Fredric B. Meyer

A Randomized, Controlled Trial of Methylprednisolone or Naloxone in the Treatment of Acute Spinal-Cord Injury

Abstract Studies in animals indicate that methylprednisolone and naloxone are both potentially beneficial in acute spinal-cord injury, but whether any treatment is clinically effective remains uncertain. We evaluated the efficacy and safety of methylprednisolone and naloxone in a multicenter randomized, double-blind, placebo-controlled trial in patients with acute spinal-cord injury, 95 percent of whom were treated within 14 hours of injury. Methylprednisolone was given to 162 patients as a bolus of 30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogram per hour for 23 hours. Naloxone was given to 154 patients as a bolus of 5.4 mg per kilogram, followed by infusion at 4.0 mg per kilogram per hour for 23 hours. Placebos were given to 171 patients by bolus and infusion. Motor and sensory functions were assessed by systematic neurologic examination on admission and six weeks and six months after injury. After six months the patients who were treated with methylprednisolone within eigh...

High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings

Neuronal oscillations span a wide range of spatial and temporal scales that extend beyond traditional clinical EEG. Recent research suggests that high-frequency oscillations (HFO), in the ripple (80-250 Hz) and fast ripple (250-1000 Hz) frequency range, may be signatures of epileptogenic brain and involved in the generation of seizures. However, most research investigating HFO in humans comes from microwire recordings, whose relationship to standard clinical intracranial EEG (iEEG) has not been explored. In this study iEEG recordings (DC - 9000 Hz) were obtained from human medial temporal lobe using custom depth electrodes containing both microwires and clinical macroelectrodes. Ripple and fast-ripple HFO recorded from both microwires and clinical macroelectrodes were increased in seizure generating brain regions compared to control regions. The distribution of HFO frequencies recorded from the macroelectrodes was concentrated in the ripple frequency range, compared to a broad distribution of HFO frequencies recorded from microwires. The average frequency of ripple HFO recorded from macroelectrodes was lower than that recorded from microwires (143.3 +/- 49.3 Hz versus 116.3 +/- 38.4, Wilcoxon rank sum P<0.0001). Fast-ripple HFO were most often recorded on a single microwire, supporting the hypothesis that fast-ripple HFO are primarily generated by highly localized, sub-millimeter scale neuronal assemblies that are most effectively sampled by microwire electrodes. Future research will address the clinical utility of these recordings for localizing epileptogenic networks and understanding seizure generation.

A retrospective analysis of pituitary apoplexy.

Thirty-seven patients with pituitary apoplexy were analyzed with an emphasis on clinical presentation and visual outcome. Their mean age was 56.6 years, with a male to female ratio of 2:1. Presenting symptoms included headache (95%), vomiting (69%), ocular paresis (78%), and reduction in visual fields (64%) or acuities (52%). Computed tomographic scanning correctly identified pituitary hemorrhage in only 46% of those scanned. Thirty-six patients underwent transsphenoidal decompression. By immunostaining criteria, null-cell adenomas were the most frequent tumor type (50%). Long-term steroid or thyroid hormone replacement therapy was necessary in 82% and 89% of patients, respectively. Long-term desmopressin therapy was required in 11%, and 64% of the male patients required testosterone replacement therapy. Surgery resulted in improvement in visual acuity deficits in 88%, visual field deficits in 95%, and ocular paresis in 100%. Analysis of the degree of improvement in preoperative visual deficits with the timing of the surgery demonstrated that those who underwent surgery within a week of apoplexy had significant recovery in their visual acuities. In the stable, conscious patient with residual vision in each eye, surgical decompression should be performed as soon as possible, because delays beyond 1 week may retard the return of visual function.

Emergency carotid endarterectomy for patients with acute carotid occlusion and profound neurological deficits

Emergency revascularization procedures for patients with acute stroke are controversial. Thirty-four patients with acute internal carotid artery occlusion documented at the time of emergency endarterectomy were analyzed. Before operation, all these patients had profound neurological deficits including hemiplegia and aphasia. There was a 94% success rate in restoring patency. In follow-up, nine patients (26.5%) had a normal neurological exam, four (11.8%) had a minimal deficit, 10 (29.4%) had a moderate hemiparesis, which was improved over their preoperative deficit, 4 (11.8%) remained hemiplegic, and seven (20.6%) died. The natural history of patients with acute carotid occlusion and profound neurological deficits is dismal. In comparison, 13 patients (38%) made a dramatic recovery. The surgical mortality rate compares favorably with the natural history. Good collateral flow was a good prognostic factor, while a simultaneous middle cerebral artery embolus was associated with a poorer prognosis. An emergency carotid endarterectomy may be indicated in selected patients with acute internal carotid artery occlusion with profound neurological deficits. Full preoperative angiography may identify those patients who would benefit from surgical intervention and reduce the operative mortality rate.

Primarily Resected Meningiomas: Outcome and Prognostic Factors in 581 Mayo Clinic Patients, 1978 Through 1988

OBJECTIVE To establish prognostic factors for recurrence and outcome of surgical treatment, with or without postoperative radiation therapy, in patients with meningiomas. MATERIAL AND METHODS From 1978 through 1988, 581 patients underwent initial resection of a previously untreated primary meningioma at Mayo Clinic Rochester. In this study cohort, the outcome and prognostic factors associated with radiographic progression-free survival were analyzed. RESULTS Gross total resection (GTR) of the meningioma was accomplished in 80% of patients; the other 20% underwent less than GTR. Perioperative mortality within 10 days was 1.6%. Overall survival was significantly decreased from that for an age- and sex-matched cohort from the US white population. Progression-free survival at 5 and 10 years was 88% and 75%, respectively, in patients who underwent GTR and 61% and 39%, respectively, in those who underwent less than GTR. Multivariate analysis showed that age younger than 40 years, male sex, less than GTR, optic nerve involvement, and 4 or more mitotic figures per 10 high-power fields were associated with decreased progression-free survival. The 581 patients had 106 first recurrences. A trend toward improved progression-free survival was noted after first recurrence when irradiation with or without operation was used in comparison with only surgical treatment (P = 0.058). CONCLUSION With only operative treatment of meningioma, the 10-year recurrence rate was 25% in patients who had GTR and 61% in those who had less than GTR. These results emphasize the need for long-term follow-up and for consideration of adjuvant radiation therapy. Patients treated at the time of recurrence seem to benefit from radiation therapy with or without surgical resection. Factors associated with recurrence were (1) less than GTR, (2) involvement of the anterior visual pathway, (3) age younger than 40 years, and (4) increased mitotic index.

Central nervous system tumors

Central nervous system tumors are relatively common in the United States, with more than 40,000 cases annually. Although more than half of these tumors are benign, they can cause substantial morbidity. Malignant primary brain tumors are the leading cause of death from solid tumors in children and the third leading cause of death from cancer in adolescents and adults aged 15 to 34 years. Common presenting symptoms include headache, seizures, and altered mental status. Whereas magnetic resonance imaging helps define the anatomic extent of tumor, biopsy is often required to confirm the diagnosis. Treatment depends on the histologic diagnosis. Benign tumors are usually curable with surgical resection or radiation therapy including stereotactic radiation; however, most patients with malignant brain tumors benefit from chemotherapy either at the time of initial diagnosis or at tumor recurrence. Metastases to the brain remain a frequent and morbid complication of solid tumors but are frequently controlled with surgery or radiation therapy. Unfortunately, the mortality rate from malignant brain tumors remains high, despite initial disease control. This article provides an overview of current diagnostic and treatment approaches for patients with primary and metastatic brain tumors.

Calcium, neuronal hyperexcitability and ischemic injury

Due to tight regulatory controls, a 10,000-fold concentration gradient exists between intracellular and extracellular free Ca2+ concentrations. With appropriate stimulus Ca2+ will rapidly flow into neurons through various types of membrane channels including voltage-dependent and receptor-operated channels. Intracellular Ca2+ concentrations are then quickly restored primarily through Ca2+-ATPase, Na+/Ca2+ exchange, and endoplasmic reticulum sequestration. It is well-known that Ca2+ is essential for neurotransmitter release. More recent investigations indicate that Ca2+ influx is essential for neuronal excitability independent from synaptic function. In fact, abnormal Ca2+ metabolism may play a dominant role in both the initiation and propagation of seizure discharge. Accordingly, Ca2+ channel blockers may represent a new therapeutic modality to treat epilepsy. Analyzed in this article are the major mechanisms by which neurons control Ca2+ fluxes and the evidence supporting the role of Ca2+ in seizure phenomena. Thereafter, an integrative theory for the role of calcium in neuronal hyperexcitability and ischemic cell death is constructed.

Surgical treatment of spontaneous spinal cerebrospinal fluid leaks

OBJECT Spontaneous spinal cerebrospinal fluid (CSF) leaks are an increasingly recognized cause of intracranial hypotension and may require neurosurgical intervention. In the present report the authors review their experience with the surgical management of spontaneous spinal CSF leaks. METHODS Between 1992 and 1997, 10 patients with spontaneous spinal CSF leaks and intracranial hypotension were treated surgically. The mean age of the seven women and three men was 42.3 years (range 22-61 years). Preoperative imaging showed a single meningeal diverticulum in two patients, a complex of diverticula in one patient, and a focal CSF leak alone in seven patients. Surgical exploration in these seven patients demonstrated meningeal diverticula in one patient; no clear source of CSF leakage could be identified in the remaining six patients. Treatment consisted of ligation of the diverticula or packing of the epidural space with muscle or Gelfoam. Multiple simultaneous spinal CSF leaks were identified in three patients. CONCLUSIONS All patients experienced complete relief of their headaches postoperatively. There has been no recurrence of symptoms in any of the patients during a mean follow-up period of 19 months (range 3-58 months; 16 person-years of cumulative follow up). Complications consisted of transient intracranial hypertension in one patient and leg numbness in another patient. Although the disease is often self-limiting, surgical treatment has an important role in the management of spontaneous spinal CSF leaks. Surgery is effective in eliminating the headaches and the morbidity is generally low. Surgical exploration for a focal CSF leak, as demonstrated on radiographic studies, usually does not reveal a clear source of the leak. Some patients may have multiple simultaneous CSF leaks.

Pathobiology of pituitary adenomas and carcinomas.

OBJECTIVE:To examine relationships between pituitary tumors and lesion size, invasiveness, resectability, deoxyribonucleic acid ploidy, cell cycle profile, mitotic activity, and immunoreactivity for MIB-1, proliferating cell nuclear antigen (PCNA), p27Kip1, and p53. PATIENTS AND METHODS:One hundred fifty-three adenomas of most pathological subtypes, including 20 medically treated and prolactin and growth hormone-containing tumors, as well as 10 premetastatic tumors and 13 pituitary carcinomas, were studied. RESULTS:Significant (P < 0.05) differences were noted between functional versus nonfunctional adenomas (percent aneuploidy, percent S phase, p27Kip1 labeling indices [LI], male sex, tumor size, and frequency of visual disturbance); Cushing’s versus silent adrenocorticotropin adenomas (percent hypertetraploidy, p53 LI, tumor size, visual disturbance, and resectability); untreated versus medically treated prolactin cell adenomas (MIB-1 LI, p53 LI, and resectability); untreated versus medically treated growth hormone-containing adenomas (percent diploidy, percent S phase, MIB-1 LI, p53 LI, and p27 LI); untreated prolactin cell adenomas versus premetastatic tumors (percent hypertetraploidy, PCNA LI, p53 LI, invasiveness, and resectability); untreated growth hormone-containing adenomas versus premetastatic tumors (percent diploidy, percent S phase, PCNA LI, p53 LI, invasiveness, and resectability); Cushing’s adenomas versus premetastatic tumors (percent diploidy, percent hypertetraploidy, percent S phase, MIB-1 LI, p53 LI, tumor size, invasiveness, visual disturbance, and resectability); Nelson’s adenomas versus premetastatic tumors (p53 LI, tumor size, invasiveness, and resectability); silent adenomas as a whole versus nonfunctional adenomas (percent nondiploid, percent S phase, invasiveness, and respectability); silent adrenocorticotropin adenomas I and II versus silent adenoma Subtype III (invasiveness); silent adrenocorticotropin adenoma Subtypes I and II versus premetastatic tumors (MIB-1 LI and invasiveness); silent adenoma Subtype III versus premetastatic tumors (PCNA and p53 LI); and premetastatic tumors versus metastatic pituitary carcinomas (MIB-1 LI). CONCLUSION:Only trends toward differences were noted between Cushing’s versus Nelson’s adenomas and between prolactinomas of reproductive female patients versus those of menopausal female patients and male patients. Too few “atypical adenomas” were encountered to permit their comparison with premetastatic tumors, but our results suggest that most pituitary carcinomas arise by malignant transformation from adenomas.

Awake craniotomy for aggressive resection of primary gliomas located in eloquent brain

OBJECTIVE To determine with intraoperative neurologic and language examinations the maximal tumor resection achievable with acceptable postoperative neurologic dysfunction in patients undergoing awake stereotactic glial tumor resection in eloquent regions of the brain. PATIENTS AND METHODS Between October 1995 and December 2000, 65 patients underwent frameless stereotactic resection of glial tumors located in functioning tissue. During the resection, continuous examinations by a neurologist and speech pathologist were performed. The goal of surgery was to resect the maximum neurologically permissible tumor volume defined on preoperative T2 imaging. Tumor resection was stopped at the onset of neurologic dysfunction. Novel segmentation software was used to measure tumor cytoreduction based on pre- and postoperative magnetic resonance imaging. All patients underwent 3-month postoperative neurologic examinations to determine functional outcomes. RESULTS The cortical and subcortical white matter tracts at risk for injury were the left frontal operculum in 15 patients, the central lobule in 38, the insula in 11, and the left angular gyrus in 1. Thirty-four (52%) had a greater than 90% reduction in T2 signal postoperatively. In 26 patients thought to have low-grade tumors based on preoperative imaging, 12 proved to have grade 3 gliomas. Forty-eight patients (74%) developed intraoperative deficits; 34 (71%) recovered to a modified Rankin grade of 0 or 1 at 3 months postoperatively, 11 (23%) achieved a modified Rankin grade of 2, and 3 patients (6%) achieved a modified Rankin grade of 3 or 4 at 3-month follow-up. There was no operative mortality; 17 patients (26%) died from tumor progression during the follow-up period. CONCLUSIONS Combining frameless computer-guided stereotaxis with cortical stimulation and repetitive neurologic and language assessments facilitates tumor resection in functioning brain regions. Resecting tumor until the onset of neurologic deficits allows for a good functional recovery. Imaging software can objectively and accurately measure preoperative and postoperative tumor volumes.