Matson Memorial Lecture
Joan L. Venes and Andrew D. Parent
Robert R. Smith and Andrew D. Parent
✓ A case of a giant anterior cerebral artery fusiform aneurysm is presented. The lesion was treated by primary excision of the involved segment with an end-to-end anastomosis of the proximal-distal segments of the anterior cerebral artery. It is believed that this technique has not been reported previously for lesions involving major intracranial arteries.
Eddie Perkins, Hitoshi Kimura, Andrew D. Parent and John H. Zhang
Object. Whether cerebral vasospasm occurs only in surface vessels or also in parenchymal arterioles is debatable. The present study was undertaken to evaluate comprehensively the microvasculature of the brainstem after experimental subarachnoid hemorrhage (SAH).
Methods. Nine mongrel dogs of either sex, each weighing between 18 and 24 kg, underwent double blood injections spaced 48 hours apart; the injections were infused into the cisterna magna immediately after angiography of the basilar arteries (BAs). Three additional dogs assigned to a control group received no blood injections. The dogs were killed on Day 7. Axial sections obtained from the midpontine region of both control dogs and animals subjected to SAH were evaluated with respect to the morphological characteristics of vessels and neurons, and for ultrastructural changes.
Severe vasospasm occurred in the BAs of all dogs subjected to SAH. Nevertheless, in these animals, the luminal areas and vessel perimeter in parenchymal arterioles, but not in parenchymal venules, were observed to have increased when compared with those of control dogs (p < 0.01, t-test). No corrugation of the internal elastic lamina was observed and smooth-muscle and endothelial cells remained normal at the ultrastructural level in the dogs with SAH.
Conclusions. In this model, vasospasm of the BAs did not extend into the region of the pons to affect the intraparenchymal arterioles. Dilation of the parenchymal arterioles might serve as compensation for reduced blood flow. Thus, no neuronal ischemia or infarction resulted in the pontine region of the brain.
Andrew D. Parent, Jose Bebin and Robert R. Smith
✓ Pituitary glands from 500 consecutive autopsies were reviewed and the findings correlated with clinical symptomatology. Occult pituitary adenomas were identified in 42 pituitary glands (8.5%). In only one case was a pituitary lesion clinically questioned, but specific hypophyseal function studies were not performed. These tumors occurred most frequently in the sixth and seventh decade of life, without obvious sex predominance. Of these patients, 48% were obese, 57% were hypertensive, and diabetes mellitus was noted in 34%. Of the 17 cases in which skull x-ray films had been taken, suspicious or abnormal areas were found in 11. The tumor size ranged from 1 to 15 mm, but was greater than 1 cm in only one case. In 34 cases, the tumor was located along the periphery of the gland. Even though the etiological and functional significance of these tumors is unclear, the clinical course appears to be relatively benign.
Jimmy D. Miller, Jogi Pattisapu, Dudley F. Peeler and Andrew D. Parent
✓ Several methods of monitoring intracranial pressure (ICP) are in current use, each with its own advantages and disadvantages. The intraventricular line has been most useful because of the ability to withdraw cerebrospinal fluid to assist in control of elevated ICP. However, masses within the brain or generalized increased ICP may compress the lateral ventricle, making insertion of the catheter difficult or impossible. The intracerebral wick records hydrostatic changes too slowly to be used clinically. Swollen cerebral tissue may occlude the subarachnoid bolt thereby dampening the recorded pressure, and epidural monitors may give falsely high recordings because of irregularities of dura or bone. The authors have developed a flaccid-cuff catheter which has proven in animals to be an effective ICP monitor. There are several advantages, such as easy insertion into the centrum semiovale, rapid response to acute pressure changes, and continued sensitivity for periods of up to 3 weeks. The flaccid catheter cuff has no tension so that the pressure across the membrane is equal to zero, simplifying calibration. This type of cuff is necessary for maximum sensitivity to interstitial, brain-tissue, and gross ICP changes. The flaccid-cuff catheter may prove to be useful in a variety of situations such as after closed head trauma or intracranial surgery to assess elevated ICP caused by edema or evolving hematoma.
John A. Lancon, Duane E. Haines, Frank A. Raila, Andrew D. Parent and V. V. Vedanarayanan
✓ Expanding cysts of the septum pellucidum, although rare, may be a cause of significant neurological dysfunction. Most become symptomatic as a result of obstruction of the interventricular foramina and produce headaches, papilledema, emesis, and loss of consciousness. Behavioral, autonomic, and sensorimotor symptoms occur when an expanding cyst impinges on the structures of the hypothalamoseptal triangle or impairs the deep cerebral venous drainage. Neuroophthalmological symptoms may develop as a consequence of hydrocephalus or direct compression of visual structures. The authors describe the case of a young boy with an expanding septum pellucidum cyst who presented with a sudden, severe headache and loss of consciousness. In addition, he had a history of hyperactivity and progressively declining school performance. All symptoms resolved following decompression of the cyst. Seventeen cases from the literature are reviewed. The pathophysiological mechanisms underlying the development of symptoms secondary to expanding septum pellucidum cysts are outlined, and the related clinical neuroanatomy is described. A model is proposed for the natural history of expanding septum pellucidum cysts that provides a rational basis for understanding their clinical behavior and response to intervention. In most cases, fenestration or shunting will relieve the obstructive hydrocephalus and mass effect caused by the cyst and will produce rapid symptomatic improvement.
Toshinari Meguro, Christoph P. R. Klett, Betty Chen, Andrew D. Parent and John H. Zhang
Object. Oxyhemoglobin (OxyHb) released from hemolysed erythrocytes has been considered to be responsible for cerebral vasospasm after subarachnoid hemorrhage. The authors previously reported that OxyHb produced apoptosis in cultured vascular endothelial cells. The change in intracellular Ca++ homeostasis was expected to be one of the possible mechanisms of the cytotoxic effects of OxyHb. This study was undertaken to investigate the protective effects of Ca++-channel blockers on OxyHb-induced apoptosis.
Methods. Cultured bovine coronary artery and brain microvascular endothelial cells (passages 5–9) were used. A cell density study, immunohistochemical staining, and DNA fragmentation analysis were performed to confirm apoptosis. Various concentrations (1–50 µM) of OxyHb were used for 24- to 72-hour incubations with and without Ca++-channel blockers.
Oxyhemoglobin produced cytotoxicity leading to cell detachment from the culture dish in time- and concentration-dependent manners. The highest dose (50 µM) of OxyHb produced cell detachment after a 24-hour incubation, and the lower doses (1–10 µM) produced cell detachment after 48 to 72 hours. Immunohistochemical analysis showed that apoptosis occurred in cells that were still attached to the side of the culture dish after 48 to 72 hours of OxyHb treatment (5 µM). The OxyHb (10 µM) produced DNA ladders at 48 to 72 hours. Three Ca++-channel blockers were used to prevent the toxic effect of OxyHb. The voltage-dependent Ca++-channel blocker nicardipine (1 µM), the voltage-independent Ca++-channel blocker econazole (10 µM), and the inorganic Ca++-channel blocker lanthanum (100 µM) all failed to prevent cell detachment or DNA ladders produced by OxyHb. These results were similar in both cell lines.
Conclusions. Oxyhemoglobin produced apoptotic changes in cultured vascular endothelial cells, and Ca++-channel blockers did not prevent OxyHb-induced apoptosis.
Yasushi Miyagi, Robin C. Carpenter, Toshinari Meguro, Andrew D. Parent and John H. Zhang
Object. Rho A, a small guanosine triphosphate—binding protein, and rho kinases have been suggested to play an important role in the agonist-induced myofilament Ca++ sensitization and cytoskeletal organization of smooth-muscle cells. To discover their possible roles in the prolonged contraction seen in cerebral vasospasm, the authors investigated the messenger (m)RNA expressions of rho A and rho-associated kinases α and β in the basilar artery (BA) of a rat double cisternal blood—injection model.
Methods. An experimental subarachnoid hemorrhage (SAH) was achieved in rats by twice injecting autologous arterial blood into the cisterna magna of each animal. The mRNAs for rho A and rho-associated kinases α and β of the rat BA were analyzed using reverse transcription—polymerase chain reaction (RT-PCR). The cisternal blood injection induced a marked corrugation of elastic lamina and contraction of smooth-muscle cells observed with the aid of light and transmission electron microscopy in the rat BA on Days 3, 5, and 7. Results of the RT-PCR revealed that mRNAs for rho A and rho kinases α and β were expressed in the rat BA and that they were significantly upregulated and reached their peaks on Day 5.
Conclusions. The mRNA upregulation of these proteins indicates that activation of rho A/rho kinase—related signal transduction pathways is involved in the development of long-lasting contraction of cerebral arteries after SAH.
Alexander Y. Zubkov, Kotaro Ogihara, Phani Tumu, Anita Patlolla, Adam I. Lewis, Andrew D. Parent and John Zhang
Object. Mitogen-activated protein kinase (MAPK) is an important signaling factor in vascular proliferation and contraction, which are the two features of cerebral vasospasm that follow subarachnoid hemorrhage. The authors studied the possible involvement of MAPK in hemolysate-induced signal transduction and contraction in rabbit basilar artery (BA).
Methods. Isometric tension was used to record the contractile response of rabbit BA to hemolysate, and Western blots were obtained using antibodies for MAPK.
The following results are reported. 1) Hemolysate produced a concentration-dependent contraction of rabbit BA; however, preincubation of arteries with the MAPK kinase (MEK) inhibitor PD-98059 markedly reduced this contraction. The administration of PD-98059 also relaxed, in a concentration-dependent fashion, the sustained contraction induced by 10% hemolysate. 2) The Janus tyrosine kinase 2 inhibitor AG-490, preincubated with arterial rings, reduced the contractile response to hemolysate but failed to relax the sustained contraction induced by this agent. The Src-tyrosine kinase inhibitor damnacanthal and the phosphatidylinositol 3—kinase inhibitor wortmannin failed to reduce hemolysate-induced contraction. 3) Hemolysate produced a time-dependent elevation of MAPK immunoreactivity as seen on Western blots of rabbit BA. The MAPK was enhanced 1 minute after hemolysate exposure and the effect reached maximum levels at 5 minutes. The immunoreactivity of MAPK decayed slowly over time, but the level of this kinase was still higher than the basal level, even at 2 hours after exposure to hemolysate. Preincubation of arteries with the MEK inhibitor PD-98059 abolished the effect of hemolysate on MAPK immunoreactivity.
Conclusions. Hemolysate produced contraction of rabbit BA, possibly by activation of MAPK, and therefore MAPK inhibitors may be useful in the treatment of cerebral vasospasm.
Kotaro Ogihara, Alexander Y. Zubkov, David H. Bernanke, Adam I. Lewis, Andrew D. Parent and John H. Zhang
Object. Oxyhemoglobin (OxyHb) is one of the most important spasmogens for cerebral vasospasm that follows aneurysmal subarachnoid hemorrhage. The cytotoxic effect of OxyHb has been documented in endothelial and smooth-muscle cells; however, the pattern of cell death—necrosis or apoptosis—as the final stage of cell damage has not been demonstrated. This study was undertaken to determine if OxyHb induces apoptotic changes in cultured bovine aortic endothelial cells.
Methods. Confluent bovine aortic endothelial cells were treated with OxyHb in a concentration- and time-dependent manner. Cell density was assayed by counting the number of cells that attached to culture dishes after exposure to OxyHb. To identify apoptotic changes, the investigators used three specific methods: DNA fragmentation (electrophoreses), the apoptotic body (transmission electron microscopy), and cleavage of poly (adenosine diphosphate ribose) polymerase (PARP [Western blotting]).
Conclusions. Oxyhemoglobin decreased cell density in a concentration- and time-dependent manner. Analysis of DNA showed a pattern of internucleosomal cleavage characteristic of apoptosis (DNA ladder). Transmission electron microscopy demonstrated condensation of nuclei and apoptotic bodies in OxyHb-treated endothelial cells. Western blotting with the PARP antibody revealed that the 116-kD PARP was cleaved to the 85-kD apoptosis-related fragment. These results for the first time demonstrated that the OxyHb induces apoptosis in cultured endothelial cells.