Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery.

The blood-brain barrier (BBB) is a major anatomical and physiological barrier limiting the passage of drugs into brain. Central nervous system tumors can impair the BBB by changing the tumor microenvironment leading to the formation of a leaky barrier, known as the blood-tumor barrier (BTB). Despite the change in integrity, the BTB remains effective in preventing delivery of chemotherapy into brain tumors. Focused ultrasound is a unique noninvasive technique that can transiently disrupt the BBB and increase accumulation of drugs within targeted areas of the brain. Herein, we summarize the current understanding of different types of targeted ultrasound mediated BBB/BTB disruption techniques. We also discuss influence of the tumor microenvironment on BBB opening, as well as the role of immunological response following disruption. Lastly, we highlight the gaps between evaluation of the parameters governing opening of the BBB/BTB. A deeper understanding of physical opening of the BBB/BTB and the biological effects following disruption can potentially enhance treatment strategies for patients with brain tumors.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience.

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Behavioural improvements with thalamic stimulation after severe traumatic brain injury.

Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS), a condition that is characterized by intermittent evidence of awareness of self or the environment. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.

Brain stimulation: history, current clinical application, and future prospects.

The dramatic effects of chronic brain stimulation in the treatment of movement disorders have spurred a renewed interest in this technique for treating a variety of other conditions. This technique has only recently begun to reach its vast clinical potential, due to a number of significant advances in basic and clinical neurosciences. Current image-guided navigation systems and intraoperative physiological mapping techniques offer more efficient, consistent, and precise targeting. Advances in neurophysiology have helped elucidate the pathophysiology of a number of disease states and thus provided for rational target selection for therapy. The latest generation of stimulation equipment allows for precise tailoring of stimulation parameters to maximize clinical benefit. These techniques are now being applied to a variety of other conditions including chronic pain, epilepsy, and psychiatric disorders.

MR safety in patients with implanted deep brain stimulation systems (DBS).

INTRODUCTION: While it is desirable to perform MRI examinations in patients with deep brain stimulators (DBS), a major safety concern exists regarding the potential for excessive heating secondary to magnetically induced electrical currents. This study was designed to determine the safety of MRI and DBS. METHODS: Standard configurations of DBS systems were tested. In vitro testing was performed using a 1.5-Tesla MR system, a gel-filled phantom, and the body and head RF coils with varying levels of RF energy (SAR). A fluoroptic thermometry system was used to record temperatures. RESULTS: Using the 1.5-T MRI and body RF transmit coil, the temperature changes ranged from 2.5 to 25.3 degrees C. Using the 1.5-T MRI and head RF transmit coil, the temperature changes ranged from 2.3 to 7.1 degrees C. CONCLUSIONS: Excessive heating does occur with certain MR imaging conditions. Under certain conditions determined in this study, patients with DBS may safely undergo anatomical MR imaging. In the future, standardized testing and more comprehensive studies will be needed to ensure the MR safety of neurostimulation systems.

Deep brain stimulation in epilepsy.

Since the pioneering studies of Cooper et al. to influence epilepsy by cerebellar stimulation, numerous attempts have been made to reduce seizure frequency by stimulation of deep brain structures. Evidence from experimental animal studies suggests the existence of a nigral control of the epilepsy system. It is hypothesized that the dorsal midbrain anticonvulsant zone in the superior colliculi is under inhibitory control of efferents from the substantia nigra pars reticulata. Inhibition of the subthalamic nucleus (STN) could release the inhibitory effect of the substantia nigra pars reticulata on the dorsal midbrain anticonvulsant zone and thus activate the latter, raising the seizure threshold. Modulation of the seizure threshold by stimulation of deep brain structures-in particular, of the STN-is a promising future treatment option for patients with pharmacologically intractable epilepsy. Experimental studies supporting the existence of the nigral control of epilepsy system and preliminary results of STN stimulation in animals and humans are reviewed, and alternative mechanisms of seizure suppression by STN stimulation are discussed.

Epidural motor cortex stimulation with functional imaging guidance.

Chronic epidural motor cortex stimulation (MCS) has been shown to have promise in the treatment of patients with refractory deafferentation pain. Precise placement of the electrode over the motor cortex region corresponding to the area of pain is essential for the success of this procedure. Whereas standard anatomical landmarks have been used in the past in conjunction with image guidance, the use of functional brain imaging can be beneficial in the precise surgical planning. The authors report the use of functional imaging-guided frameless stereotactic surgery for epidural MCS. Five patients underwent MCS in which functional imaging guidance was used. Prior to surgery, patients underwent magnetic resonance (MR) imaging with skin fiducial markers placed on standard anatomical reference prints, followed by magnetoencephalography (MEG) mapping of the sensory and motor cortices. In two patients, functional MR imaging was also performed using a motor task paradigm. The functional imaging data were integrated into a frameless stereotactic database by using a three-dimensional coregistration algorithm. Subsequently, a frameless stereotactic craniotomy was performed using the integrated anatomical and functional imaging data for surgical planning. Intraoperative somatosensory evoked potentials (SSEPs) and direct stimulation were used to confirm the target and final placement of the electrode. Direct stimulation and SSEPs performed intraoperatively confirmed the accuracy of the functional imaging data. Trial periods of stimulation successfully reduced pain in three of the five patients who then underwent permanent internal placement of the system. At a mean 6-month follow up, these patients reported an average reduction in pain of 55% on a visual analog scale. The integration of functional and anatomical imaging data allows for precise and efficient surgical planning and may reduce the time necessary for intraoperative physiological verification.

Comparison of anatomic and neurophysiological methods for subthalamic nucleus targeting.

OBJECTIVE: The subthalamic nucleus (STN) has recently become the surgical target of choice for the treatment of medically refractory idiopathic Parkinson's disease. A number of anatomic and physiological targeting methods have been used to localize the STN. We retrospectively reviewed the various anatomic targeting methods and compared them with the final physiological target in 15 patients who underwent simultaneous bilateral STN implantation of deep brain stimulators. METHODS: The x, y, and z coordinates of our localizing techniques were analyzed for 30 STN targets. Our final targets, as determined by single-cell microelectrode recording, were compared with the following: 1) targets selected on coronal magnetic resonance inversion recovery and T2-weighted imaging sequences, 2) the center of the STN on a digitized scaled Schaltenbrand-Wahren stereotactic atlas, 3) targeting based on a point 13 mm lateral, 4 mm posterior, and 5 mm inferior to the midcommissural point, and 4) a composite target based on the above methods. RESULTS: All anatomic methods yielded targets that were statistically significantly different (P < 0.001) from the final physiological targets. The average distance error between the final physiological targets and the magnetic resonance imaging-derived targets was 2.6 +/- 1.3 mm (mean +/- standard deviation), 1.7 +/- 1.1 mm for the atlas-based method, 1.5 +/- 0.8 mm for the indirect midcommissural method, and 1.3 +/- 1.1 mm for the composite method. Once the final microelectrode-refined target was determined on the first side, the final target for the contralateral side was 1.3 +/- 1.2 mm away from its mirror image. CONCLUSION: Although all anatomic targeting methods provide accurate STN localization, a combination of the three methods offers the best correlation with the final physiological target. In our experience, direct magnetic resonance targeting was the least accurate method.

A neuromodulation strategy for rational therapy of complex brain injury states.

We review initial efforts at neuromodulation in the vegetative state and organize several aspects of recent studies of the underlying neurobiology of catastrophic brain injuries. An innovative strategy for patient and target selection for neuromodulation of impaired cognitive function is outlined. Scientific and ethical issues that will attend future efforts to appropriately risk-stratify patients and initiate interventions with therapeutic intent are considered.

Neurostimulation and functional brain imaging.

Recent advancements in functional neuroimaging have furthered our understanding of the normal and pathological brain. These non-invasive imaging modalities have allowed us to study the human brain in vivo. Concurrently, the revival of neurostimulation in the treatment of pain, movement disorders, and epilepsy has allowed the synergistic combination of these two technologies. Several studies focusing on the use of functional imaging in patients with implanted neurostimulation devices are reviewed. The anticipated roles of these two disciplines are discussed.

Tremor arrest with thalamic microinjections of muscimol in patients with essential tremor.

Six patients undergoing stereotactic procedures for essential tremor received microinjections of muscimol (a gamma-aminobutyric acid-A [GABA(A)] agonist) into the ventralis intermedius thalamus in areas where tremor-synchronous cells were identified electrophysiologically with microelectrode recordings and where tremor reduction occurred with electrical microstimulation. Injections of muscimol but not saline consistently reduced tremor in each patient. The effect had a mean latency of 7 minutes and lasted an average of 9 minutes. We propose that GABA-mediated thalamic neuronal inhibition may represent a mechanism underlying the effectiveness of surgery for tremor and that GABA analogues could potentially be used therapeutically.

Contemporary management of spinal osteomyelitis.

OBJECTIVE: We review the results of treatment of a series of patients with spinal osteomyelitis, to formulate a systematic and comprehensive approach to the management of this disease in light of recent technical and conceptual advances in imaging, spinal biomechanics, and internal fixation. METHODS: We retrospectively reviewed the records for 57 consecutive patients with pyogenic spinal osteomyelitis who were treated between June 1987 and June 1995. Pain and weakness were the most common presenting symptoms. The mean duration of symptoms at the time of diagnosis was 10.6 weeks. Surgical indications included the presence or development of motor deficits with epidural compression and/or localized kyphotic deformities or the failure of medical therapy. RESULTS: Thirty-three patients underwent surgery as their initial treatment. Six additional patients experienced medical therapy failure and received subsequent surgical treatment. Seventeen patients were treated using an anterior approach only, 13 were treated using a posterior approach only, and 9 were treated using a combined anterior and posterior approach. After a minimal follow-up period of 24 months, 93% of the surgically treated patients showed neurological improvement or were neurologically intact, with a mean 16-degree decrease in localized kyphotic deformities and with solid bony fusion and resolution of pain for all patients. CONCLUSION: Early surgical decompression results in rapid improvement of neurological deficits, decreases in kyphotic deformities, and stabilization with bony fusion. The presence of active infection does not preclude the use of internal fixation. Nonsurgical management is indicated for patients with minimal or no neurological deficits and the absence of significant localized kyphotic deformities. However, 25% of patients who were initially treated nonsurgically experienced medical therapy failure and underwent surgical treatment.

Thalamic stimulation and functional magnetic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. Technical note.

The utility of functional magnetic resonance (fMR) imaging in patients with implanted thalamic electrodes has not yet been determined. The aim of this study was to establish the safety of performing fMR imaging in patients with thalamic deep brain stimulators and to determine the value of fMR imaging in detecting cortical and subcortical activity during stimulation. Functional MR imaging was performed in three patients suffering from chronic pain and two patients with essential tremor. Two of the three patients with pain had undergone electrode implantation in the thalamic sensory ventralis caudalis (Vc) nucleus and the other had undergone electrode implantation in both the Vc and the periventricular gray (PVG) matter. Patients with tremor underwent electrode implantation in the ventralis intermedius (Vim) nucleus. Functional MR imaging was performed during stimulation by using a pulse generator connected to a transcutaneous extension lead. Clinically, Vc stimulation evoked paresthesias in the contralateral body, PVG stimulation evoked a sensation of diffuse internal body warmth, and Vim stimulation caused tremor arrest. Functional images were acquired using a 1.5-tesla MR imaging system. The Vc stimulation at intensities provoking paresthesias resulted in activation of the primary somatosensory cortex (SI). Stimulation at subthreshold intensities failed to activate the SI. Additional stimulation-coupled activation was observed in the thalamus, the secondary somatosensory cortex (SII), and the insula. In contrast, stimulation of the PVG electrode did not evoke paresthesias or activate the SI, but resulted in medial thalamic and cingulate cortex activation. Stimulation in the Vim resulted in thalamic, basal ganglia, and SI activation. An evaluation of the safety of the procedure indicated that significant current could be induced within the electrode if a faulty connecting cable (defective insulation) came in contact with the patient. Simple precautions, such as inspection of wires for fraying and prevention of their contact with the patient, enabled the procedure to be conducted safely. Clinical safety was further corroborated by performing 86 MR studies in patients in whom electrodes had been implanted with no adverse clinical effects. This is the first report of the use of fMR imaging during stimulation with implanted thalamic electrodes. The authors' findings demonstrate that fMR imaging can safely detect the activation of cortical and subcortical neuronal pathways during stimulation and that stimulation does not interfere with imaging. This approach offers great potential for understanding the mechanisms of action of deep brain stimulation and those underlying pain and tremor generation.

Nonneoplastic intramedullary spinal cord lesions mimicking tumors.

OBJECTIVE: We report a group of nine patients with atypical, nonneoplastic intramedullary spinal cord lesions. By retrospectively reviewing these patients, we hoped to elucidate characteristics that would identify these patients as harboring nonneoplastic lesions before surgical intervention. METHODS: We reviewed the histological findings of 212 patients undergoing surgery for intramedullary spinal cord tumors between 1989 and 1994. We identified nine patients with nonneoplastic lesions (4%); case histories and radiographs were reviewed. RESULTS: All patients were evaluated preoperatively using magnetic resonance imaging. The extent of enhancement with gadolinium varied from homogeneous enhancement to no enhancement. All lesions showed marked T2 changes. There was a lack of significant spinal cord expansion associated with the lesions in all cases. All patients underwent surgery. The histology of the surgical specimens showed demyelinating lesions in four patients, sarcoidosis in two patients, amyloid angiopathy in two patients, and a mass of nonneoplastic inflammatory cells of unknown origin in one patient. CONCLUSION: Although it was difficult to antecedently distinguish these lesions from neoplastic spinal cord tumors by case history and physical examination, the most consistent clue was absent or minimal spinal cord expansion on the preoperative magnetic resonance images.

Intra-axial tumors of the cervicomedullary junction: surgical results and long-term outcome.

Until recently, intra-axial brainstem tumors were traditionally regarded as surgically inaccessible lesions with a uniformly poor prognosis. However, increasing data indicate that distinct subgroups of brainstem tumors exist that are amenable to surgical intervention. To address this question, we reviewed our experience in the operative management of 39 consecutive patients, in the magnetic resonance imaging (MRI) era, with intra-axial cervicomedullary tumors, in order to determine those factors associated with long-term outcome. Thirty-nine patients (26 male, 13 female) underwent surgery by a single surgeon (F.J.E.) between 1985 and 1994. Mean age of diagnosis was 14 years (range 3 months - 60 years); mean duration of preoperative symptoms was 24 weeks (range 1-168). Twenty patients presented with lower cranial nerve dysfunction and 19 presented with motor and/or sensory dysfunction. All patients were graded according to the McCormick Scale, pre- and postoperatively, and at the time of follow-up. All patients were evaluated with MRI scanning. Twenty-three patients had either previous biopsy or subtotal resection, 13 previous radiation therapy, and 6 previous chemotherapy. The mean time to follow-up was 48 months (range 7-138). Twelve patients underwent gross total resection, 7 near total resection (>90%), 15 subtotal resection (50-90%), and 5 partial resection (< 50%). Histologically, there were 15 low-grade fibrillary astrocytomas, 9 ependymomas, 7 gangliogliomas, 3 anaplastic astrocytomas, 3 juvenile pilocytic astrocytomas, and 2 mixed gliomas. Although the vast majority of tumors were low grade histologically, a higher proportion of the patients with high-grade lesions experienced tumor progression when compared to low-grade tumors (75 vs. 30%). Overall, the 5-year progression-free and total survivals were 60 and 89%, respectively. There was 1 death within the first postoperative month. Preoperative duration of symptoms greater than 15 weeks was associated with a longer progression-free survival. There was a trend for preoperative neurologic grade to predict functional neurologic outcome at follow-up. In summary, intra-axial tumors of the cervicomedullary junction are a distinct subset of brainstem tumors, predominantly of low-grade histology, with favorable long-term progression-free and total survivals following surgical resection. A long duration of preoperative symptoms may indicate an indolent clinical course and a more favorable prognosis. Our data also indicate that early surgical intervention is warranted prior to neurologic deterioration.

Magnetoencephalographic mapping: basic of a new functional risk profile in the selection of patients with cortical brain lesions.

OBJECTIVE: Surgical management of cortical lesions adjacent to or within the eloquent cerebral cortex requires a critical risk: benefit analysis of the procedure before intervention. This study introduced a measure of surgical risk, based on preoperative magnetoencephalographic (MEG) sensory and motor mapping, and tested its value in predicting surgical morbidity. METHODS: Forty patients (21 men and 19 women; mean age, 36.5 yr) with cortical lesions (12 arteriovenous malformations and 28 tumors) in the vicinity of the sensorimotor cortex were classified into high-, medium-, or low-risk categories by using the MEG-defined functional risk profile (FRP). This was based on the minimal distance between the lesion margin and the sensory and motor MEG sources, superimposed on a magnetic resonance imaging scan. Case management decisions were based on the MEG mapping-derived FRP in combination with biopsy pathological findings, radiographic findings, and anatomic characteristics of the lesion. A recently developed protocol was used to transform MEG source locations into the stereotactic coordinate system. This procedure provided intraoperative access to MEG data in combination with stereotactic anatomic data displays routinely available on-line during surgery. RESULTS: It was determined that 11 patients diagnosed as having gliomas had high FRPs. The margin of the lesion was less than 4 mm from the nearest MEG dipole or involved the central sulcus directly. A nonoperative approach was used for six patients of this group, based on the MEG mapping-derived FRP. In the group with arteriovenous malformations, 6 of 12 patients with high or medium FRPs underwent nonoperative therapy. The remaining 28 patients, whose lesions showed satisfactory FRPs, underwent uneventful lesion resection, without postoperative neurological deficits. CONCLUSION: Our results suggest that MEG mapping-derived FRPs can serve as powerful tools for use in presurgical planning and during surgery.