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Objectives Methods Results Interpretation Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials.We performed a prospective 1‐year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient‐reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1‐year progression and evaluated the potential predictive value of several baseline markers on 1‐year disease progression.At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non‐ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA).Longer disease duration, longer non‐expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1‐year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N‐acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase.Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background and objectives: Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs). Methods: Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/ paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout. Results: Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher’s exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue. Conclusion: Our unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immunemediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases. [ABSTRACT FROM AUTHOR]

The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR–aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders. [ABSTRACT FROM AUTHOR]

Objective: This study aims to report three cases of autoimmune encephalitis followed by hemophagocytic lymphohistiocytosis. Methods: Data of relevant patients treated between 2019 and 2022 were retrospectively collected from the Department of Neurology at the Second Affiliated Hospital of Guangzhou Medical University. Results: The age at onset of the three patients was 37, 63, and 36 years, respectively. All three patients were female and presented with cognitive dysfunction and seizures. Behavioral and psychological symptoms were also observed in two cases. All patients were positive for autoantibodies in both the cerebrospinal fluid and serum, while two showed multiple abnormal brain signals on magnetic resonance imaging. All patients exhibited hypocytosis and elevated soluble CD25 and serum ferritin levels. The final diagnoses in two cases were lymphomas, while the remaining case without tumors suffered from a severe infection. All patients received immunotherapy, and the two with lymphoma received anti-tumor treatment. The patient with infection died, and two patients with tumors improved after chemotherapy. Conclusion: Autoimmune encephalitis followed by hemophagocytic lymphohistiocytosis is a rare and severe condition. Prompt attention should be paid to the decline in blood cell counts, particularly in patients who show a slight improvement after immunotherapy or have a risk of lymphoma. Screening for potential tumors and infections and early treatment may help these patients. [ABSTRACT FROM AUTHOR]

Aim To examine whether changes in biomarker concentrations in patients with idiopathic normal-pressure hydrocephalus (iNPH) during 72 h of external lumbar drainage (ELD) can differentiate between responders and non-responders. Methods Twenty patients with clinical and neuroradiological signs of iNPH underwent ELD over a period of 72 h. During this period, changes in cerebrospinal fluid (CSF) concentrations of biomarkers (amyloid-β, total and phosphorylated tau proteins) and intracranial pressure were monitored, and the volume of drained CSF was measured. Changes in the concentrations of selected biomarkers at three time points (0, 36, and 72 h) during ELD were tested for association with changes in clinical condition. Results Ten patients showed significant clinical improvement after ELD, quantified as a difference of two or more points on the Mini-Mental State Examination and/or Japanese iNPH grading scale. The concentration of all tested biomarkers increased during the first 36 h. Respondents had higher Aβ 1-42 at all time points, with a significant difference seen after 72 h. They also had a significantly higher Aβ1-42/Aβ1-40 ratio at all time points. Conclusion A gradual increase in Aβ 1-42 concentration during three-day ELD represents a possible positive prognostic factor for the placement of permanent CSF drainage in patients with iNPH. [ABSTRACT FROM AUTHOR]

Preoperative risk biomarkers for delirium may aid in identifying high-risk patients and developing intervention therapies, which would minimize the health and economic burden of postoperative delirium. Previous studies have typically used single omics approaches to identify such biomarkers. Preoperative cerebrospinal fluid (CSF) from the Healthier Postoperative Recovery study of adults ≥ 63 years old undergoing elective major orthopedic surgery was used in a matched pair delirium case–no delirium control design. We performed metabolomics and lipidomics, which were combined with our previously reported proteomics results on the same samples. Differential expression, clustering, classification, and systems biology analyses were applied to individual and combined omics datasets. Probabilistic graph models were used to identify an integrated multi-omics interaction network, which included clusters of heterogeneous omics interactions among lipids, metabolites, and proteins. The combined multi-omics signature of 25 molecules attained an AUC of 0.96 [95% CI: 0.85–1.00], showing improvement over individual omics-based classification. We conclude that multi-omics integration of preoperative CSF identifies potential risk markers for delirium and generates new insights into the complex pathways associated with delirium. With future validation, this hypotheses-generating study may serve to build robust biomarkers for delirium and improve our understanding of its pathophysiology. [ABSTRACT FROM AUTHOR]

Infant meningitis remains a severe burden on global health, particularly for young infants. Traditional ultrasound imaging techniques are limited in spatial resolution to visualize white blood cells (WBCs) in the cerebrospinal fluid (CSF), which is considered a well-established marker for meningitis detection. This work presents a novel platform that uses high-resolution ultrasound to detect the backscatter signals from microscopic CSF WBCs through the anterior fontanelle of neonates and young infants. The whole system was built around a custom probe that allows for a 20 MHz focused transducer to be mechanically controlled to map the area of interest in the CSF. Data processing can be performed internally in the device without the need to extract the images for further analysis. The in vitro feasibility of the proposed solution was evaluated in imaging 7 μ m particle suspensions at different concentrations relevant to meningitis diagnosis ranging from 7- to 646-particles (pp)/ μ L. The experimental tests were conducted from a simple setup using a sample container to a more realistic setup based on an anatomical phantom of the neonatal head. The results show high-quality images, where 7 μ m particles can be resolved for the different concentrations. [ABSTRACT FROM AUTHOR]

Background: Abnormalities in ataxin‐2 associated with spinocerebellar ataxia type 2 (SCA2) may lead to widespread disruptions in the proteome. This study was performed to identify dysregulated proteome in SCA2 and to explore its clinical‐radiological correlations. Methods: Cerebrospinal fluid (CSF) samples from 21 genetically confirmed SCA2 were subjected to shotgun proteome analysis using mass spectrometry (MS) and tandem mass tag (TMT)‐based multiplexing. Proteins with at least 1.5‐fold change in abundance were identified. Their relative abundance was measured using parallel reaction monitoring (PRM) and correlated against disease‐related factors. Results: Eleven proteins were significantly upregulated in SCA2. They belonged to the family of cell adhesion molecules and granins. Their fold changes showed significant clinical, genetic, and radiological correlations. Conclusions: Significant dysregulation of CSF proteome is seen in SCA2. The dysregulated protein may have potential use in clinical evaluation of patients with SCA2. [ABSTRACT FROM AUTHOR]

Background/Objectives: Abnormalities in cerebrospinal fluid (CSF) dynamics cause diverse conditions, such as hydrocephalus, but the underlying mechanism is still unknown. Methods to study CSF dynamics in small animals have not been established due to the lack of an evaluation system. Therefore, the purpose of this research study is to establish the time-spatial labeling inversion pulse (Time-SLIP) MRI technique for the evaluation of CSF dynamics in mice. Methods: We performed the Time-SLIP technique on 10 wild-type mice and 20 Tiptoe-walking Yoshimura (TWY) mice, a mouse model of ossification of the posterior longitudinal ligament (OPLL). We defined the stir distance as the distance of CSF stirring and calculated the mean ± standard deviation. The intraclass correlation coefficient of intraobserver reliability was also calculated. Furthermore, in TWY mice, the correlation coefficient between stir distance and canal stenosis ratio (CSR) was calculated. Results: The stir distance was significantly lower in TWY mice at 12 weeks and 17 weeks of age (1.20 ± 0.16, 1.21 ± 0.06, and 1.21 ± 0.15 mm at 12 weeks and 1.32 ± 0.21, 1.28 ± 0.23, and 1.38 ± 0.31 mm at 17 weeks for examiners A, B, and C). The intrarater reliability of the three examiners was excellent (>0.90) and there was a strongly negative correlation between stir distance and CSR in TWY mice (>−0.80). Conclusions: In this study, we established the Time-SLIP technique in experimental mice. This technique allows for a better understanding of CSF dynamics in small laboratory animals. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cerebrospinal fluid (CSF) neopterin reflects inflammation of the central nervous system (CNS) and is a potentially useful biomarker for neuroinflammatory assessment and differential diagnosis. However, its optimal cut-off level in adult patients with neurological disease has not been established and it has not been adequately studied in controls. We aimed to determine its usefulness as a biomarker of neuroinflammation and the effect of age on its level. Methods: In this retrospective study, CSF neopterin was evaluated in 652 patients in 38 disease groups. Its levels were analyzed with high-performance liquid chromatography with fluorometric detection. Results: A receiver operating characteristic analysis revealed that the optimal cut-off value of 33.57 pmol/mL for CSF neopterin distinguished the control and meningitis/encephalitis groups with a sensitivity of 100.0% and specificity of 94.4%. In the control group, which consisted of 170 participants (99 men and 71 women; mean ± standard deviation age, 52.56 ± 17.99 years), age was significantly positively correlated with CSF protein (r = 0.474, p < 0.001) and CSF neopterin (r = 0.476, p < 0.001) levels but not with CSF cell count (r = 0.144, p = 0.061). Both male and female controls exhibited significant increases in CSF neopterin levels with age. Similarly, the CSF neopterin level was significantly positively correlated with age in patients with amyotrophic lateral sclerosis, independently of disease duration and respiratory function. Conclusions: CSF neopterin levels were elevated in patients with various CNS diseases, reflecting CNS inflammation; they were also elevated with age. Prospective studies are required to establish CSF neopterin as a sensitive biomarker of neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-tau181), cognitive function, and NPS. Methods: Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4. Results: The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aβ1-42 ratio was no longer associated with the NPI-Q. Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia. [ABSTRACT FROM AUTHOR]

Chiari I malformation, marked by severe headaches and potential brainstem/spinal cord issues, often requires surgical intervention when conservative methods fail. This study introduces a minimally invasive surgery (MIS) Chiari decompression technique utilizing a 3-blade retractor, aiming to reduce postoperative discomfort and optimize outcomes. Chiari type I malformation patients who underwent a MIS technique were included. Technique consisted of a minimal-soft tissue opening using a 3-blade retractor, suboccipital craniectomy, C1 laminectomy, and resection of the atlantooccipital band without a durotomy. Ten patients were treated. Mean age was 43.3 years, with 7 female patients. All patients presented with occipital headaches; 50% retroorbital pain; 40% neck, upper back, or shoulder pain; and 30% limb paresthesias. Median pre-surgical modified Rankin Scale (mRS) was 3 (2–4) and pain visual analog score (VAS) was 7 (5–9). Mean operative time was 59 (59–71) minutes, with mean blood loss of 88.5 (50–140) mL. In our sample, 90% of patients were discharged the same surgical day (mean 7.2 [5.3–7.7] hours postoperative). No immediate or delayed postoperative complications were evidenced. At 6 months, 90% of patients had mRS 0–1. At last follow-up the mean VAS was 1.5 (range: 0–4, P < 0.001). The MIS 3-blade flexible retractor technique for Chiari decompression is feasible, provides wide visualization angles of the suboccipital region and C1 arch, allows 2-surgeon work, and minimizes skin and soft tissue disruption. This combination may diminish postoperative discomfort, reduce the risk of surgical site infections, and optimize outcomes. [ABSTRACT FROM AUTHOR]

In our historical study, we are unveiling one of the very first surgical treatments of hydrocephalus originally scripted in Latin by Fabrici d'Acquapendente and then transcribed into the French language by Chez Pierre Ravaud. During the European Renaissance, Italian pioneering surgeon Fabricid'Acquapendente illustrated the technique performed at that time. Fabrici described the drainage of fluid for hydrocephalus using the insertion of a cannula. The cannula was kept in place for several days and the fluid was drained slowly and in regulated controlled amounts. Layers of bandage drapes were applied to prevent the leakage of fluid escaping from the wound. Unfortunately, we are missing some significant information regarding the surgical techniques as these were not documented by Fabrici. Although skull trephination was relatively well known, it is unsure whether at the time the cannula was inserted deep within the ventricles. Drainage of the fluid may have still occurred from the extracranial space. Moreover, we are unaware of how long the cannula was kept in place. Nonetheless, Fabrici d'Acquapendente may be considered among the first in Italy and possibly in Europe to lay down the foundations for external ventricular drainage system for hydrocephalus. [ABSTRACT FROM AUTHOR]

Neurological involvement has been widely reported in SARS-CoV-2 infection. However, viral identification in the cerebrospinal fluid (CSF) is rarely found. The aim of this study is to evaluate the accuracy of virological and immunological biomarkers in CSF for the diagnosis of neuroCOVID-19. We analyzed 69 CSF samples from patients with neurological manifestations: 14 with suspected/confirmed COVID-19, with 5 additional serial CSF samples (group A), and as a control, 50 non-COVID-19 cases (group B—26 with other neuroinflammatory diseases; group C—24 with non-inflammatory diseases). Real-time reverse-transcription polymerase chain reaction (real-time RT-PCR) was used to determine SARS-CoV-2, and specific IgG, IgM, neopterin, and protein 10 induced by gamma interferon (CXCL-10) were evaluated in the CSF samples. No samples were amplified for SARS-CoV-2 by real-time RT-PCR. The sensitivity levels of anti-SARS-CoV-2 IgG and IgM were 50% and 14.28%, respectively, with 100% specificity for both tests. CXCL-10 showed high sensitivity (95.83%) and specificity (95.83%) for detection of neuroinflammation. Serial CSF analysis showed an association between the neuroinflammatory biomarkers and outcome (death and hospital discharge) in two cases (meningoencephalitis and rhombencephalitis). The detection of SARS-CoV-2 RNA and specific immunoglobulins in the CSF can be used for neuroCOVID-19 confirmation. Additionally, CXCL-10 in the CSF may contribute to the diagnosis and monitoring of neuroCOVID-19. [ABSTRACT FROM AUTHOR]

Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 mg) induced shortterm (,24 hours) mechanical allodynia and heat hyperalgesia, a response that is compromised in Tlr7-/- or Trpa1-/- mice. Ex vivo and in vivo calcium imaging in GCaMP6-report mice revealed increased calcium signal in spinal cord afferent terminals and doral root ganglion/dorsal root ganglia neurons following spinal perfusion and intraplantar injection of let-7b. Patch-clamp recordings also demonstrated enhanced excitatory synaptic transmission (miniature excitatory postsynaptic currents [EPSCs]) in spinal nociceptive neurons following let-7b perfusion or optogenetic activation of axonal terminals. The elevation in spinal calcium signaling and EPSCs was dependent on the presence of toll-like receptor-7 (TLR7) and transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous let-7b is enriched in spinal cord synaptosome, and peripheral inflammation increased let-7b in doral root ganglion/dorsal root ganglia neurons, spinal cord tissue, and the cerebrospinal fluid. Notably, let-7b antagomir inhibited inflammatory pain and inflammation-induced synaptic plasticity (EPSC increase), suggesting an endogenous role of let-7b in regulating pain and synaptic transmission. Furthermore, intrathecal injection of let-7b, at a higher dose (10 mg), induced persistent mechanical allodynia for .2 weeks, which was abolished in Tlr7-/- mice. The high dose of let-7b also induced microgliosis in the spinal cord. Of interest, intrathecal minocycline only inhibited let-7b-induced mechanical allodynia in male but not female mice. Our findings indicate that the secreted microRNA let-7b has the capacity to provoke pain through both neuronal and glial signaling, thereby establishing miRNA as an emerging neuromodulator. [ABSTRACT FROM AUTHOR]

Background: Forty percent of patients with aneurysmatic subarachnoid hemorrhage (aSAH) develop acute hydrocephalus requiring treatment with cerebrospinal fluid (CSF) drainage. CSF cell parameters are used in the diagnosis of nosocomial infections but also reflect sterile inflammation after aSAH. We aimed to study the temporal changes in CSF parameters and compare external ventricular drain (EVD)–derived and lumbar spinal drain–derived samples. Methods: We retrospectively identified consecutive patients with aSAH treated at our neurointensive care unit between January 2014 and May 2019. We mapped the temporal changes in CSF leucocyte count, erythrocyte count, cell ratio, and cell index during the first 19 days after aSAH separately for EVD-derived and spinal drain–derived samples. We compared the sample sources using a linear mixed model, controlling for repeated sampling. Results: We included 1360 CSF samples from 197 patients in the analyses. In EVD-derived samples, the CSF leucocyte count peaked at days 4–5 after aSAH, reaching a median of 225 × 106 (interquartile range [IQR] 64–618 × 106). The cell ratio and index peaked at 8–9 days (0.90% [IQR 0.35–1.98%] and 2.71 [IQR 1.25–6.73], respectively). In spinal drain–derived samples, the leucocyte count peaked at days 6–7, reaching a median of 238 × 106 (IQR 60–396 × 106). The cell ratio and index peaked at 14–15 days (4.12% [IQR 0.63–10.61%]) and 12–13 days after aSAH (8.84 [IQR 3.73–18.84]), respectively. Compared to EVD-derived samples, the leucocyte count was significantly higher in spinal drain–derived samples at days 6–17, and the cell ratio as well as the cell index was significantly higher in spinal drain–derived samples compared to EVD samples at days 10–15. Conclusions: CSF cell parameters undergo dynamic temporal changes after aSAH. CSF samples from different CSF compartments are not comparable. [ABSTRACT FROM AUTHOR]

Background: External ventricular drain (EVD) is used for monitoring intracranial pressure or diverting cerebrospinal fluid. However, confirmation of an infection is not immediate and requires obtaining culture results, often leading to the excessive use of antibiotics. This study aimed to compare noninfectious ventriculitis and EVD infection in terms of the risk factors, predictors, prognosis, and effectiveness of care bundle interventions. Methods: This retrospective study was conducted at a medical center with 1,006 beds in northern Taiwan between January 2018 and July 2022. Standard EVD insertion protocols and care bundles have been implemented since 2018, along with the initiation of chlorhexidine. Results: In total, 742 EVD cases were identified. Noninfectious ventriculitis typically presents with fever approximately 8 days following EVD placement, whereas EVD infection typically manifests as fever after 20 days. Aneurysmal subarachnoid hemorrhage was strongly associated with the development of noninfectious ventriculitis (adjusted odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5–4.4). Alcoholism (adjusted OR 3.5, 95% CI 1.1–12.3) and arteriovenous malformation (adjusted OR 13.1, 95% CI 2.9–58.2) significantly increased the risk of EVD infection. The EVD infection rate significantly decreased from 3.6% (14 of 446) to 1.0% (3 of 219) (p = 0.03) after the implementation of chlorhexidine gluconate bathing. Conclusions: Aneurysmal subarachnoid hemorrhage or fever with neuroinflammation within 2 weeks of EVD placement is indicative of a higher likelihood of noninfectious ventriculitis. Conversely, patients with arteriovenous malformation, alcoholism, or fever with neuroinflammation occurring after more than 3 weeks of EVD placement are more likely to necessitate antibiotic treatment for EVD infection. Chlorhexidine gluconate bathing decreases EVD infection. [ABSTRACT FROM AUTHOR]

Objective: To determine the clinical spectrum, neuroimaging findings, and outcome of Acute Disseminated Encephalomyelitis (ADEM) in children. Method: We conducted a descriptive cross sectional study of all children aged 6 months to 18 years, diagnosed with ADEM at Aga Khan University Hospital, Karachi from January 2018 till December 2022. Results: This retrospective study enrolled 30 cases of ADEM, with a mean age of 6.43 ± 4.079, including 13 males and 17 females. The average hospital stay was 7.29 ± 4.379 days. The most common clinical features were fever, headache, and altered consciousness, while motor deficit was observed in 15 (53.5%) patients. Abnormal cerebrospinal fluid was found in 14 (46.6%) patients. Brain MRI identified bilateral and multifocal lesions in 22 (78.6%) patients, with brainstem lesions detected in 7 (25%) patients. Treatment included IV methylprednisolone (22; 73%), IVIG (9; 30%), or both (6; 20%). Clinical improvement was observed in 25 (89.3%) patients, with residual weakness present in eight (26%) patients at discharge. There was one reported death. Long-term complications included motor deficits, seizures, poor scholastic performance, and behavioral issues. Conclusion: The clinical presentation of ADEM is variable, but the most common symptoms are fever, headache, and altered consciousness. Despite generally favorable outcome, long-term monitoring revealed that patients may experience motor deficits, seizures, cognitive impairment, and academic difficulties. [ABSTRACT FROM AUTHOR]

Spontaneous intracranial hypotension (SIH) is a potentially debilitating condition resulting from a low cerebrospinal fluid (CSF) volume secondary to spinal CSF leakage. Characteristic clinical and radiological imaging findings are helpful in diagnosis. Herein, we present and discuss the magnetic resonance imaging (MRI) and CSF flow study of two patients with SIH and no CSF flow within the cerebral aqueduct, which is extremely rare in the literature. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) leak through petrosal air cells is a known complication after drilling the posterior wall of the internal acoustic canal (IAC) for resection of vestibular schwannoma (VS). Whereas mild pneumocephalus is common after retrosigmoid craniotomy, tension pneumocephalus has been rarely documented. To testify a case of fatal tension pneumocephalus after VS resection in a patient with ventriculo-peritoneal (VP) shunt and to propose possible recommendations to limit the risk of this dramatic complication. A case of fatal tension pneumocephalus after VS resection in presence of hidden CSF fistula is illustrated with pre- and post-operative images. In the uneventful situation of concomitant post-operative CSF fistula in presence of VP shunt, tension pneumocephalus may occur. The negative pressure created by the shunt system and the presence of osteo-dural defect allow the air to enter and, at the same time, prevent the outflow. After VS resection, tension pneumocephalus can occur as a consequence of CSF fistula from petrosal air cells in the presence of functioning VP shunt. Precautions as pre-operative increase to 'virtual-off' the pressure of the valve, subsequences CT scans after surgery and sealing of the petrous air cells are recommended to avoid such as fatal complication. [ABSTRACT FROM AUTHOR]

Contrast-induced encephalopathy (CIE) is a rare complication of angiography. According to our knowledge, the majority of CIE reports is imaging observations and rarely includes results of cerebrospinal fluid (CSF) tests. Furthermore, among the cases reporting the data for CSF testing, most of the results were normal. Here, we report a case of CIE presenting with significantly elevated levels of CSF protein. We found that the course of improvement in brain imaging findings was not consistent with the severity of clinical manifestations. The diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences were normal. Considering the lack of convenient direct indicators to observe blood-brain barrier (BBB) function, changes in the levels of CSF protein may be related to BBB permeability and recovery and may serve as a potential prognostic marker. [ABSTRACT FROM AUTHOR]

Ventriculomegaly is common in aneurysmal subarachnoid haemorrhage (aSAH). An imaging measure to predict the need for cerebrospinal fluid (CSF) diversion may be useful. The bicaudate index (BCI) has been previously applied to aSAH. Our aim was to derive and test a threshold BCI above which CSF diversion may be required. Review of prospective registry. The derivation group (2009–2015) included WFNS grade 1–2 aSAH patients who deteriorated clinically, had a repeat CT brain and underwent CSF diversion. BCI was measured on post-deterioration CTs and the lower limit of the 95% confidence interval (95%CI) was the hydrocephalus threshold. In a separate test group (2016), in WFNS ≥ 2 patients, we compared BCI on diagnostic CTs with CSF diversion within 24 hours. The derivation group (n = 62) received an external ventricular (n = 57, 92%) or lumbar drain (n = 5, 8%). Mean post-deterioration BCI was 0.19 (95%CI 0.17–0.22) for age ≤49 years, 0.22 (95%CI 0.20–0.23) for age 50–64 years and 0.24 (95%CI 0.22–0.27) for age ≥65 years. Hydrocephalus thresholds were therefore 0.17, 0.20 and 0.22, respectively. In the test group (n = 105), there was no significant difference in BCI on the diagnostic CT between good and poor grade patients aged ≤49 years (p = 0.31) and ≥65 years (p = 0.96). 30/66 WFNS ≥ 2 patients underwent CSF diversion, although only 15/30 (50%) exceeded BCI thresholds for hydrocephalus. A significant proportion of aSAH patients may undergo CSF diversion without objective evidence of hydrocephalus. Our threshold values require further testing but may provide an objective measure to aid clinical decision making in aSAH. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusions There is still disagreement about whether to routinely use spectrophotometry to detect xanthochromia in cerebrospinal fluid (CSF) or whether visual inspection is adequate. We aimed to evaluate the diagnostic accuracy of these methods in detecting an aneurysmal subarachnoid hemorrhage in patients with sudden onset severe headache.When a patient presents to the emergency department with a headache for which there is suspicion of a subarachnoid hemorrhage, the gold standard to rule this out is to perform a CSF analysis for xanthochromia with or without spectrophotometry if the cranial non‐contrast computed tomography (CT) upon admission is negative.Having applied the gold standard, we retrospectively included patients with acute headache who underwent both CT scan and CSF spectrophotometry at our hospital in the period 2002–2020. Patients were excluded if the cranial CT was interpreted as positive, there was a bloody CSF, or if visual assessment data of the CSF was unavailable. We scrutinized the patients’ medical records and evaluated the benefit of spectrophotometry compared to visual inspection. The net bilirubin absorbance cut‐off for support of subarachnoid hemorrhage was set at >0.007 absorbance units. The spectrophotometry was also considered positive if the net bilirubin absorbance was ≤0.007 and net oxyhemoglobin absorbance was ≥0.1 absorbance units. We calculated and compared the sensitivity and specificity of CSF spectrophotometry and visual inspection of the CSF.In total, 769 patients, with a mean age of 42.3 ± (standard deviation [SD] = 17.3) years, were included. The headache onset was classified as a thunderclap headache in 41.5%, and 4.7% had a sudden loss of consciousness. Fifteen patients (2%) were finally diagnosed with a subarachnoid hemorrhage, six (0.8%) had an aneurysmal subarachnoid hemorrhage, seven (0.9%) had a perimesencephalic hemorrhage, one (0.1%) had a cortical cerebral sinus venous thrombosis, and one (0.1%) had a spinal epidural hematoma. Four patients (0.5%) had a subarachnoid hemorrhage that was not detected by visual inspection, and two were caused by an aneurysmal rupture. One of these two patients died just before intervention, and the other underwent coiling for an anterior communicating aneurysm. The number needed for lumbar puncture to detect a subarachnoid hemorrhage was 51, but 128 to detect an aneurysmal hemorrhage. The corresponding numbers needed for CSF spectrophotometric analysis were 192 and 385, respectively. Spectrophotometry was positive in 31 patients (4.0%), of whom 18 (2.3%) also had visually detected xanthochromia (11 true positive). The mean net bilirubin absorbance in the 13 samples with visually clear CSF was 0.0111 ± (SD = 0.0103) absorbance units, compared to 0.0017 ± (SD = 0.0013) in the CSF with negative spectrophotometry. The corresponding figures for net oxyhemoglobin absorbance were 0.0391 ± (SD = 0.0522) versus 0.0057 ± (SD = 0.0081). The sensitivity of spectrophotometric xanthochromia detection was 100% (95% confidence interval [CI], 78–100), compared to 73% (95% CI, 45–92) for visual xanthochromia detection. The specificity of spectrophotometric xanthochromia detection was 98% (95% CI, 97–99) compared to 99% (95% CI, 98–100) for visual xanthochromia detection. Both methods had high negative predictive values: 100% (95% CI, 99.5–100) versus 99.5% (95% CI, 98.6–99.9), respectively.Both visual inspection and spectrophotometry have high diagnostic accuracy for detecting CSF xanthochromia, but the lower sensitivity of visual assessment makes it unreliable, and we recommend the use of spectrophotometry in clinical practice. [ABSTRACT FROM AUTHOR]

This article discusses a rare type of mesenchymal malignancy called EWSR1:POU2AF3(COLCA2) spindle/round cell sarcoma, which primarily affects the sinonasal tract but can also occur in other locations. The article presents a case study of a 32-year-old male patient with this type of sarcoma, describing the clinical presentation, imaging findings, histopathological characteristics, and immunohistochemical analyses. The authors emphasize the importance of molecular testing in the diagnosis of undifferentiated tumors in the sinonasal tract and highlight the significance of targeted RNA sequencing. They also discuss the prognosis and treatment options for this rare malignancy. [Extracted from the article]

Aim: To review the main pathological findings of Neuromyelitis Optica Spectrum Disorder (NMOSD) associated with the presence of autoantibodies to aquaporin-4 (AQP4) as well as the mechanisms of astrocyte dysfunction and demyelination. Methods: An comprehensive search of the literature in the field was carried out using the database of The National Center for Biotechnology Information from. Systematic searches were performed until July 2022. Results: NMOSD is an inflammatory and demyelinating disease of the central nervous system mainly in the areas of the optic nerves and spinal cord, thus explaining mostly the clinical findings. Other areas affected in NMOSD are the brainstem, hypothalamus, and periventricular regions. Relapses in NMOSD are generally severe and patients only partially recover. NMOSD includes clinical conditions where autoantibodies to aquaporin-4 (AQP4-IgG) of astrocytes are detected as well as similar clinical conditions where such antibodies are not detected. AQP4 are channel-forming integral membrane proteins of which AQ4 isoforms are able to aggregate in supramolecular assemblies termed orthogonal arrays of particles (OAP) and are essential in the regulation of water homeostasis and the adequate modulation of neuronal activity and circuitry. AQP4 assembly in orthogonal arrays of particles is essential for AQP4-IgG pathogenicity since AQP4 autoantibodies bind to OAPs with higher affinity than for AQP4 tetramers. NMOSD has a complex background with prominent roles for genes encoding cytokines and cytokine receptors. AQP4 autoantibodies activate the complement-mediated inflammatory demyelination and the ensuing damage to AQP4 water channels, leading to water influx, necrosis and axonal loss. Conclusions: NMOSD as an astrocytopathy is a nosological entity different from multiple sclerosis with its own serological marker: immunoglobulin G-type autoantibodies against the AQP4 protein which elicits a complement-dependent cytotoxicity and neuroinflammation. Some patients with typical manifestations of NMSOD are AQP4 seronegative and myelin oligodendrocyte glycoprotein positive. Thus, the detection of autoantibodies against AQP4 or other autoantibodies is crucial for the correct treatment of the disease and immunosuppressant therapy is the first choice. [ABSTRACT FROM AUTHOR]

Cryptococcal meningitis (CM) causes significant global morbidity and mortality. Current therapeutic strategies rely on deoxycholated or liposomal forms of the polyene amphotericin B. Nystatin is also a polyene with broad-spectrum antimicrobial activity. Treatment with systemic nystatin has been limited by toxicity, which is a consistent challenge with polyene therapeutics. One mechanism to improve the toxicity is usage of a liposomal form of the active agent. Previous data from a murine candidemia model indicated that liposomal nystatin may be an effective antifungal drug formulation. Since the rabbit model of CM is a highly predictive preclinical system for evaluating antifungal therapeutics, we tested the effectiveness of two doses of daily liposomal nystatin, 3 and 8 mg/kg in the rabbit model of CM. Treatment with liposomal nystatin in this model did not reduce the fungal burden in the cerebrospinal fluid. A subsequent clinical trial also did not find activity in a human population. These data indicate that liposomal nystatin in the current form and at the tested dosages is not an effective therapy for CM. The data provide further evidence for the predictive power of the rabbit model of CM as a vital preclinical system for testing novel antifungal therapeutics for CM. [ABSTRACT FROM AUTHOR]

Leucine-rich glioma-inactivated protein 1 (LGI-1) encephalitis is a rare form of autoimmune limbic encephalitis. Although relatively well documented in adults, pediatric cases are rare and remain poorly understood. We reviewed two pediatric cases of LGI-1 encephalitis from a single tertiary care facility retrospectively. The detailed analysis included assessment of the initial presentation, clinical progression, diagnostic challenges, treatments, and outcome. To contextualize the differences between pediatric and adult manifestations of disease, we compared these findings with existing literature. Both cases illustrate the diagnostic challenges faced at initial presentation due to the rarity of this diagnosis in children and the absence of characteristic faciobrachial dystonic seizures, which is common in adults. The constellation of neuropsychiatric symptoms and refractory focal seizures led to a high clinical suspicion for autoimmune encephalitis, therefore, both cases were treated empirically with intravenous methylprednisolone. The diagnosis in both cases was confirmed with positive serum antibody testing, reinforcing that LGI-1 antibodies are more sensitive in the serum rather than the cerebrospinal fluid (CSF). Seizure control and improvement in cognitive symptoms was achieved through a combination of immunotherapy and antiseizure medications. This case series underscores the significance of considering LGI-1 encephalitis in the differential diagnosis of pediatric patients exhibiting unexplained neuropsychiatric symptoms and focal seizures and emphasizes the importance of performing both serum and CSF antibody testing. It is necessary to conduct further research to identify the full range of pediatric presentations and to determine the optimal treatment protocol. [ABSTRACT FROM AUTHOR]

Cerebrovascular and neurological diseases are characterized by neuroinflammation, which alters the neurovascular unit, whose interaction with the choroid plexus is critical for maintaining brain homeostasis and producing cerebrospinal fluid. Dysfunctions in such process can lead to conditions such as idiopathic normal pressure hydrocephalus, a common disease in older adults. Potential pharmacological treatments, based upon intranasal administration, are worthy of investigation because they might improve symptoms and avoid surgery by overcoming the blood–brain barrier and avoiding hepatic metabolism. Nasal lipid nanocarriers, such as solid lipid nanoparticles, may increase the nasal retention and permeation of drugs. To this aim, green solid lipid nanoparticles, obtained by coacervation from natural soaps, are promising vehicles due to their specific lipid matrix composition and the unsaponifiable fraction, endowed with antioxidant and anti-inflammatory properties, and thus suitable for restoring the neurovascular unit function. In this experimental work, such green solid lipid nanoparticles, fully characterized from a physico-chemical standpoint, were loaded with a drug combination suitable for reverting hydrocephalus symptoms, allowing us to obtain a non-toxic formulation, a reduction in the production of the cerebrospinal fluid in vitro, and a vasoprotective effect on an isolated vessel model. The pharmacokinetics and biodistribution of fluorescently labelled nanoparticles were also tested in animal models. [ABSTRACT FROM AUTHOR]

The blood–cerebrospinal fluid barrier (BCSFB) tightly regulates molecular exchanges between the bloodstream and cerebrospinal fluid (CSF), creating challenges for effective central nervous system (CNS) drug delivery. This review assesses intrathecal (IT) nanoparticle (NP) delivery systems that aim to enhance drug delivery by circumventing the BCSFB, complementing approaches that target the blood–brain barrier (BBB). Active pharmaceutical ingredients (APIs) face hurdles like restricted CNS distribution and rapid clearance, which diminish the efficacy of IT therapies. NPs can be engineered to extend drug circulation times, improve CNS penetration, and facilitate sustained release. This review discusses key pharmacokinetic (PK) parameters essential for the effectiveness of these systems. NPs can quickly traverse the subarachnoid space and remain within the leptomeninges for extended periods, often exceeding three weeks. Some designs enable deeper brain parenchyma penetration. Approximately 80% of NPs in the CSF are cleared through the perivascular glymphatic pathway, with microglia-mediated transport significantly contributing to their paravascular clearance. This review synthesizes recent progress in IT-NP delivery across the BCSFB, highlighting critical findings, ongoing challenges, and the therapeutic potential of surface modifications and targeted delivery strategies. [ABSTRACT FROM AUTHOR]

Sleeping late has been associated with cognitive impairment, and insufficient sleep can affect the secretion of feeding-related cytokines. Feeding-related cytokines may contribute to cognitive deficits resulting from delayed bedtime. Glial cell line-derived neurotrophic factor (GDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF), which are feeding-related neurotrophic factors, have been associated with improved cognitive function and neuroprotective abilities. Enhanced expression of GDNF and MANF is linked to increased energy expenditure and hyperphagia, respectively. This study aimed to investigate the association between cerebrospinal fluid (CSF) GDNF, MANF, cognition, and sleep time and to explore the moderating effects of GDNF and MANF on cognitive impairment in individuals who sleep late. This cross-sectional study included participants (mean age 31.76 ± 10.22 years) who were categorized as ≤23 o'clock sleepers (n = 66) and >23 o'clock sleepers (n = 125) based on sleep time. Cognition was assessed using Montreal Cognitive Assessment (MoCA), and GDNF and MANF levels in CSF were measured. MANF may play a moderating role in the relationship between sleep time and cognition (R2 = 0.06, β = 0.59, p = 0.031). Age showed a negative correlation with MoCA scores (R2 = 0.08, β = −0.18), while education exhibited a positive correlation (β = 0.17, both p < 0.05). Only ≤23 o'clock sleepers exhibited a negative correlation between MANF levels and BMI (r = −0.35, p = 0.005). This study provides hitherto undocumented evidence of the potential protective effect of CSF MANF on cognitive impairment of late sleepers, which suggests that maintaining a regular sleep schedule may contribute to cognition and overall health, with MANF playing a role in this process. • CSF MANF exhibited a protective effect on the cognition of individuals who sleep late. • ≤23 o'clock sleepers exhibited a negative correlation between CSF MANF levels and BMI. • Age and education showed negative and positive correlations with MoCA, respectively. [ABSTRACT FROM AUTHOR]

This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections. Fifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14–3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes. The synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up. It is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect. This first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally. • A longitudinal investigation of 59 patients with bipolar disorder and 37 healthy individuals • A novel panel of CSF protein biomarkers of synaptic dysfunction was applied. • Intriguing trends but no statistically significant changes were found. [ABSTRACT FROM AUTHOR]

Background: Intracranial arachnoid cysts are benign collections of cerebrospinal fluid that are often asymptomatic and discovered incidentally. An interhemispheric location of these lesions is rare, with only a few such cases reported in the literature. Though spontaneous regression of arachnoid cysts has been described in other locations, to date this phenomenon has not been reported in interhemispheric fissure cysts. Observations: In this report, we describe a patient with a large, multiloculated interhemispheric arachnoid cyst diagnosed on prenatal ultrasound. She did not exhibit neurologic deficits or signs of increased intracranial pressure and was observed with serial imaging. After several years of observation, imaging revealed spontaneous and progressive decrease in the cyst size. Lessons: We illustrate a case of regression of an interhemispheric arachnoid cyst in a pediatric patient. To our knowledge, this is the first reported case of spontaneous shrinkage of an arachnoid cyst in this location. Although the current presentation is rare, this reporting adds to the current understanding of natural history of arachnoid cysts and provides an example of radiographical improvement without intervention of a cyst located within the interhemispheric fissure. [ABSTRACT FROM AUTHOR]

The early diagnosis of tuberculosis (TB) in infants is challenging owing to the non-specific clinical manifestations in infancy, particularly preterm infants. Two cases in preterm infants are reported. Case 1, conceived by in vitro fertilization (IVF), was born at 27 + 1 weeks gestational age weighing 880 g. He presented on Day 85 with intermittent fever. Following a course of systemic broadspectrum antibiotics, he deteriorated, developing acute respiratory distress syndrome (ARDS). TB Xpert polymerase chain reaction (PCR) of the sputum obtained by laryngeal aspiration confirmed Mycobacterium TB (MTB) on Day 97. He responded well to anti-tuberculosis treatment. His mother had a fever and headache and was diagnosed with COVID-19 79 days after delivery. The fever persisted for nearly 10 days after empirical treatment. She was eventually diagnosed with miliary TB and tuberculous meningitis 92 days after delivery. Case 2 was conceived by IVF and born at 36 + 6 weeks gestation weighing 2430 g. She presented on Day 15 with intermittent fever and abdominal distention. Chest and abdominal radiography demonstrated severe diffuse inflammatory changes. She had received BCG vaccination, and there was no history of contact with active TB. TB PCR of the sputum obtained by laryngeal aspiration confirmed MTB on Day 19. The asymptomatic mother was subsequently diagnosed with pulmonary and genital TB. TB should be considered as a differential diagnosis in infants with unexpected respiratory distress and fever. Women evaluated for infertility should be routinely screened for TB before receiving assisted reproductive treatment, particularly where TB is prevalent. Abbreviations: ARDS: acute respiratory distress syndrome; BPD: bronchopulmonary dysplasia; CPAP: continuous positive airway pressure; CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; IVF: in vitro fertilization; KMC: Kangaroo mother care; MDR: multidrug-resistant; MTB: Mycobacterium tuberculosis; NICU: neonatal intensive care unit; PCR: polymerase chain reaction; PS: pulmonary surfactant; SIMV: synchronised intermittent mandatory ventilation; TB: tuberculosis; CT: computed tomography; HREZ: isoniazid, rifampin, ethambutol and pyrazinamide; IGRA: interferon-γ release assay; IVF: in vitro fertilization; PCR: polymerase chain reaction; TB: tuberculosis. [ABSTRACT FROM AUTHOR]

Aquaporin-4 (AQP4) expression is associated with the development of congenital hydrocephalus due to its structural role in the ependymal membrane. Gene expression analysis of periaqueductal tissue in AQP4-knockout (KO) mice at 11 days of age (P11) showed a modification in ependymal cell adhesion and ciliary protein expression that could alter cerebrospinal fluid homeostasis. A microglial subpopulation of CD11c+ cells was overexpressed in the periaqueductal tissue of mice that did not develop hydrocephalus, suggesting a possible protective effect. Here, we verified the location of this CD11c+ expression in the corpus callosum (CC) and cerebellum of AQP4-KO mice and analysed its time course. Immunofluorescence labelling of the CD11c protein in the CC and cerebellum of WT and KO animals at P3, P5, P7 and P11 confirmed an expanded presence of these cells in both tissues of the KO animal; CD11c+ cells appeared at P3 and reached a peak at P11, whereas in the WT animal, they appeared at P5, reached their peak at P7 and were undetectable by P11. The gene expression analysis in the CC samples at P11 confirmed the presence of CD11c+ microglial cells in this tissue. Among the more than 4000 overexpressed genes, Spp1 stood out with the highest differential gene expression (≅600), with other genes, such as Gpnmb, Itgax, Cd68 and Atp6v0d2, also identified as overexpressed. Therefore, CD11c+ cells appear to be necessary for normal corpus callosum development during postnatal life, and the absence of AQP4 prolonged its expression in this tissue. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) is a rare, neurodegenerative movement disorder. Together with multiple system atrophy (MSA), Dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD), PSP forms a group of atypical parkinsonisms. The latest diagnostic criteria, published in 2017 by the Movement Disorders Society, classify PSP diagnosis into defined, probable, and possible categories based on clinical examination. However, no single test is specific and sensitive for this disease. Microribonucleic acids (miRNAs) are promising molecules, particularly in the case of diseases that lack appropriate diagnostic and treatment tools, which supports exploring their role in PSP. We aimed to systematically review the current knowledge about the role of miRNAs in PSP. This study was registered in the Open Science Framework Registry, and the protocol is available online. Primary original studies, both clinical and preclinical, written in English and assessing miRNAs in PSP were included. Systematic reviews, meta-analyses, reviews, case reports, letters to editors, commentaries, conference abstracts, guidelines/statements, expert opinions, preprints, and book chapters were excluded. The following five databases were searched: Embase, Medline Ultimate, PubMed, Scopus, and Web of Science. Each database was last searched on 18 June 2024. Eventually, nine original studies relevant to the discussed area were included. The risk of bias was not assessed. The selected research suggests that miRNAs may be considered promising biomarkers in PSP. However, the exact involvement of miRNAs in the pathogenesis of PSP is still to be determined. Several microRNAs were found to be dysregulated in patients with PSP. This applies to both brain tissue and fluids like cerebrospinal fluid CSF or blood. Several miRNAs were found that could potentially be helpful in differentiating among PSP patients, PD patients, and healthy individuals. Although some correlations and alterations have already been found, this field requires much more research. MicroRNAs are exciting and promising small molecules, and their investigation into many diseases, including PSP, may lead to significant discoveries. [ABSTRACT FROM AUTHOR]

We investigate the etiology of amyotrophic lateral sclerosis (ALS) in a 35-year-old woman presenting with progressive weakness in her left upper limb. Prior to sequencing, a comprehensive neurological work-up was performed, including neurological examination, electrophysiology, biomarker assessment, and brain and spinal cord MRI. Six months before evaluation, the patient experienced weakness and atrophy in her left hand, accompanied by brisk reflexes and Hoffman sign in the same arm. Electroneuromyography revealed lower motor neuron involvement in three body regions. Neurofilament light chains were elevated in her cerebrospinal fluid. Brain imaging showed asymmetrical T2 hyperintensity of the corticospinal tracts and T2 linear hypointensity of the precentral gyri. Trio genome sequencing identified a likely pathogenic de novo variant in the KIF1A gene (NM_001244008.2): c.574A>G, p.(Ile192Val). Pathogenic variants in KIF1A have been associated with a wide range of neurological manifestations called KIF1A-associated neurological diseases (KAND). This report describes a likely pathogenic de novo variant in KIF1A associated with ALS, expanding the phenotypic spectrum of KAND and our understanding of the pathophysiology of ALS. [ABSTRACT FROM AUTHOR]

Background: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. Methods: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48–108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. Results: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy. Conclusions: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients. [ABSTRACT FROM AUTHOR]

Background & purpose: In this retrospective study, we aimed at defining the clinical, paraclinical and outcome features of acute neurological syndromes associated with anti-GQ1b antibodies. Results: We identified 166 patients with neurological symptoms appearing in less than 1 month and anti-GQ1b antibodies in serum between 2012 and 2022. Half were female (51%), mean age was 50 years (4–90), and the most frequent clinical features were areflexia (80% of patients), distal upper and lower limbs sensory symptoms (78%), ophthalmoplegia (68%), sensory ataxia (67%), limb muscle weakness (45%) and bulbar weakness (45%). Fifty-three patients (32%) presented with complete (21%) and incomplete (11%) Miller Fisher syndrome (MFS), thirty-six (22%) with Guillain–Barre syndrome (GBS), one (0.6%) with Bickerstaff encephalitis (BE), and seventy-three (44%) with mixed MFS, GBS & BE clinical features. Nerve conduction studies were normal in 46% of cases, showed demyelination in 28%, and axonal loss in 23%. Anti-GT1a antibodies were found in 56% of cases, increased cerebrospinal fluid protein content in 24%, and Campylobacter jejuni infection in 7%. Most patients (83%) were treated with intravenous immunoglobulins, and neurological recovery was complete in 69% of cases at 1 year follow-up. One patient died, and 15% of patients relapsed. Age > 70 years, initial Intensive Care Unit (ICU) admission, and absent anti-GQ1b IgG antibodies were predictors of incomplete recovery at 12 months. No predictors of relapse were identified. Conclusion: This study from Western Europe shows acute anti-GQ1b antibody syndrome presents with a large clinical phenotype, a good outcome in 2/3 of cases, and frequent relapses. [ABSTRACT FROM AUTHOR]

Background: There is only limited data on the management of cerebrospinal fluid (CSF) fistulas after cervical endoscopic spine surgery. We investigated the current literature for treatment options and present a case of a patient who was treated with CT-guided epidural fibrin patch. Methods: We present the case of a 47-year-old female patient with a suspected CSF fistula after endoscopic decompression for C7 foraminal stenosis. She was readmitted 8 days after surgery with dysesthesia in both upper extremities, orthostatic headache and neck pain, which worsened during mobilization. A CSF leak was suspected on spinal magnetic resonance imaging. A computer tomography (CT)-guided epidural blood patch was performed with short-term relief. A second CT-guided epidural fibrin patch was executed and the patient improved thereafter and was discharged at home without sensorimotor deficits or sequelae. We investigated the current literature for complications after endoscopic spine surgery and for treatment of postoperative CSF fistulas. Results: Although endoscopic and open revision surgery with dura repair were described in previous studies, dural tears in endoscopic surgery are frequently treated conservatively. In our case, the patient was severely impaired by a persistent CSF fistula. We opted for a less invasive treatment and performed a CT-guided fibrin patch which resulted in a complete resolution of patient's symptoms. Discussion and conclusion: CSF fistulas after cervical endoscopic spine procedures are rare complications. Conservative treatment or revision surgery are the standard of care. CT-guided epidural fibrin patch was an efficient and less invasive option in our case. [ABSTRACT FROM AUTHOR]

This study established a simple, rapid, and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of contezolid and its major metabolite M2 in human plasma and cerebrospinal fluid (CSF). We used isotope-labeled internal standards (IS) along with protein precipitation to efficiently eliminate impurities. The ion transition was m/z 409.1 → 269.1 for contezolid, m/z 414.1 → 269.0 for contezolid-d5, m/z 445.1 → 385.1 for M2, and m/z 450.2 → 390.1 for M2-d5. The flow rate was 0.4 mL/min with a run time of 2.5 min. Validation results demonstrated that the calibration range was 10–5000 ng/mL for contezolid, and 5–2500 ng/mL for M2 in plasma and CSF. Both analytes exhibit excellent linear relationships (all R2 ≥ 0.99). Intra- and inter-batch accuracy and precision for all quality control (QC) levels were within ± 15%, including the lower limit of quantification (LLOQ). The recoveries of contezolid and M2 were 92.60–100.4% and 92.26–99.61% in plasma and 93.33–99.19% and 91.31–98.21% in CSF, respectively. The matrix effects for contezolid and M2 were 97.20–110.3% and 98.27–105.47% in plasma and 105.25–112.99% and 103.35–109.84% in CSF, respectively. The coefficients of variation (CV%) were ≤ 12.58%. Conteozolid and M2 remained stable in plasma and CSF. This study has established a simple and accurate method for determining contezolid and M2 in human plasma and CSF, making it a valuable tool for monitoring the efficacy of central nervous system (CNS) drugs. [ABSTRACT FROM AUTHOR]

Background. This study aimed to qualitatively and quantitatively evaluate T1-TSE, T2-TSE and 3D FLAIR sequences obtained with and without Compressed-SENSE technique by assessing the contrast (C), the contrast-to-noise ratio (CNR) and the signal-to-noise ratio (SNR). Methods. A total of 142 MRI images were acquired: 69 with Compressed-SENSE and 73 without Compressed-SENSE. All the MRI images were contoured, spatially aligned and co-registered using 3D Slicer Software. Two radiologists manually drew 12 regions of interests on three different structures of CNS: white matter (WM), grey matter (GM) and cerebrospinal fluid (CSF). Results. C values were significantly higher in Compressed-SENSE T1-TSE compared to No Compressed-SENSE T1-TSE for three different structures of the CNS. C values were also significantly lower for Compressed-SENSE 3D FLAIR and Compressed-SENSE T2-TSE compared to the corresponding No Compressed-SENSE scans. While CNR values did not significantly differ in GM-WM between Compressed-SENSE and No Compressed-SENSE for the 3D FLAIR and T1-TSE sequences, the differences in GM-CSF and WM-CSF were always statistically significant. Conclusion. Compressed-SENSE for 3D T2 FLAIR, T1w and T2w sequences enables faster MRI acquisition, reducing scan time and maintaining equivalent image quality. Compressed-SENSE is very useful in specific medical conditions where lower SAR levels are required without sacrificing the acquisition of helpful diagnostic sequences. [ABSTRACT FROM AUTHOR]

Recently developed antimigraine therapeutics targeting calcitonin gene--related peptide (CGRP) signaling are effective, though their sites of activity remain elusive. Notably, the lymphatic vasculature is responsive to CGRP signaling, but whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology is unknown. Mice with lymphatic vasculature deficient in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin-mediated (NTG-mediated) chronic migraine exhibit reduced pain and light avoidance compared with NTG-treated littermate controls. Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG revealed increased MLV-immune interactions compared with cells from untreated mice. Interestingly, the relative abundance of mucosal vascular addressin cell adhesion molecule 1--interacting (MAdCAM1-interacting) CD4+ T cells was increased in the deep cervical lymph nodes of NTG-treated control mice but not in NTG-treated CalcrliLEC mice. Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial--cadherin (VE-cadherin) rearrangement and reduced functional permeability. Likewise, intra cisterna magna injection of CGRP caused rearrangement of VE-cadherin, decreased MLV uptake of cerebrospinal fluid (CSF), and impaired CSF drainage in control mice but not in CalcrliLEC mice. Collectively, these findings reveal a previously unrecognized role for lymphatics in chronic migraine, whereby CGRP signaling primes MLV-immune interactions and reduces CSF efflux. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Creutzfeldt‐Jakob disease (CJD) is a rapidly progressive, fatal neurodegenerative disorder. This case highlights parkinsonism as a rare initial manifestation of sporadic CJD (sCJD), emphasizing the need for heightened clinical awareness to prevent misdiagnosis. Early and accurate diagnosis of sCJD is crucial for preventing potential iatrogenic transmission and optimizing patient management. Creutzfeldt‐Jakob disease (CJD) is a fatal neurodegenerative illness. While movement disorders may be present at the onset of the disease in about half of those with sporadic CJD (sCJD), parkinsonism is a rare initial presentation. In this article, we report a case of CJD with parkinsonism as the initial presentation of the disease. We report a 69‐year‐old lady with initial symptoms of gait difficulty, tremor, and bradykinesia. Later, she developed cognitive impairment, ataxia, chin tremor, and myoclonic jerks. Her condition worsened to the point of akinetic mutism. She was diagnosed with probable sCJD after detecting protein 14‐3‐3 in her cerebrospinal fluid and observing typical imaging features.This case report illustrates important aspects of an inevitably fatal and rapidly progressing disease's early presentation and clinical features. The uncommon initial presentations of sCJD should be considered with the intent of preventing misdiagnosis in the future. Early diagnosis of sCJD can prevent possible iatrogenic disease transmission and improve patient care. [ABSTRACT FROM AUTHOR]

Objective: To investigate cortical microstructural measures from diffusion MRI as "neurodegeneration" markers that could improve prognostic accuracy in mild cognitive impairment (MCI). Methods: The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non‐AD dementia was investigated. Ninety patients underwent clinical evaluation (follow‐up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status. T1‐structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD+), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices. Results: A progressive increase of whole‐brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A−T−. Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A−T− progressing to a mix of AD and non‐AD dementias). Adding whole‐brain AngleR as an N marker, produced good differentiation between stable and converting MCI A−T− patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%). Interpretation: Results support the clinical utility of cortical microstructure to aid prognosis, especially in A−T− patients. Further work will investigate other complexities of the real‐world clinical setting, including A−T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision‐making. [ABSTRACT FROM AUTHOR]

Summary: Sleep disturbances are prevalent in Alzheimer's disease (AD), affecting individuals during its early stages. We investigated associations between subjective sleep measures and cerebrospinal fluid (CSF) biomarkers of AD in adults with mild cognitive symptoms from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, considering the influence of memory performance. A total of 442 participants aged >50 years with a Clinical Dementia Rating (CDR) score of 0.5 completed the Pittsburgh Sleep Quality Index questionnaire and underwent neuropsychological assessment, magnetic resonance imaging acquisition, and CSF sampling. We analysed the relationship of sleep quality with CSF AD biomarkers and cognitive performance in separated multivariate linear regression models, adjusting for covariates. Poorer cross‐sectional sleep quality was associated with lower CSF levels of phosphorylated tau and total tau alongside better immediate and delayed memory performance. After adjustment for delayed memory scores, associations between CSF biomarkers and sleep quality became non‐significant, and further analysis revealed that memory performance mediated this relationship. In post hoc analyses, poorer subjective sleep quality was associated with lesser hippocampal atrophy, with memory performance also mediating this association. In conclusion, worse subjective sleep quality is associated with less altered AD biomarkers in adults with mild cognitive symptoms (CDR score 0.5). These results could be explained by a systematic recall bias affecting subjective sleep assessment in individuals with incipient memory impairment. Caution should therefore be exercised when interpreting subjective sleep quality measures in memory‐impaired populations, emphasising the importance of complementing subjective measures with objective assessments. [ABSTRACT FROM AUTHOR]

This contribution reviews the role of inbred and transgenic mouse strains for deciphering the mammalian melatoninergic and circadian system. It focusses on the pineal organ as melatonin factory and two major targets of the melatoninergic system, the suprachiasmatic nuclei (SCN) and the hypophysial pars tuberalis (PT). Mammalian pinealocytes sharing molecular characteristics with true pineal and retinal photoreceptors synthesize and secrete melatonin into the blood and cerebrospinal fluid night by night. Notably, neuron‐like connections exist between the deep pinealocytes and the habenular/pretectal region suggesting direct pineal‐brain communication. Control of melatonin biosynthesis in rodents involves transcriptional regulation including phosphorylation of CREB and upregulation of mPer1. In the SCN, melatonin acts upon MT1 and MT2 receptors. Melatonin is not necessary to maintain the rhythm of the SCN molecular clockwork, but it has distinct effects on the synchronization of the circadian rhythm by light, facilitates re‐entrainment of the circadian system to phase advances in the level of the SCN molecular clockwork by acting upon MT2 receptors and plays a stabilizing role in the circadian system as evidenced from locomotor activity recordings. While the effects in the SCN are subtle, melatonin is essential for PT functions. Via the MT1 receptor it drives the PT‐intrinsic molecular clockwork and the retrograde and anterograde output pathways controlling seasonal rhythmicity. Although inbred and transgenic mice do not show seasonal reproduction, the pathways from the PT are fully intact if the animals are melatonin proficient. Thus, only melatonin‐proficient strains are suited to investigate the circadian and melatoninergic systems. [ABSTRACT FROM AUTHOR]

Idiopathic intracranial hypertension (IIH) is a disorder that primarily affects obese women of reproductive age. The exact pathogenesis of IIH is unknown though multiple etiologies have been proposed. We report a case of IIH triggered by first-time Ramadan intermittent fasting (RIF) in an 18-year-old woman. Our patient developed new onset headaches, diplopia, and pulsatile tinnitus with examination notable for bilateral papilledema and lumbar puncture revealing an elevated opening pressure. Her symptoms resolved after cessation of RIF, apart from persistent left sided tinnitus which later resolved with acetazolamide administration. This case report uniquely illustrates that RIF may provoke symptomatic IIH. We hypothesize that a decreased concentration of glucagon-like peptide-1 (GLP-1) induced by fasting results in decreased GLP-1 receptor activation in the choroid plexus, allowing for increased CSF secretion into the ventricles invoking increased intracranial pressure (ICP). This theoretical mechanism provides further insight as to the possible underlying pathophysiology of IIH. [ABSTRACT FROM AUTHOR]

Guillain-Barré Syndrome (GBS) is a polyneuropathy characterized by acute-onset and immune-mediated processes, triggered by various factors. The occurence of GBS in connection with snakebites is rare. In this report, we present a rare clinical case with neuro-muscular and hematological complications following a snakebite, leading to flask quadriplegia on the 14th day during intensive care follow-up. Cerebrospinal fluid (CSF) analysis indicated albumin-cytological dissociation, and Electromyography (EMG) revealed findings consistent with acute motor axonal neuropathy, resulting in a diagnosis of GBS. After undergoing plasmapheresis once, the patient swiftly developed refractory septic shock, leading to a fatal outcome. In this study, we report a GBS case as a conseqeunce of snakebite together with a systematic review of the medical literature on the development of GBS after snakebite. Although current case reports and findings have broadened the scope of etiologic hypotheses for GBS including snake envenomation, further studies are needed to confirm the association between GBS following snakebite. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The established cerebrospinal fluid (CSF) phosphorylated tau181 (p‐tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age‐related tauopathy (PART) found in Creutzfeldt–Jakob disease (CJD) at autopsy. METHODS: We investigated CSF N‐terminal p‐tau181, p‐tau217, and p‐tau231 with in‐house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post‐mortem examination performed in patients with CJD 1.3 (0.3–14.3) months after CSF collection revealed no co‐pathology in 10, concomitant AD in 8, PART in 8, and other co‐pathologies in 3 patients. RESULTS: N‐terminal p‐tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t‐tau) in the presence of AD and PART co‐pathology (rho = 0.758–0.952, p ≤ 001). Concentrations in CJD+AD were indistinguishable from AD dementia, with the largest fold‐change in p‐tau217 (11.6), followed by p‐tau231 and p‐tau181 (3.2–4.5). DISCUSSION: Variable fold‐changes and correlation with t‐tau suggest that p‐tau closely associates with neurodegeneration and concomitant AD in CJD. Highlights: N‐terminal phosphorylated tau (p‐tau) biomarkers are increased in Creutzfeldt–Jakob disease (CJD) with and without concomitant AD.P‐tau217, p‐tau231, and p‐tau181 correlate with total tau (t‐tau) and increase in the presence of amyloid beta (Aβ) co‐pathology.N‐terminal p‐tau181 and p‐tau231 in Aβ‐negative CJD show variation among PRNP genotypes.Compared to mid‐region–targeting p‐tau181, cerebrospinal fluid (CSF) N‐terminal p‐tau has greater potential to reflect post‐mortem neuropathology in the CJD brain. [ABSTRACT FROM AUTHOR]

• Limited studies address the prognostic value of OCB counts in MS. • Higher OCB counts are associated with more upper cervical and T2 lesions in MS. • No significant association found between OCB count and EDSS or ARR. • Elevated IgG index and OCB positivity correlate with increased disability and relapse rates. • Comprehensive CSF analysis is crucial for effective MS management. Cerebrospinal fluid (CSF) biomarkers provide critical insights into the pathophysiology and progression of multiple sclerosis (MS), as this study aimed to investigate the relationships between CSF oligoclonal band (OCB) counts and the clinical course and short-term prognosis of MS patients. A retrospective cohort analysis covering a five-year period was conducted at two MS centers. Data on demographics, clinical presentation, MRI findings, EDSS scores, annualized relapse rate (ARR) in the first two years, and CSF analyses were analyzed. Among 310 patients, the ages ranged from 19 to 73 years, with a mean age of 38 years. OCBs were detected in 86.5 % (n = 268) of the patients. Those with a greater number of OCB bands had significantly more upper cervical lesions and T2 lesions (p < 0.05). A weak positive correlation was found between OCB and the IgG index score. No significant relationship was observed between band count and the ARR or EDSS score. OCB-positive patients had higher IgG index scores and more upper cervical lesions (p < 0.05). Additionally, patients with elevated IgG index levels (>0.7) exhibited significantly greater EDSS scores and more T2 lesions (p < 0.05). This study highlights the importance of OCB counts as a significant marker for assessing disease activity and progression in MS patients. These findings emphasize the need for a comprehensive approach that integrates CSF analysis with clinical and radiological data to effectively manage MS and tailor treatment strategies. [ABSTRACT FROM AUTHOR]