3. Other treatment options

## 3.1. Prevention of inflammatory and fibrotic process

Intraventricular hemorrhage, subarachnoid hemorrhage, and infection (e.g., meningitis), which can lead to restriction of CSF, are all associated with secondary inflammation and fibrosis in the subarachnoid compartment. Although many mechanisms have been proposed to explain the pathophysiology of hydrocephaly, it has not yet been fully elucidated. Common theories: hemorrhage debris or clot obstruction of the CSF circulation of the arachnoid, subarachnoid, and arachnoid fibrosis, inflammation, apoptosis, autophagia, and oxidative stress [51–54].

#### 3.2. Cerebrospinal fluid pathway modulation

Gliocytes play a destructive and curative role in the abundance of cytokines released when the brain is exposed to various lesions [55]. It also contributes to the inflammatory side by causing the structurally and functionally cleavage of the vegetative nervous system and glia cell which join the blood-brain barrier [53]. Inflammation of CSF and fibrosis is one of the general features of hydrocephaly and leads to a restriction in CSF flux. Conditions that may cause restriction include intraventricular hemorrhage, subarachnoid hemorrhage, or infection (e.g., meningitis), are all associated with secondary inflammation and fibrosis in the CSF tract, especially in the subarachnoid compartment. In children, intraventricular hemorrhage and bacterial meningitis are associated with meningeal fibrosis, which completely abolishes the subarachnoid space. In subarachnoid hemorrhagic adults, inflammation occurs in the arachnoid villi during the first week, and it is followed by collagen production [56]. Enzymatic resolution of intraventricular or subarachnoid blood collections, intervention in the inflammatory process, and the production of extracellular matrix molecules are the ways to reduce hydrocephaly development, and investigation is still going on.

#### 3.3. Thrombolytic therapy

Some researchers have conducted experimental studies to investigate the efficacy of thrombolytic therapy in preventing posthemorrhagic hydrocephaly. In 1986, Pang et al. tested the efficacy of fibrinolytic (urokinase; uPA) in the treatment of hydrocephaly for the first time and found that intraventricular administration of uPA effectively attenuated ventriculomegaly [52]. Similarly, several empirical studies have shown that intraventricular tPA administration is effective in preventing hydrocephaly after subarachnoid hemorrhage and regressing ventricular dilatation [57]. However, the development of perihematomal edema after tPA administration has increased question mark on this treatment method. Meta-analyses for the comparison of the uPA and tPA regarding the dissolution of the clot after intraventricular hemorrhage were made [58, 59]. Studies have shown that both uPA and tPA cause a decrease in ventricular volumes, but only uPA improves functional recovery significantly.

#### 3.4. Anti-inflammatory therapy

bacterial or carcinomatous meningitis, cerebrospinal fluid absorption can be reduced. Glucocorticoids can slow this inflammatory response after these conditions. However, steroids do not inhibit fibroblast growth or collagen synthesis. Intrathecal or intravenous steroids have

Some studies have shown that in autoimmune diseases associated with hydrocephaly glucocorticoids have been beneficial and corticosteroids should be considered as first-line treatment

Intraventricular hemorrhage, subarachnoid hemorrhage, and infection (e.g., meningitis), which can lead to restriction of CSF, are all associated with secondary inflammation and fibrosis in the subarachnoid compartment. Although many mechanisms have been proposed to explain the pathophysiology of hydrocephaly, it has not yet been fully elucidated. Common theories: hemorrhage debris or clot obstruction of the CSF circulation of the arachnoid, subarachnoid, and arachnoid fibrosis, inflammation, apoptosis, autophagia, and oxidative stress

Gliocytes play a destructive and curative role in the abundance of cytokines released when the brain is exposed to various lesions [55]. It also contributes to the inflammatory side by causing the structurally and functionally cleavage of the vegetative nervous system and glia cell which join the blood-brain barrier [53]. Inflammation of CSF and fibrosis is one of the general features of hydrocephaly and leads to a restriction in CSF flux. Conditions that may cause restriction include intraventricular hemorrhage, subarachnoid hemorrhage, or infection (e.g., meningitis), are all associated with secondary inflammation and fibrosis in the CSF tract, especially in the subarachnoid compartment. In children, intraventricular hemorrhage and bacterial meningitis are associated with meningeal fibrosis, which completely abolishes the subarachnoid space. In subarachnoid hemorrhagic adults, inflammation occurs in the arachnoid villi during the first week, and it is followed by collagen production [56]. Enzymatic resolution of intraventricular or subarachnoid blood collections, intervention in the inflammatory process, and the production of extracellular matrix molecules are the ways to reduce hydrocephaly development, and

Some researchers have conducted experimental studies to investigate the efficacy of thrombolytic therapy in preventing posthemorrhagic hydrocephaly. In 1986, Pang et al. tested the efficacy of fibrinolytic (urokinase; uPA) in the treatment of hydrocephaly for the first time

been used to prevent or alleviate arachnoiditis with poor results [1].

choice [42, 48–50].

82 Hydrocephalus: Water on the Brain

[51–54].

3. Other treatment options

3.1. Prevention of inflammatory and fibrotic process

3.2. Cerebrospinal fluid pathway modulation

investigation is still going on.

3.3. Thrombolytic therapy

There is a clear relationship between inflammation in the CSF tract and subsequent hydrocephaly development. Anti-inflammatory agents have been experimentally tested to prevent hydrocephaly after meningitis and posthemorrhage. There are numerous studies showing that corticosteroid therapy after acute bacterial meningitis significantly reduces hearing loss and neuroleptic sequelae, but the effects on hydrocephaly development are not fully known. Some studies have shown that the use of steroids does not change the likelihood of developing hydrocephaly or that this risk can be elevated in children [60–62].

#### 3.5. Vasoactive drugs

Nimodipine is widely used as a calcium channel blocker for the control of hypertension. Experimental studies have shown that nimodipine reduces motor and cognitive function impairment after hydrocephaly [63]. Clinical trials showed that nimodipine is safe, but there is no definitive evidence for the effectiveness in the treatment of hydrocephaly. Magnesium, a calcium antagonist, also has a weaker protective effect [64].

#### 3.6. Antioxidative therapy

Mechanical factors and reduced white matter blood flow into axonal and oligodendroglial damage can lead to neuropathophysiological damage [65]. Hypoxic changes in proteins of white matter glial and endothelial cells have been found in hydrocephaly by immunohistochemical detection of pimonidazole [66]. Antioxidant therapy is a potential pharmacological treatment for oxidative stress that is associated with brain damage in hydrocephaly. Dietary supplementation of antioxidants like oral coenzyme Q10 (CoQ10), ascorbic acid, glutathione, and lipoic acid in humans and animals reduces oxidative stress by decreasing lipid peroxidation [67].

#### 3.7. Neuron vs axon protection

Neuronal damage in the cortex has been attributed to the disturbed activity of the noradrenergic and dopaminergic neuronal systems and synaptogenesis caused by hydrocephaly [68, 69]. Morphological changes in the hydrocephalic brain with ventricular dilation occur most characteristically in the white matter [70]. Periventricular axons in hydrocephalic brains may sustain the damage in some neurons. Studies on hydrocephaly demonstrated that hippocampal neurons show various secondary abnormalities due to deafferentation [71]. In the immature brain, hydrocephaly affects developmental processes of cell genesis and myelination [68]. Potential early therapeutics are antioxidative, anti-inflammatory, antiapoptotic, and anti-excitotoxic drugs that can be used in neonatal hypoxic-ischemic brain injury. Memantine, a noncompetitive NMDA receptor antagonist, protects neurons and axons [72]. The neuronal cytoskeleton has been shown to play an important role in the maintenance of cytoplasmic morphology and axonal transport [15]. The functional effects of early shunt placement have been reported to prevent impairment of synaptogenesis and learning disability [73].

by serial lumbar punctures [67] to maintain normal-pressure hydrocephaly. The aims of this process are to reduce protein and blood in the CSF and thereby to prevent the formation of fibrin. Nonshunting surgical options include endoscopic third ventriculostomy in CSF obstruc-

Hydrocephaly: Medical Treatment

85

http://dx.doi.org/10.5772/intechopen.73668

The major three mechanisms of medical treatment of patients with hydrocephaly are based on (i) reducing CSF production, (ii) decreasing brain water content, and (iii) increasing CSF. About two-thirds of CSF is formed at the choroid plexus, and the other third is formed in the brain and spinal cord [80]. After the filtration of water across the choroidal epithelium, the increased pressure of CSF then involves active transport of water and ions across the choroidal sacs which are controlled mainly by Na+/K+ ATPase. Active secretion of water and ions by the choroidal epithelium into the ventricles are controlled by the activity of carbonic anhydrase [76]. Digoxin and ouabain are effective drugs that are used as Na+/K+ ATPase inhibitors [78]. Carbonic anhydrase inhibitors are effective drugs still used to decrease the rate of CSF production in the choroid plexus. Loop diuretic agents, such as furosemide, have also been used to

No conflict of interest was declared by the authors. The authors declared that this study had

1 Department of Anesthesiology and Reanimation, Marmara University Pendik Training and

2 Anesthesiology and Reanimation Clinics, Health Sciences University Kartal Dr. Lutfi Kirdar

[1] Poca MA, Sahuquillo J. Short-term medical management of hydrocephalus. Expert Opin-

3 Department of Pulmonary and Critical Care Medicine, Marmara University School of

\*, Reyhan Arslantas<sup>2</sup> and Umut Sabri Kasapoglu<sup>3</sup>

Medicine Pendik Training and Research Hospital, Istanbul, Turkey

ion on Pharmacotherapy. 2005 Aug;6(9):1525-1538

\*Address all correspondence to: gulfethi@gmail.com

Training and Research Hospital, Istanbul, Turkey

tions at, or distal to, the aqueduct and fenestration of the lamina terminals [80].

reduce CSF formation.

Conflict of interest

Author details

Fethi Gul1

References

received no financial support.

Research Hospital, Istanbul, Turkey

#### 3.8. Cerebral stimulants

Bifemelane is a monoamine oxidase inhibitor used as an antidepressant and cerebral metabolic activator to normalize norepinephrine in the striatum and cerebral cortex [74]. Methylphenidate acts by blocking the dopamine and norepinephrine transporters and was administered to NPH patient at the dose of 20 mg after shunting improved cognitive performance and reduced apathy [75]. In another case reports, patients with hydrocephaly and akinetic mutism responded well to bromocriptine and ephedrine [76, 77]. An unshunted severe hydrocephaly patient with self-injurious behavior responded well to trazodone (200 mg/day) [78].

## 4. Conclusions

Hydrocephaly can be defined briefly as the excess formation of cerebrospinal fluid (CSF) leading to an increase in the fluid volume of ventricles and subarachnoid spaces of the brain [1, 2]. Water is distributed in four compartments within the brain: (i) the intracellular space, (ii) the interstitial space, (iii) the cerebral ventricles and subarachnoid spaces, and (iv) the cerebral blood vessels. CSF flow obstruction in hydrocephaly leads to transependymal flow of water and electrolytes from the enlarged ventricles into the interstitial space of the brain adjacent to the ventricular wall which is called hydrocephalic edema [79]. The osmotic agents in these patients increase serum osmolality by drawing fluid from the interstitial space into the capillaries and then out of the cranium to the general circulation. Currently used osmotic diuretics for the treatment of hydrocephaly include isosorbide and mannitol. Fibrin can also deposit in arachnoid villi that can block its openings which is resulted in reduced CSF absorption. This can be ameliorated by the administration of fibrinolytic agents injected directly into the CSF or ventricular system. Hydrocephaly secondary to an IVH has been managed with intraventricular fibrinolytic therapy, alone or in combination with carbonic anhydrase inhibitors. Another situation is the reduction of CSF absorption that can be present in the acute period after subarachnoid hemorrhage and bacterial or carcinomatous meningitis. Steroids can regulate the inflammatory response after inflammation, but fibroblast growth or collagen synthesis cannot be inhibited by steroids [2].

Hydrocephaly treatment can be classified as nonsurgical and surgical, which in turn can be divided into nonshunting and shunting procedures. Nonsurgical treatment includes reducing CSF formation, and the most common drugs used for this purpose are acetazolamide and furosemide. Hydrocephaly secondary to intraventricular hemorrhage (IVH) has been treated by serial lumbar punctures [67] to maintain normal-pressure hydrocephaly. The aims of this process are to reduce protein and blood in the CSF and thereby to prevent the formation of fibrin. Nonshunting surgical options include endoscopic third ventriculostomy in CSF obstructions at, or distal to, the aqueduct and fenestration of the lamina terminals [80].

The major three mechanisms of medical treatment of patients with hydrocephaly are based on (i) reducing CSF production, (ii) decreasing brain water content, and (iii) increasing CSF. About two-thirds of CSF is formed at the choroid plexus, and the other third is formed in the brain and spinal cord [80]. After the filtration of water across the choroidal epithelium, the increased pressure of CSF then involves active transport of water and ions across the choroidal sacs which are controlled mainly by Na+/K+ ATPase. Active secretion of water and ions by the choroidal epithelium into the ventricles are controlled by the activity of carbonic anhydrase [76]. Digoxin and ouabain are effective drugs that are used as Na+/K+ ATPase inhibitors [78]. Carbonic anhydrase inhibitors are effective drugs still used to decrease the rate of CSF production in the choroid plexus. Loop diuretic agents, such as furosemide, have also been used to reduce CSF formation.
