J Neurosurg (3 Suppl Pediatrics) 104:157–159, 2006

What we don’t (but should) know about hydrocephalus

MARVIN BERGSNEIDER, M.D., MICHAEL R. EGNOR, M.D., MILES JOHNSTON, PH.D., DORY KRANZ, M.A., JOSEPH R. MADSEN, M.D., JAMES P. MCALLISTER II, PH.D., CURT STEWART, M.P.A., MARION L. WALKER, M.D., AND MICHAEL A. WILLIAMS, M.D. Department of , University of California at Los Angeles, California; Department of Neurosurgery, New York Spine and , State University of New York, Stony Brook, New York; Neuroscience Research Program, Sunnybrook & Women’s Health Sciences Centre, Toronto, Ontario, Canada; Hydrocephalus Association, San Francisco, California; Department of Neurosurgery, Boston Children’s Hospital, Boston, Massachusetts; Department of Neurosurgery, Children’s Hospital of Michigan, Detroit, Michigan; Brain Child Foundation, Carefree, Arizona; Division of Pediatric Neurosurgery, Primary Children’s Hospital, Salt Lake City, Utah; and Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland

PIn an effort to identify critical gaps in the prevailing knowledge of hydrocephalus, the authors formulated 10 key questions. 1) How do we define hydrocephalus? 2) How is cerebrosinal fluid (CSF) absorbed normally and what are the causes of CSF malabsorption in hydrocephalus? 3) Why do the ventricles dilate in communicating hydrocephalus? 4) What happens to the structure and function of the brain when it is compressed and stretched by the expanding ven- tricles? 5) What is the role of cerebrovenous pressure in hydrocephalus? 6) What causes normal-pressure hydroceph- alus? 7) What causes low-pressure hydrocephalus? 8) What is the pathophysiology of slit ventricle syndrome? 9) What is the pathophysiological basis for neurological impairment in hydrocephalus, and to what extent is it reversible? 10) How is the brain of a child with hydrocephalus different from that of a young or elderly adult? Rigorous answers to these questions should lead to more effective and reliable treatments for this disorder.

KEY WORDS • hydrocephalus • critical issues • normal-pressure hydrocephalus • treatment • pediatric neurosurgery

The problem isn’t with what we don’t know, the problem is ment of hydrocephalus. More than 30% of new shunts fail with what we do know that isn’t so. within 1 year.7,12 Fewer than one third of new shunts survive —WILL ROGERS 10 years without revision.13,15 In some large pediatric neuro- Hardly any other pathological condition has been accorded surgery services, the ratio of revisions to placement of more determined attention on the part of the medical profession new shunts is 2.5:1.15,16 Authors of a recent randomized con- . . . than has hydrocephalus. And in hardly a single other condi- trolled multicenter study have shown that a half century of tion have cures been so elusive or so often wrecked on purely research in shunt valve design has produced little if any im- mechanical obstacles. provement in the rate of shunt survival.7 —LEO DAVIDOFF, 19294 Perhaps the obstacles on which our cure for hydroceph- alus has been wrecked are conceptual. Is there more to hy- Barely 25 years after Davidoff decried the lack of a cure drocephalus than our long-held and oversimplified concept for hydrocephalus, effective shunts came into existence. Since then, thousands of children and adults have received of it as a plumbing problem of mismatched CSF production treatment for this disorder, often resulting in significant and resorption treated by the insertion shunts or the surgi- symptomatic recovery and improvement in development cal diversion of CSF flow through ? Do and functional ability. Nonetheless, Davidoff’s phrase “so we really understand how hydrocephalus and its treatment often wrecked on purely mechanical obstacles” was pro- affect the brain? As neuroscientists, we must ask the fol- phetic. Fifty years later, the mechanical obstacle of shunt lowing questions: what do we know about hydrocephalus, failure remains the rule, not the exception, in the manage- and how do we know it? And, perhaps more important, what don’t we know about hydrocephalus that we ought to Abbreviations used in this paper: CSF = ; know? ICP = ; NPH = normal-pressure hydroceph- Working together with support from the Brain Child alus; SVS = slit ventricle syndrome. Foundation, an organization dedicated to conducting inno-

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M. Bergsneider, et al. vative research in hydrocephalus, we have formulated 10 all patients when ventricular volume is reduced? Is brain questions that we believe reflect critical gaps in our knowl- reexpansion necessary for all patients to be successfully edge of hydrocephalus. Rigorous answers to these ques- treated? And why do some patients with untreated hydro- tions would produce important gains in our understanding cephalus appear to have no neurological impairment? Al- of this condition that could lead to more effective and reli- though more details of the cellular pathology associated able treatment. with hydrocephalus have been forthcoming,5,6 a true under- standing of injury mechanisms, their multiple interactions, and the role of neural plasticity has escaped us. Thus, the Question 1: How Do We Define Hydrocephalus? reasons for reconstitution of the cortical mantle are still not clear. By gaining a complete understanding of the cellular A rigorous definition of hydrocephalus is surprisingly dif- basis for cortical reexpansion, we will no doubt discover ficult and is becoming more complicated. From a physio- many of the fundamental mechanisms that put the hydro- logical perspective, the finding of enlarged ventricles com- cephalic brain at risk and provide the basis for recovery. bined with high ICP represents only one presentation along a spectrum of disorders ranging from pseudotumor cerebri to low-pressure hydrocephalus. From a clinical perspective, how should we classify patients with hydrocephalus, from Question 5: What Is the Role of Cerebrovenous truly asymptomatic to severely impaired individuals, and Pressure in Hydrocephalus? how do we measure recovery after treatment? From the ana- tomical perspective, given the success of endoscopic third Increased cerebrovenous pressure has been found in vir- in patients with communicating hydroceph- tually all clinical and experimental studies of hydrocepha- alus and shunt failure, does the concept of obstructive versus lus, and cerebrovenous hypertension also plays a role in “communicating” hydrocephalus need to be reassessed? pseudotumor cerebri. Nevertheless, displacement of venous blood is the main source of rapid compliance in the cranio- spinal axis in response to expanding masses or hydroceph- Question 2: How Is CSF Absorbed Normally and alus. The role and interactions of cerebrovenous pressure What Are the Causes of CSF Malabsorption in and blood volume in ICP pathophysiology and intractable Hydrocephalus? shunt problems deserve further investigation. Most surgeons do not question the dogma that hydro- cephalus is caused by the mechanical obstruction of the ab- sorption of CSF through the arachnoid villi, although there Question 6: What Causes NPH? is considerable evidence that the arachnoid villi are not It is not clear whether idiopathic NPH shares a common the principal sites of CSF absorption at normal CSF pres- pathophysiology with secondary communicating hydroceph- sures.1,8,17 Do lymphatic or vascular pathways mediate CSF alus of known causes. Can the cause or causes of idiopathic absorption? If CSF water can move freely, and bidirection- NPH be discovered, and thus prevented? Are there critical ally across brain capillary membranes, is it time to recon- relationships between NPH, degenerative , and sider the concept of CSF “absorption?”9,10 If we are to make subcortical ischemic vascular disease, and how do they in- progress, we must be willing to expand into an exciting, al- fluence clinical presentation and outcomes? Understanding beit more complex, scientific frontier of CSF physiology the cause of NPH may lead to preventive measures, risk fac- that relies less on bulk flow and more heavily on intimate tor–based screening, and better diagnostic tools and clinical relationships between pulsatile CSF and blood movement outcomes. within the intracranial compartment.

Question 3: Why Do the Ventricles Dilate in Question 7: What Causes Low-Pressure Communicating Hydrocephalus? Hydrocephalus? The question asked by Dandy and Blackfan3 in 1914, and Low-pressure hydrocephalus is an enigma. A clear view reiterated many times by others, has still not been answered: of this perplexing condition, in which patients with ventric- how can the ventricles dilate and the subarachnoid spaces ulomegaly show symptoms of hydrocephalus and even signs be compressed when the subarachnoid and the ventricular of despite zero or negative ICP, may provide CSF are in free communication? A static pressure gradient a much deeper understanding of hydrocephalus. in communicating hydrocephalus would seem to violate the Pascal law. Fundamentally, do we understand the patho- physiology of communicating hydrocephalus as well as we Question 8: What Is the Pathophysiology of SVS? think we do? Shunt overdrainage continues despite various valve de- signs specifically aimed to prevent it,14 and clinical experi- Question 4: What Happens to the Structure and ence suggests that the symptoms of SVS do not correlate Function of the Brain When It Is Compressed and with ICP.11 Furthermore, why does SVS appear to be asso- Stretched by the Expanding Ventricles? ciated only with shunts placed in infancy, whereas small ventricles can develop in adults with shunt-treated hydro- Why does the cortical mantle reexpand in most but not cephalus who do not have symptoms of SVS?

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What we don’t (but should) know about hydrocephalus

Question 9: What Is the Pathophysiological Basis for References Neurological Impairment in Hydrocephalus, and to 1. Bradbury MWB, Cserr HF: Drainage of cerebral interstitial What Extent Is It Reversible? fluid and of cerebrospinal fluid into lymphatics, in Johnston MG (ed): Experimental Biology of the Lymphatic Circula- Is it regional ischemia? Disruption of white matter path- tion. New York: Elsevier, 1985, Vol 9, pp 355–394 ways? Alteration of interstitial fluid volume or composi- 2. Cowan JA, McGirt MJ, Woodworth G, Rigamonti D, Williams tion? What subcellular pathways are perturbed? What is MA: The syndrome of hydrocephalus in young and middle- the proportional role of neuronal and glial dysfunction? A aged adults (SHYMA). Neurol Res 27:540–547, 2005 more thorough understanding of injury mechanisms should 3. Dandy WE, Blackfan KD: Internal hydrocephalus: an experi- lead to pharmacological treatments that can supplement mental, clinical, and pathological study. Am J Dis Child 8: CSF shunt placement.4 406–482, 1914 4. Davidoff LM: Treatment of hydrocephalus. Historical review and description of a new method. Arch Surg 18:1737–1762, Question 10: How Is the Brain of a Child With 1929 Hydrocephalus Different From That of a Young or 5. Del Bigio MR: Cellular damage and prevention in childhood hydrocephalus. Brain Pathol 14:317–324, 2004 Elderly Adult? 6. Del Bigio MR, McAllister JP II: Pathophysiology of hydro- The clinical presentation of hydrocephalus differs with cephalus, in Choux M, DiRocco CE, Hockley AD, et al (eds): 2 Pediatric Neurosurgery. London: Churchill Livingstone, age. Does this fact reflect different susceptibility and com- 1999, pp 217–236 pensatory mechanisms that depend on the age and develop- 7. Drake J, Kestle JR, Milner R, Cinalli G, Boop F, Piatt J Jr, et al: mental or involutional status of the brain? Now that more Randomized trial of cerebrospinal fluid shunt valve design in and more children with hydrocephalus are becoming adults pediatric hydrocephalus. Neurosurgery 43:294–305, 1998 with hydrocephalus, their medical care requires a better un- 8. Egnor M, Zheng L, Rosiello A, Gutman F, Davis R: A model of derstanding of the plasticity and age-related changes that pulsations in communicating hydrocephalus. Pediatr Neuro- accompany chronic hydrocephalus. The medical treatment surg 36:281–303, 2002 also requires a change in the organization of healthcare ser- 9. Greitz D, Greitz T, Hindmarsh T: A new view on the CSF-cir- vices provided by neurosurgeons and neurologists so that culation with the potential for pharmacological treatment of childhood hydrocephalus. Acta Paediatr 86:125–132, 1997 the needs of adults with hydrocephalus can be met. 10. Johnston M, Papaiconomou C: Cerebrospinal fluid transport: a lymphatic perspective. Int J Physiol 17:227–230, 2002 11. Khorasani L, Sikorski CW, Frim DM: Lumbar CSF shunting preferentially drains the cerebral subarachnoid over the ventric- Conclusions ular spaces: implications for the treatment of slit ventricle syn- There are, of course, many other important questions, drome. Pediatr Neurosurg 40:270–276, 2004 12. McGirt MJ, Leveque JC, Wellons JC III, Villavicencio AT, and this is not to say that we have not come a long way in Hopkins JS, Fuchs HE, et al: Cerebrospinal fluid shunt survival research of hydrocephalus during the last 75 years. None- and etiology of failures: a seven-year institutional experience. theless, our understanding of hydrocephalus is not nearly as Pediatr Neurosurg 36:248–255, 2002 sophisticated or complete as we might have imagined. Fifty 13. Piatt JH Jr, Carlson CV: A search for determinants of cerebro- years after the introduction of shunts for the treatment of spinal fluid shunt survival: retrospective analysis of a 14 year in- this previously untreatable disorder, we must acknowledge stitutional experience. Pediatr Neurosurg 19:233–242, 1993 that the shunt is not a cure for hydrocephalus; it is only a 14. Rekate HL: The slit ventricle syndrome: advances based on tech- “patch,” and an unreliable one at that. We know a lot about nology and understanding. Pediatr Neurosurg 40:259–263, hydrocephalus, but much of what is true about hydroceph- 2004 alus is strange, and is not necessarily the same as what we 15. Sainte-Rose C, Piatt JH, Renier D, Pierre-Kahn A, Hirsch JF, Hoffman HJ, et al: Mechanical complications in shunts. Pedi- think we know. There is surprisingly little scientific basis atr Neurosurg 17:2–9, 1991 for many of our commonly held opinions. 16. Tuli S, Drake J, Lawless J, Wigg M, Math M, Lamberti-Pasculli Our intent is to instigate a new and vigorous dialogue M: Risk factors for repeated cerebrospinal shunt failures in pedia- among neurosurgeons, neurologists, neuroscientists, and tric patients with hydrocephalus. J Neurosurg 92:31–38, 2000 research funding agencies that will promote needed ad- 17. Zakharov A, Papaiconomou C, Koh L, Djenic J, Bozanovic-So- vancements in the understanding of hydrocephalus. The re- sic R, Johnston M: Integrating the roles of extracranial lymphat- cent symposium “Hydrocephalus: Myths, New Facts, Clear ics and intracranial veins in cerebrospinal fluid absorption in Directions,” sponsored by the National Institutes of Health sheep. Microvasc Res 67:96–104, 2004 (Bethesda, MD, September 29–October 1, 2005), under- scores the need for this dialogue. Manuscript received August 23, 2005. It is time to dispense with our presuppositions, to be clear Address reprint requests to: James P. McAllister II, Ph.D., De- about what we do and do not know, to ask the basic ques- partment of Neurological Surgery, Wayne State University School tions again, and to follow confidently where the answers of Medicine, 4201 Street Antoine, Suite UHC-6E, Detroit, Michi- lead us. gan 48201. email: [email protected].

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