Petra M. Klinge

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimers disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces.Outline1 Overview2 CSF formation2.1 Transcription factors2.2 Ion transporters2.3 Enzymes that modulate transport2.4 Aquaporins or water channels2.5 Receptors for neuropeptides3 CSF pressure3.1 Servomechanism regulatory hypothesis3.2 Ontogeny of CSF pressure generation3.3 Congenital hydrocephalus and periventricular regions3.4 Brain response to elevated CSF pressure3.5 Advances in measuring CSF waveforms4 CSF flow4.1 CSF flow and brain metabolism4.2 Flow effects on fetal germinal matrix4.3 Decreasing CSF flow in aging CNS4.4 Refinement of non-invasive flow measurements5 CSF volume5.1 Hemodynamic factors5.2 Hydrodynamic factors5.3 Neuroendocrine factors6 CSF turnover rate6.1 Adverse effect of ventriculomegaly6.2 Attenuated CSF sink action7 CSF composition7.1 Kidney-like action of CP-CSF system7.2 Altered CSF biochemistry in aging and disease7.3 Importance of clearance transport7.4 Therapeutic manipulation of composition8 CSF recycling in relation to ISF dynamics8.1 CSF exchange with brain interstitium8.2 Components of ISF movement in brain8.3 Compromised ISF/CSF dynamics and amyloid retention9 CSF reabsorption9.1 Arachnoidal outflow resistance9.2 Arachnoid villi vs. olfactory drainage routes9.3 Fluid reabsorption along spinal nerves9.4 Reabsorption across capillary aquaporin channels10 Developing translationally effective models for restoring CSF balance11 Conclusion

Diagnosing idiopathic normal-pressure hydrocephalus

OBJECTIVE:The precise incidence and prevalence of idiopathic normal-pressure hydrocephalus (INPH) is not known, and evidence-based clinical diagnostic criteria have not been developed previously. This report contains evidence-based guidelines for clinical diagnosis of INPH that are intended to facilitate future epidemiological studies of INPH, promote earlier and more accurate diagnosis, and ultimately improve treatment outcome. METHODS:The criteria for the diagnosis of INPH are based on evidence from the medical literature, supplemented as necessary by expert opinion. From 1966 to 2003, 653 publications on “normal-pressure hydrocephalus” were cited in MEDLINE, including 29 articles that met the more stringent criteria of including “idiopathic normal-pressure hydrocephalus” in their title. Additional studies were considered that explicitly identified INPH cases and/or specified the criteria for a diagnosis of INPH. Studies were graded according to the class of evidence and results summarized in evidentiary tables. For issues of clinical relevance that lacked substantive evidence from the medical literature, the opinions of consulting experts were considered and contributed to “Options.” RESULTS:Evidence-based guidelines for the clinical diagnosis of INPH have been developed. A detailed understanding of the range of clinical manifestations of this disorder and adherence to practice guidelines should improve the timely and accurate recognition of this disorder. CONCLUSION:It is recommended that INPH be classified into probable, possible, and unlikely categories. We hope that these criteria will be widely applied in clinical practice and will promote greater consistency in patient selection in future clinical investigations involving INPH.

The Value of Supplemental Prognostic Tests for the Preoperative Assessment of Idiopathic Normal-pressure Hydrocephalus

OBJECTIVE:The diagnosis and management of idiopathic normal-pressure hydrocephalus (INPH) remains unclear. Moreover, the value of supplementary tests to predict which patients would benefit from placement of a shunt has not been established. This report develops evidence-based guidelines for the use of supplementary tests as an aid in prognosis. METHODS:MEDLINE searches from 1966 to the present were undertaken by use of the query NPH, normal-pressure hydrocephalus, lumbar drain, CSF [cerebrospinal fluid] tap test, and external CSF drainage in humans. This resulted in 242 articles. To provide a scientific, evidence-based review, we have chosen to restrict our analysis to clinically relevant studies usually consisting of large numbers of shunted NPH patients. Studies that did not specify INPH or secondary NPH were considered in a separate evidentiary table. RESULTS:Evidence-based guidelines for use in supplementary tests have been developed. A positive response to a 40- to 50-ml tap test has a higher degree of certainty for a favorable response to shunt placement than can be obtained by clinical examination. However, the tap test cannot be used as an exclusionary test because of its low sensitivity (26–61%). Determination of the CSF outflow resistance via an infusion test carries a higher sensitivity (57–100%) compared with the tap test and a similar positive predictive value of 75 to 92%. Prolonged external lumbar drainage in excess of 300 ml is associated with high sensitivity (50–100%) and high positive predictive value (80–100%). CONCLUSION:To date, a single standard for the prognostic evaluation of INPH patients is lacking. However, supplemental tests can increase predictive accuracy for prognosis to greater than 90%. Additional multicenter prospective randomized clinical trials are needed.

A new look at cerebrospinal fluid circulation

According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation.

Surgical management of idiopathic normal-pressure hydrocephalus.

OBJECTIVE:To develop evidence-based guidelines for surgical management of idiopathic normal-pressure hydrocephalus (INPH). Compared with the diagnostic phase, the surgical management of INPH has received less scientific attention. The quality of much of the literature concerning the surgical management has been limited by many factors. These include retrospective analysis, small patient numbers, analysis of a mixed NPH population, and sometimes a lack of detail as to what type of shunt system was used. Many earlier studies predated our current understanding of the hydrodynamics of cerebrospinal fluid shunts, and therefore, the conclusions drawn may no longer be valid. METHODS:A MEDLINE and PubMed search from 1966 to the present was conducted using the following key terms: normal-pressure hydrocephalus and idiopathic adult-onset hydrocephalus. Only English-language literature in peer-reviewed journals was reviewed. The search was further limited to articles that described the method of treatment and outcome selectively for INPH patients. Finally, only studies that included 20 or more INPH patients were considered with respect to formulating the recommendations in these Guidelines (27 articles). RESULTS:For practical reasons, it is important to identify probable shunt responders diagnosed with INPH. If the patient is an acceptable candidate for anesthesia, then an INPH-specific risk-benefit analysis should be determined. In general, patients exhibiting negligible symptoms may not be suitable candidates for surgical management, given the known risks and complications associated with shunting INPH. The choice of valve type and setting should be based on empirical reasoning and a basic understanding of shunt hydrodynamics. The most conservative choice is a valve incorporating an antisiphon device, with the understanding that underdrainage (despite a low opening pressure) may occur in a small percentage of patients because of the antisiphon device. On the basis of retrospective studies, the use of an adjustable valve seems to be beneficial in the management of INPH. CONCLUSION:The treatment of INPH should not be considered lightly, given the seriousness of the potential complications. Within these limitations and the available evidence, guidelines for surgical management were developed.

OUTCOME OF SHUNTING IN IDIOPATHIC NORMAL- PRESSURE HYDROCEPHALUS AND THE VALUE OF OUTCOME ASSESSMENT IN SHUNTED PATIENTS

OBJECTIVE:To develop guidelines for assessing shunt outcome in patients with idiopathic normal-pressure hydrocephalus (INPH). To date, the literature available on this topic has been marked by disparate definitions of clinical improvement, varying postoperative follow-up protocols and periods, and substantial differences in the postoperative management. Because specific criteria for defining clinical improvement are seldom reported, conclusions drawn about shunt outcome may be subjective. METHODS:A MEDLINE search back to 1966 was undertaken using the query NPH, normal-pressure hydrocephalus, shunting, shunt treatment, shunt response, outcome, and clinical outcome. The criteria for selection were studies that included INPH from 1966 to the present in which the outcome of INPH was reported in patient groups of 20 or more. RESULTS:To date, there is no standard for outcome assessment of shunt treatment in INPH. The variable improvement rates reported are not only because of different criteria for selection of patients but also because of different postoperative assessment procedures and follow-up intervals. CONCLUSION:Studies that have established fixed protocols for follow-up have shown that short- and long-term periods after shunting are determined by many factors. Whereas short-term results were more likely to be influenced by shunt-associated risks, long-term results were independent of factors inherent to the shunt procedure and shunt complications, i.e., death and morbidity related to concomitant cerebrovascular and vascular diseases. Studies have shown that beyond 1 year after surgery, these factors definitely influence the clinical effect of shunting, making the 1-year postshunt period a potential determinant of the shunt outcome. Guidelines for outcome assessment were developed on the basis of the available evidence and consensus of expert opinion.

Development of guidelines for idiopathic normal-pressure hydrocephalus: introduction.

OBJECTIVE:There are no currently accepted evidence-based guidelines for the diagnosis and management of the normal-pressure hydrocephalus (NPH) patient. As a result, an independent study group was assembled to address this issue and determine the feasibility of developing standardized guidelines, which would be acceptable in the United States and abroad and would be based on the available scientific evidence. The guidelines were to encompass value of clinical presentation, value of supplementary diagnostic tests, surgical management, and outcome assessment. METHODS:Initially, a series of 10 questions were formulated in the areas of pathophysiology, diagnosis, and treatment to obtain a consensus by panels of experts (see Acknowledgments) assembled in San Antonio, TX, in September 2000. This workshop provided significant insight into the difficulties in developing NPH guidelines, and a consensus was reached as to those questions involving expert opinion. Subsequently, evidentiary tables were developed on the basis of the available evidence. Only those studies with 20 or more idiopathic NPH (INPH) patients were included. RESULTS:Sensitivity, specificity, and positive and negative predictive values for INPH diagnostic criteria were assessed, and guidelines were developed on the basis of the available evidence. Recommendations for classification of INPH and additional studies were documented. CONCLUSION:The development of the guidelines was made difficult because systematic studies of INPH and patient numbers were few. It was decided to maintain the classification of NPH into two major categories, INPH and those of known cause (secondary NPH). Many studies “mixed” these classifications, and as a result, they could not be used in the evidentiary tables. Despite these problems, evidence-based guidelines were developed, and it is hoped that they will be useful in guiding clinical management of the INPH patient.

Metabolic changes in the vicinity of brain contusions: a proton magnetic resonance spectroscopy and histology study.

Proton MR spectroscopy (1H-MRS) has been previously used to monitor metabolic changes in areas of diffuse brain injury. We studied metabolism in the close vicinity of experimental traumatic brain contusions and remote on the contralateral side from 1h to 28d post-injury. Changes of creatine and phosphocreatine (Cr&PCr), N-acetylaspartate (NAA), choline (Cho), inositol (Ino), taurine (Tau), glutamate (Glu), and lactate (Lac) were assessed and compared to neuronal, glial and inflammatory changes in histology. In the pericontusional zone Cr&PCr, NAA, and Glu decreased immediately after trauma by -35%, -60%, and -37%, respectively, related to primary cell disintegration and secondary perturbations as reflected in histology. These metabolites partially recovered at 7d (-15%, -37%, and -21% respectively), in parallel to indicators of repair in immunhistochemistry. Control levels were not regained at 28d, in correlation to a decrease of viable neurons. Cho and Ino, initially lowered by -26% and -31% respectively, increased at 7d by +74% and 31%, reflecting glial activation and proliferation. The signal including the lactate resonance increased by >1000% with a maximum at 7d, possibly related to energy failure, inflammation and glial activation. A partial contribution of lipids to this signal cannot be fully excluded. The contralateral side showed mild astroglial activation in histology, but no changes in 1H-MRS. The study demonstrates the feasibility of volume selective 1H-MRS using the LCModel (Linear Combination of Model in vitro spectra of metabolites solutions) to monitor metabolic changes close to focal traumatic lesions and suggests how metabolic alterations can be differentiated in cause.

One‐year outcome in the European multicentre study on iNPH

To assess the 1‐year outcome after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH).

The European iNPH Multicentre Study on the predictive values of resistance to CSF outflow and the CSF Tap Test in patients with idiopathic normal pressure hydrocephalus

Objective The objective was to determine the sensitivity, specificity, and positive and negative predictive values of the CSF Tap Test (CSF TT) and resistance to CSF outflow (Rout) for the outcome of shunting in a sample of patients with idiopathic normal pressure hydrocephalus (iNPH). Methods 115 patients were included in this European multicentre study. Diagnosis was based on clinical symptoms and signs, and MRI changes. All patients were treated with programmable ventriculoperitoneal shunts and re-examined 12 months after surgery. Outcomes were measures with a newly developed iNPH Scale and the modified Rankin Scale (mRS). Before surgery, a CSF TT and measurement of Rout was performed, with the results blinded to all caregivers. The 12 month outcome was correlated with Rout and the result of the CSF TT. Results Rout and the results of the CSF TT showed no correlation with outcome measured by either domain, or with total iNPH score or mRS score. Only an increase in the gait task (10 m of walking at free speed) of the CSF TT correlated significantly (r=0.22, p=0.02) with improvement in iNPH score. The positive predictive value of both tests was >90% and the negative predictive value <20%. Rout >12 had an overall accuracy of 65% and the CSF TT 53%. Combining both tests did not improve their predictive power. No correlation was found between Rout and the results of the CSF TT. Conclusions Rout and the results of the CSF TT did not correlate with outcome after 12 months. Rout and CSF TT can be used for selecting patients for shunt surgery but not for excluding patients from treatment. Trial registration The study has been registered at clinicaltrials.gov, identifier NCT00874198.