Background. Methodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism, and for diagnostic work-up of cerebrospinal fluid disturbances.Methods. The magnetic resonance imaging (MRI) contrast agent gadobutrol (Gadovist) was utilized as CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the central nervous system (CNS) and is thus eliminated along extra-vascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at level of the cisterna magna in parallel with obtaining blood samples through 48 hours.Results. In a reference patient cohort (REF; n=29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n=4), idiopathic normal pressure hydrocephalus dementia (iNPH; n=7), pineal cysts (n=8), and idiopathic intracranial hypertension (IIH; n=4). Conclusion.Assessment of CSF tracer clearance is clinically feasible and may provide a way to predict extra-vascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hrs) preceded by far peak tracer enhancement at MRI in extra-cranial lymphatic structures (at about 24 hrs) as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity.
Background Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases. Methods Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references. Results Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles. Conclusions The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs.
Brain sagging dementia (BSD), caused by spontaneous intracranial hypotension (SIH), is a rare syndrome that is only recently recognized, mimicking the clinical findings of behavioral variant frontotemporal dementia (bvFTD). Being aware of its signs and symptoms is essential for early diagnosis and treatment in this potentially reversible form of dementia. Our objective was to identify cases with BSD in the literature and present its clinical characteristics, diagnostic workup, treatment options, and outcome.The review was reported according to PRISMA guidelines and registered with the PROSPERO database (CRD42020150709). MEDLINE, EMBASE, PsychINFO, and Cochrane Library were searched. There was no date restriction. The search was updated in April 2021.A total of 983 articles were screened and assessed for eligibility. Twenty-nine articles (25 case reports and four series) and 70 patients were selected for inclusion. No cranial leak cases were identified. BSD diagnosis should be made based on clinical signs and symptoms and radiological findings. There is a male predominance (F: M ratio 1:4) and a peak incidence in the 6th decade of life. The main clinical manifestation is insidious onset, gradually progressive cognitive and behavioral changes characteristic for bvFTD. Headache is present in the majority of patients (89%). The presence of brain sagging and absence of frontotemporal atrophy is an absolute criterion for the diagnosis. The CSF leak is identified with myelography and digital subtraction myelography. The treatment and repair depend on the etiology and extent of the dural defect, although an epidural blood patch is the first-line treatment in most cases. With treatment, 81% experienced partial and 67% complete resolution of their symptoms. This review highlights the most important clinical aspects of BSD. Due to the sparse evidence and lack of BSD awareness, many patients are most likely left undiagnosed. Recognizing this condition is essential to provide early treatment to reverse the cognitive and behavioral changes that may otherwise progress and fully impair the patient. Moreover, patients with longstanding SIH must be carefully assessed for cognitive and behavioral changes.
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