicing factor SF2/ASF, of which the top-ranked sites were located in exon 3. Silencing of SF2/ASF in pituitary tumor GH3 cells resulted in change of ratio between DIO1 isoforms with or without exon 3, favoring the expression of variants without exon 3. The expression of SF2/ASF mRNA in pituitary tumors was increased when compared with non-neoplastic control samples. In conclusion, we provide a new mechanism of posttranscriptional regulation of DIO1 and show deregulation of DIO1 expression in pituitary adenoma, possibly resulting from disturbed expression of SF2/ASF.

Applications of decision support systems in functional neurosurgery

Functional neurosurgery is used for treatment of conditions in central nervous system that arise from its improper physiology. One of the possible approaches is Deep Brain Stimulation (DBS). In this procedure a stimulating electrode is placed in desired brain’s area to locally affect its activity. Among others, DBS can be used as a treatment for dystonia, depression, obsessive-compulsive disorder (OCD) and Parkinson’s Disease (PD). In this paper authors focus on application of classifiers in Deep Brain Stimulation (DBS) for Parkinson’s Disease (PD). In neurosurgical treatment of the Parkinson’s Disease the target is a small (9 x 7 x 4 mm) deeply in brain situated structure called Subthalamic Nucleus (STN). The goal of the Deep Brain Stimulation is the precise permanent placement of the stimulating electrode within target nucleus. As this structure poorly visible in CT or MRI it is usually stereotactically located using microelectrode recording. Several microelectrodes are parallelly inserted into the brain and then in measured steps advanced towards expected location of the nucleus. At each step, usually from 10 mm above expected center of the STN, the neuronal activity is recorded. Because STN has a distinct physiology, the signals recorded within it also present specific features. By extraction certain attributes from recordings provided by the microelectrodes, it is possible to construct a binary classifier that provides useful discrimination. This discrimination divides the recordings into two classes, i.e. those registered within the STN and those registered outside of it. From this it is known which microelectrodes and at which depths have passed through the STN and thus a physiological map of its surrounding is made.