Spontaneous intracranial hypotension is diagnosed by a combination of lipocalin-type prostaglandin D synthase and brain-type transferrin in cerebrospinal fluid.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies. METHODS: SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting. RESULTS: Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and "brain-type" transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%. CONCLUSION: L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH. GENERAL SIGNIFICANCE: L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF.

Reversible alterations of the neuronal activity in spontaneous intracranial hypotension.

AIM: The aim of this article is to investigate the pathophysiology underlying the alternation of the cognitive function and neuronal activity in spontaneous intracranial hypotension (SIH). METHODS: Fifteen patients with SIH underwent resting-state functional magnetic resonance imaging and working-memory (WM) test one day before and one month after a surgical operation. Alternation of the cognitive function and spontaneous neuronal activity measured as amplitude of the low-frequency fluctuations (ALFF) and the functional connectivity of the default-mode network (DMN) and frontoparietal networks (FPNs) were evaluated. RESULTS: WM performance significantly improved post-operatively. Whole-brain linear regression analysis of the ALFF revealed a positive correlation between cognitive performance change and ALFF change in the precuneus while a negative correlation was found in the bilateral orbitofrontal cortices (OFCs) and right medial frontal cortex (MFC). The ALFF changes normalised with the WM performance improvement post-operatively. The FPN activity in the right OFC was also increased pre-operatively. Partial correlation analysis revealed a significant correlation between WM performance and right OFC activity controlled for right FPN activity. CONCLUSIONS: The abnormal activity of the OFCs and MFC that is not originating from the synchronous intrinsic network activity, together with the decreased activity of the central node of the DMN, could lead to cognitive impairment in SIH that is reversible through restoration of the cerebrospinal fluid.

Cerebrospinal fluid leakage after radioisotope cisternography is not influenced by needle size at lumbar puncture in patients with intracranial hypotension.

BACKGROUND: Radioisotope (RI) cisternography is considered to be the most important examination for the final diagnosis of intracranial hypotension, typically indicating cerebrospinal fluid (CSF) leakage as RI parathecal activity. Early bladder filling (EBF) of RI is another important finding. However, whether EBF without parathecal activity represents real CSF leakage due to intracranial hypotension or only an epiphenomenon of lumbar puncture causing CSF leak through a needle hole has been questioned. METHODS: To address this issue, we performed quantitative analysis of RI cisternography on 171 patients with suspected intracranial hypotension using different needle sizes (22 G, 23 G and 25 G) and compared RI residual activity in the CSF at different time points after injection. We also analyzed occurrence of early bladder filling and post-lumbar puncture headache. RESULTS: No significant difference in RI residual activity was identified between the 22 G, 23 G and 25 G groups. The incidence of parathecal activity and early bladder filling was not significantly different between groups. The 22 G and 23 G groups had a higher but non-significant incidence of post lumbar headache. CONCLUSION: The results suggest that needle size, at least for 22-25 G, does not affect the results of RI cisternographic diagnostic tests for CSF leakage and bladder filling in intracranial hypotension.

Chronic Subdural Hematoma Associated with Spontaneous Intracranial Hypotension: Therapeutic Strategies and Outcomes of 55 Cases.

Spontaneous intracranial hypotension (SIH) has increasingly been recognized, and it is well known that SIH is sometimes complicated by chronic subdural hematoma (SDH). In this study, 55 cases of SIH with SDH were retrospectively analyzed, focusing on therapeutic strategies and outcomes. Of 169 SIH cases (75 males, 84 females), 55 (36 males, 19 females) were complicated by SDH. SIH was diagnosed based on clinical symptoms, neuroimaging, and/or low cerebrospinal fluid pressure. Presence of orthostatic headache and diffuse meningeal enhancement on magnetic resonance imaging were regarded as the most important criteria. Among 55 SIH with SDH cases, 13 improved with conservative treatment, 25 initially received an epidural blood patch (EBP), and 17 initially underwent irrigation of the hematomas. Of the 25 initially treated with EBP, 7 (28.0%) needed SDH surgery and 18 (72.0%) recovered fully without surgery. Of 17 SDH cases initially treated with surgery, 6 (35.7%) required no EBP therapy and the other 11 (64.3%) needed EBP and/or additional SDH operations. In the latter group, 2 cases had transient severe complications during and after the procedures. One of these 2 cases developed a hoarse voice complication. Despite this single, non-severe complication, all enrolled in this study achieved good outcomes. The present study suggests that patients initially receiving SDH surgery may need additional treatments and may occasionally have complications. If conservative treatment is insufficient, EBP should be performed prior to hematoma irrigation.

Histopathologic amelioration of fibroproliferative change in rat irradiated lung using soluble transforming growth factor-beta (TGF-beta) receptor mediated by adenoviral vector.

PURPOSE: To investigate whether an adenoviral-mediated soluble transforming growth factor-beta (TGF-beta) type II receptor could ameliorate fibroproliferative change in rat irradiated lung. METHODS AND MATERIALS: We used an adenoviral vector expressing a soluble TGF-beta receptor (AdT beta-ExR), which adsorbs TGF-beta and inhibits the function of the wild-type receptor as a dominant-negative mutant. Rats were i.v. injected with either 0.5 mL of AdT beta-ExR (1.0 x 10(9) plaque-forming units/mL) or AdLacZ (1.0 x 10(9) plaque-forming units/mL), a control adenovirus expressing bacterial beta-galactosidase, or saline, then 3 days later they received 4-MV X-ray irradiation of 30 Gy in a single fraction to the right lung. Eight weeks after irradiation, the rats were killed, and their right lungs were examined histopathologically. The respiratory rates of all rats were observed with a charge-coupled device video system before the rats were irradiated and killed. RESULTS: A significant increase in breathing rates was observed in the saline- or AdLacZ-infected rats. The respiratory rate of the AdT beta-ExR-treated rats was significantly lower than that in the saline- or AdLacZ-infected rats. Fibroproliferative change in the irradiated lung was markedly reduced in the AdT beta-ExR-treated rats in comparison with the saline- or AdLacZ-infected rats. With respect to active TGF-beta 1 expression, myofibroblast proliferation, and macrophage/monocyte infiltration, the findings were identical to those for fibroproliferative change. CONCLUSIONS: Our results indicate that TGF-beta plays a critical role in radiation-induced fibroproliferation of the lung and suggest that the adenoviral-mediated soluble TGF-beta receptor may have potential for use in the amelioration of this intractable pulmonary damage.

Combined argatroban and edaravone caused additive neuroprotection against 15 min of forebrain ischemia in gerbils.

We investigated whether or not a combination of the selective thrombin inhibitor, argatroban, and the free radical scavenger, edaravone (MCI-186), ameliorates postischemic hypoperfusion and decreases mortality after 15 min of forebrain ischemia in the gerbil. Argatroban or edaravone alone significantly increased postischemic cerebral blood flow and attenuated brain edema after reperfusion. However, only the combination increased the survival ratio (P<0.05 by Mantel-Cox) and protected the damage of neuronal cells. The present study indicates that anticoagulants and free radical scavengers reciprocally function to inhibit the progression of ischemic cell damage and that a combination of these types of drugs will help to improve the outcomes after cerebral ischemia.

Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit vascular endothelial growth factor (VEGF) secretion from human glioblastoma cells.

We investigated the effects of histone deacetylase (HDAC) inhibitors such as sodium butyrate (SB) and trichostatin A (TSA) on the expression of vascular endothelial growth factor (VEGF) by human glioblastoma T98G, U251MG, and U87MG cells. The glioblastoma cells secreted three VEGF isoforms, VEGF (189), (165), and (121), although the expression levels of VEGF differed between the cell types. Treatment with either 5mM SB or 100 ng/ml TSA reduced VEGF secretion in conditioned media and reduced VEGF mRNA expression. We also studied the expression of VEGF-B, -C, and -D mRNA in human glioblastoma cells and their modulation by HDAC inhibitors. The PCR products of VEGF-B (357bp), VEGF-C (501bp), and VEGF-D (484bp) were amplified in all glioblastoma cells examined. Treatment with SB reduced the expression of VEGF-D mRNA in U251MG cells and the expression of VEGF-B mRNA in U87MG cells. TSA treatment reduced the expression of VEGF-D in U251MG cells. These results suggest that HDAC inhibitors reduce VEGF secretion and modulate the expression of the other VEGF family members, and therefore may inhibit angiogenesis in glioblastoma tissues.

FGF-mediated induction of ciliary body tissue in the chick eye.

Upon morphogenesis, the simple neuroepithelium of the optic vesicle gives rise to four basic tissues in the vertebrate optic cup: pigmented epithelium, sensory neural retina, secretory ciliary body and muscular iris. Pigmented epithelium and neural retina are established through interactions with specific environments and signals: periocular mesenchyme/BMP specifies pigmented epithelium and surface ectoderm/FGF specifies neural retina. The anterior portions (iris and ciliary body) are specified through interactions with lens although the molecular mechanisms of induction have not been deciphered. As lens is a source of FGF, we examined whether this factor was involved in inducing ciliary body. We forced the pigmented epithelium of the embryonic chick eye to express FGF4. Infected cells and their immediate neighbors were transformed into neural retina. At a distance from the FGF signal, the tissue transitioned back into pigmented epithelium. Ciliary body tissue was found in the transitioning zone. The ectopic ciliary body was never in contact with the lens tissue. In order to assess the contribution of the lens on the specification of normal ciliary body, we created optic cups in which the lens had been removed while still pre-lens ectoderm. Ciliary body tissue was identified in the anterior portion of lens-less optic cups. We propose that the ciliary body may be specified at optic vesicle stages, at the same developmental stage when the neural retina and pigmented epithelium are specified and we present a model as to how this could be accomplished through overlapping BMP and FGF signals.

Folding of the tectal cortex by local remodeling of neural differentiation.

The folding pattern of the brain cortex is a precisely regulated process, but the mechanism involved during development remains unclear. A proposed theory predicts that the initiation of cortical folding depends, at least partly, on nonuniform distribution of neuronal differentiation and neurite growth. We tested this theory experimentally, by remodeling the normal pattern of neuronal cell differentiation within the embryonic optic tectum. Multiple foci of activated fibroblast growth factor signaling were created in the tectal cortex to locally change the neural differentiation and axonal growth patterns. At these foci, tectal cells remained undifferentiated and their radial and tangential migration was suppressed. These local changes in the neuronal cell differentiation resulted in a conversion of the tectal cortex from smoothly extended into precociously folded. The results provide in vivo experimental evidence that microscopic changes in the neuronal cell differentiation pattern can induce or remodel the folding pattern of the brain cortex.