Cerebral microvascular abnormalities in patients with idiopathic intracranial hypertension.

AIM: Idiopathic intracranial hypertension (IIH) is characterized by symptoms indicative of increased intracranial pressure (ICP), such as headache and visual impairment. We have previously reported that brain biopsies from IIH patients show patchy astrogliosis and increased expression of the water channel aquaporin-4 (AQP4) at perivascular astrocytic endfeet. METHODS: The present study was undertaken to investigate for ultrastructural changes of the cerebral capillaries in individuals with IIH. We examined by electron microscopy (EM) biopsies from the cortical parenchyma of 10 IIH patients and 8 reference subjects (patients, not healthy individuals), in whom tissue was retrieved from other elective and necessary brain surgeries (epilepsy, tumors or vascular diseases). IIH patients were diagnosed on the basis of typical clinical symptoms and abnormal intracranial pressure wave amplitudes during overnight ICP monitoring. RESULTS: All 10 IIH patients underwent shunt surgery followed by favorable clinical outcome. EM revealed abnormal pericyte processes in IIH. The basement membrane (BM) showed more frequently evidence of degeneration in IIH, but neither the BM dimensions nor the pericyte coverage differed between IIH and reference tissue. The BM thickness increased significantly with increasing age. Reference individuals were older than IIH cases; observations may to some extent be age-related. CONCLUSION: The present study disclosed marked changes of the cerebral cortical capillaries in IIH patients, suggesting that microvascular alterations are involved in the evolvement of IIH.

Brain Capillary Ultrastructure in Idiopathic Normal Pressure Hydrocephalus: Relationship With Static and Pulsatile Intracranial Pressure.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease of unknown cause. We investigated the morphology of capillaries in frontal cortex biopsies from iNPH patients and related the observations to overnight intracranial pressure (ICP) scores. A biopsy (0.9×10 mm) was taken from where the ICP sensor subsequently was inserted. Brain capillaries were investigated by electron microscopy of biopsies from 27 iNPH patients and 10 reference subjects, i.e. patients (not healthy individuals) without cerebrospinal fluid circulation disturbances, in whom normal brain tissue was removed as part of necessary neurosurgical treatment. Degenerating and degenerated pericyte processes were identified in 23/27 (85%) iNPH and 6/10 (60%) of reference specimens. Extensive disintegration of pericyte processes were recognized in 11/27 (41%) iNPH and 1/10 (10%) reference specimens. There were no differences in basement membrane (BM) thickness or pericyte coverage between iNPH and reference subjects. The pulsatile or static ICP scores did neither correlate with the BM thickness nor with pericyte coverage. We found increased prevalence of degenerating pericytes in iNPH while the BM thickness and pericyte coverage did not differ from the reference individuals. Observations in iNPH may to some extent be age-related since the iNPH patients were significantly older than the reference individuals.

Human and mouse cortical astrocytes differ in aquaporin-4 polarization toward microvessels.

Aquaporin-4 (AQP4), the predominant water channel in the brain, is expressed in astrocytes and ependymal cells. In rodents AQP4 is highly polarized to perivascular astrocytic endfeet and loss of AQP4 polarization is associated with disease. The present study was undertaken to compare the expression pattern of AQP4 in human and mouse cortical astrocytes. Cortical tissue specimens were sampled from 11 individuals undergoing neurosurgery wherein brain tissue was removed as part of the procedure, and compared with cortical tissue from 5 adult wild-type mice processed similarly. The tissue samples were immersion-fixed and prepared for AQP4 immunogold electron microscopy, allowing quantitative assessment of AQP4's subcellular distribution. In mouse we found that AQP4 water channels were prominently clustered around vessels, being 5 to 10-fold more abundant in astrocytic endfoot membranes facing the capillary endothelium than in parenchymal astrocytic membranes. In contrast, AQP4 was markedly less polarized in human astrocytes, being only two to three-fold enriched in astrocytic endfoot membranes adjacent to capillaries. The lower degree of AQP4 polarization in human subjects (1/3 of that in mice) was mainly due to higher AQP4 expression in parenchymal astrocytic membranes. We conclude that there are hitherto unrecognized species differences in AQP4 polarization toward microvessels in the cerebral cortex.

Cortical astrogliosis and increased perivascular aquaporin-4 in idiopathic intracranial hypertension.

The syndrome idiopathic intracranial hypertension (IIH) includes symptoms and signs of raised intracranial pressure (ICP) and impaired vision, usually in overweight persons. The pathogenesis is unknown. In the present prospective observational study, we characterized the histopathological changes in biopsies from the frontal brain cortical parenchyma obtained from 18 IIH patients. Reference specimens were sampled from 13 patients who underwent brain surgery for epilepsy, tumors or acute vascular diseases. Overnight ICP monitoring revealed abnormal intracranial pressure wave amplitudes in 14/18 IIH patients, who underwent shunt surgery and all responded favorably. A remarkable histopathological observation in IIH patients was patchy astrogliosis defined as clusters of hypertrophic astrocytes enclosing a nest of nerve cells. Distinct astrocyte domains (i.e. no overlap between astrocyte processes) were lacking in most IIH biopsy specimens, in contrast to their prevalence in reference specimens. Evidence of astrogliosis in IIH was accompanied with significantly increased aquaporin-4 (AQP4) immunoreactivity over perivascular astrocytic endfeet, compared to the reference specimens, measured with densitometry. Scattered CD68 immunoreactive cells (activated microglia and macrophages) were recognized, indicative of some inflammation. No apoptotic cells were demonstrable. We conclude that the patchy astrogliosis is a major finding in patients with IIH. We propose that the astrogliosis impairs intracranial pressure-volume reserve capacity, i.e. intracranial compliance, and contributes to the IIH by restricting the outflow of fluid from the cranium. The increased perivascular AQP4 in IIH may represent a compensatory mechanism to enhance brain fluid drainage.

Antisecretory factor (AF) exerts no effects on intracranial pressure (ICP) waves and ICP in patients with idiopathic normal pressure hydrocephalus and idiopathic intracranial hypertension.

BACKGROUND: Antisecretory factor (AF) and derivates thereof counteract brain edema and inflammation, and normalize ICP dynamics. The aim of the present study was to assess whether AF normalized the abnormal ICP waves, indicative of impaired intracranial compliance, seen in patients with idiopathic normal pressure hydrocephalus (iNPH) and idiopathic intracranial hypertension (IIH). The hypothesis was that brain swelling contributes to the abnormal ICP waves. METHODS: The study enrolled patients undergoing diagnostic ICP wave monitoring for either iNPH or IIH. The ICP waves and ICP were recorded continuously before and after oral administration of Salovum® (0.5 g/kg body weight/day divided by three doses), a freeze-dried egg yolk enriched in AF activity. Mean ICP wave amplitude (MWA), mean ICP wave rise time coefficient (MWRTC), and mean ICP were compared before and after Salovum® administration. RESULTS: A total of 10 iNPH patients and 8 IIH patients were included. No significant changes in the ICP wave indices or ICP were seen after Salovum® administration. Neither any significant time-dependent effect was observed. CONCLUSION: The lack of effect of Salovum® on ICP wave indices and ICP in iNPH and IIH may provide indirect evidence that brain swelling does not play a crucial role in the ICP wave indices or ICP of these conditions.