Potential neurotoxicity of titanium implants: Prospective, in-vivo and in-vitro study.

Titanium dioxide (TiO2) is a frequently used biomaterial, particularly in orthopedic and dental implants, and it is considered an inert and benign compound. This has resulted in toxicological scrutiny for TiO2 in the past decade, with numerus studies showing potential pathologic downstream effects. Herein we describe case report of a 77-year-old male with subacute CNS dysfunction, secondary to breakdown of a titanium-based carotid stent and leading to blood levels 1000 times higher (3 ppm) than the reported normal. We prospectively collected tissues adjacent to orthopedic implants and found a positive correlation between titanium concentration and time of implant in the body (r = 0.67, p < 0.02). Rats bearing titanium implants or intravascularly treated with TiO2 nanoparticles (TiNP) exhibited memory impairments. A human blood-brain barrier (BBB) in-vitro model exposed to TiNP showed paracellular leakiness, which was corroborated in-vivo with the decrease of key BBB transcripts in isolated blood vessels from hippocampi harvested from TiNP-treated mice. Titanium particles rapidly internalized into brain-like endothelial cells via caveolae-mediated endocytosis and macropinocytosis and induced pro-inflammatory reaction with increased expression of pro-inflammatory genes and proteins. Immune reaction was mediated partially by IL-1R and IL-6. In summary, we show that high levels of titanium accumulate in humans adjacent to orthopedic implants, and our in-vivo and in-vitro studies suggest it may be neurotoxic.

Use of a single [123I]-FP-CIT SPECT to predict the severity of clinical symptoms of Parkinson disease.

The aim of this study was to assess the ability of a single SPECT performed in the early stage of Parkinson's disease (PD) to predict disease severity in 19 patients with early PD. [(123)I]-FP-CIT striatal uptake was expressed as a ratio of specific:nonspecific uptake for defined brain areas. Clinical severity was determined by the UPDRS at baseline and 12-15 months following the SPECT procedure. [(123)I]-FP-CIT uptake in the contralateral putamen and striatum was correlated with UPDRS score at baseline, with a more significant correlation after 1-year interval. [(123)I]-FP-CIT uptake in all areas was correlated with bradykinesia and rigidity subscores only at follow up visit. Significant correlations were found between [(123)I]-FP-CIT uptake in the contralateral striatum, putamen and caudate and the difference between motor scores of 1-year interval (DeltaUPDRS). These results suggest that disease severity might be anticipated by a single SPECT at an early stage of the disease.

DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke.

BACKGROUND AND PURPOSE: DP-b99 is a chelator of zinc and calcium ions that acts selectively within cell membranes and has neuroprotective properties in animal models of stroke. We present the results of a multicenter, double-blind, placebo-controlled, randomized trial to assess the safety and potential protective effects of DP-b99 in acute ischemic stroke. METHODS: One hundred and fifty stroke patients with signs of cortical involvement and a National Institutes of Health Stroke Scale (NIHSS) score of 7 to 20 received a 4-day course of intravenous 1 mg/kg per day DP-b99 or placebo within 1 to 9 hours of stroke onset. Treatment with recombinant tissue plasminogen activator was not allowed. RESULTS: No major differences in mortality rate, causes of death, adverse events, safety laboratory tests, and ECG parameters were found between the 2 groups. The baseline NIHSS score of the 72 DP-b99- and 75 placebo-treated patients in the intent-to-treat cohort was (mean+/-SD) 12.2+/-4.0 and 12.6+/-3.3, respectively; the time to needle (mean+/-SD) was 6:36+/-1:47 and 6:28+/-1:33 hours, respectively; and the age (mean+/-SD) was 73.3+/-9.9 and 72.0+/-9.6 years, respectively. The 90-day median change from baseline (the primary end point) was -6.0 and -5.0 NIHSS points in the DP-b99 and placebo groups, respectively (nonsignificant). At 90 days, there was a significantly better outcome in the DP-b99 group compared with the placebo group (modified Rankin scale score of 0, 1, or same as prestroke): 30.6% and 16.0%, respectively (P=0.05). The recovery rate was unaffected by the time to needle. Further analyses indicated that the 90-day median change from baseline in patients with an entry NIHSS score of 10 to 16 was 8.0 and 5.0 points in the DP-b99 and placebo groups, respectively (P=0.03). CONCLUSIONS: In this small-scale study, the primary end point of change in NIHSS score from baseline to 90 days was not met. However, secondary end points demonstrated a significantly improved 90-day recovery rate with treatment with DP-b99 when compared with placebo. In addition, in patients with baseline NIHSS scores of 10 to 16, a significant post hoc change in NIHSS score from baseline to day 90 was observed. No major safety problems were identified. These findings need to be confirmed with a larger prospective study of strokes involving the cortex.

I-123 MIBG cardiac scintigraphy and autonomic test evaluation in multiple sclerosis patients.

Autonomic symptoms are common in multiple sclerosis (MS) patients and may cause significant disability. The purpose of this study was to evaluate direct cardiac sympathetic denervation in MS patients with I-123 MIBG cardiac scintigraphy compared with other parasympathetic electrophysiological examinations of autonomic dysfunction. Ten patients with MS and 7 age- and sex-matched control subjects were prospectively evaluated. The neurological deficit and disability stages of the patients were rated according to the Kurtzke Expanded Disability Status Scale (EDSS). Autonomic tests included the R-R interval, Valsalva ratio and standup test. All patients and control subjects had planar and SPECT cardiac scintigraphy with I-123 MIBG injection. Seven MS patients had relapsing-remitting (R-R) type and three had secondary progressive type (SP). A pathological MIBG cardiac washout rate was found in 3/10 MS patients, all of them with SP-MS. The other seven had normal washout rates. No correlation was found between the scan and the individual parasympathetic autonomic test results. I-123 MIBG myocardial scintigraphy may detect direct disturbances of the sympathetic cardiac function in patients with MS in addition to parasympathetic dysfunction tests and can be an important additional means of assessing autonomic pathways. Determination in MS of the co-existence of autonomic dysfunction, especially the cardiac sympathetic involvement in the SP type, may aid in evaluation of disease severity and cardiac function follow-up.

Lamotrigine and catamenial epilepsy.

Catamenial epilepsy (CE) is characterized by epileptic seizures in the female occurring rhythmatically with the menstrual cycle. Hormonal mechanisms have been proposed as a cause of this epileptic form. Few reports about the efficacy of anti-epileptic drugs (AEDs) have been published. We studied prospectively women with CE who were treated with lamotrigine (LTG) for a period of 3 months in order to evaluate its efficacy, measuring the progesterone levels before and after LTG at the same time. LTG seemed to be efficacious in 66% of women, meaning the disappearance of seizures or reduction of 50% or more of the number of seizures. The reported side effects were few and mild, and the drug was well tolerated. Serum progesterone levels were found to rise during LTG treatment.

Surgical resection of left atrial myxoma presenting with acute multiple hemorrhagic cerebral infarctions: a case report.

Brain ischemia resulting from left atrial myxoma embolization has been well documented. In contrast, the link between the development of intracerebral hemorrhage and myxoma in these patients has little coverage in the literature. The main theory describing this relationship stems from the fact that cardiac myxoma cells metastasize to the brain's vessels, causing destruction of the arterial wall with subsequent formation of fusiform aneurysm and further intracranial bleeding. It is assumed that when a diagnosis of left atrial myxoma with neurologic manifestations is made, surgical resection should be performed without delay to prevent repeated tumor embolization; however, systemic anticoagulation treatment during cardiac surgery with cardiopulmonary bypass is not recommended immediately after intracerebral hemorrhage occurs because of the possibility of extending the infarct's size. We describe a patient with acute hemorrhagic brain infarction and an echocardiographically demonstrated left atrial myxoma that was surgically resected successfully in the acute phase after the onset of the neurologic symptoms.

[Guideliness for the management of stroke--2008 invasive measures for prevention of ischemic stroke].

Stroke is a major cause of morbidity and mortality in Israel and the main cause for neurological disability among adults. Continued efforts for its prevention and treatment began a long time ago and currently persist. During the last decade, these efforts have resulted in a number of significant breakthroughs. Consequently, several new guidelines and consensus statements from Europe and North America have been published. In Israel, up to date, guidelines have been published only for acute stroke treatment, as well as for its prevention by medical means. The present guideline is supplemental to the previous papers and focuses on the invasive options to treat specific risk factors and conditions, when appropriate, for primary and secondary stroke prevention.

Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1).

BACKGROUND AND PURPOSE: The NeuroThera Effectiveness and Safety Trial-1 (NEST-1) study evaluated the safety and preliminary effectiveness of the NeuroThera Laser System in the ability to improve 90-day outcomes in ischemic stroke patients treated within 24 hours from stroke onset. The NeuroThera Laser System therapeutic approach involves use of infrared laser technology and has shown significant and sustained beneficial effects in animal models of ischemic stroke. METHODS: This was a prospective, intention-to-treat, multicenter, international, double-blind, trial involving 120 ischemic stroke patients treated, randomized 2:1 ratio, with 79 patients in the active treatment group and 41 in the sham (placebo) control group. Only patients with baseline stroke severity measured by National Institutes of Health Stroke Scale (NIHSS) scores of 7 to 22 were included. Patients who received tissue plasminogen activator were excluded. Outcome measures were the patients' scores on the NIHSS, modified Rankin Scale (mRS), Barthel Index, and Glasgow Outcome Scale at 90 days after treatment. The primary outcome measure, prospectively identified, was successful treatment, documented by NIHSS. This was defined as a complete recovery at day 90 (NIHSS 0 to 1), or a decrease in NIHSS score of at least 9 points (day 90 versus baseline), and was tested as a binary measure (bNIH). Secondary outcome measures included mRS, Barthel Index, and Glasgow Outcome Scale. Primary statistical analyses were performed with the Cochran-Mantel-Haenszel rank test, stratified by baseline NIHSS score or by time to treatment for the bNIH and mRS. Logistic regression analyses were conducted to confirm the results. RESULTS: Mean time to treatment was >16 hours (median time to treatment 18 hours for active and 17 hours for control). Time to treatment ranged from 2 to 24 hours. More patients (70%) in the active treatment group had successful outcomes than did controls (51%), as measured prospectively on the bNIH (P=0.035 stratified by severity and time to treatment; P=0.048 stratified only by severity). Similarly, more patients (59%) had successful outcomes than did controls (44%) as measured at 90 days as a binary mRS score of 0 to 2 (P=0.034 stratified by severity and time to treatment; P=0.043 stratified only by severity). Also, more patients in the active treatment group had successful outcomes than controls as measured by the change in mean NIHSS score from baseline to 90 days (P=0.021 stratified by time to treatment) and the full mRS ("shift in Rankin") score (P=0.020 stratified by severity and time to treatment; P=0.026 stratified only by severity). The prevalence odds ratio for bNIH was 1.40 (95% CI, 1.01 to 1.93) and for binary mRS was 1.38 (95% CI, 1.03 to 1.83), controlling for baseline severity. Similar results held for the Barthel Index and Glasgow Outcome Scale. Mortality rates and serious adverse events (SAEs) did not differ significantly (8.9% and 25.3% for active 9.8% and 36.6% for control, respectively, for mortality and SAEs). CONCLUSIONS: The NEST-1 study indicates that infrared laser therapy has shown initial safety and effectiveness for the treatment of ischemic stroke in humans when initiated within 24 hours of stroke onset. A larger confirmatory trial to demonstrate safety and effectiveness is warranted.

Monotherapy of lamotrigine versus carbamazepine in patients with poststroke seizure.

OBJECTIVES: The incidence of seizures is known to be high in the elderly. The most common cause of an unprovoked seizure in the elderly population is stroke. These patients require effective and well-tolerated antiepileptic treatment because they frequently experience other medical conditions and use other medications that can interact with the antiepileptic treatment. The aim of the study was to analyze the tolerability and efficacy of lamotrigine (LTG) versus sustained-release carbamazepine (CBZ) treatment in newly diagnosed symptomatic poststroke seizure. METHODS: Sixty-four patients with a first post episode of seizures were randomized in a 1:1 ratio to either LTG or CBZ treatment and were followed up prospectively for up to 12 months for efficacy and tolerability of the drugs. RESULTS: More patients in the LTG group were seizure-free (72%) versus those in the CBZ group (44%; P = 0.06), but the numbers did not reach statistical significance because of a relative small number of study patients. The number of patients who withdraw from the study because of adverse events was statistically significantly less in the LTG group (3%) compared with the CBZ group (31%; P = 0.02). CONCLUSIONS: The LTG treatment in poststroke seizures versus CBZ treatment is a relatively better-tolerated drug and can be acceptable as initial treatment in this specific group of patients.

A new scale for assessing patients with vertebrobasilar stroke-the Israeli Vertebrobasilar Stroke Scale (IVBSS): inter-rater reliability and concurrent validity.

OBJECTIVES: Most of existing stroke scoring systems have limited ability to evaluate patients with cerebrovascular events in the vertebrobasilar territory. We devised a new scale, the Israeli Vertebrobasilar Stroke Scale (IVBSS) in order to directly and more accurately assess clinical deficits of patients with vertebrobasilar stroke. The present study measured the reliability and validity of the IVBSS. PATIENTS AND METHODS: Forty-three patients (mean age+/-S.D., 70.9+/-8.8 years, 27 males) with vertebrobasilar stroke were evaluated with the IVBSS (11 items), the NIH Stroke Scale (NIHSS) and the disability modified Rankin Scale (mRS) by independent examiners. Interobserver agreement was rated by weighted kappa statistics for each item and the total IVBSS score. Validity was examined with Spearman rank coefficients to compare the IVBSS with NIHSS and mRS. RESULTS: Excellent reliability was demonstrated between the examiners for almost each item and the total score of the IVBSS (kappa>0.75). The total IVBSS score was strongly associated with NIHSS and mRS results (r=0.80 and 0.76, respectively; P<0.0002). CONCLUSIONS: The IVBSS is a valid instrument that allows the assessment of patients with vertebrobasilar stroke with high reliability. Further observations are warranted to determine the predictive value of the IVBSS for stroke outcome.

[Guidelines for the management of stroke--2007 prevention of ischemic stroke--general approach and medical treatment].

Stroke is a major cause of morbidity and mortality in Israel, the third most common cause of death and the main cause for neurological disability among adults. During the last decade several significant breakthroughs have occurred in the management of stroke and consequently several new guidelines and consensus statements from Europe and North America have been published. The new data necessitate a reappraisal of our approach to the management of stroke as well as to its primary prevention. The present guidelines focus on primary and secondary stroke prevention by medical means and provide detailed, updated, clinical guidelines for most specific risk factors and conditions, ways to investigate the underlying stroke mechanism and its preferred medical treatment. Invasive (surgical, stent insertion, correction of cardiac anomalies etc.) will be dealt with separately.

Low-level laser therapy applied transcranially to rats after induction of stroke significantly reduces long-term neurological deficits.

BACKGROUND AND PURPOSE: Low-level laser therapy (LLLT) modulates various biological processes. In the present study, we assessed the hypothesis that LLLT after induction of stroke may have a beneficial effect on ischemic brain tissue. METHODS: Two sets of experiments were performed. Stroke was induced in rats by (1) permanent occlusion of the middle cerebral artery through a craniotomy or (2) insertion of a filament. After induction of stroke, a battery of neurological and functional tests (neurological score, adhesive removal) was performed. Four and 24 hours poststroke, a Ga-As diode laser was used transcranially to illuminate the hemisphere contralateral to the stroke at a power density of 7.5 mW/cm2. RESULTS: In both models of stroke, LLLT significantly reduced neurological deficits when applied 24 hours poststroke. Application of the laser at 4 hours poststroke did not affect the neurological outcome of the stroke-induced rats as compared with controls. There was no statistically significant difference in the stroke lesion area between control and laser-irradiated rats. The number of newly formed neuronal cells, assessed by double immunoreactivity to bromodeoxyuridine and tubulin isotype III as well as migrating cells (doublecortin immunoactivity), was significantly elevated in the subventricular zone of the hemisphere ipsilateral to the induction of stroke when treated by LLLT. CONCLUSIONS: Our data suggest that a noninvasive intervention of LLLT issued 24 hours after acute stroke may provide a significant functional benefit with an underlying mechanism possibly being induction of neurogenesis.

Prospective evaluation of malignant middle cerebral artery infarction with blood-brain barrier imaging using Tc-99m DTPA SPECT.

BACKGROUND: Malignant middle cerebral artery (MMCA) infarction is associated with severe brain edema which may lead to a rapid deterioration of consciousness, increase of intracranial pressure, brain midline shift and finally, herniation. We examined the correlation between the degree of the blood-brain barrier (BBB) permeability and MMCA. METHODS: Twenty-five consecutive patients (17 men and 8 women, mean age 62.1+/-10.1) were included in the study. Each patient had a daily clinical examination, and the neurological deficits were scored using NIHSS score. A CT without contrast material was performed in all patients. (99m)Tc-DTPA SPECT was performed at 36 h after the stroke. A quantitative index of BBB breakdown (disruption index) was calculated. RESULTS: The mean volume of stroke was 138+/-87 cm(3). The mean DTPA disruption index was 6.6+/-4.6 (range 1.0-21.0). The mean NIHSS score was 14+/-4 (p=0.2). Five of 25 patients had brain herniation as evidenced on brain CT. The volume of stroke was only marginally elevated in patients with herniation (p=0.062). All patients showed significant, inverse correlation between NIHSS score and DTPA uptake (r=-0.43, p=0.033). There was a significant correlation between the extent of DTPA distribution (more than one vascular territory) and the occurrence of herniation (p<0.001). CONCLUSIONS: DTPA-SPECT imaging is a reliable complementary predictive tool in patients with an MCA stroke. The specific pattern found on DTPA SPECT, compatible with diffuse BBB disruption, may be of value in predicting "malignant MCA."

In vivo imaging of apoptosis in patients with acute stroke: correlation with blood-brain barrier permeability.

BACKGROUND: We wished to determine the ability of radiolabeled annexin V to concentrate at sites of ischemic injury in patients with acute cerebral stroke. Secondly, we sought to correlate annexin V imaging in these patients with the degree of blood-brain barrier (BBB) breakdown. METHODS: Twelve patients with acute stroke had a complete neurological examination, including the National Institutes of Health (NIH) stroke scale and the Glasgow Coma Score (GCS). A non-contrast CT scan was performed on all patients. A SPECT of the brain was obtained 2 h after injection of annexin V. The integrity of the BBB was evaluated in seven patients using Tc-99m-DTPA brain SPECT. RESULTS: All patients had an infarct in the MCA territory. Eight patients had abnormal increased annexin V activity, which was more common in patients with cortical strokes (P = 0.01). The concentration of annexin had no correlation to the volume of stroke, but it was significantly and inversely related to the GCS on admission (r = -0.7, P = 0.02). Foci of apoptosis were noted contralateral to the affected hemisphere as well. All seven patients who underwent DTPA SPECT showed breakdown of the BBB. DTPA uptake was significantly and positively associated with NIH score (r = 0.80, P = 0.01) and inversely associated with GCS (r = -0.89, P = -0.03). CONCLUSION: This study shows that it is possible to identify in vivo regions of ischemic neuronal injury using radiolabeled annexin V in patients with acute stroke. Annexin imaging can play a major role in the selection of therapy in the initial period following stroke in adults.

Visual spatial neglect in multiple sclerosis.

Neuropsychological dysfunction in multiple sclerosis (MS) patients is now a well-established clinical finding. We examined the entity of visual spatial neglect in demyelinating disease and its correlation to the functional and neuroradiological parameters. The phenomenon of visual spatial neglect was examined in 20 (5 male and 15 female) MS patients. Two different examination methods were used--the line bisection test and the random shape cancellation test. The results were compared with 20 aged matched control individuals. The correlation of the visual spatial neglects to neurological deficits and handicaps, using Kurtzke's Expanded Disability Status Scale (EDSS), as well as with the MRI's neuroradiological findings, was analyzed. A highly significant different result on the line bisection test for three various line lengths (p = .006, p < .0001, p < .001) with displacement towards the right side was found. In all the cancellation subtests, a significant difference in error rate was found in comparing patients to controls toward a higher one on the left side of the MS patients (p = .005, p < .002, p < .0001 and p = .02 in the left side subtest, and p = n.s. in the right side subtest). There was no significant correlation between the cancellation tests and bisection results and the EDSS scale data, as well as with the neuroradiological findings. The present results demonstrate the presence of visual spatial neglect among MS patients, even without the demonstration of a characteristic neuroanatomical lesion. The hypotheses for this finding are discussed with a stress on the possibility of disruption of multiple intrahemispheric connections, especially under the condition of asymmetry of dominance regarding spatial attention.

[Guidelines for the management of acute stroke--2005].

Stroke is a major cause for morbidity and mortality in Israel, the third most common cause of death and the main cause for neurological disability among adults. Several significant breakthroughs occurred over recent years in the management of stroke, and acute stroke has increasingly been recognized as a medical emergency--a "brain attack" comparable to a "heart attack". Several new scientific publications, guidelines and consensus statements from Europe and North America necessitate a paradigm shift in the management of acute stroke. The guidelines focus on a number of issues: acute stroke as a medical emergency, dedicated stroke units, early reperfusion therapy for acute ischemic stroke, emergency management and general stroke treatment, use of diagnostic tests in the acute phase, and the prevention and treatment of complications.

The significance of prestroke aspirin dosage in fatal outcome of acute stroke.

BACKGROUND: Aspirin is an effective and generally accepted treatment drug during the acute stage of ischemic brain infarction. The association between the pretreatment aspirin dosage and fatal outcome among these treated patient groups has not been analyzed previously. OBJECTIVE: The aim of the study was to evaluate 14- and 30-day poststroke survival in patients treated with 325 mg immediately on admission to the hospital for prestroke antiaggregation/anticoagulation treatment. METHODS: This prospective study was conducted in a government tertiary care facility. The medical records of all 1245 patients admitted to the hospital for stroke from 1997 to 2002 were reviewed. The association between demographic parameters, stroke risk factors, stroke subtype, prestroke antiaggregation/anticoagulation treatment, and risk of fatal poststroke outcome, 14 days and 30 days after the event, was analyzed using Cox survival analyses. RESULTS: During the 14-day poststroke period, 320 patients (25%) died. By day 30 poststroke, 386 patients (31%) had died. Older age, female gender, chronic heart disease, and cardiac arrhythmias were associated with increased risk of increased fatal outcome. Mortality was higher in patients with stroke caused by cardioembolism (P < 0.0001) and was significantly lower in patients with small-vessel occlusion (P < 0.0001). Prestroke medium-dose aspirin treatment was associated with a relative reduction in 30-day poststroke period mortality (P < 0.0001). Conversely, prestroke low-dose aspirin treatment was associated with increased mortality (P < 0.0001). CONCLUSION: Prestroke medium-dose aspirin treatment was associated with reduced 30-day poststroke mortality, whereas low-dose prestroke aspirin therapy was associated with increased 30-day poststroke mortality.

Auditory hallucinations in acute stroke.

Auditory hallucinations are uncommon phenomena which can be directly caused by acute stroke, mostly described after lesions of the brain stem, very rarely reported after cortical strokes. The purpose of this study is to determine the frequency of this phenomenon. In a cross sectional study, 641 stroke patients were followed in the period between 1996-2000. Each patient underwent comprehensive investigation and follow-up. Four patients were found to have post cortical stroke auditory hallucinations. All of them occurred after an ischemic lesion of the right temporal lobe. After no more than four months, all patients were symptom-free and without therapy. The fact the auditory hallucinations may be of cortical origin must be taken into consideration in the treatment of stroke patients. The phenomenon may be completely reversible after a couple of months.

Diagnosing brain death using the transcranial Doppler with a transorbital approach.

BACKGROUND: Transcranial Doppler is a sensitive instrument for the diagnosis of brain death. The guidelines for the determination of brain death include the demonstration of specific blood flow patterns in the anterior and posterior circulation systems. A limitation of this method is the frequent false finding of no flow, especially when using the transtemporal approach in older women. OBJECTIVE: To evaluate the efficacy of the transorbital approach in the diagnosis of brain death using transcranial Doppler. METHODS: A prospective controlled, diagnostic test study was performed. Transorbital, transtemporal, and transforaminal approaches were used. Fifty-seven patients (29 men and 28 women; mean +/- SD age, 68.2 +/- 12.1 years) with clinically determined brain death were examined. RESULTS: In 45 patients, oscillatory flow or systolic spikes were found in all approaches. In 4 patients, no flow was detected. In 6 patients, oscillatory flow or systolic spikes were found in 2 approaches, including the transorbital one. In 2 patients, a positive finding was demonstrated only using the transorbital approach. Using the transorbital approach, the percentage of positive findings with definitive diagnoses of brain death rose from 79% to 88%. CONCLUSION: The transorbital approach is a useful addition for the diagnosis of brain death, using the transcranial Doppler technique.