Ali H. Mesiwala

High-intensity focused ultrasound selectively disrupts the blood-brain barrier in vivo

High-intensity focused ultrasound (HIFU) has been shown to generate lesions that destroy brain tissue while disrupting the blood-brain barrier (BBB) in the periphery of the lesion. BBB opening, however, has not been shown without damage, and the mechanisms by which HIFU induces BBB disruption remain unknown. We show that HIFU is capable of reversible, nondestructive, BBB disruption in a targeted region-of-interest (ROI) (29 of 55 applications; 26 of 55 applications showed no effect); this opening reverses after 72 h. Light microscopy demonstrates that HIFU either entirely preserves brain architecture while opening the BBB (18 of 29 applications), or generates tissue damage in a small volume within the region of BBB opening (11 of 29 applications). Electron microscopy supports these observations and suggests that HIFU disrupts the BBB by opening capillary endothelial cell tight junctions, an isolated ultrastructural effect that is different from the mechanisms through which other (untargeted) modalities, such as hyperosmotic solutions, hyperthermia and percussive injury disrupt the BBB.

Long-term outcome of superficial temporal artery-middle cerebral artery bypass for patients with moyamoya disease in the US

OBJECT The authors report the long-term results of a series of direct superficial temporal artery-middle cerebral artery (STA-MCA) bypass procedures in patients with moyamoya disease from the western US. METHODS All patients with moyamoya disease treated at the University of Washington from 1990 through 2004 (39 patients) were included in this study. Patients underwent pre- and postoperative evaluation of cerebral perfusion dynamics. Surgical revascularization procedures were performed in all patients with impaired cerebral blood flow (CBF) findings. RESULTS The mean age of patients at diagnosis was 34 years (range 10-55 years). All 39 patients had impaired CBF and/or vasomotor reserve and underwent revascularization procedures: 26 patients underwent bilateral operations, 13 unilateral (65 total procedures). An STA-MCA bypass was technically possible in 56 procedures (86.2%); saphenous vein interposition grafts were required in 3 procedures (4.6%); encephaloduroarteriosynangiosis was performed in 6 procedures (9.2%). Three patients died due to postoperative complications, yielding a procedure-related mortality rate of 4.61%, and 8 experienced non-life threatening complications (for a procedure-related rate of 12.3%). Long-term follow-up appeared to indicate a reduction in further ischemic events in surviving patients compared with the natural history. Cerebral perfusion dynamics improved postoperatively in all 36 surviving patients. CONCLUSIONS Moyamoya disease may differ in the US and Asia, and STA-MCA bypass procedures may prevent future ischemic events in patients with this condition.

Transcranial doppler grading criteria for basilar artery vasospasm

OBJECTIVE:Transcranial Doppler (TCD) criteria for basilar artery (BA) vasospasm are poorly defined, and grading criteria for vertebrobasilar vasospasm are unavailable. The purpose of the present study was to define TCD grading criteria for BA vasospasm on the basis of the absolute flow velocities and the intracranial to extracranial flow velocity ratios for the posterior circulation, and to improve the sensitivity and specificity of TCD for diagnosis of BA vasospasm. METHODS:One hundred twenty-three patients with aneurysmal subarachnoid hemorrhage underwent 144 cerebral arteriograms with views of the BA during the acute phase of vasospasm (Days 3–14 after hemorrhage). BA diameters were measured and compared with diameters obtained from baseline arteriograms. Both BA and extracranial vertebral artery flow velocities were measured by TCD within 4 hours before the arteriogram. RESULTS:The velocity ratio between the BA and the extracranial vertebral arteries (VA) strongly correlated with the degree of BA narrowing (r2 = 0.648; P < 0.0001). A ratio higher than 2.0 was associated with 73% sensitivity and 80% specificity for BA vasospasm. A ratio higher than 2.5 with BA velocity greater than 85 cm/s was associated with 86% sensitivity and 97% specificity for BA narrowing of more than 25%. A BA/VA ratio higher than 3.0 with BA velocities higher than 85 cm/s was associated with 92% sensitivity and 97% specificity for BA narrowing of more than 50%. CONCLUSION:The BA/VA ratio improves the sensitivity and specificity of TCD detection of BA vasospasm. On the basis of the BA/VA ratio and BA mean velocities, we suggest new TCD grading criteria for BA vasospasm.

Spontaneous Cerebellar Hemorrhage due to a Juvenile Pilocytic Astrocytoma

A 13-year-old boy presented to the emergency room with headaches and ataxia. Imaging studies revealed a cerebellar hemorrhage within a posterior fossa tumor. The patient underwent complete resection of this lesion and made a full recovery. Microscopic examination of this lesion revealed a juvenile pilocytic astrocytoma.

The effects of hydrogen peroxide on brain and brain tumors

BACKGROUND Hydrogen peroxide (HP) is routinely used during neurosurgical procedures to augment hemostasis after intracranial tissue resection. Elsewhere in the body, HP is used to kill resection margin tumor cells; in vitro studies support these clinical uses. The effects of HP on brain and brain tumors have not been evaluated. In this study, the in vitro and in vivo effects of HP on both rat and human brain parenchyma and brain tumors were examined. METHODS Antitumor activity of varied concentrations of HP (0-30%) on cultured primary and metastatic brain tumors (n = 13) was compared with the effects of various concentrations of ethanol (0-50%). Studies were performed in rats to characterize HP-induced tissue changes that occurred when HP-soaked pledgets were placed on the arachnoid surface and along resection margins (n = 5). Additionally, the effect of HP on human brain along tumor resection cavities was investigated (n = 10). RESULTS While HP demonstrated concentration-dependent tumoricidal effects in vitro, similar to results achieved with ethanol, HP caused significant injury to arachnoid and stroma with neuronal and glial injury to a depth of 1 mm in rats. Three percent HP-soaked pledgets placed in resection cavities of excised brain tumors induced similar injury in human brain. CONCLUSION HP irreversibly damages mesothelial and neural tissue. Although HP appears to have tumoricidal effects in vitro, it should be used with caution in humans because of risks of collateral injury to surrounding normal brain. HP may prove most beneficial for discrete lesions, such as pituitary tumors and metastases.

The Diagonal Ventricular Dimension: A Method for Predicting Shunt Malfunction on the Basis of Changes in Ventricular Size

OBJECTIVE Serial computed tomographic and magnetic resonance imaging studies are critical in the evaluation of patients who present with symptoms and signs of recurrent hydrocephalus or possible ventricular shunt malfunction. Subtle changes in ventricular volume or complex variations in ventricular anatomy often make subjective assessment of changes in ventricular size difficult, and no previously described method relates these changes to intracranial pressure or shunt system function. The purpose of this study was to develop an objective, reproducible, simple linear method of detecting changes in ventricular size that provides an accurate reflection of shunt function on the basis of serial imaging studies. METHODS We developed a simple, linear estimate of ventricular volume—the diagonal ventricular dimension—to objectively assess changes in ventricular size on serial computed tomographic scans and magnetic resonance imaging scans. Serial imaging studies for 14 patients ages 1.6 to 71 years who underwent evaluation for shunt malfunction were used in this study. The sensitivity and specificity of this method in predicting shunt malfunction was compared with other well-established linear estimates of ventricular size as well as with a radiologist’s interpretation of the same studies. The “gold standard” for measuring the status of ventricular shunt system function in this study was the measurement of intracranial pressure via shunt tap or surgical exploration results. RESULTS The sensitivity (100%) and specificity (100%) of the diagonal ventricular dimension in detecting changes in ventricular size consistent with shunt malfunction was superior to that of any other linear estimate and to a radiologist’s interpretation of the same films. CONCLUSION The diagonal ventricular dimension provides an objective, simple linear method of assessing changes in ventricular size that correlates well with shunt system function in the context of a collaborative examination.

On-line flow cytometry for real-time surgical guidance.

OBJECTIVE:This study tests the feasibility of using on-line analysis of tissue during surgical resection of brain tumors to provide biologically relevant information in a clinically relevant time frame to augment surgical decision making. For the purposes of establishing feasibility, we used measurement of deoxyribonucleic acid (DNA) content as the end point for analysis. METHODS:We investigated the feasibility of interfacing an ultrasonic aspiration (USA) system with a flow cytometer (FC) capable of analyzing DNA content (DNA-FC). The sampling system design, tissue preparation requirements, and time requirements for each step of the on-line analysis system were determined using fresh beef brain tissue samples. We also compared DNA-FC measurements in 28 nonneoplastic human brain samples with DNA-FC measurements in specimens of 11 glioma patients obtained from central tumor regions and surgical margins after macroscopically gross total tumor removal to estimate the potential for analysis of a biological marker to influence surgical decision making. RESULTS:With minimal modification, modern FC systems are fully capable of real-time, intraoperative analysis of USA specimens. The total time required for on-line analysis of USA specimens varies between 36 and 63 seconds; this time includes delivery from the tip of the USA to complete analysis of the specimen. Approximately 60% of this time is required for equilibration of the DNA stain. When compared with values for nonneoplastic human brain samples, 50% of samples (10 of 20) from macroscopically normal glioma surgical margins contained DNA-FC abnormalities potentially indicating residual tumor. CONCLUSION:With an interface of existing technologies, DNA content of brain tissue samples can be analyzed in a meaningful time frame that has the potential to provide real-time information for surgical guidance. The identification of DNA content abnormalities in macroscopically normal tumor resection margins by DNA-FC supports the practical potential for on-line analysis of a tumor marker to guide surgical resections. The development of such a device would provide neurosurgeons with an objective method for intraoperative analysis of a clinically relevant biological parameter that can be measured in real time.

Diffusion-Weighted Magnetic Resonance Image of a Pediatric Spinal Epidermoid Cyst

Accessible online at: www.karger.com/journals/pne We report the case of an 8-year-old boy who presented with a several month history of severe bilateral leg and back pain. His neurological examination was normal without any cutaneous spine lesions. He had no prior history of a lumbar puncture. Preoperative imaging studies included lumbar spine computerized tomography (CT) and magnetic resonance (MR) imaging which revealed an intradural extramedullary spinal mass from L1 to L2 (fig. 1a–c). He subsequently underwent gross total resection of this mass (fig. 2), and neuropathology was consis-

Brainstem hypoperfusion in severe symptomatic vasospasm following aneurysmal subarachnoid hemorrhage: role of basilar artery vasospasm.

SummaryBackground. The hemodynamic effects of vertebrobasilar vasospasm are ill defined. The purpose of this study was to determine the effects of basilar artery (BA) vasospasm on brainstem (BS) perfusion. Methods. Forty-five patients with delayed ischemic neurological deficits (DIND) following aneurysmal subarachnoid hemorrhage (SAH) underwent cerebral angiography prior to decision-making concerning endovascular treatment. BA diameter was compared with baseline angiogram. Regional brainstem (BS) cerebral blood flow (CBF) was qualitatively estimated by 99mTc ethyl cysteinate dimer single photon emission computed tomography (ECD-SPECT). Findings. Delayed BS hypoperfusion was found in 22 (48.9%) of 45 patients and BA narrowing of more than 20% was found in 23 (51.1%). Seventeen of 23 (73.9%) patients with BA narrowing of more than 20% experienced BS hypoperfusion compared to 6 of 22 (27.3%) patients with minimal or no narrowing (p = 0.0072). Patients with severe and moderate BS hypoperfusion had higher degree of BA narrowing compared to patients with normal BS perfusion and mild BS hypoperfusion (p < 0.001). The three-month outcome of patients n-22) with BS hypoperfusion was significantly worse compared to patients (n-23) with unimpaired (p = 0.0377, odd ratio for poor outcome 4, 1.15–13.9 95% confidence interval). Interpretation. These findings suggest that the incidence of BA vasospasm in patients with severe symptomatic vasospasm is high and patients with significant BA vasospasm are at higher risk to experience BS ischemia. Further studies should be done to evaluate the effects of endovascular therapy on BS perfusion and the impact of BS ischemia on morbidity and mortality of patients with severe symptomatic vasospasm.

Focused ultrasound opens the blood–brain barrier invivo

The blood–brain barrier (BBB) consists of specialized endothelial cells that line the capillaries within the brain whose overlapping regions are held firm by ‘‘tight junctions.’’ In the central nervous system (CNS) the BBB plays a protective role, restricting the movement of molecules into the brain. It is also the major impediment to the flux of therapeutic drugs into the CNS. High‐intensity focused ultrasound (HIFU) has been shown to induce the displacement of ordinarily impermeable vital dyes from the blood stream into the brain without damage to the CNS in the proximity of the flux. However, there has been no elucidation of the biological response to ultrasound that allows this flux. We show using a rat model that, by opening the tight junctions or by causing the endothelial cells to retract, HIFU can selectively disrupt the BBB in a reversible, controlled manner without injury to the surrounding CNS. Moreover, this effect reverses within 96 h. We believe that this work will lay the foundation for the...