Paul G. Matz

Heme-oxygenase-1 induction in glia throughout rat brain following experimental subarachnoid hemorrhage

The heme released following subarachnoid hemorrhage is metabolized by heme-oxygenase (HO) to biliverdin and carbon monoxide (CO) with the release of iron. The HO reaction is important since heme may contribute to vasospasm and increase oxidative stress in cells. HO is comprised of at least two isozymes, HO-2 and HO-1. HO-1, also known as heat shock protein HSP32, is inducible by many factors including heme and heat shock. HO-2 does not respond to these stresses. To begin to examine HO activity following subarachnoid hemorrhage (SAH), the expression of HO-1 and HO-2 was investigated after experimental SAH in adult rats. Immunocytochemistry for HO-1, HO-2 and HSP70 proteins was performed at 1, 2, 3 and 4 days after injections of lysed blood, whole blood, oxyhemoglobin and saline into the cisterna magna. A large increase in HO-1 immunoreactivity was seen in cells throughout brain following injections of lysed blood, whole blood, and oxyhemoglobin but not saline. Lysed blood, whole blood and oxyhemoglobin induced HO-1 in all of the cortex, hippocampus, striatum, thalamus, forebrain white matter and in cerebellar cortex. HO-1 immunoreactivity was greatest in those regions adjacent to the basal subarachnoid cisterns where blood and oxyhemoglobin concentrations were likely highest. Double immunofluorescence studies showed the HO-1 positive cells to be predominately microglia, though HO-1 was induced in some astrocytes. HO-1 expression resolved by 48 h. HO-2 immunoreactivity was abundant but did not change following injections of blood. A generalized induction of HSP70 heat shock protein was not observed following injections of lysed blood, whole blood, oxyhemoglobin, or saline. These results suggest that HO-1 is induced in microglia throughout rat brain as a general, parenchymal response to the presence of oxyhemoglobin in the subarachnoid space and not as a stress response. This microglial HO-1 response could be protective against the lipid peroxidation and vasospasm induced by hemoglobin, by increasing heme clearance and iron sequestration, and enhancing the production of the antioxidant bilirubin.

Heme Oxygenase-1 is Induced in Glia Throughout Brain by Subarachnoid Hemoglobin

The heme oxygenase-1 gene, HO-1, induced by heme, ischemia, and heat shock, metabolizes heme to biliverdin, free iron, and carbon monoxide. Though the distribution of HO-1 has been described in normal rat brain, little is known about how extracellular heme proteins in the subarachnoid space distribute in brain. To address this issue, hemoglobin was injected into the cisterna magna of adult rats. Expression of HO-1 in these animals was compared with saline-injected, BSA-injected, and uninjected controls. Western blot analysis showed that 24 hours after injection oxyhemoglobin increased HO-1 levels approximately four- to fivefold in all brain regions studied compared with saline-injected and BSA-injected controls. In the brain, HO-1 immunoreactivity was evident at 4 hours and peaked at 24 hours after oxyhemoglobin injections, returning to control levels by 4 to 8 days. This HO-1 induction was detected mainly in cells with small, rounded somas bearing two to four truncated processes, a morphology consistent with that of microglia. These cells were double-stained with the microglial marker, OX42, in every brain region examined. It is proposed that subarachnoid hemoglobin may be taken up into microglia wherein heme induces HO-1.

The natural history of cervical spondylotic myelopathy

OBJECT The objective of this systematic review was to use evidence-based medicine to delineate the natural history of cervical spondylotic myelopathy (CSM) and identify factors associated with clinical deterioration. METHODS The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to the natural history of CSM. Abstracts were reviewed and studies meeting the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. RESULTS The natural history of CSM is mixed: it may manifest as a slow, stepwise decline or there may be a long period of quiescence (Class III). Long periods of severe stenosis are associated with demyelination and may result in necrosis of both gray and white matter. With severe and/or long lasting CSM symptoms, the likelihood of improvement with nonoperative measures is low. Objectively measurable deterioration is rarely seen acutely in patients younger than 75 years of age with mild CSM (modified Japanese Orthopaedic Association scale score > 12; Class I). In patients with cervical stenosis without myelopathy, the presence of abnormal electromyography findings or the presence of clinical radiculopathy is associated with the development of symptomatic CSM in this patient population (Class I). CONCLUSIONS The natural history of CSM is variable, which may affect treatment decisions.

An evidence-based clinical guideline for the diagnosis and treatment of cervical radiculopathy from degenerative disorders

Abstract Background context The North American Spine Society (NASS) Evidence-Based Clinical Guideline on the Diagnosis and Treatment of Cervical Radiculopathy from Degenerative Disorders provides evidence-based recommendations on key clinical questions concerning the diagnosis and treatment of cervical radiculopathy from degenerative disorders. The guideline addresses these questions based on the highest quality clinical literature available on this subject as of May 2009. The guideline’s recommendations assist the practitioner in delivering optimum efficacious treatment of and functional recovery from this common disorder. Purpose Provide an evidence-based educational tool to assist spine care providers in improving quality and efficiency of care delivered to patients with cervical radiculopathy from degenerative disorders. Study design Systematic review and evidence-based clinical guideline. Methods This report is from the Cervical Radiculopathy from Degenerative Disorders Work Group of the NASS’ Evidence-Based Clinical Guideline Development Committee. The work group consisted of multidisciplinary spine care specialists trained in the principles of evidence-based analysis. Each member of the group formatted a series of clinical questions to be addressed by the group. The final questions agreed on by the group are the subjects of this report. A literature search addressing each question using a specific search protocol was performed on English language references found in MEDLINE, EMBASE (Drugs and Pharmacology), and four additional evidence-based databases. The relevant literature was then independently rated by a minimum of three reviewers using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final recommendations to answer each clinical question were arrived at via work group discussion, and grades were assigned to the recommendations using standardized grades of recommendation. In the absence of Levels I to IV evidence, work group consensus statements have been developed using a modified nominal group technique, and these statements are clearly identified as such in the guideline. Results Eighteen clinical questions were formulated, addressing issues of natural history, diagnosis, and treatment of cervical radiculopathy from degenerative disorders. The answers are summarized in this article. The respective recommendations were graded by the strength of the supporting literature, which was stratified by levels of evidence. Conclusions A clinical guideline for cervical radiculopathy from degenerative disorders has been created using the techniques of evidence-based medicine and best available evidence to aid both practitioners and patients involved with the care of this condition. The entire guideline document, including the evidentiary tables, suggestions for future research, and all references, is available electronically at the NASS Web site ( www.spine.org ) and will remain updated on a timely schedule.

Heme oxygenase-1 and heat shock protein 70 induction in glia and neurons throughout rat brain after experimental intracerebral hemorrhage.

OBJECTIVE Current experimental evidence demonstrates the development of ischemic regions adjacent to and spatially remote from an intracerebral hematoma. The cause of this ischemia is uncertain. Because ischemia is a known inducer of stress genes, we investigated the induction of two stress proteins, heme oxygenase (HO)-1 and heat shock protein (Hsp) 70, after intracerebral hemorrhage in the rat. METHODS Immunocytochemistry for HO-1, Hsp70, and HO-2, the constitutive isoform of the HO enzyme, was performed 1, 2, and 4 days after striatal injection of saline, whole blood, or lysed blood. Immunocytochemistry for HO-1, HO-2, and Hsp70 was also performed 1 day after cortical injection of saline, whole blood, or lysed blood. RESULTS After striatal injection of lysed and whole blood, the HO-1 protein was induced in glia throughout the hemisphere ipsilateral to the hematoma, and HO-1 immunoreactivity persisted for at least 4 days. After cortical injection of lysed and whole blood, HO-1 was induced in glia throughout the neocortex. Neuronal induction of HO-1 was also observed after cortical injection of lysed blood but not whole blood or saline. After striatal injection of lysed blood, Hsp70 was induced in glia surrounding the hematoma and in neurons from the neocortex overlying the hematoma and the striatum adjacent to the hematoma. After cortical injection of lysed blood, Hsp70 was induced in neurons throughout the neocortex and hippocampus bilaterally. In contrast, after whole blood and saline injection into cortex, Hsp70 induction was observed only in scattered neurons surrounding the hematoma cavity. CONCLUSION Our results demonstrate that blood in the brain parenchyma induces the HO-1 stress protein but does not significantly alter HO-2 immunostaining. Our results also demonstrate that lysed blood induces Hsp70 in multiple regions of the brain and that the stress response of the brain differs depending on whether lysed blood is injected into the cortex or striatum. These results suggest that blood lysis may play an unforeseen role in the stress response of the brain to intracerebral hemorrhage.

Cervical surgical techniques for the treatment of cervical spondylotic myelopathy.

OBJECT The objective of this systematic review was to use evidence-based medicine to compare the efficacy of different surgical techniques for the treatment of cervical spondylotic myelopathy (CSM). METHODS The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to anterior and posterior cervical spine surgery and CSM. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. RESULTS A variety of techniques have improved functional outcome after surgical treatment for CSM, including anterior cervical discectomy with fusion (ACDF), anterior cervical corpectomy with fusion (ACCF), laminoplasty, laminectomy, and laminectomy with fusion (Class III). Anterior cervical discectomy with fusion and ACCF appear to yield similar results in multilevel spine decompression for lesions at the disc level. The use of anterior plating allows for equivalent fusion rates between these techniques (Class III). If anterior fixation is not used, ACCF may provide a higher fusion rate than multilevel ACDF but also a higher graft failure rate than multilevel ACDF (Class III). Anterior cervical discectomy with fusion, ACCF, laminectomy, laminoplasty, and laminectomy with arthrodesis all provide near-term functional improvement for CSM. However, laminectomy is associated with late deterioration compared with the other types of anterior and posterior surgeries (Class III). CONCLUSIONS Multiple approaches exist with similar near-term improvements; however, laminectomy appears to have a late deterioration rate that may need to be considered when appropriate.

Cervical laminoplasty for the treatment of cervical degenerative myelopathy.

OBJECT The objective of this systematic review was to use evidence-based medicine to examine the efficacy of cervical laminoplasty in the treatment of cervical spondylotic myelopathy (CSM). METHODS The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to cervical laminoplasty and CSM. Abstracts were reviewed and studies meeting the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons and Congress of Neurological Surgeons. RESULTS Cervical laminoplasty has improved functional outcome in the setting of CSM or ossification of the posterior longitudinal ligament. Using the Japanese Orthopaedic Association scale score, approximately 55-60% average recovery rate has been observed (Class III). The functional improvement observed after laminoplasty may be limited by duration of symptoms, severity of stenosis, severity of myelopathy, and poorly controlled diabetes as negative risk factors (Class II). There is conflicting evidence regarding age, with 1 study citing it as a negative risk factor, and another not demonstrating this result. CONCLUSIONS Cervical laminoplasty is recommended for the treatment of CSM or ossification of the posterior longitudinal ligament (Class III).

Clinical prognostic indicators of surgical outcome in cervical spondylotic myelopathy.

OBJECT The objective of this systematic review was to use evidence-based medicine to assess whether clinical factors predict surgical outcomes in patients undergoing cervical surgery. METHODS The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to clinical preoperative factors. Abstracts were reviewed, and studies that met the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. RESULTS Preoperative sensory-evoked potentials may aid in providing prognostic information in selected patients in whom clinical factors do not provide clear guidance (Class II). Age, duration of symptoms, and preoperative neurological function may commonly affect outcome (Class III). CONCLUSIONS Age, duration of symptoms, and preoperative neurological function should be discussed with patients when surgical intervention for cervical spondylotic myelopathy is considered. Preoperative sensory-evoked potentials may be considered for patients in whom clinical factors do not provide clear guidance if such information would potentially change therapeutic decisions.

Cell Death After Exposure to Subarachnoid Hemolysate Correlates Inversely With Expression of CuZn–Superoxide Dismutase

Background and Purpose Subarachnoid hemolysate (SAH) has been associated with oxidative brain injury, cell death, and apoptosis. We hypothesized that over-expression of CuZn–superoxide dismutase (CuZn-SOD) would protect against injury after SAH, whereas reduction of its expression would exacerbate injury. Methods Saline (n=16) or hemolysate (n=50) was injected into transgenic mice overexpressing CuZn-SOD (SOD1-Tg), CuZn-SOD heterozygous knockout mutants (SOD1+/−), and wild-type littermates (Wt). Mice were killed at 24 hours. Stress gene induction was evaluated by immunocytochemistry and Western blotting for hemeoxygenase-1 and heat shock protein 70. Apoptosis was evaluated by 3′-OH nick end-labeling and DNA gel electrophoresis. Cell death was quantified through histological assessment after cresyl violet staining. Results Histological assessment demonstrated neocortical cell death in regions adjacent to the blood injection. Overall cell death was reduced 43% in SOD1-Tg mutants (n=6) compared with Wt littermates (n=6;P <0.02). In contrast, cell death was increased >40% in SOD1+/− mutants (n=6;P <0.05). Both hemeoxygenase-1 and heat shock protein 70 were induced after SAH. Apoptosis was also present after SAH, as evidenced by 3′-OH end-labeling and DNA laddering. However, the degree of stress gene induction and apoptosis did not vary between Wt, SOD1-Tg, and SOD1+/− mice. Conclusions The extent of CuZn-SOD expression in the cytosol correlates with cell death after exposure to SAH in a manner separate from apoptosis. Overexpression of CuZn-SOD may potentially be an avenue for therapeutic intervention.

Laminectomy and fusion for the treatment of cervical degenerative myelopathy

OBJECT The objective of this systematic review was to use evidence-based medicine to examine the efficacy of cervical laminectomy and fusion for the treatment of cervical spondylotic myelopathy (CSM). METHODS The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to cervical laminectomy, fusion, and CSM. Abstracts were reviewed, after which studies that met the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Class I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations which contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer-review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. RESULTS Cervical laminectomy with fusion (arthrodesis) improves functional outcome in patients with CSM and ossification of the posterior longitudinal ligament (OPLL). Functional improvement is similar to laminectomy or laminoplasty for patients with CSM and OPLL. In contrast to laminectomy, cervical laminectomy with fusion it is not associated with late deformity (Class III). CONCLUSIONS Laminectomy with fusion (arthrodesis) is an effective strategy to improve functional outcome in CSM and OPLL.