A brainstem variant of reversible posterior leukoencephalopathy syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS) is caused by various heterogeneous factors, the commonest being hypertension, followed by nonhypertensive causes such as eclampsia, renal diseases and immunosuppressive therapy. Patients with RPLS exhibit bilateral white and gray matter abnormalities in the posterior aspects of the cerebral hemispheres. However, this syndrome may affect the brainstem predominantly, and these cases are designated as hypertensive brainstem encephalopathy. We present here two patients with reversible brainstem encephalopathy: one with hypertension and the other without hypertension. These patients presented with swelling and diffuse hyperintensities of the brainstem in fluid-attenuated inversion-recovery (FLAIR) and T2-weighted MRI, but with relatively mild clinical symptoms. They recovered without major neurological deficits, but had residual lacunar lesions in the pons. Reversible brainstem encephalopathy with characteristic MRI features was found in both hypertensive and nonhypertensive patients. These patients were diagnosed with a brainstem variant of RPLS, which is potentially fully reversible after an adequate treatment, and therefore should be carefully differentiated from other brainstem disease conditions.

Astroglial expression of ceramide in Alzheimer's disease brains: a role during neuronal apoptosis.

Accumulating evidences indicate that ceramide is closely involved in apoptotic cell death in neurodegenerative disorders and aging. We examined ceramide levels in the cerebrospinal fluid (CSF) or brain tissues from patients with neurodegenerative disorders and the mechanism of how intra- and extracellular ceramide was regulated during neuronal apoptosis. We screened the ceramide levels in the CSF of patients with neurodegenerative disorders, and found that ceramide was significantly increased in patients with Alzheimer's disease (AD) than in patients with age-matched amyotrophic lateral sclerosis (ALS) and other neurological controls. With immunohistochemistry in AD brains, ceramide was aberrantly expressed in astroglia in the frontal cortices, but not detected in ALS and control brains. To explore for the regulation of ceramide in astroglia in Alzheimer's disease brains, we examined the metabolism of ceramide during neuronal apoptosis. In retinoic acid (RA)-induced neuronal apoptosis, RA slightly increased de novo synthesis of ceramide, but interestingly, RA dramatically inhibited conversion of [14C] ceramide to glucosylceramide (GlcCer), suggesting that the increase of ceramide mass is mainly due to inhibition of the ceramide-metabolizing enzyme GlcCer synthase. In addition, a significant increase of the [14C] ceramide level in the culture medium was detected by chasing and turnover experiments without alteration of extracellular [14C] sphingomyelin levels. A 2.5-fold increase of ceramide mass in the supernatant was also detected after 48 h of treatment with RA. These results suggest a regulatory mechanism of intracellular ceramide through inhibition of GlcCer synthase and a possible role of ceramide as an extracellular/intercellular mediator for neuronal apoptosis. The increased ceramide level in the CSF from AD patients, which may be derived from astroglia, raises a possibility of neuronal apoptosis by the response to intercellular ceramide in AD.

The action mechanism of cyclooxygenase-2 inhibitor for treatment of experimental allergic neuritis.

We previously reported the effect of a cyclooxygenase (COX)-2 inhibitor, nimesulide, on experimental allergic neuritis (EAN) in both the induction and effector phases, in contrast to the usual COX inhibitor, which was effective only when administered in the induction phase. To assess the mechanism of action of a COX-2 inhibitor, we studied the expression of COX-2 and assayed plasma levels of prostaglandins, and also compared the clinical effect of a COX-2 inhibitor with a 5-lipoxygenase (LO) inhibitor, which is responsible for another pathway of arachidonic acid metabolism. Nerves of EAN rats showed distinct expression of COX-2, which is derived mostly from endoneurial macrophages. Treatment with a COX-2 inhibitor had no effect on its expression. However, prostaglandin estradiol (E(2)) concentration of plasma was significantly lower compared with the control group. The LO inhibitor showed no clinical effect. These results suggest that a selective COX-2 inhibitor is effective in the effector phase by its influence on macrophages that are responsible for nerve degeneration.

Aberrant expression of cyclin-dependent kinase 5 in inclusion body myositis.

OBJECTIVE: To investigate abnormal protein expression in inclusion body myositis (IBM). BACKGROUND: In IBM, ectopic deposition of beta-amyloid protein as well as several other proteins in some muscle fibers occurs. Some, but not all, of these proteins are also expressed in myofibrillar myopathy (MFM). The authors recently reported aberrant expressions of several cyclin-dependent kinases (CDKs)-enzymes regulating the cell replication cycle-in MFM. They therefore tested the notion that aberrant expression of CDKs also occurs in IBM. Among CDKs, CDK1, CDK2, and CDK5 have been demonstrated to phosphorylate tau, which is a component of inclusions in IBM. CDK5 appears in a stage of myogenesis when CDK1 and CDK2 are downregulated. METHODS: Cryostat sections of muscle specimens from 10 patients with sporadic IBM were immunostained for CDK1, CDK2, and CDK5. Fourteen patients with polymyositis and eight individuals with dermatomyositis served as disease control subjects. RESULTS: In IBM, numerous CDK5-positive inclusions were present in vacuolated fibers. CDK5 expression was not observed in any disease control subject. Regenerating fibers expressed CDK1 and CDK2 in all diseases. CONCLUSION: The results suggest that cyclin-dependent kinases (CDK)5, but no other CDKs, is involved in the formation of inclusions in IBM.

Enhancement of TNF-alpha production by ganglioside GM2 in human mononuclear cell culture.

Some gangliosides have been regarded as autoantigens of immune-mediated neurological disorders such as Guillain-Barré syndrome (GBS), Miller Fisher syndrome and multifocal motor neuropathy. On the other hand, proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), may be important in the pathogenesis of some neuroimmunological disorders. To clarify the interactions between immune cells and gangliosides, we investigated the effects of gangliosides on the production of proinflammatory cytokines in peripheral blood mononuclear cell (PBMC) cultures. We found that ganglioside GM2 markedly enhances the production of TNF-alpha and that TNF-alpha induction by coated GM2 is still more marked. These findings suggest that immune cells, especially monocytes/macrophages, cause inflammation upon encountering GM2.

The effect of cyclooxygenase-2 inhibitor on experimental allergic neuritis.

We studied the effect of the cyclooxygenase (COX)-2 inhibitor nimesulide on experimental allergic neuritis (EAN). In rats fed with nimesulide starting on day 1 post inoculation, the clinical EAN score was significantly lower and the maximal clinical score was reduced compared with the control group. Even if given after the onset of clinical signs, the clinical score was reduced and improvement was faster than the control group. Nimesulide inhibited decreases in weight in the experimental group. The histopathological observations of the sciatic nerve showed a decreased incidence of degenerated nerve fibers in the experimental group. Although the exact mechanism of its efficacy is not clear, a COX-2 inhibitor may have potential as an additional therapeutic agent in human inflammatory neuropathies.

Mechanisms of tissue injury in vasculitic neuropathies.

We studied the expression of candidate molecules for tissue injury in vasculitic neuropathies immunohistochemically, using samples obtained by nerve biopsy from seven patients with necrotizing angitis. In the involved vessels of all samples, numerous infiltrating cells were positive for perforin, nitric oxide synthase (m-NOS), cyclooxygenase-2 (COX-2), or matrix metalloproteinase-1 (MMP-1). Cell-mediated cytotoxicity may be involved in the pathogenesis of small vessel injury in vasculitic neuropathies. In the endoneurium following axonal degeneration, scattered and phagocytosing macrophages showed immunostaining for m-NOS and MMP-1, but COX-2 was all but restricted to phagocytosing macrophages. This suggests a role for prostaglandins in nerve damage.

Tumor necrosis factor-alpha in peripheral nerve lesions.

Immunocytochemical expression of tumor necrosis factor-alpha (TNF-alpha) was examined in nerve biopsy samples of patients with various disorders, focusing on nerve injury. TNF-alpha was mainly associated with phagocytosing macrophages in acute axonal injury, but the staining was more frequently seen in sections from patients with vasculitis than with metabolic neuropathy. Ramifield macrophages outside nerve fibers were also positive for TNF-alpha in the acute stage of vasculitis. In active demyelinating lesions from patients with chronic inflammatory demyelinating neuropathy (CIDP), macrophages outside nerve fibers showed weak staining with TNF-alpha, but the cells adhering to myelinated nerve fibers showed definite staining. This may be due, in part, to the smouldering course of CIDP, and expression may be up-regulated transiently during the demyelinating process. These results indicate that macrophages, as the effector cells for both axonal injury and active demyelination, express TNF-alpha, buth their activation mechanisms may vary among vasculitis, metabolic axonopathy and inflammatory demyelination.

[Familial Binswanger-type encephalopathy with Sneddon syndrome].

We reported a family with early onset cerebrovascular disease. Patient 1 (a 36-year-old man) demonstrated a combination of livedo reticularis and cerebral infarction as previously described as Sneddon syndrome. He also showed transient focal neurologic symptoms and mild dementia. Patient 2 (an elder sister of Patient 1) was suffering from migraine. Their father and paternal uncle died of cerebral infarction, which had developed in their thirties or forties. Patients 1 and 2 showed MRI findings compatible with encephalopathy with Binswanger-type. Contrary to the previous reports on Binswanger-type encephalopathy, both of these patients demonstrated decreased levels of fibrinogen as well as those of factor V, together with negative antiphospholipid antibody. Thus, juvenile onset, autosomal dominant inheritance, the diversity of clinical findings and the coagulopathy in this family were characteristic features. The level of thrombin-antithrombin III complex (TAT) was markedly increased in Patient 1. Treatment with antithrombin (argatroban 20mg i.v. everyday for 28 days) not only reduced the level of TAT but also improved the livedo reticularis and neurological findings. Although gene analysis has not been performed yet on this family, this condition is similar to cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), which involve juvenile cerebral infarction and dementia as well as migraine.

Diminished nocturnal blood pressure decline and lesion site in cerebrovascular disease.

BACKGROUND AND PURPOSE: Many studies have suggested that diminished nocturnal blood pressure decline in hypertensive cardiovascular disease is associated with the extent of hypertensive vascular disease. In our previous observation of cerebrovascular disease, however, we found reduced nocturnal blood pressure decline to be associated not only with the extent of hypertensive vascular disease but also with the specific location of cerebrovascular lesions. The purpose of this study was to elucidate the mechanism of nocturnal blood pressure decline in cerebrovascular disease. Moreover, to clarify whether reduced nocturnal blood pressure decline occurs before cerebrovascular disease, we examined patients with recurring episodes. METHODS: Ambulatory blood pressure monitoring was carried out every 30 minutes in 14 control subjects, 15 hypertensive subjects, 90 patients with cerebrovascular disease (16 single lacunar infarctions, 15 multiple lacunar infarctions, 10 putaminal hemorrhages, 14 thalamic hemorrhages, 11 pontine base infarctions, 15 pontine tegmentum infarctions, 8 pontine hemorrhages, 13 wide cortical infarctions), and 7 patients with recurring stroke episodes. The percentage of nocturnal blood pressure decline and the correlations for systolic blood pressure and heart rate were calculated. RESULTS: The percentage of nocturnal blood pressure decline was significantly smaller in the groups with multiple lacunar infarction (systolic, P < .001; diastolic, P < .01), thalamic hemorrhage (P < .01, P < .05), pontine tegmentum infarction (P < .01, P < .05), and pontine hemorrhage (both P < .05). The correlation between systolic blood pressure and heart rate was not significant for almost all the groups with diminished blood pressure decline. CONCLUSIONS: Diminished nocturnal blood pressure decline in cerebrovascular disease is thought to be caused by specific injury to the central autonomic nervous system such as the striatum, diencephalon, midbrain, and pontine tegmentum and their connecting fibers.