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ARTICLES: G.D. Silverberg, G. Heit, S. Huhn, R.A. Jaffe, S.D. Chang, H. Bronte–Stewart, E. Rubenstein, K. Possin, and T.A. Saul The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type Neurology 2001; 57: 1763-1766 [Abstract] [Full text] [PDF]

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Reply to Letter to the Editor

Gerard D Silverberg   (18 February 2002)

The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type

Robert A Fishman   (18 February 2002)

Reply to Letter to the Editor 18 February 2002
Gerard D Silverberg Stanford University Medical Center Stanford CA Send Correspondence to journal: Re: Reply to Letter to the Editor geralds{at}leland.stanford.edu Gerard D Silverberg	As we stated in the discussion section of our paper, [1] we fully agree with Dr. Fishman that compliance changes and variation in absorption rates may be important sources of error in measuring CSF production using the Masserman technique. However, we do not believe that the CSF production decrease seen in the AD patients can be accounted for by compliance differences between the older PD patients and the AD patients for the following reasons. 1. The degree of ventricular and subarachnoid space enlargement in our AD patients was not great. The AD patients were part of a clinical trial studying the effect of chronic CSF drainage in the progression of AD. The inclusion criteria for the study determined that the AD patients were very early in the course of their disease, MMSE scores between 15 and twenty-five. 2. The exclusion criteria excluded patients with very large ventricles in order to exclude patients who may have been suffering from dementia associated with hydrocephalus. Indeed, many of the AD patients had normal to only mildly enlarged ventricles, and there was little difference in the MRI appearance of the intracranial CSF space between the older PD patients and the AD patients. However, there was an apparent difference in the CSF space between the older and younger PD patients, related to aging and the duration of their PD, but interestingly, the difference in the CSF production rates in these two groups was not significant. 3.The mean opening pressure (OP) and compliance measurements were not different in the older PD patients compared to the AD patients: OP for AD=14.16 cm H2O vs. 12.58 cm H2O for the PD patients, p=0.46. Mean compliance measurements (dV/dP) were 0.92 for the AD patients and 1.18 for the PD patients, p=0.52. (Some of these data were in our original submission but were not felt to be central to the paper and were edited out). Unfortunately, there is no good way to control for CSF absorption variations with any measurement technique. One can assume that there would be similar variations in both the older PD and the AD groups, since, as we noted in the paper, age appears to be a primary determinant in the resistance to CSF absorption. We also agree with Dr. Fishman that a less invasive and less error-prone measurement method for CSF production rates would be important. To that end we are working on an MRI approach and we hope to be able to report on whether that technique confirms our observations on the decrease in CSF production in AD or not. Reference: 1) Silverberg GD, Heit G, Huhn S, et al. The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology 2001; 57:1763-66.
The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type 18 February 2002
Robert A Fishman University of California San Francisco Send Correspondence to journal: Re: The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type aon{at}itsa.ucsf.edu Robert A Fishman	The recent paper by Silverberg et al. [1] concludes that the rate of CSF production is reduced in Alzheimer’s disease compared to PD patients, based on observations made using the Masserman technique. In 1931 Masserman calculated the rate of CSF formation in patients by measuring the time needed for the CSF pressure to return to its initial level following drainage of a standard volume of CSF by lumbar puncture. After drainage of 20 to 35 ml, of CSF, pressure was restored at a rate of about 0.32 ml./minute. Silverberg et al. modified the technique to removing 3ml. via a ventricular catheter. The Masserman technique has long been criticized because it assumed a constant rate of CSF formation and absorption. The rate of formation is relatively stable but the absorption rate varies greatly with changes in intracranial pressure. Silverberg et al. [1] failed to consider the important role of intracranial compliance in determining the pressure changes that occur following CSF drainage. Intracranial compliance, defined as dv/dp (change in volume/change in pressure), is calculated from the pressure changes that follow drainage of small volumes, 1 to 5 ml. of ventricular fluid, inducing an increase in compliance. [2] (Small volumes of saline may be injected into the ventricle to induce a decrease in compliance.) Unfortunately the pressure changes induced by the drainage of 3 ml of ventricular fluid were not reported. Silverberg et. al. assumed that the slower return of the ventricular pressure to the initial level in AD patients reflects a reduced rate of CSF formation. To the contrary, their data, at least in part, are explained by the increase in CSF volume that is associated with cerebral atrophy in AD patients and concomitant changes in intracranial compliance. The modified Masserman technique is not suitable when comparing patients with different cerebral and ventricular volumes. The assumed decrease in CSF formation calculated in the AD patients is artifactual secondary to the increased CSF volume and brain atrophy. The Pappenheimer method of ventriculo – lumbar perfusion [2] minimizes the effect of different ventricular volumes in calculating CSF formation rates. The title of the paper is misleading. The rate of CSF formation is uncertain in Alzheimer’s disease and the conclusion that is reduced is not supported by the data presented by the authors. A method for measuring CSF formation and absorption rates less invasive that the Pappenheimer method and more reliable than the Masserman method is sorely needed. References: 1)Silverberg GD, Heit G, Huhn S, et al. The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology 2001; 57:1763-66. 2)Fishman, R. A. Cerebrospinal fluid in Diseases of the Nervous System. Second Edition. 432 pp. W.B. Saunders, Philadelphia. 1992. Formation of the CSF p. 24-32; Pressure-Volume Relationships: Intracranial Compliance and Elastance. pp. 84-88.