Tanvir F. Choudhri

Use of a Spectrophotometric Hemoglobin Assay to Objectively Quantify Intracerebral Hemorrhage in Mice

BACKGROUND AND PURPOSEnThere is great interest in developing novel anticoagulant or thrombolytic strategies to treat ischemic stroke. However, at present there are limited means to accurately assess the hemorrhagic potential of these agents. The present studies were designed to develop and validate a method to accurately quantify the degree of intracerebral hemorrhage (ICH) in murine models.nnnMETHODSnIn a murine model, ICH was induced by stereotaxic intraparenchymal infusion of collagenase B alone (6 x 10(-6) U; n = 5) or collagenase B followed by intravenous recombinant tissue plasminogen activator (rt-PA) (0.1 mg/kg; n = 6). Controls consisted of either sham surgery with stereotaxic infusion of saline (n = 5) or untreated animals (n = 5). ICH was (1) graded by a scale based on maximal hemorrhage diameter on coronal sections and (2) quantified by a spectrophotometric assay measuring cyanomethemoglobin in chemically reduced extracts of homogenized murine brain. This spectrophotometric assay was validated with the use of known quantities of hemoglobin or autologous blood added to a separate cohort of homogenized brains. With this assay, the degree of hemorrhage after focal middle cerebral artery occlusion/reperfusion was quantified in mice treated with postocclusion high-dose intravenous rt-PA (10 mg/kg; n = 11) and control mice subjected to stroke but treated with physiological saline solution (n = 9).nnnRESULTSnKnown quantities of hemoglobin or autologous blood added to fresh whole brain tissue homogenates showed a linear relationship between the amount added and optical density (OD) at the absorbance peak of cyanomethemoglobin (r = 1.00 and .98, respectively). When in vivo studies were performed to quantify experimentally induced ICH, animals receiving intracerebral infusion of collagenase B had significantly higher ODs than saline-infused controls (2.1-fold, increase; P = .05). In a middle cerebral artery occlusion and reperfusion model of stroke, administration of rt-PA after reperfusion increased the OD by 1.8-fold compared with animals that received physiological saline solution (P < .001). When the two methods of measuring ICH (visual score and OD) were compared, there was a linear correlation (r = .88). Additional experiments demonstrated that triphenyltetrazolium staining, which is commonly used to stain viable brain tissue, does not interfere with the spectrophotometric quantification of ICH.nnnCONCLUSIONSnThese data demonstrate that the spectrophotometric assay accurately and reliably quantifies murine ICH. This new method should aid objective assessment of the hemorrhagic risks of novel anticoagulant or thrombolytic strategies to treat stroke and can facilitate quantification of other forms of ICH.

Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain.

Endothelial CD39 metabolizes ADP released from activated platelets. Recombinant soluble human CD39 (solCD39) potently inhibited ex vivo platelet aggregation in response to ADP and reduced cerebral infarct volumes in mice following transient middle cerebral artery occlusion, even when given 3 hours after stroke. Postischemic platelet and fibrin deposition were decreased and perfusion increased without increasing intracerebral hemorrhage. In contrast, aspirin did not increase postischemic blood flow or reduce infarction volume, but did increase intracerebral hemorrhage. Mice lacking the enzymatically active extracellular portion of the CD39 molecule were generated by replacement of exons 4-6 (apyrase-conserved regions 2-4) with a PGKneo cassette. Although CD39 mRNA 3 of the neomycin cassette insertion site was detected, brains from these mice lacked both apyrase activity and CD39 immunoreactivity. Although their baseline phenotype, hematological profiles, and bleeding times were normal, cd39(-/-) mice exhibited increased cerebral infarct volumes and reduced postischemic perfusion. solCD39 reconstituted these mice, restoring postischemic cerebral perfusion and rescuing them from cerebral injury. These data demonstrate that CD39 exerts a protective thromboregulatory function in stroke.

Neuropsychometric Changes in Patients After Carotid Endarterectomy

BACKGROUND AND PURPOSEnOne hundred twelve patients undergoing elective carotid endarterectomy for symptomatic and asymptomatic carotid artery stenosis were enrolled in a prospective study to evaluate the incidence of change in postoperative cerebral function.nnnMETHODSnPatients were evaluated preoperatively and postoperatively before hospital discharge and at follow-up 1 and 5 months later with a battery of neuropsychometric tests. The results were analyzed by both event-rate and group-rate analyses. For event-rate analysis, change was defined as either a decline or improvement in postoperative neuropsychometric performance by 25% or more compared with a preoperative baseline.nnnRESULTSnApproximately 80% of patients showed decline in one or more test scores, and 60% had one or more improved test scores at the first follow-up examination. The percentage of declined test scores decreased and the percentage of improved test scores increased with subsequent follow-up examinations. Group-rate analysis was similar for group performance on individual tests. However, a decline in performance was seen most commonly on verbal memory tests, and improved performance was seen most commonly on executive and motor tests.nnnCONCLUSIONSnNeuropsychometric evaluation of patients undergoing carotid endarterectomy for significant carotid artery stenosis demonstrates both declines and improvements in neuropsychometric performance. The test changes that showed decreased performance may be associated with ischemia from global hypoperfusion or embolic phenomena, and the improvement seen may be related to increased cerebral blood flow from removal of stenosis.

The natural history of cervical spondylotic myelopathy

OBJECTnThe objective of this systematic review was to use evidence-based medicine to delineate the natural history of cervical spondylotic myelopathy (CSM) and identify factors associated with clinical deterioration.nnnMETHODSnThe National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to the natural history of CSM. Abstracts were reviewed and studies meeting the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons.nnnRESULTSnThe natural history of CSM is mixed: it may manifest as a slow, stepwise decline or there may be a long period of quiescence (Class III). Long periods of severe stenosis are associated with demyelination and may result in necrosis of both gray and white matter. With severe and/or long lasting CSM symptoms, the likelihood of improvement with nonoperative measures is low. Objectively measurable deterioration is rarely seen acutely in patients younger than 75 years of age with mild CSM (modified Japanese Orthopaedic Association scale score > 12; Class I). In patients with cervical stenosis without myelopathy, the presence of abnormal electromyography findings or the presence of clinical radiculopathy is associated with the development of symptomatic CSM in this patient population (Class I).nnnCONCLUSIONSnThe natural history of CSM is variable, which may affect treatment decisions.

Cervical surgical techniques for the treatment of cervical spondylotic myelopathy.

OBJECTnThe objective of this systematic review was to use evidence-based medicine to compare the efficacy of different surgical techniques for the treatment of cervical spondylotic myelopathy (CSM).nnnMETHODSnThe National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to anterior and posterior cervical spine surgery and CSM. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons.nnnRESULTSnA variety of techniques have improved functional outcome after surgical treatment for CSM, including anterior cervical discectomy with fusion (ACDF), anterior cervical corpectomy with fusion (ACCF), laminoplasty, laminectomy, and laminectomy with fusion (Class III). Anterior cervical discectomy with fusion and ACCF appear to yield similar results in multilevel spine decompression for lesions at the disc level. The use of anterior plating allows for equivalent fusion rates between these techniques (Class III). If anterior fixation is not used, ACCF may provide a higher fusion rate than multilevel ACDF but also a higher graft failure rate than multilevel ACDF (Class III). Anterior cervical discectomy with fusion, ACCF, laminectomy, laminoplasty, and laminectomy with arthrodesis all provide near-term functional improvement for CSM. However, laminectomy is associated with late deterioration compared with the other types of anterior and posterior surgeries (Class III).nnnCONCLUSIONSnMultiple approaches exist with similar near-term improvements; however, laminectomy appears to have a late deterioration rate that may need to be considered when appropriate.

Surgical Management of High-grade Intracranial Dural Arteriovenous Fistulas: Leptomeningeal Venous Disruption without Nidus Excision

OBJECTIVEnOf intracranial dural arteriovenous malformations (AVMs), those with cortical venous drainage pose the greatest risk of hemorrhaging. Given recent advances in endovascular, surgical, and radiosurgical techniques, the optimal management of these dural AVMs is controversial. For surgical candidates, the choice of intraoperative techniques remains unclear. Several authors have suggested that surgical clipping of the draining vein close to the nidus of dural AVMs can provide adequate treatment for some lesions. However, recent reports have also promoted partial or complete surgical resection of these lesions.nnnMETHODSnWe present five cases of dural AVMs with cortical venous drainage that were surgically treated by the senior author between 1993 and 1996, and we review their management. Our series includes two frontal, one temporal, and two occipital lesions. Three patients presented with intracerebral hemorrhages, one with headache and eye pain, and one without symptoms. All five patients demonstrated venous aneurysms associated with the AVMs. Two patients underwent incomplete endovascular embolization before surgery. Operative management in all cases involved clipping of the draining vein as close as possible to the AVMs, together with extensive cautery of the surrounding dura.nnnRESULTSnPostoperative angiography demonstrated complete angiographic obliteration in all cases. The four symptomatic patients all experienced clinical improvement postoperatively. The asymptomatic patient remained asymptomatic. With a mean follow-up period of 29 months, no patient has developed recurrent symptoms.nnnCONCLUSIONnSurgical clipping of the draining vein close to dural AVMs has proven safe and effective in our experience. Given the highly vascular nature of dural AVMs, often near major dural sinuses, surgical resection of these lesions may not be indicated.

Cervical laminoplasty for the treatment of cervical degenerative myelopathy.

OBJECTnThe objective of this systematic review was to use evidence-based medicine to examine the efficacy of cervical laminoplasty in the treatment of cervical spondylotic myelopathy (CSM).nnnMETHODSnThe National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to cervical laminoplasty and CSM. Abstracts were reviewed and studies meeting the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons and Congress of Neurological Surgeons.nnnRESULTSnCervical laminoplasty has improved functional outcome in the setting of CSM or ossification of the posterior longitudinal ligament. Using the Japanese Orthopaedic Association scale score, approximately 55-60% average recovery rate has been observed (Class III). The functional improvement observed after laminoplasty may be limited by duration of symptoms, severity of stenosis, severity of myelopathy, and poorly controlled diabetes as negative risk factors (Class II). There is conflicting evidence regarding age, with 1 study citing it as a negative risk factor, and another not demonstrating this result.nnnCONCLUSIONSnCervical laminoplasty is recommended for the treatment of CSM or ossification of the posterior longitudinal ligament (Class III).

Clinical prognostic indicators of surgical outcome in cervical spondylotic myelopathy.

OBJECTnThe objective of this systematic review was to use evidence-based medicine to assess whether clinical factors predict surgical outcomes in patients undergoing cervical surgery.nnnMETHODSnThe National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to clinical preoperative factors. Abstracts were reviewed, and studies that met the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons.nnnRESULTSnPreoperative sensory-evoked potentials may aid in providing prognostic information in selected patients in whom clinical factors do not provide clear guidance (Class II). Age, duration of symptoms, and preoperative neurological function may commonly affect outcome (Class III).nnnCONCLUSIONSnAge, duration of symptoms, and preoperative neurological function should be discussed with patients when surgical intervention for cervical spondylotic myelopathy is considered. Preoperative sensory-evoked potentials may be considered for patients in whom clinical factors do not provide clear guidance if such information would potentially change therapeutic decisions.

Laminectomy and fusion for the treatment of cervical degenerative myelopathy

OBJECTnThe objective of this systematic review was to use evidence-based medicine to examine the efficacy of cervical laminectomy and fusion for the treatment of cervical spondylotic myelopathy (CSM).nnnMETHODSnThe National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to cervical laminectomy, fusion, and CSM. Abstracts were reviewed, after which studies that met the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Class I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations which contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer-review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons.nnnRESULTSnCervical laminectomy with fusion (arthrodesis) improves functional outcome in patients with CSM and ossification of the posterior longitudinal ligament (OPLL). Functional improvement is similar to laminectomy or laminoplasty for patients with CSM and OPLL. In contrast to laminectomy, cervical laminectomy with fusion it is not associated with late deformity (Class III).nnnCONCLUSIONSnLaminectomy with fusion (arthrodesis) is an effective strategy to improve functional outcome in CSM and OPLL.

Influence of smoking, hypertension, and sex on the phenotypic expression of familial intracranial aneurysms in siblings.

OBJECTIVE To investigate the effects of smoking, hypertension, and sex on the phenotypic expression of familial intracranial aneurysms (FIAs). METHODS We retrospectively reviewed the case records of 806 consecutive patients undergoing aneurysm surgery at our institution (1986–1995) and discovered 24 families with at least two affected siblings. Prevalence rates for the smoking, hypertension, and sex risk factors in these nuclear families were compared with those of patients with sporadic intracranial aneurysms (SIAs) and population-based control patients. RESULTS Affected family members with FIAs exhibited prevalence rates of smoking and hypertension (74% and 43%, respectively) that tended to be higher than those of population-based control patients (52% [P < 0.005] and 36% [P = not significant (NS)], respectively) and comparable to those of patients with SIAs (64% [P = NS] and 40% [P = NS], respectively). A positive association existed between FIA formation and female sex but was somewhat less strong than that observed in the SIAs (59% FIAs, 71% SIAs, 50% control patients). In addition, the prevalence rates of smoking, hypertension, and female sex were higher in affected family members with FIAs than in their unaffected siblings (58% [P < 0.05], 28% [P = 0.06], and 39% [P < 0.05], respectively). Individuals in families with expressed FIAs who had high aneurysmal penetrance had a greater tendency to be smokers, hypertensive, and female (74%, 59%, and 55%, respectively) than did their low-penetrance counterparts (61% [P = 0.1], 27% [P < 0.05], and 45% [P = NS], respectively). CONCLUSION Together these data suggest that hypertension, smoking, and female sex increase the likelihood that a member of a family with an expressed FIA will have an aneurysm. These observations may prove helpful in guiding the use of screening studies and encouraging education about the potential risks of continued tobacco use and untreated hypertension in this patient cohort.