Best of JNSPG - 75th Anniversary

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Pathophysiology and treatment of focal cerebral ischemia

Part I: Pathophysiology

Bo K. Siesjö

✓ This article examines the pathophysiology of lesions caused by focal cerebral ischemia. Ischemia due to middle cerebral artery occlusion encompasses a densely ischemic focus and a less densely ischemic penumbral zone. Cells in the focus are usually doomed unless reperfusion is quickly instituted. In contrast, although the penumbra contains cells “at risk,” these may remain viable for at least 4 to 8 hours. Cells in the penumbra may be salvaged by reperfusion or by drugs that prevent an extension of the infarction into the penumbral zone. Factors responsible for such an extension probably include acidosis, edema, K+/Ca++ transients, and inhibition of protein synthesis.

Central to any discussion of the pathophysiology of ischemic lesions is energy depletion. This is because failure to maintain cellular adenosine triphosphate (ATP) levels leads to degradation of macromolecules of key importance to membrane and cytoskeletal integrity, to loss of ion homeostasis, involving cellular accumulation of Ca++, Na+, and Cl, with osmotically obligated water, and to production of metabolic acids with a resulting decrease in intra- and extracellular pH.

In all probability, loss of cellular calcium homeostasis plays an important role in the pathogenesis of ischemic cell damage. The resulting rise in the free cytosolic intracellular calcium concentration (Ca++) depends on both the loss of calcium pump function (due to ATP depletion), and the rise in membrane permeability to calcium. In ischemia, calcium influx occurs via multiple pathways. Some of the most important routes depend on activation of receptors by glutamate and associated excitatory amino acids released from depolarized presynaptic endings. However, ischemia also interferes with the intracellular sequestration and binding of calcium, thereby contributing to the rise in intracellular Ca++.

A second key event in the ischemic tissue is activation of anaerobic glucolysis. The main reason for this activation is inhibition of mitochondrial metabolism by lack of oxygen; however, other factors probably contribute. For example, there is a complex interplay between loss of cellular calcium homeostasis and acidosis. On the one hand, a rise in intracellular Ca++ is apt to cause mitochondrial accumulation of calcium. This must interfere with ATP production and enhance anaerobic glucolysis. On the other hand, acidosis must interfere with calcium binding, thereby contributing to the rise in intracellular Ca++.

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A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival

Michel Lacroix, Dima Abi-Said, Daryl R. Fourney, Ziya L. Gokaslan, Weiming Shi, Franco DeMonte, Frederick F. Lang, Ian E. McCutcheon, Samuel J. Hassenbusch, Eric Holland, Kenneth Hess, Christopher Michael, Daniel Miller, and Raymond Sawaya

Object. The extent of tumor resection that should be undertaken in patients with glioblastoma multiforme (GBM) remains controversial. The purpose of this study was to identify significant independent predictors of survival in these patients and to determine whether the extent of resection was associated with increased survival time.

Methods. The authors retrospectively analyzed 416 consecutive patients with histologically proven GBM who underwent tumor resection at the authors' institution between June 1993 and June 1999. Volumetric data and other tumor characteristics identified on magnetic resonance (MR) imaging were collected prospectively.

Conclusions. Five independent predictors of survival were identified: age, Karnofsky Performance Scale (KPS) score, extent of resection, and the degree of necrosis and enhancement on preoperative MR imaging studies. A significant survival advantage was associated with resection of 98% or more of the tumor volume (median survival 13 months, 95% confidence interval [CI] 11.4–14.6 months), compared with 8.8 months (95% CI 7.4–10.2 months; p < 0.0001) for resections of less than 98%. Using an outcome scale ranging from 0 to 5 based on age, KPS score, and tumor necrosis on MR imaging, we observed significantly longer survival in patients with lower scores (1–3) who underwent aggressive resections, and a trend toward slightly longer survival was found in patients with higher scores (4–5). Gross-total tumor resection is associated with longer survival in patients with GBM, especially when other predictive variables are favorable.

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Endoscopic endonasal transsphenoidal surgery: experience with 50 patients

Hae-Dong Jho and Ricardo L. Carrau

✓ An endoscope was used in transsphenoidal surgery and eventually replaced the operating microscope as the tool for visualization. This study focuses on 50 patients (28 females and 22 males) with a median age of 38 years (range 14–88 years). Initially, four patients underwent operation via a sublabial—transseptal approach using a rigid endoscope in conjunction with an operating microscope. The 48 subsequent operations were performed through a nostril using only rigid endoscopes. Forty-four patients had pituitary adenomas and six had various other lesions. Thirteen patients had microadenomas, 16 had intrasellar macroadenomas, nine had macroadenomas with suprasellar extension, and six had invasive macroadenomas involving the cavernous sinus. Seven patients had recurrent pituitary adenomas and 25 had hormonesecreting adenomas (eight patients with Cushing's disease and 17 patients with prolactinomas). Among the eight patients with Cushing's disease, seven had resolution of hypercortisolism clinically and chemically. Of the 17 patients with prolactinomas, 10 improved clinically with normal serum prolactin levels, four improved clinically with elevated serum prolactin levels, and three had residual tumors in the cavernous sinus. Among the 19 patients with nonsecreting adenomas, 16 underwent total resection and three subtotal resection leaving residual tumor in the cavernous sinus. Postoperatively, all patients who had undergone endonasal endoscopic surgery had unobstructed nasal airways with minimal discomfort. More than half of the patients required only an overnight hospitalization.

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Guglielmi detachable coil embolization of acute intracranial aneurysm: perioperative anatomical and clinical outcome in 403 patients

Fernando Viñuela, Gary Duckwiler, and Michel Mawad

✓ From December 1990 to July 1995, the investigators participated in a prospective clinical study to evaluate the safety of the Guglielmi detachable coil (GDC) system for the treatment of aneurysms. This report summarizes the perioperative results from eight initial interventional neuroradiology centers in the United States. The report focuses on 403 patients who presented with acute subarachnoid hemorrhage from a ruptured intracranial aneurysm. These patients were treated within 15 days of the primary intracranial hemorrhage and were followed until they were discharged from the hospital or died.

Seventy percent of the patients were female and 30% were male. The patients' mean age was 58 years old. Aneurysm size was categorized as small (60.8%), large (34.7%), and giant (4.5%); and neck size was categorized as small (53.6%), wide (36.2%), fusiform (6%), and undetermined (4.2%). Fifty-seven percent of the aneurysms were located in the posterior circulation and 43% in the anterior circulation.

Eighty-two patients were classified as Hunt and Hess Grade I (20.3%), 105 Grade II (26.1%), 121 Grade III (30%), 69 Grade IV (17.1%), and 26 Grade V (6.5%). All patients in this study were excluded from surgical treatment either because of anticipated surgical difficulty (69.2%), attempted and failed surgery (12.7%), the patient's poor neurological (12.2%) or medical (4.7%) status, and/or refusal of surgery (1.2%).

The GDC embolization was performed within 48 hours of primary hemorrhage in 147 patients (36.5%), within 3 to 6 days in 156 patients (38.7%), 7 to 10 days in 71 patients (17.6%), and 11 to 15 days in 29 patients (7.2%). Complete aneurysm occlusion was observed in 70.8% of small aneurysms with a small neck, 35% of large aneurysms, and 50% of giant aneurysms. A small neck remnant was observed in 21.4% of small aneurysms with a small neck, 57.1% of large aneurysms, and 50% of giant aneurysms. Technical complications included aneurysm perforation (2.7%), unintentional parent artery occlusion (3%), and untoward cerebral embolization (2.48%). There was a 8.9% immediate morbidity rate related to the GDC technique. Seven deaths were related to technical complications (1.74%) and 18 (4.47%) to the severity of the primary hemorrhage.

The findings of this study demonstrate the safety of the GDC system for the treatment of ruptured intracranial aneurysms in anterior and posterior circulations. The authors believe additional randomized studies will further identify the role of this technique in the management of acutely ruptured incranial aneurysms.

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Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders

Alim Louis Benabid, Pierre Pollak, Dongming Gao, Dominique Hoffmann, Patricia Limousin, Emmanuel Gay, Isabelle Payen, and Abdhelhamid Benazzouz

✓ Tremor was suppressed by test stimulation of the thalamic ventralis intermedius (VIM) nucleus at high frequency (130 Hz) during stereotaxy in nonanesthetized patients suffering from Parkinson's disease or essential tremor. Ventralis intermedius stimulation has since been used by the authors over the last 8 years as a treatment in 117 patients with movement disorders (80 cases of Parkinson's disease, 20 cases of essential tremor, and 17 cases of various dyskinesias and dystonias including four multiple sclerosis). Chronic electrodes were stereotactically implanted in the VIM and connected to a programmable stimulator. Results depend on the indication. In Parkinson's disease patients, tremor, but not bradykinesia and rigidity, was selectively suppressed for as long as 8 years. Administration ofl-Dopa was decreased by more than 30% in 40 Parkinson's disease patients. In essential tremor patients, results were satisfactory but deteriorated with time in 18.5% of cases, mainly for patients who presented an action component of their tremor. In other types of dyskinesias (except multiple sclerosis), results were much less favorable. Fifty-nine patients underwent bilateral implantation and 14 other patients received implantation contralateral to a previous thalamotomy. Thirty-seven patients (31.6%) experienced minor side effects, which were always well tolerated and immediately reversible. Three secondary scalp infections led to temporary removal of the implanted material. There was no permanent morbidity. This tremor suppression effect could be due to the inhibition or jamming of a retroactive loop. Chronic VIM stimulation, which is reversible, adaptable, and well tolerated even by patients undergoing bilateral surgery (74 of 117 patients) and by elderly patients, should replace thalamotomy in the regular surgical treatment of parkinsonian and essential tremors.

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Pathophysiology of syringomyelia associated with Chiari I malformation of the cerebellar tonsils

Implications for diagnosis and treatment

Edward H. Oldfield, Karin Muraszko, Thomas H. Shawker, and Nicholas J. Patronas

✓ The mechanisms previously proposed for the progression of syringomyelia associated with Chiari I malformation of the cerebellar tonsils are controversial, leave many clinical observations unexplained, and underlie the prevalence of different operations currently used as initial treatment. To explore the mechanism of syringomyelia progression in this setting, the authors used anatomical and dynamic (phase-contrast and phase-contrast cine) magnetic resonance (MR) imaging, and intraoperative ultrasonography to examine the anatomy and dynamics of movement of the cerebellar tonsils, the wall of the spinal cord surrounding the syrinx, and the movement of cerebrospinal fluid (CSF) and syrinx fluid at rest, during the respiratory and cardiac cycles, and during Valsalva maneuver in seven affected patients.

In all patients the cerebellar tonsils occluded the subarachnoid space at the level of the foramen magnum. Syringomyelia extended from the cervical to the lower thoracic segment of the spinal cord. No patient had evidence of a patent communication between the fourth ventricle and the syrinx on anatomical MR images, dynamic MR images, or intraoperative ultrasound studies. Dynamic MR images of three patients revealed abrupt downward movement of the spinal CSF and the syrinx fluid during systole and upward movement during diastole, but limited movement of CSF across the foramen magnum during the cardiac cycle. Intraoperative ultrasound studies demonstrated abrupt downward movement of the cerebellar tonsils during systole that was synchronous with sudden constriction of the spinal cord and syrinx. Decompression of the foramen magnum was achieved via suboccipital craniectomy, laminectomy of C-1 and C-2, and dural grafting, leaving the arachnoid intact. Immediately after surgery, the pulsatile downward thrust of the tonsils and constriction of the spinal cord and syrinx disappeared. Syringomyelia resolved within 1 to 6 months after surgery in all patients.

Observations by the authors suggest the following previously unrecognized mechanism for progression of syringomyelia associated with occlusion of the subarachnoid space at the foramen magnum. The brain expands as it fills with blood during systole, imparting a systolic pressure wave to the intracranial CSF that is accommodated in normal subjects by sudden movement of CSF from the basal cisterns to the upper portion of the spinal canal. With obstruction to rapid movement of CSF at the foramen magnum, the cerebellar tonsils, which plug the subarachnoid space posteriorly, move downward with each systolic pulse, acting as a piston on the partially isolated spinal CSF and producing a systolic pressure wave in the spinal CSF that acts on the surface of the spinal cord. This causes progression of syringomyelia by abruptly compressing the cord and propelling the fluid in the syrinx longitudinally with each pulse, and may be responsible for the origin and maintenance of syringomyelia by the pulsatile pressure waves forcing CSF into the cord through the perivascular and interstitial spaces. Effective treatment occurs when the systolic pressure wave transmitted by the cerebellar tonsils is eliminated by relieving the obstruction to rapid movement of subarachnoid CSF across the foramen magnum. The presence of this mechanism can be detected preoperatively on dynamic MR images and during surgery on ultrasound studies by the pulsatile excursion of the wall of the spinal cord surrounding the syrinx and by its immediate disappearance and the expansion of the syrinx during forced inspiration after decompression of the tonsils. Effective treatment is achieved with bone and dural decompression of the foramen magnum alone, without entering the arachnoid.

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Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms

Charles H. Tator and Michael G. Fehlings

✓ In patients with spinal cord injury, the primary or mechanical trauma seldom causes total transection, even though the functional loss may be complete. In addition, biochemical and pathological changes in the cord may worsen after injury. To explain these phenomena, the concept of the secondary injury has evolved for which numerous pathophysiological mechanisms have been postulated. This paper reviews the concept of secondary injury with special emphasis on vascular mechanisms. Evidence is presented to support the theory of secondary injury and the hypothesis that a key mechanism is posttraumatic ischemia with resultant infarction of the spinal cord. Evidence for the role of vascular mechanisms has been obtained from a variety of models of acute spinal cord injury in several species. Many different angiographic methods have been used for assessing microcirculation of the cord and for measuring spinal cord blood flow after trauma. With these techniques, the major systemic and local vascular effects of acute spinal cord injury have been identified and implicated in the etiology of secondary injury.

The systemic effects of acute spinal cord injury include hypotension and reduced cardiac output. The local effects include loss of autoregulation in the injured segment of the spinal cord and a marked reduction of the microcirculation in both gray and white matter, especially in hemorrhagic regions and in adjacent zones. The microcirculatory loss extends for a considerable distance proximal and distal to the site of injury. Many studies have shown a dose-dependent reduction of spinal cord blood flow varying with the severity of injury, and a reduction of spinal cord blood flow which worsens with time after injury. The functional deficits due to acute spinal cord injury have been measured electrophysiologically with techniques such as motor and somatosensory evoked potentials and have been found proportional to the degree of posttraumatic ischemia. The histological effects include early hemorrhagic necrosis leading to major infarction at the injury site.

These posttraumatic vascular effects can be treated. Systemic normotension can be restored with volume expansion or vasopressors, and spinal cord blood flow can be improved with dopamine, steroids, nimodipine, or volume expansion. The combination of nimodipine and volume expansion improves posttraumatic spinal cord blood flow and spinal cord function measured by evoked potentials. These results provide strong evidence that posttraumatic ischemia is an important secondary mechanism of injury, and that it can be counteracted.

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The International Cooperative Study on the Timing of Aneurysm Surgery

Part 2: Surgical results

Neal F. Kassell, James C. Torner, John A. Jane, E. Clarke Haley Jr., Harold P. Adams, and participants

✓ A prospective, observational clinical trial was conducted by the International Cooperative Study on the Timing of Aneurysm Surgery to determine the best time in relation to the hemorrhage for surgical treatment of ruptured intracranial aneurysms. Sixty-eight centers contributed 3521 patients in a 2½-year period beginning in December, 1980. Analysis by a prespecified “planned” surgery interval demonstrated that there was no difference in early (0 to 3 days after the bleed) or late surgery (11 to 14 days). Outcome was worse if surgery was performed in the 7 to 10-day post-bleed interval. Surgical results were better for patients operated on after 10 days. Patients alert on admission fared best; however, alert patients had a mortality rate of 10% to 12% when undergoing surgery prior to Day 11 compared with 3% to 5% when surgery was performed after Day 10. Patients drowsy on admission had a 21% to 25% mortality rate when operated on up to Day 11 and 7% to 10% with surgery thereafter. Overall, early surgery was neither more hazardous nor beneficial than delayed surgery. The postoperative risk following early surgery is equivalent to the risk of rebleeding and vasospasm in patients waiting for delayed surgery.

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A proposed grading system for arteriovenous malformations

Robert F. Spetzler and Neil A. Martin

✓ An important factor in making a recommendation for treatment of a patient with arteriovenous malformation (AVM) is to estimate the risk of surgery for that patient. A simple, broadly applicable grading system that is designed to predict the risk of morbidity and mortality attending the operative treatment of specific AVM's is proposed. The lesion is graded on the basis of size, pattern of venous drainage, and neurological eloquence of adjacent brain. All AVM's fall into one of six grades. Grade I malformations are small, superficial, and located in non-eloquent cortex; Grade V lesions are large, deep, and situated in neurologically critical areas; and Grade VI lesions are essentially inoperable AVM's.

Retrospective application of this grading scheme to a series of surgically excised AVM's has demonstrated its correlation with the incidence of postoperative neurological complications. The application of a standardized grading scheme will enable a comparison of results between various clinical series and between different treatment techniques, and will assist in the process of management decision-making.

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Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas

A cooperative clinical trial

Michael D. Walker, Eben Alexander Jr., William E. Hunt, Collin S. MacCarty, M. Stephen Mahaley Jr., John Mealey Jr., Horace A. Norrell, Guy Owens, Joseph Ransohoff, Charles B. Wilson, Edmund A. Gehan, and Thomas A. Strike

✓ A controlled, prospective, randomized study evaluated the use of 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) and/or radiotherapy in the treatment of patients who were operated on and had histological confirmation of anaplastic glioma. A total of 303 patients were randomized into this study, of whom 222 (73%) were within the Valid Study Group (VSG), having met the protocol criteria of neuropathology, corticosteroid control, and therapeutic approach. Patients were divided into four random groups, and received BCNU (80 mg/sq m/day on 3 successive days every 6 to 8 weeks), and/or radiotherapy (5000 to 6000 rads to the whole brain through bilateral opposing ports), or best conventional care but no chemotherapy or radiotherapy. Analysis was performed on all patients who received any amount of therapy (VSG) and on the Adequately Treated Group (ATG), who had received 5000 or more rads radiotherapy, two or more courses of chemotherapy, and had a minimum survival of 8 or more weeks (the interval that would have been required to have received either the radiotherapy or chemotherapy). Median survival of patients in the VSG was, best conventional care: 14 weeks (ATG: 17.0 weeks); BCNU: 18.5 weeks (ATG: 25.0 weeks); radiotherapy: 35 weeks (ATG: 37.5 weeks); and BCNU plus radiotherapy: 34.5 weeks (ATG: 40.5 weeks). All therapeutic modalities showed some statistical superiority compared to best conventional care. There was no significant difference between the four groups in relation to age distribution, sex, location of tumor, diagnosis, tumor characteristics, signs or symptoms, or the amount of corticosteroid used. An analysis of prognostic factors indicates that the initial performance status (Karnofsky rating), age, the use of only a surgical biopsy, parietal location, the presence of seizures, or the involvement of cranial nerves II, III, IV, and VI are all of significance. Toxicity included acceptable, reversible thrombocytopenia and leukopenia.