Meyer, Fredric B.

AbstractOBJECTIVEAn excruciating headache of instantaneous onset is known as a thunderclap headache. A subarachnoid hemorrhage is the prototypical cause, but other serious disorders may also present with a thunderclap headache, including cerebral venous sinus thrombosis, carotid artery dissection, and pituitary apoplexy. We report a group of patients with thunderclap headaches as the initial manifestation of spontaneous intracranial hypotension caused by a spinal cerebrospinal fluid leak.METHODSAmong 28 patients with spontaneous intracranial hypotension due to a documented spinal cerebrospinal fluid leak, four (14%) initially experienced an excruciating headaches of instantaneous onset.RESULTSThe mean age of the four patients (two men and two women) was 35 years (range, 24–45 yr). Nuchal rigidity was present in the three patients who sought early medical attention, and they underwent emergency computed tomographic scanning, lumbar puncture, and cerebral angiography to rule out an aneurysmal subarachnoid hemorrhage. The delay between the onset of headache and diagnosis of intracranial hypotension ranged from 4 days to 5 weeks. A fourth patient did not seek medical attention until 1 month after the ictus.CONCLUSIONSpontaneous intracranial hypotension should be included in the differential diagnosis of thunderclap headache, even when meningismus is present.

Rupture of an intracranial aneurysm (subarachnoid hemorrhage) is a potentially devastating condition frequently complicated by delayed cerebral ischemia from sustained contraction of intracranial arteries (cerebral vasospasm). There is mounting evidence linking the formation of intracranial aneurysms and the pathogenesis of post-subarachnoid hemorrhage vasospasm to aberrant bioavailability and action of the vasodilator molecule nitric oxide generated by isoforms of nitric oxide synthase. In humans, the gene encoding the endothelial isoform of nitric oxide synthase (eNOS) is known to be polymorphic, with certain polymorphisms associated with increased cardiovascular disease susceptibility. In this prospective clinical study involving 141 participants, we used gene microarray technology to demonstrate that the eNOS gene intron-4 27-base pair variable number tandem repeat polymorphism (eNOS 27 VNTR) predicts susceptibility to intracranial aneurysm rupture, while the eNOS gene promoter T-786C single nucleotide polymorphism (eNOS T-786C SNP) predicts susceptibility to post-subarachnoid hemorrhage vasospasm. We believe that genetic information such as this, which can be obtained expeditiously at the time of diagnosis, may be used as a helpful adjunct to other clinical information aimed at predicting and favorably modifying the clinical course of persons with intracranial aneurysms.

Gene transfer involves the use of an engineered biologic vehicle known as a vector to introduce a gene encoding a protein of interest into a particular tissue. In diseases with known defects at a genetic level, gene transfer offers a potential means of restoring a normal molecular environment via vector-mediated entry (transduction) and expression of genes encoding potentially therapeutic proteins selectively in diseased tissues. The technology of gene transfer therefore underlies the concept of gene therapy and falls under the umbrella of the current genomics revolution. Particularly since 1995, numerous attempts have been made to introduce genes into intracranial blood vessels to demonstrate and characterize viable transduction. More recently, in attempting to translate cerebrovascular gene transfer technology closer to the clinical arena, successful transductions of normal human cerebral arteries ex vivo and diseased animal cerebral arteries in vivo have been reported using vasomodulatory vectors. Considering the emerging importance of gene-based strategies for the treatment of the spectrum of human disease, the goals of the present report are to overview the fundamentals of gene transfer and review experimental studies germane to the clinical translation of a technology that can facilitate genetic modification of cerebral blood vessels.

This experiment examined the effects of nitric oxide (NO) synthase inhibition on brain intracellular pH, regional cortical blood flow, and NADH fluorescence before and during 3 h of focal cerebral ischemia using in vivo fluorescence imaging. Thirty fasted rabbits under 1% halothane were divided into four treatment groups receiving N ω -nitro-L-arginine methyl ester (L-NAME) intravenously at 20 min prior to ischemia (0.1, I, and 10 mg/kg and 1 mg/kg + 5 mg/kg L-arginine) and two control groups (nonischemic and ischemic). In ischemic controls, brain pH i declined to 6.73 ± 0.03 at 30 min and remained acidotic through the remainder of the ischemic period. In the 0.1 mg/kg group, brain pH i fell after 30 min of ischemia to 6.76 ± 0.05 ( p < 0.05), but then improved progressively despite occlusion. In the 1 mg/kg group, brain pH i remained normal despite middle cerebral artery (MCA) occlusion. In the 10 mg/kg group and in the combined L-NAME + L-arginine group, pH i fell after 30 min of ischemia to 6.81 ± 0.03 ( p < 0.05) and remained acidotic. During occlusion, regional cortical blood flow dropped in a dose-dependent manner. After 3 h of ischemia, regional cortical blood flow was 33.9 ± 10.9 and 25.1 ± 8.9 ml/100 g/min at doses of 0.1 and 10.0 mg/kg, respectively. L-NAME treatment did not significantly alter the increased NADH fluorescence that accompanied occlusion. This study shows that L-NAME can prevent intracellular brain acidosis during focal cerebral ischemia independent from regional cortical blood flow changes. This experiment suggests that NO is involved in pH i regulation during focal cerebral ischemia.

Gene therapy is being investigated as a putative treatment option for cardiovascular diseases, including cerebral vasospasm. Because there is presently no information regarding gene transfer to human cerebral arteries, the principal objective of this study was to characterize adenovirus-mediated expression and function of recombinant endothelial nitric oxide synthase (eNOS) gene in human pial arteries. Pial arteries (outer diameter 500 to 1000 μm) were isolated from 30 patients undergoing temporal lobectomy for intractable seizures and were studied using histologic staining, histochemistry, electron microscopy, and isometric force recording. Gene transfer experiments were performed ex vivo using adenoviral vectors encoding genes for bovine eNOS (AdCMVeNOS) and Escherichia coli β-galactosidase (AdCMVLacZ). In transduced arteries, studied 24 hours after exposure to vectors, expression of recombinant β-galactosidase and eNOS was detected by histochemistry, localizing mainly to the adventitia (n = 4). Immunoelectron microscopy localized recombinant eNOS in adventitial fibroblasts. During contractions to U46619, bradykinin-induced relaxations were significantly augmented in AdCMVeNOS-transduced rings compared with control and AdCMVLacZ-transduced rings ( P < 0.01; n = 6). The NOS inhibitor L-nitroarginine methylester (L-NAME) caused significantly greater contraction in AdCMVeNOS-transduced rings ( P < 0.001; n = 4) and inhibited bradykinin-induced relaxations in control and transduced rings ( P < 0.001; n = 6). The current findings suggest that in AdCMVeNOS-transduced human pial arteries, expression of recombinant eNOS occurs mainly in adventitial fibroblasts where it augments relaxations to NO-dependent agonists such as bradykinin. Findings from the current study might be beneficial in future clinical applications of gene therapy for the treatment or prevention of cerebral vasospasm.

Background and Purpose—We sought to determine the incidence of recurrent stenosis after carotid endarterectomy.Methods—One thousand consecutive carotid endarterectomy patients were followed prospectively. The surgery was performed in a standard fashion. Cerebral protection was provided with intraoperative electroencephalographic monitoring and selective shunting. All arteriotomies were repaired with a patch graft. Each patient was seen 3 months after surgery and then yearly, with a duplex ultrasound obtained at each visit. Evidence for new ischemic events or recurrent stenosis of ≥70% was recorded.Results—The 30-day combined minor and major stroke and death rate was 1.9%. At 7.1-year follow-up, 0.1% of patients had recurrent stenosis ≥70%, the majority of which were asymptomatic.Conclusions—Carotid endarterectomy is a low-risk procedure for the treatment of carotid occlusive disease, with excellent long-term durability. Although less invasive, carotid angioplasty must demonstrate equal robustness in long-term follow-up before it is considered a routine alternative to surgery.