Neurofilament light chain is elevated in patients with newly diagnosed idiopathic intracranial hypertension: A prospective study.

BACKGROUND: Idiopathic intracranial hypertension is a secondary headache disorder potentially causing visual loss. Neurofilament light chain is a candidate, prognostic biomarker, but further studies of neuronal biomarkers are needed. Our objective was to investigate neurofilament light chain in cerebrospinal fluid (cNfL) and plasma (pNfL), amyloid-beta 42 (Aß-42), total-tau and phosphorylated-tau in cerebrospinal fluid in new-onset idiopathic intracranial hypertension. METHODS: Prospective case-control study including new-onset idiopathic intracranial hypertension and age, sex and BMI matched controls. Biomarkers were compared between patients and controls and related to papilledema, visual fields and opening pressure. RESULTS: We included 37 patients and 35 controls. Patients had higher age-adjusted cNfL (1.4 vs. 0.6 pg/mL, p-adjusted < 0.001), pNfL (0.5 vs. 0.3 pg/mL, p-adjusted < 0.001) and total-tau/Aß-42 (0.12 vs. 0.11, p-adjusted = 0.039). Significant, positive linear correlations were found between cNfL, pNfL, total-tau/Aß-42 and opening pressure. Patients with severe papilledema had elevated cNfL compared to mild-moderate papilledema (median cNfL: 4.3 pg/mL (3.7) versus 1.0 pg/mL (1.4), p-adjusted = 0.009). cNFL was inversely associated with perimetric mean deviation (r = -0.47, p-adjusted < 0.001). CONCLUSIONS: cNfL, pNfL and total-tau/Aß-42 were elevated in new-onset idiopathic intracranial hypertension. cNfL was associated with severity of papilledema and visual field defects at diagnosis. This indicates early axonal damage. Neurofilament light chain is a candidate biomarker for disease severity.

Is increased activator protein 1 in cerebrospinal fluid as a potential biomarker that distinguishes idiopathic intracranial hypertension from multiple sclerosis?

OBJECTIVES: To distinguish whether idiopathic intracranial hypertension (IIH) is a condition predisposing to multiple sclerosis (MS) or an isolated disease, the current gene transcription factor Activator Protein-1 (AP-1) was evaluated with its potential to differentiate both diseases. BACKGROUND: The aim of this study was to investigate the use of AP-1 as biomarkers for the discrimination of IIH and MS. METHODS: AP-1, TNF-α, and IL-6 protein values in the CSF of the cases were evaluated by the ELISA method. The numerical measures of the groups and the ability of AP-1 to distinguish the groups were analyzed with the ROC curve. RESULTS: There was no difference between the groups in CSF TNF-α, IL-6, CSF, and serum biochemistry analyses. However, it was determined that the AP-1 concentration (pg/ml) was significantly higher in the IIH group, the sensitivity of AP-1 in separating those with IIH was 75%, and the specificity in separating those with MS was 60% in those with an AP-1 concentration of 606.5 and above. CONCLUSION: According to our results, the fact that CSF TNF-α and IL-6 values did not differ in IIH compared to MS revealed that IIH could not methodologically control MS, and AP-1 was a supportive parameter in differentiating both diseases (Tab. 2, Fig. 1, Ref. 31).

Cerebrospinal fluid proteins in idiopathic intracranial hypertension: An exploratory SWATH proteomics analysis.

PURPOSE: The pathogenesis of idiopathic intracranial hypertension (IIH) is currently poorly understood. This exploratory study aimed to identify potential cerebrospinal fluid (CSF) biomarkers in IIH cases compared to controls using SWATH-MS proteomics approach. EXPERIMENTAL DESIGN: CSF samples were collected prospectively from IIH cases and control subjects which were subjected to SWATH-MS based untargeted proteomics. Proteins with fold change > 1.5 or < 0.67 and p-value < 0.05 were considered significantly differentially expressed. Data are available via ProteomeXchange with identifier PXD027751. Statistical analysis was conducted in R version 3.6.2. RESULTS: We included CSF samples from 33 subjects, consisting of 13 IIH cases and 20 controls. A total of 262 proteins were identified in Proteinpilot search. Through SWATH analysis, we quantified 232 proteins. We observed 37 differentially expressed proteins between the two groups with 24 upregulated and 13 downregulated proteins. There were two differential proteins among overweight versus non-overweight IIH cases. Network for 23 proteins was highly connected in the interaction analysis. CONCLUSIONS AND CLINICAL RELEVANCE: Neurosecretory, neuroendocrine, and inflammatory proteins were predominantly involved in causing IIH. This exploratory study served as a platform to identify 37 differentially expressed proteins in IIH and also showed significant differences between overweight and non-overweight IIH patients.

Elevated neurofilament light chain CSF/serum ratio indicates impaired CSF outflow in idiopathic intracranial hypertension.

BACKGROUND: Impaired cerebrospinal fluid (CSF) homeostasis is central to the pathogenesis of idiopathic intracranial hypertension (IIH), although the precise mechanisms involved are still not completely understood. The aim of the current study was to assess the CSF/serum ratio of neurofilament light chain levels (QNfL) as a potential indicator of functional CSF outflow obstruction in IIH patients. METHODS: NfL levels were measured by single molecule array in CSF and serum samples of 87 IIH patients and in three control groups, consisting of 52 multiple sclerosis (MS) patients with an acute relapse, 21 patients with an axonal polyneuropathy (PNP), and 41 neurologically healthy controls (HC). QNfL was calculated as the ratio of CSF and serum NfL levels. Similarly, we also assessed the CSF/serum ratio of glial fibrillary acidic protein (QGFAP) levels to validate the QNfL data. Routine CSF parameters including the CSF/serum albumin ratio (QAlb) were determined in all groups. Lumbar puncture opening pressure of IIH patients was measured by manometry. RESULTS: CSF-NfL levels (r = 0.29, p = 0.008) and QNfL (0.40, p = 0.0009), but not serum NfL (S-NfL) levels, were associated with lumbar puncture opening pressure in IIH patients. CSF-NfL levels were increased in IIH patients, MS patients, and PNP patients, whereas sNfL levels were normal in IIH, but elevated in MS and PNP. Remarkably, QNfL (p < 0.0001) as well as QGFAP (p < 0.01) were only increased in IIH patients. QNfL was positively correlated with CSF-NfL levels (r = 0.51, p = 0.0012) and negatively correlated with S-NfL levels (r = - 0.51, p = 0.0012) in HC, while it was only positively associated with CSF-NfL levels in IIH patients (r = 0.71, p < 0.0001). An increase in blood-CSF barrier permeability assessed by QAlb did not lead to a decrease in QNfL in any cohort. CONCLUSIONS: The observed elevation of QNfL in IIH patients, which was associated with lumbar puncture opening pressure, indicates a reduced NfL transition from the CSF to serum compartment. This supports the hypothesis of a pressure-dependent CSF outflow obstruction to be critically involved in IIH pathogenesis.

Dysregulation of Amino Acid, Lipid, and Acylpyruvate Metabolism in Idiopathic Intracranial Hypertension: A Non-targeted Case Control and Longitudinal Metabolomic Study.

Background: Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure occurring predominantly in women with obesity. The pathogenesis is not understood. We have applied untargeted metabolomic analysis using ultrahigh-performance liquid chromatography-mass spectrometry to characterize the cerebrospinal fluid (CSF) and serum in IIH compared to control subjects. Methods and findings: Samples were collected from IIH patients (n = 66) with active disease at baseline and again at 12 months following therapeutic weight loss. Control samples were collected from gender- and weight-matched healthy controls (n = 20). We identified annotated metabolites in CSF, formylpyruvate and maleylpyruvate/fumarylpyruvate, which were present at lower concentrations in IIH compared to control subjects and returned to values observed in controls following weight loss. These metabolites showed the opposite trend in serum at baseline. Multiple amino acid metabolic pathways and lipid classes were perturbed in serum and CSF in IIH alone. Serum lipid metabolite pathways were significantly increased in IIH. Conclusions: We observed a number of differential metabolic pathways related to amino acid, lipid, and acylpyruvate metabolism, in IIH compared to controls. These pathways were associated with clinical measures and normalized with disease remission. Perturbation of these metabolic pathways provides initial understanding of disease dysregulation in IIH.

Cerebrospinal fluid levels of sortilin-1, lipocalin-2, autotaxin, decorin and interleukin-33 in patients with idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is characterized by increased cerebrospinal fluid (CSF) pressure of unknown cause. It has been suggested that the inflammatory process plays a role in the pathophysiology of the disease. Sortilin-1, lipocalin-2, autotaxin, decorin, and interleukin-33 (IL-33) are among the factors involved in inflammatory processes. OBJECTIVE: To investigate the CSF levels of sortilin-1, lipocalin-2, autotaxin, decorin, and IL-33 in patients with IIH. METHODS: A total of 24 IIH patients and 21 healthy controls were included in the study. Demographic characteristics of the patients and of the control group as well as CSF pressures were evaluated. Sortilin-1, lipocalin-2, autotaxin, decorin and IL-33 levels in the CSF were measured. RESULTS: The CSF levels lipocalin-2, sortilin-1, autotaxin, IL-33 and CSF pressure were significantly higher in the patients group compared with the control group (p < 0.001). Decorin levels were reduced in patients (p < 0.05). There was no correlation between the autotaxin and IL-33 levels and age, gender, CSF pressure, and body mass index. The results of our study showed that inflammatory activation plays an important role in the development of the pathophysiology of IIH. In addition, the fact that the markers used in our study have never been studied in the etiopathogenesis of IIH is important in explaining the molecular mechanism of this disease. CONCLUSION: Studies are needed to evaluate the role of these cytokines in the pathophysiology of the disease. It is necessary to evaluate the effects of these molecules on this process.

ANTECEDENTES: A hipertensão intracraniana idiopática (HII) é caracterizada pelo aumento da pressão do líquido cefalorraquidiano (LCR) de causa desconhecida. Tem sido sugerido que o processo inflamatório desempenha um papel na fisiopatologia da doença. Sortilina-1, lipocalina-2, autotaxina, decorina e interleucina-33 (IL-33) estão entre os fatores envolvidos nos processos inflamatórios. OBJETIVO: Investigar os níveis de sortilina-1, lipocalina-2, autotaxina, decorina e IL-33 no LCR de pacientes com HII. MéTODOS: Um total de 24 pacientes com HII e 21 controles saudáveis foram incluídos no estudo. Foram avaliadas as características demográficas dos pacientes e do grupo controle, bem como as pressões liquóricas. Os níveis de sortilina-1, lipocalina-2, autotaxina, decorina e IL-33 no LCR foram medidos. RESULTADOS: Os níveis no líquido cefalorraquidiano lipocalina-2, sortilina-1, autotaxina, IL-33 e pressão liquórica foram significativamente maiores no grupo de pacientes em comparação com o grupo controle (p < 0,001). Os níveis de decorina foram reduzidos nos pacientes (p < 0,05). Não houve correlação entre os níveis de autotaxina e IL-33 e idade, sexo, pressão liquórica e índice de massa corporal. Os resultados do nosso estudo mostraram que a ativação inflamatória desempenha um papel importante no desenvolvimento da fisiopatologia da HII. Além disso, o fato de os marcadores utilizados em nosso estudo nunca terem sido estudados na etiopatogenia da HII é importante para explicar o mecanismo molecular dessa doença. CONCLUSãO: Estudos são necessários para avaliar o papel dessas citocinas na fisiopatologia da doença. É necessário avaliar os efeitos dessas moléculas nesse processo.

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway.

OBJECTIVE: To determine whether the metabolites of Kynurenine pathway (KP) could serve as biomarkers for distinguishing between viral CNS infections and autoimmune neuroinflammatory diseases, especially anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and herpes virus encephalitis (HSE). METHODS: This study enrolled CSF samples from 76 patients with viral CNS infections, autoimmune neuroinflammatory, and non-inflammatory neurological diseases. We measured cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and kynurenine (Kyn) by ELISA. RESULTS: Kyn concentrations and Kyn/Trp ratios were highly increased (p < 0.001, viral vs. autoimmune) in viral CNS infections, whereas patients with autoimmune neuroinflammatory and non-inflammatory diseases exhibited low concentrations. Furthermore, Kyn concentrations and Kyn/Trp ratio turned out to be excellent biomarkers to distinguish between herpes simplex encephalitis (HSE) and NMDARE (AUC 0.920 and AUC 0.906), whereas Trp concentrations were similar in all three groups. INTERPRETATION: The results suggest that elevated CSF Kyn concentrations and Kyn/Trp ratio may serve as biomarkers for distinguishing viral CNS infections from autoimmune neuroinflammatory diseases. In particular, the distinction between HSE and NMDARE is of great clinical relevance. Further studies are warranted to investigate the potential of CSF Kyn levels and Kyn/Trp ratio as routine parameters in patients with CNS diseases.

COVID-19 and chronic fatigue syndrome: Is the worst yet to come?

There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a "post-COVID-19 fatigue syndrome" is essential for the development of preventive and early treatment methods for this syndrome. In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain. Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.

Serum glial fibrillary acidic protein (GFAP)-antibody in idiopathic intracranial hypertension.

AIM: Idiopathic intracranial hypertension (IIH), a disease of obscure origin, is characterized by headache and visual disturbances due to increased intracranial pressure. Recent line of evidence has suggested involvement of inflammation in IIH pathogenesis thus bringing forward anti-glial autoimmunity as a potential contributor of IIH. Glial fibrillary acidic protein (GFAP) is a major astrocytic autoantigen associated with a specific form of meningoencephalitis. MATERIALS AND METHODS: In this study, we investigated the presence of GFAP-antibody in 65 sera (49 obtained during active disease and 16 during remission) and in 15 cerebrospinal fluid (CSF) samples of 58 consecutively recruited IIH patients using cell based assay and indirect immunohistochemistry. RESULTS: GFAP-antibody was found in active period sera of 2 IIH patients with classical symptoms and good treatment response. Two remission period sera obtained at different time points from one of these cases showed lower titers of GFAP-antibody positivity. IgG from positive samples yielded an astrocytic immunoreactivity pattern. None of the CSF samples showed GFAP-antibodies. CONCLUSIONS: These results suggest that anti-astrocyte autoimmunity might be present in a fraction of IIH patients. Exact pathogenic significance of this association needs to be further studied.

The effect of intracerebral structure volumes on idiopathic intracranial hypertension.

BACKGROUND: This aim of this study was to assess the effect of idiopathic intracranial hypertension (IIH) in the development of intracranial hypertension by measuring patients' cerebrospinal fluid (CSF), brain, and segment volumes. IIH is a disease of unknown cause characterized by chronic CSF pressure elevation and papillary edema. Under the Monro-Kellie doctrine, efforts have been made to explain the disease through an increase in the volumes of one or two of brain, blood or CSF in the intracranial cavity, although these have not been completely successful. METHODS: Twelve IIH patients diagnosed based on the modified Dandy criteria and 15 age- and sex-compatible healthy controls were included in the study. Cases' 3D T1 sequence images were evaluated using the voxel-based volumetric analysis system (volBrain). Intracranial cavity extraction, macrostructures, and subcortical structure volumes were measured and compared. RESULTS: No statistically significant differences were observed between control cases' and IIH patients' CSF, cerebrum, cerebellum, brainstem, and subcortical structure volumes. CONCLUSION: IIH arises from a chronic cause that does not impair the volumetric balance between structures inside the intracerebral cavity.

Cerebrospinal fluid analysis in 108 patients with progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Routine CSF parameters, like CSF cell count, protein concentration, Qalbumin, or intrathecal immunoglobulin synthesis are mostly considered normal. However, this has not been investigated systematically. METHODS: We analyzed routine CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab-treated multiple sclerosis (n = 54) and human immunodeficiency virus (HIV)-infection (n = 25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The total PML cohort was compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). Multiple sclerosis and HIV patients were additionally compared with their own non-PML control groups. RESULTS: The PML group showed an elevated cell count (p < 0.001) compared to the control group, however, this effect was mainly driven by HIV-PML patients. This subgroup also demonstrated a significantly higher proportion of patients with a disturbed blood-CSF-barrier function. CONCLUSIONS: This comprehensive, retrospective study on CSF diagnostic analysis in PML patients provides insight into the CSF of those patients. It demonstrates that CSF composition in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.

The effect of CSF drain on the optic nerve in idiopathic intracranial hypertension.

BACKGROUND: Elevation of intracranial pressure in idiopathic intracranial hypertension induces an edema of the prelaminar section of the optic nerve (papilledema). Beside the commonly observed optic nerve sheath distention, information on a potential pathology of the retrolaminar section of the optic nerve and the short-term effect of normalization of intracranial pressure on these abnormalities remains scarce. METHODS: In this exploratory study 8 patients diagnosed with idiopathic intracranial hypertension underwent a MRI scan (T2 mapping) as well as a diffusion tensor imaging analysis (fractional anisotropy and mean diffusivity). In addition, the clinical presentation of headache and its accompanying symptoms were assessed. Intracranial pressure was then normalized by lumbar puncture and the initial parameters (MRI and clinical features) were re-assessed within 26 h. RESULTS: After normalization of CSF pressure, the morphometric MRI scans of the optic nerve and optic nerve sheath remained unchanged. In the diffusion tensor imaging, the fractional anisotropy value was reduced suggesting a tissue decompression of the optic nerve after lumbar puncture. In line with these finding, headache and most of the accompanying symptoms also improved or remitted within that short time frame. CONCLUSION: The findings support the hypothesis that the elevation of intracranial pressure induces a microstructural compression of the optic nerve impairing axoplasmic flow and thereby causing the prelaminar papilledema. The microstructural compression of the optic nerve as well as the clinical symptoms improve within hours of normalization of intracranial pressure.

Immune Cell Profiling of the Cerebrospinal Fluid Provides Pathogenetic Insights Into Inflammatory Neuropathies.

Objective: Utilize immune cell profiles in the cerebrospinal fluid (CSF) to advance the understanding and potentially support the diagnosis of inflammatory neuropathies. Methods: We analyzed CSF cell flow cytometry data of patients with definite Guillain-Barré syndrome (GBS, n = 26) and chronic inflammatory demyelinating polyneuropathy (CIDP, n = 32) based on established diagnostic criteria in comparison to controls with relapsing-remitting multiple sclerosis (RRMS, n = 49) and idiopathic intracranial hypertension (IIH, n = 63). Results: Flow cytometry revealed disease-specific changes of CSF cell composition with a significant increase of NKT cells and CD8+ T cells in CIDP, NK cells in GBS, and B cells and plasma cells in MS in comparison to IIH controls. Principal component analysis demonstrated distinct CSF immune cells pattern in inflammatory neuropathies vs. RRMS. Systematic receiver operator curve (ROC) analysis identified NKT cells as the best parameter to distinguish GBS from CIDP. Composite scores combing several of the CSF parameters differentiated inflammatory neuropathies from IIH and GBS from CIDP with high confidence. Applying a novel dimension reduction technique, we observed an intra-disease heterogeneity of inflammatory neuropathies. Conclusion: Inflammatory neuropathies display disease- and subtype-specific alterations of CSF cell composition. The increase of NKT cells and CD8+ T cells in CIDP and NK cells in GBS, suggests a central role of cytotoxic cell types in inflammatory neuropathies varying between acute and chronic subtypes. Composite scores constructed from multi-dimensional CSF parameters establish potential novel diagnostic tools. Intra-disease heterogeneity suggests distinct disease mechanisms in subgroups of inflammatory neuropathies.

A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics.

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.

Evaluation of CSF flow metrics in patients with communicating hydrocephalus and idiopathic intracranial hypertension.

PURPOSE: To search for CSF dynamics of idiopathic intracranial hypertension (IIH) and communicating hydrocephalus and any correlation between MRI findings, CSF metrics and CSF opening pressure in IIH. MATERIALS AND METHODS: Healthy subjects (30) and subjects with IIH (29) and high-pressure communicating hydrocephalus (43) were enrolled. Nonparametric Kruskal-Wallis test (p = 0.05) was used to compare three groups, Mann-Whitney U test with Bonferroni correction to compare two groups (p = 0.016). Correlation of MRI findings of IIH with CSF metrics and CSF opening pressure was analyzed by Spearman's Rank correlation coefficient (p = 0.05). RESULTS: In IIH, no correlation between MRI findings and aqueductal stroke volume (ASV) but statistically significantly CSF opening pressure in the presence of transverse sinus compression was noted. Comparing with healthy subjects, ASV was nonsignificantly lower and standardized diastolic and sum and difference of systolic and diastolic flow durations were statistically significantly lower. Comparing with hydrocephalus, the width of prepontine cistern (PPC)/the width of aqueductus sylvii (AS) was significantly higher and other CSF metrics with standardized systolic and sum of systolic and diastolic flow durations were significantly lower. In hydrocephalus, ASV and peak velocities were significantly higher. Compared with normal group, PPC/AS and reverse/forward flow duration were significantly lower and other CSF metrics were significantly higher. CONCLUSION: In hydrocephalus, significant increase in ASV and peak velocities were noted. In IIH, CSF opening pressure was statistically significantly high in the presence of transverse sinus compression and standardized diastolic flow durations were statistically significantly short that are probably effects of increased impedance of CSF flow against increased intracranial pressure and unchanged or even decreased intraventricular CSF volume.

Impaired cerebrospinal fluid pressure.

Abnormalities of cerebrospinal fluid (CSF) pressure are relatively common and may lead to a variety of symptoms, with headache usually being the most prominent one. The clinical presentation of alterations in CSF pressure may vary significantly and show a striking similitude to several primary headache syndromes. While an increase in CSF pressure may be of primary or secondary origin, a pathologic decrease of CSF pressure is usually the result of a meningeal rupture with a resulting leakage of CSF. The pathophysiologic mechanisms of idiopathic intracranial hypertension (IIH) remain largely unknown. However recent evidence indicates that an abnormality in CSF outflow and absorption is likely to play a significant role. Treatment usually consists of a combination of weight loss and a pharmacologic approach using carbonic anhydrase inhibitors. Recent results of the first randomized, double-blind, placebo-controlled trial (RCT) with acetazolamide proved its efficacy in reducing headache and visual disturbances. Clinical evidence suggests efficacy for topiramate and furosemide but no RCT has been conducted to date to confirm these results. In contrast to IIH, spontaneous intracranial hypotension frequently remits spontaneously without specific treatment. If necessary, treatment options range from conservative methods to epidural blood or fibrin sealant patches and surgical interventions.

Cerebrospinal fluid total protein in idiopathic intracranial hypertension.

OBJECTIVE: To evaluate the relationship between CSF total protein concentration (CSF protein) and CSF opening pressure in idiopathic intracranial hypertension (IIH), and to explore the association of age, gender, race, BMI, and Humphrey visual field mean deviation (HVF MD) with CSF total protein. METHODS: The medical records of all IIH patients seen between 1989 and 2016 at one institution were systematically reviewed for demographics, CSF opening pressure, CSF contents, and HVF MD (at initial evaluation and most recent follow-up). Linear regression of CSF protein on CSF opening pressure was performed also considering BMI, age, gender, race, HVF MD, and year of lumbar puncture. RESULTS: We included 266 IIH patients (13 pre-pubertal children, 35 post-pubertal children, 218 adults). There was a negative linear association between CSF opening pressure and CSF protein: CSF protein decreased by 0.18mg/dL for each 1cm H2O increase in CSF opening pressure (p<0.001). After controlling for CSF opening pressure, mean CSF protein was 4.1mg/dL higher in white patients than in black patients (p<0.001). Multivariable analysis found that CSF opening pressure (p=0.007), white race (p<0.001), and HVF MD (most recent follow-up, worst eye, p=0.05) remained independently associated with CSF protein controlling for year of lumbar puncture and age. CONCLUSIONS: There was a negative association between CSF protein and CSF opening pressure. After controlling for CSF opening pressure, CSF protein was higher in white patients and unaffected by age, gender, or BMI. Our findings help clarify inconsistent results of prior studies, but do not really help clarify IIH pathophysiology.

Intracranial elastance is increased in idiopathic intracranial hypertension.

BACKGROUND AND PURPOSE: To date, no pathophysiological model has sufficiently accounted for all the findings encountered in patients with idiopathic intracranial hypertension (IIH). Intracranial elastance is an index of volume-buffering capacity known to play a role in certain disorders of cerebrospinal fluid (CSF) dynamics, which has not been previously investigated in relation to IIH patients. METHODS: This was a single-center retrospective cohort study from 1 July 2011 to 1 July 2016. Values for opening pressure (PO ), closing pressure (PC ) and volume (V) of CSF removed were collected, as well as demographic and clinical covariates. Intracranial elastance (E) and pressure-volume index (PVI) were calculated according to established equations: E = (PO -PC )/V and PVI = V/log10 (PO /PC ), respectively. Those with an alternative central nervous system pathology, including meningitis, encephalitis and normal pressure hydrocephalus were excluded. Eligible patients were subdivided into two groups based on final diagnosis: a control group and an IIH group. RESULTS: In our cohort (n = 49), a significant association of both E (P < 0.0001) and PVI (P = 0.005) with a diagnosis of IIH was observed. Median E was 0.45 [interquartile range (IQR) 0.29-0.63] in the control group and 1 (IQR 0.59-1.29) in the IIH group, and median PVI was 98.07 (IQR 59.92-135.86) in the control group and 64.1 (IQR 42.4-91.7) in the IIH group. Neither E nor PVI were significantly associated with age, gender or body mass index. PVI was independent of opening pressure. CONCLUSIONS: As calculated by clinically accessible indices, our study provides evidence that intracranial elastance is increased in IIH, reflecting a novel insight into disease pathogenesis.