Surviving 10 years with deep brain stimulation for Parkinson's disease--a follow-up of 79 patients.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) for severe Parkinson's disease (PD) outperforms the best medical treatment in controlling motor symptoms and improving quality of life. Nevertheless disease progression cannot be controlled, and the development of dementia over time is nearly inevitable, often resulting in nursing home placement. Ten-year survival, development of hallucinations, dementia and nursing home placement were examined and adverse events were assessed. METHOD: Patient files were scrutinized from baseline up to 10 years of treatment or death on all 79 PD patients treated with DBS of the subthalamic nucleus from 1998 to 2003 at Aarhus University Hospital. RESULTS: Twenty-four patients died during the follow-up period of 10 years. Age above 60 years at surgery increased mortality 2.3-fold (P = 0.04). Of the 55 surviving patients 29 (53%) were demented and 19 (35%) were in nursing homes. Average time from operation to dementia was 5.6 ± 2.9 years. Hallucinations and nursing home placement were associated with increased mortality. CONCLUSION: Survival of 70% after a mean of 25 years of PD including 10 years with DBS illustrates that this is a selected group of PD patients. The prevalence of dementia steadily increased after surgery as expected from disease progression and can be an early event. Compared with the few similar long-term studies, the present study presents a larger cohort followed at the same DBS center for a longer period of time and none was lost to follow-up, making conclusions more valid. The present findings are of significant prognostic help for the patient, caregiver and physician when treatment with DBS has to be decided.

MRI verified STN stimulation site--gait improvement and clinical outcome.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in alleviating Parkinson's disease (PD) symptoms (tremor, rigidity and bradykinesia) and may improve gait and postural impairment associated with the disease. However, improvement of gait is not always as predictable as the clinical outcome. This may relate to the type of gait impairment or localization of the active DBS contact. METHODS: The active contact was visualized on peri-operative magnetic resonance imaging in 22 patients with idiopathic PD, consecutively treated with bilateral STN DBS. Stimulation site was grouped as either in the dorsal/ventral STN or medial/lateral hereof and anterior/posterior STN or medial/lateral hereof. The localization was compared with relative improvement of clinical outcome (UPDRS-III). In 10 patients, quantitative gait analyses were performed, and the improvement in gait performance was compared with stimulation site in the STN. RESULTS: Of 44 active contacts, 77% were inside the nucleus, 23% were medial hereof. Stimulation of the dorsal half improved UPDRS-III significantly more than ventral STN DBS (P = 0.02). However, there were no differences between anterior and posterior stimulation in the dorsal STN. Step velocity and length improved significantly more with dorsal stimulation compared with ventral stimulation (P = 0.03 and P = 0.02). Balance during gait was also more improved with dorsal stimulation compared with ventral stimulation. CONCLUSIONS: Deep brain stimulation of the dorsal STN is superior to stimulation of the ventral STN. Possible different effects of stimulation inside the nucleus underline the need for exact knowledge of the active stimulation site position to target the most effective area.

Chronic subthalamic high-frequency deep brain stimulation in Parkinson's disease--a histopathological study.

This study describes the pathological findings in the brain of a patient with Parkinson's disease (PD) treated with bilateral subthalamic high-frequency deep brain stimulation (STN DBS) for 29 months prior to death. After routine neuropathological examination, tissue blocks containing the electrode tracts, the subthalamic nucleus (STN), the substantia nigra and the pre-frontal cortex were paraffin embedded and cut into 5-microm-thick serial sections and stained with several conventional staining methods and immunohistochemistry. Bilateral nigral depigmentation, cell loss and Lewy body formation confirmed the diagnosis of PD. Microscopic evaluation furthermore confirmed the location of the electrodes in the STN. The electrode tracts were surrounded by a 150-microm-wide glial fibrillary acidic protein (GFAP)-positive capsule consisting of a thin collagen layer lining the lumen of the tract, whilst an area with few cells and axons constituted the capsule wall towards the surrounding normal brain tissue. The brain tissue appeared normal outside the capsule boundaries with no difference in areas of stimulation compared with areas of no stimulation. Our results correspond with previous studies performed after fewer months of STN DBS and indicate mild histopathological changes in the vicinity of the electrode tract, appearing to result from the electrode placement and not from the electrical stimulation.

A MRI-compatible stereotaxic localizer box enables high-precision stereotaxic procedures in pigs.

We present a nonmagnetic Plexiglas stereotaxic localizer box that can be fitted directly to the pig skull by aluminum screws, allowing stereotaxic MRI or ventriculography and subsequent high-precision stereotaxic procedures. The localizer box was used to target the subthalamic nucleus (STN) bilaterally in five female Göttingen minipigs. Stereotaxic markers were inserted in the pig skull, the head fixated in the localizer box by aluminum screws inserted bilaterally in the zygoma bone with the hard palate locked on a horizontal palate holder. MRI was obtained on a 3T-MR-imager revealing the relation between the inserted markers and the estimated STN-position, and thus the target coordinates. After the MRI, a stereotaxic frame with attached micromanipulator was locked on to the localizer box converting it into a stereotaxic device. The stereotaxic markers were exposed and used as starting point for the stereotaxic procedure, whereby a microelectrode for electrolytic lesioning was inserted in the STN. Postmortem histological analysis revealed 70% correct STN-targeting. The average distance from the lesion center to the STN center was 1.2 mm with a S.D. of 1.1 mm. The most displaced lesion being 3.6 mm from the STN center. We conclude that the described localizer box secure firm head fixation, allowing stereotaxic MRI and subsequent conversion into a stereotaxic device for high-precision stereotaxic procedures.

Focal changes of oxygen consumption in cerebral cortex of patients with Parkinson's disease during subthalamic stimulation.

Motor symptoms of Parkinson's disease (PD) are substantially improved by bilateral high-frequency electrical stimulation of the subthalamic nucleus (STN). Altered cerebral blood flow (CBF) in a network of frontal cortical and subcortical structures has been reported in numerous studies of patients undergoing subthalamic stimulation. However, CBF is a controversial indicator of brain activation because measures of blood flow bear a variable relation to measures of brain work and energy metabolism. We hypothesized that STN stimulation would alter the rate of oxygen consumption (CMRO(2)) in cerebral cortical areas in proportion to previously reported changes in CBF in patients undergoing stimulation at rest. We used quantitative PET to map CMRO(2) in brain of seven patients with Parkinson's disease, first in a baseline condition with pause of stimulation and medication for a period of 12 h, and again after 4 h of stimulation. Comparison of these two conditions revealed activation of CMRO(2) in the cerebellum, and in specific posterior neocortical regions, most notably in the left lingual gyrus and in the right lateral occipitotemporal gyrus, both of which latter regions are linked to higher-order visual processing. CMRO(2) was unaffected in the frontal cortex. Thus, the present findings do not support the original hypothesis, but suggest that STN stimulation increases energy metabolism in the posterior cerebral cortex, especially in regions involved in perception of movement and the direction of movement to visual cues.

Dual channel deep brain stimulation system (Kinetra) for Parkinson's disease and essential tremor: a prospective multicentre open label clinical study.

OBJECTIVES: To evaluate the safety and efficacy of a new dual channel stimulator (Kinetra) in patients with severe Parkinson's disease (PD) or essential tremor (ET). METHODS: 111 patients with PD and 18 with ET were studied. Leads were implanted into the subthalamic nucleus (STN) or internal globus pallidus of patients with the akinetic/rigid type of PD. Leads were implanted into the ventral intermediate nucleus (VIM) of the thalamus or the STN in patients with the tremor dominant type of PD and in those with ET. Technical data on the device and adverse events occurring during the study were documented. Patients were assessed with established and validated clinical scales before surgery and at three and six months' follow up. RESULTS: No device failure or unexpected adverse events occurred during the study. The dual channel stimulator used in stimulation of the STN, internal globus pallidus, and VIM in PD and ET was as safe and effective as the single channel stimulators in use. Mortality, morbidity, and infections were documented in the 129 treated patients. The parameter settings were similar to those usually programmed with single channel stimulators. Time spent in the operating room to implant the Kinetra system was systematically documented. In the PD group, improvement in the unified Parkinson's disease rating scale motor score, decrease in medication OFF periods, and reduced levodopa induced dyskinesia by bilateral STN stimulation were similar to those previously reported with bilaterally applied single channel stimulators. In the ET group upper and lower limb tremor scores were reduced by VIM stimulation. Activities of daily living improved in both disease groups. CONCLUSION: The Kinetra facilitated bilateral deep brain stimulation implantation surgery and is easy to use. It offers more advantages for the patient than the single channel stimulators; consequently, this new device may be recommended to treat patients with severe PD and ET.

New strategies for the treatment of Parkinson's disease hold considerable promise for the future management of neurodegenerative disorders.

Neurodegenerative diseases are often considered incurable with no efficient therapies to modify or halt the progress of disease, and ultimately lead to reduced quality of life and to death. Our knowledge of the nervous system in health and disease has, however, increased considerably during the last fifty years and today, neuroscience reveals promising new strategies to deal with disorders of the nervous system. Some of these results have been implemented with success in the treatment of Parkinson's disease, a common neurodegenerative illness affecting approximately 1% of the population aged seventy or more. Parkinson's disease is characterized by a massive loss of dopaminergic neurons in the substantia nigra, leading to severe functional disturbance of the neuronal circuitry in the basal ganglia. A thorough description of basal ganglia circuitry in health and disease is presented. We describe how the functional disturbances seen in Parkinson's disease may be corrected at specific sites in this circuitry by medical treatment or, in advanced stages of Parkinson's disease, by neurosurgical methods. The latter include lesional surgery, neural transplantation and deep brain stimulation, together with future treatment strategies using direct or indirect implantation of genetically modified cell-lines capable of secreting neurotrophic factors or neurotransmitters. Advantages and disadvantages are briefly mentioned for each strategy and the implications for the future and the possible use of these interventions in other neurodegenerative diseases are discussed, with special emphasis on deep brain stimulation.

[Surgical treatment of Parkinson disease and essential tremor]. / Kirurgisk behandling af Parkinsons sygdom og essentiel tremor.

Recognition of the often failing effect of levodopa treatment as Parkinson's disease (PD) progresses has led to the resumption of surgical treatment. In the 1950'ies and 1960'ies pallidotomy and thalamotomy were commonly performed to reduce parkinsonian symptoms, whilst today these permanent lesions are replaced by Deep Brain Stimulation (DBS) of implanted leads. The advantages of DBS in either the subthalamic nuclei (STN) or the internal part of the globus pallidus are that implantation of leads into these nuclei can be performed bilaterally, and that DBS is a reversible treatment. Pallidotomy and thalamotomy are permanent lesions and if performed bilaterally these lesions often cause unacceptable complications. Bilateral stimulation of the STN is often preferred due to the reduction of rigidity, hypokinesia and tremor as well as the significant reduction of dyskinesias and off-periods. The motor functions are significantly improved and stabilized.

[Treatment of severe Parkinson disease with electric stimulation of the subthalamic nuclei]. / Behandling af svaer Parkinsons sygdom med elektrisk stimulation i nucleus subthalamicus.

INTRODUCTION: Patients with Parkinson's disease suffering from severe fluctuations, i.e. dyskinesias and on-off periods and/or severe tremor, who cannot be improved by adjustment of the medical treatment, can be treated with deep brain stimulation via leads implanted bilaterally into the subthalamic nuclei. METHODS: Nine patients with advanced idiopathic Parkinson's disease were treated with stereotactic and bilateral implantation of leads into the subthalamic nuclei. All patients had levodopa responsive Parkinson's disease and levodopa induced fluctuations in the form of on-off periods and dyskinesias. The mean age was 61 years and the mean duration of disease 15 years. The patients were followed for 12 months and evaluated with the Unified Parkinson's Disease Rating Scale off and on medications before and after lead implantation. RESULTS: The Hoehn & Yahr stage fell from 3.9/2.8 before lead implantation and off/on medication to 3.0/2.3 with lead stimulation turned on and off/on medication. The activity of daily living (ADL) index was significantly improved and reduced from 27/13 before lead implantation and off/on medication to 12/7 with the stimulation turned on and off/on medication i.e. with 55%/46% on stimulation. The motor score was likewise significantly improved and reduced from 55/28 to 24/17 i.e. with 56%/39% on stimulation. The most important results of deep brain stimulation in the subthalamic nuclei is the significant reduction of the motor fluctuations. On stimulation off periods were reduced from 30% to 6% and the dyskinesias were significantly reduced from 47% to 14% of the daytime. The mean dose of levodopa equivalent medication was reduced with 26%. DISCUSSION: In conclusion, patients with advanced Parkinson's disease and levodopa induced fluctuations can be successfully treated with bilateral high frequency electric stimulation of leads implanted into the subthalamic nuclei.

Citalopram treatment of traumatic brain damage in a 6-year-old boy.

Traumatic brain damage may cause acute emotional symptoms such as uncontrolled crying, apathy, and sleep problems. Rehabilitation may be less effective in patients afflicted by these symptoms. Citalopram, a selective serotonin reuptake inhibitor (SSRI), has a documented immediate and dramatic effect on pathological crying in stroke patients. The present case history of a 6-year-old boy with a traumatic right-sided hemorrhage in the basal ganglia indicates that early SSRI treatment has a dramatic effect on pathological crying and in addition may have a concomitant beneficial effect on motor paresis, sleep disturbance, and neurobehavioral problems.

Effect of nimodipine on cerebral blood flow and cerebrovascular reactivity after subarachnoid haemorrhage.

The aim of the present study was to investigate the effect of nimodipine on autoregulation of cerebral blood flow (CBF), CO2 reactivity and cerebral oxygen metabolism (CMRO2) in patients with subarachnoid haemorrhage (SAH). Eight patients with severe SAH were studied with repeated CBF and CMRO2 measurements on the first day of the bleeding and after at least 12 h of treatment of nimodipine. An initial resting study, an autoregulation study and a hyperventilation study was performed. CBF was measured using the 133-Xenon intravenous method. CMRO2 was calculated as AVDO2 x CBF. Nimodipine did not significantly change CBF and CMRO2 in the initial resting study. After induced arterial hypotension intact autoregulation was found before as well as after treatment with nimodipine. Beneficial effects of nimodipine were found on CO2 reactivity and CMRO2 during hypotension that may be explained as a positive effect on cerebral ischaemia.

Fetal neocortical transplants grafted to the cerebral cortex of newborn rats receive afferents from the basal forebrain, locus coeruleus and midline raphe.

Fetal cerebral neocortex (E15-17) was grafted into the cerebral hemisphere of newborn (0-1 day old) rats. Grafts were placed into cortical aspiration lesion cavities made immediately prior to grafting. At maturity, transplant afferents were examined by injecting the retrogradely transported fluorescent dyes diamidino yellow and fast blue into the grafts. Retrogradely-labeled neurons were histologically observed within several regions of the host brain including the basal forebrain, locus coeruleus and dorsal raphe areas. The topographical distribution within these areas resembled the normal labeling patterns described in previous reports.

Fetal cortical transplants in the cerebral hemisphere of newborn rats: a retrograde fluorescent analysis of connections.

Fetal cerebral neocortex (E15-17) was grafted into the cortex of newborn (0-1 day old) rats. In some animals the tissue was grafted just caudal to cortical aspiration lesions made immediately prior to grafting. At maturity, transplant efferents were examined by use of the retrogradely transported fluorescent dyes Fast Blue and Diamidino Yellow. Dyes were principally injected in various combinations into the host pyramidal tract decussation and into cervical and lumbar spinal cord levels. In addition some of these animals received injections into the host cortex opposite the transplant, into the ipsilateral thalamus or into the transplant. Transplants were recovered in 26 of 30 animals, and they were typically larger in recipients sustaining aspiration lesions. Histologically, transplants commonly demonstrated laminar patterns that resembled normal cortical supra- and infragranular laminae. Numerous retrogradely-labeled neurons were counted within transplants after injections of fluorescent tracers into the host pyramidal tract decussation or cervical spinal cord. These cells were often located appropriately in areas resembling infragranular layers. Retrogradely labeled neurons were also found within transplants after injections into the host cortex or thalamus. Additionally, numerous host neurons were labeled after Diamidino Yellow injections into the transplant. These findings demonstrate an exchange of connections between host and transplant and suggest the establishment of normal connection patterns.

Neonatal hippocampal neurons, retrogradely labeled with granular blue, survive intracerebral grafting and explantation to tissue culture.

Previous studies have shown that developing neocortical neurons labeled in situ by retrograde axonal transport of the fluorescent dye Granular Blue can retain this dye for at least 2 months essentially without fading or leakage. In this study, retrograde labeling with Granular Blue was used to label neonatal rat hippocampal neurons prior to intracerebral grafting to uninjected littermates, and explantation as slice cultures. Hippocampal regio inferior and hilar neurons labeled through their developing commissural axons were found to survive axotomy and subsequent grafting and explantation for at least 3 and 8 weeks, respectively. The labeling helped define the developmental differentiation of the neurons at the time of manipulation and provides a new method for identification of a specific population of transplanted or explanted neurons.

Non-cholinergic afferents determine the distribution of the cholinergic septohippocampal projection: a study of the AChE staining pattern in the rat fascia dentata and hippocampus after lesions, X-irradiation, and intracerebral grafting.

The acetylcholinesterase (AChE) activity of the rat hippocampus and fascia dentata depends on an intact septohippocampal connection, and histochemical staining for AChE is commonly used to monitor the distribution of the cholinergic septohippocampal projection. It is also characteristic that the laminae of low or moderate to dense AChE staining in the hippocampus and fascia dentata coincide with the terminal fields of the major non-cholinergic, afferent pathways. While studying lesion-induced collateral sprouting and aberrant axonal growth of these pathways we observed that the AChE staining pattern changed in accordance with the reorganized distribution of the non-cholinergic pathways, and this occurred even without direct interfering with the septohippocampal projection itself. Widening and narrowing of the medial perforant path and mossy fiber terminal zones thus resulted in corresponding changes in the bands of AChE staining normally associated with these zones. Expansion of the commissural-associational hippocampodentate projections and the lateral perforant path was in a similar way paralleled by a widening of the AChE-poor zones which normally overlap with the termination of these projections. Observations of the same kind were made in intracerebral transplants of fascia dentata innervated by various host afferents, and in rats subjected to neonatal X-irradiation, where the mossy fiber projection is reduced and aberrant perforant pathways project into CA3 due to a reduced formation of granule cells. The observed sets of changes with linkage between the different non-cholinergic projections and the activity of AChE in their respective terminal fields were accordingly reproduced under several different experimental conditions. It could not be explained alone by interaction between the septal afferents and their target cells. We therefore conclude that the density and laminar distribution of the AChE activities within the hippocampus and fascia dentata are determined at least in part by the major afferent, non-cholinergic nerve connections. We suggest that the effect occurs through direct axonal interaction or through changes in the receptiveness of the common dentate and hippocampal target cells.

Transplantation of fetal cortex to the brain of newborn rats: a retrograde fluorescent analysis of callosal and thalamic projections from transplant to host.

Fetal cerebral cortical tissue was transplanted into the cerebral hemisphere of 0-1-day-old rats. In some cases, the transplants were placed into or adjacent to cortical lesion cavities made immediately prior to transplantation. Injections at maturity of fast blue and diamidino yellow into the host contralateral cortex and ipsilateral thalamus demonstrated the presence of callosal and thalamic projections from transplant to host. Numerous single-labeled neurons were often arranged in cell bands or clusters. This apparent topography and the absence of double-labeling resembled normal labeling patterns.