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James P. McAllister II, Michael A. Williams, Marion L. Walker, John R. W. Kestle, Norman R. Relkin, Amy M. Anderson, Paul H. Gross and Samuel R. Browd

Building on previous National Institutes of Health-sponsored symposia on hydrocephalus research, “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes” was held in Seattle, Washington, July 9–11, 2012. Plenary sessions were organized into four major themes, each with two subtopics: Causes of Hydrocephalus (Genetics and Pathophysiological Modifications); Diagnosis of Hydrocephalus (Biomarkers and Neuroimaging); Treatment of Hydrocephalus (Bioengineering Advances and Surgical Treatments); and Outcome in Hydrocephalus (Neuropsychological and Neurological). International experts gave plenary talks, and extensive group discussions were held for each of the major themes.

The conference emphasized patient-centered care and translational research, with the main objective to arrive at a consensus on priorities in hydrocephalus that have the potential to impact patient care in the next 5 years. The current state of hydrocephalus research and treatment was presented, and the following priorities for research were recommended for each theme. 1) Causes of Hydrocephalus—CSF absorption, production, and related drug therapies; pathogenesis of human hydrocephalus; improved animal and in vitro models of hydrocephalus; developmental and macromolecular transport mechanisms; biomechanical changes in hydrocephalus; and age-dependent mechanisms in the development of hydrocephalus. 2) Diagnosis of Hydrocephalus—implementation of a standardized set of protocols and a shared repository of technical information; prospective studies of multimodal techniques including MRI and CSF biomarkers to test potential pharmacological treatments; and quantitative and cost-effective CSF assessment techniques. 3) Treatment of Hydrocephalus—improved bioengineering efforts to reduce proximal catheter and overall shunt failure; external or implantable diagnostics and support for the biological infrastructure research that informs these efforts; and evidence-based surgical standardization with longitudinal metrics to validate or refute implemented practices, procedures, or tests. 4) Outcome in Hydrocephalus—development of specific, reliable batteries with metrics focused on the hydrocephalic patient; measurements of neurocognitive outcome and quality-of-life measures that are adaptable, trackable across the growth spectrum, and applicable cross-culturally; development of comparison metrics against normal aging and sensitive screening tools to diagnose idiopathic normal pressure hydrocephalus against appropriate normative age-based data; better understanding of the incidence and prevalence of hydrocephalus within both pediatric and adult populations; and comparisons of aging patterns in adults with hydrocephalus against normal aging patterns.

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Michael A. Williams, James P. McAllister, Marion L. Walker, Dory A. Kranz, Marvin Bergsneider, Marc R. Del Bigio, Laurel Fleming, David M. Frim, Katrina Gwinn, John R. W. Kestle, Mark G. Luciano, Joseph R. Madsen, Mary Lou Oster-Granite and Giovanna Spinella

Object

Treatment for hydrocephalus has not advanced appreciably since the advent of cerebrospinal fluid (CSF) shunts more than 50 years ago. Many questions remain that clinical and basic research could address, which in turn could improve therapeutic options. To clarify the main issues facing hydrocephalus research and to identify critical advances necessary to improve outcomes for patients with hydrocephalus, the National Institutes of Health (NIH) sponsored a workshop titled “Hydrocephalus: Myths, New Facts, and Clear Directions.” The purpose of this paper is to report on the recommendations that resulted from that workshop.

Methods

The workshop convened from September 29 to October 1, 2005, in Bethesda, Maryland. Among the 150 attendees was an international group of participants, including experts in pediatric and adult hydrocephalus as well as scientists working in related fields, neurosurgeons, laboratory-based neuroscientists, neurologists, patient advocates, individuals with hydrocephalus, parents, and NIH program and intramural staff. Plenary and breakout sessions covered injury and recovery mechanisms, modeling, biomechanics, diagnosis, current treatment and outcomes, complications, quality of life, future treatments, medical devices, development of research networks and information sharing, and education and career development.

Results

The conclusions were as follows: 1) current methods of diagnosis, treatment, and outcomes monitoring need improvement; 2) frequent complications, poor rate of shunt survival, and poor quality of life for patients lead to unsatisfactory outcomes; 3) investigators and caregivers need additional methods to monitor neurocognitive function and control of CSF variables such as pressure, flow, or pulsatility; 4) research warrants novel interdisciplinary approaches; 5) understanding of the pathophysiological and recovery mechanisms of neuronal function in hydrocephalus is poor, warranting further investigation; and 6) both basic and clinical aspects warrant expanded and innovative training programs.

Conclusions

The research priorities of this workshop provide critical guidance for future research in hydrocephalus, which should result in advances in knowledge, and ultimately in the treatment for this important disorder and improved outcomes in patients of all ages.

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James P. McAllister II, Ramin M. Abdolvahabi, Marion L. Walker, Jerald A. Mitchell and Hazel C. Jones

Object

Despite the investigations that have linked hydrocephalus to reproductive system abnormalities, no researchers have attempted to identify the pathophysiological mechanism of this relationship. Because the role of the hypothalamic gonadotrophin-releasing hormone (GnRH) system in the regulation of reproductive functions is well established, the authors used immunohistochemical and radioimmunoassay (RIA) techniques to determine the morphological and biochemical effects of hydrocephalus on the hypothalamic GnRH system.

Methods

Hypothalamic GnRH levels, fiber density, and cell types were studied in 21- and 50-day-old control and congenitally hydrocephalic Texas rats. Results of RIA indicated a significant (8.4%) increase in GnRH in 21-day-old hydrocephalic rats (9.17 ± 0.64 pg/ng total protein) compared with that in controls (0.97 ± 0.74 pg/ng total protein). In addition, the 50-day-old hydrocephalic animals had a significantly higher level of GnRH compared with age-matched controls (20.4 pg/ng compared with 1.88 ± 2.1 pg/ng total protein). This increase was accompanied by changes in the fiber appearance and a shift from low GnRH producing cells to high GnRH producing cells in the hydrocephalic animals; however, there was no significant difference in the fiber density between the control and hydrocephalic animals at 21 days. In addition, poor neurological scores correlated with the severity of hydrocephalus.

Conclusions

These results demonstrated that hypothalamic GnRH levels are significantly affected by fetal-onset hydrocephalus and that the mechanisms responsible for these effects may take place at the cellular rather than the gross structural level. Furthermore, they suggest that impairments in the GnRH system may be protracted in neonates and infants with hydrocephalus, and thus may be overcome by relatively early treatment with ventricular diversion. However, the clinical implications of GnRH perturbations in shunt-dependent patients must await a forthcoming study in shunted animals.

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James P. McAllister II and Janet M. Miller

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James P. McAllister II

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Martin U. Schuhmann, Kimberly R. Ostrowski, Emily J. Draper, Jau-Wen Chu, Steven D. Ham, Sandeep Sood and James P. McAllister

Object

Shunt infections and their management remain a clinically important problem in patients with hydrocephalus. The authors evaluated, in comparison with traditional parameters, C-reactive protein (CRP) in blood/serum (S-CRP) and in cerebrospinal fluid (CSF; C-CRP) for its power to identify and treat patients with infected shunts.

Methods

On 84 different occasions, CSF and blood samples from 59 children suspected of having shunt/CSF infections were obtained and evaluated. An infection was proven by a CSF culture in 35 of 84 evaluations. Values for S-CRP in infected individuals were higher than in noninfected ones (91.8 ± 70.2 mg/L compared with 16.1 ± 28.3 mg/L, p < 0.0001). The sensitivity of S-CRP testing was 97.1%, the specificity 73.5%, the negative predictive value 97.3%, and the receiver operating characteristic area 91.6%. The probability of shunt/CSF infection—provided that the S-CRP level was greater than 7 mg/L—rose from 41.7% (prevalence) to a posttest level of 72.3%. Specificity and posttest probability were 87.8 and 87.2%, respectively, if cases with other concurrent infections were excluded. The probability of missing a CSF/shunt infection at an S-CRP lower than 7 mg/L was 2.7%. All other diagnostic parameters did not yield useful test results. The rate of reinfection was elevated in patients in whom S-CRP levels were greater than 7 mg/L at the time of shunt reimplantation.

Conclusions

Analysis of these data suggests that the S-CRP level should be included in the first-line workup of patients with suspected shunt/CSF infection. It seems justified to avoid performing a shunt tap if S-CRP levels are less than 7 mg/L. A larger multicenter trial is necessary to confirm these promising diagnostic results and to deliver hard data concerning whether or not a normalized S-CRP level is a reliable indicator of successful antibiotic therapy and whether a shunt can be safely reimplanted.

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Ramin Eskandari, James P. McAllister II, Janet M. Miller, Yuchuan Ding, Steven D. Ham, David M. Shearer and John S. Way

Object. The authors of previous studies have suggested that connectivity within the cerebral cortex may be irreversibly altered by hydrocephalus. To examine connectivity-related changes directly, the authors conducted a study in which they used an axonal tracer in an animal model of infantile hydrocephalus.

Methods. In five hydrocephalic kittens low-pressure ventriculoperitoneal (VP) shunts were placed 10 to 14 days after induction of hydrocephalus by intracisternal kaolin injections. Wheat germ agglutinin-conjugated horseradish peroxidase was injected laterally into the motor cortex in hydrocephalic animals 9 to 15 days after kaolin injection, and 1, 2, and 4 weeks after VP shunt insertion in shunt-treated animals, and in age-matched controls.

Reduction of antero- and retrograde labeling was most profound within the contralateral cortex and portions of the midbrain. Thalamic nuclei exhibited reductions in anterograde and retrograde labeling. Labeling within cell bodies of the ventral tegmental area decreased greatly in animals with untreated hydrocephalus, in which retrograde labeling was reduced in the locus coeruleus but did not affect the raphe nucleus. Shunt treatment increased both antero- and retrograde labeling of contralateral motor cortex to near-normal levels. Thalamic relay nuclei recovered antero- and retrograde labeling, although not to levels exhibited in controls. Shunt therapy restored cellular labeling within the ventral tegmental area and locus coeruleus. Recovery of labeling occurred as early as 7 days after shunt insertion.

Conclusions. Collectively, analysis of these data indicates the following. 1) Cortical connectivity involving both afferent and efferent pathways was impaired in untreated hydrocephalic animals. 2) Shunt therapy improved both cortical afferent and efferent connectivity. 3) Complete reestablishment of the cortical efferent pathways, however, did not occur. Cortical pathway dysfunction, if permanent, could cause many of the motor and cognitive deficits seen clinically in children with hydrocephalus.

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James P. McAllister II, Arcangela S. Wood, Martha J. Johnson, Robert W. Connelly, David J. Skarupa, Michelle Secic, Mark G. Luciano, Neil G. Harris and Hazel C. Jones

Although neonatal hydrocephalus often results in residual neurological impairments, little is known about the cellular mechanisms responsible for these deficits. The immediate early gene, fos (c-fos), functions as a “third messenger” to regulate protein synthesis and is a good marker for neuronal activation. To identify functional changes in neurons at the cellular level, the authors quantified fos RNA expression and localized fos protein in the H-Tx rat model of congenital hydrocephalus. Tissue samples from sensorimotor and auditory regions were obtained from hydrocephalic rats and age-matched, normal litter mates at 1, 6, 12, and 21 days of age (four-six animals in each group) and processed for immunohistochemical analysis of fos and Northern blot analysis of RNA. At 12 days of age, hydrocephalic animals exhibited significant decreases in the ratio of fos immunoreactive cells to Nissl-stained neurons from both cortical regions, but no statistical differences were noted in fos expression. At 21 days of age, both the ratio of fos immunoreactive cells to Nissl-stained neurons and fos expression decreased significantly. The number of fos-positive neurons decreased in all cortical layers but was most prominent in layers V through VI. This decrease did not appear to be caused by neuronal death because examination of Nissl-stained sections revealed many viable neurons within the areas where fos immunoreactivity was absent. These results suggest that progressive neonatal hydrocephalus reduces the capacity for neuronal activation in the cerebral cortex, primarily in those neurons that provide corticofugal projections, and that this impairment may begin during relatively early stages of ventriculomegaly.

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James P. McAllister II, Todd A. Maugans, Mitseh V. Shah and Raymond C. Truex Jr.

✓ To determine the effects of increased cerebrospinal fluid (CSF) pressure on neuronal morphology, obstructive hydrocephalus was induced by injecting kaolin into the fourth ventricle and cisterna magna of 1-day-old rats. The animals were sacrificed 10 to 12 days later, at which time severe ventriculomegaly and cortical thinning were apparent in the parieto-occipital region. Tissue from this area was processed by rapid Golgi methods. Well impregnated pyramidal neurons were examined by light microscopy, and their somatic and dendritic features compared to those of age-matched littermate controls. The somata of medium pyramidal neurons were unaffected, but their basilar dendrites had fewer branches and those that remained were shorter. A variable reduction in dendritic spines occurred, such that some branches were totally denuded while others exhibited spine densities similar to those seen in control animals. The most striking alteration was the occurrence of frequent dendritic varicosities. These enlargements of the dendritic shaft separated by extremely thin constrictions gave the affected segment a beaded appearance. Both dendritic spine loss and varicosity formation were most notable on distal portions of individual branches and within regions of the dendritic tree closest to the ventricular and meningeal surfaces. These alterations are consistent with other reports of dendritic changes associated with aging, mental retardation, and alcohol exposure. These observations suggest that hydrocephalus causes dendritic deterioration or retardation of dendritic maturation. The fact that neuronal morphology was not more severely affected may indicate that these effects are reversible.