Intrathecal Cerebrospinal Fluid Research Articles

Clinical characteristics and their influences on the survival of leptomeningeal metastasis derived from lung adenocarcinoma harboring epithelial growth factor receptor mutation

Objective: To analyze the clinical characteristics of leptomeningeal metastasis (LM) patients from epithelial growth factor receptor (EGFR)-mutated lung adenocarcinoma, and their impacts on the survival of the patients. Methods: From July 2018 to July 2022, the clinicopathological data of 81 patients diagnosed as EGFR-mutated lung adenocarcinoma LM by cytopathology who admitted to the Department of Oncology of Xiangya Hospital of Central South University were retrospectively analyzed, including 33 males and 48 females. The age ranged from 31 to 76 years, with a median age of 54 years. All the 81 patients were followed up, with a median follow-up of 21.0 months (95%CI: 12.5 to 29.5 months). The Kaplan Meier method was used to draw survival curve. Cox proportional hazards regression model was used to analyze the impact of the factors on the survival of patients. Results: Among the 81 patients, the interval between the initial diagnosis of lung cancer and the pathological diagnosis of LM in cerebrospinal fluid (CSF) was 0-108 months, with a median interval of 14 months. Fifty-two patients (64.2%) used the third-generation epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs), while 17 patients (21.0%) used EGFR-TKIs in combination with other drugs, and 12 patients (14.8%) were treated with best supportive care (BSC). Sixty patients (74.1%) had a Kanofsky performance status (KPS) score of less than 60 points, and 71 patients (87.7%) had brain parenchymal metastasis and/or spinal metastasis. Twenty-two patients (27.2%) used pemetrexed through intrathecal CSF, and 17 patients (21.0%) used pemetrexed through the Ommaya sac to the CSF of the ventricle. The incidence of adverse event related to the administration of pemetrexed through CSF was 64.1% (25/39), mainly manifested as myelosuppression, including 22 patients of leukocyte reduction, 25 patients of hemoglobin reduction, and 14 patients of platelet reduction. The median post-leptomeningeal metastasis overall survival (pLM-OS) in 81 patients was 11.0 (95%CI: 7.7-14.3) months. KPS score≥60 points (HR=0.407, 95%CI: 0.170-0.973, P=0.043), CSF cytology negative after treatment (vs persistent positive, HR=0.351, 95%CI: 0.155-0.792, P=0.012), intraventricular administration of pemetrexed (vs non intraventricular administration of pemetrexed, HR=0.319, 95%CI: 0.137-0.745, P=0.008) and the treatment with third-generation EGFR-TKIs after LM (vs EGFR-TKIs in combination with other drugs, HR=0.486, 95%CI: 0.237-0.998, P=0.049) were a factor affecting pLM-OS of patients. Conclusions: Brain parenchyma, or/and spine are the most sites where the LM patients concurrently metastasize. KPS score≥60 points and CSF cytology negative after treatment, intraventricular administration of pemetrexed and the treatment with third-generation EGFR-TKIs are indictors affecting pLM-OS of the patients.

Impact of Neurapheresis System on Intrathecal Cerebrospinal Fluid Dynamics: A Computational Fluid Dynamics Study.

It has been hypothesized that early and rapid filtration of blood from cerebrospinal fluid (CSF) in postsubarachnoid hemorrhage patients may reduce hospital stay and related adverse events. In this study, we formulated a subject-specific computational fluid dynamics (CFD) model to parametrically investigate the impact of a novel dual-lumen catheter-based CSF filtration system, the Neurapheresis™ system (Minnetronix Neuro, Inc., St. Paul, MN), on intrathecal CSF dynamics. The operating principle of this system is to remove CSF from one location along the spine (aspiration port), externally filter the CSF routing the retentate to a waste bag, and return permeate (uncontaminated CSF) to another location along the spine (return port). The CFD model allowed parametric simulation of how the Neurapheresis system impacts intrathecal CSF velocities and steady-steady streaming under various Neurapheresis flow settings ranging from 0.5 to 2.0 ml/min and with a constant retentate removal rate of 0.2 ml/min simulation of the Neurapheresis system were compared to a lumbar drain simulation with a typical CSF removal rate setting of 0.2 ml/min. Results showed that the Neurapheresis system at a maximum flow of 2.0 ml/min increased average steady streaming CSF velocity 2× in comparison to lumbar drain (0.190 ± 0.133 versus 0.093 ± 0.107 mm/s, respectively). This affect was localized to the region within the Neurapheresis flow loop. The mean velocities introduced by the flow loop were relatively small in comparison to normal cardiac-induced CSF velocities.

Characterization of intrathecal cerebrospinal fluid geometry and dynamics in cynomolgus monkeys (macaca fascicularis) by magnetic resonance imaging.

Recent advancements have been made toward understanding the diagnostic and therapeutic potential of cerebrospinal fluid (CSF) and related hydrodynamics. Increased understanding of CSF dynamics may lead to improved detection of central nervous system (CNS) diseases and optimized delivery of CSF based CNS therapeutics, with many proposed therapeutics hoping to successfully treat or cure debilitating neurological conditions. Before significant strides can be made toward the research and development of interventions designed for human use, additional research must be carried out with representative subjects such as non-human primates (NHP). This study presents a geometric and hydrodynamic characterization of CSF in eight cynomolgus monkeys (Macaca fascicularis) at baseline and two-week follow-up.Results showed that CSF flow along the entire spine was laminar with a Reynolds number ranging up to 80 and average Womersley number ranging from 4.1–7.7. Maximum CSF flow rate occurred ~25 mm caudal to the foramen magnum. Peak CSF flow rate ranged from 0.3–0.6 ml/s at the C3-C4 level. Geometric analysis indicated that average intrathecal CSF volume below the foramen magnum was 7.4 ml. The average surface area of the spinal cord and dura was 44.7 and 66.7 cm2 respectively. Subarachnoid space cross-sectional area and hydraulic diameter ranged from 7–75 mm2 and 2–3.7 mm, respectively. Stroke volume had the greatest value of 0.14 ml at an axial location corresponding to C3-C4.

Far-lateral Transcondylar Approach to Anterior Foramen Magnum Lesions - Our Experience.

Background:Initial surgical management of the anterior foramen magnum lesions through the posterior approaches was fraught with unacceptable morbidity, mortality, and incomplete removal. The far-lateral approach provides excellent exposure and access to these lesions resulting in complete excision of these lesions with reduced frequency of unwanted complications.Materials and Methods:Eight patients with lesions anterior to the brainstem and upper cervical cord were surgically treated using the far-lateral transcondylar approach. Two of these patients had a meningioma while three patients had “white epidermoid.” One patient had a vertebral artery (VA) aneurysm while another was a rare case of lower brainstem compression by the VA and the last was a clival chordoma. The technical aspects of this surgical procedure are briefly illustrated in this article.Results:Total excision was achieved in five neoplastic cases while subtotal excision was done in one case. The VA aneurysm was satisfactorily clipped while in the brainstem compression patient, microvascular decompression was done. The VA aneurysm patient developed postoperative lower cranial nerve palsies. There were no fresh postoperative deficits in any of the other patients. One patient had an unexplained sudden cardiorespiratory arrest 18 h after the surgery and succumbed. One patient had cerebrospinal fluid (CSF) otorrhea which was satisfactorily managed by intrathecal CSF drainage.Conclusion:The far-lateral transcondylar approach provides excellent approach to lesions located anterior to the brainstem and upper cervical cord. Total excision of these benign lesions is safely possible through this approach.

Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: A glymphatic magnetic resonance imaging study

The glymphatic system plays a key role for clearance of waste solutes from the rodent brain. We recently found evidence of glymphatic circulation in the human brain when using magnetic resonance imaging (MRI) contrast agent as cerebrospinal fluid (CSF) tracer in conjunction with multiple MRI acquisitions (gMRI). The present study explored the hypothesis that reduced glymphatic clearance in entorhinal cortex (ERC) may be instrumental in idiopathic normal pressure hydrocephalus (iNPH) dementia. gMRI acquisitions were obtained over a 24–48 h time span in cognitively affected iNPH patients and non-cognitively affected patients with suspected CSF leaks. The CSF tracer enrichment was determined as changes in normalized MRI T1 signal units. The study included 30 patients with iNPH and 8 individuals with suspected CSF leaks (i.e. reference individuals). Compared to reference individuals, iNPH patients presented with higher medial temporal lobe atrophy score and Evan's index and inferior ERC thickness. We found delayed clearance of the intrathecal CSF tracer gadobutrol from CSF, the ERC and adjacent white matter, suggesting impaired glymphatic circulation. Reduced clearance and accumulation of toxic waste product such as amyloid-β may be a mechanism behind dementia in iNPH. Glymphatic MRI (gMRI) may become a tool for assessment of early dementia.

The cerebrospinal fluid immunoglobulin transcriptome and proteome in neuromyelitis optica reveals central nervous system-specific B cell populations.

BackgroundNeuromyelitis optica (NMO) is a severe demyelinating disorder of the central nervous system (CNS) associated with the presence of an autoimmune antibody response (AQP4-IgG) against the water channel aquaporin-4 (AQP4). It remains unclear whether pathologic AQP4-IgG in the CNS is produced entirely by peripheral plasma cells or is generated in part by infiltrating B cells. To determine the overlap of AQP4-IgG idiotypes between the CNS and periphery, we compared the immunoglobulin G (IgG) transcriptome of cerebrospinal fluid (CSF) plasmablasts with the CSF and serum IgG proteomes in 7 AQP4-seropositive NMO patients following exacerbation.MethodsCSF variable region Ig heavy- (VH) and light-chain (VL) transcriptome libraries were generated for each patient from CSF plasmablasts by single cell sorting, reverse transcriptase polymerase chain reaction (RT-PCR), and DNA sequencing. Recombinant antibodies were generated from clonally expanded, paired VH and VL sequences and tested for AQP4-reactivity by cell-binding assay. CSF and serum IgG fractions were searched for sequences that matched their respective CSF IgG transcriptome. Matching peptides within the same patient’s CSF and serum IgG proteomes were also identified.ResultsIn each NMO patient, we recovered CSF IgG VH and VL sequences that matched germline-mutated IgG protein sequences from the patient’s CSF and serum IgG proteomes. Although a modest variation was observed between patients, the overlap between the transcriptome and proteome sequences was found primarily, but not exclusively, within the CSF. More than 50% of the CSF IgG transcriptome sequences were exclusively found in the CSF IgG proteome, whereas 28% were found in both the CSF and blood IgG proteome, and 18% were found exclusively in the blood proteome. A comparable distribution was noted when only AQP4-specific IgG clones were considered. Similarly, on average, only 50% of the CSF IgG proteome matched corresponding peptide sequences in the serum.ConclusionsDuring NMO exacerbations, a substantial fraction of the intrathecal Ig proteome is generated by an intrathecal B cell population composed of both novel and peripherally-derived clones. Intrathecal CSF B cell clones may contribute to NMO disease exacerbation and lesion formation and may be an important target for preventative therapies.

Intrathecal lactate predicting hydrocephalus after aneurysmal subarachnoid hemorrhage

BackgroundEvidence shows possible benefits from continuous drainage by lumbar drain after aneurysmal subarachnoid hemorrhage (SAH). Under the hypothesis that compartmentalization occurs between the ventricle and subarachnoid space after massive SAH, this study aimed to evaluate the biochemical differences between ventricular and intrathecal cerebrospinal fluid (CSF) and assess the role of CSF lactate in shunt-dependent hydrocephalus (SDHC) after aneurysmal SAH. Materials and methodsPatients with modified Fisher grade III/IV aneurysmal SAH who underwent early obliteration were evaluated. Intrathecal and intraventricular CSF were obtained on day 7 post-SAH to measure their biochemical composition in terms of total protein, glucose, ferritin, and lactate. The associations of SDHC with the clinical parameters and CSF data were analyzed. ResultsThere were 28 patients (mean age, 55.4 y; males, 46.6%), including 18 (64.3%) with SDHC. Intrathecal CSF had significantly higher levels of total protein, ferritin, hemoglobin, and lactate but lower glucose level than intraventricular CSF (all P < 0.0001). By multivariate analysis of clinical and CSF parameters, elevated intrathecal CSF lactate (P = 0.036) and the presence of intraventricular hemorrhage (P = 0.05) were independent factors associated with SDHC. Moreover, intrathecal lactate >5.5 μM effectively predicted the occurrence of SDHC (odds ratio: 32, 95% confidence interval: 3.8–270.8; P = 0.0015). ConclusionsBy compartmentalization of the subarachnoid space after SAH, intrathecal lactate level is a useful predictive parameter for long-term SDHC in patients with aneurysmal SAH patients.

A prospective evaluation of hemodynamic management in acute spinal cord injury patients

Prospective observational study of acute spinal cord-injured (SCI) patients. To determine how effectively mean arterial blood pressure (MAP) and spinal cord perfusion pressure (SCPP) are maintained at target levels in acute SCI patients. Single-institution study at a Canadian level-one trauma center. Twenty-one individuals with cervical or thoracic SCI were enrolled within 48 h of injury. A lumbar intrathecal drain was inserted for monitoring intrathecal cerebrospinal fluid pressure (ITP). The MAP was monitored concurrently with ITP, and the SCPP was calculated. Data was recorded hourly from the time of first assessment until at least the end of the 5th day post injury. All subjects had at least one recorded episode with a MAP below 80 mm Hg, and 81% had at least one episode with a MAP below 70 mm Hg. On average, subjects with cervical injuries had 18.4% of their pressure recordings below 80 mm Hg. Subjects with thoracic cord injuries had on average 35.9% of their MAP recordings <80 mm Hg. It is common practice to establish MAP targets for optimizing cord perfusion in acute SCI. This study suggests that even in an acute SCI referral center, when prospectively scrutinized, the actual MAP may frequently fall below the intended targets. Such results raise awareness of the vigilance that must be kept in the hemodynamic management of these patients, and the potential discrepancy between routinely setting target MAP according to 'practice guidelines' and actually achieving them.

Cerebrospinal Fluid Pressure Measurement in the Ovine Intrathecal Space: A Preliminary Study towards the Diagnosis of Intrathecal Drug Administration Catheter Dislodgement or Occlusion

Background and Objective: Intrathecal drug delivery catheter malfunctions are a principal cause of therapy interruption. We determined that normal baseline intrathecal cerebrospinal fluid (CSF) pressure recordings could be obtained in an ovine model and in a catheter dislodgement scenario. Methods: Two sheep were implanted with spinal catheters: 2 in the T₆ epidural space in sheep No. 1; 1 T₆ intrathecal catheter plus 1 L₂ epidural catheter with a deliberate CSF leak to simulate dislodgement in sheep No. 2. Pressure waves were recorded intraoperatively and at multiple times after the implantation in the awake condition. On day 21, the animals were anesthetized for pressure recordings while on and temporarily off mechanical ventilation. They were then necropsied. Results: CSF pressure waves were obtained in this animal model under anesthesia with or without mechanical ventilation and in the awake state. Fluid accumulation at the tip of a dislodged (epidural) catheter temporarily caused apparent coupling of fluid pressures across the dura. An unintentional extraspinal fluid collection in sheep No. 2 was associated with a raised baseline epidural pressure. Conclusions: These findings support the notion that pressure sensors can play a role in determining the status of intraspinal drug delivery catheters.

Clinical Application of Modest Hypothermia after Spinal Cord Injury

There is widespread interest in the use of hypothermia in the treatment of CNS injury. While there is considerable experience in the use of cooling for a variety of brain pathologies, limited data exist after spinal cord injury. In the past few years, technological advances in the induction and maintenance of cooling have been achieved and can potentially allow for a more accurate evaluation of this form of treatment. We report a series of 14 patients with an average age of 39.4 years (range, 16-62 years) with acute, complete (AIS A) cervical spinal cord injuries who underwent a protocol using an intravascular cooling catheter to achieve modest (33 degrees C) systemic hypothermia. There was an excellent correlation between intravascular and intrathecal cerebrospinal fluid temperature. The average time between injury and induction of hypothermia was 9.17 +/- 2.24 h (mean +/- SEM); the time to target temperature was 2.72 +/- 0.42 h; the duration of cooling at target temperature was 47.6 +/- 3.1 h; the average total length of time of cooling was 93.6 +/- 4 h. There was a positive correlation between temperature and heart rate. Most documented adverse events were respiratory in nature. We were able to effectively deliver systemic cooling using the cooling catheters with minimal variation in body temperature. The study represents the largest, modern series of hypothermia treatment of acute spinal cord injury with intravascular cooling techniques and provides needed baseline data for outcome studies to include larger multi-center, randomized trials.

Enhancement by Grapefruit Juice of Morphine Antinociception

The aim of this study was to investigate the effect of grapefruit juice intake on the antinociception of morphine in rats. The antinociception of morphine (30 mg/kg, per os (p.o.)) was significantly enhanced by the oral administration of grapefruit juice (2 ml/rat). Further, the effect of grapefruit juice was examined in morphine-tolerant rats. The repeated administration of morphine (100 mg/kg p.o.) for 5 d caused a marked decrease in the antinociception, indicating the development of morphine-tolerance. In the morphine-tolerant rats, oral administration of grapefruit juice potentiated significantly the antinociceptive effect of morphine. To examine the pharmacokinetics of morphine after the repeated treatment with morphine for 5 d, microdialysis probes were implanted into the jugular vein and spinal intrathecal space in rats. The morphine concentrations in the blood and intrathecal cerebrospinal fluid (CSF) were gradually decreased by the repeated treatment with morphine. The grapefruit juice treatment significantly increased the blood concentration of morphine in morphine-tolerant rats. These results suggest that oral administration of grapefruit juice enhances the morphine antinociception by increasing the intestinal absorption of this agent.

Different distribution of morphine and morphine-6 beta-glucuronide after intracerebroventricular injection in rats.

(1) We investigated the distribution of morphine and morphine-6beta-glucuronide (M6G) in the brain and spinal cord after intracerebroventricular (i.c.v.) injection of each drug in rats. (2) The cerebrospinal fluid (CSF) concentration of M6G was 5-37 times greater than that of morphine 10, 60 and 120 min after the i.c.v. injection. The apparent elimination clearance of M6G from the CSF was 10 times lower than that of morphine. (3) The intrathecal CSF concentration of M6G measured by the microdialysis method was 29-79 times greater than that of morphine, and M6G was rapidly distributed into the intrathecal space after the i.c.v. injection. (4) M6G was detected in the cerebrum, brainstem, cerebellum and spinal cord at concentrations 2-21 times higher than morphine after the i.c.v. injection of each drug. The distribution volume of M6G in rat brain slices was three times lower than that of morphine, and close to the extracellular fluid space in the brain regions corresponding to the vicinity of the opioid receptors. (5) These brain distribution characteristics of M6G, namely, low clearance from the central nervous system, localization in the extracellular fluid and rapid distribution into the intrathecal space, may contribute to the potent analgesic effect of M6G after i.c.v. injection.

Classic and unusual appearances of hydatid disease in children.

In endemic regions, hydatid disease is commoner in children than in adults. The hydatid cysts may have classic appearances, but unusual sites and appearances may cause diagnostic difficulties. To assess the classic and unusual appearances of hydatid disease in children. A 3-year retrospective review of available imaging of proven hydatid disease at a tertiary paediatric institution. RESULTS. Review of imaging of 21 children (9 boys, 12 girls), with a mean age of 8 years and 1 month, demonstrated cysts in the liver ( n=9), lung ( n=8), brain ( n=7), spleen ( n=2), heart ( n=1), orbit ( n=1) and soft tissues ( n=1). Multi-organ involvement occurred in eight cases with two cases that did not involve the liver. Complicated cysts were found in 13 cases and usually involved the liver ( n=8) and lung ( n=5). An unusual case of spontaneous cerebrospinal fluid (CSF) spread was also documented. Hydatid disease in children classically involves the liver, lung and brain but can involve almost any organ and numerous organs simultaneously. Whether hydatid disease is discovered incidentally or by intentional imaging, extended imaging is recommended to identify multifocal disease which may also display complicated cysts that may assist in the diagnostic process. All patients with one known site should undergo a minimum of an abdominal US and CT scan of the chest and brain. CT may be used instead of US of the abdomen, and MRI may be used to replace CT of the brain. Over 50% of cases in our study showed complicated cysts. Unique findings of this study include multi-organ involvement without liver cysts. Multiplicity and complications of cysts can assist diagnosis. Intraventricular and intrathecal CSF spread of a spontaneously ruptured intracerebral cyst has not, to our knowledge, been previously reported.

Effects of Preemptive or Postinjury Intrathecal Local Anesthesia on Persistent Nociceptive Responses in Rats

Although experimental evidence indicates that preemptive intrathecal treatment with local anesthetics reduces postinjury neuronal hyperexcitability, clinical evidence indicates that preemptive treatments do not consistently reduce postoperative pain. The current study used experimental models of postinjury nociception, in which rats received subcutaneous or intraarticular injections of the irritant formalin, to evaluate the effects of peripheral inflammation, or the use of agents supplemental to anesthesia, as possible confounding influences on the effectiveness of preinjury and postinjury intrathecal local anesthetic treatments. In experiment 1, lumbar intrathecal lidocaine (30 microliters, 2%), given either 5 min before or 5 min after hind paw injection of 50 microliters of varying concentrations of formalin, was compared with intrathecal cerebrospinal fluid, for their effects on nociceptive responses in the late phase of the formalin test. Furthermore, the effect of hind paw injection of 50 microliters of 2.5, 3.75, or 5.0% formalin on peripheral inflammation was assessed by measuring plasma extravasation in the hind paws of rats given Evans Blue dye (50 mg/kg, intravenous). In experiment 2, rats received a deep tissue injury (100 microliters of 5.0% formalin into the knee joint) while under halothane anesthesia. In addition to halothane (3-4%), rats received either saline, pentobarbital (13 mg/kg, intraperitoneal), or pentobarbital + morphine (0.5 mg/kg, intravenous), with or without preinjury or postinjury spinal anesthesia using intrathecal bupivacaine (30 microliters, 0.75%), to assess the effects of supplemental treatments on the preemptive effects of intrathecal bupivacaine. Lumbar intrathecal lidocaine pretreatment, but not posttreatment, significantly reduced late phase nociceptive responses to hind paw injections of 2.5% formalin. The preemptive effects of lidocaine were overridden in rats that received hind paw injections of 3.75 and 5.0% formalin. Hind paw injection of 50 microliters of 3.75 or 5.0%, but not 2.5% formalin produced an increase in plasma extravasation. Either pentobarbital or pentobarbital + morphine treatment, or a pentobarbital + morphine treatment and postinjury treatment with intrathecal bupivacaine failed to produce a significant reduction in the nociceptive response to the deep tissue injury. However, rats that received pentobarbital + morphine treatments and intrathecal bupivacaine before the injury had significantly reduced nociceptive responses to deep tissue injury when compared to the saline control group, but not to the group that received pentobarbital + morphine treatment and postinjury treatment with bupivacaine. The current results attest to the important effects of ongoing inputs from inflamed tissue, and the use of supplemental treatments, as important confounding factors that may influence the effectiveness of preemptive spinal anesthesia for postoperative pain.

A study of intrathecal, cerebrospinal fluid-to-brain exchange

A cerebrospinal fluid (CSF) to brain exchange has been postulated for lipid-soluble and small molecular substances and has led to nearly 100 attempts per year to produce central effects via intrathecal injections. With few exceptions, however, modern neurological practice has avoided this approach because of its demonstrated ineffectiveness and dangers. The practicability of an intrathecal CSF to brain exchange was tested by cisternal infusions of mock CSF at different infusion pressures that might counteract central nervous system intoxications of systemic origin. Those efforts failed in different test situations with each of three barbiturates. Steady state doses at a selected level of barbiturate anesthesia were the same, whether induced by cisternal infusion or intravenously, and this was true for barbiturates of widely different lipid solubility. The cerebral response to pentylenetetrazol was delayed well beyond its rate of response when introduced intravenously. These results suggested that the bulk clearance rate and venous resorption of CSF were sufficient to prevent significant diffusion of the barbiturate or even mock CSF into the brain following intrathecal injection. Because central effects that follow venous resorption may be confused with direct central effects, many previous clinical reports are questioned. Apparent exceptions to the ineffectiveness of intrathecal therapy, such as spinal anesthesia, were discussed in terms of their special local effects. The relative effectiveness of intrathecal agents should be evaluated by comparing maintenance doses for a given central effect, when produced by both intrathecal and i.v. routes. Previous reports on rates of intrathecal infusion, intracranial pressure relationships, and the relative safety of such infusions were confirmed and extended.