Review Received: March 23, 2017 Accepted after revision: May 2, 2017 Published online: August 11, 2017

Pediatr Neurosurg DOI: 10.1159/000477175

Cerebrospinal Fluid Biomarkers of Pediatric Hydrocephalus David D. Limbrick Jr Leandro Castaneyra-Ruiz Roland H. Han Daniel Berger James P. McAllister Diego M. Morales Division of Pediatric Neurosurgery, Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA

Abstract Hydrocephalus (HC) is a common, debilitating neurological condition that requires urgent clinical decision-making. At present, neurosurgeons rely heavily on a patient’s history, physical examination findings, neuroimaging, and clinical judgment to make the diagnosis of HC or treatment failure (e.g., shunt malfunction). Unfortunately, these tools, even in combination, do not eliminate subjectivity in clinical decisions. In order to improve the management of infants and children with HC, there is an urgent need for new biomarkers to complement currently available tools and enable clinicians to confidently establish the diagnosis of HC, assess therapeutic efficacy/treatment failure, and evaluate current and future developmental challenges, so that every child has access to the resources they need to optimize their outcome and quality of life. © 2017 S. Karger AG, Basel

© 2017 S. Karger AG, Basel E-Mail [email protected] www.karger.com/pne

Introduction

Hydrocephalus (HC) is a common, debilitating neurological condition that affects 1 in every 1,000 individuals across the USA and up to 1 in 500 in the developing world [1]. HC results from an imbalance in cerebrospinal fluid (CSF) production and resorption, and typically causes enlargement of the cerebral ventricles and increased intracranial pressure. Untreated or inadequately treated HC results in significant neurological morbidity, developmental disability, or death. Particularly in pediatrics where infants may be unable to convey their symptoms, making an accurate diagnosis of HC or shunt malfunction may be extremely challenging. Physical findings such as enlarging head circumference, tenseness of the anterior fontanel, and splaying of the cranial sutures are crude parameters, and changes in vital signs occur only very late in the disease course. Image-based measurements of ventricular size have thus become the de facto guide for these diagnostic dilemmas; however, ventricular morphology is an imperfect metric for treatment decisions [2] as it is often affected by prior neurological injury, atrophy, or altered white matter development, all of which are common in individuals at risk of HC. Furthermore, ventricular size may not change in the setting of treatment failure. To advance this field and improve the outcomes of indiDavid D. Limbrick Jr, MD, PhD Neurosurgeon-in-Chief, St. Louis Children’s Hospital 1 Children’s Place, Suite 4S20 St. Louis, MO 63110 (USA) E-Mail limbrickd @ wustl.edu

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Keywords Hydrocephalus · Congenital hydrocephalus · Posthemorrhagic hydrocephalus · Intraventricular hemorrhage · Cerebrospinal fluid · Biomarker

Hydrocephalus: A Complex, Multidimensional Disease

HC in infants and children may result from a number of different etiologies, which may be associated with comorbid neurological injury or systemic disease and be influenced by genetic, environmental, and geographic factors. Globally, infection resulting from neonatal sepsis is the most common cause of pediatric HC (postinfectious HC, PIH) [3], but posthemorrhagic HC (PHH) is the most common cause in North America [4]. Other common causes of pediatric HC include congenital nonhemorrhagic HC (CHC), HC associated with spina bifida (SB/ HC), brain tumors, and traumatic brain injury (TBI) [5]. Regardless of etiology, HC is a multidimensional disease characterized by myriad pathophysiological processes, including structural deformation, impaired cerebral blood flow and ischemia, periventricular axonal injury and demyelination, abnormal energetics and metabolism, altered neurotransmitter and neuromodulator levels, neuroinflammation, and apoptosis (reviewed in [4, 6–10]). While complex, the broad involvement of cellular pathways in multiple cell types, including neurons, microglia, and glial and ependymal cells, creates a rich pool of candidate biomarkers of HC.

CSF Biomarkers Reflect Brain Physiology

Biomarkers are emerging in many fields as valuable diagnostic tools and predictors of clinical course and therapeutic efficacy. CSF is a highly regulated fluid with a molecular diversity dependent on the local neurophysiological and neuropathophysiological processes. Thus, CSF components have been extensively evaluated as responsive and quantifiable biomarkers of neurological diseases such as Alzheimer disease (AD), amyotrophic lateral sclerosis, TBI, and even adult-onset normal-pressure HC (NPH) [11–16]. In pediatric HC, etiology-dependent disturbances in CSF hydrodynamics create additional complexity in CSF 2

Pediatr Neurosurg DOI: 10.1159/000477175

biomarker analysis and interpretation. For example, in the case of obstructive HC (e.g., aqueductal obstruction), elevated CSF protein concentrations may be secondary to CSF stasis. Conversely, in HC associated with periventricular or ependymal injury (e.g., PHH or PIH), such elevations may be related to tissue injury, blood products, or local or systemic inflammatory processes. Altered CSF proteins may also result in part from injury to the cerebral glymphatic system, which mediates fluid transit through paravascular pathways along penetrating arterioles and venules [17, 18]. Impairment of glymphatics has been shown to alter parenchymal protein clearance and increase the CSF levels of specific candidate biomarkers in TBI [20, 21]. An increase in total CSF protein through any or all of these mechanisms would be expected to increase the CSF-parenchymal osmotic/oncotic gradient, potentially increasing CSF volume and contributing to ventriculomegaly and HC. Thus, while the most direct impact of CSF biomarkers may be to provide important diagnostic, prognostic, and therapeutic information to clinicians, they also yield unique insights into ongoing time- and etiology-dependent pathophysiological processes and their effects on the developing brain.

Discovery-Validation Platform for Development of CSF Biomarkers

As a field, we are gaining momentum in the search for biomarkers of pediatric HC. While preliminary investigations into individual candidate CSF biomarkers have spanned nearly 3 decades (Table  1), progress has been hastened in recent years by integrating “omics” technologies [21–23] and multiplex analyses [24, 25]. Proteomicsbased discovery-validation paradigms have been employed to investigate the CSF of infants and children with HC [21, 23]. Since many biomarkers tend to be moderate- and low-abundance proteins, tandem immunoaffinity or other adjunctive fractionation techniques have been developed to remove nonspecific, high-abundance proteins such as blood proteins and keratins, in order to increase the yield of lower-abundance proteins [21, 23]. Pairing such separation strategies with proteomics has enabled the identification of a large cohort of proteins unique to CSF including cell adhesion molecules, synaptic proteins, and markers of oxidative stress and neuronal death in the CSF of children with HC largely resulting from brain tumors or CHC [21]. Similarly, tandem immunoaffinity proteomics has been used to study the CSF of preterm neonates with and Limbrick Jr/Castaneyra-Ruiz/Han/Berger/ McAllister/Morales

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viduals with HC, there is an urgent need to develop new biomarkers to complement existing image-based measures of ventricular size and facilitate the clinical diagnosis of HC, assess treatment efficacy (shunt malfunction, treatment failure, or overdrainage), stratify disease severity for clinical trials, predict neurodevelopmental outcomes, and ensure access to appropriate therapies.

Table 1. Overview of specific CSF biomarkers of pediatric hydrocephalus by etiology

Inflammation IL-1β IL-6 IL-8 IL-18 TNF-α IFN-g LTC4/LTD4 Eosinophilia PMN leukocytes Growth factors HGF NGF NT-3 SCF TGF-β1 TGF-β2

+

PHH

References

+

Schmitz et al. 2007 [44], Savman, et al. 2002 [45] Savman et al. 2002 [45], Baumeister et al. 2000 [46] Savman et al. 2002 [45] Schmitz et al. 2007 [44], Sival et al. 2008 [47] Savman et al. 2002 [45] Sival et al. 2008 [47] White et al. 1990 [48] Fulkerson et al. 2008 [49] (elevated in infections) Fulkerson et al. 2011 [50] (elevated in infections)

+ + + + +

+ +

+ + +

+ +

+ + +

Okamoto et al. 2010 [51] Hochhaus et al. 2001 [39], Mashayekhi and Salehi 2005 [52] Hochhaus et al. 2001 [39] Naureen et al. 2014 [43] Heep et al. 2004 [37], Whitelaw et al. 1999 [53], Chow et al. 2005 [54] Chow et al. 2005 [54]

+ + +

+ +

Cell membrane/extracellular matrix APP + + + Aβ42 sAPPα + + sAPPβ + + BCAN + AQP4 + CSPG + EPO + + Hypoxanthine + MBP + MMP-9 + Nitrated-CSPG + NPBI + sFas + Fas receptor + TPO + VEGF + + Cell adhesion and cytoskeleton L1CAM + NCAM-1 + NCAM-2 Tau + c-Tau + pTau + NFL GFAP Miscellaneous FDP PAI-1 TxB2 s-100, s-100b s-100b, NSE 5-HT, 5-HIAA sMAC

SB/HC

+ –, + +

+

+ +

+ + + + + +

+

+ + + + +

+

+

+

CSF Biomarkers of Hydrocephalus

Limbrick et al. 2017 [26], Morales et al. 2017 [27] Limbrick et al. 2017 [26], Talab et al. 2009 [55] Limbrick et al. 2017 [26], Morales et al. 2017 [27] Limbrick et al. 2017 [26], Morales et al. 2017 [27] Morales et al. 2012 [23] Castaneyra-Ruiz et al. 2013 [56], Ortega et al. 2016 [57] Chow et al. 2005 [54] Koehne et al. 2002 [41] Bejar et al. 1983 [58] Beems et al. 2003 [40], Longatti et al. 1993 [42], Naureen et al. 2013 [59] Okamoto et al. 2008 [51], 2010 [60] Chow et al. 2005 [54], Krueger 2004 [61] Savman et al. 2001 [62] Schmitz et al. 2011 [63], Felderhoff-Mueser et al. 2001 [64] Naureen et al. 2014 [43] Reinhold et al. 2007 [65] Heep et al. 2004 [37], Koehne et al. 2002 [41], Naureen et al. 2014 [43] Limbrick et al. 2017 [26], Morales et al. 2017 [27], Ortega et al. 2016 [57] Limbrick et al. 2017 [26], Morales et al. 2017 [27] Morales et al. 2012 [23] Limbrick et al. 2017 [26], Talab et al. 2009 [55], de Bont et al. 2008 [66] Cengiz et al. 2008 [67] Limbrick et al. 2017 [26], Morales et al. 2017 [27] Whitelaw et al. 2001 [68] Beems et al. 2003 [40], Naureen et al. 2013 [59], Whitelaw et al. 2001 [68] Whitelaw et al. 1991 [69] Hansen et al. 1997 [70] White et al. 1990 [48] Whitelaw et al. 2001 [68] Beems et al. 2003 [40] (HC etiology not defined) Gopal et al. 2007 [71] Ramos et al. 2016 [72] (elevated in infections)

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3

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CHC

5 8 6

S2

7 4 3 2

S1

1 HBB

HBA2

HBG2

CHGA

BCAN NCAM-1

Fig. 1. Cerebrospinal fluid proteomics in posthemorrhagic hydro-

cephalus of prematurity. This heat map shows the mean intensity z score for all proteins identified using tandem immunoaffinity proteomics. Several proteins of interest are highlighted. KRT, keratin; HBB, hemoglobin β; HBA2, hemoglobin α2; HBG2, hemoglobin γG; CHGA, chromogranin A; BCAN, brevican; NCAM-1,

without PHH. CSF from infants with PHH demonstrated striking and specific increases in the levels of >400 proteins, including those involved in the regulation of cell adhesion, the extracellular matrix, the cytoskeleton, and oxidative metabolism, all of which mediate neurodevelopmental processes at various levels [23] (Fig. 1). In these proteomics analyses, amyloid precursor protein (APP), neural cell adhesion molecule (NCAM-1), L1 neural cell adhesion molecule (L1CAM), and brevican were shown to be particularly robust candidates as CSF biomarkers of PHH. In subsequent studies using conventional protein quantification methods such as enzyme-linked immunosorbent assays, these specific proteins have been examined in several focused investigations [23, 26–28]. As this example shows, effective biomarker development often begins with rational experimental discovery but must be followed by rigorous, targeted validation.

CSF Biomarkers of Posthemorrhagic Hydrocephalus

Based on initial discovery-validation proteomics pathway results, the relationship between validated candidate CSF biomarkers and PHH has been investigated. Upon 4

Pediatr Neurosurg DOI: 10.1159/000477175

APP

L1CAM

neural cell adhesion molecule 1; APP, amyloid precursor protein; L1CAM, L1 cell adhesion molecule. S1 and S2 refer to ventricular CSF samples acquired from a preterm infant with PHH at the time of treatment initiation (S1) and 7 days later (S2). Reproduced with permission from Morales et al. [23].

examination of lumbar CSF levels of APP, soluble APPα (sAPPα), sAPPβ, NCAM-1, L1CAM, Tau, phosphorylated Tau (pTau), and total CSF protein (TP) among infants with no known neurological disease, intraventricular hemorrhage (IVH) grades I/II, IVH grades III/IV, PHH, hypoxic-ischemic injury, and ventricular enlargement without HC, CSF APP, sAPPα, L1CAM, and TP were found to be selectively increased in PHH compared with the other conditions. Importantly, the findings suggest that these markers may be able to discriminate PHH from other conditions that affect preterm infants. For example, with an appropriate cut point, CSF sAPPα demonstrated 91% sensitivity and 95% specificity for PHH, as well as an odds ratio for PHH of 200.0 with a relative risk of 46.9 [27]. In infants undergoing active temporizing treatment via percutaneous ventricular reservoir taps, CSF levels of APP, NCAM-1, and L1CAM (but not TP) paralleled ventricular size in a time-locked fashion (Fig. 2) [28]. Indeed, preliminary data described in the same report suggested that these CSF biomarkers also track intracranial pressure in real time.

Limbrick Jr/Castaneyra-Ruiz/Han/Berger/ McAllister/Morales

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KRT

0.60 10

0.45

Normalized APP

20 FOR

sAPP į, ng/mL

H IE

VE W O H

III H

PH H

/ IV

I

30

0 0

5 10 Weeks relative to RES surgery

Fig. 2. Cerebrospinal fluid amyloid precursor protein levels parallel ventricular size in posthemorrhagic hydrocephalus of prematurity. Frontal occipital horn ratio (FOR; red, left y axis), APP concentration (blue, right y axis), and total protein (TP; black, right y axis) plotted versus time after ventricular reservoir (RES) surgery in 2 infants. Each FOR data point is accompanied by an ultrasound image for the selected patient at that particular time point. Reproduced with permission from Morales et al. [28].

CSF Biomarkers of Congenital Hydrocephalus

The term “congenital hydrocephalus” is used to refer to a broad range of HC etiologies with fetal or neonatal onset. Recent data suggest that CHC may result from genetic or epigenetic abnormalities in cell junction biology [29, 30], ependymal cell polarity, defects in primary or motile cilia [31–34], subventricular precursor cell biology (e.g. migration) [35], or other developmental pathology [1, 36]. Limited research has been conducted into CSF biomarkers of CHC. Heep et al. [37, 38] showed that levels of TGF-β1 and aminoterminal propeptide of type I collagen varied by HC etiology, with lower values in CHC and SB/HC relative to PHH. A more recent investigation CSF Biomarkers of Hydrocephalus

Fig. 3. Lumbar cerebrospinal fluid levels of soluble amyloid precursor protein-α are selectively elevated in posthemorrhagic hydrocephalus of prematurity. Levels in 6 different subject groups were compared: (1) control subjects (no known neurological insult or injury), (2) IVH grades I/II, (3) IVH grades III/IV, (4) PHH, (5) HIE, and (6) VEWOH. Boxes represent the median with 25th and 75th percentiles and the whiskers depict the interquartile range multiplied by 1.5. The PHH levels were significantly different from all other groups (**  p < 0.050). HIE, hypoxic ischemic encephalopathy; IVH, intraventricular hemorrhage; PHH, posthemorrhagic hydrocephalus; sAPPα, soluble amyloid precursor protein α; VEWOH, ventricular enlargement without hydrocephalus. Reproduced with permission from Morales et al. [27].

of the CSF of infants with untreated CHC showed consistent increases over control subjects in CSF APP (Fig. 3), sAPPα, sAPPβ, amyloid-β42 (Aβ42), Tau, pTau, L1CAM, and NCAM-1, but not aquaporin 4 (AQP4) or TP [26]. While the levels of several CSF biomarkers were predictive of CHC, particularly in children ≤1 year of age, CSF sAPPα levels showed the strongest relationship to CHC, with 94% sensitivity, 97% specificity, and an odds ratio of 528.0; infants with CSF sAPPα levels above the cut point were 32 times more likely to have CHC.

CSF Biomarkers of Hydrocephalus Associated with Spina Bifida

Although several studies have examined CSF protein levels in HC cohorts in which SB/HC is a large component, few have measured relative levels in this etiology compared to others [39–42]. Naureen et al. [43] studied levels of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), vimentin, and CNPase in HC sepaPediatr Neurosurg DOI: 10.1159/000477175

5

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0.75

IV

0 5 10 Weeks relative to RES surgery

0 I/ I

0

1,000

V

0

2,000

IH

0.45

1,500

3,000

CT RL

4,000

Total protein, njg/mL

0.60

Color version available online

3,000

8,000

APP, ng/mL

FOR

0.75

**

4,000

Classification and Description of Specific CSF Biomarkers

A substantial body of literature has implicated a diverse array of CSF proteins as possible biomarkers of HC. These proteins can be classified by their roles in physiology and development under normal or pathological conditions. As such, most candidate CSF biomarkers of HC fall broadly into 4 categories, though considerable overlap exists: regulators of inflammation, regulators of cell adhesion and cytoskeleton, regulators of the extracellular matrix, and growth factors/neurotrophic proteins. Please refer to Table 1 for an overview of much of the work to date on CSF biomarkers of pediatric HC.

CSF Biomarkers: Common Pathways for Pediatric Hydrocephalus and Neurological Injury?

Many of the CSF biomarkers of pediatric HC examined to date have been investigated in other neurological conditions, in particular neurodegenerative diseases such as AD [73–76] and NPH [77–81]. APP, tau, and their derivative isoforms have been well characterized in the CSF of patients with AD and NPH, showing some similarities to the findings detailed in this review. In fact, earlier studies of CSF biomarkers for pediatric HC leveraged the CSF protein studies of AD and NPH as a rational starting point for biomarker discovery. However, CSF proteomics studies of PHH validated this strategy and provided strong evidence for APP as a CSF biomarker of pediatric HC. Morales et al. [23] found that, in PHH, APP and related isoforms demonstrated the largest fold-change in levels among CSF protein mediators of neurodevelopment, and this increase was responsive to ventricular decompression. That CSF APP is elevated in pediatric HC is not entirely surprising, since APP is released in the setting of axonal injury (e.g. TBI [82–86]), and HC-related ventriculomegaly causes deformation and axonal pathology [87, 88] as well as long-term injury to the periventricular white matter [89]. Furthermore, APP and its derivative isoforms are important trophic factors with criti6

Pediatr Neurosurg DOI: 10.1159/000477175

cal roles in synaptogenesis and other aspects of neurodevelopment [90–92], raising the question of whether CSF APP might find a role as a biomarker of neurodevelopmental outcome. Another common thread across neurological diseases is an increase in the CSF level of the microtubule-associated protein tau. Tau, which originates from axons and oligodendrocytes and serves to stabilize the axonal cytoskeleton [93], is elevated in AD, neurodegenerative “tauopathies,” and TBI, where it is associated with adverse neurological outcomes. CSF tau has been shown to be increased over control in CHC, while ptau was increased in PHH [26, 27]. While these data are compelling, it remains unclear if CSF proteins such as tau and APP are specific to disorders of CSF hydrodynamics or are markers of neurological injury more generally.

CSF Biomarker Panels and Multidimensional Instruments

For CSF biomarkers to be clinically useful, they must be specific for pediatric HC, and ideally they should be specific for discrete etiological subtypes of pediatric HC. Because HC is a complex neurobiological disease, it is unlikely that a single CSF biomarker will provide this level of discrimination. However, a panel of several biomarkers in a multiplexed analysis could potentially provide information to aid clinical diagnosis and the assessment of therapeutic efficacy, disease severity, and neuropsychological performance for different subtypes of HC. The biomarkers in such a panel may include well-characterized proteins such as APP and tau, but also ones associated with specific HC etiologies, such as ependymal or barrier proteins for PHH, or ciliary proteins for CHC. Indeed, a multidimensional instrument incorporating clinical factors and radiological parameters in addition to CSF biomarkers could be developed to further enhance diagnostic or predictive performance.

Challenges in CSF Biomarker Investigation

Identification and validation of CSF biomarkers of human pediatric HC have been challenging, primarily due to the heterogeneity of the condition and, as a result, the relative infrequency of any specific etiology. This is particularly true in CHC, where a wide variety of genetic events may result in HC, and in PIH, which may result from numerous infectious organisms. CSF sample hetLimbrick Jr/Castaneyra-Ruiz/Han/Berger/ McAllister/Morales

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rated by etiology, and found increased GFAP in PHH as well as increased MBP in PHH and SB/HC. In another study of 9 different CSF biomarkers, the Fas receptor and vascular endothelial growth factor (VEGF) levels were elevated in PHH and SB/HC and stem cell factor (SCF) was elevated in SB/HC.

erogeneity is also a factor in PHH, where the affected infants may have any number of other acute or chronic diseases or complications related to prematurity (e.g., necrotizing enterocolitis, chronic lung disease, and sepsis), all of which may impact the biomarker levels in the blood and possibly also in the CSF. Another challenge encountered in human pediatric HC CSF biomarker studies is that true age-matched “control” CSF samples do not exist. Studies must rely on samples from infants and children who had CSF removed during the course of clinical evaluation and treatment for a different condition, and so cannot be considered as true healthy controls. Further, CSF biomarker comparison studies must acknowledge or account for rostrocaudal protein gradients, with often unpredictable differences in the abundance of CSF proteins in the ventricle of the brain versus the lumbar cistern [94, 95]. These challenges can be addressed by rigorously validating CSF biomarker findings on a large scale. Multiinstitutional CSF repositories, such as those maintained through the Hydrocephalus Clinical Research Network (HCRN) and the Hydrocephalus Association Network for Discovery Science (HANDS), allow testing in a large number of samples across multiple institutions from different regions and countries. Findings validated across this broad pool are more generalizable, robust, and re-

producible than single-institution results. Of course, cross-validating, or reverse-translating, findings from humans to experimental models enables rigorous, wellcontrolled, hypothesis-driven research to examine not just the responsiveness of these CSF biomarkers under specific conditions, but also the biological mechanisms and pathways implicated by the CSF biomarkers themselves.

Conclusion

Novel biomarkers of pediatric HC are urgently needed to improve the outcomes of infants and children affected by this disease. Significant progress has been made in developing CSF biomarkers of pediatric HC, especially in the areas of PHH and CHC. A multidimensional instrument that integrates clinical factors, radiological parameters, and CSF and/or serum biomarkers would greatly improve the management of pediatric HC. This instrument would enable clinicians to confidently establish the diagnosis of HC, assess therapeutic efficacy or treatment failure, and evaluate current and future developmental challenges, so that every child has access to the appropriate resources they need to optimize their outcome and quality of life.

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Cerebrospinal Fluid Biomarkers of Pediatric Hydrocephalus.

Hydrocephalus (HC) is a common, debilitating neurological condition that requires urgent clinical decision-making. At present, neurosurgeons rely heav...
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