Noradrenergic modulation of subthalamic nucleus activity in human: metoprolol reduces spiking activity in microelectrode recordings during deep brain stimulation surgery for Parkinson's disease.

BACKGROUND: Reversible changes in subthalamic nucleus (STN) activity, detected by microelectrode recording (MER), are reported in three patients who received an intravenous betablocker, metoprolol, during deep brain stimulation (DBS) for Parkinson's disease (PD). METHODS: Metoprolol (MP) was given intravenously to reduce blood pressure during surgery. Systolic blood pressure dropped by 4, 11 and 17%, indicating a systemic beta - adrenoceptor blocking effect. FINDINGS: In all patients, the bursting spiking activity of the STN was temporarily suppressed, after the application of MP. Unexpectedly, a transient reduction in Parkinson symptoms (rigidity) was recorded during suppression of STN spiking activity in patient 2. CONCLUSION: The reversible suppression of STN activity and Parkinson symptoms with the beta1-selective adrenoceptor antagonist MP has not been reported. It supports the theory, that--as recently reported in the rat--the human STN is influenced by adrenergic inputs. This report supports the possible application of adrenergic antagonist drugs for the use in Parkinson's disease and advocates additional neurophysiological and pharmacological research in this field.

Imaging and Surgical Findings in Patients with Hemi-Laryngopharyngeal Spasm and the Potential Role of MRI in the Diagnostic Work-Up.

BACKGROUND AND PURPOSE: Hemi-laryngopharyngeal spasm is a recently discovered condition characterized by episodic coughing and unilateral throat contractions that may lead to severe stridor. These symptoms are caused by a vascular compression of the ipsilateral vagus nerve, typically the PICA. Microvascular decompression of the vagus nerve has been demonstrated to be a potential cure for this neurovascular compression syndrome. The main aim of this study was to clarify the role of MR imaging in the diagnostic work-up of this rare condition. MATERIALS AND METHODS: We describe the imaging and surgical findings of 3 patients from our prospective case series of patients with hemi-laryngopharyngeal spasm from 2015 to 2017. Second, the imaging data of 100 patients (control cohort) with symptoms unrelated to hemi-laryngopharyngeal spasm were reviewed to investigate the rate and degree of neurovascular conflict of the vagus nerve. RESULTS: All patients with hemi-laryngopharyngeal spasm reported to date have had vascular compression of the vagus nerve due to the PICA. In the control cohort, there was a good interrater agreement in scoring the "contact" and "compression" of the vagus nerve (κ = 0.73. P = < .001). The frequency of contact or compression of the vagus nerve was approximately 50%. The PICA was the most frequent vessel involved in 74%. CONCLUSIONS: The presence of unilateral neurovascular contact or compression of the vagus nerve does not confirm the diagnosis of hemi-laryngopharyngeal spasm. The MR imaging finding of ipsilateral vascular compression of the vagus nerve is a necessary but not sufficient finding for the diagnosis of hemi-laryngopharyngeal spasm.

Electrophysiologic Validation of Diffusion Tensor Imaging Tractography during Deep Brain Stimulation Surgery.

BACKGROUND AND PURPOSE: Diffusion tensor imaging fiber tractography-assisted planning of deep brain stimulation is an emerging technology. We investigated its accuracy by using electrophysiology under clinical conditions. We hypothesized that a level of concordance between electrophysiology and DTI fiber tractography can be reached, comparable with published modeling approaches for deep brain stimulation surgery. MATERIALS AND METHODS: Eleven patients underwent subthalamic nucleus deep brain stimulation. DTI scans and high-resolution T1- and T2-weighted MR imaging was performed at 3T. Corticospinal tracts were traced. We studied electrode positions and current amplitudes that elicited corticospinal tract effects during the operation to determine relative corticospinal tract distance. Postoperatively, 3D deep brain stimulation electrode contact locations and stimulation patterns were applied for the same corticospinal tract distance estimation. RESULTS: Intraoperative electrophysiologic (n = 40) clinical effects in 11 patients were detected. The mean intraoperative electrophysiologic corticospinal tract distance was 3.0 ± 0.6 mm; the mean image-derived corticospinal tract distance (DTI fiber tractography) was 3.0 ± 1.3 mm. The 95% limits of agreement were ±2.4 mm. Postoperative electrophysiology (n = 44) corticospinal tract activation effects were encountered in 9 patients; 39 were further evaluated. Mean electrophysiologic corticospinal tract distance was 3.7 ± 0.7 mm; for DTI fiber tractography, it was 3.2 ± 1.9 mm. The 95% limits of agreement were ±2.5 mm. CONCLUSIONS: DTI fiber tractography depicted the medial corticospinal tract border with proved concordance. Although the overall range of measurements was relatively small and variance was high, we believe that further use of DTI fiber tractography to assist deep brain stimulation procedures is advisable if inherent limitations are respected. These results confirm our previously published electric field simulation studies.

Human neural graft function in rats treated with anti-interleukin II receptor antibody.

Prolonged immunosuppression with cyclosporin A allows survival of human xenografts in the rat Parkinsonian model but the drug has side effects. Ideally immunosuppression should be of short duration, to minimize the chance of infection, yet be capable of supporting long term survival of the transplanted tissue. We report that short term treatment with an anti-rat interleukin II receptor (IL2R) monoclonal antibody (MAb) resulted in apparently permanent survival of human fetal dopaminergic grafts in "Parkinsonian" rats. The recipients remained healthy and the excellent survival of the transplants suggests that the antibody injection strategy would almost certainly abrogate allograft rejection and raises the possibility that xenogenic dopaminergic neurones could be used as donor tissue in humans.

The antioxidant enzyme quinone reductase is up-regulated in vivo following cerebral ischemia.

An astrocyte antioxidant enzyme, quinone reductase (QR), was studied in vivo to assess whether its activity was up-regulated following cerebral ischemia. Rats were given a unilateral focal cerebral infarct and regions of interest within the ischemic penumbra compared to the non-ischemic side for QR activity. At 7 days post-ischemia, QR activity was significantly up-regulated within cells of astrocyte morphology in the cortex (p = 0.007) and subcortical (p = 0.005) areas adjacent to the infarct. This enzyme activity peaked at 7 days but was still significantly up-regulated at 14 days. Up-regulation of QR activity occurs within the ischemic penumbra of a stroke in this animal model and may contribute to factors that limit ischemic damage to neurons in this area.

Circling behaviour in 6-hydroxydopamine-lesioned rats given pulsed levodopa is reduced more by lesions in the entopeduncular nucleus/substantia nigra pars reticulata than in the subthalamic nucleus.

Rats unilaterally lesioned with 6-hydroxydopamine to deplete striatal dopamine received daily injections of levodopa methyl ester in combination with benserazide. Delayed lesions in the subthalamic nucleus (Group 2) or entopeduncular nucleus and substantia nigra par reticulata (Group 3) were made, unilateral to the dopamine depletion. Apomorphine-induced rotation was significantly reduced in Group 2 versus sham-operated controls (P < 0.006) and in Group 3 versus Group 2 (P < 0.03). Results suggest that enhanced apomorphine-induced rotation in this model is mediated through both the striatopallidal and striatonigral pathway.

Ketamine and phencyclidine cause a voltage-dependent block of responses to L-aspartic acid.

Excitatory amino acids depolarize central mammalian neurons by increasing membrane conductance. This increase in conductance can be voltage-dependent (i.e. N-methyl-D-aspartate or L-aspartic acid (L-ASP)) or voltage-independent (i.e. kainic acid (KA)) depending on whether or not the channel is blocked by Mg2+ [8,9]. Intracellular recordings were made from dissociated mouse spinal cord cells and conductance was calculated using constant current techniques. The dissociative anesthetics, ketamine and phencyclidine caused a selective depression in the change in conductance evoked by L-ASP but not that by KA. Under whole cell voltage-clamp (in the absence of extracellular Mg2+) this depression of responses to L-ASP was found to be highly voltage-dependent suggesting a blockade of the channel.

Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson's disease.

Human retinal pigment epithelial (hRPE) cells are dopaminergic support cells in the neural retina. Stereotaxic intrastriatal implantation of hRPE cells attached to gelatin microcarriers (Spheramine) in rodent and non-human primate models of Parkinson's disease (PD) produces long term amelioration of motor and behavioral deficits, with histological and PET evidence of cell survival without immunosuppression. Long-term safety in cynomologous monkeys has also been demonstrated. Six H&Y stage III/IV PD patients were enrolled in a one-year, open-label, single center study to evaluate the safety and efficacy of Spheramine (approximately 325,000 cells) implanted in the most affected post-commissural putamen. All patients tolerated the implantation of Spheramine well and demonstrated improvement. At 6, 9, and 12 months post-operatively, the mean UPDRS-Motor score "off", the primary outcome measure, improved 33%, (n = 6), 42% (n = 6), and 48% (n = 3), respectively. No "off-state" dyskinesias have been observed. Based on these preliminary results, Spheramine appears to show promise in treating late stage PD patients.

Immunosuppression for neural xenografts: a comparison of cyclosporin and anti-CD25 monoclonal antibody.

OBJECT: The goal of this study was to compare the effects of short- and long-term immunosuppression induced by cyclosporin with those of immunosuppression induced by a monoclonal antibody against the rat interleukin-2 receptor (anti-CD25 mAb) in rats with xenografts. METHODS: The authors compared the in vivo function and final histological characteristics of fetal mouse mesencephalon xenografts in hemiparkinsonian rats in which immunosuppression was induced by: 1) a short course (2 weeks) of cyclosporin; 2) a long course (8 weeks) of cyclosporin; or 3) a short course of treatment with anti-CD25 mAb. Adult Wistar rats were unilaterally lesioned with 6-hydroxydopamine in their medial forebrain bundle, after which their rotational behavior in response to methamphetamine was quantified. Four groups of 20 rats with rotations numbering greater than six turns per minute received fetal mouse mesencephalon transplants to their dopamine-denervated striatum. Group 1 received no immunosuppression therapy; Group 2 received daily intraperitoneal injections of 10 mg/kg cyclosporin for 2 weeks; Group 3 received daily intraperitoneal injections of 10 mg/kg cyclosporin for 8 weeks; and Group 4 received daily intraperitoneal injections of 1 mg/kg anti-CD25 mAb for 2 weeks. The rats were tested for rotational behavior every 4 weeks and killed after 16 weeks. Surviving xenografts were assessed using immunohistochemical staining for a mouse neuronal marker (Thy-1.2). Sixteen weeks after transplant, there were significantly more surviving xenografts in Groups 3 (p < 0.001) and 4 (p < 0.001) compared with control Group 1 (Fisher's exact test) and significantly better functioning xenografts in Groups 3 (p < 0.01) and 4 (p < 0.05) compared with control Group 1 (contrasts of groups following analysis of variance with Bonferroni correction). CONCLUSIONS: A short course of anti-CD25 mAb-induced immunosuppression was as effective as a long course of cyclosporin-induced immunosuppression in this model.

Reduced xenograft rejection in rat striatum after pretransplant photodynamic therapy of murine neural xenografts.

OBJECT: The goal of this study was to develop a method of reducing neural xenograft rejection by pretreating the graft with photodynamic therapy (PDT). METHODS: Xenograft cell suspensions were prepared from fetal mouse mesencephalon, after which they were incubated for 30 minutes with various concentrations of a photosensitizer, verteporfin for injection, and light exposure. The xenograft cell suspensions were injected into the dopamine-depleted striata of 40 hemiparkinsonian rats assigned to different treatment groups. Four weeks after transplantation, xenograft function (determined by methamphetamine-induced rotation) and survival (determined by immunohistochemical staining for murine neurons) were compared. Group 1 animals (xenografts pretreated with 25 ng/ml verteporfin) and Group 3 animals (no verteporfin pretreatment, but daily administration of cyclosporin A) had significantly better xenograft survival and function compared with control animals (no pretreatment with verteporfin). Group 2 animals (xenografts pretreated with 250 ng/ml verteporfin) had no significant improvement. CONCLUSIONS: This work demonstrates improved neural xenograft survival and function when using pretransplant PDT of the graft in a rodent model. The potential benefits of this new therapy are its convenience (one pretransplant treatment) and its compatibility with host immunosuppression.

Unilateral pallidotomy for reduction of parkinsonian pain.

OBJECT: The goal of this study was to determine whether unilateral pallidotomy reduces parkinsonian pain. METHODS: Twenty-one patients suffering from Parkinson's disease (PD) were followed prospectively for 1 year after they had undergone a unilateral pallidotomy to assess the procedure's effect on pain related to PD. Pain unrelated to PD was not studied. Patients scored the level of their PD pain on an ordinal scale (0-10 points) preoperatively and 6 weeks and 1 year postoperatively. The results were analyzed using Wilcoxon's paired-ranks test (with Bonferroni correction) and showed a significant reduction in overall pain scores at 6 weeks (p < 0.001) and 1 year (p = 0.001) following pallidotomy. Various types of PD pain are described and their possible pathophysiological mechanisms are presented. CONCLUSIONS: Unilateral pallidotomy significantly reduces pain attributable to Parkinson's disease.

A prospective randomized comparison of CT and MRI pre-operative localization for pallidotomy.

OBJECTIVE: During the pallidotomy procedure, is pre-operative localization with MRI more accurate than CT and does it result in a significant difference in surgical outcome? METHODS: Twenty-four Parkinson's Disease patients received a unilateral pallidotomy for their motor symptoms. Dyskinesia was scored pre- and six weeks postoperatively. All patients had a pre-operative CT scan and MRI to calculate the target co-ordinates. Patients were then randomly selected to proceed with either the CT or MRI coordinates. The final position for the lesion was determined with intraoperative macrostimulation and impedance measurements. The percentage improvement of dyskinesia was noted for each patient and the two groups compared by the Mann-Whitney test. The distance from the final target to the MRI and CT pre-operative co-ordinates were calculated for each patient. The mean distance for each modality was then compared by Student's t-test. The number of electrode repositionings was also recorded for each patient and the two groups compared by the nonparametric Mann-Whitney test. RESULTS: Although the MRI co-ordinates were significantly (p<0.023) closer to the final target, this did not translate into a significant reduction in electrode repositionings. There was no significant difference in the improvement in dyskinesia between the two groups. CONCLUSIONS: The pre-operative MRI co-ordinates were significantly (p=0.023) closer to the final target than those from the CT. The potential advantages and disadvantages of both imaging modalities are reviewed. There was no significant difference in surgical outcome using either MRI or CT for pre-operative localization in pallidotomy.

Hemorrhagic moyamoya disease during pregnancy.

BACKGROUND: Intracranial hemorrhage in pregnant patients with Moyamoya disease is rare. We review the case of one such patient who presented with pre-eclampsia and a catastrophic intracerebral hemorrhage in order to highlight the associated management difficulties. METHODS: A case of a pregnant (31 weeks) female brought to the emergency department with hypertension and a progressive decrease in her level of consciousness is presented. She rapidly developed a dilated right pupil and left extensor posturing. A CT scan of her head showed a large putamenal intracerebral hemorrhage. She was intubated, ventilated and given intravenous mannitol and magnesium sulfate. She underwent a simultaneous craniotomy and Cesarean section. Post-operatively the patient's ICP and jugular venous saturation were monitored in the intensive care unit. RESULTS: The patient delivered a 1185 g infant who did well. The patient's ICP was well controlled until the tenth post-operative day when she developed malignant brain edema and died. CONCLUSION: This case highlights three important points. First, simultaneous craniotomy and Cesarean section can be performed. Second, intraoperative control of bleeding Moyamoya vessels is described. Third, the difficult post-operative management of these cases is highlighted. The literature regarding Moyamoya disease and pregnancy is reviewed and some recommendations for the management of this rare but potentially deadly condition are presented.

Evidence of ancillary trigeminal innervation of levator palpebrae in the general population.

The cranial synkineses are a group of disorders encompassing a variety of involuntary co-contractions of the facial, masticatory, or extraocular muscles that occur during a particular volitional movement. The neuroanatomical pathways for synkineses largely remain undefined. Our studies explored a normal synkinesis long observed in the general population - that of jaw opening during efforts to open the eyelids widely. To document this phenomenon, we observed 186 consecutive participants inserting or removing contact lenses to identify jaw opening. Seeking electrophysiological evidence, in a second study we enrolled individuals undergoing vascular decompression for trigeminal neuralgia or hemifacial spasm, without a history of jaw-winking, ptosis, or strabismus, to record any motor responses in levator palpebrae superioris (LPS) upon stimulation of the trigeminal motor root. Stimulus was applied to the trigeminal motor root while an electrode in levator recorded the response. We found that 37 participants (20%) opened their mouth partially or fully during contact lens manipulation. In the second study, contraction of LPS with trigeminal motor stimulation was documented in two of six patients, both undergoing surgery for trigeminal neuralgia. We speculate these results might provide evidence of an endogenous synkinesis, indicating that trigeminal-derived innervation of levator could exist in a significant minority of the general population. Our observations demonstrate plasticity in the human cranial nerve innervation pattern and may have implications for treating Marcus Gunn jaw-winking.

Minimizing brain shift during functional neurosurgical procedures - a simple burr hole technique that can decrease CSF loss and intracranial air.

BACKGROUND: Exact stereotactic placement of deep brain stimulation electrodes during functional stereotactic neurosurgical procedures can be impeded by intraoperative brain shift. Brain shift has been shown to correlate with the amount of intracranial (subdural) air detected on early postoperative imaging studies. We report a simple burr hole technique that reduces the loss of cerebrospinal fluid (CSF) and has the potential to significantly reduce the amount of postoperative intracranial air. MATERIAL AND METHODS: A total of 16 patients were studied with half (group 2) receiving the burr hole technique designed to seal the CSF space and thereby reducing CSF loss. The other 8 patients (group 1) received the standard burr hole technique. The 2 groups were of similar age, gender, diagnosis (Parkinson's disease, n=14; cervical dystonia n=2), and surgical targets. All patients received bilateral electrodes either in the subthalamic nucleus (STN, n=14) or in the globus pallidum internus (GPi, n=2) avoiding transventricular trajectories. Early postoperative 3-dimensional computed tomography (3D CT) was used to check for possible bleeding, DBS lead location, and the amount of intracranial air. Intracranial air was assessed manually in a volumetric slice-by-slice approach in the individual postoperative CT and the groups compared by t-test. RESULTS: Group 2 showed significantly lower postoperative intracranial air volumes (4.86 ± 4.35cc) as compared to group 1 (27.59 ± 17.80 cc, p=0.0083*). The duration of surgery, however, was significantly longer for group 1 (435 ± 56.05 min) as compared to group 2 (316 ± 34.79 min,p=0.00015*).The time span between the conclusion of the operation and postoperative 3DCT was similar for both groups. CONCLUSION: This new and simple burr hole technique was associated with a significant reduction in postoperative intracranial air. Reduction of intracranial air will ultimately reduce brain shift. That total operation time does not influence intracranial air is discussed as well as the limitations of this pilot series. In the authors' opinion, this straightforward and cost-effective technique has the potential to reduce brain shift and to increase DBS placement accuracy during functional stereotactic neurosurgical procedures performed in the seated or half-sitting position. A larger more standardized patient series is necessary to substantiate the findings.

Fiber tracking with distinct software tools results in a clear diversity in anatomical fiber tract portrayal.

BACKGROUND: Fiber tract portrayal, based on diffusion tensor imaging (DTI), is becoming more and more important in functional neuronavigation. No standard exists to guarantee anatomically correct fiber tract depiction for neurosurgical purposes. Therefore, showing the anatomically correct extension of fiber tracts beyond the pure connection of functional areas remains an area of important research and investigation. Standards for fiber tracking software applications are elusive. The purpose of this study was to compare the performance of different fiber tracking software tools (FT-tools). We tested the software performance, comparability and anatomical accuracy of the tracking results of several programs. MATERIAL AND METHODS: A single DTI dataset of a healthy control subject was submitted to four different fiber tracking software applications (two commercial, two freeware), three of them based on Fiber Assignment by Continuous Tracking, one based on the Tensorline Propagation Algorithm. The corticospinal tract (CST) was investigated. The tracking procedure was controlled by the following input variables: single regions of interest (ROIs): brain stem, or internal capsule, or subcortical white matter of the precentral gyrus; background threshold, fractional anisotropy (FA) threshold, maximum fiber angulation and fiber length. Tracking results were compared for 2-D correlated triplanar images (axial, coronal, sagittal) and in 3-D. For all FT-tools, the time used to generate the CST was measured. The inter-rater variability for tracking time and for the tracked CST volumes was recorded for two of the four FT-tools. RESULTS AND CONCLUSIONS: Distinct FT-tools performed very differently with respect to the time required to achieve CST portrayal (track generation time varied between 16 and 50 min). None of the software applications was able to display the CST in its full anatomical extent. Especially the lateral precentral areas were not pictured. Surprisingly, the application of the four distinct FT-tools did not lead to comparable tracking results. As very similar or identical tracking algorithms were used, this difference cannot be easily explained. Clearly, neurosurgeons have to be cautious about applying fiber tracking results intraoperatively, especially when dealing with an abnormal or distorted fiber tract anatomy. The authors recommend the use of adjunct strategies such as intraoperative electrophysiology to enhance patient safety and improve anatomical accuracy when using tracking results for surgical procedures.

Localization of the subthalamic nucleus: optimization with susceptibility-weighted phase MR imaging.

BACKGROUND AND PURPOSE: On clinical MR images, the subthalamic nuclei (STN) are poorly delineated from adjacent structures, impeding safe direct targeting for placement of electrodes in the treatment of Parkinson disease. Susceptibility-weighted MR phase imaging offers improved contrast and spatial resolution at reduced imaging times relative to clinically used T2-weighted spin-echo imaging for STN visualization. Our purpose was to assess STN visibility by using phase imaging, comparing phase and magnitude images obtained concurrently by using susceptibility-weighted imaging (SWI). The goal was to identify an efficient scanning protocol for high-quality phase images of STN. MATERIALS AND METHODS: Seventy-eight SWI scans were acquired at 3T by using different TEs and acceleration factors. STN visibility and delimitation from adjacent structures were scored from 0 (not interpretable) to 5 (excellent). Regression analyses assessed the relationship of STN visibility to scanning parameters RESULTS: STN were identified at all studied TEs on phase images. Visibility and delimitation of STN were consistently superior on phase images compared with magnitude images. Good visualization (score of >or=4) of STN on phase imaging occurred at a mean TE of 20.0 ms and a sensitivity encoding (SENSE) of 1.40. Scores of STN visualization on phase images were dependent on SENSE (P < .002) and TE (P < .031). Good delimitation of the STN on phase imaging occurred at a mean TE of 21.6 ms and a SENSE of 1.36. CONCLUSIONS: Visualization and delimitation of STN was superior on phase images and was achieved at 3T in <2.5 minutes. A TE of 20 ms and an acceleration factor of

Recurrent trigeminal neuralgia secondary to Teflon felt.

The authors present a case of a 45-year-old man with recurrent trigeminal neuralgia twelve years after microvascular decompression. The patient underwent surgical reexploration of the trigeminal nerve. A piece of hardened Teflon felt was found piercing a hole through the trigeminal nerve. No other compression of the nerve was found. Removal of the Teflon felt resolved the neuralgia. To the authors knowledge this is the first report of recurrent trigeminal neuralgia due to such a mechanism. This case emphasises the need for further improvement of the surgical technique for microvascular decompression of the trigeminal neuralgia.

Hypomania as an adverse effect of subthalamic nucleus stimulation: report of two cases.

Mania following subthalamic nucleus (STN) deep brain stimulation (DBS) is well described and obvious to both the patient and their physician. The authors describe two patients who developed hypomania following STN-DBS but were unaware of their mood disturbance. Two Parkinson's patients with no previous mood disorders received bilateral STN electrodes. Both experienced dramatic improvement in their motor function and neither complained of any side effects. Their families reported detrimental hypomanic behaviour. Readjusting the stimulation parameters resolved the hypomania with continued motor benefits. The authors draw attention to potential adverse effects of STN-DBS that might be neglected by patients.

Artistic assault: an unusual penetrating head injury reported as a trivial facial trauma.

The authors report a case of penetrating head injury that presented with a deceptively mild complaint. To our knowledge, it is the first report of a paint brush penetrating the brain. The patient reported being punched in the left eye and presented with a minor headache, swelling around the left orbit, a small cut on the cheek and slightly reduced left eye abduction. After radiological evaluation, a penetrating head injury was diagnosed. Under general anesthesia, through a lateral eyelid incision a 10.5 cm long paint brush, which had penetrated from the left orbit to the right thalamus, was removed. No post-operative infection was seen at six months follow-up. This brief report serves to highlight that penetrating brain injury can occur without neurological deficit and that a minimally invasive surgical approach was successful in avoiding any complications.