J. Paul Muizelaar

Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group

Background and Purpose— In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods— An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results— It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. Conclusion— The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111).

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain-linked oxidative phosphorylation. was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg -1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-l11 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAO-linked substrates, and the accompanied energy coupling capacities measured ...

A Cohort Study of the Safety and Feasibility of Intraventricular Urokinase for Nonaneurysmal Spontaneous Intraventricular Hemorrhage

BACKGROUND AND PURPOSE Small case series have reported potential benefit from thrombolysis after spontaneous intraventricular hemorrhage (IVH). Our objective was to review our experience using intraventricular urokinase (UK) in treating selected patients with IVH. METHODS Using medical records, we identified all patients who received ventriculostomies for CT-confirmed nonaneurysmal nontraumatic spontaneous IVH from December 1992 through November 1996. We reviewed charts and CT images and examined the data for associations with specific outcomes. RESULTS We identified 40 patients, 18 treated with ventriculostomy alone and 22 receiving adjunctive intraventricular UK. The initial Glasgow Coma Scale (GCS) scores of the two groups were similar (P = 0.5). While there was a trend for patients with any intraparenchymal hemorrhage (IPH) to receive UK (P = 0.07), the mean size of IPH in those who received ventriculostomy alone was larger than in those who received adjunctive UK (P = 0.002). There was lower mortality in the group treated with UK (31.8 versus 66.7%; P = 0.03), but there was only a trend toward an increase in favorable outcome (22.2% versus 36.4%; P = 0.3). Overall, the most significant association with outcome was neurological condition at presentation (GCS >5 versus < or = 5; P = 0.003). Receiving UK did not increase the occurrence of complications or hospital length of stay for survivors (P = 0.5). CONCLUSIONS Intraventricular UK remains a safe and potentially beneficial intervention. While it appeared to lower mortality, a randomized, placebo-controlled trial is needed to explore whether the therapy can increase the incidence of favorable outcomes.

A New Method for Quantitative Regional Cerebral Blood Volume Measurements Using Computed Tomography

BACKGROUND AND PURPOSE Knowledge of cerebral blood volume (CBV) is invaluable in identifying the primary cause of brain swelling in patients with stroke or severe head injury, and it might also help in clinical decision making in patients thought to have hemodynamic transient ischemic attacks (TIAs). This investigation is concerned with the development and clinical application of a new method for quantitative regional CBV measurements. METHODS The technique is based on consecutive measurements of cerebral blood flow (CBF) by xenon/CT and tissue mean transit time (MTT) by dynamic CT after a rapid iodinated contrast bolus injection. CBV maps are produced by multiplication of the CBF and MTT maps in accordance with the Central Volume Principle: CBV = CBF x MTT. The method is rapid and easily implemented on CT scanners with the xenon/CBF capability. It yields CBV values expressed in milliliters of blood per 100 grams of tissue. RESULTS The method was validated under controlled physiological conditions causing changes that were determined both with our technique and from pressure-volume index (PVI) measurements. The two independent estimates of CBV changes were in agreement within 15%. CBV measurements using this method were carried out in normal volunteers to establish baseline values and to compare with values using the ratio-of-areas method for calculating both CBF and CBV from the dynamic study alone. Average CBV was 5.3 mL/100 g. The method was also applied in 71 patients with severe head injuries and in 1 patient with hemodynamic TIAs. CONCLUSIONS The primary conclusions from this study were (1) the proposed method for measuring CBV accurately determines changes in CBV; (2) the MTT x CBF determinations are in agreement with the ratio-of-areas method for CBV measurements in normal volunteers and are consistent with other methods reported in the literature; (3) MTTs are significantly prolonged early after severe head injury, which when combined with the finding of decreased CBF and increased arteriovenous difference of oxygen indicates increased cerebrovascular resistance due to narrowing of the microcirculation consistent with the presence of early ischemia; and (4) CBV in the patient with TIAs was increased in the hemisphere with the occluded internal carotid artery, indicating compensatory vasodilation and probable hemodynamic cause.

Cerebral perfusion and blood flow in neurotrauma.

Abstract Post-traumatic cerebral ischemia is associated with a poor prognosis. Optimization of cerebral perfusion and blood flow thus plays a key role in contemporary head injury management. However, understanding of the pathophysiology of severe head injury is required for optimal patient management. This article explains the relationships between cerebral blood flow and metabolism and summarizes the current understanding of how these parameters can be helpful in the treatment of patients with severe head injuries. [Neurol Res 2001; 23: 167-174]

Abnormal Responses of the Human Cerebral Microcirculation to Papaverin During Aneurysm Surgery

Background and Purpose— The role of the cerebral microcirculation in delayed ischemia after subarachnoid hemorrhage remains obscure. To test the hypothesis that cerebral arterioles have a reduced capacity to dilate after subarachnoid hemorrhage, we studied the microvascular responses to papaverine (PPV) in patients undergoing aneurysm surgery. Method— In 14 patients undergoing aneurysm surgery, the diameter changes of cortical microvessels after topical application of PPV were observed using orthogonal polarizing spectral imaging. Results— In control subjects, neither arterioles nor venules showed diameter changes in response to topical PPV. In patients operated <48 hours after subarachnoid hemorrhage, PPV resulted in vasodilatation of arterioles with 45±41% increase in arteriolar diameter (P=0.012). In 2 of these patients, arteriolar diameter returned below baseline value. In patients undergoing late aneurysm clipping, the diameter increase of the arterioles after PPV was 25±24% (not significant). In 2 patients of this group, no vasodilatation but focal arteriolar narrowing occurred. Conclusions— In patients with subarachnoid hemorrhage, unpredictable response patterns to PPV were observed with “rebound” vasoconstriction suggesting increased contractility of the microcirculation. Yet, diminished vasodilatory capacity of the cerebral microcirculation after subarachnoid hemorrhage was not confirmed by this study.

Outcome of aneurysmal subarachnoid hemorrhage in patients 66 years of age and older

The outcome at three months after aneurysmal SAH in a group of older patients and a group of younger patients is compared. The patients were admitted within 72 hours of their SAH. Of 61 patients 66 years of age and older, comprising 13% of the whole patient group, 52% died, 12% remained dependent and 36% became independent. In the younger group, 55% had an independent outcome (p less than 0.01). In contrast to what we expected in the older patient group, not extracranial, but intracranial events (re-bleeds, infarcts, hydrocephalus) were by far the most frequent cause of deterioration.

Upper thoracic spine arthroplasty via the anterior approach Case report

Significant progress has been made in lumbar and cervical disc replacement therapy. Several cervical disc prostheses have recently gained FDA approval. Although arthroplasty has not been previously described in the thoracic spine, selected patients with long-segment fusion to the level of C-7 have altered cervicothoracic and upper thoracic biomechanics and may benefit from motion-preservation therapy for T1-2 disc herniation. Currently, FDA-approved prostheses are indicated only for patients with single-level degenerative disc disease between C-3 and C-7 and no history of cervical arthrodesis. The authors describe a 52-year-old woman who had previously undergone C3-7 fusion and returned 4 years later with symptoms of C-8 myeloradiculopathy and radiological evidence of T1-2 degenerative disc disease. She underwent T1-2 arthroplasty in which a Prestige artificial cervical disc was placed via an anterior cervicothoracic approach. Motion at C7-T1 and T1-2 was preserved, and the patient made an excellent clinical recovery.