Roberto Delfini

Temporal window of metabolic brain vulnerability to concussion: A pilot 1H-magnetic resonance spectroscopic study in concussed athletes - Part III

OBJECTIVE In the present study, the occurrence of the temporal window of brain vulnerability was evaluated in concussed athletes by measuring N-acetylaspartate (NAA) using proton magnetic resonance (H-MR) spectroscopy. METHODS Thirteen nonprofessional athletes who had a sport-related concussive head injury were examined for NAA determination by means of H-MR spectroscopy at 3, 15, and 30 days postinjury. All athletes but three suspended their physical activity. Those who continued their training had a second concussive event and underwent further examination at 45 days from the initial injury. The single case of one professional boxer, who was studied before the match and 4, 7, 15, and 30 days after a knockout, is also presented. Before each magnetic resonance examination, patients were asked for symptoms of mild traumatic brain injury, including physical, cognitive, emotional, and sleep disturbances. Data for H-MR spectroscopy recorded in five normal, age-matched, control volunteers, who were previously screened to exclude previous head injuries, were used for comparison. Semiquantitative analysis of NAA relative to creatine (Cr)- and choline (Cho)-containing compounds was performed from proton spectra obtained with a 3-T magnetic resonance system. RESULTS Regarding the values of the NAA-to-Cr ratio (2.21 +/- 0.11) recorded in control patients, singly concussed athletes, at 3 days after the concussion, showed a decrease of 18.5% (1.80 +/- 0.04; P < 0.001). Only a modest 3% recovery was observed at 15 days (1.88 +/- 0.1; P < 0.001); at 30 days postinjury, the NAA-to-Cr ratio was 2.15 +/- 0.1, revealing full metabolic recovery with values not significantly different from those of control patients. These patients declared complete resolution of symptoms at the time of the 3-day study. The three patients who had a second concussive injury before the 15-day study showed an identical decrease of the NAA-to-Cr ratio at 3 days (1.78 +/- 0.08); however, at 15 days after the second injury, a further diminution of the NAA-to-Cr ratio occurred (1.72 +/- 0.07; P < 0.05 with respect to singly concussed athletes). At 30 days, the NAA-to-Cr ratio was 1.82 +/- 0.1, and at 45 days postinjury, the NAA-to-Cr ratio showed complete recovery (2.07 +/- 0.1; not significant with respect to control patients). This group of patients declared a complete resolution of symptoms at the time of the 30-day study. CONCLUSION Results of this pilot study carried out in a cohort of singly and doubly concussed athletes, examined by H-MR spectroscopy for their NAA cerebral content at different time points after concussive events, demonstrate that also in humans, concussion opens a temporal window of brain metabolic imbalance, the closure of which does not coincide with resolution of clinical symptoms. The recovery of brain metabolism is not linearly related to time. A second concussive event prolonged the time of NAA normalization by 15 days. Although needing confirmation in a larger group of patients, these results show that NAA measurement by H-MR spectroscopy is a valid tool in assessing the full cerebral metabolic recovery after concussion, thereby suggesting its use in helping to decide when to allow athletes to return to play after a mild traumatic brain injury.

Temporal window of metabolic brain vulnerability to concussions: Mitochondrial-related impairment - Part I

OBJECTIVE In the present study, we investigate the existence of a temporal window of brain vulnerability in rats undergoing repeat mild traumatic brain injury (mTBI) delivered at increasing time intervals. METHODS Rats were subjected to two diffuse mTBIs (450 g/1 m height) with the second mTBI delivered after 1 (n = 6), 2 (n = 6), 3 (n = 6), 4 (n = 6), and 5 days (n = 6) and sacrificed 48 hours after the last impact. Sham-operated animals were used as controls (n = 6). Two further groups of six rats each received a second mTBI after 3 days and were sacrificed at 120 and 168 hours postinjury. Concentrations of adenine nucleotides, N-acetylated amino acids, oxypurines, nucleosides, free coenzyme A, acetyl CoA, and oxidized and reduced nicotinamide adenine dinucleotides, oxidized nicotinamide adenine dinucleotide phosphate, and reduced nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide phosphate nicotinic coenzymes were measured in deproteinized cerebral tissue extracts (three right and three left hemispheres), whereas the gene expression of N-acetylaspartate acylase, the enzyme responsible for N-acetylaspartate (NAA) degradation, was evaluated in extracts of three left and three right hemispheres. RESULTS A decrease of adenosine triphosphate, adenosine triphosphate /adenosine diphosphate ratio, NAA, N-acetylaspartylglutamate, oxidized and reduced nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide, and acetyl CoA and increase of N-acetylaspartate acylase expression were related to the interval between impacts with maximal changes recorded when mTBIs were spaced by 3 days. In these animals, protracting the time of sacrifice after the second mTBI up to 1 week failed to show cerebral metabolic recovery, indicating that this type of damage is difficult to reverse. A metabolic pattern similar to controls was observed only in animals receiving mTBIs 5 days apart. CONCLUSION This study shows the existence of a temporal window of brain vulnerability after mTBI. A second concussive event falling within this time range had profound consequences on mitochondrial-related metabolism. Furthermore, because NAA recovery coincided with normalization of all other metabolites, it is conceivable to hypothesize that NAA measurement by 1H-NMR spectroscopy might be a valid tool in assessing full cerebral metabolic recovery in the clinical setting and with particular reference to sports medicine in establishing when to return mTBI-affected athletes to play. This study also shows, for the first time, the influence of TBI on acetyl-CoA, N-acetylaspartate acylase gene expression, and N-acetylaspartylglutamate, thus providing novel data on cerebral biochemical changes occurring in head injury.

The effect of intensive insulin therapy on infection rate, vasospasm, neurologic outcome, and mortality in neurointensive care unit after intracranial aneurysm clipping in patients with acute subarachnoid hemorrhage: a randomized prospective pilot trial.

It is unclear if avoiding hyperglycemia during intensive care after acute brain injury improves morbidity, mortality, and neurologic outcome. This prospective randomized trial tested whether intensive insulin therapy affected infection rates, vasospasm, mortality, or long-term neurologic outcome in subarachnoid hemorrhage patients during their intensive care unit (ICU) stay. Comparison was made against conventional insulin therapy using a randomized trial design. The primary outcome measure was infection rate until the fourteenth postoperative day in the ICU or until patient discharge. Secondary end points were the incidence of vasospasm until the fourteenth postoperative day in the ICU or until patient discharge, and neurologic outcome and mortality at 6 months follow-up. A total of 78 patients were prospectively enrolled and randomly assigned either to conventional insulin therapy or to intensive insulin therapy (38 and 40 patients, respectively). The infection rate during the study was significantly higher in patients who received conventional insulin therapy than in patients who received intensive insulin therapy (42% vs. 27%; P<0.001). The incidence of vasospasm during the study was also similar in conventional and intensive therapy groups (31.5% vs. 27.6% in the conventional and intensive insulin therapy groups; P=0.9). Overall mortality rates at 6 months were similar in the 2 groups (18% vs.15%; P=0.9), as was the neurologic outcome at 6 months [modified Rankin score >3 in 22/38 patients (57.8%) in the conventional therapy group vs. 21/40 patients (52.5%) in the intensive insulin therapy group; P=0.7]. Intensive insulin therapy in patients with acute subarachnoid hemorrhage admitted to a postoperative neurosurgical ICU after surgical clipping of intracranial aneurysms decreases infection rates. The benefit of strict glycemic control on postoperative vasospasm, neurologic outcome, and mortality rates does not seem to be affected by intensive insulin therapy.

Long-term follow-up of intramedullary spinal cord tumors : A series of 202 cases

OBJECTIVE:To review a series of patients who underwent surgical removal of intramedullary spinal cord tumors, focusing on the long-term functional outcome, recurrence rates for the various tumors, and technical problems continually debated in neurosurgical practice. METHODS:From December 1972 to June 2003, 202 patients underwent removal of intramedullary tumors. Lesions were located in the cervical spinal cord in 61 patients (30%), at a dorsal site in 60 (29%), at a cervicodorsal site in 51 (25%), and in the medullary cone in 30 (15%). The most frequent histological tumor types were astrocytomas (86 patients, 42%) and ependymomas (68 patients, 34%). RESULTS:Of the 68 ependymomas, 55 (81%) were completely removed and 13 (19%) incompletely removed. In 66% of the patients (42 patients), the presenting signs and symptoms remained unchanged at long-term follow-up; in 25% (16 patients), they improved; and in 9% (6 patients), the clinical status worsened. Of the 27 Grade I astrocytomas, 22 (81%) were completely removed and 5 (19%) incompletely removed. Functional assessment of the 23 patients available at “late” follow-up showed that 26% (6 of 23 patients) had improved, 9% (2 of 23 patients) had worsened, and 66% (15 of 23 patients) remained unchanged from preoperative status. Conversely, of the 41 Grade II astrocytomas, only 5 (12%) were completely removed, and 10% had improved. None of the 18 Grade III to IV astrocytomas could be completely removed. In 61% (11 of 18 patients), the postoperative functional status worsened. CONCLUSION:Determinant predictors of a good outcome after surgery for intramedullary spinal cord tumors are histological type of lesion, complete removal of the lesion, and a satisfactory neurological status before surgery.

Safety and Efficacy of Intensive Insulin Therapy in Critical Neurosurgical Patients

Background:Intensive insulin therapy to maintain blood glucose at or below 6.11 mm reduces morbidity and mortality after cardiac surgery and morbidity in medical intensive care unit (ICU) patients. The authors investigated the clinical safety and outcome effects of intensive insulin therapy compared to conventional insulin therapy in patients receiving postoperative intensive care after neurosurgical procedures. Methods:In this prospective randomized controlled trial, 483 patients undergoing elective or emergency brain surgery were prospectively and randomly assigned either to intensive insulin therapy (241 patients), receiving insulin titrated to maintain blood glucose levels within the range of 4.44–6.11 mm, or to conventional insulin therapy (242 patients), receiving insulin to maintain blood glucose levels below 11.94 mm. Primary endpoint was incidence of hypoglycemia (defined as blood glucose < 2.78 mm). Efficacy measures included the length of ICU stay, infection rate, and 6 months follow-up Glasgow outcome scale score and overall survival. Results:Hypoglycemia episodes were more frequent in patients receiving intensive insulin therapy, median (min–max): 8 (0–23) versus 3 (0–4); P < 0.0001. The length of stay in the ICU was shorter (6 vs. 8 days; P = 0.0001), and the infection rate was lower (25.7% vs. 39.3%; P = 0.0018). Glasgow outcome scale score and overall survival at 6 months were similar in the two groups. Conclusions:Intensive insulin therapy in patients admitted to a postoperative neurosurgical ICU after brain surgery is associated with iatrogenic hypoglycemia, but it can also reduce the infection rate and shorten the ICU stay.

Cerebral Oxidative Stress and Depression of Energy Metabolism Correlate with Severity of Diffuse Brain Injury in Rats

OBJECTIVE:The combined effect of traumatic brain injury (TBI) and secondary insult on biochemical changes of cerebral tissue is not well known. For this purpose, we studied the time-course changes of parameters reflecting ROS-mediated oxidative stress and modifications of cell energy metabolism determined in rats subjected to cerebral insult of increasing severity. METHODS:Rats were divided into four groups: 1) sham-operated, 2) subjected to 10 minutes of hypoxia and hypotension (HH), 3) subjected to severe diffuse TBI, and 4) subjected to severe diffuse TBI + HH. Rats were killed at different times after injury, and analyses of malondialdehyde, ascorbate, high-energy phosphates, nicotinic coenzymes, oxypurines, nucleosides, and N-acetylaspartate (NAA) were made by high-performance liquid chromatography on whole-brain tissue extracts. RESULTS:Data indicated a close relationship between degree of oxidative stress and severity of brain insult, as evidenced by the highest malondialdehyde values and lowest ascorbate levels in rats subjected to TBI + HH. Similarly, modifications of parameters related to cell energy metabolism were modulated by increasing severity of brain injury, as demonstrated by the lowest values of energy charge potential, nicotinic coenzymes, and NAA and the highest levels of oxypurines and nucleosides recorded in TBI + HH rats. Both the intensity of oxidative stress-mediated cerebral damage and perturbation of energy metabolism were minimally affected in rats subjected to HH only. CONCLUSION:These results showed that the severity of brain insult can be graded by measuring biochemical modifications, specifically, reactive oxygen species-mediated damage, energy metabolism depression, and NAA, thereby validating the rodent model of closed-head diffuse TBI coupled with HH and proposing NAA as a marker with diagnostic relevance to monitor the metabolic state of postinjured brain.

Temporal window of metabolic brain vulnerability to concussions: oxidative and nitrosative stresses - part II

OBJECTIVE In the present study, we investigated the occurrence of oxidative and nitrosative stresses in rats undergoing repeat mild traumatic brain injury (mTBI) delivered with increasing time intervals. METHODS Rats were subjected to two diffuse mTBIs (450 g/1 m height), with the second mTBI delivered after 1 (n = 6), 2 (n = 6), 3 (n = 6), 4 (n = 6), or 5 days (n = 6). The rats were sacrificed 48 hours after the last mTBI. Sham-operated animals were used as controls (n = 6). Concentrations of biochemical indices of oxidative stress (malondialdehyde, ascorbic acid, reduced and oxidized glutathione) and nitrosative stress (nitrite, nitrate) were synchronously measured by high-performance liquid chromatography in deproteinized tissue extracts (three right + three left hemispheres for each group of animals). RESULTS Increase of malondialdehyde, reduced/oxidized glutathione ratio, nitrite, nitrate, and decrease of ascorbic acid and glutathione were dependent on the interval between impacts with maximal changes recorded when mTBIs were spaced by 3 days. Biochemical markers of oxidative and nitrosative stresses were near control levels only in animals receiving mTBIs 5 days apart. CONCLUSION This study shows the remarkable negative contribution of reactive oxygen species overproduction and activation of inducible nitric oxide synthase in repeat mTBI. Because these effects were maximal when mTBIs were spaced by 3 days, it can be inferred that occurrence of a second mTBI within the temporal window of brain vulnerability not only causes profound derangement of mitochondrial functions, but also induces sustained oxidative and nitrosative stresses. Both phenomena certainly play a major role in the overall brain tissue damage occurring under these pathological conditions.

Large sphenoid wing meningiomas involving the cavernous sinus: Conservative surgical strategies for better functional outcomes

OBJECTIVE:The ability to resect meningiomas that involve the medial and anterior compartments of the cavernous sinus has been refuted. In this retrospective study, we determined the efficacy of total resection of meningiomas that invade the cavernous sinus but are restricted to the lateral compartment. METHODS:We reviewed the charts of 38 consecutive patients with sphenocavernous, clinoidocavernous, and sphenoclinoidocavernous meningiomas who underwent surgical treatment. We assessed early and late cranial nerve morbidity, extent of resection, and long-term outcome (mean, 96 mo). RESULTS:In all patients, tumors exceeded 3 cm diameter. In 22 of 24 patients, total microscopic excision was achieved in tumors that involved only the lateral compartment of the cavernous sinus and touched or partially encased the cavernous internal carotid artery (i.e., modified Hirsch Grades 0 and 1, respectively). In 2 of 24 patients, remaining tumor infiltrated the superior orbital fissure. All 14 patients who had tumors that encased (with or without narrowing) the cavernous segment of the internal carotid artery (Hirsch Grades 2–4) underwent incomplete resection. Among 38 patients, mortality was 0%, late cranial nerve deficits remained in 6 (16%), and late Karnofsky Performance Scale scores exceeded 90 in 34 patients (90%). Four patients (10.5%) developed a recurrence or regrowth. Of 20 patients who were treated with either linear accelerator-based stereotactic radiosurgery or fractionated conformal radiotherapy, 11 had residual tumor and a moderate to high proliferative index, 4 had atypical tumors and 1 had angioblastic meningioma after total excision, 2 had regrowth, and 2 had recurrent tumors. In 18 (90%) of the 20 patients who underwent radiation, tumor size was reduced or controlled. CONCLUSION:On the basis of this study and a review of the literature, we demonstrate that sphenocavernous, clinoidocavernous, and sphenoclinoidocavernous meningiomas of Hirsch Grades 0 and 1 can be excised from the lateral compartment of the cavernous sinus without postoperative mortality and with acceptable rates of morbidity. Residual tumor in the medial compartment (Hirsch Grades 2–4) may be treated with some form of radiation therapy or observation.

Prognostic factors in intramedullary astrocytomas

This report presents a retrospective prognostic study of 65 patients with intramedullary astrocytoma surgically treated between 1953 and 1990. Median survival and statistical survival at 5 years were assessed in relation to clinical, histological and therapeutic factors for each patient. Results showed that factors positively influencing the prognosis are low histological grade of the tumour and good pre- and post-operative general conditions. Among the grade II astrocytomas, the fibrillary and protoplasmatic types presented longer survival times regardless of the type of removal performed. In anaplastic astrocytomas the simultaneous presence of certain morphological features indicative of higher malignancy negatively influenced survival. The degree of resection did not influence average survival within each histological grade.

Intraneural synovial cyst of the peroneal nerve: Report of two cases and review of the literature

We report two cases of peroneal nerve compression caused by an intraneural synovial cyst and discuss the pathogenesis, clinical and electrophysiological diagnosis, and treatment of these uncommon lesions in the light of the salient published work on the subject.