Marco Cimatti

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.

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.

Hypothesis of the postconcussive vulnerable brain: Experimental evidence of its metabolic occurrence

OBJECTIVE:We evaluated the effects of two consecutive concussive injuries on brain energy metabolism and N-acetylaspartate (NAA) to investigate how the temporal interval between traumatic events influences overall injury severity. METHODS:Rats were injured to induce diffuse traumatic brain injury (TBI) (mild, 450 g/1 m; severe, 450 g/2 m). In two groups, two mild TBIs were delivered in 3- or 5-day intervals. Three additional animal groups were used: single mild TBI, single severe TBI, and sham. All animals were killed 48 hours postinjury. Adenosine 5′-triphosphate (ATP), adenosine diphosphate, and NAA concentrations were analyzed with high-performance liquid chromatography on deproteinized whole brain extracts. RESULTS:In control animals, the NAA concentration was 9.17 ± 0.38 &mgr;mol/g wet weight, the ATP concentration was 2.25 ± 0.21 &mgr;mol/g wet weight, and the ATP-to-adenosine diphosphate ratio was 9.38 ± 1.23. These concentrations decreased to 6.68 ± 1.12 &mgr;mol/g wet weight, 1.68 ± 0.24 &mgr;mol/g wet weight, and 6.10 ± 1.21 &mgr;mol/g wet weight, respectively, in rats that received two mild TBIs at a 5-day interval (P < 0.01; not different from results in rats with single mild TBI). When a second TBI was delivered after 3 days, the NAA concentration was 3.86 ± 0.53 &mgr;mol/g wet weight, the ATP concentration was 1.11 ± 0.18 &mgr;mol/g wet weight, and the ATP-to-adenosine diphosphate ratio was 2.64 ± 0.43 (P < 0.001 versus both controls and 3-day interval; not different from rats receiving a single severe TBI). CONCLUSION:The biochemical modification severity in double TBI is dependent on the interval between traumatic events, which demonstrates the metabolic state of the vulnerable brain after mild TBI. These data support the hypothesis of the application of proton magnetic resonance spectroscopy to measure NAA as a possible tool to monitor the full recovery of brain metabolic functions in the clinical setting, particularly in sports medicine.

Extremely delayed cerebral metastasis from renal carcinoma: report of four cases and critical analysis of the literature.

Brain metastases from renal carcinoma may appear even a long time after surgical treatment of the primary tumor. The authors present 2 series of patients, one of which has already been published and the other new, for a total of 4 cases of brain metastasis from renal carcinoma with late onset, which occurred 13, 17, 26 and 12 years after primary surgical treatment. The other cases described in the literature were also critically reviewed.

Post-traumatic intracranial meningiomas.

The authors present 20 cases of likely post-traumatic intracranial meningiomas selected according to the conditions specified in the relevant literature. The relationship between head injury and subsequent development of meningioma remains a controversial and fascinating subject. The etiopathogenetic mechanisms and clinical features of our patients and those of the literature are discussed.

The Real Impact of an Intraoperative Magnetic Resonance Imaging–Equipped Operative Theatre in Neurovascular Surgery: The Sapienza University Experience

The fundamental role of technological instruments in contemporary Neurosurgery is undisputed, and intraoperative magnetic resonance imaging (MRI) represents one of the best examples. The use of a modern high-field magnet and the possibility to match the MRI with an operative microscope and an integrated neuronavigation system has led to successful results in the surgical treatment of different diseases. At our institute, we have performed surgery routinely with the aid of intraoperative MRI over the last 15 years. The aim of this article is to report our experience in the management of neurovascular lesions with the use of this device. We experienced that intraoperative MRI enhanced the surgical experience, leading to an improved postoperative outcome in the treatment of different lesions, such as arteriovenous malformations, dural arteriovenous fistulas, intracranial cavernous angiomas, and intracranial aneurysms. There are several advantages provided by the use of intraoperative MRI. The use of intraoperative MRI coupled with the planning station and the neuronavigation system allows one to obtain preoperative 3-dimensional reconstructions of the vessels, which aids the definition of the anatomy of each neurovascular lesion. Furthermore, the possibility performing an intraoperative scan allows a comparison with preoperative images and, subsequently, the updating of the surgical strategy. Intraoperative diffusion-weighted imaging can detect possible territorial ischemia that would be amenable to intensive treatment. Although increased costs, increased surgical times, increased anesthesiology times, and the possible increased risk of surgical infection may represent some major limitation, the use of intraoperative MRI-equipped operative theaters with integrated neuronavigation systems can prove extremely helpful in the management of neurovascular conditions.

Completely Thrombosed Distal Middle Cerebral Artery Aneurysm Mimicking a Cavernous Angioma: Case Report and Review of the Literature

BACKGROUND Distal middle cerebral artery (MCA) aneurysms originate from branches of MCA distal to its main bifurcation or the peripheral branches. Distal MCA aneurysms are uncommon compared with saccular aneurysms, which develop along the proximal trunks of MCA. However, thrombotic aneurysms, characterized by organized intraluminal thrombus and solid mass, are frequently in the large and giant size range, whereas complete thrombosis of non-giant MCA aneurysms is very rare. CASE PRESENTATION We present the clinical case of a 53 years-old woman with a completely thrombosed medium distal MCA aneurysm mimicking a cavernous angioma. She came to our emergency department after the onset of tinnitus and persistent headache. Magnetic resonance imaging performed subsequently showed a nodular mass surrounded by edema located in the temporal lobe with a homogeneous peripheral contrast enhancement. Furthermore, angiography showed regular flow in the MCA and confirmed the diagnosis of cavernous angioma. The patient underwent surgery, and the lesion was found to be a thrombosed aneurysm originating from the distal temporal branch of the left MCA (M2 segment). CONCLUSIONS To our knowledge, this is the first report of a thrombosed distal medium MCA aneurysm that mimicked a cavernous angioma. The completely thrombosed aneurysm can be confused with intracranial lesions or cavernous malformations, which can have similar radiographic features without angiographic anomalies, so it is mandatory to consider the possibility of a thrombosed aneurysm for a correct differential diagnosis.

Adult Spinal Deformity in the Elderly. Preliminary Clinical and Radiological Results in 22 Patients Treated by a Two Times Minimally Invasive Spine Surgery

Introduction The adult spinal deformity (ASD) seems, in the last years, in a progressive increment. It should be in relation to the aging of the population. This trend leads to a progression of the disability and the reduction of the quality of life of these patients. The surgical correction of the ASD obtained by a traditional “open” surgery can often be incompatible with the co-morbidities of these patients. The minimally invasive surgery for correction of the deformities (MISDEF) can offer technical nuances, such as reduce of intraoperative blood loss and quickly recovery, which can lead the opportunities for these patients to approach the surgery. We present the preliminary results of our observational study on the radiological correction and clinical results of old patients affected by ASD treated by MISDEF. Methods Observational study with 20 months of follow-up. Twelve patients affected by low-back pain, sciatalgia and/cruralgia, neurological claudication were enrolled in this study. All the patients underwent to a MISDEF based on a percutaneous transpedicular stabilization plus a lateral or transforaminal interbody fusion. We collected all the radiological datas, such as sagittal vertical axis (SVA), sacral slope (SS), pervic tilt (PT), pelvic incidence (PI), lumbar lordosis (LL) and coronal cob (CC) and the clinical status, oswestry disability index (ODI) and SF-36. Results The mean age was 70 years (65 – 78 years), 3 men and 9 women. 7 patients presented a lumbar left side convex scoliosis, while 5 patients presented a right side one. All the patients underwent to a 2 times surgery: the first time was a lateral access, the second time was the posterior access. The side for the lateral interbody fusion was the concave side of the scoliosis. L4L5 segment was always been approached for a transforaminal interbody fusion. The proximal strumental vertebra was T10. The mean intraoperative blood loss was 500 cc. All the patients were mobilized within 2 days. The ODI and SF36 evidenced a statistically improvement (p < 0,05). No evidence of infections, neurological deficit, failure of the implant and/or loosening of correction were documented in the follow up. Conclusions The MISDEF offers, even for elderly patients with co-morbidities, a valid and secure surgical solution for the correction of the ASD. From the results of our study appeared a good compliance of these techniques for all the patients, with a good result even at 20 months of follow-up. We considered that the opportunity to separate the surgical correction of the deformity in 2 times surgery seems to be a better and secure solution especially for elderly patients.

Primary Lymphomas of the Skull Base from a Neurosurgical Perspective: Review of the Literature and Personal Experience

Abstract Primary lymphomas of the skull base are exceedingly rare and thus not commonly dealt with in everyday clinical practice. Primary diffuse large B cell lymphoma is the most commonly found (30‐40% of primary non‐Hodgkin lymphomas of the bone). This article reports a case of primary lymphoma of the skull base and reviews all the relevant literature in the PubMed, National Institutes of Health Library, and Google Scholar databases to outline the clinical, diagnostic, and surgical traits of this yet widely unexplored pathology. The incidence of cases peaks between 60 and 70 years of age; those affected tend to be mostly male. The clinical presentation of this pathology is usually abrupt with headache and acute deficit of cranial nerves that improves dramatically with intravenous corticosteroid therapy. The abducens nerve is most commonly involved. Imaging can be unclear because corticosteroid medications can significantly alter magnetic resonance imaging findings, at least in the early stages of the disease, similarly to what happens for primary brain lymphomas (“the ghost tumor”). Cavernous sinus, parasellar region, upper clivus, and Meckel cave are usually found to be already affected by the time a diagnosis can be made. The intracavernous internal carotid artery is usually encased by the lesion rather than displaced. Because of the anatomical pattern of primary lymphomas of the skull base and their well‐known chemosensitivity, surgery is usually only used for diagnosis. Surgical approaches for primary lymphoma of the skull base include transcranial and transnasal‐transsphenoidal endoscopy and microsurgery as well as other minimally invasive techniques. Due to the rarity of this neoplasm, there are no definitive data regarding the overall survival rate among patients.