Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis

Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF-alpha and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.

[The hospitalized patient with fever and mental status changes]

The case is discussed of a 74-year-old patient hospitalised with acute colitis, who newly developed headache, fever, and mental status changes on the 14th day after admission. The course of the disease was characterised by rapid progression with loss of consciousness and the development of extensive brain oedema, despite broad-spectrum antibiotic therapy. The patient died on the 17th of hospitalisation.

Nervous system dysfunction in Henoch-Schonlein syndrome: systematic review of the literature

OBJECTIVE: CNS or peripheral nervous system dysfunction sometimes occurs in Henoch-Schönlein patients. METHODS: We review all Henoch-Schönlein cases published after 1969 with CNS dysfunction without severe hypertension and neuroimaging studies (n = 35), cranial or peripheral neuropathy (n = 15), both CNS and peripheral nervous system dysfunction without severe hypertension (n = 2) or nervous system dysfunction with severe hypertension (n = 2). Forty-four of the 54 patients were <20 years of age. RESULTS: In patients with CNS dysfunction without or with severe hypertension the following presentations were observed in decreasing order of frequency: altered level of consciousness, convulsions, focal neurological deficits, visual abnormalities and verbal disability. Imaging studies disclosed the following lesions: vascular lesions almost always involving two or more vessels, intracerebral haemorrhage, posterior subcortical oedema, diffuse brain oedema and thrombosis of the superior sagittal sinus. Following lesions were noted in the subjects with cranial or peripheral neuropathy without severe hypertension: peroneal neuropathy, peripheral facial palsy, Guillain-Barré syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex. Persisting signs of either CNS (n = 9) or peripheral (n = 1) nervous system dysfunction were sometimes reported. CONCLUSIONS: In Henoch-Schönlein syndrome, signs of nervous system dysfunction are uncommon but clinically relevant. This review helps clinicians managing Henoch-Schönlein syndrome with nervous system dysfunction.

Post-mortem whole body computed tomography of opioid (heroin and methadone) fatalities: frequent findings and comparison to autopsy

OBJECTIVE To investigate frequent findings in cases of fatal opioid intoxication in whole-body post-mortem computed tomography (PMCT). METHODS PMCT of 55 cases in which heroin and/or methadone had been found responsible for death were retrospectively evaluated (study group), and were compared with PMCT images of an age- and sex-matched control group. Imaging results were compared with conventional autopsy. RESULTS The most common findings in the study group were: pulmonary oedema (95 %), aspiration (66 %), distended urinary bladder (42 %), cerebral oedema (49 %), pulmonary emphysema (38 %) and fatty liver disease (36 %). These PMCT findings occurred significantly more often in the study group than in the control group (p < 0.05). The combination of lung oedema, brain oedema and distended urinary bladder was seen in 26 % of the cases in the study group but never in the control group (0 %). This triad, as indicator of opioid-related deaths, had a specificity of 100 %, as confirmed by autopsy and toxicological analysis. CONCLUSIONS Frequent findings in cases of fatal opioid intoxication were demonstrated. The triad of brain oedema, lung oedema and a distended urinary bladder on PMCT was highly specific for drug-associated cases of death. KEY POINTS Frequent findings in cases of fatal opioid intoxication were investigated. Lung oedema, brain oedema and full urinary bladder represent a highly specific constellation. This combination of findings in post-mortem CT should raise suspicion of intoxication.