Prolonged inflammation leads to ongoing damage after spinal cord injury.

The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.

Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults.

BACKGROUND: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. METHODS: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. RESULTS: All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. CONCLUSIONS: These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.

The relationship between localized subarachnoid inflammation and parenchymal pathophysiology after spinal cord injury.

Subarachnoid inflammation following spinal cord injury (SCI) can lead to the formation of localized subarachnoid scarring and the development of post-traumatic syringomyelia (PTS). While PTS is a devastating complication of SCI, its relative rarity (occurring symptomatically in about 5% of clinical cases), and lack of fundamental physiological insights, have led us to examine an animal model of traumatic SCI with induced arachnoiditis. We hypothesized that arachnoiditis associated with SCI would potentiate early parenchymal pathophysiology. To test this theory, we examined early spatial pathophysiology in four groups: (1) sham (non-injured controls), (2) arachnoiditis (intrathecal injection of kaolin), (3) SCI (35-g clip contusion/compression injury), and (4) PTS (intrathecal kaolin+SCI). Overall, there was greater parenchymal inflammation and scarring in the PTS group relative to the SCI group. This was demonstrated by significant increases in cytokine (IL-1α and IL-1ß) and chemokine (MCP-1, GRO/KC, and MIP-1α) production, MPO activity, blood-spinal cord barrier (BSCB) permeability, and MMP-9 activity. However, parenchymal inflammatory mediator production (acute IL-1α and IL-1ß, subacute chemokines), BSCB permeability, and fibrous scarring in the PTS group were larger than the sum of the SCI group and arachnoiditis group combined, suggesting that arachnoiditis does indeed potentiate parenchymal pathophysiology. Accordingly, these findings suggest that the development of arachnoiditis associated with SCI can lead to an exacerbation of the parenchymal injury, potentially impacting the outcome of this devastating condition.

The effects of intrathecal injection of a hyaluronan-based hydrogel on inflammation, scarring and neurobehavioural outcomes in a rat model of severe spinal cord injury associated with arachnoiditis.

Traumatic spinal cord injury (SCI) comprises a heterogeneous condition caused by a complex array of mechanical forces that damage the spinal cord - making each case somewhat unique. In addition to parenchymal injury, a subset of patients experience severe inflammation in the subarachnoid space or arachnoiditis, which can lead to the development of fluid-filled cavities/syringes, a condition called post-traumatic syringomyelia (PTS). Currently, there are no therapeutic means to address this devastating complication in patients and furthermore once PTS is diagnosed, treatment is often prone to failure. We hypothesized that reducing subarachnoid inflammation using a novel bioengineered strategy would improve outcome in a rodent model of PTS. A hydrogel of hyaluronan and methyl cellulose (HAMC) was injected into the subarachnoid space 24 h post PTS injury in rats. Intrathecal injection of HAMC reduced the extent of fibrosis and inflammation in the subarachnoid space. Furthermore, HAMC promoted improved neurobehavioural recovery, enhanced axonal conduction and reduced the extent of the lesion as assessed by MRI and histomorphometric assessment. These findings were additionally associated with a reduction in the post-traumatic parenchymal fibrous scar formation as evidenced by reduced CSPG deposition and reduced IL-1α cytokine levels. Our data suggest that HAMC is capable of modulating inflammation and scarring events, leading to improved functional recovery following severe SCI associated with arachnoiditis.

Breakthrough neurological manifestation during appropriate antituberculous therapy of miliary tuberculosis.

We report a 20-month-old girl with miliary pulmonary tuberculosis and normal neurological findings. While on treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol for 1 month, she developed weakness of the lower extremities without meningism or altered consciousness. A computerized tomogram revealed tuberculomas and basal arachnoiditis. The cerebrospinal fluid findings were compatible with tuberculous meningitis. She responded well to systemic corticosteroids.

[Clinico-immunological comparisons in cerebral arachnoiditis]. / Kliniko-immunologicheskie sopostavleniia pri tserebral'nykh arakhnoiditakh.

106 patients with cerebral arachnoiditis diagnosed according to pneumoencephalographic and computer-tomographic findings were studied. 65 patients had clinical signs of progredient disease (lability and an increase of neurologic symptoms). In 41 patients clinical pattern was stable during several years. In the patients with a progredient course of the disease investigation of the immune status revealed that aggravation of clinical symptoms is accompanied by a decrease of a number of T-lymphocytes, an increase of the levels of immunoglobulins A and G as well as of P-proteins and of a general activity of serum interferons. Such alterations were not observed in patients with a stable course of the disease.

[The characteristics of the functional activity of cellular immunity factors in relation to the use of general anesthetics from different pharmacological groups in operations for optic nerve neurolysis]. / Osobennosti funktsional'noi aktivnosti faktorov kletochnogo immuniteta v zavisimosti ot ispol'zovaniia obshchikh anestetikov razlichnykh farmakologicheskikh grupp pri operatsiiakh nevroliza zritel'nykh nervov.

The functional activity of cellular immunity was studied in 26 patients with opticochiasmatic arachnoiditis as a model of autoimmune involvement of the brain after administration of common anesthetics of different pharmacological groups. Injection of ketamine as the induction and basic component of general combined anesthesia leads to reduction of neurosensitization induced by the pathologic process; it is paralleled by the optimal activation of the suppressor component of lymphocytes and a reduction of sensitization to brain antigen. In contrast to ketamine, barbiturates augment neurosensitization and lead to depression of the lymphocyte activity, this confirming the anti-immunopathological effect of barbituric acid derivatives. Ketamine is advisable for patients with various immunopathological states.

Surgical treatment of "hindbrain related" syringomyelia: new data for pathogenesis.

52 patients with "hindbrain related" syringomyelia underwent surgical treatment. All patients underwent primary reconstructive surgery at the craniovertebral junction. Terminal ventriculostomy was performed as the secondary operation in 2 cases. The surgical treatment arrested progression of signs in 33 (63.5%), stabilized disease in 9 (17%) cases. Postoperative deterioration occurred in 8 (15%) cases. Mortality was 4% (2 patients). Percutaneous or intra-operative injection of myodil and gas into the syrinx, as well as CT, revealed the existence of communication with the 4th ventricle in 14 patients. Investigation of cerebrospinal and syrinx fluid revealed increased level of IgG, IgM or IgA in the syrinx fluid in 16 out of 22 patients. Immunohistological examination of pia mater revealed specific staining for IgG. Thus, syrinx formation may be due to synergic action of hydrodynamic and immunopathological mechanisms. Results indicate that early surgical treatment is preferable to patients with hindbrain anomalies and hydromyelia. We consider primary reconstructive operation at the posterior fossa as the preferred surgical management of "hindbrain related" syringomyelia.

[Clinico-immunologic studies in rhinosinusogenic cerebral arachnoiditis]. / Kliniko-immunologicheskie issledovaniia rinosinusogennykh tserebral'nykh arakhnoiditov.

This is a comparative clinico-immunological investigation of 30 virtually healthy persons and 42 patients with rhinosinusogenic cerebral arachnoiditis. In patients considerable changes were detected in immune indices, both cellular and humoral, with a secondary immune deficiency and autoimmune disorders. The group at high risk of immune deficiency was singled out. In each patient the quantifying of the abnormal immune indices can provide additional criterion to evaluation of prognosis of the disease and efficiency of treatment.

[Changes in the immune reactivity of the body in cerebral arachnoiditis]. / Izmenenie immunnoi reaktivnosti organizma pri tserebral'nom arakhnoidite.

The author evaluates the dynamics of immune reactivity of the body in patients with cerebral arachnoiditis with consideration of main clinical syndrome--hypertensive-hydrocephalic, epileptiform, autonomic-vascular dystonia syndromes in different variants of the course of the process. It is shown that regression of immune insufficiency did not depend on the leading clinical syndrome. The question of including immunomodulators for correction of immune insufficiency is discussed.

[The role of the immune system in the development of rhinosinusogenous intracranial complications (abscess, arachnoiditis)]. / Rol' immunnoi sistemy v razvitii rinosinusogennykh vnutricherepnykh oslozhnenii (abstsess, arakhnoidit).

The article analyses the results of some modern immunological methods of examination in 49 patients with various rhinosinusogenous intracranial complications. It was found that secondary immunodeficiency develops in this group of patients, which is often attended with an autoimmune component. Both the nonspecific defence factors and the organism's specific immune response are impaired in this case. There was a direct relationship between the depth of the immunity disorders and the severity of the clinical course of the disease. The results obtained may be used as auxiliary and prognostic criteria in appraising the patients' condition. The results of the study indicate that rhinosinusogenous intracranial complications should be managed by pathogenetically substantiated therapy with the use of immunocorrective agents in a complex with other types of treatment.

[Diagnostic value of spinal fluid immunoglobulins in cerebral arachnoiditis]. / Diagnosticheskoe znachenie immunoglobulinov spinnomozgovoi zhidkosti pri tserebral'nykh arakhnoiditakh.

The authors believe that the deficiency of immunoglobulins A in the cerebrospinal fluid (CSF) of patients with arachnoiditis may be explained by an increase in their consumption due to antigenic aggression in relation to the meninges, which results in extremely low values of the circulating immunoglobulins A. The absence of immunoglobulins A in the CSF of patients with cerebral arachnoiditis is one of the components of its pathogenesis owing to impairment of permeability of the blood brain barrier and fixation of antigens in the tissues of the brain and meninges.