2. Medical treatment options

Cerebrospinal fluid shunting is the standard treatment for hydrocephaly, but there are certain medical treatment approaches alternatively applied alone or in combination with shunting.

cerebrospinal fluid production. In clinical practice, the most frequently used drug which inhibits carbonic anhydrase and treats hydrocephaly patients is acetazolamide (ACZ) [6–11].

Temporary relief of increased CSF until surgical intervention is

Temporary relief of increased CSF until surgical intervention is

Relief through drainage of

Relief through drainage of

No direct evidence of effectiveness versus waiting until surgical intervention is possible; potential increased risk of

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Possible increased risk of infection from

Shunt collapse, infection, shunt failure, possible need for surgical adjustment or

Occlusion of puncture site, difficulty performing procedure, infection, hemorrhage, nerve damage

complications

replacement

multiple perforations

possible

possible

excess CSF

excess fluid

Intervention Indication Outcome Complications

Decrease production of CSF due to increased fluid

Remove excess CSF through the spine to reduce pressure

CSF, cerebrospinal fluid; ETV, endoscopic third ventriculostomy [2].

All classifications of hydrocephaly in which patient can undergo surgery

excretion

ETV Obstructive hydrocephaly, shunt failure

Table 1. Treatment options for hydrocephaly.

Acetazolamide (2-acetylamino-1,3,4-thiadiazole-5-sulfonamide) is a sulphonamide derivative with a potent inhibitory effect on carbonic anhydrase, which was first synthesized by Roblin and Clapp in 1950 [12]. Acetazolamide has been used in the treatment of cardiac edema, glaucoma, urinary alkalinization, metabolic alkalosis, and acute mountain sickness [1, 10, 13]. Numerous experimental and clinical studies have shown reduction in CSF production after ACZ administration. Effective doses of acetazolamide, which penetrate the blood-brain barrier to reach the choroid plexus and depress CSF flow, are on the order of 20 mg/kg [2, 6, 11, 14–18]. However, there is no standard dose of acetazolamide; the starting dose is 500 mg two times daily and a maximum dose of 4 g twice daily [19]. Recommended starting dose in children is 25 mg/kg per day with a maximum dose of 100 mg/kg or 2 g per day [20]. Complete inhibition of choroid plexus reduces CSF production by 50%, which was obtained after administration of

In some cases, despite the reduction in CSF production, ACZ treatment could not reduce intracranial pressure, on the contrary of increasing it. This unexpected effect may be due to an

Hypersensitivity especially sulfur allergy and hepatic failure are contraindications for ACZ and also relatively contraindicated in patients with a history of renal stones [19]. An important side effect of acetazolamide is the development of hyperchloraemic metabolic acidosis with hypokalemia. Other adverse effects include dysgeusia, paresthesia, fatigue, nausea, diarrhea, and polyuria [17]. These side effects are usually dose related. For this reason monitoring of

indirect effect of ACZ on cerebral vessels and blood flow of the cerebrum [1].

2.1.1.1. Acetazolamide

Medication (furosemide, acetazolamide)

Lumbar puncture

Shunt placement

5–20 mg/kg of ACZ [6, 11].

Treatment of hydrocephaly depends on its cause. Medical treatment is used to delay surgical procedures in hydrocephaly. Medical treatment is not effective in long-term treatment of chronic hydrocephaly but can be resumed to balance CSF dynamics (production or absorption) during this interim period. Medications include decreasing CSF secretion by the choroid plexus (acetazolamide), increasing CSF reabsorption (isosorbide, furosemide), or osmotic diuretics which increase water excretion and are used to reduce intracranial pressure (Table 1) [1, 2].

#### 2.1. Reducing cerebrospinal fluid production

#### 2.1.1. Carbonic anhydrase inhibitors

Carbonic anhydrases are a family of metalloenzymes present in the renal cortex, gastric mucosa, pancreas, liver, lungs, ciliary body, and brain, which catalyze the reversible hydration of carbon dioxide and bicarbonate. Thus, this allows to regulate intra- and extracellular concentrations of CO2, H<sup>+</sup> , and HCO3 [1, 6]. These enzymes are also found in the glia and the choroid plexus which plays secretory roles in the brain. Enzyme concentration is greater than the ciliary body in the choroid plexus [1, 6].

Complete choroid plexus carbonic anhydrase inhibition reduces cerebrospinal fluid (CSF) production by 50%. Many studies have shown that inhibition of carbonic anhydrase reduces


#### Table 1. Treatment options for hydrocephaly.

cerebrospinal fluid production. In clinical practice, the most frequently used drug which inhibits carbonic anhydrase and treats hydrocephaly patients is acetazolamide (ACZ) [6–11].

#### 2.1.1.1. Acetazolamide

symptoms are headache, difficulty in walking, lossing the ability in hard activities, decrease in mental abilities, vomiting, and lethargy. A headache may even awaken the patient from sleep in case of increased intracranial pressure (ICP). Papilledema is more common in adults than

Hydrocephaly can be classified according to the site of CSF flow obstruction or impairment as internal hydrocephaly CSF accumulation which occurs in ventricles and external hydrocephaly in which the accumulation of CSF occurs in subarachnoid space in cerebral cortical surfaces. Hydrocephaly is classified into two groups according to its cause: communicating and noncommunicating hydrocephaly. In communicating hydrocephaly, CSF flows from lateral ventricles into cerebral and spinal subarachnoid space (SAS). In contrast, noncommunicating hydrocephaly flow of the CSF through ventricles is interrupted for any reason. The obstruction of CSF flow in noncommunicating hydrocephaly may happen either internal or external to the ventricles. On the other hand, the overproduction of CSF may cause an accumulation at any site of the brain. Hydrocephaly can be classified according to the duration of development into three groups, which are acute, subacute, and chronic hydrocephaly. Another classification of hydrocephaly is the disorder into high-pressure and normal-pressure hydrocephaly

Cerebrospinal fluid shunting is the standard treatment for hydrocephaly, but there are certain medical treatment approaches alternatively applied alone or in combination with shunting.

Treatment of hydrocephaly depends on its cause. Medical treatment is used to delay surgical procedures in hydrocephaly. Medical treatment is not effective in long-term treatment of chronic hydrocephaly but can be resumed to balance CSF dynamics (production or absorption) during this interim period. Medications include decreasing CSF secretion by the choroid plexus (acetazolamide), increasing CSF reabsorption (isosorbide, furosemide), or osmotic diuretics which increase water excretion and are used to reduce intracranial pressure (Table 1) [1, 2].

Carbonic anhydrases are a family of metalloenzymes present in the renal cortex, gastric mucosa, pancreas, liver, lungs, ciliary body, and brain, which catalyze the reversible hydration of carbon dioxide and bicarbonate. Thus, this allows to regulate intra- and extracellular con-

choroid plexus which plays secretory roles in the brain. Enzyme concentration is greater than

Complete choroid plexus carbonic anhydrase inhibition reduces cerebrospinal fluid (CSF) production by 50%. Many studies have shown that inhibition of carbonic anhydrase reduces

[1, 6]. These enzymes are also found in the glia and the

children.

78 Hydrocephalus: Water on the Brain

(NPH) [1–5].

2. Medical treatment options

2.1. Reducing cerebrospinal fluid production

the ciliary body in the choroid plexus [1, 6].

, and HCO3

2.1.1. Carbonic anhydrase inhibitors

centrations of CO2, H+

Acetazolamide (2-acetylamino-1,3,4-thiadiazole-5-sulfonamide) is a sulphonamide derivative with a potent inhibitory effect on carbonic anhydrase, which was first synthesized by Roblin and Clapp in 1950 [12]. Acetazolamide has been used in the treatment of cardiac edema, glaucoma, urinary alkalinization, metabolic alkalosis, and acute mountain sickness [1, 10, 13].

Numerous experimental and clinical studies have shown reduction in CSF production after ACZ administration. Effective doses of acetazolamide, which penetrate the blood-brain barrier to reach the choroid plexus and depress CSF flow, are on the order of 20 mg/kg [2, 6, 11, 14–18]. However, there is no standard dose of acetazolamide; the starting dose is 500 mg two times daily and a maximum dose of 4 g twice daily [19]. Recommended starting dose in children is 25 mg/kg per day with a maximum dose of 100 mg/kg or 2 g per day [20]. Complete inhibition of choroid plexus reduces CSF production by 50%, which was obtained after administration of 5–20 mg/kg of ACZ [6, 11].

In some cases, despite the reduction in CSF production, ACZ treatment could not reduce intracranial pressure, on the contrary of increasing it. This unexpected effect may be due to an indirect effect of ACZ on cerebral vessels and blood flow of the cerebrum [1].

Hypersensitivity especially sulfur allergy and hepatic failure are contraindications for ACZ and also relatively contraindicated in patients with a history of renal stones [19]. An important side effect of acetazolamide is the development of hyperchloraemic metabolic acidosis with hypokalemia. Other adverse effects include dysgeusia, paresthesia, fatigue, nausea, diarrhea, and polyuria [17]. These side effects are usually dose related. For this reason monitoring of electrolytes is suggested during acetazolamide treatment, and potassium and bicarbonate replacement therapies are required for reducing the adverse effect of ACZ [1].

Only recommend isosorbide for short-term treatment of hydrocephaly with constant surveillance to prevent hypernatremic dehydration. However, osmotic agents are not preferred in the

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Mannitol is a six-carbon alcohol with a molecular weight of 182. This osmotic agent is not metabolized and is excreted by glomerular filtration, without any important tubular reabsorption or secretion. Also, mannitol induces an increase in serum osmolality and an osmotic gradient between the serum and intracranial compartment. Thus, removal of brain water causes to reduce ICP. Mannitol has been widely used to reduce intracranial and intraocular pressures because of its osmotic diuretic action and presumed antioxidant properties for many years. Mannitol is poorly absorbed from the gastrointestinal tract if administered orally;

A dose of 0.25–1 g/kg (20% solution) mannitol is administered intravenously and infused over 5 min. Intracranial pressure should fall in 60–90 min [1, 10]. In most cases, after the administration of a bolus of mannitol, intracranial pressure rapidly decreases, but in some patients, it

The effect of mannitol in the treatment of hydrocephaly has been reported in only a few studies. Hayden et al. showed that the administration of mannitol induces rapidly decreased ICP, but this effect lasted only 3–4 h and was followed by a rebound of ICP above baseline [41]. Ma et al. showed that mannitol and corticosteroids represent an effective treatment approach

Mannitol produces a diuresis more than a natriuresis, and if free water losses are excessive,

Glycerol is an oral osmotic agent, reduces intracranial pressure in adults with brain tumors, and was suggested as a possible agent for managing hydrocephaly [43]. On the contrary, uncontrolled trials did not support its use. Glycerol had no effect in premature infants with hydrocephaly and did not treat hydrocephaly in adults with metastatic brain cancer [44, 45].

Glucocorticoids have been used for decades in a range of neurological disorders associated with raised intracranial pressure [2]. Experimental studies have shown that glucocorticoids reduced CSF production and CSF flow [46, 47]. Glucocorticoids have also been used to reduce

In intraventricular hemorrhage (IVH) cases, the blood clot in the ventricular system can interrupt normal CSF flow. After the acute period of the subarachnoid hemorrhage and

it would cause osmotic diarrhea, so it must be given parenterally [10, 38–40].

for patients with autoimmune diseases associated with hydrocephaly [42].

treatment of hydrocephaly at present [1, 31, 33, 37].

can worsen intracranial hypertension [10].

hypernatremia and hyperkalemia may ensue [10].

the fibrosis in the subarachnoid compartment [2].

2.2.2. Mannitol

2.2.3. Glycerol

2.3. Increasing CSF absorption

2.3.1. Glucocorticoids

In expert opinion, acetazolamide is the most suitable drug alone or in combination with furosemide for treatment of hydrocephaly [1].

## 2.1.2. Furosemide

Furosemide selectively inhibits sodium reabsorption in the nephron at the loop of Henle, which is a potent loop diuretic used to treat high blood pressure, congestive heart failure, and swelling due to excess body water and also used in hyperkalemia and acute renal failure [1, 10]. Studies have shown that furosemide reduces the production of cerebrospinal fluid by inhibiting the transport of Cl to the cerebrospinal fluid [21–24]. In the medical treatment of hydrocephaly, the usual dose of furosemide is 1 mg/kg/day divided into two doses/day [25, 26]. Adverse effects of furosemide therapy are serum electrolyte disturbances, hypotension, and ototoxicity; for this reason, electrolyte levels have to be followed closely [10].

## 2.1.3. Combined therapy of furosemide and acetazolamide

Studies have shown that combination therapy of furosemide and acetazolamide was not effective in decreasing the frequency of shunting or death. Therefore, this therapy is not recommended [2, 26–29].

#### 2.2. Osmotic diuretics

The proximal tubule and descending limb of Henle's loop are freely permeable to water. Osmotic diuretic agents are freely filtered at the glomerulus, undergo minimal reabsorption by the renal tubules causes water to be retained in these segments and promotes water diuresis. Four osmotic diuretics are available: glycerin, isosorbide, mannitol, and urea; mannitol is the most commonly used in clinical practice and the most extensively studied. Osmotic diuretics are used to increase water excretion and to promote prompt removal of renal toxins and also are used to reduce intracranial pressure [10, 30].

#### 2.2.1. Isosorbide

Isosorbide (1,4:3,6-dianhydro-d-glucitol) is an osmotic agent developed for the treatment of glaucoma. It has also been shown to reduce the intracranial pressure [31, 32]. The single oral dose of isosorbide significantly reduces intraventricular pressure. Multiple studies showed the usual dose of isosorbide, which is 2–3 g/kg/day given at intervals of 6–12 h [33, 34].

Lorber et al. have studied the use of isosorbide in patients with various types of hydrocephaly; they reported that patient did not require shunt insertions after prolonged medication with isosorbide. But isosorbide did not replace than surgery and was less efficient than surgery [34–36].

Lorber concluded that isosorbide was safe in a large number of patients; adverse effects were less, and less frequent biochemical monitoring was required [34].

Only recommend isosorbide for short-term treatment of hydrocephaly with constant surveillance to prevent hypernatremic dehydration. However, osmotic agents are not preferred in the treatment of hydrocephaly at present [1, 31, 33, 37].
