PRIMARY MECHANISMS

Exerpted from Del Bigio MR, McAllister JP II: Hydrocephalus - pathophysiology, In: Choux M, DiRocco CE, Hockley AD, Walker ML (eds.), Pediatric Neurosurgery, Churchill Livingstone, London, 217-236, 1999

Primary pathophysiological mechanisms associated with hydrocephalus (Table 1) are usually those that have been identified in other forms of traumatic brain injury. The mass effects that compression and stretch produce are the most conspicuous findings in hydrocephalus, but ischemia also plays an important role. As ventriculomegaly becomes more severe, cerebral interstitial edema develops in periventricular regions as well as in cortical gray matter. Disturbances in the blood brain barrier have also been reported in hydrocephalus. Not only could this defect dramatically change the internal milieu of the brain, but recent interpretations of bulk CSF flow also suggest that compensatory drainage pathways may utilize the open blood brain barrier.

Table 1 Primary Mechanisms Secondary Mechanisms Compression Cell Death - neurons & glia Stretch1 Axonal Degeneration Ischemia2/hypoxia Synaptic Degeneration Edema Dendritic Deterioration Blood Brain Barrier Breakdown Impaired Axoplasmic Flow Intraventricular Hemorrhage Demyelination   Altered Neurotransmitter Levels   Gliosis   Decreased/Anaerobic Metabolism   Neurotoxicity   1 Most notable in skull expansion (pediatric) 2 Any reduction in cerebral blood flow > 25% 3 Primarily associated with syringomyelia       Mechanism Examples Cell Death Axotomy and retrograde pyknosis Deafferentation and anterograde pyknosis NAA1 increases Gliosis Reactive astrocytosis and microgliosis Metabolism Anaerobic metabolism in white matter Connectivity Synaptic degeneration Dendritic deterioration Neurotransmitter decreases Axonal pathway damage Axonal transport impairments Demyelination Neurotoxicity Blood Brain Barrier breakdown

Intraventricular hemorrhage and the ependymal inflammation that ensues are well-known causes of hydrocephalus, especially in pre-term infants. Rupture of vessels in the periventricular white matter and internal capsule can also result from stretching these structures during the progression of hydrocephalus. Hydrocephalus has been caused by infectious agents that cause inflammation and hypertrophy of the ventricular lining and meninges, as well as tumors that obstruct ventricular channels. The two latter causative agents, however, have not been included as primary mechanisms because they do not result directly from the condition of hydrocephalus.

In general, secondary mechanisms represent the specific effects of compression, stretch, ischemia, inflammation, and altered homeostasis on cell function and structure within the hydrocephalic brain (Table 2). These mechanisms have only been revealed within the past 10 years with the advent of appropriate animal models, and so the list of processes, their specific targets, and their relative roles in the pathophysiology of hydrocephalus represent an active area of ongoing research.

Table 2

PRIMARY PATHOPHYSIOLOGIC MECHANISMS

Compression

Since hydrocephalus is defined, regardless of the etiology, as an enlargement of the cerebral ventricles or subarachnoid spaces, the most apparent Primary mechanisms are compression and stretch, which produce readily detectable distortion of brain tissue adjacent to the expanding ventricles (Table 1). Compression is usually most notable in the cortical mantle, where gray and white matter can be reduced to less than 2 cm in the human brain, resulting in predictable neurological deficits (Hanigan, 1991). Traditionally, thinning of the cortical mantle has been used as a guide to outcome {}, but this feature is not reliable unless thickness is less than 2 cm. The discrepancies between mantle thickness and outcome highlight the need for more research on the pathophysiology of hydrocephalus. Although subcortical structures have not been studied extensively, they too exhibit considerable compression. The effects on diencephalic structures have been largely ignored, perhaps because the third ventricle remains relatively slit-like, but our recent quantitative studies suggest that the third ventricle can increase 3 times its original size in an adult canine model of obstructive hydrocephalus (compared to a 10-fold enlargement of the lateral ventricles).

Stretch

The effects of stretch on the cortical mantle are probably just as damaging as compression. This mechanism is a prominent force in pediatric brains, when not only does the expandable skull allow considerable centrifugal movement, but many growing axonal projections are seeking pathways and targets within distorted fields of gray and white matter. The added burden of stretch on the cerebral cortex is clearly demonstrated in two of the most widely used animal models of neonatal and infantile hydrocephalus. In both H-Tx rats and kittens after about 3 weeks of progressive untreated hydrocephalus, the cerebral cortex is only 1-2 mm thick (Fig. 1). The cortical mantle appears to suffer the most from centrifugal stretch, with the periventricular white matter exhibiting marked pathologic features, but the fimbria can also be stretched longitudinally (Table 1).

Insert Figure 1: MRIs of H-Tx rat and Kitten

Ischemia

Both experimental and clinical studies confirm that cerebral blood flow (CBF) is reduced during hydrocephalus {2,5,101,137,256,287,289}. This decrease appears to be a global response, with nearly all brain regions exhibiting reductions to 40-64% of normal (Table 3). While these preliminary findings, and those of others {} indicate that ischemia plays an important role in the pathophysiology of hydrocephalus, a complete understanding of this mechanism has been limited because several specific questions remain unanswered: (1) Do the reductions in CBF reach ischemic levels? Previous studies from our lab and others indicate that the lowest flow rates of 22 ml/min/100g occur in the hippocampus, while the cortex exhibits slightly higher flow rates {256}. Therefore, it appears that during hydrocephalus CBF does not fall below the customary cutoff for cerebral ischemia of 18 ml/min/100g {336}. However, this threshold has been obtained from studies that examine acute changes in stroke models, and may not be applicable for chronic disorders. Studies that correlate CBF with metabolic and functional changes throughout the course of ventriculomegaly are needed to determine if this cutoff is valid for chronic hydrocephalus.

(2) When do CBF alterations occur? Although several single photon emission computed tomography (SPECT) studies have demonstrated decreases in cerebral perfusion in patients with acute {287} and normal pressure hydrocephalus {351,354,353,352,5,289,296,320}, no longitudinal studies have addressed this important question. This information would be extremely valuable in determining when to intervene during the progression of hydrocephalus.

(3) Where do CBF alterations occur? Tedeschi et al. {6}have concluded that the pattern of CBF reductions measured with SPECT in patients with NPH is heterogeneous and unpredictable, with decreases ranging from focal to diffuse. In patients, failure to detect a pattern of regional changes is in large part due to the multiplicity of causes and natural history of the disorder. These uncertainties make correlations between cerebral perfusion decreases and neurologic deficits very difficult. Clearly, more controlled studies in which regional changes in CBF can be compared with functional assessments in the same subject are needed to resolve these issues.

(4) What are the consequences of impaired CBF? Because direct comparisons have not been made between CBF and cerebral metabolism, the immediate and long-term consequences of reduced CBF in hydrocephalus are not clear. As described in more detail below, the acute response may involve changes in energy utilization, such as conversion from aerobic to anaerobic glycolysis {203,206}, or decreased oxygen availability. This alteration may not be reflected in diminished neuron function, but could leave cells more vulnerable to subsequent changes in energy sources, as suggested by Chumas et al. {10}. At some point, CBF decreases may cause structural changes in neurons, which could be irreversible and lead to permanent functional deficits.

(5) Why does CBF change in hydrocephalus? The cause of CBF changes is currently unclear, but most authors speculate that initially mechanical forces compress the brain parenchyma and decrease the caliber of cerebral capillaries. Consistent with this hypothesis is the finding that morphologic changes in cerebral blood vessels occur during hydrocephalus. Clinical and experimental studies report stretching and distortion of large arteries {230} and draining veins {122}, and reduced density and caliber of capillaries {76,7,71,150,176,175,192}. Our laboratory {350} has reported quantitative decreases in the size and amount of blood vessels in hydrocephalic kittens that could not be completely reversed by shunting. These effects on vessel caliber and number could be a direct result of expanding ventricles, which would exert both compressive and tensile pressures on blood vessels. These mechanical forces could be supplemented by the interstitial edema that is known to occur during chronic hydrocephalus {8,14,52,131,145,305,180}. As other cellular elements are affected and the blood brain barrier is altered {265}, additional influences on CBF may arise from progressive tissue damage. These structural changes underscore the need to evaluate both CBF and blood vessel morphology during hydrocephalus, so that cause and effect relationships can be established.

Insert Table 3: Cerebral blood flow in multiple regions of control and kaolin-injected hydrocephalic kittens.

Edema

In patients and animals with hydrocephalus, CT and MRI have revealed periventricular edema, especially when ICP is increased {Asada, et al., 1978; Drake, et al., 1989; Hiratsuka, et al., 1982; Murata, et al., 1981). Morphologically, enlarged extracellular spaces have been visualized in the periventricular white matter of humans {Di Rocco, et al., 1977; Struck and Hemmer, 1964) and animals (James, et al., 1980; Rubin, et al., 1976c; Weller and Wisniewski, 1969}, and further studies in mice {McLone, et al, 1971}, rabbits {Higashi, et al., 1986}, cats {Hochwald, et al., 1975; Kriebel et al., 1993;Takei, et al., 1987; Wright et al., 1990} and dogs {Fishman and Greer, 1963; Inaba, et al., 1984} suggest that edema may occur up to 3 mm from the lateral ventricles. In hydrocephalic patients, Foncin et al. (1976) have reported enlarged extracellular spaces in superficial cortex, a distance of about 2 cm from the lateral ventricle. This apparent pathological finding may in fact represent a useful compensatory pathway for CSF, since tracers have been shown to move from the ventricular system into the cortical parenchyma {Levin, et al., 1971; Lux, et al., 1970; Page, 1985; Shaywitz, 1972; Strecker, et al., 1974; Tamaki, et al., 1990; Wislocki and Putnam, 1921).

Controversy persists over the extent of edema and alterations in tissue water content during hydrocephalus. Normal extracellular spaces have been observed in the caudate nucleus of moderately hydrocephalic animals (Del Bigio and Bruni, 1988b; Page, et al., 1979; Torvik and Stenwig, 1977), suggesting that subcortical structures react differently than cortex. McLone, et al. {1973}, using perhaps the most reliable rapid freezing techniques, report that extracelluar spaces are compressed in superficial cortex during acute stages of hydrocephalus, and only expand during later stages in association with tissue damage. These findings have been confirmed by several measurements of either no change in cortical water content {Granholm, 1966; Higashi, et al., 1986; Tamaki, et al., 1990}, or decreased water content in hydrocephalic animals {Azzi, et al., 1992; Del Bigio and Bruni, 1987a; Higashi, et al., 1989} and patients {Penn and Bacus, 1984}. Thus, the extrusion of fluid (water and blood) from the brain seems to be responsible, in part, for the decrease in brain volume that occurs during acute phases of hydrocephalus {Hakim, et al., 1976}. [from Chapter 1: Despite these changes, homeostasis of brain potassium and calcium ions is not adversely affected, at least not in the H?Tx rat with congenital hydrocephalus (Keep and Jones, 1989).]