Tiit Mathiesen

Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy

&NA; Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in inflammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated inflammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. Tactile hypersensitivity (‘allodynia’) was present in all Gazelius model rats whereas only 38 and 29% of the Bennett and Seltzer models, respectively, displayed this sign of neuropathy. The inflammatory reactions in rats with and without tactile allodynia were compared. Monocytes/macrophages (ED‐1), natural killer cells, T lymphocytes, and the pro‐inflammatory cytokines tumor necrosis factor‐&agr; (TNF‐&agr;) and interleukin‐6 (IL‐6), were significantly upregulated in all nerve injured rats in comparison to sham‐operated controls. Interestingly, ED‐1‐, TNF‐&agr;‐ and IL‐6‐positive cells increased more markedly in allodynic Bennett and Seltzer rats than in non‐allodynic ones. The magnitude of the inflammatory response does not seem to relate to the extent of damage to the nerve fibers because axotomized rats displayed much lower upregulation. Our findings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL‐6 and TNF‐&agr;. This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED‐1 and IL‐6‐positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro‐inflammatory interleukins after nerve damage could influence the development of neuropathic pain.

Recurrence of cranial base meningiomas.

OBJECTIVE Long-term data on the natural history of traditionally treated cranial base meningiomas are necessary to judge the benefit of modern cranial base techniques for individual patients and to understand when nonradical surgery of a meningioma is in the interest of the patient. The only available means of obtaining such data is investigation of patients treated before the present surgical era. METHODS The records of 315 patients who were operated on at Karolinska Hospital between January 1, 1947, and December 31, 1982, were reviewed. Of the patients, 10.8% died perioperatively and 9.7% died within 10 years. The remaining patients were followed for 10 to 36 years (mean, 18 yr). RESULTS The 5-year recurrence rate was 4% for patients undergoing radical surgery (Grades 1 and 2) and 25 to 45% for patients undergoing Grade 3 or 4 operations. Follow-up periods longer than 5 years revealed that 16% of Grade 1 and 20% of Grade 2 patients had symptomatic recurrences, whereas a majority of Grade 4 and 5 patients showed symptomatic progression. Forty-two of 69 patients who underwent Grade 4 or 5 operations died as a result of their tumors, usually within 10 years after the first operation. No patients who underwent Grade 4 or 5 operations were free from symptomatic progression after 20 years. The tumor progression or recurrence was usually detected within the 1st 10 years, but late recurrences were seen < or = 25 years after the operation. The worst outcome was found in medial sphenoid wing/clinoidal meningiomas and in tumors invading the cavernous sinus. Subfrontal tumors showed unexpectedly high recurrence rates, with a mortality rate < or = 14% in the late phase. CONCLUSION The findings emphasized the necessity to plan the management of patients with cranial base meningiomas according to a 10- to 20-year perspective. Patients must be followed to evaluate the treatment results and to detect recurrences. Nonradical surgery must be viewed as a temporizing or palliative measure; a continued search for means of radical tumor treatment is warranted in these often surgically difficult tumors.

Intracerebral inflammation after human brain contusion.

OBJECTIVE This study was undertaken to analyze the inflammatory components in contused human brain tissue to compare the findings with previous experimental data regarding the pathogenesis of brain contusions. METHODS Contused brain tissue biopsies were obtained from 12 consecutive patients undergoing surgery for brain contusions 3 hours to 5 days after trauma. Inflammatory and immunological components were analyzed by immunohistochemistry. RESULTS In patients undergoing surgery less than 24 hours after trauma, the inflammatory response was limited to vascular margination of polymorphonuclear cells. In patients undergoing surgery 3 to 5 days after trauma, however, a massive inflammatory response consisting of monocytes/macrophages, reactive microglia, polymorphonuclear cells, and CD4- and CD8-positive T lymphocytes was detected. Human lymphocyte antigen-DQ was expressed on reactive microglia and infiltrating leukocytes in the late patient group. In addition, CD1a, which is a marker for antigen-presenting dendritic cells, was detected in a subgroup of microglial cells. CONCLUSION The results corroborated hypotheses derived from experimental data. In the early phase after contusional trauma, inflammation is mainly intravascular and dominated by polymorphonuclear cells. The inflammation was parenchymal in patients undergoing surgery 3 to 5 days after trauma. The brain swelling seemed to be biphasic, the delayed phase correlating with a parenchymal inflammation. The inflammatory cells may produce several potentially harmful effects, such as acute cellular degeneration; they may also lead to degenerative long-term effects.

Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models.

Objective To investigate which of three subarachnoid hemorrhage (SAH) models is the most suitable for studies of pathological and pathophysiological processes after SAH. Methods SAH was induced in rats via intracranial endovascular perforation (perforation model), blood injection into the cisterna magna (300 microl), or blood injection into the prechiasmatic cistern (200 microl). The subarachnoid blood volume was quantitatively measured. Cerebral blood flow (CBF) (as assessed with laser Doppler flowmetry), intracranial pressure, and mean arterial blood pressure were recorded for 90 minutes after SAH. Mortality was recorded, and neuronal death was assessed in animals that survived 7 days after SAH. Results The subarachnoid blood volume was close to the injected amount after prechiasmatic SAH. In the other models, the volume varied between 40 and 480 microl. The mortality rates were 44% in the perforation SAH group, 25% in the prechiasmatic SAH group, and 0% in the cisterna magna SAH group; the corresponding values for neuronal death were 11, 44, and 28%. Cerebral perfusion pressure approached baseline values within 5 minutes after SAH in all three models. CBF decreased to approximately 35% of baseline values immediately after SAH in all groups; it gradually increased to normal values 15 minutes after SAH in the cisterna magna SAH group and to 60 and 89% of baseline values 90 minutes post-SAH in the perforation and prechiasmatic SAH groups. CBF was significantly correlated with the subarachnoid blood volume. Conclusion The prechiasmatic SAH model seems to be the most suitable for study of the sequelae after SAH; it produces a significant decrease in CBF, an acceptable mortality rate, and substantial pathological lesions, with high reproducibility. The CBF reduction is predominantly dependent on the amount of subarachnoid blood.

Adult Nestin-expressing Subependymal Cells Differentiate to Astrocytes in Response to Brain Injury

The adult brain contains a small population of central nervous system (CNS) cells in the subependyma which, like embryonic CNS progenitor cells, express the intermediate filament nestin. In this report, the differentiation capacity in vivo of these cells was analysed following a standardized trauma. Before the trauma, the subependymal cells expressed nestin but not the astrocytic and neuronal differentiation markers glial fibrillary acidic protein (GFAP) and neurofilament respectively. In response to injury, the majority of the subependymal cells coexpressed nestin and GFAP, but never nestin and neurofilament. Furthermore, cells coexpressing nestin and GFAP were found progressively further away from the subependyma and closer to the lesion at later time points after the injury, indicating that these cells migrate towards the lesion. Nestin was in addition re‐expressed in reactive astrocytes near the lesion and in non‐reactive astrocytes very far from the lesion throughout the ipsilateral cortex. In conclusion, our data indicate that the nestin‐positive subependymal cells are an in vivo source for the generation of new astrocytes but not neurons after injury, and that nestin re‐expression in astrocytes following traumatic stimuli can be used as a sensitive marker for astroglial activation.

Intracerebral inflammatory response to experimental brain contusion.

SummaryThe inflammatory reaction following experimental brain contusion was studied by immunohistochemistry in 22 rats during the first 16 days after trauma. An inflammatory mononuclear cell response was evident on day 2, with a maximum on days 5–6 and signs remained still 16 days after the trauma. The time course of the cellular infiltration adjacent to the lesion correlated with blood brain barrier dysfunction in the contralateral side of the traumatized hemisphere. The cellular infiltrate comprised NK cells, T-helper cells and T-cytotoxic/suppressor cells as well as monocytes/macrophages. Most of the macrophages appeared to be activated by T-cells. Surprisingly, polymorphonuclear cells appeared less engaged than mononuclear cells in the inflammation.The demonstration of immunocompetent cells and the induction of MHC-1 and MHC-II antigen provides a substrate for inflammatory reactions similar to those that cause neurological damage in inflammatory diseases such as viral infections, multiple sclerosis and experimental allergic encephalitis. Our observations indicate that the role of the inflammatory reactions may have a role, hitherto neglected, in the pathogenesis of secondary traumatic brain injury.

Incidence trends of adult primary intracerebral tumors in four Nordic countries

Brain tumors are some of the most lethal adult cancers and there is a concern that the incidence is increasing. It has been suggested that the reported increased incidence can be explained by improvements in diagnostic procedures, although this has not been totally resolved. The aim of our study was to describe the incidence trends of adult primary intracerebral tumors in four Nordic countries during a period with introduction of new diagnostic procedures and increasing prevalence of mobile phone users. Information about benign and malignant primary intracerebral tumor cases 20–79 years of age was obtained from the national cancer registries in Denmark, Finland, Norway and Sweden for the years 1969–98 and estimates of person‐years at risk were calculated from the information obtained from national population registries. Annual age standardized incidence rates per 100,000 person‐years were calculated and time trends analyses were carried out using Poisson regression. The overall incidence of all intracerebral tumors ranged from 8.4–11.8 for men and 5.8–9.3 for women, corresponding to an average annual increase of 0.6% for men (95% confidence interval [CI] = 0.4, 0.7) and 0.9% for women (95% CI = 0.7, 1.0). The increase in the incidence was confined to the late 1970s and early 1980s and coinciding with introduction of improved diagnostic methods. This increase was largely confined to the oldest age group. After 1983 and during the period with increasing prevalence of mobile phone users, the incidence has remained relatively stable for both men and women.

Experimental subarachnoid hemorrhage: cerebral blood flow and brain metabolism during the acute phase in three different models in the rat.

OBJECTIVETo study the cerebral metabolism and its relationship to cerebral blood flow (CBF) acutely after subarachnoid hemorrhage (SAH). METHODSSAH was induced in rats by endovascular perforation of the internal carotid artery, blood injection into the prechiasmatic cistern or the cisterna magna. CBF (measured by laser Doppler flowmetry), cerebral perfusion pressure, O2 tension, and extracellular levels of glucose, lactate, and pyruvate were monitored during 90 minutes after SAH. CBF (assessed by 125I-antipyrine autoradiography), arteriovenous O2 difference, and cerebral metabolic rate of O2 were calculated at 15 or 90 minutes after SAH. RESULTSAfter a transient reduction, cerebral perfusion pressure normalized within 5 minutes after SAH in all groups. There was a transient global decrease in CBF after SAH: its duration depended on the severity of the hemorrhage. CBF of less than 20% of baseline was observed for at least 15 minutes in 25% and 14% of the animals after perforation and prechiasmatic SAH, respectively. In all SAH groups, O2 tension was suddenly reduced to approximately 40% of baseline and gradually increased, reaching 70 to 90% of baseline 90 minutes after SAH. The cerebral metabolic rate of O2 was reduced only at 15 minutes after perforation and prechiasmatic SAH, but arteriovenous O2 difference was normal in all groups. During 30 minutes after perforation SAH, a 50% decrease in glucose and a threefold increase in lactate and pyruvate levels were observed. CONCLUSIONThe data suggest that SAH induced an acute global decrease in CBF together with a depression in the cerebral metabolism. The degree of the changes was related to the severity of the hemorrhage. The metabolic derangements were not always explained by ischemic episodes.

Temporal profiles and cellular sources of three nitric oxide synthase isoforms in the brain after experimental contusion.

OBJECTIVE Nitric oxide (NO) is a universal mediator of biological effects in the brain. It has been implicated in the pathophysiological processes of traumatic brain injury. Understanding its pathophysiological role in vivo requires an understanding of the cellular sources and tissue compartments of the differentially regulated NO synthase (NOS) isoforms. This study was undertaken to investigate the cellular sources and tissue compartments of NO produced after experimental brain contusions in rats, by analysis of the early expression of the three isoforms of NOS, i.e., the inducible, endothelial, and neuronal isoforms. METHODS Focal brain contusions were produced in 24 rats using a weight-drop model. The animals were killed 6, 12, 24, 36, or 48 hours after trauma. Sections were analyzed by immunohistochemical and immunofluorescence analyses. Double staining assays were used to define which cells produced the different NOS isoforms. RESULTS Increases in endothelial NOS-, inducible NOS (iNOS)-, and neuronal NOS-positive cells were detectable by 6 hours after trauma. Endothelial NOS and iNOS levels peaked at 6 and 12 hours, respectively. Expression of neuronal NOS initially increased to a peak at 12 hours but then decreased to a level lower than that in control samples at 36 hours. Endothelial NOS was expressed exclusively in endothelial cells, whereas iNOS was expressed in neutrophils and macrophages. Neuronal NOS was predominantly detected in neurons but was also unexpectedly detected in polymorphonuclear cells. CONCLUSION In this model, the most striking finding regarding NO-producing enzymes was the expression of iNOS in polymorphonuclear cells and macrophages, cells that invade injured brain tissue. iNOS is thus implicated as a therapeutic target in contusional injuries. This pattern of NOS expression cannot be generalized to all types of brain injuries. The different compartments and cells that can produce NO are differentially regulated; therefore, compartmentalization can explain why NO is beneficial or detrimental, depending on the circumstances. A knowledge of different potential sites and sources of NO is required for any attempts to interfere with the pathophysiological properties of NO.

Visual Outcome of Tuberculum Sellae Meningiomas after Extradural Optic Nerve Decompression

OBJECTIVE:Meningiomas of the tuberculum sellae have a close relationship with the optic apparatus. Even modern series show a 10 to 20% risk of visual deterioration after surgery. We have attempted to improve visual outcome by extradural decompression of the optic canal and anterior clinoid process, followed by intradural release of the optic nerve; this study provides an analysis of visual outcomes with this approach. METHODS:Treatment, histopathology, and follow-up data of 29 consecutive patients undergoing surgery for tuberculum sellae meningiomas with initial release of the optic nerve were prospectively collected. RESULTS:Radical tumor removal was possible in all 23 patients with primary tumors and in three out of six patients with recurrent tumors. All patients but two of the worst affected with preoperative visual compromise improved from surgery; there were no instances of visual deterioration. Five patients with normal preoperative vision remained intact and visual improvement was 22 (91%) out of 24 patients in the remaining patients. In total, 13 patients (42%) had completely normal vision at follow-up. Mainly patients younger than 60 years experienced complete normalization after surgery. Two patients underwent transsphenoidal surgery for cerebrospinal fluid leaks. Postoperative endocrinological symptoms were temporary diabetes insipidus in one patient and permanent diabetes insipidus in another patient undergoing elective sectioning of the pituitary stalk because of a recurrent tumor with invasive growth into the stalk. CONCLUSION:Adding early optic nerve decompression by extradural clinoidectomy and optic canal unroofing to a frontopterional approach seemed to improve visual outcomes because there were no instances of visual deterioration. Simpson Grade 1 to 2 removal was possible in all patients with primary surgery, whereas recurrent cases could only be treated with lower grades of radicality. Radical removal, however, required readiness to reoperate for cerebrospinal fluid leakage at the site of the drilled tumor origin in bone.