Darko D.Lavrenčič posted comments
Dr. Wei-Che Lin
Email to colleagues
Prof. Maria I. Argyropoulou
Dr. Olivier Balédent
Prof. Jeffrey S. Kroin
Prof. Miles G. Johnston
Cochrane Library review; September 2002
Dr. Devin K. Binder
Cochrane Library review; July, August 2002
Dr. Wouter I. Schievink
Dr. Noam Alperin
Prof. Gerald D. Silverberg
Prof. David N. Levine
Prof. Mary E. Kerr
Ruth Porter, M.R.C.P.
Prof. David  Woollam

Darko D. Lavrenčič posted comments

February 2018

The recent state of a hundred years old classic hypothesis of the cerebrospinal fluid physiology.
Orešković D, Radoš M, Klarica M.
Croat Med J. 2017 Dec 31;58(6):381-383. 1 comment

Darko Lavrencic 2018 Feb 12 02:33 a.m.
Thesis: there is third circulation, antithesis: there is no third circulation. We are looking for synthesis.


It has been postulated: “The thesis is an intellectual proposition. The anti-thesis is a critical perspective on the thesis. The synthesis solves the conflict between the thesis and anti-thesis by reconciling their common truths, and forming a new proposition”.
The dialectic triad thesis-antithesis-synthesis originate with Johann Gottlieb Fichte.


April 2017

A Surgical Method to Improve the Homeostasis of CSF for the Treatment of Alzheimer’s Disease.
Qin Y.Front Aging Neurosci. 2016. 1 comment

Darko Lavrencic 2017 Apr 18 12:16 p.m.
I believe that implantable systems for continuous liquorpheresis and CSF replacement could be successfully used also for intracranial hypotension-hypovolemia syndrome as it could be caused by decreased CSF formation. See: http://www.med-lavrencic.si/research/correspondence/


Implantable Systems for Continuous Liquorpheresis and CSF Replacement.
Menéndez González M.Cureus. 2017.

Darko Lavrencic 2017 Apr 18 12:03 p.m.
I believe that implantable systems for continuous liquorpheresis and CSF replacement  could be successfully used also for intracranial hypotension-hypovolemia syndrome as it could be caused by decreased CSF formation. See: http://www.med-lavrencic.si/research/correspondence/

Manuel Menéndez González 2017 Apr 21 01:51 a.m.
Yes, right. Though that would be an application to adjust pressures. There are many other potential applications where modifying the composition of CSF may represent a treatment of the condition.


Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles.
Hladky SB.Fluids Barriers CNS. 2016. 1 comment

Darko Lavrencic 2017 Apr 15 4:10 p.m.
There are three levels of research on intracraniospinal anatomy and fluids:
1) Research at the basic level: intracraniospinal anatomy, cells, barriers, biochemical fluids exchange, flow patterns, composition, etc.
2) Physiological intracraniospinal hydrodynamics
3) Pathological hydrodynamic changes and anatomic adaptations
Contemporary stage of research is predominantly still at the first level. The problems of the first level limit the solutions to the second and the third level.
Hypothesis “The Intracraniovertebral Volumes, the Cerebrospinal Fluid Flow and the Cerebrospinal Fluid Pressure, Their Homeostasis and Its Physical Regulation” is at the second level of research: http://www.med-lavrencic.si/research/the-intracraniovertebral-volumes/.

May 2014, June, Avgust 2015

Orešković D. The controversy on choroid plexus function in cerebrospinal fluid production in humans: how long different views could be neglected? Croat Med J. 2015 Jun 19;56(3):306-10.

PubMed Commons, comment:
Darko Lavrencic 2015 Aug 06 04:06 a.m.
This dispute looks like the story “Blind men and an elephant”:
And so these men of Hindustan
Disputed loud and long,
Each in his own opinion
Exceeding stiff and strong,
Though each was partly in the right
And all were in the wrong.
(John Godfrey Saxe)

Mokri B. Spontaneous CSF leaks: low CSF volume syndromes.
Neurol Clin. 2014 May;32(2):397-422. doi: 10.1016/j.ncl.2013.11.002. Epub 2014 Feb 28.
Abstract. Practically all cases of spontaneous intracranial hypotension results from spontaneous cerebral spinal fluid (CSF) leaks, often at the level of the spine and only rarely from the skull base. The triad of orthostatic headaches, diffuse pachymeningeal enhancement on head imaging and low CSF opening pressure is considered the hallmark of these leaks but substantial variability is noted in most aspects of this disorder including in features of the headaches, imaging and CSF findings, response to treatment and outcome.

PubMed Commons, comment:
Darko Lavrencic 2015 Jun 23 01:13 a.m.
(R)evolving concept of spontaneous intracranial hypotension: from Georg(es) Schaltenbrand coming back to Georg(es) Schaltenbrand, see http://www.med-lavrencic.si/research/correspondence/

Schievink WI, Maya MM, Chu RM, Moser FG. False localizing sign of cervico-thoracic CSF leak in spontaneous intracranial hypotension.
Neurology. 2015 Jun 16;84(24):2445-8. doi: 10.1212/WNL.0000000000001697. Epub 2015 May 15.
Abstract. OBJECTIVE: Spontaneous spinal CSF leaks are an important cause of new-onset headaches. Such leaks are reported to be particularly common at the cervico-thoracic junction. The authors undertook a study to determine the significance of these cervico-thoracic CSF leaks. METHODS: The patient population consisted of a consecutive group of 13 patients who underwent surgery for CSF leak repair based on CT myelography showing CSF extravasation at the cervico-thoracic junction but without any evidence of an underlying structural lesion. RESULTS: The mean age of the 9 women and 4 men was 41.2 years. Extensive extrathecal longitudinal CSF collections were demonstrated in 11 patients. At surgery, small leaking arachnoid cysts were found in 2 patients. In the remaining 11 patients, no clear source of CSF leakage could be identified at surgery. Resolution of symptoms was achieved in both patients with leaking arachnoid cysts, but in only 3 of the 11 patients with negative intraoperative findings. Postoperative spinal imaging was performed in 9 of the 11 patients with negative intraoperative findings and showed persistence of the longitudinal intraspinal extradural CSF. Further imaging revealed the site of the CSF leak to be ventral to the thoracic spinal cord. Five of these patients underwent microsurgical repair of the ventral CSF leak with resolution of symptoms in all 5 patients. CONCLUSIONS: Cervico-thoracic extravasation of dye on myelography does not necessarily indicate the site of the CSF leak. Treatment directed at this site should not be expected to have a high probability of sustained improvement of symptoms.

PubMed Commons, comment:
Darko Lavrencic 2015 Jun 22 03:53 a.m.
Your conclusions indicate that spinal extrathecal CSF collections are not the cause but direct consequence of intracranial hypotension/CSF hypovolemia, regardless of CSF leakage. For the most probable cause of intracranial hypotension/CSF hypovolemia see http://www.med-lavrencic.si/research/correspondence/

Thomas Brinker, Edward Stopa, John Morrison and Petra Klinge
Review. A new look at cerebrospinal fluid circulation.
Fluids and Barriers of the CNS 2014, 11:10  doi:10.1186/2045-8118-11-10
http://www.fluidsbarrierscns.com   PubMed

Comment: Experimental hydrocephalus
Darko Lavrencic   (2014-05-07 10:13)
I have a comment in regard to the following statement in the article: “However, the novel concepts are also challenged mainly by the lack of validated supporting data. For example, Klarica et al. failed to reproduce the historical experiments of Dandy, since no circulation of CSF was found along a plastic cannula introduced into the aqueduct of cats.«
In the article by Dandy and Blackfan, which you cite, it is said »a piece of cotton in a small gelatin capsule … into the aqueduct of Sylvius, where it is deposited. «
In the article by Oreskovic, Klarica and Vukic ( here I would like to point out the correct order of authors as opposed to “Klarica, Oreskovic and Vukic” used in the article), which you cite, it is said  “A plastic cannula was introduced into the aqueduct of Sylvius through the vermis cerebelli and the outflow of CSF from the cannula was used as the CSF formation and circulation index” (also described in other similar articles by the above authors).
Dandy and Blackfan blocked CSF flow in the aqueduct of Sylvius, while Oreskovic, Klarica and Vukic allowed CSF flow in the aqueduct of Sylvius through cannula. Can we assume that both experimental methods are the same?
If the release of freshly actively formatted CSF happens during diastole when brain and choroid plexus shrink and create relative negative pressure in brain ventricles, this could explain hydrocephalus in Dandy and Blackfan experiment. For the comment on Oreskovic, Klarica and Vukic experiment, please see my on-line comment (Lavrencic 2013).
References: Lavrencic, D. D. (2013). “During which phase of cardiac cycle is freshly actively formatted (FAF) cerebrospinal fluid (CSF) released into the brain ventricles: systole or diastole?”. Retrieved 30 April 2013, from  http://www.med-lavrencic.si/download/Lavrencic_CSF_release_cardiac_cycle.pdf

Response to the comment of Lavrencic D.D. Experimental hydrocephalus
Thomas Brinker   (2014-05-07 21:47)  Neurosurgery Foundation Providence
Dear colleague Lavrencic,
Thank you for your comment. The statement you refer to does not compare the methods of the experiments of Dandy and Klarica and his group, instead it compares the experimental results; experiments of the former author indicate an aqueductal CSF flow, while the results of the latter authors showed the absence of such a flow. The paper is correctly cited in the reference section. Klarica was named at this point since he is obviously the senior author, present in each of the pubmed listed publications of the Zagreb based CSF research group.

Dr. Wei-Che Lin
Chang Gung University College of Medicine, Kaohsiung, Taiwan
7. April – 14. May 2015


Dear Wei-Che Lin, MD, PhD and Colleagues,
I have read your article “Application of Cine Phase Contrast MRI in Spontaneous Intracranial Hypotension Before and After Treatment.” (Yang, Chen et al. 2014) with great interest, specifically where you say »Patients with SIH showed lower CSF flow compared to healthy subjects, but this decreased CSF flow was shown by cine PC MRI to be gradually recovered after treatment«
It can be concluded from your results that, as a matter of fact, it was primarily CSF formation that was restored after patients’ treatment, since net caudal CSF flow is a consequence of CSF formation.
Your results are yet another proof that spontaneous intracranial hypotension was caused by decreased CSF formation and successful restoration of it was achieved with treatment of »CSF leakage«.
What is your opinion about this?
Darko D. Lavrenčič

Yang, I.-H., et al. (2014). “Application of Cine Phase Contrast MRI in Spontaneous Intracranial Hypotension Before and After Treatment.” 放射線學雜誌 39(3): 67-76

Dear Dr. Darko D. Lavrenčič,
In rationale, the cause of SIH is not the result of decreased CSF formation. On the contrary, the CSF secretion might be constant or probably increasing in SIH patients, but we cannot prove it in current studies yet.
Wei Che Lin, MD, PhD and colleagues

Dear Dr. Wei-Che Lin,
It is my firm belief, that SIH (caused by decreased CSF formation) could be successfully treated causally by an intrathecal infusion of artificial (mock) CSF into CSF space to restore the optimal CSF space, CSF pressure and CSF formation (net caudal CSF flow). Theoretically, the intrathecal infusion would initially restore the volume of CSF space and the CSF pressure, while the continuing of intrathecal infusion for 24 hours or more would restore also the CSF formation (net caudal CSF flow ). CSF pressure should be monitored during the intrathecal infusion, with regular checking of CSF formation (net caudal CSF flow) and CSF space.
Darko D. Lavrenčič

Email to colleagues
1. July 2014

In the CSF circulation review (http://www.fluidsbarrierscns.com/content/11/1/10) there was an opened discussion about CSF circulation – whether it exists or not. I posted a comment to the article (http://www.fluidsbarrierscns.com/content/11/1/10/comments ) where I cited my on-line commentary “During which phase of cardiac cycle is freshly actively formatted (FAF) cerebrospinal fluid (CSF) released into the brain ventricles: systole or diastole? “ (http://www.med-lavrencic.si/research/csf-release-during-cardiac-cycle/).
I believe it is possible to verify when FAF CSF is released into the brain ventricle by using MRI. That is by analyzing the volume of ventricle(s) at the beginning of systole (i.e. the ending of diastole) and the end of systole (i.e. beginning of diastole) compared to volumes of caudal and rostral CSF flow.If the CSF volume of CSF caudal flow is greater than the difference between brain ventricle(s) volume(s) at the beginning of systole and the end of it, then FAF CSF releases during systole.If the CSF volume of CSF rostral flow is smaller than the difference between brain ventricle(s) volume(s) at the end of diastole and the beginning of it, then FAF CSF releases during diastole.
The question is: Is there a way to actually verify it with MRI?
It would be interesting to analyze with MRI whether CSF net caudal flow is reduced significantly or is even absent in the head down position compared to supine or sitting position. This could verify whether a relative negative pressure is required for the release of FAF CSF into the brain ventricles.
Does MRI allow testing human CSF circulation in a position ‘upside down’?
Darko D. Lavrenčič

Dr. Olivier Balédent
Jules Verne University of Picardie, Amiens, France
January 2004

Questions (Olivier Balédent) and answers (Darko D.Lavrenčič):

Question: I do not know what do you mean by a passive depression?
Answer: Marvin Bergsneider says: “There has been a long-standing debate as to whether the CSF production rate is constant irrespective of intracranial pressure…” [1]. The hypothesis presents CSF formation as dependent on CSF pressure. The CSF pressure directly, without any active regulatory mechanism, therefore, passively, influences the CSF formation, i.e., the higher the CSF pressure the lower the CSF formation.

Question: I do not understand why the pressure of compartment IV is specific (what do you mean by “specific”).
Answer: From a hydrostatic point of view the pressure is transmitted among intracraniovertebral volumes through direct contact, e.g., brain parenchyma and cerebrospinal fluid are separated by pia mater that does not represent a barrier from a hydrostatic point of view. In contrast, the CSF space and volume IV (spinal extradural space and cranial venous sinuses) are separated by dura mater, which is nearly rigid in cranial part (at points compressible, especially transverse-sigmoid sinus joint) and to certain degree elastic in the spinal part, and thus influence the pressure transmission between the two spaces so that dura mater is able to maintain a certain pressure difference between compartment III (CSF space) and compartment IV. That is why this latter mechanism is called specific.

Question: Why do you affirm that the disturbance in compartments always occurs primarily?
Answer: The hypothesis is not dealing with conditions in which just hydrostatic pressure changes are involved, e.g., body posture, scuba diving etc. From a hydrodynamic point of view we must first have a volume change, which would secondarily have a pressure change, when a body remains in the same posture and in a stable environment.

Question: Can you explain how you obtained all your figures, are they taken from literature or are they your own work?
Answer: All figures are my own personal illustration of the presented hypothesis and have never been published anywhere in other literature.

Question: What do you mean by “quality” of arachnoidal villi?
Answer: Arachnoidal villi are the sites of removal. They could be morphologically and functionally altered e.g., inflammation of them could cause decreased CSF removal while their degeneration could cause increased CSF removal.

Question: It is difficult for me to accept the figure which represents the volume III (CSF space), according to Monro-Kellie doctrine and Marmarou pressure-volume variation law, I do not understand why CSF volume decreases, after point A, while at the same time the pressure increases?
Answer: The Monro-Kellie doctrine and the Marmarou pressure-volume variation law say that if you add some new volume into the cranial vault the intracranial pressure would increase e.g., if patient experiences epidural hematoma of five ml, this will increase intracranial pressure by translocation of nearly five ml CSF from cranial to spinal part of CSF space, which is enabled by elastic dural sac. At this point you must turn to Fig.5 presenting volume III (CSF space) as a secondary result of the intracranial pressure change. If the intracranial pressure occurs between point A and point B-high, then the CSF formation at this higher pressure is lower then CSF removal, therefore this dynamic process would cause that the volume III (CSF space) starts to decrease. The decrease of volume III would cause the decrease of CSF pressure until equilibrium between CSF formation and CSF removal re-established. The final result of this dynamic process is that the optimal CSF pressure is re-established where there exists a five ml epidural hematoma and a volume III (CSF space), which is decreased for five ml. Experimentally, the new volume could be added directly (e.g., five ml of artificial CSF) into the CSF space (this could never happen naturally, without invasive medical procedure). The starting CSF volume in this case would be increased for five ml and the above-mentioned dynamic process would decrease it for five ml.

Question: If your figure concerning CSF flow represents the difference between CSF formation and CSF removal flow, the curve will be different (see attached file).
Answer: The CSF flow (per hour) is defined in the hypothesis by the amount of CSF volume transported from sites of CSF formation to sites of CSF removal. This means that e.g., if there is zero CSF removal at very high pressure, there would also be zero CSF flow and the temporary CSF formation could still be present. This temporary CSF formation contributes solely to the increase of CSF volume, but it is not in any case representative of CSF flow, because there is zero CSF volume transport from the sites of CSF formation to the sites of CSF removal. In the opposite situation, e.g., if there is zero CSF formation at very low CSF pressure, then again, there would also be zero CSF flow while the temporary CSF removal could still be present. This temporary CSF removal contributes solely to the decrease of CSF volume, but it is not in any case representative of CSF flow, because there is zero CSF volume transport from the sites of CSF formation to the sites of CSF removal. Thank you for your graph, which accurately represents the dynamic net CSF volume change from another perspective and as new illustration provides better understanding of the hypothesis. Relation between CSF formation and CSF removal depicts positive values as CSF accumulation in CSF space and negative values as CSF depletion in CSF space.

Question: If it is possible for you I would like to study your original paper, what was the revue?
Answer: Original paper was edited and published by myself [2]. It is accessible in the Slovene National and University Library as a book (thesis) published by author with the Catalogue Number II 229751. The printed version on my website includes photocopies of all figures from original paper, the original text being retyped for minor style/language improvements and spelling/grammar corrections, while the subject and presentation of the hypothesis remained unchanged.

1) Bergsneider M. Evolving concepts of cerebrospinal fluid physiology. Neurosurg Clin N Am 2001;12(4):631-8.
2) Lavrencic D. The Intracraniovertebral Volumes, the Cerebrospinal Fluid Flow and the Cerebrospinal Fluid Pressure, Their Homeostasis and Its Physical Regulation.

Prof. Maria I. Argyropoulou
University of Ioannina, Greece
November 2003

Dear Professor Maria I. Argyropoulou,
In your article [1] you are reporting the measurements of the systolic and the diastolic cerebrospinal fluid (CSF) flow volume at the level of the aqueduct of Sylvius during spontaneous intracranial hypotension (SIH) and after recovery of the patient:

During SIH:  after recovery:
Systole: 0,013 ml/cardiac cycle 0,039 ml/cardiac cycle
Diastole: 0,011 ml/cardiac cycle 0,016 ml/cardiac cycle

I have calculated from your measurements the net caudal CSF flow by subtracting the diastolic flow from the systolic flow per cardiac cycle:

During SIH: after recovery:
Net caudal flow:  0,002 ml/cardiac cycle 0,023 ml/cardiac cycle

In my opinion, the results of the net caudal flow are very important because a 11,5-fold rate difference (0,021 ml/cardiac cycle) occurs between them. Your measurements clearly show that during SIH the CSF flow was very low due to decreased CSF formation that has caused secondary CSF hypovolemia. I would suggest to consider in your case the decreased CSF formation to be, most probably, the primal cause of SIH.
Darko D.Lavrenčič

1) Metafratzi Z, Argyropoulou MI, Mokou-Kanta C, Konitsiotis S, Zikou A, Efremidis SC. Spontaneous intracranial hypotension: morphological findings and CSF flow dynamics studied by MRI. Eur Radiol 2003 Nov

Prof. Jeffrey S. Kroin
Rush-Presbyterian-Luke’s Medical Center, Chicago
January 2003

Dear Professor Jeffrey S.Kroin and Colleagues,
I have read your article [1] with great attention. Your valuable experimental evidence on a rat model is supporting my hypothesis presented on web page http://www.med-lavrencic.si/raziskava.htm and my opinions expressed on web page http://www.med-lavrencic.si/correspondence.htm.
I believe that the intracraniovertebral volumes’ homeostatic equilibrium i.e. volumes’ balance is relatively stable regardless to different body postures i.e. standing up, lying or hanging with head upside down. The relative hydrostatic pressure difference among CSF pressures and opposite hydrostatic pressures at CSF drainage paths remains relatively constant during different body postures while passively floating CSF formation/removal homeostatic equilibrium along the CSF formation curve supports this stable volumes’ balance at the expense of CSF flow: when standing up it is increased and when hanging down it is decreased.
What is your opinion about this?
Darko D.Lavrenčič

1) Kroin JS, Nagalla SK, Buvanendran A, McCarthy RJ, Tuman KJ, Ivankovich AD. The mechanisms of intracranial pressure modulation by epidural blood and other injectates in a postdural puncture rat model.Anesth Analg. 2002 Aug;95(2):423-9

Prof. Miles G. Johnston
University of Toronto
November 2002

Dear Professor Miles G.Johnston,
I have read the abstract of your article: “Johnston M,Papaiconomou C. Cerebrospinal fluid transport: a lymphatic perspective. News Physiol Sci. 2002 Dec;17:227-30” with great interest. I believe that the classical hypothesis based on CSF drainage exclusively into the cranial venous sinuses (prevailing for three decades) seriously underestimated or even neglected prior evidences of other CSF drainage paths. Robert Elman reported in 1923: “A foreign, non-toxic, isotonic solution, introduced into the sub-arachnoidal space by the replacement of an equal quantity of cerebrospinal fluid, escaped from the cord through arachnoidal, mesothelial cell-nests and made its way into veins outside the cord and possibly also into lymphatic channels in this region” [1]. After the acceptance of the classical hypothesis any new evidences of other CSF drainage paths was completely ignored in textbooks. I believe that other CSF drainage paths allow regular CSF removal at CSF pressures lower than 68 mm H20 (venous hydrostatic pressure in superior sagittal sinus).
What is your opinion about this?
Darko D.Lavrenčič

1) Elman R.Spinal arachnoid granulations with especial reference to cerebrospinal fluid. Johns Hopkins Hosp. Bull. Mar 1923;385 :99-104

Dear Darko Lavrencic,
In terms of CSF absorption, we now believe that the current concepts are incorrect. We believe that the majority of CSF absorption takes place into lymphatic vessels external to the brain and spinal cord. There is considerable experimental evidence that CSF is absorbed from the spinal subarachnoid compartment. The problem with the spinal arachnoid projections is that many of these are not associated with veins. Therefore, their role is unclear. In any event, it looks like the majority of CSF transport occurs into lymphatics at low to moderate CSF pressures. Only at very high pressures, can any case be made for CSF transport into the cranial venous sinuses.
Miles Johnston, Ph.D.

Cochrane Library review item entitled “Shunting for Normal Pressure Hydrocephalus (NPH)”. September 2002

Darko D.Lavrenčič’s comments entitled “A severe complication of shunt” (review comments).

Devin K. Binder, M.D., Ph.D.
University of San Francisco
September 2002

Dear Dr.Devin K.Binder and Colleagues,
It was very interesting to read your article “Intrathecal saline infusion in the treatment of obtundation associated with spontaneous intracranial hypotension: technical case report. Neurosurgery. 2002 Sep;51(3):830-7.”, specifically where you conclude that for life threatening low ICP syndrome the therapy of choice is intrathecal infusion as it is proposed in literature [1,2,3]. You find epidural blood patching not effective in such case as it was already previously reported [2]. Did you consider applying artificial CSF infusion instead of saline one? What was the CSF pressure at the time you have applied epidural blood patching after the recovery of the patient?
Darko D.Lavrenčič

1) Zlotnik EI, Stolkarts IZ.[Cerebrospinal fluid hypotension after brain surgery]Zh Vopr Neirokhir Im N N Burdenko. 1984 Mar-Apr;(2):48-53.
2) Pleasure SJ, Abosch A, Friedman J, Ko NU, Barbaro N, Dillon W, Fishman RA, Poncelet AN. Spontaneous intracranial hypotension resulting in stupor caused by diencephalic compression.Neurology. 1998 Jun;50(6):1854-7.
3) Darko D.Lavrenčič’s comments (review comments ) and response from the lead author of Cochrane Library review item entitled “Epidural blood patching for preventing and treating post-dural puncture headache”. July – August 2002.

Dear Darko Lavrencic,
I am of the opinion that this condition is more common than most people think, I have seen at least two people since this report that meet the diagnosis. You make an interesting point about artificial CSF solution (ACSF) rather than saline infusion. As you probably know, normal saline solution is slightly acidic (pH about 5) and may be painful to an awake patient. To answer your second question, the ICP remained normal after epidural blood patch (10-18 cm H2O).
Devin K. Binder, M.D., Ph.D.

Cochrane Library review item entitled “Epidural blood patching for preventing and treating post-dural puncture headache”
July, August 2002

Darko D. Lavrenčič’s comments and response from the lead author of Cochrane Library review (review comments )

Dr. Wouter I. Schievink
University of California, Irvine
April 2002

Dear Dr. Wouter I.Schievink,
It was very interesting to read your article: “Spontaneous Spinal Cerebrospinal Fluid Leaks: A Review. Neurosurg Focus 9(1), 2000” and specifically where you say: “Not infrequently, a “dry tap” is initially encountered, and CSF can only be obtained with a Valsalva maneuver, placing the patient in an upright position, or with aspiration by using a syringe. A sucking noise has also been described as the stylet is withdrawn and air enters the subarachnoid space, indicating sub atmospheric pressure”.
I wonder how CSF leakage could cause negative pressure in entire CSF space and how it could take place from lower to higher hydrostatic pressure. This is not compatible with basic physical hydrodynamic law that liquid is moving only from higher to lower pressure. As you mention there can be a sucking noise as the stylet is withdrawn, indicating that an anti-leaking i.e. reverse leaking is taking place.
According to the probable mechanism presented on my website www.med-lavrencic.si the regular CSF removal is taking place during negative CSF pressure. Oncotic pressure difference between CSF and venous blood in spinal extradural veins plexuses could be the only possible force that could create a negative pressure in entire CSF space.
Darko D.Lavrenčič

Dr. Noam Alperin
University of Illinois at Chicago
March 2002

Dear Dr. Noam Alperin,
I have read some of your articles about MRI in connection with CSF hydrodynamics. I would like to inform you of a CSF hydrodynamic mechanism I suggest on my website www.med-lavrencic.si. Have you measured CSF flow with MRI technique on patients with intracranial hypotension hypovolemic syndrome or obstructive hydrocephalus?
Darko D.Lavrenčič

Darko Lavrencic,
Please email me a brief summary of the mechanism you are referring to.
Dr. Alperin

Dear Dr. Noam Alperin,
Fig.5 shows basic relations between intracranial pressure (as independent variable) and CSF formation, CSF removal, volume of CSF space and CSF flow (as dependent variables). From B-low to B-high is physiological phase of homeostasis that maintains homeostatic equilibrium (optimal ICP, formation, removal, CSF volume and flow). In pathophysiological phase beyond B-high the relation between formation and removal is reverse (formation higher than removal) so the final result is self-sustaining state of maximal ICP, maximal volume of CSF space and zero flow (various clinical pictures with high ICP around 30 mmHg). In pathophysiological phase below B-low the removal is higher than formation so the final result is minimal CSF pressure with minimal CSF space volume and zero flow (clinical picture: intracranial hypotension hypovolemic syndrome). Masserman based techniques and perfusion based techniques are inappropriate as far as measuring formation, removal, volumes and flow in pathophysiological phases are concerned. I see MRI based techniques as the only optional technique to analyse what is really happening in pathophysiological phases where we haven’t got answers to the opened questions yet.
Darko D.Lavrenčič

Prof. Gerald D. Silverberg
University Medical Center Stanford
February, March 2002

Dear Professor Gerald D. Silverberg,
It was very interesting to read your article: “The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology 2001 Nov 27;57(10):1763-“. Your results indicate that CSF production is markedly reduced in patients with AD. Please see on my website www.med-lavrencic.si a possible homeostatic mechanism. What was the difference between CSF pressure of both groups ?
Darko D.Lavrenčič

Dear Darko Lavrencic,
There was no difference in opening pressure or measured compliance between the two groups. The data was sent in response to a criticism of the article by Dr. Fishman and should be appearing shortly in Neurology.
GD Silverberg

Dear Professor Gerald Silverberg,
Regarding your response “On-line Post-Publication Peer Review. Neurology. February 18, 2002”, I specifically agree with your statements: “Unfortunately, there is no good way to control for CSF absorption variations with any measurement technique”, “We also agree with Dr.Fishman that a less invasive and less error-prone measurement method for CSF production rates would be important (Dr.Fishman: “sorely needed”). To that end we are working on an MRI approach”.
Darko D.Lavrenčič

Prof. David N. Levine
New York University School of Medicine
December 2001

Dear Professor David N. Levine,
It was very interesting to read your article “The pathophysiology of lumbar puncture headache. J Neurol Sci 2001 Nov 15;192(1-2):1-8”. There are many questions opened. I am sending to you a hypothesis of probable mechanism, which could explain some questions. According to the hypothesis there is no “CSF leaking” but regular CSF removal during intracranial hypotension (hypovolemic) syndrome (pathophysiological phase of intracranial spinal volumes homeostasis). Elasticity of dural sac plays key role. Epidural injections of blood or saline give immediate relief by elevating ICP from pathophysiological to physiological phase of homeostasis, which restore CSF space.
Darko D.Lavrenčič

Dear Darko Lavrencic,
The ideas are very interesting, although they are somewhat unorthodox. The usual view is that the rate of CSF formation is constant, except possibly for a mild decrease at high CSF pressure; and the rate of CSF removal is linearly related to the difference between CSF pressure and dural venous sinus pressure. Your hypothesis certainly allows for greater complexities, including the prediction of self-sustaining states of low CSF volume at very low pressure and high CSF volume at very high pressure. I wonder what evidence exists for such states.
David Levine

Dear Professor David N. Levine,
I am very aware of my unorthodox view on the issue, which has been even more unusual at the time of publishing it. Contemporary view on relation between CSF formation and CSF removal mainly deals with the physiological phase of homeostasis in cranial part. During intracranial hypovolemic hypotension syndrome (which is a self-sustaining state without therapy or until other bio mechanisms start to take place and influence on relation between CSF formation and CSF removal) spinal processes play key role as shown by radioisotope cisternography. It clearly shows that there is no CSF flow (no formation and no removal) in cranial part; removal or ‘leaking’ takes place in spinal part. Spinal part contributes one fourth of total CSF transport in sheep (Bozanovic-Sosic R, Mollanji R., Johnston MG. Spinal and cranial contributions to total cerebrospinal fluid transport. Am J Physiol Regul Integr Comp Physiol 2001 Sep;281(3):R909-16). Can we rely only on the removal depending on the difference between CSF pressure and dural venous sinus pressure?
How a very high self-sustaining ICP is behaving has been documented by Mary E. Kerr et al. (Mary E. Kerr et al. Dose response to cerebrospinal fluid drainage on cerebral perfusion in traumatic brain-injured adults. Neurosurg Focus 11(4):Article 1,2001). If there were complete ventricular block of CSF flow, which prevents any CSF removal from ventricles while there is still persisting some CSF formation (contribution to CSF volume), the skull would explode. The stop of CSF formation must occur at certain high ICP.
Your hypothesis on mechanism about processes, which cause headache during intracranial spinal hypotension hypovolemic syndrome, is perfectly compatible with overall intracraniovertebral volumes homeostasis in pathophysiological phase.
Darko D.Lavrenčič

Prof. Mary E. Kerr
University of Pittsburgh
November 2001, January 2002

Dear Professor Mary E. Kerr,
It was very interesting to read your article: “Dose response to cerebrospinal fluid drainage on cerebral perfusion in traumatic brain-injured adults. Neurosurg Focus 11(4): Article 1, 2001”. I believe that you can achieve permanent relief instead of a temporary one. Increasing the amount of drainage in pathophysiological zone will cause the enter into physiological zone by crossing turning point B-high. Physiological homeostatic mechanism will rebuild optimal volumes, pressure and flow. For the mechanism see attached files.
Darko D.Lavrenčič

Dear Darko Lavrencic,
What we also did, but was not reported in this manuscript, was a fourth trial after the first three randomly ordered drainages and that was to drain until no further CSF was removed. Again the result was temporary. I believe that there are subsets of patients that CSF drainage is effective and there are periods after injury when CSF drainage is more effective than others but more research needs done in this population to sort it out. What we don’t know at all is whether CSF drainage has any negative effects on outcome.
Mary Kerr

Dear Professor Mary Kerr,
If the result of the fourth trial restores starting high ICP it could be caused by de-compensated condition (Fig. 6) with decreased removal curve. Do you have any data of CSF transport during the trial?
Darko D.Lavrenčič

Dear Darko Lavrencic
There was an extremely similar response in the ICP during each successive trial. The fourth trial we removed CSF “until it stopped draining” but again we saw the ICP return to baseline levels in most patients within 10-15 minutes. This was very surprising to us.
Unfortunately we did not collect data regarding CSF transport.
Mary Kerr

Dear Professor Mary Kerr,
Your findings clearly show how self-sustained high ICP is restoring its starting high ICP after CSF drainage. Such results are expected according to pathophysiological high ICP phase of intracraniovertebral volumes homeostasis, which I have presented to you. Therefore I am very pleased by your valuable contribution to CSF pathophysiology.
Darko D.Lavrenčič

Ruth Porter, M.R.C.P.
Deputy Director, The CIBA Foundation, London
February 1971

Dear Darko Lavrencic,
I have asked two very knowledgeable workers in this field about your paper on intracraniovertebral volumes and I am sorry to say that I cannot be very much help over it. It is obviously a very thoughtful commentary and your hypothesis needs to be proved or disproved. As far as publication is concerned, I would suggest that you would have to do a bit more experimental work before submitting the paper to a journal. I do hope this letter won’t be too much of a disappointment to you because it really is an excellent study and an interesting idea.
Ruth Porter, M.R.C.P.

Prof. David Woollam
Emmanuel College Cambridge, UK
November 1969

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Dear Darko Lavrencic,
I am very interested in your hypothesis. As I work through it I am taking the liberty of editing the English in case you wish to publish it in the B.M.J. which as you may know has a special series weekly of ideas, hypotheses etc. If you are in this country do come and see me.
David Woollam