Indirect Spinal Canal Decompression Using Ligamentotaxis Compared With Direct Posterior Canal Decompression in Thoracolumbar Burst Fractures: A Prospective Randomized Study.

Background: There is still no standard of care to manage thoracolumbar burst fractures. With all the recent advances, posterior approaches are still one of the mainstays of treatment. On the other hand, while spinal canal decompression in neurological impaired patients is an important goal of treatment, its technique remains controversial.This study compared the effects of direct laminectomy decompression against ligamentotaxis/indirect canal decompression on neurological and radiographic improvements. Methods: A prospective double-blind randomized clinical trial was conducted on 60 thoracolumbar burst-fracture patients meeting our inclusion and exclusion criteria. They were randomized into 2 treatment arms: (1) direct decompression using laminectomy and (2) indirect decompression using ligamentotaxis/distraction. Each patient was observed for 6 months, and their neurological and radiographical data were collected prospectively. Statistical analysis was done by the Student t test, Friedman test, Mann Whitney-U test, Wilcoxon ranked test, and 1-way analysis of variance. Results: Among 60 patients enrolled in our study, each treatment arm had an improvement in Frankel scores but there was no difference between the groups at any given time. After 6 months of surgery, local sagittal kyphosis improved in both groups (from 32.2 to 7.43 and 29.93 to 8.77 for the indirect and direct groups, respectively), as well as anterior vertebral height ratio (from 57.73 to 70.7 and 62.17 to 66.27 for the indirect and direct group, respectively) and posterior vertebral height ratio (from 61.17 to 74.87 and 64 to 67.5 for the indirect and direct group, respectively). For between-group comparisons after 6 months, there was a significant difference only for posterior vertebral height ratio (P = 0.040). Conclusion: Posterior approaches with ligamentotaxis have shown to be safe and may present the same outcome as direct decompression techniques using wide laminectomy.

Quercetin mitigates anxiety-like behavior and normalizes hypothalamus-pituitary-adrenal axis function in a mouse model of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a major public health risk for developing anxiety-related disorders and hypothalamus-pituitary-adrenal (HPA) axis dysregulation in humans. Extensive research has shown that dietary intake or supplementation of the natural flavonoid quercetin might be useful for treating anxiety-related symptoms. The objectives of this study were to determine whether quercetin treatment can attenuate anxiogenic-like behaviors and normalize HPA axis function in mice with mTBI. Animals subjected to mTBI were treated daily with quercetin (50 mg/kg) or diazepam (positive control, 3 mg/kg) for 14 days. Four behavioral tests (open field, plus maze, light-dark box, and zero maze) were used to assess anxiety-related behaviors in mice. To evaluate HPA axis function, adrenocorticotropic hormone and corticosterone were measured in the serum of mice after the anxiety tests. Quercetin treatment was found to significantly reduce anxiety-like behaviors in mTBI-induced mice. A strength of this study is the consistency of results among anxiety tests. The dysregulation of the HPA axis in mTBI-induced mice treated with quercetin was also attenuated, with decreased levels of adrenocorticotropic hormone and corticosterone. The effects of quercetin were comparable with those of diazepam treatment. Taken together, these results suggest that quercetin might be useful for treating anxiety-related symptoms and HPA axis hyperreactivity in patients with mTBI.

The blockade of corticotropin-releasing factor 1 receptor attenuates anxiety-related symptoms and hypothalamus-pituitary-adrenal axis reactivity in mice with mild traumatic brain injury.

Recent studies have shown that mild traumatic brain injury (mTBI) is associated with higher risk for anxiety-related disorders. Dysregulation in the hypothalamus-pituitary-adrenal (HPA) axis following mTBI has been proposed to be involved in the development of neurobehavioral abnormalities; however, the underlying mechanisms are largely unknown. The aim of this study was to determine whether the corticotropin-releasing-factor-1 (CRF-1) receptor is involved in the regulation of anxiety-related symptoms in a mouse model of mTBI. Animals with or without mTBI received intracerebroventricular injections of a CRF-1 receptor agonist (CRF; 0.01 nmol/mouse) or antagonist (antalarmin; 1 µg/mouse) for 5 days, and then the animals were subjected to anxiety tests (light-dark box and zero maze). The levels of adrenocorticotropic hormone and corticosterone, the most important markers of HPA axis, were also measured after behavioral tests. Our results indicated that mTBI-induced anxiety-related symptoms in mice through increased levels of adrenocorticotropic hormone and corticosterone, showing HPA axis hyperactivity. Interestingly, activation of CRF receptor by a subthreshold dose of CRF resulted in significant increases in anxiety-like behaviors and HPA axis response to stress, whereas blockade of CRF receptors by a subthreshold dose of antalarmin decreased anxiety-related symptoms and HPA axis response to stress in mTBI-induced mice. Collectively, these findings suggest that the CRF-1 receptor plays an important role in the regulation of anxiety-related behaviors following mTBI induction in mice and support the hypothesis that blockade of the CRF-1 receptor may be a promising therapeutic target for anxiety-related disorders in patients with TBI.

Serotonin 5-HT1A receptors modulate depression-related symptoms following mild traumatic brain injury in male adult mice.

Traumatic brain injury is a complex phenomenon leading to neurological diseases and persistent disability that currently affects millions of people worldwide. Increasing evidence shows that a wide range of patients with mild traumatic brain injury (mTBI) suffer from depression during the initial stages of injury and the post-acute stages of recovery. However, the underlying mechanisms involved in depression following mTBI are still not fully understood. The aim of this study was to determine whether serotonin 5-hydroxytryptamine-1A (5-HT1A) receptor is involved in the regulation of depression-related behaviors following mild traumatic brain injury in mice. Mice with or without mTBI received intracerebroventricular injections of 5-HT1A receptor agonist (8-OH-DPAT) or antagonist (WAY-100635) for 5 days, then animals were subjected to behavioral tests. Four behavioral tests including novelty-suppressed feeding test, forced swim test, sucrose preference test and tail suspension test were used to evaluate depression-related symptoms in animals. Our results indicated that mTBI induction increased depression-like symptoms through altering serotonin 5-HT1A receptor activity in the brain. Activation of 5-HT1A receptor by a subthreshold dose of 8-OH-DPAT led to a significant decrease in depression-like behaviors, whereas blockade of 5-HT1A receptor by a subthreshold dose of WAY-100635 resulted in a considerable increase in depression-like phenotypes in mTBI-induced mice. The major strength of the present study is that depression-related symptoms were assessed in four behavioral tests. The present study supports the idea that disturbances in the function of serotonergic system in the brain following mTBI can play an important role in the regulation of depression-related behaviors.

Anxiolytic- and antidepressant-like effects of Silymarin compared to diazepam and fluoxetine in a mouse model of mild traumatic brain injury.

Clinical and experimental studies have shown that mild traumatic brain injury (mTBI) is associated with increased anxiety- and depression-related behaviors and inflammation in the brain. Unfortunately, there are no specific therapies for long-term behavioral consequences of mTBI. This study set out to determine whether silymarin treatment compared to diazepam (DZP) and fluoxetine (FLX) can reduce neuroinflammation, anxiety- and depression-like behaviors after mTBI induction in mice. We used open field, elevated plus maze, light-dark box, zero maze, sucrose preference, forced swim, and tail suspension tests to assess anxiety and depression-like behaviors in mTBI-induced mice. The levels of tumor necrosis factor (TNF)-α protein, a marker of inflammation, in the prefrontal cortex and hippocampus was also measured. This study identified that the long-term treatment with DZP, FLX or SIL results in decreased anxiety and depression-like behaviors in mTBI-induced mice. The results also showed that these drugs reduced TNF-α levels in the prefrontal cortex and hippocampus. In addition, there were no significant differences between the effects of SIL and DZP or SIL and FLX on behavioral and cytokine levels in mTBI-induced mice. Our findings support the idea that mTBI could be a risk factor for anxiety- and depression-related disorders and neuroinflammation in the brain. Taken together, this study demonstrates that DZP, FLX or SIL can significantly reduce anxiety- and depression-like symptoms, and neuroinflammation after mTBI induction in mice.

A comprehensive review of the clivus: anatomy, embryology, variants, pathology, and surgical approaches.

INTRODUCTION: The clivus is a bony structure formed by the fusion of the basioccipital and basispheniod bone at the sphenooccipital synchondrosis. This downward sloping structure from the dorsum sellae to the foramen magnum is derived from mesoderm and ectoderm properties. METHODS: This comprehensive review of the clivus will discuss its basic anatomy, embryology, pathological findings, and surgical implications. The clivus is an endochondral bone, formed under two processes; first, a cartilaginous base is developed, and it is secondly reabsorbed and replaced with bone. Knowledge of its embryological structure and growth of development will clarify the pathogenesis of anatomical variants and pathological findings of the clivus. CONCLUSIONS: Understanding the anatomy including proximity to anatomical structures, adjacent neurovasculature properties, and anatomical variants will aid neurosurgeons in their surgical management when treating pathological findings around the clivus.

A comprehensive review with potential significance during skull base and neck operations, Part II: glossopharyngeal, vagus, accessory, and hypoglossal nerves and cervical spinal nerves 1-4.

Knowledge of the possible neural interconnections found between the lower cranial and upper cervical nerves may prove useful to surgeons who operate on the skull base and upper neck regions in order to avoid inadvertent traction or transection. We review the literature regarding the anatomy, function, and clinical implications of the complex neural networks formed by interconnections between the lower cranial and upper cervical nerves. A review of germane anatomic and clinical literature was performed. The review is organized into two parts. Part I discusses the anastomoses between the trigeminal, facial, and vestibulocochlear nerves or their branches and other nerve trunks or branches in the vicinity. Part II deals with the anastomoses between the glossopharyngeal, vagus, accessory and hypoglossal nerves and their branches or between these nerves and the first four cervical spinal nerves; the contribution of the autonomic nervous system to these neural plexuses is also briefly reviewed. Part II is presented in this article. Extensive and variable neural anastomoses exist between the lower cranial nerves and between the upper cervical nerves in such a way that these nerves with their extra-axial communications can be collectively considered a plexus.

Anastomoses between lower cranial and upper cervical nerves: a comprehensive review with potential significance during skull base and neck operations, part I: trigeminal, facial, and vestibulocochlear nerves.

Descriptions of the anatomy of the neural communications among the cranial nerves and their branches is lacking in the literature. Knowledge of the possible neural interconnections found among these nerves may prove useful to surgeons who operate in these regions to avoid inadvertent traction or transection. We review the literature regarding the anatomy, function, and clinical implications of the complex neural networks formed by interconnections among the lower cranial and upper cervical nerves. A review of germane anatomic and clinical literature was performed. The review is organized in two parts. Part I concerns the anastomoses between the trigeminal, facial, and vestibulocochlear nerves or their branches with any other nerve trunk or branch in the vicinity. Part II concerns the anastomoses among the glossopharyngeal, vagus, accessory and hypoglossal nerves and their branches or among these nerves and the first four cervical spinal nerves; the contribution of the autonomic nervous system to these neural plexuses is also briefly reviewed. Part I is presented in this article. An extensive anastomotic network exists among the lower cranial nerves. Knowledge of such neural intercommunications is important in diagnosing and treating patients with pathology of the skull base.

Cranioplasty in medieval Persia and the potential spread of this knowledge to Europe.

INTRODUCTION: Skull trepanation is an ancient and often religious act found in remains from around the world. However, cranioplasty for the surgical treatment of skull pathologies is a relatively recent phenomenon. In this paper, we focus on the account of skull injury and cranioplasty in medieval Persia. MATERIALS AND RESULTS: Herein, we describe and translate the over 500-year-old writings of the Persian physician Baha al-Dowleh Razi regarding cranioplasty in an excerpt from his book entitled Khulasat al-Tajarib (Summary of Experiences). This early writer detailed the methods and indications for cranioplasty including the use of xenographs. Additionally, we attempt to trace this early understanding of skull surgery and follow its possible spread to Europe. CONCLUSIONS: It is such early experiences and methods of cranial surgery on which we base our current understanding of neurosurgery.

Rabi Rashidi (Rashidi Quarters): a late thirteen to early fourteenth century Middle Eastern Medical School.

INTRODUCTION: Following the Mongolian invasion of the Middle East in the thirteenth century, a regional power called the Ilkhanid emerged and was ruled by the heirs of Temujin from Mongolia. Embracing present-day Iran, Iraq, Afghanistan, Azerbaijan, areas of Russia, Turkey, and Pakistan, and nearby Middle Eastern territories, the Ilkhanid state patronized medicine and various other professions. Centered in Tabriz (Tauris), a city in the northwest of present-day Iran, was a non-profit-making educational and medical complex founded by Grand Minister Rashid al-Din Fazlollah Hamadani. METHODS: This paper reviews the literature regarding the rise and fall of the thirteenth century university and the Rabi Rashidi, emphasizing the structure of its medical school. CONCLUSIONS: The background training of Rashid al-Din and his keen interest in science turned this complex, Rabi Rashidi (literally meaning the Rashidi Quarters), into a cosmopolitan university that freely trained medical scholars nationally and internationally. The possibility that Rashid al-Din was inspired by university developments in Europe is discussed.

The role of cross-link augmentation on fusion rate and patient satisfaction among patients with traumatic thoracolumbar spinal fracture: A randomized clinical trial.

INTRODUCTION AND OBJECTIVES: Most of the studies evaluating the effect of cross links on spinal stability are performed in vitro on porcine or human spine segments and there is limited data regarding clinical benefits of cross link augmentation in traumatic injuries. In this study we aimed to evaluate the effects of cross-links insertion between rods on the fusion rates and post-surgical patients' satisfaction among patients with traumatic thoracolumbar fractures who underwent posterior spinal fixation with pedicle screws. MATERIALS AND METHODS: This study was conducted as a randomized clinical trial on 60 patients suffering from traumatic thoracolumbar vertebrae fractures. Patients were randomized into three groups: A (without any cross-link), B (One cross-link insertion) and C (two cross-links insertion). Six months after surgery outcomes were evaluated: fusion rates (plain X-ray and CT scan), Back pain (Visual Analog Scale) and patient satisfaction (fair, good, excellent). RESULTS: In group A 13 (65%) patients had structured bone fusion, but in 7 (35%) patients bone fusion was not observed. In both groups B and C, 19 patients (95%) had bone fusion, but only in 1 patient (5%) fusion failed (p=0.009). In group A, fair satisfaction has the highest rate (8 patients (40%)) compared to the other groups. The highest reported severity of back pain was observed in group A while the lowest reported intensity of back pain was related to group B (p=0.001). CONCLUSIONS: Adding cross link to posterior spinal fixations of patients with traumatic thoracolumbar fractures can be associated with better final fusion results and patients' satisfaction. However it is necessary to design studies with greater sample sizes to confirm this theory. TRIAL REGISTRATION NUMBER: IRCT20120527009878N3.

The role of cross-link augmentation on fusion rate and patient satisfaction among patients with traumatic thoracolumbar spinal fracture: A randomized clinical trial.

INTRODUCTION AND OBJECTIVES: Most of the studies evaluating the effect of cross links on spinal stability are performed in vitro on porcine or human spine segments and there is limited data regarding clinical benefits of cross link augmentation in traumatic injuries. In this study we aimed to evaluate the effects of cross-links insertion between rods on the fusion rates and post-surgical patients' satisfaction among patients with traumatic thoracolumbar fractures who underwent posterior spinal fixation with pedicle screws. MATERIALS AND METHODS: This study was conducted as a randomized clinical trial on 60 patients suffering from traumatic thoracolumbar vertebrae fractures. Patients were randomized into three groups: A (without any cross-link), B (One cross-link insertion) and C (two cross-links insertion). Six months after surgery outcomes were evaluated: fusion rates (plain X-ray and CT scan), Back pain (Visual Analog Scale) and patient satisfaction (fair, good, excellent). RESULTS: In group A 13 (65%) patients had structured bone fusion, but in 7 (35%) patients bone fusion was not observed. In both groups B and C, 19 patients (95%) had bone fusion, but only in 1 patient (5%) fusion failed (p=0.009). In group A, fair satisfaction has the highest rate (8 patients (40%)) compared to the other groups. The highest reported severity of back pain was observed in group A while the lowest reported intensity of back pain was related to group B (p=0.001). CONCLUSIONS: Adding cross link to posterior spinal fixations of patients with traumatic thoracolumbar fractures can be associated with better final fusion results and patients' satisfaction. However it is necessary to design studies with greater sample sizes to confirm this theory. TRIAL REGISTRATION NUMBER: IRCT20120527009878N3.

Silymarin sex-dependently improves cognitive functions and alters TNF-α, BDNF, and glutamate in the hippocampus of mice with mild traumatic brain injury.

AIMS: Mild traumatic brain injury (mTBI) is an important risk factor for cognitive impairment. Despite intense efforts to develop efficient treatments, the current therapies are not often effective and far from satisfactory. Silymarin has been suggested as a therapeutic agent in the treatment of traumatic brain injury. This study aimed to determine whether silymarin can exert neuroprotective effects on memory impairment following mTBI in mice. MAIN METHODS: After mTBI induction, mice were treated with silymarin once daily for 20 consecutive days by oral gavage. To investigate cognitive functions, animals were subjected to Y-maze, novel-object recognition, and Morris-water maze. Levels of tumor necrosis factor (TNF)-α, glutamate, and brain derived neurotrophic factor (BDNF) were measured in the hippocampus. KEY FINDINGS: Our findings showed that mTBI resulted in a significant decline in memory in the Y-maze and Morris-water maze in both sexes, whereas only impaired cognitive function in males in the novel-object recognition. We found notable increases in TNF-α and glutamate levels in the hippocampus of both sexes, while there was only a significant decrease in hippocampal BDNF in mTBI-induced females. In addition, silymarin treatment improved cognitive impairments in mTBI-induced males but not in females. Silymarin significantly reduced TNF-α and glutamate levels, and increased BDNF levels in the hippocampus of mTBI-induced male but not in female mice. SIGNIFICANCE: This study demonstrates that silymarin treatment sex-dependently improves cognitive impairment in mTBI-induced mice, and suggests that silymarin may be a therapeutic agent for cognitive decline following mTBI in males. Further studies are needed to establish the validity of these findings in humans.

The contralateral long thoracic nerve as a donor for upper brachial plexus neurotization procedures: cadaveric feasibility study.

OBJECT: Various donor nerves, including the ipsilateral long thoracic nerve (LTN), have been used for brachial plexus neurotization procedures. Neurotization to proximal branches of the brachial plexus using the contralateral long thoracic nerve (LTN) has, to the authors' knowledge, not been previously explored. METHODS: In an attempt to identify an additional nerve donor candidate for proximal brachial plexus neurotization, the authors dissected the LTN in 8 adult human cadavers. The nerve was transected at its distal termination and then passed deep to the clavicle and axillary neurovascular bundle. This passed segment of nerve was then tunneled subcutaneously and contralaterally across the neck to a supra- and infraclavicular exposure of the suprascapular and musculocutaneous nerves. Measurements were made of the length and diameter of the LTN. RESULTS: All specimens were found to have a LTN that could be brought to the aforementioned contralateral nerves. Neural connections remained tension free with left and right neck rotation of approximately 45 degrees . The mean length of the LTN was 22 cm with a range of 18-27 cm. The overall mean diameter of this nerve was 3.0 mm. No gross evidence of injury to surrounding neurovascular structures was identified in any specimen. CONCLUSIONS: Based on the results of this cadaveric study, the use of the contralateral LTN may be considered for neurotization of the proximal musculocutaneous and suprascapular nerves.

Surgical and anatomical landmarks for the perineal branch of the posterior femoral cutaneous nerve: implications in perineal pain syndromes. Laboratory investigation.

OBJECT: The perineal branch of the posterior femoral cutaneous nerve (PBPFCN) has received little attention in the literature. Because perineal pain syndromes can be disabling and pudendal nerve surgical decompression/block is often not efficacious, an anatomical study of this cutaneous nerve of the perineum seemed warranted. METHODS: The authors dissected 20 adult cadavers (40 sides) to identify the branching pattern and landmarks for the PBPFCN. RESULTS: This branch arose directly from the posterior femoral cutaneous nerve in 55% of sides and from the inferior cluneal nerve in 30% of sides. It was absent in 15% of sides. On average, the nerve coursed 4 cm inferior to the termination of the sacrotuberous ligament onto the ischial tuberosity. No PBPFCN was found to pierce the sacrotuberous ligament. The PBPFCN provided 2-3 branches to the medial thigh that continued on to the scrotum and labia major. In general, 2 small ascending branches were identified. In males, one ascending branch traveled inferior to the corpora cavernosum and anterior to the spermatic cord to cross the midline. The other ascending branch traveled to skin at the junction of the perineum and adductor tendon. A single descending branch, approximately 2 mm in diameter, traveled to the inferior scrotum anterior to the testicle in the male specimens and the lower labia majora in the female specimens. Communications between the PBPFCN and the perineal branch of the pudendal nerve were common. CONCLUSIONS: Entrapment of the PBPFCN may be the cause of some forms of the perineal pain syndrome. Specific knowledge of the PBPFCN may assist surgeons in releasing and anesthetizing this cutaneous nerve of the perineum.

The petrosal nerves: anatomy, pathology, and surgical considerations.

The literature lacks a comprehensive review of the petrosal nerves, which often have a complicated course and nomenclature. The medical literature was reviewed comprehensively for information regarding the anatomy, pathology, and surgery of the petrosal nerves. The terminology and anatomy of the petrosal nerves are often complicated. Our review found multiple nomenclatures used in the description of these structures. Information regarding the petrosal nerves may assist those who observe or operate at or near the skull base. To our knowledge, this is the first comprehensive review of these structures.

Minocycline prevents the development of depression-like behavior and hippocampal inflammation in a rat model of Alzheimer's disease.

RATIONALE: Considerable clinical and experimental studies have shown that depression-related disorders are the most common neuropsychiatric symptoms in Alzheimer's disease (AD), affecting as many as 20-40% of patients. An increasing amount of evidence shows that monoamine-based antidepressant treatments are not completely effective for depression treatment in patients with dementia. Minocycline, a second-generation tetracycline antibiotic, has been gaining research and clinical attention for the treatment of different neuropsychiatric disorders, and more recently depression symptom in humans. METHODS: In the present study, we investigated the effects of Aß1-42 administration alone or in combination with minocycline treatment on depression-like behaviors and anti/pro-inflammatory cytokines such as interleukin(IL)-10, IL-ß, and tumor necrosis factor (TNF)-α in the hippocampus of rats. RESULTS: Our results showed that Aß1-42 administration increased depression-related behaviors in sucrose preference test, tail suspension test, novelty-suppressed feeding test, and forced swim test. We also found significant increases in IL-1ß and TNF-α levels in the hippocampus of Aß1-42-treated rats. Interestingly, minocycline treatment significantly reversed depression-related behaviors and the levels of hippocampal cytokines in Aß1-42-treated rats. CONCLUSION: These findings support the idea that there is a significant relationship among AD, depression-related symptoms, and pro-inflammatory cytokines in the brain, and suggest that antidepressant-like impacts of minocycline could be due to its anti-inflammatory properties. This drug could be of potential interest for the treatment of depression in patients with Alzheimer's disease.

Insertion of the pectoralis major into the shoulder joint capsule.

The pectoralis major muscle is subject to various morphologies. One presumably very rare variation is insertion of this muscle into the shoulder joint. During the routine dissection of the right upper extremity of an adult male cadaver a distinct separate tendinous insertion into the shoulder joint capsule was identified. This vertical tendon (7 mm x 6 cm) traveled just lateral to the long head of the biceps brachii muscle and terminated into the fibrous aspect of the joint capsule without penetrating it. Mechanical traction on the humeral attachment of the pectoralis major resulted in anteroinferior displacement of the shoulder joint capsule. The possible embryologic origin of this variation is discussed. Clinicians may wish to consider potential attachment of the pectoralis major into the capsule of the shoulder joint in diagnosing pathology of this region.

François Magendie (1783-1855) and his contributions to the foundations of neuroscience and neurosurgery.

François Magendie lived during a tumultuous period in French history. Although this early medical pioneer made significant contributions to the fields of neuroanatomy, physiology, and pharmacology, little information is found in the non-French literature regarding this significant person in history. Based on this review, one could also consider this trained surgeon as an early pioneer of neurosurgery. For example, he is known to have used Galvanic current to treat various neuralgias, described a technique for extracting cerebrospinal fluid and quantitated and described its characteristics in normal and pathological specimens, and elucidated the functions of the the cranial nerves using vivisection. Additionally, he accurately described the functions of the dorsal and ventral rootlets using vivisection, and realized that the exposed meninges were susceptible to painful stimuli. Our current knowledge is based on the early contributions of scientists such as François Magendie.

The potential role of carbon dioxide in the neuroimmunoendocrine changes following cerebral ischemia.

Carbon dioxide (CO(2)) interacts in complex ways with the brain and the endocrine and immune systems. Arterial CO(2) may be elevated or decreased following cerebral ischemia-reperfusion injury or stroke. The aim of the present review is to delineate potential changes in the neuroimmunoendocrine system following cerebral ischemia-reperfusion injury and to provide evidence for the modulatory role of carbon dioxide in this setting. It appears that lesions of the right and left cerebral hemispheres are associated with different patterns of immune activation and cytokine release. Changes in arterial CO(2) can profoundly alter the neuroimmunoendocrine system, especially the hypothalamic-pituitary-adrenal (HPA) axis and the production of pro-inflammatory cytokines. Hypercapnia activates the HPA axis, exerts antiinflammatory and antioxidant effects, and can alter the secretion and function of various brain neurotransmitters. There is conflicting evidence surrounding arterial CO(2): its effects on the ischemic brain may be either beneficial or deleterious. Mild hypercapnia may exert some neuroprotection following cerebral ischemia, but severe hypercapnia may aggravate neuronal injury by extra- and intra-cellular acidification and/or impairment of cellular calcium hemostasis. Future studies are required to delineate the potential relationship between arterial CO(2) and prognosis and long-term survival following cerebral ischemia-reperfusion injury. "Therapeutic hypercapnia" seems to be a promising approach to the treatment of stroke patients, and its use should be justified by further experimental and clinical studies.