Obstructive Hydrocephalus

#### **Chapter 5**

## Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus

*Ashish Chugh, Sarang Gotecha, Prashant Punia and Neelesh Kanaskar*

#### **Abstract**

The foramen of Monro has also been referred to by the name of interventricular foramen. The structures comprising this foramen are the anterior part of the thalamus, the fornix and the choroid plexus. Vital structures surround the foramen, the damage to which can be catastrophic leading to disability either temporary or permanent. In the literature it has been shown that tumors occurring in the area of interventricular foramen are rare and usually cause hydrocephalus. The operative approach depends upon the location of the tumor which can be either in the lateral or the third ventricle. Various pathologies which can lead to foramen of Monro obstruction and obstructive hydrocephalus include colloid cyst, craniopharyngioma, subependymal giant cell astrocytoma [SEGA], Neurocysticercosis, tuberculous meningitis, pituitary macroadenoma, neurocytoma, ventriculitis, multiseptate hydrocephalus, intraventricular hemorrhage, functionally isolated ventricles, choroid plexus tumors, subependymomas and idiopathic foramen of monro stenosis. In this chapter, we will discuss the various lesions at the level of foramen of Monro causing obstructive hydrocephalus and the management and associated complications of these lesions based on their type, clinical picture and their appearance on imaging.

**Keywords:** Foramen of Monro, interventricular foramen, obstruction, obstructive hydrocephalus, raised intracranial pressure

#### **1. Introduction**

The foramen of Monro has also been referred to by the name of interventricular foramen. The first description of this foramen was given by Alexander Monro in the year 1783 and 1797. The authors of that era were of the opinion that the use of nomenclature 'foramen of monro' was incorrect; instead 'interventricular foramen' would be more apt. Their reason was that Monro had interpreted the connection between lateral and the third ventricle in an incorrect way.

The structures comprising this foramen are the anterior part of the thalamus, the fornix and the choroid plexus. Vital structures surround the foramen, the damage to which can be catastrophic leading to disability either temporary or permanent.

The dimension of this foramen is not even 1 centimeter and thus the area present for any operative intervention is very small. It is not an easy task for the surgeons to excise the lesion as well as safeguard the vital surrounding structures at the same time.

In the literature it has been shown that tumors occurring in the area of interventricular foramen are rare and usually cause hydrocephalus. The operative approach depends upon the location of the tumor which can be either in the lateral or the third ventricle [1].

In this chapter, we will discuss the various lesions at the level of foramen of Monro causing obstructive hydrocephalus and the management and associated complications of these lesions based on their type, clinical picture and their appearance on imaging.

#### **2. History and anatomy**

#### **2.1 Introduction**

Fluid balance in central nervous system is basically maintained by cerebrospinal fluid [CSF], which is derived from blood and secreted by choroid plexus lining ventricles of the brain. CSF plays a major buoyancy role in the mechanical support to central nervous system.

Circulation of CSF through ventricular system of cerebral cortex takes place in such a way that there is free communication between cerebral and spinal subarachnoid compartment. It start from lateral ventricular cavities passing through foramen of Monro, then entering into third ventricle passing down along aqueduct of Sylvius and reaching fourth ventricle. The exit from fourth ventricle takes place through foramen of Luschka and foramen of Magendie to subarachnoid space around brainstem and spinal cord [2].

#### **2.2 History**

Foramen of Monro is named after a Scottish physician Alexander Monro Secundus [1733–1817], he was third son of Alexander Monro Primus and Isabella MacDonald. He matriculated at Edinburg University in 1745 and received his medical degree in 1755 [3]. He assisted his father Alexander primus in teaching anatomy who held the chair of anatomy at Edinburg University. Monro Secundus recorded detailed descriptions and illustrations regarding communication between lateral and third ventricle of the brain as well as describing changes seen in hydrocephalus [4].

Monro also made several important observations about cranial cavity with application of physical principles to the intracranial contents. George Kellie former student of Monro also studied about blood volume in human brains and reached the same conclusion as his mentor which is now known as Monro-Kellie hypothesis which states that the sum of volumes of brain parenchyma, CSF, and intracranial blood is constant [5].

#### **2.3 Embryology**

Central nervous system starts developing from fourth week of intrauterine life. Neural tube formed shows closure of anterior neuropore by middle of fourth week and posterior neuropore by end of fourth week. Cranial end of neural tube shows three dilated brain vesicles as prosencephalon [forebrain], mesencephalon [midbrain] and rhombencephalon [hindbrain]. The procesencephalon further subdivides into an anterior telencephalon which forms two cerebral hemisphere having

*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

#### **Figure 1.**

*A] Human embryo, approximately 10.2 mm long, left lateral surface of the diecephlon and telencephalon removed. B] Human embryo 13.6 mm long, median section. C] Human fetus, approximately 3 months old, median section showing medial surface of enlarged telencephalon and diencephalon with interventricular foramen of Monro. [Gray H. THE ANATOMICAL BASIS OF MEDICINE AND SURGERY. 40th ed. Susan Standring, Elsevier Churchill Livingstone New York; 2008. p.381–383.*

#### **Figure 2.**

*Sagittal section of brain showing following cerebrum, cerebellum and brainstem:A] frontal lobe, B] Paritel lobe, C] occipital lobe, D] cerebellum, E] corpus callosum, F] septum Pellucidum, G] fornix, H] thalamus, I] hypothalamus, J] pons, K] midbrain, L] medulla oblongata, black arrow- opening of interventricular foramen of Monro, yellow star – Interthalamic adhesion, black dotted line – Thalamohypothalamic sulcus.*

lateral ventricle cavities and posterior diencephalon having third ventricle cavity. The commencement of cerebral diverticula from the wall of forebrain persists as interventricular foramen of Monro [6]. Ventricular cavities of brain develop in the neural tube and their enlargement depends of differential growth of the brain vesicles. Out of the three brain vesicles the cavity of the forebrain gives rise to two lateral and third ventricles. Lateral ventricle grows as outpouching from the rostral end of third ventricle and both are interconnected via foramen of Monro (**Figure 1**).

#### **2.4 Gross anatomy**

Foramen of Monro is small slit like communicating channel between paired lateral ventricle and third ventricle cavity on either side which become clinically significant when obstructed thus leading to non-communicating hydrocephalus.

Foramen of Monro is located at the junction of roof and anterior wall of lateral ventricle thus bounded anteriorly by the body and column of fornix and posteriorly by anterior nucleus of thalamus (**Figure 2**). Size and shape of the foramen correlates with that of ventricles. In an embryo it is large and circular and as the ventricle size increases, it narrows into a slit like opening. Not only choroid plexus but posterior choroidal, superior choroidal arteries, thalamostriate and septal veins also pass through it (**Figure 2**).

### **3. Neuro radiology**

See **Figure 3**.

#### **3.1 Spectrum of foramen of Monro lesions causing obstructive hydrocephalus (Table 1)**

The 3rd ventricle is bounded by the interventricular foramen on either side where the roof and anterior wall of the third ventricle meet the body of the fornix along with the column anterior to the foramen. Posteriorly it is related to the thalamus [anterior pole].

Literature shows that tumors in the vicinity of the foramen are uncommon and usually cause hydrocephalus. Various pathologies which can lead to foramen of Monro obstruction and obstructive hydrocephalus include colloid cyst, craniopharyngioma, subependymal giant cell astrocytoma [SEGA], neurocysticercosis, tuberculous meningitis, pituitary macroadenoma, neurocytoma, ventriculitis, multiseptate hydrocephalus, intraventricular hemorrhage,

**Figure 3.** *Normal interventricular foramen and its relations on MRI.*

*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*


**Table 1.**

*Classification of foramen of monro lesions causing obstructive hydrocephalus.*

functionally isolated ventricles, choroid plexus tumors, subependymomas and idiopathic foramen of Monro stenosis.

#### **4. Colloid cyst**

#### **4.1 Introduction**

Colloid cysts are rare, congenital, histologically benign tumors which represent upto 2% of all intracranial neoplasms and correspond to approximately 15–20% of the intraventricular tumors [7]. They occur most commonly in the 3rd to 5th decades of life. They are usually solitary and sporadic, although rare examples of cysts on other locations and familial forms are known. They occur in the posterior end of the foramen of Monro in the anterior and antero-superior part of the third ventricle [8].

The colloid cyst is an epithelial lined cyst filled with gelatinous material which commonly contains mucin, old blood cholesterol and ions and may vary in size from 3 to 40 mm in diameter. However size of the cyst does not appear to be a reliable predictor of outcome, as death may occur even with smaller lesions [9]. Types of colloid material seen can be a] greenish liquid b] greenish liquid with cholesterol c] whitish colloid d] greenish colloid e] mixed.

The precise embryopathogenesis of colloid cyst is poorly understood and still a topic of debate. Various theories proposed are a] origin from either the diencephalic vesicle or the persistence of embryonic paraphysis b] derived from neuroepithelium c] remnant of respiratory epithelium and d] an ependymal cyst from the diencephalon [10].

Clinical presentation is heterogenous and may be intermittent, self- resolving and non-specific. Obstructive hydrocephalus is precipitated by growth of the colloid cyst blocking CSF flow through one or both foramen of Monro and may produce raised intracranial pressure [ICP] by intermittent obstruction of the passage of CSF at the level of interventricular foramen, acting like a legger of a ball as historically described by Dandy in 1933 [8].

#### **4.2 Clinical features**

Defining the natural history of colloid cyst reliably has been challenging due to the small number of cases in most case series. Majority of colloid cysts present as an

#### *Cerebrospinal Fluid*

incidental finding while imaging the brain for unrelated symptoms. Symptoms due to colloid cyst often result from different forms of hydrocephalus as well as irritation of major important centers around the third ventricle [11].

They do not have any intrinsic pathological properties and cause symptoms by acting as inert masses. 90% are asymptomatic and stable, while 10% are found to increase in size and cause hydrocephalus. Sudden increase in size can lead to drop attacks, dementia, coma, and death.

Headaches are the most common symptom of colloid cyst ranging from 65–100% of cases according to literature. The headaches are typically severe and intense, throbbing or aching in quality and can be bifrontal or generalized in location and can be precipitated, aggrevated or relieved by head movement or position changes. With progression in size of the cyst, the headaches become more frequent and can be accompanied frequently by nausea, vomiting, blurred vision,

#### **Figure 4.**

*Case of a small colloid cyst presenting with drop attacks [A-D]: A] pre-op CT showing a hyperdense SOL at foramen of Monro. B] Endoscopic view of the ventricular anatomy and colloid cyst. C] Normal ependyma with 3rd ventricular floor post excision. D] Post op CT showing complete excision of lesion with re-established CSF flow across foramen of monro.*

*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

gait ataxia, cognitive decline and less frequently by dizziness, tinnitus and dysautonomic symptoms like abdominal pain, tachycardia, hyperthermia, bradycardia and sweating. Other uncommon symptoms include personality changes, memory disorders, psychiatric disorders and olfactory and gustatory hallucinations. Rapid deterioration due to acute hydrocephalus can occur in 3–35% of patients with an associated 5–38% risk of death [11–13].

#### **4.3 Neuroradiology**

Due to the different composition and density of contents, which depends on the quantity of cholesterol and proteins, colloid cysts may have a diverse appearance on imaging. Cysts with high cholesterol and protein content are hyperdense on plain CT, hyperintense on T1 and hypointense on T2 weighted images.

Computed Tomography [CT]: On CT, the colloid cyst is typically a well-defined, round or oval hyperdense mass in the anterior third ventricle at the foramen of Monro. Precontrast scans show a] hyperdense lesions in approximately 2/3rd cases, b] isodense in 1/3rd cases and c] rarely can be hypondense or show calcifications. (**Figure 4**).

On post contrast CT, colloid cysts usually do not show enhancement. Less commonly they may show mild to moderate contrast enhancement. In some cases, thin rim of contrast enhancement may be present which is thought to represent the cyst capsule [8].

#### **Figure 5.**

*case of a large colloid cyst presenting with signs of raised ICP A] & B] preoperative Sagittal T1 and Coronal T2 images isodense third ventricular lesion extending into the septum pellucidum. C] preoperative contrast enhanced axial image D] intraoperative image with whitish colloid material being excised E] & F] postoperative T1 sagittal and T2 coronal images showing near total excision.*

#### **4.4 Magnetic Resonance Imaging**

MRI is the investigation of choice for imaging colloid cysts. On MR imaging, some lesions may show intracystic fluid levels or central and peripheral components in the lesions whereas some lesions are homogenous in appearance.

On T1 Sequencing, colloid cyst is homogenously hyperintense in about 50% of cases while the other lesions can be hyperintense, isointense or hypointense. On T2 Sequence imaging, most colloid cysts are hypointense. Low signal intensity on T2 imaging may correspond to the viscous contents of the colloid cyst and thus harder to aspirate. Post contrast enhancement of the cyst is not seen usually and rarely a peripheral enhancement will be noted around the cyst which represents a vessel stretched over the colloid cyst. (**Figure 5**)

Colloid cysts usually have a similar intensity to surrounding CSF on FLAIR sequencing and may have decreased signal intensity on diffusion weighted imaging [10].

#### **4.5 Treatment**

For patients who are symptomatic and have a higher degree of ventriculomegaly, more immediate surgical options include craniotomy for microsurgical resection, neuroendoscopic removal, and CSF -diversion with ventriculo-peritoneal [VP] shunts.

The transcallosal microsurgery and endoscopic approach were compared for the first time by Lewis et al. in 1994. The findings of their comparison were shorter stay in the hospital and early recovery in the endoscopic approach group [14].

In a study by N.B. Levine et al. from 1991 to 2004, the conclusion was made that endoscopy approach should be offered to all patients as the first line of management [15].


**Table 2.** *Colloid cyst risk score.* *Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

In 2016, Beaumont et al. published the Colloid Cyst Risk Score [CCRS], a method used to stratify the risk of a patient to develop obstructive hydrocephalus and guide physicians to choose appropriate treatment pathways. Risk of lesion progression and obstructive hydrocephalus is more with a CCRS ≥4 [13] (**Table 2**).

In 2016, Suresh Nair et al. published a study which was done from 1980 to 2011, 275 cases were managed by interhemispheric transcallosal approach, twenty-two by transcortical approach and 8 by endoscopic approach. They concluded that open microsurgical approach is the gold standard surgical treatment for colloid cyst [16].

*Author recommendations:* Neuroendoscopic approach can be offered as the first line treatment for colloid cyst as it can be used for all classic colloid cysts irrespective of the cyst site.

The entry burr hole should be 1 cm lateral to the usual Kocher's point to facilitate endoscopic septostomy. Depending on the intraoperative bleeding, consistency of the cyst and the extent of resection, the decision to place a post-operative EVD can be customized, which can be removed after 4–5 days. Rarely, VP shunt might be needed in these cases.

Case illustrations (**Figures 4** and **5**).

#### **5. Craniopharyngioma**

#### **5.1 Introduction**

Craniopharyngioma [CP] is a benign tumor originating from the squamous epithelial residual cells anywhere along the obscured craniopharyngeal duct from Rathke's cleft to the floor of the third ventricle and they constitute 2–4% of intracranial neoplasms [17]. They often present a surgical challenge to the neurosurgeons because of their central location and proximity to surrounding neural structures namely the hypothalamus, pituitary gland, the optic apparatus, circle of Willis, brainstem and temporal lobes.

Pathologically these tumors are classified into two types: adamantinomous CP [ACP] and papillary CP [PCP]. ACPs are more common than PCPs, are pathologically distinct, are composed of cystic "motor oil-like" component and solid component with frequent calcifications and are more common in pediatric population while PCPs are more common in the adult population [18].

The most common location of craniopharyngioma is the sellar and suprasellar region with 95% of the tumors having a suprasellar component. The suprasellar component of the tumor grows in various directions compressing the surrounding structures. The anatomical proximity of the tumors to the major CSF pathways may result in compression of various parts of the ventricular system causing obstructive hydrocephalus. Obstruction in these cases can be seen at the following levels a] basal cisterns b] invasion and obstruction of the inlet and outlet of the third ventricle c] foramen of Monro and rarely d] posterior displacement of the brainstem with occlusion of the Sylvian aqueduct [19].

Kassam et al. classified suprasellar craniopharyngiomas on the basis of relationship of the tumor to the infundibulum and pituitary stalk as observed in the surgical field on endoscopic viewing which is as follows: I] pre-infundibulum: Its lateral relation are carotid arteries, below by the diaphragm sella, infundibulum in the dorsal portion, and displaced chiasm in the roof. II] trans-infundibulum: The rostral extent of the tumor is bounded by the anterior portion of the hypothalamus. III] retro-infundibulum: a] Extending into the third ventricle. b] Extending into the inter-peduncular cistern. It is bounded anteriorly by the stalk and posteriorly by the mammillary bodies and basilar apex. IV] intra-ventricular and/or optic recess [20].

Generally Kassam's type III and type IV tumors present with obstruction at the level of foramen of Monro.

#### **5.2 Clinical features**

Clinical manifestations are related to hypothalamic and pituitary deficiencies, visual impairment and raised intracranial pressure [17].

Headaches are seen in about 50% of patients which may be due to raised intracranial pressure or due to meningeal irritation from the cystic fluid and can be associated with nausea and vomiting.

Symptoms of endocrine dysfunction are seen in 52–87% of patients which are caused by tumor or treatment related lesions to the hypothalamic–pituitary axis that affect the secretion of growth hormone [GH] in about 75% patients, gonadotropins [FSH/LH] in about 40% patients and adrenocorticotropic hormone [ACTH] in about 25% patients. Patients can also present with vasopressin deficiency causing diabetes insipidus in about 20% of cases.

#### **5.3 Investigations**

Evaluation and management of craniopharyngioma requires an interdisciplinary approach by endocrinologist, neuro-ophthalmologist and neurosurgeon.

#### **5.4 Neuroradiology**

Both CT and MRI are helpful for diagnosis of craniopharyngiomas which are heterogenous tumors with solid, cystic and calcified components.. PCPs are usually solid tumors with rare cystic transformations and calcifications. Radiological features of ACPs can be summarized by the 90% rule i.e. 90% of tumors are predominantly cystic, 90% show more or less prominent calcifications and about 90% take up contrast in the cyst wall [21].

CT provides details of the sellar anatomy as well as information related to cystic and solid components of the tumor, local invasion, compression of adjacent structures and calcifications.

MRI is also useful for the topographic and structural evaluation of craniopharyngiomas. These tumors are isointense or hypointense on T1 weighted images, hypointense or hyperintense on T2 weighted images and show contrast enhancement. This variability in MRI findings are due to varying proportions of solid and cystic components and presence of cholesterol, keratin, hemorrhage and amount of calcification.

#### **5.5 Treatment**

The choice of the surgery depends on the anatomical location of the tumor. It has been reported that gross total resection causes more neurological deficits and does not improve the chances of its recurrence. The Endoscopic approach is not recommended for very large tumors with solid component, calcifications or vascular invasion. Kassam's type I and type II tumors can be approached by endoscopic transnasal transsphenoidal technique. However for Kassam's type III and type IV tumors have to be approached by endoscopic transventricular or transcranial approaches (**Table 3**).

The decision regarding the approach to the lesion is guided by the following factors a] consistency of the lesion b] calcification c] lateral and extraventricular extension of the tumor.

*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

#### **Table 3.**

*Algorithm for surgical approaches for predominantly third ventricular craniopharygiomas.*

*Authors recommendations:* In the event of endoscopic transventricular approach for craniophryngiomas, the authors strongly recommend endoscopic septostomy and post operative EVD placement in all the cases. VP shunt may be required for permanent CSF drainage depending on the extent of resection. The incidence of postoperative VP shunt at a later date is relatively more common in craniopharyngiomas than colloid cyst. Also Omaya reservoir can be placed post operatively for intralesional bleomycin in predominantly cystic lesions limited to the third ventricle, although the authors have a limited experience regarding the same.

In a study by Deopujari et al. from 2000 to 2016 it was stated that suprasellar craniopharyngiomas with a major cystic component can be best managed by a combined endoscopic transcranial and transnasal approach [22].

Case illustration (**Figure 6**).

The toxic radioactive substances like bleomycin, interferon alpha can be given in craniopharyngiomas with cystic component only to promote sclerosis and fibrosis. One of the major disadvantages of this approach is that it can produce severe neurotoxicity and leakage of the sclerosing substance [23].

For cystic craniopharyngiomas radioisotopes can be implanted through an endoscopic approach. However, there are no standard guidelines for the intra cystic dosage and the toxicity level of these drugs along with tumor control dosage, all these makes this therapeutic option difficult to follow [24].

**Figure 6.**

*case of craniopharyngioma [Kassam's type III] presenting with dwarfism and raised ICP A] pre-operative non contrast axial CT B], C] & D] pre-operative contrast enhanced axial, coronal and sagittal CT images respectively E] & F] postoperative non contrast axial and sagittal CT image.*

#### **6. Subependymal Giant Cell Astrocytoma [SEGA]**

#### **6.1 Introduction**

SEGA also known as Subependymal Giant Cell Tumor [SGCT] are clinically benign [WHO grade 1], slow growing tumors which usually arise in the periventricular regions in the proximity of the foramen of Monro. They are associated with tuberous sclerosis complex [TSC], which is a systemic autosomal disease characterized by Vogt's clinical triad of mental retardation, seizures and facial angiofibroma. TSC has a prevalence ranging from 5 to 20% with radiographic evidence of subependymal nodules which are a precursor of SEGA seen in 90% of TSC patients [25, 26].

These are histologically benign tumors and do not undergo malignant transformation. The lesions which are over 10 mm in diameter at the foramen of Monro can cause obstruction of CSF flow leading to progressive dilatation of the lateral ventricles and raised ICP and cause the clinical manifestations associated with SEGA [25].

#### **6.2 Clinical features**

Preoperative diagnosis of SEGA takes into account the age, clinical condition of the patients and the location of the tumor. In cases where neurocutaneous manifestations of TSC which include mental retardation, seizures and adenoma sebacum [Vogt's triad] are present, early diagnosis of TSC is possible. However solitary

#### *Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

lesions without clinical or radiological features of TSC have also been reported and these patients almost always present urgently due to raised ICP.

In the early stage, patients can present with insidious onset subtle behavior changes, cognitive impairment or seizures. Features of raised ICP like headache and vomiting are present due to increase in size of the lesion causing obstructive hydrocephalus or due to intratumoural or intraventricular hemorrhage [26, 27].

#### **6.3 Investigations**

CT and MRI characteristics in SEGA are usually nonspecific. Patient factors which include age and location of the lesion are useful indicators in establishing diagnosis. Although nonspecific, radiological findings show a well circumscribed lesion at the foramen of Monro which is isodense or slightly hyperdense on CT with rare thin calcifications, hypointense on T1, hyperintense on T2 with marked contrast enhancement [26, 28].

#### **6.4 Treatment**

SEGAs are considered to be benign lesions and excision of the tumor is considered to be curative in patients presenting with a single lesion. Surgical treatment is indicated in cases of symptomatic SEGA or patients presenting with acute increase

#### **Figure 7.**

*Young male patient with cutaneous manifestations of TSC presented with sudden onset altered sensorium A] Preoperative CT brain a circumscribed lesion in the right foramen of Monro region with calcification, hemorrhage and obstructive hydrocephalus B] Preoperative MRI showing heteregenous enhancement with mixed cystic and solid areas and multi-stage hemorrhages C] Clinical picture showing cutaneous manifestations of Tuberous Sclerosis Complex D] Follow up CT brain at 2 years showing near total excision of the tumor except the calcified part with resolution of hydrocephalus.*

#### **Figure 8.**

*20 year old female with cuteneous manifestations of TCS presenting with raised ICPA]& B] preoperative MRI showing a contrast enhancing solid lesion at the level of right foramen of Monro leading to univentricular [right lateral ventricle] hydrocephalus. C] & D] endoscopic septostomy was done to deal with the obstructed right ventricle with endoscopic biopsy which was suggestive of SEGA. E] & F] postoperative imaging showing septostomy defect. Later patient was managed with m-TOR inhibitors [rapamycin] with progression free survival over a period of 2 year follow up.*

in intracranial pressure due to obstructive hydrocephalus [29]. Other alternative treatment options are Gamma Knife radiosurgery [GKR] or the mechanistic target of rapamycin [mTOR] inhibitors which can reduce the size of the mass in TSC. GKR showed promising results for many types of benign brain tumors, including gliomas, with a low incidence of side effects [30].

Authors recommendations: In our experience, SEGA's were operated by open transcallosal/ transventricular approaches to the lateral ventricle. As these tumors are generally solid and firm in consistency, they are not amenable to endoscopic excision.

Case Illustrations (**Figures 7**–**9**).

#### **7. Neurocysticerosis**

#### **7.1 Introduction**

Neurocysticercosis [NCC] occurs when larval stage of the tapeworm Taenia Solium migrates to the central nervous system. It is the most common helminthic infestation of the central nervous system and usually manifests as acute seizure, epilepsy, progressively worsening headache or focal deficit [31].

The cysts reach the ventricular system through the choroid plexus and are more frequently found in the fourth ventricle. This can be attributed to the gravitational

**Figure 9.**

*Mentally retarded child with neurocutaneous markers of TSC presented with raised ICP Figure A], B] & C] MRI revealing large solid enhancing lesion with calcifications at the level of Foramen of monro extending into the lateral ventricle, third ventricle and involving the septum pellucidum causing obstructive hydrocephalus. D], E] & F] Post- operative image showing near total excision with VP shunt in situ [which was done at a later date].*

forces which favor migration from supratentorial ventricles or the cysts may directly enter through the choroid plexus [32].

The locations of intraventricular cysts determine the natural history of the disease. Ones attached to the ventricular wall involutes and eventually resolve, while the cysts which are not attached may migrate and block the cerebrospinal flow causing obstructive hydrocephalus. Hydrocephalus can occur either due to ventricular obstruction or arachnoiditis. Sites of obstruction include foramen of Monro, third ventricle, aqueduct of Sylvius and fourth ventricle [32, 33].

#### **7.2 Clinical features**

Active intraventricular cysts may remain asymptomatic for years and may become symptomatic if they obstruct the CSF flow leading to hydrocephalus and raised ICP. Abrupt obstruction may lead to acute hydrocephalus and present with features of hydrocephalus which include headache, nausea, vomiting, diplopia, restlessness, seizures, respiratory changes, bradycardia, hypertension, altered sensorium and papilledema or may present infrequently with features of Brun's syndrome [34].

Death of an intraventricular cyst larva can lead to liberation of antigenic substances being released into the ventricular system with local reactions causing an inflammatory response throughout the ventricular system. These patients will present with features of raised ICP, meningoencephalitis, focal neurological deficits and inflammatory reaction detectable in CSF [35].

#### **7.3 Investigations**

The diagnosis of intraventricular NCC is based on systematic clinical evaluation, neuroimaging and serology. However the role of serology is limited due to low sensitivity and specificity. Various serological tests include a] antibody testing with immunoblot assay using T. solium antigens on serum or CSF samples b] direct antigen testing of Taenia solium antigen with ELISA using a monoclonal antibody against Taenia saginata HP10 antigens on CSF or serum samples c] detection of Taenia solium specific DNA in CSF by polymerase chain reaction [36].

#### **7.4 Neuroradiology**

Identification of scolex in a cystic lesion is the pathognomonic radiological finding in NCC [32, 34, 35]. Non-contrast CT is sensitive for parenchymal and calcified lesions but is not sensitive for extraparenchymal disease. CT may fail to demonstrate small cysts that do not deform the ventricles as a] they share the same density of CSF b] the cyst wall and the scolex are not visible c] the cyst does not show contrast enhancement.

MRI is the investigation of choice for extraparenchymal NCC as the MRI properties of the scolex or the cystic fluid differ and inflammation is marked with hyperintensity signals which allow a reliable diagnosis.

A viable active intraventricular cyst appears as a well defined thin walled cystic lesion of 10–20 mm in diameter which is hypointense on T1 with a thin rim of hyperintensity. The scolex is seen as an eccentric rounded or elongated enhancing mural nodule of 2-4 mm in diameter within the cyst cavity. On T2 weighted imaging, the contents of the cyst are isointense with the surrounding tissues with an hyperintense scolex. Contrast enhanced T1 weighted MRI imaging shows contrast ring enhancement of the cysts with surrounding edema.

#### **7.5 Treatment**

Treatment modalities include antiparasitic drugs, surgery and symptomatic medications. Medical management includes a] corticosteroids for meningitis, cysticercal encephalitis and angitis b] antiparasitic drugs which include praziquantel and albendazole [36].

Principles of surgery include treatment of hydrocephalus and removal of cyst. Modalities of surgical intervention include a] emergency ventriculostomy b] placement of VP shunt c] Neuroendoscopic or microsurgical extirpation of obstructing cysts.

As these cysts are not densely adherent to the ventricular wall endoscopic approach is the preferred surgical option. There is usually no enhancement of the cyst wall but in cases where the cyst wall is enhancing, it is suggestive of either ependymal inflammation or adherence of cyst wall to the ependyma. Thus, the decision to approach these lesions endoscopically, in cases of enhancing cyst wall, should be taken with caution. Psarros et al. in his study made an observation that despite rupture of the cyst and spillage of contents in the ventricle, ventriculitis was not seen. Continuous perioperative irrigation with ringers solution helps in removing the debris and provides clear vision [37].

*Authors recommendations:* Post operative External ventricular drain [EVD] should be placed to address the spillage of contents in the ventricle, but however in our experience we did not find any inflammatory reaction because of the cyst contents.

Case Illustration (**Figure 10**).

#### **Figure 10.**

*12 year female presented with Bruns syndrome [episodic symptoms of raised intracranial pressure]. A], B] & C] MRI images showing a cystic lesion in the left lateral ventricle obstructing the left foramen of Monro leading to obstructive hydrocephalus and deviation of the septum pellucidum to the right. D] & E] intraoperative photo showing the excision of the white cyst wall with complete decompression of the left foramen of Monro. F] Postoperative image showing complete excision with midline septum pellucidum.*

#### **8. Tubercular meningitis**

#### **8.1 Introduction**

TBM, a frequent form of central nervous system tuberculosis is a serious neurological disease with significant mortality and morbidity. In India, the estimated mortality due to TBM is approximately 1.5/100,000 population. Neurological complications like cerebral infarctions and hydrocephalus are common and may cause worsening of prognosis [38].

Hydrocephalus, one of the most common complications of TBM, can occur early or late in the clinical course and can also be associated with the commencement of anti-tubercular drugs.

Hydrocephalus in TBM could be either of communicating or obstructive type, the former being more common. The main cause of hydrocephalus in both types is by presence of thick basilar exudates in the subarachnoid spaces or the ventricular pathways [39].

Obstructive hydrocephalus results from block or compression within the fourth ventricle due to exudates or leptomeningeal scar tissue or obstruction of aqueduct of Sylvius due to strangulation of brainstem by exudates or subependymal tuberculoma [40].

Foramen of Monro is anatomically narrowed by the bulk of the choroid plexus which is susceptible to obstruction due to a] meningeal inflammation leading to raised CSF protein content rendering the CSF more viscous and compromising CSF flow b] focal ventriculitis c] exudates/ scarring in the region of foramen of monro [41].

#### **8.2 Clinical features**

Progression of disease in patients with obstructive hydrocephalus in TBM is generally rapid as compared to those presenting with communicating hydrocephalus [42].

In addition to the primary and constitutional symptoms of tubercular meningitis, obstructive hydrocephalus should be suspected in any patient with TBM presenting with sudden onset altered sensorium with or without presence of papilledema or in patients complaining of rapidly progressive headache with or without blurring of vision.

#### **8.3 Neuroradiology**

Contrast enhanced CT and MRI are helpful in diagnosing the complications of TBM which include presence of hydrocephalus, subependymal seepage, tuberculomas infarcts, edema, nodular enhancing lesions and basal exudates [40].

#### **8.4 Treatment**

Medical management includes: antituberculous therapy, steroids, dehydrating agents like mannitol and diuretics such as frusemide and acetazolamide to reduce CSF production [40, 43].

Surgical management includes CSF diversion surgery which can be done conventionally with a VP shunt or neuroendoscopically.

The advantages of neuroendoscopy are:


#### **Figure 11.**

*A] Intra-operative image showing obstruction at the level of foramen of Monro with ependymal tubercles B] perforation of the septum followed by dilatation with C] balloon catheter and D] dilating forceps E] post foraminoplasty restoration of caliber of the foramen of monro with no damage to surrounding structures.*

*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*


In a study by Chugh et al. [43]. it was concluded that in cases of TBM with hydrocephalus endoscopic procedures can be offered as the first line of management as it provides the added advantage of performing septostomy, monroplasty and biopsy at the same sitting.

Case Illustration (**Figure 11**).

#### **9. Pituitary adenoma**

#### **9.1 Introduction**

Pituitary tumors are a heterogenous group of CNS lesions that are usually benign and constitute 10–15% of all primary intracranial tumors in adults. They can be divided on the basis of their size into macradenomas [diameter more than 10 mm] and microadenomas [size less than 10 mm. Nonfunctioning pituitary adenomas with diameter exceeding 40 mm are considered as giant adenomas. These adenomas are rare and frequently invade the suprasellar structures causing mass effect [44, 45].

Obstructive hydrocephalus due to a pituitary adenoma is rare with very less literature available, limited to case reports. Hydrocephalus is rarely the presenting symptom or can occur during the course of the disease.

Various mechanisms of development of hydrocephalus in pituitary adenomas include: a] due to lesser resistance, most pituitary macroadenomas have cranial and anterior extension. The tumor grows along the pituitary stalk upwards through the sellar diaphragm to impinge on the recesses of the third ventricle. In rare cases, the tumor becomes large enough to obstruct the intraventricular foramen leading to secondary hydrocephalus. b] some tumors extend along the floor of the third ventricle and obstruct the Sylvian aqueduct causing obstructive hydrocephalus. c] through obliteration of suprasellar cistern [46].

#### **9.2 Clinical features**

Clinical manifestations of giant pituitary adenomas can be secondary to compression of the surrounding structures, pituitary hormone deficiency or hypopituitarism and tumor hypersecretion [44, 46, 47]. Common manifestations of non functioning pituitary adenomas include headache, visual impairment and visual field defects. Obstructive hydrocephalus is characterized by symptoms of raised ICP which include headache, nausea, vomiting, blurring of vision, memory loss, irritability, personality changes, papilledema, sleep disturbances, gait disturbances, loss of bladder control and coma. Involvement of the frontal lobes can be associated with generalized seizures and dementia. Extension of the tumor into the cavernous sinus can be associated with third, fourth and sixth nerve palsy.

#### **9.3 Investigations**

Necessary investigations for diagnosing a pituitary tumor include hormonal profile, neuroradiology and fundoscopy.

#### **9.4 Neuroradiology**

Contrast enhanced MRI is the investigation of choice for size and location of the tumor and its relation to surrounding structures [48]. CT can provide additional information which include identification of bone destruction and confirmation of suspected intra/parasellar calcifications (**Figure 12**).

#### **Figure 12.**

*60 years old male presented with gradual diminution of vision with altered sensorium with A], B] & C] preoperative scans showing a sellar, suprasellar and right parasellar lesion [pituitary adenoma] with a cystic lesion superior to the adenoma causing right foramen of Monro obstruction. D] Intraoperative picture during transnasal transsphenoidal showing complete decompression of the sellar and suprasellar part of the lesion with the diaphragm Sella herniating in the Sella. E], F] postoperative CT showing decompression of the sellar lesion but persistence of the cystic lesion in the right lateral ventricle. G] Neuroendoscopic exploration of the right ventricle shows cystic lesion with xanthochromic fluid with underlying foramen of Monro. H] Post cyst decompression, foraminoplasty being performed. I] Rest of the lateral ventricle examined for remnants of cyst. Also a septostomy was performed and Ommaya reservoir placed post operatively. J], K] & L] post operative scan revealing adequate decompression of the ventricular system with tip of Ommaya at the level of foramen of Monro.*

*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

#### **9.5 Management**

The goals of surgery include tumor removal, relieving mass effect, improving visual abnormalities, reducing hormone hypersecretion to normal levels and preserving pituitary function [44, 46].

The various modalities of treatment include

a] transsphenoidal approach b] transcranial approach c] combined or two stage approach

In a study by B.K.Ojha et al. it was documented that, a combined transsphenoidal and simultaneous transventricular/endoscopic approach is a safe and effective option for giant pituitary macroadenomas in which tumor dimensions, consistency or history of previous surgical treatment were indicative of incomplete removal by single approach alone [49].

Case Illustration.

#### **10. Intraventricular hemorrhage**

#### **10.1 Introduction**

Intraventricular hemorrhage [IVH] are classified as a] primary – involving the ventricular system and adjacent ventricular lining without associated parenchymal or subarachnoid hemorrhage which occurs in about 30% of cases. b] secondaryprimary intracerebral hemorrhage [ICH] or subarachnoid hemorrhage [SAH] extending into the ventricular system which occurs in about 70% of patients and is an independent predictor of poor outcome [50].

Pathophysiology of obstructive hydrocephalus in IVH is due to the blood clot blockage in the CSF pathway. Other contributory factors causing hydrocephalus in these cases include a] release of inflammatory mediators by the blood components causing a secondary response b] damage to the ependymal cells lining the ventricles due to inflammation c] fibrosis and scarring of the arachnoid granulations d] complement activation [51].

#### **10.2 Neuroradiology**

CT is the investigation of choice for diagnosing IVH with or without ICH as it allows for rapid diagnosis and prompt management (**Figure 13**). Blood is easily identified on CT as a white hyperdense lesion. CT is also useful to identify other important factors such as edema and hydrocephalus. Pattern and topography of bleeding can give important clues about the secondary causes of IVH and additionally CT angiography or contrast enhanced CT can be done for the same [52].

MRI is equally effective to identify acute hemorrhage. It is useful to distinguish between hemorrhage and an ischemic stroke, although it would be a less preferable investigation in an emergency situation [53].

#### **10.3 Treatment**

Goal of treatment is to limit hemorrhagic mass effect, edema, obstructive hydrocephalus by rapid removal of blood and blood products from the ventricular system [54]. Modalities of treatment in these cases include a] EVD insertion b] EVD combined with use of thrombolytics c] Neuroendoscopic aspiration.

*Case Illustration* (**Figure 13**).

#### **Figure 13.**

*CT scan A: showing IVH with dilated ventricles. B: Showing EVD in-situ with resolution of IVH and hydrocephalus.*

#### **11. Ventriculitis**

#### **11.1 Introduction**

Nosocomial infection of the central nervous system are a serious complication of patients undergoing neurosurgical procedures like craniotomy, placement of invasive neuromonitoring technique, EVD catheters or CSF shunts.

EVD, which is a common procedure for controlling and monitoring raised ICP secondary to acute occlusive hydrocephalus has an associated major complication of bacterial colonization of the catheter and subsequent retrograde infection resulting in encephalitis, ventriculitis, meningitis, brain abscess, subdural empyema or even sepsis [55].

Ventriculitis, also termed as ependymitis, ventricular empyema, pyocephalus, ventricular abscess or pyogenic ventriculitis, is the inflammation of the ependymal lining of the cerebral ventricles. It can be secondary to meningitis, cerebral abscess, EVD or shunt related, trauma, CSF leak or as a complication of intrathecal chemotherapy.

Incidence of ventriculitis according to literature ranges from 5–20% and incidence of ventricular catheter related ventriculitis ranges from 5–45% [56].

Most common pathogens causing ventriculitis are skin flora which include *staphylococcus epidermidis* [70%] and *staphylococcus aureus* [10%]. Other less common pathogens include gram negative rods [Klebsiella spp., *E. Coli*, Pseuodomonas spp], anaerobes and candida spp. [56].

Obstructive hydrocephalus in these cases is due to the obstruction caused by the exudates, adhesions and septations at the level of foramen of Monro or the aqueduct.

#### **11.2 Clinical features**

Patients can present with headache, nausea and vomiting, fever, altered mental state, meningism, focal neurological deficits and features of secondary hydrocephalus and raised ICP. On local examination over the subcutaneous shunt tubing, erythema or tenderness can be seen suggestive of infection [57].

#### **11.3 Investigations**

Diagnosis of ventriculitis is done by CSF examination and neuroradiology.

#### **11.4 Neuroradiology**

Ultrasound can be performed for neonates by using a high-frequency transducer through the anterior fontanelle in coronal and sagittal planes. The most common findings include an irregular and echogenic ependyma, the presence of intraventricular debris and stranding, intraventricular adhesions and septae associated with ventricular dilatation [58].

Noncontrast CT may be nonspecific which include dependent hyperdense ventricular debris, univentricular or biventricular hydrocephalus, periventricular low density and features of underlying abnormality. Contrast enhanced CT shows homogenous enhancement of the ependymal lining of the ventricles (**Figure 14**).

MRI findings are similar to CT, with the ventricular debris hyperintense T1 weighted images and hypointense on T2 weighted images, with high signal on DWI, reduced ADC value and are seen as fluid levels of high signal intensity on FLAIR images [57].

#### **11.5 Treatment**

On clinical suspicion of nosocomial ventriculitis, empiric antibiotic therapy should be initiated.

Surgical modalities for ventriculitis include a] intraventricular/intrathecal antibiotics b] continuous intraventricular irrigation therapy using a closed drainage system c] neuroendoscopic ventricular lavage with septostomy/ monroplasty [59].

Rational for early surgery in ventriculitis: The rapid development of polydrugresistant class of gram-negative bacteria, poor passage of antibiotics in the intraventricular space after intravenous injection and hampered CSF flow from ventricles along with infection cause the ventricles to become an enclosed system in

#### **Figure 14**

*5 year female child presented with A] monoventricular [left lateral ventricle] hydrocephalus post EVD insertion. B] Intraoperative evidence of exudates causing blockage of left foramen of Monro. C] Intraventricular exudates were cleared. D] Foraminoplasty done with E] Septostomy. As there was evidence of exudates in the right lateral ventricle which could be seen from the septostomy, neuroendoscopic lavage was given bilaterally. EVD was inserted on the left side. F] Immediate postoperative radiology showing bilaterally equal ventricles with resolving hydrocephalus.*

which infected CSF collects and the low concentration of antibiotics after intravenous injection is insufficient to kill the bacteria [60].

The endoscope allows seeing the entire cavity of the ventricles and also facilitating endoscopic lavage and clearance of the infected CSF. The decrease in infective load increases the effectiveness of the intrathecal antibiotics. Lavage inside the ventricles with continuous irrigation over a prolonged period has been reported with favorable outcomes.

*Authors recommendations:* We are of the opinion that in cases of ventriculitis a biventricular lavage with removal of ventricular exudates and adhesions is better than dealing the infection through one ventricle only.

Case Illustration (**Figure 14**).

#### **12. Central neurocytoma**

#### **12.1 Introduction**

Central neurocytoma is a rare benign tumor of neuronal differentiation that is classified as grade II by World Health Organization [WHO]. They comprise about 0.1 to 0.5% of all brain tumor and are typically seen in young adults around the third decade. They are characteristically located in the supratentorial ventricular system more commonly involving the foramen of Monro and in lesser frequency in the third and fourth ventricle [61].

#### **12.2 Clinical features**

These patients present with signs and symptoms of raised ICP induced by obstructive hydrocephalus [61, 62]. Typical clinical symptoms include headache, nausea, vomiting, seizures, paresthesias, balance problems, decreased consciousness, weakness, memory and visual disturbances. In rare cases, IVH may also occur.

#### **12.3 Neuroradiology**

On noncontrast CT, central neurocytoma appears hyperdense with calcifications seen in around 50% of cases which are usually punctate in nature [62, 63]. Cystic degeneration, seen usually in larger tumors can lead to heterogenous appearance of the tumor. CNs have mild to moderate enhancement on contrast enhanced CT. On MRI, CNs are hypo to isointense on T1, iso to hyperintense on T2, with moderate contrast enhancement (**Figure 15**).

#### **12.4 Treatment**

Surgical management with gross total resection is the treatment of choice [62, 64]. Goals of surgery are a] to establish the CSF pathway, determine the histopathological diagnosis and establish maximal surgical resection with minimum risk of neurological impairment. Radiotherapy to the tumor bed is debatable and is indicated in cases with incomplete resection to prevent tumor progression and recurrence. Stereotactic radiosurgery has also been proved to be effective compared to radiotherapy in terms of diminishing tumor recurrences and radiation associated complications in these cases.

In a study by Chun li et al. on 9 cases of central neurocytoma 2 patients died in the postoperative period. They concluded that the possibility of recurrence of

*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

#### **Figure 15.**

*30 year male patient presented with features of raised ICP with MRI findings suggestive of a lesion arising from the septum pellucidum causing obstruction at the level of right foramen of Monro. Endoscopic surgery was planned to decompress the tumor with biopsy. However owing to intraoperative intratumoral hemorrhage, a decompressive craniectomy had to be performed and the tumor was decompressed through transcortical route. Biopsy was suggestive of central neurocytoma [WHO grade 2] with MIB1-Labeling index following which patient was referred for radiotherapy.*

central neurocytomas should be considered based on the histologic features, especially proliferation index [MIB1-LI] [65].

*Case Illustration* (**Figure 15**).

#### **13. Functionally isolated ventricles**

In some cases, rapid therapeutic drainage of one lateral ventricle particularly after a low pressure VP shunt, can cause an ipsilateral slit ventricle which functionally obstructs the foramen of Monro [66]. This functional obstruction may lead to dilatation of the contralateral ventricle.

The treatment of choice of functional ventriculomegaly is neuroendoscopic intervention with septostomy with third ventriculostomy (**Figure 16**).

*Case Illustration* (**Figure 16**).

#### **Figure 16.**

*34 year male, recently shunted for TBM with hydrocephalus was referred with altered sensorium. MRI brain was suggestive VP shunt in situ in right lateral ventricle and asymmetric dilatation of the left lateral ventricle. Neuroendoscopy did not reveal any obstruction at the foramen of monro and hence septostomy was done following which patient improved.*

#### **14. Subependymomas**

#### **14.1 Introduction**

Subependymomas are rare, benign, indolent tumors of ependymal origin which comprise of 0.2%–0.7% of all intracranial tumors. They are slow growing neoplasms frequently seen in middle aged men more commonly in the fourth [50–60%] and the lateral [30–40%] ventricles. They also have a predilection for the spine and are seen in the cervical and cervicothoracic region [67, 68].

These tumors are frequently asymptomatic found incidentally on autopsy or on neuroimaging done for other medical indications.

#### **14.2 Clinical features.**

Symptomatic presentation depends on the location and size of the lesion. According to literature, tumors located at the septum pellucidum and the foramen of Monro with a size of more than 4 cms were more likely to become symptomatic with signs of raised ICP. Cases with spontaneous intratumoral hemorrhage have also been reported causing obstructive hydrocephalus. Despite the benign nature of the tumor, cases of tumor recurrence and CNS metastasis have also been reported [69, 70].

#### **14.3 Neuroradiology**

Radiological appearance of these tumors can vary depending on their location. On MRI, these tumors are typically well demarcated nodular lesions typically in the fourth or lateral ventricle which are hypo to isointense on T1 weighted images, hyperintense on T2 weighted images with minimum contrast enhancement [68, 69].

#### **14.4 Treatment**

Total surgical resection is the treatment of choice as these tumors are well demarcated, noninvasive and avascular. Role of postoperative radiation is debatable and is reserved in cases with subtotal surgical resection or in case of recurrence [71, 72].

#### **15. Idiopathic Foramen of Monro stenosis**

Idiopathic stenosis of foramen of Monro is a rare cause of enlargement of the lateral ventricles. It can occur due to an absent or stenosed foramen of Monro or when a membrane occludes a normal sized foramen of Monro. Patients are usually asymptomatic but can occasionally present with symptoms of raised ICP [71, 73].

Contrast enhanced MRI is the investigation of choice to exclude other causes of foramen of Monro obstruction and to assess the presence of potential membranes. In addition Cine-MRI CSF flowmetry is done to display CSF flow dynamics and velocity and to determine the site of CSF flow obstruction [73].

Neuroendoscopy is the treatment of choice as endosopic fenestration, foraminoplasty and septostomy can be done safely and effectively with this technique and spare the patient lifelong cumulative risk of shunt failure [74].

#### **16. Choroid plexus tumors**

#### **16.1 Introduction**

Choroid plexus tumors [CPTs] are rare intraventricular papillary tumors derived from choroid plexus epithelium which account for 0.3%–0.7% of all intracranial tumors, 2–6% of pediatric brain tumors, 10–20% of brain tumors in children less than 1 year and less than 1% of all adult intracranial tumors. The spectrum of choroid plexus tumors include a] WHO grade I choroid plexus papilloma b] WHO grade II atypical choroid plexus papilloma and c] WHO grade III choroid plexus carcinoma. Choroid plexus papillomas are more common than choroid plexus carcinomas in ratio of about 5: 1 [72, 75].

CPTs arise wherever choroid plexus tissue exists; the lateral ventricle being the most common site [50% of cases] followed by fourth ventricle [40%], third ventricle [5%] and multiple ventricles [5%] [75, 76].

#### **16.2 Clinical features**

CPTs most commonly present with signs of raised ICP and hydrocephalus [77–79]. Hydrocephalus can result due to overproduction of CSF, IVH, obstruction of CSF flow or impaired absorption. In addition to symptoms of raised intracranial pressure, patients may also present with seizures, focal neurological deficits, complications of chronic raised intracranial pressure like CSF rhinorrhea and visual disorientation, macrocephaly, and gait unsteadiness. Specific clinical symptoms can also be present according to the location of the tumor. Diencephalic seizures and bobble head doll syndrome- due to compression of the thalamus, signs of brainstem compression, cranial nerve palsies and cerebellar dysfunctions- due to posterior fossa CPTs, endocrine disturbances, precocious puberty, diabetes insipidus or diencephalic disorders- due to tumor in the third ventricle.

#### **16.3 Neuroradiology**

On Non contrast CT [NCCT], these tumors are seen as isodense to hyperdense intraventricular masses with intense contrast enhancement [72, 80].

MRI is the investigation of choice for these tumors. On MRI, CPTs appear as a large intraventricular lesion with irregular enhancing margins. They are isointense to slightly hyperintense on T1 weighted images, slightly hyperintense on T2 weighted images and show significant contrast enhancement.

#### **16.4 Treatment**

Maximum surgical resection followed by non-standardized use of adjuvant chemotherapy and radiotherapy is the treatment of choice for CPTs [75, 81].

#### **17. Management of Foramen of Monro obstruction**

#### **17.1 Diagnosis of foramen of Monro obstruction**

A detailed clinico-radiological examination is mandatory for diagnosis of foramen of Monro obstruction. Clinical manifestations and radiological features of

various pathologies causing foramen of monro obstruction have already been discussed earlier in this chapter. Radiological features suggestive of foramen of monro obstruction include a] univentricular or biventricular hydrocephalus b] nonvisualization of the third ventricle c] obvious pathology seen in the third or lateral ventricle in the vicinity of the foramen.

#### **17.2 Management**

Nonoperative management: nonoperative management of foramen of Monro obstruction can be contemplated for very few indications like in patients with a small IVH causing hydrocephalus or in cases of idiopathic foramen of Monro obstruction with no signs of raised ICP.

#### **17.3 Surgical management**

Surgical management of the foramen of Monro obstruction depends on the pathology causing the obstruction. Approach can be done either by a] open craniotomy b] neuroendoscopy.

#### **17.4 Open Craniotomy approaches**

There are many surgical approaches for approaching tumors of the ventricular system. The open approach to foramen of Monro lesions depends on whether the lesion is predominant in the lateral or third ventricle. Microneurosurgical techniques used to reach the frontal horn of the lateral ventricles and foramen of Monro are a] frontal transcortical approach and b] anterior transcallosal approach [82]. Approach to foramen of monro lesions predominantly in third ventricle can be done by lamina terminalis approach either through the pterional or subfrontal corridors (**Figure 17**).

**Figure 17.** *Surgical approaches to the frontal horn of the lateral ventricle or third ventricle.*

#### **18. Endoscopic approach**

#### **18.1 Endoscopic anatomy**

Anatomical landmarks important to be recognized while performing neuroendoscopic approach to the lateral and third ventricle for performing septostomy and foraminoplasty include: the anterior caudate vein, thalamostriate vein, septal vein, choroid plexus and foramen of Monro (**Figure 18**).

#### **18.2 Introduction**

With recent advances in endoscopic techniques, neuroendoscopy has become the first line of management for intraventricular pathologies. Endoscopic approach to the foramen of Monro can be considered as minimally invasive version of the open transcortical approach with the added advantage of panoramic view which can be achieved by angling the scope or using scopes of different viewing angles. With recent advances in scope instrumentation, bimanual dissection of pathologies has also become possible. The definitive treatment of the lesion by endoscopic approach can always be supplemented with septostomy and monroplasty/foraminoplasty.

#### **18.3 Septostomy**

Endoscopic septostomy allows to bypass a unilateral foramen of Monro obstruction creating a CSF circulation between the obstructed ventricle and the opposite lateral ventricle that communicates with the third ventricle by the normal foramen of Monro [77]. This communication between both the lateral ventricles converts them into a single compartment thus allowing both the ventricles to be drained by one shunt in cases of bilateral foramen of Monro obstruction.

For performing a septostomy, a linear incision is generally taken 5-6cms lateral to the midline which is more lateral than the incision taken for endoscopic third ventriculostomy. The use of navigation also helps in deciding the site of the incision. A semicircular incision may be opted if we are planning to insert an Ommaya reservoir.

*Authors recommendations:* The site of septostomy on the septum pellucidum is generally posterosuperior to the foramen of Monro, posterior to the anterior septal vein, at the point where the septum appears to be avascular and thinned out. The

**Figure 18.** *Anatomy of the lateral ventricle.*

**Figure 19.** *A] Septum pelucidum being probed in a avascular area B] post- perforation, dilatation of septostomy with balloon dilator C] opposite ventricular wall seen through septostomy.*

probing of the septum with the blunt tip of the bipolar probe also gives the surgeon an idea of the thickness of septum pellucidum. If tumor biopsy or resection is planned simultaneously, septostomy should precede the biopsy or resection as bleeding while dealing with the tumor may obscure the anatomical orientation making the septostomy difficult (**Figure 19**).

Intraventricular hemorrhage has been documented as a complication in literature and the possible reason is injury to the contralateral septal vein during the septostomy being performed. However, no such experience has been encountered by the authors.

In a study by Oertel et al. septostomy was performed 5–10 mm posterior to the interventricular foramen, in the middle of the corpus callosum [CC] and the fornix [83]. In a study by Hamada et al. perforation of the septum was done between the anterior and posterior septal vein [78]. In a study by Roth et al. perforation was done in the anterior septal area, at the level of the interventricular foramen, midway between the corpus callosum and the fornix [79].

The largest study on the procedure of endoscopic septostomy was done by P.R. Aldana and their inference was that septostomy is the most adequate surgery for unilateral obstruction at the interventricular foramen level [84].

#### **19. Endoscopic Foraminoplasty**

Endoscopic foraminoplasty at the interventricular foramen level is not very commonly reported in the literature. It was reported for the first time by Oi et al. [85]. This procedure establishes back the connection between the lateral and the third ventricle. It obviates the need of a shunt and avoids its related complications. For performing foraminoplasty, the incision and entry of the scope is similar to that of septostomy.

On entry to the ventricle, the foramen of Monro is recognized by choroid plexus and the thalamostriate and septal veins.

Endoscopic foraminoplasty can be performed by:


*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*


#### **Figure 20.**

*foraminoplasty can be done by A] excision of lesion B] removal of blood products C] removal of exudates D] removal of adhesions E] dilatation with dilator forceps F] dilatation with balloon catheter.*

#### **Table 4.** *Algorithm for surgical management of foramen of Monro obstruction.*

As it always carries a risk of recurrent obstruction because of the scarring, foraminoplasty should be supplemented with a septostomy. The procedure of dilatation carries the risk of injury to the septal vein or thalamostriate vein and there can also be injury to the fornix leading to memory problems. However, in our experience, we have never encountered vascular injury in any of our cases. In 1 case, injury to the fornix was seen. However, postoperatively, the patient did not experience any memory problems (**Figure 20**) (**Table 4**).

#### **20. Conclusion**

Lesions causing foramen of Monro obstruction resulting in hydrocephalus are a fairly uncommon entity encountered in neurosurgical practice with craniopharyngioma and colloid cysts being the most common pathology in children and adults respectively.

Treatment consists of open craniotomy for solid tumors and endoscopic approaches (transnasal transsphenoidal and cranial) for cystic lesions. Endoscopic approach is particularly helpful in decreasing the convalescence period and postoperative complications and thus, should be offered as a first line of treatment whenever suited.

Septostomy should be a part of standard treatment in all the patients having foramen of Monro obstruction so as to obviate the need of added shunt procedures.

Although small solid lesions less than 2 cms in size can be addressed by endoscopic approach, the learning curve required for endoscopic approach to deal with solid lesions is very steep. Thus, correct patient selection is of utmost importance for optimal patient outcome.

#### **Author details**

Ashish Chugh<sup>1</sup> , Sarang Gotecha<sup>1</sup> \*, Prashant Punia<sup>1</sup> and Neelesh Kanaskar<sup>2</sup>

1 Department of Neurosurgery, Dr.D.Y.Patil Medical College, Pimpri, Pune, India

2 Department of Anatomy, Dr.D.Y.Patil Medical College, Pimpri, Pune, India

\*Address all correspondence to: dr.sarangsgotecha@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

#### **References**

[1] Cai Q, Wang J, Wang L, Deng G, Chen Q, Chen Z. A classification of lesions around interventricular foramen and its clinical value. :8.

[2] Gray H, Williams PL. Gray's Anatomy: The Anatomical Basis of Medicine and Surgery. 38th ed. Churchill Livingstone, 1995; 1202–1205 p.

[3] Doctors Monro: A Medical Saga. By R. E. Wrightst. Clair, 8½ 5½ in. Pp. 190, with 8 plates. 1964. London: Wellcome Historical Medical Library. 30s. British Journal of Surgery. 2005 Dec 8;52(4):317–317.

[4] Monro A. Observations on the structure and functions of the nervous system: illustrated with tables [Internet]. Edinburgh [u.a.]; 1783. X, 176 S., zahlr. Ill. Available from: https:// doi.org/10.11588/diglit.4812

[5] Mokri B. The Monro-Kellie hypothesis: applications in CSF volume depletion. Neurology. 2001 Jun 26;56 (12):1746–8.

[6] Dutta AK. Essentials of Human Embryology. 5th ed. Current Books International.2006.; 261–263 p.

[7] Chugh A, Gotecha S, Punia P, Patil A, Kotecha M. Neuroendoscopic Excision of Third Ventricular Colloid Cysts. IJNNS. 2018;10(4):157–64.

[8] Ravnik J, Bunc G, Grcar A, Zunic M, Velnar T. Colloid cysts of the third ventricle exhibit various clinical presentation: a review of three cases. Bosn J of Basic Med Sci. 2014 Aug 14;14 (3):132.

[9] Tenny S, Thorell W. Colloid Brain Cyst. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 [cited 2021 May 30]. Available from: http://www.ncbi.nlm.nih.gov/books/ NBK470314/

[10] Armao D, Castillo M, Chen H, Kwock L. Colloid Cyst of the Third Ventricle: Imaging-pathologic Correlation. 2000;8.

[11] Decq P, Goutagny S, Staquet H, Iakovlev G, Krichen W, Faillot T, et al. Hydrocephalus and Colloid Cysts. In: Cinalli G, Özek MM, Sainte-Rose C, editors. Pediatric Hydrocephalus [Internet]. Cham: Springer International Publishing; 2019 [cited 2021 May 30]. p. 797–819. Available from: http://link. springer.com/10.1007/978-3-319-27250- 4\_13

[12] California Institute Of Behavioral Neurosciences & Psychology, Adjepong D. Interventricular Colliodal Cyst: A Literature Review. SCTI. 2020 May 20;4(2):1–4.

[13] Beaumont TL, Limbrick DD, Rich KM, Wippold FJ, Dacey RG. Natural history of colloid cysts of the third ventricle. JNS. 2016 Dec;125(6): 1420–30.

[14] Lewis AI, Crone KR, Taha J, van Loveren HR, Yeh H-S, Tew JM. Surgical resection of third ventricle colloid cysts: Preliminary results comparing transcallosal microsurgery with endoscopy. Journal of Neurosurgery. 1994 Aug;81(2):174–8.

[15] Levine N, Miller M, Crone K. Endoscopic Resection of Colloid Cysts: Indications, Technique, and Results during a 13-Year Period. Minim Invasive Neurosurg. 2007 Dec;50(6): 313–7.

[16] Nair S, Gopalakrishnan C, Menon G, Easwer H, Abraham M. Interhemispheric transcallosal transforaminal approach and its variants to colloid cyst of third ventricle: Technical issues based on a single institutional experience of 297 cases. Asian J Neurosurg. 2016;11(3):292.

[17] Fernandez-Miranda JC, Gardner PA, Snyderman CH, Devaney KO, Strojan P, Suárez C, et al. Craniopharyngioma: A pathologic, clinical, and surgical review. Eisele DW, editor. Head Neck. 2012 Jul; 34(7):1036–44.

[18] Lubuulwa J, Lei T. Pathological and Topographical Classification of Craniopharyngiomas: A Literature Review. J Neurol Surg Rep. 2016 Aug 22; 77(03):e121–7.

[19] Siomin V, Constantini S. Treatment of Hydrocephalus in Suprasellar Lesions. In: Cinalli G, Sainte-Rose C, Maixner WJ, editors. Pediatric Hydrocephalus [Internet]. Milano: Springer Milan; 2005 [cited 2021 Jun 14]. p. 163–70. Available from: https:// doi.org/10.1007/978-88-470-2121-1\_12

[20] Kassam AB, Gardner PA, Snyderman CH, Carrau RL, Mintz AH, Prevedello DM. Expanded endonasal approach, a fully endoscopic transnasal approach for the resection of midline suprasellar craniopharyngiomas: a new classification based on the infundibulum. JNS. 2008 Apr;108(4): 715–28.

[21] Müller HL. The Diagnosis and Treatment of Craniopharyngioma. Neuroendocrinology. 2020;110(9–10): 753–66.

[22] Deopujari CE, Karmarkar VS, Shah N, Vashu R, Patil R, Mohanty C, et al. Combined endoscopic approach in the management of suprasellar craniopharyngioma. Childs Nerv Syst. 2018 May;34(5):871–6.

[23] Ortiz Torres M, Shafiq I, Mesfin FB. Craniopharyngioma. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 [cited 2021 Jun 14]. Available from: http://www.ncb i.nlm.nih.gov/books/NBK459371/

[24] Varlotto J, DiMaio C, Grassberger C, Tangel M, Mackley H, Pavelic M, et al.

Multi-modality management of craniopharyngioma: a review of various treatments and their outcomes. Neuro-Oncology Practice. 2016 Sep 1;3(3): 173–87.

[25] Sterman H, Furlan AB, Matushita H, Teixeira MJ. Subependymal giant cell astrocytoma associated with tuberous sclerosis presenting with intratumoral bleeding. Case report and review of literature. Childs Nerv Syst. 2013 Feb;29 (2):335–9.

[26] Stavrinou P, Spiliotopoulos A, Patsalas I, Balogiannis I, Karkavelas G, Polyzoidis K, et al. Subependymal giant cell astrocytoma with intratumoral hemorrhage in the absence of tuberous sclerosis. J Clin Neurosci. 2008 Jun;15 (6):704–6.

[27] Moavero R, Pinci M, Bombardieri R, Curatolo P. The management of subependymal giant cell tumors in tuberous sclerosis: a clinician's perspective. Childs Nerv Syst. 2011 Aug; 27(8):1203–10.

[28] Moncef B. Management of subependymal giant cell tumors in tuberous sclerosis complex: the neurosurgeon's perspective. World J Pediatr. 2010 May;6(2):103–10.

[29] Kim J-Y, Jung T-Y, Lee K-H, Kim S-K. Subependymal Giant Cell Astrocytoma Presenting with Tumoral Bleeding: A Case Report. Brain Tumor Res Treat. 2017 Apr;5(1):37–41.

[30] Beaumont TL, Limbrick DD, Smyth MD. Advances in the management of subependymal giant cell astrocytoma. Childs Nerv Syst. 2012 Jul; 28(7):963–8.

[31] Shah H, Jain K, Shah J. Endoscopic excision of intraventricular neurocysticercosis blocking foramen of Monro bilaterally. Asian J Neurosurg. 2016;11(2):176.

#### *Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

[32] Arshad F, Rao S, Kenchaiah R, Prasad C, Shashidhar A. Intraventricular neurocysticercosis presenting as Bruns' syndrome: An uncommon presentation. Egypt J Neurol Psychiatry Neurosurg. 2020 Dec;56(1):54.

[33] Jensen TO, Post JJ. Intraventricular neurocysticercosis: Presentation, diagnosis and management. Asian Pacific Journal of Tropical Medicine. 2016 Aug;9(8):815–8.

[34] Shahani L, Mejia R, Garnes ND. Intraventricular Taenia solium Cysts Presenting with Bruns Syndrome and Indications for Emergent Neurosurgery. The American Journal of Tropical Medicine and Hygiene. 2015 Jun 3;92 (6):1261–4.

[35] Cuetter AC, Andrews RJ. Intraventricular neurocysticercosis: 18 consecutive patients and review of the literature. FOC. 2002 Jun;12(6):1–7.

[36] Rodriguez S, Dorny P, Tsang VCW, Pretell EJ, Brandt J, Lescano AG, et al. Detection of Taenia solium Antigens and Anti–T. solium Antibodies in Paired Serum and Cerebrospinal Fluid Samples from Patients with Intraparenchymal or Extraparenchymal Neurocysticercosis. J Infect Dis. 2009 May 1;199(9):1345–52.

[37] Psarros TG, Krumerman J, Coimbra C. Endoscopic management of supratentorial ventricular neurocysticercosis: case series and review of the literature. Minim Invasive Neurosurg. 2003 Dec;46(6):331–4.

[38] Chan KH, Cheung RTF, Fong CY, Tsang KL, Mak W, Ho SL. Clinical relevance of hydrocephalus as a presenting feature of tuberculous meningitis. Q JM. 2003 Sep 1;96(9): 643–8.

[39] Raut T, Garg RK, Jain A, Verma R, Singh MK, Malhotra HS, et al. Hydrocephalus in tuberculous meningitis: Incidence, its predictive

factors and impact on the prognosis. Journal of Infection. 2013 Apr;66(4): 330–7.

[40] Rajshekhar V. Management of hydrocephalus in patients with tuberculous meningitis. Neurol India. 2009;57(4):368.

[41] Sharma C, Acharya M, Kumawat BL, Kochar A. "Trapped temporal horn" of lateral ventricle in tuberculous meningitis. Case Reports. 2014 Apr 4;2014(apr03 2): bcr2014203837–bcr2014203837.

[42] Goel A. Tuberculous meningitis and hydrocephalus. :1.

[43] Chugh A, Husain M, Gupta RK, Ojha BK, Chandra A, Rastogi M. Surgical outcome of tuberculous meningitis hydrocephalus treated by endoscopic third ventriculostomy: prognostic factors and postoperative neuroimaging for functional assessment of ventriculostomy. J Neurosurg Pediatr. 2009 May;3(5):371–7.

[44] Rawska A, Sałek M, Nowakowska M, Bąk M, Jamroz-Wiśniewska A, Rejdak K. Successful surgical treatment in a patient with a giant pituitary macroadenoma accompanied by obstructive hydrocephalus. J Pre Clin Clin Res. 2019 Sep 27;13(3):130–3.

[45] Zhang D, Chen J, Li Z, Wang J, Han K, Hou L. Clinical features and management of nonfunctioning giant pituitary adenomas causing hydrocephalus. Oncotarget. 2018 Mar 16;9(20):15409–17.

[46] Verhelst J, Berwaerts J, Abs R, Dua G, Weyngaert DVD, Mahler Ch. Obstructive Hydrocephalus as Complication of a Giant Nonfunctioning Pituitary Adenoma: Therapeutical Approach. Acta Clinica Belgica. 1998 Jan;53(1):47–52.

[47] Iglesias P, Rodríguez Berrocal V, Díez JJ. Giant pituitary adenoma: histological types, clinical features and therapeutic approaches. Endocrine. 2018 Sep;61(3):407–21.

[48] Bashari WA, Senanayake R, Fernández-Pombo A, Gillett D, Koulouri O, Powlson AS, et al. Modern imaging of pituitary adenomas. Best Practice & Research Clinical Endocrinology & Metabolism. 2019 Apr;33(2):101278.

[49] Ojha BK, Husain M, Rastogi M, Chandra A, Chugh A, Husain N. Combined trans-sphenoidal and simultaneous trans-ventricularendoscopic decompression of a giant pituitary adenoma: case report. Acta Neurochir. 2009 Jul;151(7):843–7.

[50] Hanley D, Naff N, Harris D. Intraventricular Hemorrhage: Presentation and Management Options. Seminars in Cerebrovascular Diseases and Stroke. 2005 Sep;5(3):209–16.

[51] Bu Y, Chen M, Gao T, Wang X, Li X, Gao F. Mechanisms of hydrocephalus after intraventricular haemorrhage in adults. Stroke Vasc Neurol. 2016 Mar;1 (1):23–7.

[52] Sahni R, Weinberger J. Management of intracerebral hemorrhage. Vasc Health Risk Manag. 2007;3(5):701–9.

[53] Nyquist P. Management of acute intracranial and intraventricular hemorrhage. Crit Care Med. 2010 Mar; 38(3):946–53.

[54] Basaldella L, Marton E, Fiorindi A, Scarpa B, Badreddine H, Longatti P. External ventricular drainage alone versus endoscopic surgery for severe intraventricular hemorrhage: a comparative retrospective analysis on outcome and shunt dependency. Neurosurg Focus. 2012 Apr;32(4):E4.

[55] Beer R, Lackner P, Pfausler B, Schmutzhard E. Nosocomial

ventriculitis and meningitis in neurocritical care patients. J Neurol. 2008 Nov;255(11):1617–24.

[56] Humphreys H, Jenks PJ. Surveillance and management of ventriculitis following neurosurgery. Journal of Hospital Infection. 2015 Apr; 89(4):281–6.

[57] Harris L, Munakomi S. Ventriculitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 [cited 2021 May 30]. Available from: http:// www.ncbi.nlm.nih.gov/books/ NBK544332/

[58] Mohan S, Jain KK, Arabi M, Shah GV. Imaging of Meningitis and Ventriculitis. Neuroimaging Clinics of North America. 2012 Nov;22(4):557–83.

[59] Tabuchi S, Kadowaki M. Neuroendoscopic surgery for ventriculitis and hydrocephalus after shunt infection and malfunction: Preliminary report of a new strategy. Asian J Endosc Surg. 2015 May;8(2): 180–4.

[60] Remeš F, Tomáš R, Jindrák V, Vaniš V, Šetlík M. Intraventricular and lumbar intrathecal administration of antibiotics in postneurosurgical patients with meningitis and/or ventriculitis in a serious clinical state: Clinical article. JNS. 2013 Dec;119(6):1596–602.

[61] Runderawala H, Kantharia A, Oak P, Mahore A. Central Neurocytoma - A Rare Brain Tumor. J Assoc Physicians India. 2018 Apr;66(4):77–8.

[62] Lee SJ, Bui TT, Chen CHJ, Lagman C, Chung LK, Sidhu S, et al. Central Neurocytoma: A Review of Clinical Management and Histopathologic Features. Brain Tumor Res Treat. 2016;4(2):49.

[63] Ravikanth R. Neuroradiological and histopathological findings of intraventricular central neurocytoma. CHRISMED J Health Res. 2017;4(2):125.

#### *Lesions at the Foramen of Monro Causing Obstructive Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99594*

[64] Marri M, Ahmad I, Ahmad K, Ashfaq Z. Central neurocytoma of the third ventricle: Case report and treatment review. Egyptian Journal of Basic and Applied Sciences. 2017 Dec;4 (4):361–5.

[65] Chen C-L, Shen C-C, Wang J, Lu C-H, Lee H-T. Central neurocytoma: a clinical, radiological and pathological study of nine cases. Clin Neurol Neurosurg. 2008 Feb;110(2):129–36.

[66] Atalay B, Yilmaz C, Cekinmez M, Altinors N, Caner H. Treatment of hydrocephalus with functionally isolated ventricles. Acta Neurochir (Wien). 2006 Dec;148(12):1293–6.

[67] Jain A, Amin AG, Jain P, Burger P, Jallo GI, Lim M, et al. Subependymoma: clinical features and surgical outcomes. Neurological Research. 2012 Sep;34(7): 677–84.

[68] Hernandez-Duran S, Yeh-Hsieh T-Y, Salazar-Araya C. Pedunculated intraventricular subependymoma: Review of the literature and illustration of classical presentation through a clinical case. Surg Neurol Int. 2014;5(1):117.

[69] Varma A, Giraldi D, Mills S, Brodbelt AR, Jenkinson MD. Surgical management and long-term outcome of intracranial subependymoma. Acta Neurochir. 2018 Sep;160(9):1793–9.

[70] Schroeder J, LeFever D, Entezami P, Mrak RE. Multiple supratentorial subependymomas causing obstructive hydrocephalus. BMJ Case Reports. 2017 Jun 3;bcr-2016-215625.

[71] Gomez-Ruiz N, Polidura MC, Crespo Rodriguez AM, Arrazola García J. Idiopathic stenosis of foramina of Monro in an asymptomatic adult patient: a rare entity radiologists should be aware of. BJR|case reports. 2020 Jun; 6(2):20190102.

[72] Jaiswal S, Behari S, Jain V, Vij M, Mehrotra A, Kumar B, et al. Choroid

plexus tumors: A clinico-pathological and neuro-radiological study of 23 cases. Asian J Neurosurg. 2013;8(1):29.

[73] Boruah DK, Arora M, Prakash A, Baishya H, Chakraborty P. IDIOPATHIC UNILATERAL FORAMEN OF MONRO STENOSIS: NEUROIMAGING FINDINGS IN THREE PATIENTS. jebmh. 2016 Apr 28;3(34):1673–5.

[74] Kalhorn SP, Strom RG, Harter DH. Idiopathic bilateral stenosis of the foramina of Monro treated using endoscopic foraminoplasty and septostomy. FOC. 2011 Apr;30(4):E5.

[75] Cannon DM, Mohindra P, Gondi V, Kruser TJ, Kozak KR. Choroid plexus tumor epidemiology and outcomes: implications for surgical and radiotherapeutic management. J Neurooncol. 2015 Jan;121(1):151–7.

[76] Lam S, Lin Y, Cherian J, Qadri U, Harris DA, Melkonian S, et al. Choroid Plexus Tumors in Children: A Population-Based Study. Pediatr Neurosurg. 2013;49(6):331–8.

[77] Giammattei L, Aureli V, Daniel R-T, Messerer M. Neuroendoscopic septostomy: Indications and surgical technique. Neurochirurgie. 2018 Jun;64 (3):190–3.

[78] Hamada H, Hayashi N, Kurimoto M, Umemura K, Hirashima Y, Endo S. Neuroendoscopic septostomy for isolated lateral ventricle. Neurol Med Chir (Tokyo). 2003 Dec;43(12):582–7; discussion 588.

[79] Roth J, Olasunkanmi A, Rubinson K, Wisoff JH. Septal vein symmetry: implications for endoscopic septum pellucidotomy. Neurosurgery. 2010 Dec;67(2 Suppl Operative):395–401.

[80] Sun MZ, Oh MC, Ivan ME, Kaur G, Safaee M, Kim JM, et al. Current management of choroid plexus carcinomas. Neurosurg Rev. 2014 Apr; 37(2):179–92.

[81] Menon G, Nair S, Baldawa S, Rao R, Krishnakumar K, Gopalakrishnan C. Choroid plexus tumors: An institutional series of 25 patients. Neurol India. 2010; 58(3):429.

[82] Tubbs RS, Oakes P, Maran IS, Salib C, Loukas M. The foramen of Monro: a review of its anatomy, history, pathology, and surgery. Childs Nerv Syst. 2014 Oct;30(10):1645–9.

[83] Oertel JMK, Schroeder HWS, Gaab MR. Endoscopic stomy of the septum pellucidum: indications, technique, and results. Neurosurgery. 2009 Mar;64(3): 482–91; discussion 491-493.

[84] Aldana PR, Kestle JRW, Brockmeyer DL, Walker ML. Results of endoscopic septal fenestration in the treatment of isolated ventricular hydrocephalus. Pediatr Neurosurg. 2003 Jun;38(6):286–94.

[85] Oi S, Enchev Y. Neuroendoscopic foraminal plasty of foramen of Monro. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2008 Sep 1;24: 933–42.

Section 4 Infection

#### **Chapter 6**

### Infections in CSF Shunts and External Ventricular Drainage

*Roger Bayston*

#### **Abstract**

Infection in those with hydrocephalus shunts or external drains (EVDs) can cause serious central nervous system damage with lasting sequelae. The infections usually involve bacterial colonisation and biofilm formation in the catheters. The nature and sources of pathogens and preventive measures are discussed. The risks of infection in shunts and EVDs is different. Infection in shunts is almost always initiated at their insertion or revision (exceptions are described). In contrast, in EVDs, the risk of infection persists throughout their use. The pathogen profile is also different. These factors are important considerations when planning preventive measures. Newer strategies such as antimicrobial catheters are discussed. Diagnosis of EVD infections in an already ill patient is difficult but guidelines can be useful. Treatment of the shunt and EVD infections are also addressed, with reference to modes and routes of antibiotic administration.

**Keywords:** Hydrocephalus, shunt, external ventricular drain, infection, biofilm, diagnosis, treatment, prevention, prophylactic antibiotics, antimicrobial catheters

#### **1. Introduction**

Though several historical attempts had been made to drain excess cerebrospinal fluid (CSF) in cases of hydrocephalus, this remained largely unsuccessful until the advent of valved shunting devices in the 1950's in USA. More recently endoscopic third ventriculostomy has been used in selected patients, but shunting is still the usual method of treatment of hydrocephalus. In patients with raised intracranial pressure due to trauma, malignancy or haemorrhage, where it is hoped the situation is temporary, external ventricular drainage (EVD) is often used. This temporary method of control of intracranial pressure is also used after shunt removal for infection, before insertion of a new shunt. The risks for infection in the two modes of treatment are different.

Infection in shunts appeared soon after they became more widely used [1], though for some time their cause and treatment remained poorly understood, until it was realised in the early 1970's that most were caused by a bacterium, *Staphylococcus epidermidis*, that hitherto had been considered a harmless commensal and common culture contaminant [2]. The mechanisms of infection and reasons for difficulty in treatment have been clarified over the subsequent decades.

EVD has a very long history, but infection remained a major problem until the introduction of sterile closed systems of drainage in 1941 [3]. It is still a matter of

concern and more recent increases in infections due to multi-drug-resistant (MDR) bacteria have exacerbated this.

Infections in shunts lead to repeated operations and courses of antibiotics and can lead to further cognitive impairment. Infections in EVDs lead to longer hospital stay, courses of antibiotics, and worse overall neurosurgical outcomes. In both cases death can result. Prompt diagnosis and appropriate treatment are essential, and prevention should be the primary goal. These can be achieved best with an understanding of the underlying science.

#### **2. Aetiology and incidence**

Infection rates have fallen in both shunting and EVD since the 1970's when up to 23% of shunts were reported as becoming infected [4, 5]. More recent rates for shunt infection have been below 10%, with 6% reported in a clinical trial [6]. However, it has been clear for some time that the infection rate in infants shunted when less than 6 months of age is significantly higher [7, 8] sometimes approaching 15–20% of operations [9].

The reported infection rate in EVDs is very variable, mainly due to difficulties in diagnosis, diagnostic criteria used and significant differences in underlying pathologies between patient groups studied. Earlier studies reported higher rates, 15–23% [10, 11] while slightly later studies reported 7.5% more in keeping with our own observations [12, 13].

#### **2.1 Causative organisms in shunt infection**

Since the first reports of shunt infection, staphylococci have predominated in shunt infection, with the majority being coagulase – negative staphylococci (CoNS). Of these, most are *Staphylococcus epidermidis*. A minority of staphylococci are *Staphylococcus aureus*. The proportion of these that are methicillin- resistant (MRSA) varies between countries according to national MRSA epidemiology [14], but in most countries especially The Netherlands, Scandinavia and United Kingdom, the proportion of MRSA in shunt infections is low [15]. However, methicillin resistance in CoNS is now common [16, 17]. Another important shunt pathogen is *Cutibacterium* (*Propionibacterium*) *acnes* [18, 19], found mainly in adolescents and adults. This bacterium is under-reported and probably accounts for some of the "culture-negative" shunt infections, as it is anaerobic and slow-growing, taking up to 14 days to appear in culture. Infection with gram negative bacteria such as *Escherichia coli* and *Klebsiella pneumoniae* is less common [15, 16, 20] and probably occurs more commonly in shunted infants than in adults [21].

#### **2.2 Causative organisms in EVD infection**

Most cases of ventriculitis associated with EVD use are caused by staphylococci [13, 22, 23] but there is evidence that the proportion of gram negative bacteria might be increasing. Chatzi et al. [24] reported 81% of their EVD infections were due to MDR gram negative bacteria, mainly *Acinetobacter baumannii*; similar proportions were reported by others [25, 26]. Another matter of concern is the increase in enterococcal infections, reflecting the rise of this MDR gram positive bacterium in general surgical site infections. Notable differences between pathogens in shunts and EVDs are the increasing proportion of MDR gram negative bacteria and the occurrence of polymicrobial infections in EVD, uncommon in shunts.

#### **3. Mechanisms of infection**

#### **3.1 Shunts**

The main source of pathogens in shunts is the patient's skin [8, 27]. Skin commensals such as CoNS and *C acnes* cannot be eradicated by skin preparation, and they easily enter the incision where they are able to gain access to the shunt and possibly the ventricular system during shunt insertion. Once inside the shunt tubing, they attach to the surface of the silicone, after which they begin to proliferate. This proliferation is slow, because the carbon and nitrogen sources in CSF are insufficient to support vigorous bacterial growth, and in particular it has a very low iron content [28]. However, the plaques of bacteria eventually develop into a biofilm. Biofilms are communities of micro-organisms usually attached to a surface, and they are very common in device infections and in the environment. They are also the preferred mode of growth, rather than the very artificial growth conditions applied in the laboratory. It is interesting that the first report of a biofilm in a medical device was from a shunt infection [29]. This early report was produced in response to the need to explain why antibiotic treatment, shown to be effective against shunt pathogens in the laboratory, was ineffective in treating shunt infections. It is now generally accepted that biofilms explain this difficulty, which is found in infections in other implants. The early report postulated that the biofilm structure was maintained by a glycosaminoglycan produced by the bacteria, and that antibiotics were unable to penetrate this effectively. Further research has confirmed the chemistry of the biofilm matrix (though it is now accepted that other components are present). Later studies have confirmed the presence of bacterial biofilms in infected shunts [30, 31]. It is now realised that most antibiotics can penetrate bacterial biofilms effectively [32], but that they fail to kill the constituent bacteria [33–35]. This is because, when bacteria attach to a surface and develop a biofilm, they change their metabolism in order to conserve energy, and this involves downregulating all inessential functions such as cell wall synthesis, most protein synthesis and DNA replication. All these are target sites for common antibiotics, and the concentration of antibiotic needed to even reduce the numbers of biofilm bacteria is 500 to 1000 fold higher than that found in the laboratory [32]. This explains why antibiotic treatment alone is usually ineffective against biofilm infections.

Bacteria are shed from biofilms and this is one way in which they might reach the ventricular system, but bacteria also spread along the inside surfaces of the tubing, and they might also be introduced from the incision during shunt insertion.

#### **3.2 EVD**

EVD infections also involve biofilm formation inside the tubing as well as externally to it in the subcutaneous tunnel, and all shunt and EVD pathogens including *C acnes* and *Acinetobacter baumannii* produce biofilms [36, 37].

#### **3.3 Periods of risk for infection**

Generally shunts are at risk of infection only at insertion or revision, but exceptions are postoperative CSF leak from the incision, and later skin erosion over the shunt or perforation of abdominal viscus. Skin erosion might be due to pressure in a debilitated patient, or to poor tissue coverage and skin health in premature infants, or to malnutrition. The viscus most often perforated by the lower catheter is the

intestine. Reports in the literature often concern children and surprisingly, many are brought to the emergency room by parents worried that they have a parasitic infection, based on the lower catheter protruding from the anus [38]. Unlikely though this may seem, we have also seen two similar cases. There are often several bacteria of enteric origin, including anaerobes, in the CSF but the patients are often not as ill as might be expected.

It is generally agreed that the risk to shunts from bacteraemia during dental treatment is extremely small and does not warrant antibiotic prophylaxis. Haematogenous infection in both VP and VA shunts is very uncommon.

The period of risk for EVDs is very different. Access by skin bacteria is possible during insertion of the EVD, but the main risk extends for the time the EVD is in place, and is from skin bacteria that migrate from the exit site, from interventions such as CSF sampling and drug administration, flushing for blockage and changes of collection system.

#### **4. Diagnosis**

#### **4.1 Shunt infections**

The features of infection are different in VP and VA shunts. The discharge of bacteria and inflammatory products from an infected VP shunt into the peritoneal cavity triggers a local inflammatory response that often results in obstruction of the outflow of CSF. Sometimes this involves the greater omentum, and a CSF-filled cyst is formed around the end of the shunt [39]. This inflammatory response causes distal-end blockage of the shunt and return of the symptoms of hydrocephalus. This is the main reason for the important difference in time of presentation between infected VP and VA shunts: VP shunt infections usually present within months of operation, while VA shunt infections can present years later. However, CSF pseudocysts can present many years after shunt insertion with no evidence of infection [40].

In view of the presenting symptoms in VP shunt infection being those of raised intracranial pressure, it is important to distinguish between a non-infected blockage and one arising from shunt infection. Features of VP shunt infection include fever, headache, vomiting and irritability, though all of these are variable in consistency and can be due to non-infective obstruction. If the symptoms appear within 6–8 months of insertion or revision, this increases the likelihood of infection. If there is erythema over the catheter track then this is an important sign, but it is not always present. Abdominal ultrasound may show adhesions or cyst formation. Shunt aspiration will reveal bacteria on gram film and/or culture, but will not always show raised white cell count or other CSF abnormalities. In the absence of clear indications, there is often reluctance to aspirate the shunt due to concern for introduction of infection, but this risk is slight. Blood culture is usually negative. Blood C-reactive protein (CRP) is useful as it is often raised as part of the tissue inflammatory response. The features of VP shunt infection therefore include:

Presentation <6-8 months of operation Symptoms of shunt obstruction Erythema over the catheter track Raised C-reactive protein Pyrexia Bacteria in gram stain and culture of aspirated CSF

Gram film examination is useful even if the CSF appears to be clear to the naked eye, as if bacteria can be seen it can make an early diagnosis irrespective of culture results. If culture is negative in the presence of a positive gram film then further measures can be taken such as extended anaerobic culture.

As not all VP shunt infections are contracted at operation, there will be some resulting from skin erosion over the valve or perforation of abdominal viscus but these are uncommon and the diagnosis is usually obvious. Haematogenous shunt infections are extremely rare. "Late" infections sometimes occur, due especially to *C acnes*, but those due to *Streptococcus pneumoniae*, *Neisseria meningitidis* or *Haemophilus influenzae* are almost always community-acquired meningitis in a person with a shunt, not a shunt infection, and this has important implications for treatment.

Presentation of VA shunt infection is often also within a few months of operation but in this case it can extend to several years later, leading to the unfounded suspicion that these infections are not contracted at surgery. Those VA shunt infections that present after more than 1–2 years are sometimes associated with immune complex disease. Here, the bacterial antigen discharging from the shunt into the bloodstream provokes an antibody response, and eventually the concentrations of circulating antigen and antibody combine into insoluble complexes that are deposited mainly on basement membranes [41, 42]. The skin, lungs, joints and renal glomerulae are particularly affected [43]. VA shunt infections can therefore present as chronic skin lesions (some haemorrhagic), chronic non-productive cough, swollen painful joints or haematuria. This often leads to initial referral to dermatology, respiratory medicine, rheumatology [44], orthopaedics and nephrology [45], and the diagnosis of shunt infection is sometimes missed or delayed. The causative bacteria in such cases are usually either CoNS or *C acnes*. Immune complex disease usually resolves on shunt removal.

Again aspiration of CSF from the shunt reservoir usually reveals the infecting bacterium. Blood cultures are usually positive but in very longstanding cases the pathogen might be non-culturable, or might appear as the biofilm phenotype known as small colony variants (SCV) which can be difficult to identify in the clinical laboratory [46, 47]. Iron-unresponsive anaemia is often a feature, and complement C3 and C4 levels are usually low due to complement consumption. CRP is often normal. An antibody assay has been used to diagnose late-presenting VA shunt infection [48, 49].

#### **4.2 EVD infection**

Diagnosis of infection in EVDs is often difficult. Features consistent with a diagnosis of ventriculitis are often present in patients with traumatic brain injury or stroke, and fever, with raised CSF white cell count, raised CSF protein level, disturbance of consciousness, Glasgow Coma Score, and inflammatory markers such as CRP are not helpful [50, 51]. In order to overcome the problem of raised white blood cell counts in patients with blood in the CSF, an index has been proposed, based on comparison of white cells and red cells in CSF and blood [52] but the number of patients in their study was small. A raised level of soluble Triggering Receptor Expressed on Myeloid cells (s-TREM) in CSF has been reported to be a reliable marker of ventriculitis even in the presence of haemorrhage [53] and this merits further investigation.

However, a positive culture result from CSF has been held to be the "gold standard," yet this is fraught with problems. Many isolates are skin commensals, and might be either pathogens or contaminants, or might be colonising the distal parts of the ventricular catheter but absent from the ventricles. If a recognised pathogen such as *S aureus* or *A baumannii* is isolated then this is generally taken as a reason to begin definitive treatment, but more than a single isolate of the same strain of CoNS is usually required. Isolates from broth cultures alone should usually be disregarded as likely contaminants, and broth cultures are generally unhelpful. Some have advocated daily CSF aspiration and examination [54] but this has not been found to be reliable in diagnosing or predicting ventriculitis [55], and has been identified as a risk factor for EVD infection. Therefore, in addition to a positive CSF culture, the Infectious Diseases Society of America (IDSA) recommendation is: "*New* headache, fever, evidence of meningeal irritation, seizures, and/or *worsening* mental status are suggestive of ventriculitis or meningitis in the setting of recent trauma or neurosurgery (strong, moderate evidence)" [56]. This guidance applies the need for the feature to be "new" and this is an important consideration in those patients already showing non-specific symptoms due to their underlying pathology.

#### **5. Treatment**

#### **5.1 Shunt infections**

There are several obstacles in the way of successful treatment of shunt infections. Though in most institutions, MRSA is not a common shunt pathogen, many CoNS are multi-resistant including to methicillin and other beta-lactam antibiotics. Another problem is the poor CSF penetration of most antibiotics given intravenously [57] so CSF levels are below the minimum bactericidal concentration (MBC). A third problem is the presence of shunt pathogens as biofilms in the catheter, as eradication of these requires up to 1000 times more antibiotic than the MBC measured in the laboratory [32]. The best chance of successful treatment of shunt infection is therefore shunt removal followed by a course of antibiotics and usually EVD before replacement with a new shunt if required [58]. This topic has been further confirmed by a review by James et al. [59]. A study in children showed 88% first-time cure using shunt removal, antibiotics and EVD, a lower success rate with an immediate shunt replacement protocol, but only 33% success with antibiotics and no shunt removal [60]. In many such studies there is also a disturbingly high mortality rate in those managed with shunt retention. Once the shunt is removed, this leaves a residue of infection in the ventricular system, and as it has arisen from the biofilm in the catheters it is likely to exhibit the biofilm phenotype and have a raised MBC. However, the problem of CSF penetration now becomes paramount. Ventriculitis caused by CoNS or *C acnes* does not give rise to vigorous inflammatory response [61], and this limits access of antibiotics to the CSF. Several factors apart from inflammation also influence the penetration of antibiotics into CSF [57]. Many antibiotics that could be used to treat ventriculitis fail to achieve sufficient concentrations in the CSF [62–64], and this has led to consideration of additional intraventricular administration via EVD [65]. Such a protocol was recommended by the British Society for Antimicrobial Chemotherapy [66] for staphylococcal infections, consisting of intraventricular vancomycin 20 mg daily, and oral or intravenous (IV) rifampicin 300 mg twice daily (15 mg/kg daily for children). The protocol has been shown to reduce the risk of relapse and to shorten the course of treatment needed [67, 68]. However, the association of variable to low antibiotic penetration with clinical failure has been questioned [69], but much of the information on antibiotic penetration into the CSF comes from patients with meningitis, and it is accepted that in ventriculitis the penetration is lower, especially when staphylococci are involved. A general principle is that if CSF antibiotic levels that reach the MIC can be achieved by intravenous administration, then this is sufficient, but the MBC is

#### *Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

probably more important and this needs to be 5–8 times the MIC to ensure clinical success [70]. It is generally agreed that intraventricular administration of vancomycin is safe, irrespective of CSF levels, which can reach 100 mg/L, though some have advocated monitoring of CSF levels and dosage adjustment [68], which we have not found necessary. This is not necessarily true of all antibiotics: gentamicin CSF trough levels must be maintained below 5–20 mg/L [71], and betalactams should not be given by the intraventricular route due to neurotoxicity [72].

Though the general principle is that successful management of shunt infection can be best achieved by shunt removal, linezolid, an oxazolidinone antibiotic, might offer some prospect of retaining an infected functioning shunt due to its excellent CSF penetration and its anti-biofilm activity. An in vitro study has shown that linezolid in concentrations achievable in CSF can eradicate staphylococcal biofilms, including those of MRSA, from shunt catheters [73]. Linezolid gives high CSF levels even after oral administration [74, 75] and it has been used successfully in a small number of cases of shunt infection. Success has been achieved against vancomycin partially – resistant MRSA in shunt infection with shunt removal [76, 77]. In some cases it has been used without shunt removal. One case due to meticillin-resistant CoNS responded to oral linezolid without shunt removal after failed therapy with IV vancomycin and cefotaxime [78], and a further two, one due to MRSA and the other to meticillin-resistant CoNS, were initially unsuccessfully treated with IV vancomycin and ceftriaxone, but responded without shunt removal after IV linezolid. Further trials of this mode of management are urgently needed.

An exception to the rule that shunt removal should be the management of choice applies to those with a shunt who contract community-acquired meningitis, due to *S pneumoniae*, *H influenzae* or *N meningitidis*. As noted above, these are not true shunt infections, and the bacteria appear unable to colonise the shunt in the same way as other organisms. Clinical experience has shown that a conservative approach consisting of usual treatment for meningitis is almost always successful, and the patients usually recover quickly [79–83].

#### **5.2 EVD infections**

The general principles of treatment of shunt infections apply to EVD-associated ventriculitis, in that bacterial biofilms are involved and there may be difficulty in achieving sufficiently high CSF antibiotic levels during IV administration. An important difference from shunt infections is the much higher proportion of infections caused by gram negative bacteria, many of which are multi – drug - resistant. These include *K pneumoniae*, *A baumannii* and *Pseudomonas aeruginosa*, though the last are less common.

As soon as a diagnosis of certain or probable ventriculitis is made the EVD catheter should be removed. Failure to remove the infected EVD catheter was identified as a significant risk for treatment failure and mortality [84]. Once a new EVD catheter has been placed, appropriate antibiotic treatment should begin, and this should be guided by laboratory identification and antibiotic susceptibilities. IV colistin does not reliably result in sufficient CSF levels [85]. Again the question of IV or intraventricular administration or both arises, but the EVD makes intraventricular administration (IVT) easier. Recent guidelines from the Neurocritical Care Society [86] recommend the use of IVT "…in patients who fail to respond to IV antimicrobials alone or when organisms have high MICs to antimicrobials that do not achieve high CSF concentrations, especially MDR organisms." In a study of 31 cases, caused mainly by *Enterobacter* spp., *Ps aeruginosa* or *Stenotrophomonas* (*Xanthomonas*) *maltophilia*, the 13 cases which received IVT gentamicin as well as IV antibiotics had a higher cure rate and a lower relapse rate (0/13 vs. 6/18) [71]. None of these cases

were due to *A baumannii*, which is often susceptible only to colistin. In a small study of two groups of nine patients with ventriculitis due to *A baumannii*, one group had both IV and IVT colistin while the other had IV only [87]. CSF sterilisation was achieved in 100% of those having IVT therapy (vs 33%) and the five deaths due to ventriculitis occurred in the IV - only group but none in the IV + IVT group. Cure is also reported when IVT colistin is used without IV colistin [88], so avoiding some of the systemic toxicity. Some strains of *A baumannii* are now resistant to colistin, but there is in vitro evidence of useful synergy with rifampicin, which suppressed emergence of colistin resistance as well as killing of a colistin-resistant strain. A combination of colistin and rifampicin was effective against colistin – resistant strains of *K pneumoniae* in vitro [89]. There are a few clinical reports of synergy with rifampicin, and especially if the mutual protection against resistance can be confirmed, this might improve prospects of treatment.

#### **6. Risk factors and prevention**

#### **6.1 Shunts**

Most analyses of risks for shunt infection identify shunting below the age of 1 year as a factor [8, 14, 90]. Young age or prematurity at shunting and intraventricular haemorrhage have been identified on univariate analysis but only young age on multivariate analysis, suggesting that age was the factor and the other two were dependent factors [91]. Why this should be has been debated. The main source of shunt pathogens being the patient's skin, any factor that influences this adversely might be expected to increase the risk. Premature infants have a high risk of intraventricular haemorrhage, and they often have been in hospital separated from their mothers before shunting, and it has been found that their skin bacterial densities were significantly higher, and that their skin bacteria were more likely to be able to adhere to silicone [8]. Loss of close maternal contact means that the babies become colonised with hospital strains of staphylococci that appear to be more virulent as shunt pathogens.

CSF protein content at the time of shunt insertion has been suspected to be a risk factor for infection, but this has been discounted [92, 93] though it may indicate a higher risk of re-infection after treatment of an initial shunt infection [94], possibly suggesting an incomplete eradication of the initial infection.

Intra-operative interventions to reduce the risk of shunt infection include "bundles" which are widely recognised in infection control and prevention to be effective if correctly applied. Choux et al. [95] introduced a protocol consisting of a range of sixteen measures such as restricting the number of people in the operating theatre to four, shunt insertion first thing in the morning, neonates before older children, limiting duration of surgery to 20–40 minutes, as well as technical surgical stipulations regarding a no-touch technique for the shunt, haemostasis and wound closure. On applying this to 1197 procedures he reduced the infection rate to 0.17%. Similar measures have been introduced such as use of a dedicated neurosurgical theatre, all passage into and out of the theatre prohibited, and no more than seven people present. Skin preparation used two separate applications, and both drapes and the peritoneal catheter introducers were smeared with povidone iodine which was also used to irrigate the incision and the surgeon's gloves. Using this protocol the infection rate was 0.57% [96]. The Hydrocephalus Clinical Research Network has also published protocols aimed at reducing shunt infection [97]. The refined protocol has eight essential steps, reduced from eleven in earlier versions. Results of 1935 procedures at eight centres showed an overall infection

#### *Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

rate of 6% with 77% compliance with the protocol. Infection rates differed significantly between centres in full compliance and those which were not (5% vs. 8.7%, p = 0.005). Others have used similar protocols [98, 99]. One problem with these protocols is that they are difficult to compare, and almost none of the measures are evidence-based. However, this is considered acceptable in view of the usual fall in infection rate when they are introduced. An important aspect of bundles is mentioned by Choux [95] and emphasised by Choksey [96]: to be fully effective they must be made compulsory and violations must be detected and remedied. Though many components of the protocols are "common sense" measures such as rigorous asepsis, their main mechanism might be behavioural change in personnel, and this is not necessarily teachable and exportable to other institutions. Interestingly, few "bundles" mention the possible use of laminar flow ventilation in the OR. Choksey [96] used a laminar flow hood, while Pirotte [98] did not: both reduced their shunt infection rate to <1%. Though laminar flow ventilation was recommended for arthroplasty, recently several centres have reported either no benefit, or in some cases a small but significant increase in infection rate [100, 101].

However, certain constituent measures deserve attention. Many use antiseptics to either irrigate the incision or to isolate the wound skin edges [102], a measure suggested some time ago [103–105]. It is clear that skin bacteria enter the incision from this source [27, 106]. It is important that the contribution of patient skin bacteria is minimised by avoiding contact with skin edges by gloves, instruments or shunt components, and measures to isolate them might be helpful in this regard. Surgeons' gloves become contaminated early in the operation and double – gloving is recommended so that the contaminated outer pair can be discarded before the shunt is handled. At this point it is advisable to rinse the gloved hands in antiseptic before touching the shunt, or to use a "no - touch" technique. Double gloving was introduced in a sequential study but without removal of the outer pair, as the presumption was that the source of shunt pathogens was glove perforation [107]. However, the diagnostic criteria in this study are in doubt as most of the "infections" were culture-negative, and the change of outer glove remains the most important measure.

It is important to remember that, irrespective of the antiseptic used, pre-operative skin preparation does not sterilise the skin. Much of the literature discusses the merits of various antiseptics but relies on skin swabs for evaluation, though most of the skin flora reside in the glands and follicles in the dermis [108]. When full thickness skin biopsies have been used they have shown that, irrespective of the agent used, while the numbers of bacteria can be reduced they cannot be eradicated, and they will re-emerge during surgery. The numbers of bacteria required to cause an infection in the presence of a biomaterial such as a shunt are at least ten thousand – fold fewer that those needed in its absence [109]. While there is little evidence that chlorhexidine is better than povidone iodine it is clear that the alcohol version of either is superior to the aqueous version, and it is possible that the alcohol component is the major antiseptic factor [110].

Adhesive drapes are not of proven benefit in preventing the skin bacteria from entering the incision, even when iodine-treated. They are, however, useful in covering the cloth drapes and providing a dry aseptic surface. Shaving of head hair is now accepted as unnecessary and possible a risk for infection [111], and clipping should be carried out with scissors if necessary, and the hair prepared as for the skin.

The use of pre-operative prophylactic antibiotics is controversial [112]. Most of the reports, including where infection rates are considered unacceptably high, are from centres using antibiotic prophylaxis. Again the issue of timely penetration of IV antibiotics into the CSF is important, and most studies have found ineffective peri-operative levels. They also do not act rapidly enough to affect the numbers

of skin bacteria in the incision during shunt insertion, and while this remains as a risk to the shunt, they might act to reduce postoperative wound infection. Intraoperative IVT vancomycin has not been shown to reduce shunt infection rate, probably due to the slow kill rate, but an interesting finding has been reported [113]. In this study, when only IV antibiotics were used, the infection rate was 6.74%; when IVT gentamicin was added, the infection rate was similar at 5.45%; when both IVT gentamicin and IVT vancomycin were used together, the infection rate fell to 0.41%. This interesting observation needs to be confirmed.

Another approach is the use of triclosan - coated sutures [114]. Though numbers of patients were small, when triclosan - coated sutures were compared with plain sutures in a randomised controlled trial, there was a reduction in shunt infection rate from 21% to 4.3%. Some, but not all, infections were postoperative wound suppurations.

There is increasing use of topical application of vancomycin powder before fascial closure in spinal surgery with significant infection reduction and low toxicity compared to IV vancomycin prophylaxis. The same approach has been used in a small uncontrolled series of shunt insertions with a reduction of shunt infection from 5.8% to 0% though the postoperative revision rate was unaltered [115]. The diagnostic criteria for shunt infection were not clear but this use of vancomycin is safe and effective in spine surgery and might be useful in shunt surgery.

It appears that attempts to prevent skin bacteria from accessing the shunt during surgery are only partly successful, and further measures are needed. Systemic prophylactic antibiotics are well researched but an unacceptably high infection rate remains. This has led to development of shunt materials intended to reduce bacterial colonisation of the catheters and therefore shunt infection.

Antimicrobial shunt catheters have been available for some time. Coating the shunt surface with a hydrophilic material as in the Bioglide catheter is intended to reduce bacterial attachment, and if the catheter is soaked in a solution of antibiotic then this has been claimed to add to the effect. The catheters have been evaluated in vitro using rigorous clinically predictive tests and though they did reduce bacterial attachment they were found not to be effective in preventing colonisation by staphylococci [116] even when soaked in gentamicin or vancomycin [117]. Clinical assessment [118, 119] has confirmed this. Silver in various forms has been promoted as a useful antimicrobial for implantable devices, but variable results have been reported. Shunt catheters impregnated with nanoparticulate silver, a particularly active form, have been marketed. Again an in vitro evaluation has found that they failed to prevent colonisation by staphylococci, *C acnes* or *E coli*, and this has been confirmed in a large randomised controlled clinical trial [6]. Silver undoubtedly has antibacterial activity, but the concentrations of silver ions needed are also cytotoxic, and silver ions combine avidly with chloride and protein. As it is likely that a prolonged duration of antimicrobial activity of at least a few days is required to prevent survival and regrowth of bacteria in shunt catheters, and as antimicrobial coatings are easily removed by CSF flow and obliterated by protein deposition, a system is needed that maintains an antimicrobial surface. One such system distributes molecules of antimicrobials throughout the silicone matrix, allowing them to migrate freely to replenish the surface when CSF removes molecules from there, so maintaining an antimicrobial surface for sufficient time, in this case for over 40 days [120]. This system is unaffected by protein. When the clinically predictive tests are applied in vitro, the antimicrobial catheters remain free of bacterial colonisation even after serial high - dose bacterial challenge. Clinical studies have demonstrated reduction in shunt infection [121] and considerable cost savings [122] as well as reduction in systemic antibiotic use. A large randomised controlled trial comparing antimicrobial, silver and plain shunts found that the antimicrobial

#### *Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

shunts gave a statistically significant reduction in shunt infections while results for silver-processed shunts were indistinguishable from those of plain catheters [6].

The question of whether to use prophylactic antibiotics for people with shunts who undergo dental treatment has been raised frequently. Studies have shown that the risk is negligible, and there is no evidence that bacteria of oral origin have caused shunt infections, whether VP or VA, after dental treatment [123]. It is likely that antibiotic prophylaxis used in this way treats the dental practitioner but is of no benefit to the patient.

#### **6.2 EVDs**

Whether risks of infection are different if the EVD is inserted in the intensive care unit or the operating room (OR) is debatable. In one study there were fewer infections in those inserted in the OR but this difference was not statistically significant [124]. While the OR might offer a more controllable aseptic environment, transfer of acutely ill patients to the OR for this purpose might pose additional risks [125].

Periprocedural prophylactic antibiotics are commonly used. However, many centres use prolonged antibiotic prophylaxis throughout the EVD use. Flibotte et al. [126] used either nafcillin or vancomycin but noted that most infections were still due to gram positive pathogens, and that their use of prolonged nafcillin appeared to lead to an increase in resistance to this antibiotic. Wong and Poon [127] reported a comparison of two regimens for prolonged prophylaxis but did not comment on the influence on resistance, but a later study by the same authors [128] using the same regimen found three cases of pseudomembranous colitis due to *Clostridioides difficile*, one of whom required total colectomy. A similar experience was reported [129] reducing the number of *C difficile* infections in the ICU from 19 to 5 by changing the antibiotic prophylaxis regimen from prolonged to peri-procedural with no change in ventriculitis rate. Antimicrobial impregnated EVD catheters were used in both phases of both these studies [128, 129]. In another study comparing prolonged and peri-procedural antibiotics there was no difference in infection rate, the difference being a saving of \$80,000 a year in drug costs [130]. Murphy et al. [131] also compared a period when prolonged antibiotics were used with a period where only periprocedural antibiotics were given; in both periods antimicrobial EVD catheters were used. The infection rate in the periprocedural-only period actually fell from 1.35/1000 catheter days to 0.54/1000 catheter days, though this was not statistically significant. Remarkably, there was a significantly higher rate of bloodstream infections (BSI) and pneumonia (VAP) in the prolonged – antibiotics period, and the drug cost for treating these infections were \$155,253 but there were no cases of BSI or VAP in the second periprocedural - only period.

Antimicrobial catheters have been developed for EVDs as for shunts, though there have been fewer clinical trials. The hydrophilic-coated catheters intended to reduce infection by preventing bacterial attachment have already been discussed; these have not been successful. Silver-processed catheters have shown non-significant results in some clinical studies [132–135]. One three-phase retrospective/ sequential study showed that introduction of silver-processed catheters reduced the infection rate from 3.8% to zero, though due to small numbers this was not statistically significant [136]. A randomised prospective controlled trial comparing silver-processed with plain catheters has reported a significant reduction in ventriculitis from a very high rate of 21.4% to 12.3%, a fall that just met statistical significance p = 0.0427 [137]. A thorough assessment of the value of silver-processed EVD catheters [138] has found no significant overall difference in infection rate in a meta-analysis but did identify a statistically significant reduction in infection due to gram positive bacteria (6.7–2%, p = 0.002). The conclusion was that silver-processed catheters require further evaluation, and that they have no activity against gram negative bacteria. This was confirmed in vitro using the same rigorous clinically – predictive testing used for shunts, when silver-processed EVD catheters were found to show a weak activity against *S epidermidis* but none against gram negative bacteria [139].

An antibiotic-impregnated catheter containing rifampicin and minocycline (VentriClear, Cook Inc) is available in USA, and Bactiseal (Codman Integra Life Sciences) that contains rifampicin and clindamycin, produced by a different process, is available worldwide. A significant (p = 0.002) reduction in ventriculitis has been reported when VentriClear catheters were used, from 9.4% to 1.3% [140]. Harrop et al. [12] carried out a five -phase prospective cohort study. Phase I, the baseline, showed a rate of 6.7%, and the introduction of a standardised protocol in Phase II did not reduce this (8.2%). However, in Phase III the Bactiseal catheter was included, and the infection rate fell to 1% (p = 0.0005). This catheter gave an unacceptable rate of occlusion and its use was discontinued, and reversion to the Phase II protocol showed a return to a 7.6% rate. In Phase V, the VentriClear catheter was introduced and the ventriculitis rate again fell to 0.9% (p = 0.0001). Though a sequential cohort study, this provided strong evidence that both antimicrobial catheters were effective. This was confirmed by a comparison of VentriClear with Bactiseal [141] using alternating 3-month periods when 129 patients received either a VentriClear or a Bactiseal catheter. No cases of ventriculitis were recorded in the study, showing that both were equally effective in this study. No excess of occlusion was recorded with either catheter. A series involving historical controls found a reduction of ventriculitis from 15% in plain catheters to 5% in Bactiseal catheters but this failed to reach statistical significance [142]. Bactiseal was compared with plain EVD catheters in an interesting study in which CSF samples were taken every 2 days, and if culture-positive, irrespective of clinical evidence, the catheter was changed and 10 days of intraventricular antibiotics were given [143]. In this study there were no cases of clinical infection in either group. As with shunts, there is no evidence that antimicrobial-impregnated EVD catheters increase the risk of bacterial resistance, and in reducing the need for systemic antibiotics for prophylaxis and treatment of infections they are likely to contribute to reduction of antimicrobial resistance generally. This has been underlined by three studies in which prolonged systemic antibiotic prophylaxis for EVD has been compared with use of the Bactiseal catheter. In two studies the antimicrobial catheter gave equivalent protection against ventriculitis but avoided the serious risk of *C difficile* infection [128, 129], a known consequence of over-use of antibiotics. In the third study [131] the Bactiseal EVD catheter was used but in one group, prolonged antibiotic prophylaxis were added. There was no difference in ventriculitis rate between the two groups, but there was a significantly higher rate of BSI and VAP, requiring further courses of antibiotics for treatment, again contributing to antimicrobial resistance. While good quality randomised controlled trials are needed for antimicrobial - impregnated EVD catheters, the studies so far strongly suggest that they can reduce the incidence of ventriculitis by gram positive bacteria, but there is currently no EVD catheter available that protects against gram negative bacteria, which are increasing in frequency and importance. An experimental antimicrobial EVD catheter that can protect against colonisation by MDR gram negative bacteria including *A baumannii* has been developed but is not yet clinically available [144].

There is general agreement that the EVD catheter must be tunnelled subcutaneously for approximately 5 cm away from the burr hole, but some prefer to tunnel for much longer. When the exit site was placed in the lower chest or upper abdomen, no infections were reported in the first 16 days. In those 45 requiring EVD for longer,

four developed ventriculitis [145]. In a study using a long tunnel of at least 20 cm an infection rate significantly lower than those reported in the literature using conventional tunnels was noted, though an antimicrobial EVD catheter was also used [146]. However, Leung et al. [147] found no advantage in a longer tunnel.

The infection rate for EVDs is said to rise with duration of use, though this is sometimes contested. The duration of EVD use has frequently been identified as a risk factor for infection. As the increase in infection appears to begin after about 5 days, suggestions have been made that changing the EVD catheter at this stage might avoid the subsequent rise in infection rate [148]. However, this practice has been shown not to help [149, 150] and might increase the risk [151]. The risk for ventriculitis increases in most studies until about 10–12 days then levels off. The message is that the EVD should be removed as soon as possible when no longer needed.

EVD pathogens are more varied, and more likely to be MDR gram negative bacteria than those found in shunts. They might originate on the patient's body surfaces, ears and respiratory tract as broad-spectrum antibiotics given for chest infections and other purposes promote colonisation of these sites with such organisms. The intensive care environment is often a source of such bacteria due to the throughput of very sick patients and heavy use of antibiotics. This environment includes all inanimate surfaces, textiles and water sources [152, 153]. The EVD must be managed with careful attention to aseptic technique, and breaches of the system should be avoided unless absolutely necessary. This includes CSF sampling for monitoring purposes. The practice of daily CSF sampling is said to enable early diagnosis of infection [154, 155], but represents a risk for introduction of infection, and CSF sampling is best confined to cases where there is a suspicion of infection [155].

As with shunts, the introduction of "bundles" has usually been associated with a reduction in infection rate. Korinek et al. [156] developed a bundle protocol and introduced a violation score to monitor it. Their ventriculitis rate fell from 9.9% to 4.6%, and the most significant factors in infected patients were CSF leak and protocol violation, which in the infected cases was 4 times higher p < 0.0001. The value of this approach was also demonstrated by others with a significant fall in infection rate [155, 157]. Importantly, the bundle approach should include full involvement of all personnel involved and should be monitored and regular feedback given on violations and infection rates. Again, not all of the constituents of the bundle are evidence – based and they vary between reports, but the behaviour change brought about by this approach is the most important factor.

#### **7. Conclusions**

Infection in shunting and EVD is often devastating. Prevention is paramount and a greater understanding of the science and the risk factors should inform more effective measures including surgical practice and OR discipline. Antimicrobial catheters are useful in reducing infection in shunts and EVDs, but the problem of gram negative infection needs to be addressed. There should be no delay in instituting effective treatment, including removal of hardware and ensuring adequate levels of antibiotics. Successful first pass treatment should be the goal. Treatment without hardware removal, using relatively new antibiotics, should be thoroughly investigated in view of the potential benefits.

Importantly, the contribution of overuse or misuse of antibiotics to the increasing problem of antimicrobial resistance both locally and globally should be kept in mind.

### **Conflict of interest**

The author is the inventor of the "Bactiseal" antimicrobial catheter, but he has not and does not receive any royalties or other payment. He receives speaker fees from Codman Inc., but not for personal gain and these are paid to his University.

### **Author details**

Roger Bayston

Academic Unit of Injury, Inflammation and Recovery Science, School of Medicine, University of Nottingham, Nottingham, United Kingdom

\*Address all correspondence to: roger.bayston@nottingham.ac.uk

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

#### **References**

[1] Carrington KW. Ventriculovenous shunt using the Holter valve as a treatment of hydrocephalus. J Michigan Med Soc. 1959;58:373-376.

[2] Holt RJ. The classification of staphylococci from colonised ventriculo-atrial shunts. J Clin Pathol.1969;22:475-482.

[3] Ingraham FD, Matson DD, Alexander E, Woods RP. Studies in the treatment of experimental hydrocephalus. J Neuropath Exp Neurol. 1948;7:123-143

[4] Shurtleff DB, Folz EL, Christie D. Ventriculoauriculostomy-associated infection: a 12-year study. J Neurosurg. 1971;35:686-694.

[5] Schoenbaum SC, Gardner P, Shillito J. Infections of cerebrospinal fluid shunts: epidemiology, clinical manifestations and therapy. J Infect Dis. 1975;131:543-552.

[6] Mallucci CL, Jenkinson MD, Conroy EJ, Hartley JC, Brown M, Dalton J, Kearns T, Moitt T, Griffiths MJ, Culeddu G, Solomon T, Hughes D, Gamble C. Antibiotic or silver versus standard ventriculoperitoneal shunts (BASICS): a multicentre, single-blinded, randomised trial and economic evaluation. Lancet. 2019;394:1530-1539. doi.org/10.1016/S0140-6736(19) 31603-4

[7] Renier D, Lacombe J, Pierre-Kahn A, Sainte-Rose C, Hirsch J-F. Factors causing acute shunt infection. J Neurosurg. 1984;61:1072-1078.

[8] Pople IK, Bayston R, Hayward RD. Infection of cerebrospinal fluid shunts in infants: a study of etiological factors. J Neurosurg. 1992;77:29-36.

[9] Kulkani AV, Drake JM, Lambert-Pasculli M. Cerebrospinal fluid shunt infection: a prospective study of risk factors. J Neurosurg. 2001;94: 195-201.

[10] Schade RPS, Schinkel J, Visser LG, van Dijk JMC, Voormolen JHCV, Kuijper EJK. Bacterial meningitis caused by the use of ventricular or lumbar cerebrospinal fluid catheters. J Neurosurg. 2005;102:229-234.

[11] Hoefnagel D, Dammers R, ter Laak-Poort MP, Avezaat CJJ. Risk factors for infections related to external ventricular drainage. Acta Neurosurg (Wien). 2008;150:209-214. DOI 10.1007/s00701-007-1458-9

[12] Scheithauer S, Bürgel U, Bickenbach J, Häfner H, Haase G, Waitschies B, Reinges MHT, Lemmen SW. External ventricular and lumbar drainage -associated meningoventriculitis: prospective analysis of time-dependent infection rates and risk factors. Infection. 2010;38:205-209. DOI: 10.1007/ s15101-010-0006-3

[13] Harrop JS, Sharan AD, Ratcliff J, Prasad S, Jabbour P Evans JJ, Veznedaroglu E, Andrews DW, Maltenfort M, Liebman K, Flomenberg P, Sell B, Baranoski AS, Fonshell C, Reiter D, Rosenwasser RH. Impact of a standardised protocol and antibiotic – impregnated catheters on ventriculostomy infection rates in cerebrovascular patients. Neurosurg. 2010;67:187-191.

[14] Lee JK, Seok JY, Lee JH, Choi EH, Phi JH, Kim SK, Wang KC, Lee HJ. Incidence and risk factors of ventriculoperitoneal shunt infections in children: a study of 333 consecutive shunts in 6 years. J Korean Med Sci. 2012;27:1563-1568

[15] James G, Hartley JC, Morgan RD, Ternier J. Effect of introduction of

antibiotic – impregnated shunt catheters on cerebrospinal fluid shunt infection in children: a large single-center retrospective study. J Neurosurg Pediatr. 2014;13:101-106

[16] Farber SH, Parker SL, Adogwa O, McGirt MJ, Rigamonti D. Effect of antibiotic-impregnated shunts on infection rate in adult hydrocephalus: a single institution's experience. Neurosurg. 2011;69:625-629.DOI: 10.1227/NEU.0b013e31821bc435

[17] Lee MJ, Pottinger PS, Butler-Wu S, Bumgarner RE, Russ SM, Matsen FA. Propionibacterium persists in the skin despite standard surgical preparation. J Bone Joint Surg. 2014;96:1447-1450. DOI: org/10.2106/jbjs.m.01474

[18] Arnell K, Cesarini K, Lagerqvist-Widh A, Wester T, Sjölin J. Cerebrospinal fluid shunt infections in children over a 13-year period: anaerobic cultures and comparison of clinical signs of infection with *Propionibacterium acnes* and with other bacteria. J. Neurosurg. Pediatr. 2008;**1:**366-372.

[19] Thompson TP, Albright AL. *Propionibacterium acnes* infections of cerebrospinal fluid shunts. Child's Nerv Syst. 1998;14:378-380

[20] Conen A, Walti LN, Merlo A, Fluckiger U, Battegay M, Trampuz A. Characteristics and treatment outcome of cerebrospinal fluid shunt-associated infections in adults: a retrospective analysis over an 11 -year period. Clin Infect Dis. 2008;47:73-82. DOI: 10.1086/588298

[21] Arnell K, Enblad P, Wester T, Sjölin J. Treatment of cerebrospinal fluid infections in children using systemic and intraventricular antibiotic therapy in combination with externalization of the ventricular catheter: efficacy in 34 consecutively

treated infections. J Neurosurg Pediatr.2007;107:213-219

[22] Park J, Choi Y-J, Ohk B, Chang H-H. Cerebrospinal fluid leak at percutaneous exit of ventricular catheter as a crucial risk factor for external ventricular drainage-related infection in adult neurosurgical patients. World Neurosurg. 2018;109:e398-e403. DOI. org/10.1016/j.wneu.2017.09.190

[23] Walti LN, Conen A, Coward J, Jost GF, Trampuz A. Characteristics of infections associated with external ventricular drains of cerebrospinal fluid. J Infect. 2013;66:424-431. DOI: 10.1016/j.jinf.2012.12.010

[24] Chatzi M, Karvouniaris M, Makris D, Tsimitrea E, Gatos C, Tasou A, Manzarlis K, Zakinthinos E. Bundle of measures for external cerebral ventricular drainage-associated ventriculitis. Crit Care Med. 2014;41:66- 73. DOI: 10.1097/CCM.0b013e3182 9a70a5

[25] Lyke KE, Obasanjo OO, Williams MA, O'Brien M, Chotani R, Peri TM. Ventriculitis complicating use of intraventricular catheters in adult neurosurgical patients. Clin Infect Dis. 2001;33:2028-2033.

[26] Chi H, Chang K-Y, Chang H-C, Chiu, N-C, Huang F-Y. Infections associated with indwelling ventriculostomy catheters in a teaching hospital. Internat J Infect Dis. 2010;14:e216-e219. DOI: 10.1016/j. ijid.2009.04.0006

[27] Bayston R, Lari J.A study of the sources of infection in colonised shunts. Dev Med Child Neurol. 1974;32:16-22

[28] LeVine SM, Wulser MJ, Lynch SG. Iron quantification in cerebrospinal fluid. Anal Biochem. 1998;265:74-78. DOI: 10.1006/abio.1998.2903

*Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

[29] Bayston R, Penny SR. Excessive production of mucoid substance in Staphylococcus SIIA: a possible factor in colonisation of Holter shunts. Dev Med Child Neurol. 1972;14:25-28

[30] Guevara JA, Zuccaro G, Trevisan A, Denoya CD. Bacterial adhesion to cerebrospinal fluid shunts. J Neurosurg. 1987;67:438-445.

[31] Fux CA, Quigley M, Worel AM, Post C, Zimmerli S, Ehrlich G, Veeh RH. Biofilm-related infections of cerebrospinal fluid shunts. Clin Microbiol Infect. 2006;12:331-337.

[32] Darouiche RO, Dhir A, Miller AJ, Landon GC, Raad II, Musher DM. Vancomycin penetration into biofilm covering infected prostheses and effect on bacteria. J Infect Dis.1994;170: 720-723.

[33] Gilbert P, Maira-Litran T, McBain AJ, Rickard AH, Whyte FW. The physiology and collective recalcitrance of microbial biofilm communities. Adv. Microb. Physiol. 2002;46:202-256.

[34] Duguid IG, Evans E, Brown MRW, Gilbert P. Effect of biofilm culture upon the susceptibility of *Staphylococcus epidermidis* to tobramycin. J Antimicrob Chemother*.* 1992;30, 803-810.

[35] Anwar H, Costerton JW. Effective use of antibiotics in the treatment of biofilm-associated infections. *ASM News Journal* 1992;58, 665-668.

[36] Choi AHK, Slamti L, Avci FY, Pier G, Maira-Litran T. The *pgaABCD* Locus of *Acinetobacter baumannii* Encodes the Production of Poly-beta-1- 6-*N*-Acetylglucosamine, Which Is Critical for Biofilm Formation. J Bacteriol. 2009;191:5953-5963. DOI: 10.1128/JB.00647-09

[37] Bayston R, Ashraf W, Barker-Davies R, Tucker E, Clement R,

Clayton J, Freeeman BJC, Nuradeen B. Biofilm formation by *Propionibacterium acnes* on biomaterials in vitro and in vivo: impact on diagnosis and treatment. J Biomed Mater Res A. 2006;81:705-709. DOI: 10.1002/ jbm.a.31145

[38] Ghritlaharey RK, Budhwani KS, Shrivastava DK, Gupta G, Kushwaha AS, Chanchlani R, Nanda M. Trans-anal protrusion of ventriculoperitoneal shunt catheter with silent bowel perforation: report of ten cases in children. Pediatr Surg Int. 2007;23:575-580.

[39] Bayston R, Spitz L. Infective and cystic causes of malfunction of ventriculoperitoneal shunts. Zeit Kinderchirurg. 1977;22,419-424.

[40] Tamura A, Shida D, Tsutsumi K. Abdominal cerebrospinal fluid pseudocyst occurring 21 years after ventriculoperitoneal shunt placement: a case report. BMC Surg. 2013;13:27. DOI: 10.1186/1471-2482-13-27

[41] Bayston R, Swinden J.The aetiology and prevention of shunt nephritis. Z Kinderchir. 1979.28:377-384

[42] Haffner D, Schinderer F, Aschoff A, Matthias S, Waldherr R, Schärer K. The clinical spectrum of shunt nephritis. Nephrol Dial Transplant. 1997;12:1143- 1148. DOI: 10.1093/ndt/12.6.1143

[43] ter Borg EJ, van Rijswijk MH, Kallenberg CG. Transient arthritis with positive tests for rheumatoid factor as presenting sign of shunt nephritis. Ann Rheum Dis. 1991;50:182-183.

[44] Legoupil N, Ronco P, Berenbaum F. Arthritis-related shunt nephritis in an adult. Rheumatol. 2003;42:698-699.

[45] Vella J, Carmody M, Campbell E, Browne O, Doyle G, Donohoe J. Glomerulonephritis after ventriculoatrial shunt. Q Med J. 1995;88:911-918. [46] Ben-Ami R, Navon-Venezia S, Schwartz D, Carmeli Y. Infection of a Ventriculoatrial Shunt with Phenotypically Variable *Staphylococcus epidermidis* Masquerading as Polymicrobial Bacteremia Due to Various Coagulase-Negative Staphylococci and *Kocuria varians.* J Clin Microbiol. 2003; 2444-2447. DOI: 10/1128/jcm.41,6,2444-2447.2003

[47] Spanu T, Romano L, D'Inzeo T, Masucci L, Albanese A, Papacci F, Marchese E, Sanguinetti M, Fadda G. Recurrent ventriculoperitoneal shunt infection caused by small-colony variants of *Staphylococcus aureus*. Clin Infect Dis. 2005;41:48-52.

[48] Holt RJ. The early serological detection of colonisation by *Staphylococcus epidermidis* of ventriculoatrial shunts. Infection. 1980;8:8-12.

[49] Clayton J, Bayston R, Donald F. Occult ventriculo-atrial shunt infection: a forgotten condition. Cerebrospinal Fluid Res. 2005;2(suppl 1):S23. doi:10.1186/1743-8454-2-S1-S23

[50] Muttaiyah S, Ritchie S, Upton A, Roberts S. Clinical parameters do not predict infection in patients with external ventricular drains: a retrospective observational study of daily cerebrospinal fluid analysis. J Med Microbiol. 2008;57:207-209. DOI 10.1099/jmm.0.47518-0

[51] Beer R, Lackner P, Pfausler B, Schmutzhard E. Nosocomial ventriculitis and meningitis in neurocritical care patients. J Neurol. 2008;255:1617-1624.

[52] Pfausler B, Beer R, Engelhardt K, Kemmler G, Mohsenipour I, Schmutzhard E. Cell index- a new parameter for the early diagnosis of ventriculostomy (external ventricular drainage) – related ventriculitis in patients with intraventricular

hemorrhage? Acta Neurochir (Wien). 2004;146:477-481. DOI 10.1007/ s00701-004-0258-8

[53] Gordon M, Ramirez P, Soriano A, Palomo M, Lopex-Ferraz C, Villareal E,Meseguer S, Gomez MD, Folgado C, Bonatre J. Diagnosing external ventricular drain-related ventriculitis by means of local inflammatory response: soluble triggering receptor expressed on myeloid cells-1. Crit Care. 2014;18:567 DOI.org/10.1186/s13054-014-0567-0

[54] Pfisterer W, Mühlbauer M, Czech T, Reinprecht A. Early diagnosis of external ventricular drainage infection. Results of a prospective study. J Neurol Neurosurg Psychiatr. 2003;74:929-932. DOI: 10.1136/jnnp.74.7.929

[55] Schade RP, Schinkel J, Roelandse FW, Geskus RB, Visser LG, van Dijk JM, Voormolen JHC, van Pelt H, Kuijper EJ. Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis. J Neurosurg. 2006;104:101– 108. DOI: 10.3171/jns.2006.104.1.101

[56] Tunkel AR, Hasbun R, Bhimraj A, Byers K, Kaplan SL, Scheld WM, van der Beek D, Bleck TP, Garton HJL, Zunt JR. 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for healthcare-associated ventriculitis and meningitis. Clin Infect Dis. 2017;64:701-706. doi.org/10.1093/ cid/ciw861

[57] Lutsar I, McCracken GH, Friedland IR. Antibiotic pharmaco dynamics in cerebrospinal fluid. Clin Infect Dis. 1998;27:1117-1129.

[58] James HE, Walsh JW, Wilson HD, Connor JD, Bean JR, Tibbs PA. Prospective randomized study of therapy in cerebrospinal fluid shunt infection. Neurosurg. 1980;7:459-463. *Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

[59] James HE, Bradley JS: Aggressive management of shunt in- fection: combined intravenous and intraventricular antibiotic therapy for twelve or less days. Pediatr Neurosurg. 2008;44:104– 111.

[60] Schreffler RT, Schreffler AJ, Wittler RR. Treatment of cerebrospinal fluid shunt infections: a decision analysis. Pediatr Infect Dis J. 2002;21:632-636.

[61] Sullins AK, Abdel-Rahman SM. Pharmacokinetics of antibacterial agents in the CSF of children and adolescents. Pediatr Drugs. 2013;15:93- 117. DOI: 10.1007/s40272-013-0017-5

[62] Edwards MS, Baker CJ, Butler KM, Mason EO, Laurent JP, Cheek WR. Penetration of cefuroxime into ventricular fluid in cerebrospinal fluid shunt infections. Antimicrob Ag Chemother. 1989;33:1108-1110.

[63] Jorgensen L, ReiterPD, Freeman JE, Winston KR, Fish D, McBride LA, Handler MH. Vancomycin Disposition and Penetration into Ventricular Fluid of the Central Nervous System following Intravenous Therapy in Patients with Cerebrospinal Devices. Pediatr Neurosurg. 2007;43:449-455. DOI: 10.1159/000108786

[64] Pfausler B, Spiss H, Beer R, Kampfl A, Engelhardt K, Schober M, Schmutzhard E. Treatment of staphylococcal ventriculitis associated with external cerebrospinal fluid drains: a prospective randomized trial of intravenous compared with intraventricular vancomycin therapy. J Neurosurg. 2003;98:1040-1044.

[65] Nau R, Blei C, Eiffert H. Intrathecal antibacterial and antifungal therapies. Clin Microbiol Rev. 2020;33e00190-19. DIO.org/10.1128/CMR.00190-19

[66] Brown EM, de Louvois J, Bayston R, Hedges AJ, Johnston RA, Lees P.

Infection in Neurosurgery Working Party of the British Society for Antimicrobial Chemotherapy. Antimicrobial prophylaxis in neurosurgery and after head injury. Lancet 1994;344:1547 -1551.

[67] Bayston R, Hart CA, Barnicoat M. Intraventricular vancomycin in the treatment of ventriculitis associated with cerebrospinal fluid shunting and drainage. J Neurol Neurosurg Psychiatr. 1987;50:1419-1423.

[68] Thompson JB, Einhaus S, Buckingham S, Phelps SJ. Vancomycin for treating cerebrospinal fluid shunt infections in pediatric patients. J Pediatr Pharmacol Ther. 2005;10:14-25.

[69] Beach JE, Perrott J, Turgeon RD, Ensom MHH. Penetration of vancomycin into the cerebrospinal fluid: a systematic review. Clin Pharmacokinet. 2017;56:1479-1490. DOI: 10.1007/s40262-017-1548-y

[70] Kossman T, Hans V, Stocker R, Imhof H-G, Joos B, Trentz O, Morganti-Kossman MC. Penetration of cefuroxime into the cerebrospinal fluid of patients with traumatic brain injury. J Antimicrob Chemother. 1996;37: 161-167.

[71] Tängden T, Enblad P, Ullberg M, Sjölin J. Neurosurgical Gram-negative bacillary ventriculitis and meningitis: a retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases. Clin Infect Dis. 2011;52:1310-1316.

[72] Wen DY, Bottini AG, Hall WA, Haines SJ. Infections in neurologic surgery. The intraventricular use of antibiotics. Neurosurg Clin N Am. 1992;3:343-54.

[73] Bayston R, Ullas G, Ashraf W. Action of linezolid or vancomycin on biofilms in ventriculoperitoneal shunts in vitro. Antimicrob Agents Chemother. 2012;56:2842-2845. DOI: 10.1128/ AAC.06326-11

[74] Diekma DI, Jones RN. Oxazolidinones: a review. Drugs. 2000;59:7-16.

[75] Gill CJ, Murphy MA, Hamer DH. Treatment of *Staphylococcus epidermidis* ventriculo- peritoneal shunt infection with linezolid. J Infect. 2002;45:129-132

[76] Amod F, Moodley I, Peer AKC, Sunderland J, Lovering A, Wooton M, Navdi S, Vawda F. Ventriculitis due to a hetero strain of vancomycin intermediate *Staphylococcus aureus* (hVISA): successful treatment with linezolid in combination with intraventricular vancomycin. J Infect. 2005;50:252-257.

[77] Cook AM, Ramsey CN, Martin CA, Pittman T. Linezolid for the treatment of a heteroresistant *Staphylococcus aureus* shunt infection. Ped Neurosurg. 2005;41:102-104. DOI: 10.1159/ 000085165

[78] Castro P, Soriano A, Escrich C, Villalba G, Sarasa M, Mensa J. Linezolid treatment of ventriculoperitoneal shunt infection without implant removal. Eur J Clin Microbiol Infect Dis. 2005;24:603- 606. DOI 10.1007/s10096-005-0015-9

[79] Patriarca PA, Lauer BA. Ventriculoperitoneal shunt-associated infection due to *Haemophilus influenzae*. Pediatr. 1980;65:1007-1009.

[80] Rennals MB, Wald ER. Treatment of *Haemophilus influenzae* type b meningitis in children with cerebrospinal fluid shunts. J Pediatr. 1980;97:424-426.

[81] Petrak RM, Pottage JC, Harris AA, Levin S. *Haemophilus influenzae* meningitis in the presence of a cerebrospinal fluid shunt. Neurosurg. 1986; 18:79-81.

DOI:10.1227/00006123-198601000- 00013

[82] Stern S, Bayston R, Hayward RJ. *Haemophilus influenza*e meningitis in the presence of cerebrospinal fluid shunts. Childs Nerv Syst. 1988;4:164-165.

[83] O'Keeffe PT, Bayston R. Pneumococcal meningitis in a child with a ventriculoperitoneal shunt. J Infect. 1991;22:77-79.

[84] Rodríguez-Lucas C, Fernández J, Martínez-Sela M, Álvarez-Vega M, Moran N, Garcia A, Menendez C, Garcia Prieto E, Rodriguez-Guardado A. *Pseudomonas aeruginosa* nosocomial meningitis in neurosurgical patients with intraventricular catheters: therapeutic approach and review of the literature. Enferm Infecc Microbiol Clin. 2020;38:54-58. DOI: 10.1016/j. eimc.2019.04.033

[85] Markantonis SL, Markou N, Fousteri M, Sakellaridis N, Karatzas S, Alamanos I, Dimipoulou E, Baltopoulos G. Penetration of colistin into cerebrospinal fluid. Antimicrob Ag Chemother. 2009;53:4907-4910. DOI: 10.1128/AAC.00345-09

[86] Fried HI, Barnett RN, Rowe AS, Zabramski JM, Andaluz N, Bhimraj A, Guanci MM, Seder DB, Singh JM. The insertion and management of external ventricular drains: an evidence-based consensus statement. Neurocrit Care. 2016;24:61-81. DOI 10.1007/ s12028-015-0224-8

[87] De Bonis P, Lofrese G, Scoppettuolo G, Spanu T, Cultrera R, Labonia M, Cavallo MA, Mangiola A, Anile C, Pompucci A. Intraventricular versi]us intravenous colistin for the treatment of extensively drug – resistant *Acinetobacter baumannii* meningitis. Europ J Neurol. 2016;23:68-75. DOI: 10.1111/ene.12789

*Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

[88] Bargiacchi O, Rossati A, Car P, Brustia D, Brondolo R, Rosa F, Garavelli PL, de Rosa FG. Intrathecal/ intraventricular colistin in external ventricular device-related infections by multi-drug resistant Gram negative bacteria: case reports and review. Infection. 2014;42:801-809. DOI: 10.1007/s15010-014-0618-0

[89] Tascini C, Tagliaferri E, Giani T, Leonildi A, Flammini S, Casini B, Lewis R, Ferranti S, Rossolini GM, Menichetti F. Synergistic activity of colistin plus rifampin against colistinresistant KPC-producing *Klebsiella pneumoniae*. Antimicrob Agents Chemother. 2013;57:3990-3993.

[90] Renier D, Lacombe J, Pierre-Kahn A, Sainte-Rose C, Hirsch J-F. Factors causing acute shunt infection. J Neurosurg. 1984;61: 1072-1078.

[91] McGirt MJ, Zaas A, Fuchs HE, George TM, Kaye K, Sexton DJ. Risk factors for pediatric ventriculoperitoneal shunt infection and predictors of infectious pathogens. Clin Infect Dis. 2003;36:858-862.

[92] Brydon HL, Bayston R, Hayward R, Harkness W. Reduced bacterial adhesion to hydrocephalus shunt catheters mediated by cerebrospinal fluid proteins. J Neurol Neurosurg Psychiatr. 1996;60:671-675.

[93] Fulkerson DH, Vachhrajani S, Bohnstedt BN, Patel NB, Patel AJ, Fox BD, Jea A, Boaz JC. Analysis of the risk of shunt failure or infection related to cerebrospinal fluid cell count, protein level, and glucose levels in low-birthweight premature infants with posthemorrhagic hydrocephalus. J neurosurg Pediatr. 2011;7:147-151. DOI: 10.3171/2010.11.PEDS10244

[94] Simon TD, Kronman MP, Whitlock KB, Gove NE,

Mayer-Hamblett N, Browd SR, Cochrane DD, Holubkov R, Kulkarni AV, Langley M, Limbrick DD, Luerssen TG, Oakes WJ, Riva - Cambrin J, Rozelle C, Shannon C, Tamber M, Wellons JC, Whitehead WE, Kestle JRW. Reinfection after treatment of first cerebrospinal fluid shunt infection: a prospective observational cohort study. J Neurosurg Pediatr. 2018;21:346-358. DOI: 10.3171/2017.9. PEDS17112

[95] Choux M, Genitori L, Lang D, Lena G. Shunt implantation: reducing the incidence of shunt infection. J Neurosurg. 1992;77:875-880.

[96] Choksey MS, Malik IA. Zero tolerance to shunt infections: can it be achieved? J Neurol Neurosurg Psychiatr. 2007;75:87-91.

[97] Kestle JRW, Holubkov R, Cochrane DD, Kulkarni AV, Limbrick DD, Luerssen TG, Oakes WJ, Riva-Cambrin J, Rozelle C, Simon TD, Walker ML, Wellons JC, Browd SR, Drake JM, Shannon CN, Tamber MS, Whitehead WE. A new Hydrocephalus Research Network protocol to reduce cerebrospinal fluid shunt infection. J Neurosurg Pediatr. 2016;17:391-396. DOI: 10.3171/2015.8.PEDS15253

[98] Pirotte BJ, Lubansu A, Bruneau M, Loqa C, Van Cutsem N, Brotchi J: Sterile surgical technique for shunt placement re- duces the shunt infection rate in children: preliminary analy- sis of a prospective protocol in 115 consecutive procedures. Childs Nerv Syst 2007;23**:**1251-1261.

[99] Hommelstad J, Madsø A, Eide PK: Significant reduction of shunt infection rate in children below 1 year of age after implementation of a perioperative protocol. Acta Neurochir (Wien). 2013;155:523-531.

[100] Hooper GJ, Rothwell AG, Frampton C, Wyatt MC. Does the use of laminar flow and space suits reduce early deep infection after total hip and knee replacement? J Bone Joint Surg. 2011;93:85-90.

[101] Gastmeier P, Breier AC, Brandt C. Influence of laminar airflow on prosthetic joint infections: a systematic review. J Hosp Infect. 2012;81:73-78.

[102] Thompson DNP, Hartley JC, Hayward RD. Shunt infection: is there a near-miss scenario? J Neurosurg. 2007;106:15-19.

[103] Velghe L, Dereymaeker A, van der Voorde H. Swabbing of operative field in neurosurgery: analysis of 1000 controls. Acta Neurosurg (Wien). 1964; II:686-693.

[104] Tabara Z, Forrest DM. Colonisation of CSF shunts: preventive measures. Z Kinderchir. 1982;37:156-158.

[105] Fitzgerald R, Connelly B. An operative technique to reduce valve colonisation. Z Kinderchir. 1984;39(suppl II)107-109.

[106] Raahave D. Bacterial density in operation wounds. Acta Chir Scand.1974;8:585-593.

[107] Tulipan N, Cleves MA. Effect of an intraoperative double-gloving strategy on the incidence of cerebrospinal fluid shunt infection. J Neurosurg Pediatr. 2006;104:5-8.

[108] Selwyn S, Ellis H. Skin bacteria and skin disinfection reconsidered. Br Med J. 1972;1:136-140.

[109] Elek SO, Conen PE. The virulence of *Staphylococcus pyogenes* for man: a study of the problems of wound infection. Br J Exp Pathol. 1957;38: 573-86.

[110] Maiwald M, Chan ESY. The forgotten role of alcohol: a systematic review and meta-analysis of the clinical efficacy and perceived role of chlorhexidine in skin antisepsis. PLoS One. 2012;7: e44277. doi:10.1371/ journal.pone.0044277

[111] Broekman MLD, van Beijnum J, Peul WC, Regli L. Neurosurgery and shaving: what's the evidence? J Neurosurg. 2011;115:670-678.

[112] Klimo P, Flannery AM. Pediatric hydrocephalus: systematic literature review and evidence – based guidelines Part 6: preoperative antibiotics for shunt surgery in children with hydrocephalus: a systematic review and meta-analysis. J Neurosurg Pediatr. 2015;16:237-239. DOI: 10.3171/2015.3.PEDS14326a

[113] Ragel BT, Brown SR, Schmidt RH. Surgical shunt infection: significant reduction when using intraventricular and systemic agents. J. Neurosurg. 2006;105**:**242-247.

[114] Rozelle CJ, Leonardo J, Li V. Antimicrobial suture wound closure for cerebrospinal fluid shunt surgery: a prospective, double-blinded, randomized controlled trial. J Neurosurg Pediatr. 2008;2:111-117. DOI: 10.3171/PED/2008/2/8/111

[115] Krause M, Mahr CV, Dchob S, Nestler U, Wachowiak R. Topical instillation of vancomycin lowers the rate of CSF shunt infections in children. Child's Nerv Syst. 2019;35:1155-1157. doi. org/10.1007/s00381-019-04185-1

[116] Bridgett MJ, Davies MC, Denyer SP, Eldridge PR. In vitro assessment of bacterial adhesion to hydromer – coated cerebrospinal fluid shunts. Biomaterials. 1993;14:184-188.

[117] Bayston R, Bhundia C, Ashraf W. Hydromer – coated catheters to prevent shunt infection? J Neurosurg Pediatr. 2005;102:207-212.

[118] Kaufmann AM, Lye T, Redekop G, Brevner A, Hamilton M, Kozey M,

*Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

Easton D. Infection rates in standard vs hydrogel coated ventricular catheters. Can J Neurol Sci. 2004;31:506-510.

[119] Kestle JRW, Riva-Cambrin J, Wellons JC, Kulkarni AV, Whitehead WE, Walker ML, Oakes WJ, Drake JM, Luersssen TG, Simon TD, Holubkov R. A standardized protocol to reduce cerebrospinal fluid shunt infection: the hydrocephalus clinical research network quality improvement initiative. J Neurosurg Pediatr. 2011;8:22-29. DOI: 10.3171/2011.4. PEDS10551

[120] Bayston R, Lambert E. Duration of protective activity of cerebrospinal fluid shunt catheters impregnated with antimicrobial agents to prevent bacterial catheter- related infection.J Neurosurg. 1997;87:247-251.

[121] Thomas R, Lee S, Patole S, Rao S. Antibiotic – impregnated catheters for the prevention of CSF shunt infections: a systematic review and meta-analysis. B J Neurosurg. 2012;26:175-184. DOI: 10.3109/02688697.2011.603856

[122] Edwards NC, Engelhart L, Casamento EM, McGirt MJ: Costconsequence analysis of antibioticimpregnated shunts and external ventricular drains in hydrocephalus. J Neurosurg. 2015;122:139-147.

[123] Lockhart PB, Loven B, Brennan MT, Fox PC. The evidence base for the efficacy of antibiotic prophylaxis in dental practice. J Amer Dent Assoc. 2007;138:458-474.

[124] Foreman PM, Hendrix P, Griessenauer CJ, Schmalz PG, Harrigan MR. External ventricular drain placement in the intensive care unit versus operating room: evaluation of complications and accuracy. Clin Neurol Neurosurg. 2015;128:94-100.

[125] Gigante P, Hwang BY, Appelboom G, Kellner CP, Kellner MA, Connolly ES. External ventricular drainage following aneurysmal subarachnoid haemorrhage. B J Neurosurg. 2010;24:625-632. DOI: 10.3109/02688697.2010.505989

[126] Flibotte JJ, Lee KE, Koroshetz WJ, Rosand J, McDonald CT. Continuous Antibiotic Prophylaxis and Cerebral Spinal Fluid Infection in Patients with Intracranial Pressure Monitors. Neurocrit Care. 2004;1:61-68.

[127] Wong GKC, Poon WS, Lyon D, Wai S. Cefepime vs. Ampicillin/ Sulbactam and Aztreonam as antibiotic prophylaxis in neurosurgical patients with external ventricular drain: result of a prospective randomized controlled clinical trial. J Clin Pharm Therapeut. 2006;31:231-235.

[128] Wong GK, Ip M, Poon WS, Mak CW, Ng RY. Antibioticsimpregnated ventricular catheter versus systemic antibiotics for prevention of nosocomial CSF and non-CSF infections: a prospective randomised clinical trial. J Neurol Neurosurg Psychiatr. 2010;81:1064-1067.

[129] Dellit TH, Chan JD, Fulton C, et al. Reduction in *Clostridium difficile* infections among neurosurgical patients associated with discontinuation of antimicrobial prophylaxis for the duration of external ventricular drain placement. Infect Control Hosp Epidemiol. 2014;35:589-590.

[130] Alleyne CH, Hassan M, Zabramski JM. The efficacy and cost of prophylactic and perioprocedural antibiotics in patients with external ventricular drains. Neurosurg. 2000;47:1124-1127.

[131] Murphy RKJ, Liu B, Srinath A, Reynolds MR, Liu J, Craighead MC, Camins BC, Dhar R, Kummer TT, Zipfel GJ. No additional protection against ventriculitis with prolonged systemic antibiotic prophylaxis for

patients treated with antibiotic-coated external ventricular drains. J Neurosurg. 2015;122:1120-1126. DOI: 10.3171/2014.9.JNS132882

[132] Fichtner J, Guresir E, Seifert V, Raabe A. Efficacy of silver- bearing external ventricular drainage catheters: a retrospective analysis. J Neurosurg. 2010;112:840-846.

[133] Lemcke J, Depner F, Meier U. The impact of silver nanoparticle-coated and antibiotic-impregnated external ventricular drainage catheters on the risk of infections: a clinical comparison of 95 patients. Acta Neurochir Suppl. 2012;114:347-350.

[134] Lajcak M, Heideche V, Haude KH, Rainov NG. Infection rates of external ventricular drains are reduced by the use of silver-impregnated catheters. Acta Neurochir. 2010; 155:875-881. DOI 10.1007/s00701-013-1637-9

[135] Zakaria R, Tripathy S, Srikandarajah N, Rothburn MM, Lawson DD. Reduction of drainassociated cerebrospinal fluid infections in neurosurgical inpatients: a prospective study. J Hosp Infect. 2013;84:215-221.

[136] Lwin S, Low SW, Choy DKS, Yeo TT, Chou N. External ventricular drain infections: successful implementation of strategies to reduce infection rate. Singapore Med J. 2012;53:2555-259.

[137] Keong NC, Bulters DO, Richards HK, Farrington M, Sparrow OC, Pickard JD, Hutchinson PJ, Kirkpatrick PJ. The SILVER (Silver Impregnated Line Versus EVD Randomized trial): a double-blind, prospective, randomized, controlled trial of an intervention to reduce the rate of external ventricular drain infection. Neurosurg. 2012;71:394-403.

[138] Atkinson RA, Fikrey L, Vail A, Patel HC. Silver-impregnated external -ventricular -drain -related cerebrospinal fluid infections: a metaanalysis. J Hosp Infect. 2013;92:263-272. DOI.org/10.1016/j.jhin.2015.09.014

[139] Bayston R, Vera L, Mills A, Ashraf W, Stevenson O, Howdle SM. Antimicrobial activity of silverprocessed catheters for neurosurgery. J Antimicrob Agents Chemother. 2010;65:258-265. doi:10.1093/jac/dkp420

[140] Zabramski JM, Whiting D, Darouiche RO, Horner TG, Olson J, Robertson C, Hamilton AJ. Efficacy of antimicrobial- impregnated external ventricular drain catheters: a prospective, randomized, controlled trial. J Neurosurg. 2003;98:725-730.

[141] Abla AA, Zabramski JM, Jahnke HK, Fusco D, Nakaji P: Comparison of two antibioticimpregnated ventricular catheters: a prospective sequential series trial. Neurosurg. 2011; 68:437-442.

[142] Muttaiyah S, Ritchie S, John S, Mee E, Roberts S. Efficacy of antibioticimpregnated external ventricular drain catheters. J Clin Neurosci. 2010;17:296- 298. doi:10.1016/j.jocn.2009.06.016

[143] Tamburrini G, Massimi L, Caldarelli M, Di Rocco C. Antibiotic impregnated external ventricular drainage and third ventriculostomy in the management of hydrocephalus asso- ciated with posterior cranial fossa tumours. Acta Neurochir (Wien) 2008;150:1049-1055.

[144] Bayston R, Ashraf W, Pelegrin I, Fowkes K, Bienemann AS, Singleton WGB, Scott IS. An external ventricular drainage catheter impregnated with rifampicin, trimethoprim and triclosan, with extended activity against MDR gram negative bacteria: an invitro and in vivo *Infections in CSF Shunts and External Ventricular Drainage DOI: http://dx.doi.org/10.5772/intechopen.98910*

study. J Antimicrob Chemother. 2019;74:2959-1264. doi:10.1093/ jac/dkz293

[145] Khanna RK, Rosenblum ML, Rock JP, Malik GM (1995) Prolonged external ventricular drainage with percutaneous long-tunnel ventriculostomies. J Neurosurg. 1995;83:791-794. DOI 10.1007/ s00701-007-1458-9

[146] Collins CDE, Hartley JC, Chakraborty A, Nolan D, Thompson P. Long subcutaneous tunnelling reduces infection rates in paediatric external ventricular drains. Child's Nerv Syst. 2014;30:1671-1678. DOI: 10.1007/ s00381-014-2523-3

[147] Leung GKK, Ng KB, Taw BBT, Fan YW. Extended subcutaneous tunnelling technique for external ventricular drainage. B J Neurosurg. 2007;21:359-364. DOI: 10.1080/02688690701392881

[148] Mayhall CG, Archer NH, Lamb VA, Spadora AC, Baggett JW, Ward JD, Narayan RK. Ventriculostomy-related infections. A prospective epidemiologic study. N Engl J Med. 1984;310:553-559.

[149] Wong GK, Poon WS, Wai S, Yu LM, Lyon D, Lam JM. Failure of regular external ventricular drain exchange to reduce cerebrospinal fluid infection: result of a randomised controlled trial. J Neurol Neurosurg Psychiatr.2002; 73:759-761.

[150] Lo CH, Spelman D, Bailey M, Cooper DJ, Rosenfeld JV, Brecknell JE. External ventricular drain infections are independent of drain duration: an argument against elective revision. J Neurosurg. 2007;106:378-383.

#### [151] Mayer C, Albert R,

Proescholdt MA, Bele S, Woertgen C, Brawanski A. Can a regular change of external ventricular drainage (EVD) prevent cerebrospinal fluid infection in patients with intracranial hemorrhage? German Med Sci. 2006; www.egms.de/ en/meetings/ dgnc2006/06dgnc250.shtml

[152] Bianco A, Quirino A, Giordano M, Marano V, Rizzo C, Liberto MC, Foca A, Pavia M. Control of carbapenemresistant Acinetobacter baumannii outbreak in an intensive care unit of a teaching hospital in southern Italy. BMC Infect Dis. 2016;16:747. DOI: 10.1186/ s12879-016-2036-7

[153] Chia PY, Sengupta S, Kukreja A, Ponnampalavanar SSL, Ng OT, Marimutjhu K. The role of hospital environment in transmission of multidrug-resistant gram -negative organisms. Antimicrob Res Infect Control. 2020;9:1-11. DOI.org/10.1186/ s13756-202-0685-1

[154] Moon HJ, Kim SD, Lee JB, Lim DJ, Park JY. Clinical analysis of external ventricular drainage related ventriculitis. J Korean Neurosurg Soc. 2007;41:236-240.

[155] Leverstein-van Hall MA, Hopmans TE, van der Sprenkel JW, Blok HE, van der Mark WA, Hanlo PW, Bonten MJM. A bundle approach to reduce the incidence of external ventricular and lumbar drain-related infections. J Neurosurg. 2010;112:345- 353. DOI: 10.3171/2009.6.JNS09223

[156] Korinek A-M, Reina M, Boch AL, Rivera AO, DE Bels D, Puybasset L. Prevention of external ventricular drain-related ventriculitis. Acta Neurochir (Wien) 2005;147:39 – 45. DOI 10.1007/s00701-004-0416-z

[157] Dasic D, Hanna SJ, Bojanic S, Kerr RSC. External ventricular drain infection: the effect of a strict protocol on infection rates and a review of the literature. Br J Neurosurg 2006;20:296- 300. DOI: 10.1080/0268869060 0999901

Section 5

## Germinal Matrix Hemorrhage

#### **Chapter 7**

## Germinal Matrix-Intraventricular Hemorrhage: Current Concepts and Future Direction

*Sadhika Sood and Rohit Gulati*

#### **Abstract**

Germinal Matrix Hemorrhage-Intraventricular hemorrhage (IVH) is a bleed of multifactorial etiology involving the highly vascular and delicate neuro-glial precursors in the developing brain. It poses a challenging complication in preterm newborns. This chapter provides a focused discussion on the current concepts in pathogenesis, management, and complications of IVH. The radiological findings at diagnosis and follow-up and the cytological features of CSF will be valuable to both frontline and diagnostic healthcare providers. The chapter also reviews the ongoing scientific development in the field. The authors believe that this chapter will be a valuable tool for all healthcare providers (students, physicians, and in nursing care) in managing this challenging condition.

**Keywords:** Germinal matrix hemorrhage, intraventricular hemorrhage, IVH, intracranial hemorrhage, superficial siderosis, central nervous system, cerebrospinal fluid, genetic alterations, cranial ultrasound, preterm complications, low birth weight

#### **1. Introduction**

The germinal matrix (GM) is a specialized layer of glial and neuronal precursor cells in the periventricular region of the brain with high metabolic activity, which is strongly dependent on its rich vascularity and rapid angiogenesis [1]. The dense and fragile vasculature makes GM selectively vulnerable to hemorrhage. Germinal matrix – intraventricular hemorrhage (GM-IVH) is the most common type of intracranial hemorrhage in preterm infants. A combination of increased perinatal stress, poor cerebral autoregulation, and inherent fragility of the nascent vessels in the germinal matrix increases the likelihood of the development of GM-IVH in preterm infants. Also, there is evidence of occurrence in-utero and among full-term infants, however, such cases are rare [2]. The germinal matrix disappears by 36–37 weeks of gestation (wg), so GM-IVH is more likely in preterm infants than full term.

The global incidence of GM-IVH among preterm infants ranges from 14.7% to 44.7%, with variations across gestational age groups, countries, and antenatal and neonatal care [3]. The widespread use of cranial ultrasonography since the early 1980s, increasing knowledge of risk factors, antenatal steroid usage, and improved intensive care have improved incidence, survival, and morbidity of GMH [4]. However, GMH continues to remain a significant healthcare issue in preterm infants and a recognizable cause of long-term neurological and behavioral issues in survivors.

### **2. Germinal matrix-intraventricular hemorrhage**

#### **2.1 Pathogenesis**

Developmentally, GM is located in the ganglionic eminence of the brain and is most pronounced in the caudate nucleus. The thickness and density of GM vasculature are higher than other brain areas and begin to decrease after 24 weeks of gestation (wg) and almost disappear at 36–37 wg with increasing fetal maturity [1, 5]. A significant bleed in the highly vascular GM breaks the associated ependyma to involve the lateral cerebral ventricle constituting intraventricular hemorrhage (IVH) [6, 7]. The incidence of GMH-IVH increases with decreasing gestation age at birth in preterm infants [8–10].

The pathogenesis of GM-IVH is complex and heterogeneous. The blood–brain barrier (BBB) associated with GM vasculature is distinct from the remaining areas in the brain due to diminished: 1) pericytes, 2) fibronectin in the basal lamina, and 3) GFAP (glial fibrillary acidic protein) in astrocyte endfeet (**Figure 1**). The paucity of three essential components of the BBB leads to the altered structural integrity of GM vasculature. First, pericytes play an essential role in BBB development, especially in early angiogenesis, extracellular matrix production, and endothelial maturation [11]. The paucity of pericytes in GM is associated with diminished levels of TGF-β [12] and predisposition to hemorrhage in dilatated blood vessels in experimental models [13]. Second, fibronectin, a high molecular weight glycoprotein, is selectively deficient in the GM basement membrane [14]. Fibronectin polymerizes to provide structural integrity to blood vessels and is dependent on TGF-β for its upregulation. While other basement membrane components, including Collagen I, II, IV, laminin, and perlecan, are similar to other components in the human brain [14, 15]. Third, astrocytes provide vascular integrity by sheathing the predominance of the BBB with their GFAP rich extensions (endfeet). Autopsy studies in premature infants show decreased GFAP expressing astrocyte endfeet in GM than

#### **Figure 1.**

*Diagrammatic representation of the coronal section of a preterm brain to highlight the factors contributing to the labile structure of the blood brain barrier in the germinal matrix and pathogenesis of the GM-IVH.*

#### *Germinal Matrix-Intraventricular Hemorrhage: Current Concepts and Future Direction DOI: http://dx.doi.org/10.5772/intechopen.99275*

cerebral cortex and white matter [16]. These make the blood–brain barrier fragile and more susceptible to hemorrhage.

Microscopically the GM vasculature has been described as circular in coronal sections, compared to elongated and flat vessels in other areas of the brain, representing the immaturity of the vessels from rapid angiogenesis and high endothelial turnover [17]. In addition, immunofluorescence and electron microscopy have shown a paucity of pericytes in the GM vascular environment [12].

Finally, fluctuations in cerebral blood flow precipitate into hemorrhage in the delicate GM. In addition, defects in the hemostatic mechanisms expectantly promote hemorrhage [6, 7].

Germinal matrix cells being metabolically active precursor neuronal and glial cells in the early stages of maturation demand a specialized and rich blood supply. This requirement is met by accelerated angiogenesis dependent on high levels of vascular endothelial growth factors (VEGF) and angiopoietin-2 and low expression of TGF-β [1]. Also, the GM is in a state of relative hypoxia, a driving force for continuous angiogenesis [6, 7]. Intriguingly, this may explain the near absence of GM-IVH after over 3–5 days of birth irrespective of the duration of gestation. Likely, higher oxygenation following birth inhibits rapid angiogenesis. Thus, a labile combination of metabolically active immature/precursor cells with a rich but "structurally weak" vasculature provided a high-risk background for bleeding, especially with high-velocity cerebral blood flow.

Among many factors associated with alteration in cerebral blood flow, severe respiratory distress syndrome, patent ductus arteriosus, high central venous, and hypercarbia are most prominent. While autoregulation maintains constant cerebral blood flow, this mechanism is impaired in premature infants with lower birth weight. Thus, changes in blood volume or pressure are more likely to affect cerebral circulation. Interestingly, the results of studies directly comparing impaired autoregulation with GMH-IVH have been mixed [18–20] and provide an opportunity for further research in this direction. As seen in pneumothorax and mechanical ventilation (on high mean airway pressure mode), high central venous pressure stands out as a solid contender to contribute to IVH. This is also concordant with the venous nature of GM-IVH [21]. Interestingly, mechanical ventilation in synchronized and intermittent mandatory mode prevents higher velocity/turbulence of cerebral blood than fixed frequency/pressure modes.

Significant other risk factors affecting include prolonged labor, maternal chorioamnionitis, early-onset sepsis, development of respiratory distress, recurrent tracheal suctioning (supportive care especially during mechanical ventilation), and hypoxia. While most of these factors impact cerebral blood flow, infectious and hypoxic etiologies alter the GM microvasculature. The role of hypotension and rapid sodium bicarbonate infusion in the causation of IVH are inconclusive.

#### **2.2 Diagnosis**

Clinical manifestations of GM-IVH include asymptomatic to subtle alterations in consciousness, limb and eye movement, and changes in muscular tone following IVH. Further, severe cases may be associated with cardiorespiratory distress and progression to seizures, hypotonia, or decerebrate posturing [22].

Cranial ultrasound (CUS) remains the most practical and well-utilized approach for diagnosing and monitoring GM-IVH evolution. Newer ultrasound devices with high-frequency transducers allow for enhanced evaluation. Epidemiologically, surviving infants born preterm at 24 weeks have a higher incidence (10–25%) of high-grade GM-IVH (grade 3–4) as compared to preterm infants born after 28 weeks (<5%) [8–10]. Almost half the cases of postnatal GM-IVH present on the

first day of life, with nearly ~90% presenting within the first 72 hours. As discussed in pathogenesis, increased oxygenation after birth likely stabilizes the GM-BBB and makes infants almost resistant to GM-IVH after the first week of life irrespective of gestational age [23]. Therefore, regular CUS schedules have been recommended based on the gestational age at birth and when otherwise clinically indicated [24].

Traditionally, GM-IVH had been graded into four categories based on the extent of hemorrhage beginning in the venule that drains into the subependymal collector veins: grade-1 representing subependymal hemorrhage; grade-2 with limited (filling <50% of normal-sized ventricles) IVH; and grade-3 with extensive IVH. Grade-4 was defined as IVH with parenchymal extension [25]. However, the latter was better identified as parenchymal venous infarction (PVI), though parenchymal extension does also rarely occurs [26]. Interestingly, PVI may occur in all, including lower grades (1 and 2) of GM-IVH [22]. Since PVI is associated with long-term complications and risk of mortality (based on location and extent), a three-stage grading with an additional description of PVI has been recommended [22, 24] (**Figure 2**). In addition, early GMH may alter local neuronal and glial precursors with neurological consequences, description of location of bleed in addition to grade is suggested.

On CUS, grade 1 GMH is subependymal, hyperechoic, and globular. Evaluation in both coronal and sagittal planes helps distinguish a small GMH from choroid plexus on an initial diagnostic scan. Also, echogenicity at the caudothalamic groove (usual site for GMH) in the late neonatal period likely represents hyperechoic germinolysis and not late GMH [27]. Distinguishing pure subependymal bleed from IVH may be challenging on CUS. Indirect signs of hyperechoic ependymal changes, which usually occur 2 to 4 weeks after IVH, and insonation through mastoid fontanelle are helpful in this distinction [24] and aid prognostication and counseling.

#### **Figure 2.**

*GMH/IVH: Origin and grading. GMH starts in a venule that drains into lateral subependymal collector veins; it extends into white matter by virtue of venous compression and infarction; bottom row: T2-weighted MRI of GMH with limited IVH and limited venous infarct. (Derived from Parodi et al. [24]).*

#### *Germinal Matrix-Intraventricular Hemorrhage: Current Concepts and Future Direction DOI: http://dx.doi.org/10.5772/intechopen.99275*

Clot changes overtime should also be recorded. A subacute clot or clot remnants early after birth may represent an antenatal hemorrhage.

PVI typically is identified as a triangular echo density in the periventricular white matter adjacent to the GMH. The infarct may not touch the GMH initially and may or may extend into the GMH depending on severity. Infarcts eventually evolve into cavitary lesions, and porencephaly ensues in 1–2 months [24]. This cavitation is asymmetric, unilateral, and permanent in contrast to cysts of periventricular leukomalacia (symmetric, bilateral, and transient) [22].

A quarter of infants with GM-IVH develop posthemorrhagic ventricular dilatation (PHVD) due to imbalanced production and resorption of CSF. This dilatation occurs a few days to weeks after IVH and is followed by subsequent regression [28]. PHVD is more common in higher grades but can occur in all cases with IVH. Thus, serial CUS is recommended in IVH cases until term-equivalent age. While a subset of cases resolves spontaneously, balancing the complications of compression versus those of surgical management (tapping, shunt) remains a challenge [29]. PVHD, as expected, is associated with a poor neurological outcome in the long term.

#### **2.3 Genetic factors in GM-IVH**

Thrombophilic genotype is frequently associated with a subset of severe GM-IVH patients with atypical clinical presentation. The atypical presentation includes periventricular hemorrhagic infarction presenting within 6 hours of birth or after four days of birth, in the absence of secondary inciting factors like sepsis. Factor V Leiden mutation was the most common genetic alteration, frequently with mothers being carriers. Prothrombin mutations and polymorphism of the *MTHFR* gene were also reported [30]. Previous studies have shown an association of a thrombophilic profile with early grade 1–2 GMH [31, 32]. Polymorphism of TNF-α has been associated with an increased risk of GMH-IVH [33]. Of interest, the same study showed an association of polymorphism in TGF-β with a fatal outcome but not with IVH.

Mutations of the *COL4A1* gene, coding for type IV collagen *α*-chain-1, have rarely been reported in a subset of preterm IVH [30, 34]. A pair of dizygotic twins showed a heterozygous duplication at exon 4 of the highly conserved and ubiquitous *COL4A1.* Interestingly, the mother and maternal grandmother of the twins were heterozygous carriers and were asymptomatic. Also, the study evaluated 39 other cases of preterm IVH and detected no mutations in *COL4A1,* indicating its rarity [34]. Previous studies have revealed no alteration in type IV collagen components in the basement membrane in GM [14, 15].

Experimental models have shown tropomyosin receptor kinase B (TrkB) to influence the inflammatory status in the microenvironment following GMH by influencing the phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/ forkhead box protein O1 (FoxO1) pathway [35].

Overall, genetic alteration in components of vascular structure, coagulation mechanism, and inflammatory pathways have been described in a subset of GM-IVH. The authors believe that recent progress in inflammation and growing knowledge of inflammasome complex may be employed towards further research in this direction.

#### **2.4 Prevention**

Our understanding of IVH due to a structurally labile and immature vasculature in the germinal matrix and alterations in cerebral blood flow in premature infants forms the focus of most strategies to prevent GM-IVH. In principle, delay of preterm birth relies on decreasing GM vascular density with advanced gestational age. Moreover, high postnatal oxygen levels in the infant mediate the stabilization of the GM blood vasculature and ensure freedom from IVH in 3–5 days after birth, highlighting the critical importance of timeliness in management and prevention.

#### *2.4.1 Specific strategies for prevention*

Steroids (glucocorticoids) like dexamethasone and betamethasone are administered to pregnant women in premature labor under 34 wg. Glucocorticoids cause a selective inhibition of blood vessels in the GM- BBB that lack adequate pericyte coverage, inhibit angiogenesis, and subsequently stabilize vasculature [12, 14, 36]. In addition, prenatal corticosteroid assists in development lungs surfactant and protect against respiratory distress syndrome. The latter effect also prevents turbulent cerebral blood flow. Prenatal corticosteroid usage is one of the rare factors that has consistently been associated with a reduction in occurrence and severity of IVH [37, 38].

Indomethacin is a non-selective cyclooxygenase (COX) inhibitor and reduces severe IVH, especially in males [39, 40]. Indomethacin is employed for closure of patent ductus arteriosus that in turn prevents altered cerebral blood flow. It also suppresses angiogenesis by COX-2 inhibition [1]. Although indomethacin can decrease IVH in the short term, its usage is not associated with reducing long-term neurological complications such as cerebral palsy, deafness, and blindness [41–43]. Hence, indomethacin has limited acceptance and is based on regional preferences.

Prenatal care and transport: It is recommended that pregnant mothers be given adequate antenatal care and those in preterm labor be transported (while pregnant) to tertiary care units better equipped to manage both mother and child. Transportation of extremely premature infants has long been associated with the increased occurrence and severe IVH [44].

It is beneficial to note that antenatal phenobarbital and magnesium, vitamin-K, and fresh frozen plasma did not influence the occurrence of IVH [45–49].

Intriguing preclinical studies show time-sensitive windows for therapeutic pharmacological targeting of the GM "weakened" BBB by altering the integrin-β8 and TGF-β pathways [50].

#### **2.5 Management**

Currently, there is a paucity of active treatment strategies for the management of established GM-IVH. Maintaining blood pressure levels and respiratory status, with judicious use of IV fluids, blood transfusions, and respiratory support (if needed), might prevent the progression of hemorrhage. Electroencephalogram (EEG) monitoring should be done in the presence of seizures [3]. Apart from supportive treatment, emphasis is laid on the preservation of cerebral perfusion and the prevention of complications. Monitoring twice weekly with CUS for four weeks (or similar) and then weekly till term equivalent age recommended to evaluate GMH and post hemorrhage hydrocephalus (PHH).

#### *2.5.1 Post-natal effective nursing care*

Multiple trials and observational studies have focused on the relative head position of premature infants soon after birth in relation to IVH. These positional strategies focus mainly on maintaining adequate cerebral blood flow.

While previous studies on the effect on neutral head position found no significant association with the occurrence of IVH [51], these studies were also limited

*Germinal Matrix-Intraventricular Hemorrhage: Current Concepts and Future Direction DOI: http://dx.doi.org/10.5772/intechopen.99275*

by small sample size [52]. More recently, efficient, supportive nursing intervention in premature infants during the first 72 hours of birth has been associated with decreased incidence and progression of GM-IVH [53]. This four-pronged approach includes midline head position, head elevation of the incubator, and slow vascular flushing/withdrawal of blood, and sudden elevation of the legs. First, the head in midline position ensures adequate venous drainage. Head rotation impedes jugular venous outflow on the ipsilateral side and may cause congestion, relative hypoxia and eventually aid GMH [54]. Second, incubator head lift (15–30 degrees) enhances gravitational cerebral venous drainage [55]. Third, sudden elevation of legs, as in to change diapers, may result in increased venous return, increase cardiac preload, thereby altering cerebral perfusion. Finally, avoiding rapid (lasting <30 seconds) vascular flushing/blood collection can avoid a transient though significant alteration in cerebral blood flow [56]. The effect of the intervention was stronger in infants born before 27 wg [53]. While previous studies on the effect on neutral head position found no significant association with the occurrence of IVH [51], these studies were limited by small sample size [52]. A more recent meta-analysis showed the limited utility of supine midline head position for the prevention of GM-IVH. However, midline head position with an elevation of incubator head was associated with lower mortality [57]. Overall, concomitant intervention with neutral head position, the elevation of incubator head, and avoidance of sudden leg elevation and sudden vascular volumetric changes provide evidence for a better outcome.

#### **2.6 Complications and potential treatment strategies**

The survivors of severe GMH frequently develop post-hemorrhagic hydrocephalus (PHH). A subset of these cases requires surgical shunting, which is not without its complications, including infections, obstruction, and displacement [58]. In addition, the cerebroventricular dilatation causes physical pressure on the brain parenchyma and is associated with neurological impairment in the long term. Mechanism of PHH: Obstruction of the cerebral aqueduct, foramina of Luschka and Magendie, and subarachnoid outflow passages by blood clots/microthrombi may cause PHH. Historically, fibrinolytic therapy has not been successful in the management of PHH.

The tissue macrophage system responds to intracranial hemorrhage similar to other locations in the body. Red blood cells (RBCs) are phagocytosed by macrophages (erythrophages), and subsequently, hemoglobin is degraded. Iron mainly converts to coarse, irregular hemosiderin granules and porphyrin rings into bilirubin. In exceptional circumstances with closed compartments and lower oxygen tension, such as intracranial bleed, hematoidin, a crystalline, reduced biliverdin product may be formed. Post hemorrhagic components are frequently encountered on light microscopic evaluation of the cerebrospinal fluid (CSF), as early as 1–2 days after bleeding [59, 60]. In addition to the erythrophagocytosis, cellular components of the ventricular lining (ependymal cells and choroid plexus cells) and rarely, precursor germinal matrix cells (due to close proximity with disrupted ventricular lining) may be identified in CSF analysis [61–63].

Superficial siderosis (SS) is the deposition of hemosiderin in the subpial layers of CNS, resulting in sensorineural hearing loss and cerebellar ataxia in most adults cases [64]. Susceptibility weighted imaging (SWI), an MRI sequence, identified SS in the ependymal layer, brain stem, cerebellum with vermis, and Sylvian fissures. Interestingly the depth of SS correlated with the increasing grade of GM-IVH. Also, brain stem and cerebellar SS appear to relate more to IVH than cerebellar hemorrhage [65].

A review of scientific literature shows the following current trends exploring the management of GMH and prevention of complications.

#### *2.6.1 Iron in the manifestation of PHH*

Experimental models have shown the role of iron (from red blood cells) to develop brain edema and acute ventricular dilatation [66]. As proof of principle, iron chelation with deferoxamine has showed reduced long term PHH after GMH in neonatal rats [67, 68]. Another group found biliverdin reductase to enhance CD36 expression in scavenging microglia and hematoma resolution through NOS/ TLR4 pathway [69]. Additionally, iron overload has been associated with increased aquaporin-4 expression [70]. However, diuretic treatment has not been found to be beneficial.

Along similar lines, "normal appearing" white matter in preterm infants with severe GM-IVH, at term equivalent age, showed paramagnetic (positive magnetic) susceptibility, likely due to diffusion of iron into the periventricular white matter [71]. This radiological finding may be employed as an innovative methodology for future research focusing on the spatial impact of iron deposition on long-term neurological consequences.

#### *2.6.2 Role of inflammation and gliosis*

Post GMH levels of pro-inflammatory markers like TNFα are elevated. In response to hemorrhage and associated tissue injury, resident microglia are activated in an inflammatory process [72–74]. Additional experimental models have shown microglial proliferation surrounding the clot with phosphorylated ERK. Minocycline and cannabinoid receptor-2 agonists have also shown promise to curb down inflammation [75]. CD200Fc inhibits inflammation following GMH likely by mediating CD200R1/Dok1 pathway [76]. IVH has been shown to cause a TLR4 and NF-κβ based inflammatory pathway mediated increase in CSF production in the choroid plexus. As a proof of principle, amelioration of these mediators was associated with control of CSF production and improvement in PHH [77]. The role of M2 microglia stimulation through the PPARγ and CD36 scavenger receptor for shortterm resolution of hematoma has also shown promising results for further clinical evaluation [78]. NT-4 controls neuroinflammation by interacting with TrkB to induces PI3K-Akt pathway and inhibits downstream FoxO1 in experimental models [35]. These results promise potential for clinical utility in the management of PHH.

Extracellular matrix (ECM), especially components fibronectin and vitronectin, are elevated post-GMH and are hypothesized to deposit (like microthrombi), potentially causing CSF obstruction [75, 79–81]. TGF-β may be induced by thrombin and promotes the production of ECM, especially TGF-β1 isoform whose levels have been elevated in studies after GMH. It's inhibition has been associated with attenuated PHH and neurological decline [75, 81]. While GFAP expression is markedly increased in experimental IVH models, umbilical cord mesenchymal stem cell infusion has been associated with a decline in GFAP expression and subsequent PHH development [82]. The role of GFAP and astrocytes in gliosis post IVH requires further attention. More recently, astrogliosis was associated with redistribution of aquaporin-4 and altered CSF dynamics. Olomoucine controlled scarring and attenuated PHH by inhibition of cyclin-dependent kinase (CDK) [83]. Secukinumab, monoclonal IgG1κ targeting IL17a, is protective against reactive astrogliosis following GMH, partly by regulating IL-17RA/(C/EBPβ)/SIRT1 pathways [84].

*Germinal Matrix-Intraventricular Hemorrhage: Current Concepts and Future Direction DOI: http://dx.doi.org/10.5772/intechopen.99275*

#### *2.6.3 Long term complications of low grade (grade 1: 2) GM-IVH*

While neurological complications in survivors of high-grade GM-IVH are well documented, the impact of low-grade IVH currently continues to be better understood. Low-grade IVH was associated with moderate to severe neurodevelopmental impairment (NDI) and without association with cerebral palsy [85]. A case-controlled retrospective study using CUS found no significant impact of low-grade GM-IVH on neurological complications of cerebral palsy and neurodevelopmental delay evaluated during 18–30 months after birth [86]. Both these studies were limited in power and in analysis by more sensitive MR-based techniques [87]. A more recent MR-based study has revealed microstructural impairment of white matter related to neurodevelopmental impairment at 24 months in early GMH [88]. Similarly, magnetic resonance with 3D pseudo-continuous arterial spin-labeling (pCASL) perfusion sequence-based study has shown consistently lower CBF in the posterior cortical and subcortical gray matter regions in preterm neonates with low grade IVH [89]. This regional susceptibility also requires correlation with long term studies. From a developmental perspective, neurological alterations are not incompatible with low-grade IVH. GMH may lead to altered myelination in the white matter since ganglionic eminence is the seat of oligodendroglial precursor cells that migrate to cerebral white matter areas to produce myelin later in the third trimester [90]. Besides, GM is involved in the development of GABAergic interneurons significant for high-level cognitive function [91].

#### **3. Conclusion**

Germinal matrix intraventricular hemorrhage is the most common intracranial hemorrhage in newborns, particularly preterm neonates. Improvements in obstetric and neonatal care have led to increased survival of preterm infants. Despite extensive research and preventive measures, the incidence of associated complications and mortality remains high. The GM is highly susceptible to hemorrhage due to a combination of delicate vasculature and fluctuations of cerebral perfusion, uncontrolled by autoregulatory mechanisms. Genetic factors and coagulation disorders may factor in if present. Obstetric and neonatal clinicians should use the available knowledge to prevent the occurrence of and progressions of hemorrhages. Therapeutic options for the management of GM-IVH are predominantly limited to supportive care and monitoring. Shunts have proven to be effective in challenging cases of PHH. Current and ongoing improvement in the molecular understanding of GM-IVH and its complications using multi-omics investigations is essential to develop biomarkers and therapeutic strategies.

#### **Acknowledgements**

The authors thank Mr. Fredrik Skarstedt for his immense support with digital image preparation.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Cerebrospinal Fluid*

#### **Author details**

Sadhika Sood1 and Rohit Gulati<sup>2</sup> \*

1 Kasturba Medical College, Manipal Academy of Higher Education, Mangalore, India

2 Clinical Pathology, Indiana University School of Medicine, Indianapolis, Indiana, USA

\*Address all correspondence to: rogulati@iu.edu

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Germinal Matrix-Intraventricular Hemorrhage: Current Concepts and Future Direction DOI: http://dx.doi.org/10.5772/intechopen.99275*

#### **References**

[1] Ballabh, P., et al., *Angiogenic inhibition reduces germinal matrix hemorrhage.* Nat Med, 2007. **13**(4): p. 477-485.

[2] Morioka, T., et al., *Fetal germinal matrix and intraventricular hemorrhage.* Pediatr Neurosurg, 2006. **42**(6): p. 354-361.

[3] Egesa, W.I., et al., *Germinal Matrix-Intraventricular Hemorrhage: A Tale of Preterm Infants.* Int J Pediatr, 2021. **2021**: p. 6622598.

[4] Yeo, K.T., et al., *Improving incidence trends of severe intraventricular haemorrhages in preterm infants <32 weeks gestation: a cohort study.* Arch Dis Child Fetal Neonatal Ed, 2020. **105**(2): p. 145-150.

[5] Ballabh, P., A. Braun, and M. Nedergaard, *The blood-brain barrier: an overview: structure, regulation, and clinical implications.* Neurobiol Dis, 2004. **16**(1): p. 1-13.

[6] Ballabh, P., *Intraventricular hemorrhage in premature infants: mechanism of disease.* Pediatr Res, 2010. **67**(1): p. 1-8.

[7] Ballabh, P., *Pathogenesis and prevention of intraventricular hemorrhage.* Clin Perinatol, 2014. **41**(1): p. 47-67.

[8] Fellman, V., et al., *One-year survival of extremely preterm infants after active perinatal care in Sweden.* Jama, 2009. **301**(21): p. 2225-2233.

[9] Ancel, P.Y., et al., *Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study.* JAMA Pediatr, 2015. **169**(3): p. 230-238.

[10] Stoll, B.J., et al., *Neonatal outcomes of extremely preterm infants from the* 

*NICHD Neonatal Research Network.* Pediatrics, 2010. **126**(3): p. 443-456.

[11] Armulik, A., et al., *Pericytes regulate the blood-brain barrier.* Nature, 2010. **468**(7323): p. 557-561.

[12] Braun, A., et al., *Paucity of pericytes in germinal matrix vasculature of premature infants.* J Neurosci, 2007. **27**(44): p. 12012-12024.

[13] Lindahl, P., et al., *Pericyte loss and microaneurysm formation in PDGF-Bdeficient mice.* Science, 1997. **277**(5323): p. 242-245.

[14] Xu, H., et al., *Maturational changes in laminin, fibronectin, collagen IV, and perlecan in germinal matrix, cortex, and white matter and effect of betamethasone.* J Neurosci Res, 2008. **86**(7): p. 1482-1500.

[15] Anstrom, J.A., et al., *Morphometric assessment of collagen accumulation in germinal matrix vessels of premature human neonates.* Neuropathol Appl Neurobiol, 2005. **31**(2): p. 181-190.

[16] El-Khoury, N., et al., *Astrocyte end-feet in germinal matrix, cerebral cortex, and white matter in developing infants.* Pediatr Res, 2006. **59**(5): p. 673-679.

[17] Ballabh, P., A. Braun, and M. Nedergaard, *Anatomic analysis of blood vessels in germinal matrix, cerebral cortex, and white matter in developing infants.* Pediatr Res, 2004. **56**(1): p. 117-124.

[18] Tsuji, M., et al., *Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants.* Pediatrics, 2000. **106**(4): p. 625-632.

[19] Soul, J.S., et al., *Fluctuating pressurepassivity is common in the cerebral circulation of sick premature infants.* Pediatr Res, 2007. **61**(4): p. 467-473.

[20] Wong, F.Y., et al., *Impaired autoregulation in preterm infants identified by using spatially resolved spectroscopy.* Pediatrics, 2008. **121**(3): p. e604-e611.

[21] Ghazi-Birry, H.S., et al., *Human germinal matrix: venous origin of hemorrhage and vascular characteristics.* AJNR Am J Neuroradiol, 1997. **18**(2): p. 219-229.

[22] Volpe, J., *Neurology of the Newborn*. 2008, Philadelphia, PA: Saunders Elsevier. 1120.

[23] Dolfin, T., et al., *Incidence, severity, and timing of subependymal and intraventricular hemorrhages in preterm infants born in a perinatal unit as detected by serial real-time ultrasound.* Pediatrics, 1983. **71**(4): p. 541-546.

[24] Parodi, A., et al., *Cranial ultrasound findings in preterm germinal matrix haemorrhage, sequelae and outcome.* Pediatr Res, 2020. **87**(Suppl 1): p. 13-24.

[25] Papile, L.A., et al., *Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.* J Pediatr, 1978. **92**(4): p. 529-534.

[26] Volpe, J.J., *Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis.* Semin Pediatr Neurol, 1998. **5**(3): p. 135-151.

[27] Horsch, S., P. Kutz, and C. Roll, *Late germinal matrix hemorrhage-like lesions in very preterm infants.* J Child Neurol, 2010. **25**(7): p. 809-814.

[28] Murphy, B.P., et al., *Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome.* Arch Dis Child Fetal Neonatal Ed, 2002. **87**(1): p. F37-F41.

[29] Robinson, S., *Neonatal posthemorrhagic hydrocephalus from prematurity: pathophysiology and current treatment concepts.* J Neurosurg Pediatr, 2012. **9**(3): p. 242-258.

[30] Harteman, J.C., et al., *Atypical timing and presentation of periventricular haemorrhagic infarction in preterm infants: the role of thrombophilia.* Dev Med Child Neurol, 2012. **54**(2): p. 140-147.

[31] Göpel, W., et al., *Low prevalence of large intraventricular haemorrhage in very low birthweight infants carrying the factor V Leiden or prothrombin G20210A mutation.* Acta Paediatr, 2001. **90**(9): p. 1021-1024.

[32] Debus, O., et al., *Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly.* Arch Dis Child Fetal Neonatal Ed, 1998. **78**(2): p. F121-F124.

[33] Adcock, K., et al., *The TNF-alpha -308, MCP-1 -2518 and TGF-beta1 +915 polymorphisms are not associated with the development of chronic lung disease in very low birth weight infants.* Genes Immun, 2003. **4**(6): p. 420-6.

[34] Bilguvar, K., et al., *COL4A1 mutation in preterm intraventricular hemorrhage.* The Journal of pediatrics, 2009. **155**(5): p. 743-745.

[35] Wang, T., et al., *NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after germinal matrix hemorrhage in neonatal rats.* J Neuroinflammation, 2020. **17**(1): p. 158.

[36] Vinukonda, G., et al., *Effect of prenatal glucocorticoids on cerebral vasculature of the developing brain.* Stroke, 2010. **41**(8): p. 1766-1773.

[37] Roberts, D. and S. Dalziel, *Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm* 

*Germinal Matrix-Intraventricular Hemorrhage: Current Concepts and Future Direction DOI: http://dx.doi.org/10.5772/intechopen.99275*

*birth.* Cochrane Database Syst Rev, 2006(3): p. Cd004454.

[38] Shankaran, S., et al., *Relationship between antenatal steroid administration and grades III and IV intracranial hemorrhage in low birth weight infants. The NICHD Neonatal Research Network.* Am J Obstet Gynecol, 1995. **173**(1): p. 305-312.

[39] Ment, L.R., et al., *Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial.* Pediatrics, 1994. **93**(4): p. 543-550.

[40] Fowlie, P.W. and P.G. Davis, *Prophylactic indomethacin for preterm infants: a systematic review and metaanalysis.* Arch Dis Child Fetal Neonatal Ed, 2003. **88**(6): p. F464-6.

[41] Schmidt, B., et al., *Long-term effects of indomethacin prophylaxis in extremelylow-birth-weight infants.* N Engl J Med, 2001. **344**(26): p. 1966-1972.

[42] Fowlie, P.W. and P.G. Davis, *Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.* Cochrane Database Syst Rev, 2002(3): p. Cd000174.

[43] Fowlie, P.W., P.G. Davis, and W. McGuire, *Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.* Cochrane Database Syst Rev, 2010. **2010**(7): p. Cd000174.

[44] Mohamed, M.A. and H. Aly, *Transport of premature infants is associated with increased risk for intraventricular haemorrhage.* Arch Dis Child Fetal Neonatal Ed, 2010. **95**(6): p. F403-F407.

[45] Crowther, C.A., D.D. Crosby, and D.J. Henderson-Smart, *Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage.* Cochrane

Database Syst Rev, 2010. **2010**(1): p. Cd000229.

[46] Thorp, J.A., et al., *Antepartum vitamin K and phenobarbital for preventing intraventricular hemorrhage in the premature newborn: a randomized, double-blind, placebo-controlled trial.* Obstet Gynecol, 1994. **83**(1): p. 70-76.

[47] Kaempf, J.W., et al., *Antenatal phenobarbital for the prevention of periventricular and intraventricular hemorrhage: a double-blind, randomized, placebo-controlled, multihospital trial.* J Pediatr, 1990. **117**(6): p. 933-938.

[48] Beverley, D.W., et al., *Prevention of intraventricular haemorrhage by fresh frozen plasma.* Arch Dis Child, 1985. **60**(8): p. 710-713.

[49] Basu, S.K., et al., *Immediate clinical outcomes in preterm neonates receiving antenatal magnesium for neuroprotection.* J Perinat Med, 2011. **40**(2): p. 185-189.

[50] Santhosh, D., et al., *Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention.* Dis Model Mech, 2019. **12**(11).

[51] Romantsik, O., M.G. Calevo, and M. Bruschettini, *Head midline position for preventing the occurrence or extension of germinal matrix-intraventricular hemorrhage in preterm infants.* Cochrane Database Syst Rev, 2017. **7**(7): p. Cd012362.

[52] de Bijl-Marcus, K.A., et al., *The Effect of Head Positioning and Head Tilting on the Incidence of Intraventricular Hemorrhage in Very Preterm Infants: A Systematic Review.* Neonatology, 2017. **111**(3): p. 267-279.

[53] Flores, J.J., et al., *A comprehensive review of therapeutic targets that induce microglia/macrophage-mediated hematoma resolution after germinal* 

*matrix hemorrhage.* J Neurosci Res, 2020. **98**(1): p. 121-128.

[54] Pellicer, A., et al., *Noninvasive continuous monitoring of the effects of head position on brain hemodynamics in ventilated infants.* Pediatrics, 2002. **109**(3): p. 434-440.

[55] Schrod, L. and J. Walter, *Effect of head-up body tilt position on autonomic function and cerebral oxygenation in preterm infants.* Biol Neonate, 2002. **81**(4): p. 255-259.

[56] Schulz, G., et al., *Slow blood sampling from an umbilical artery catheter prevents a decrease in cerebral oxygenation in the preterm newborn.* Pediatrics, 2003. **111**(1): p. e73-e76.

[57] Romantsik, O., M.G. Calevo, and M. Bruschettini, *Head midline position for preventing the occurrence or extension of germinal matrix-intraventricular haemorrhage in preterm infants.* Cochrane Database Syst Rev, 2020. **7**(7): p. Cd012362.

[58] Vassilyadi, M., et al., *Functional outcomes among premature infants with intraventricular hemorrhage.* Pediatr Neurosurg, 2009. **45**(4): p. 247-255.

[59] Hennrick, K. and D. Yang, *Hematoidin.* Blood, 2014. **124**(13): p. 2158.

[60] Gulati, R. and M.P. Menon, *Indicators of true intracerebral hemorrhage: hematoidin, siderophage, and erythrophage.* Blood, 2015. **125**(23): p. 3664.

[61] Wysozan, T.R. and R. Gulati, *Revisiting germinal matrix and ventricular lining cells in cerebrospinal fluid: Potential mimickers of intracranial malignancy.* Diagn Cytopathol, 2021. **49**(3): p. 449-451.

[62] Fernandes, S.P. and L. Penchansky, *Tumorlike clusters of immature cells in* 

*cerebrospinal fluid of infants.* Pediatr Pathol Lab Med, 1996. **16**(5): p. 721-729.

[63] Fischer, J.R., et al., *Blast-like cells in cerebrospinal fluid of neonates. Possible germinal matrix origin.* Am J Clin Pathol, 1989. **91**(3): p. 255-258.

[64] Kumar, N., et al., *Superficial siderosis.* Neurology, 2006. **66**(8): p. 1144-1152.

[65] Albayram, M.S., et al., *Frequency, Extent, and Correlates of Superficial Siderosis and Ependymal Siderosis in Premature Infants with Germinal Matrix Hemorrhage: An SWI Study.* AJNR Am J Neuroradiol, 2020. **41**(2): p. 331-337.

[66] Strahle, J.M., et al., *Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage.* Neurosurgery, 2014. **75**(6): p. 696-705; discussion 706.

[67] Klebe, D., et al., *Acute and delayed deferoxamine treatment attenuates long-term sequelae after germinal matrix hemorrhage in neonatal rats.* Stroke, 2014. **45**(8): p. 2475-2479.

[68] Li, Q., et al., *Targeting Germinal Matrix Hemorrhage-Induced Overexpression of Sodium-Coupled Bicarbonate Exchanger Reduces Posthemorrhagic Hydrocephalus Formation in Neonatal Rats.* J Am Heart Assoc, 2018. **7**(3).

[69] Zhang, Y., et al., *Bliverdin reductase-A improves neurological function in a germinal matrix hemorrhage rat model.* Neurobiol Dis, 2018. **110**: p. 122-132.

[70] Qing, W.G., et al., *Brain edema after intracerebral hemorrhage in rats: the role of iron overload and aquaporin 4.* J Neurosurg, 2009. **110**(3): p. 462-468.

[71] Tortora, D., et al., *Quantitative susceptibility map analysis in preterm neonates with germinal* 

*Germinal Matrix-Intraventricular Hemorrhage: Current Concepts and Future Direction DOI: http://dx.doi.org/10.5772/intechopen.99275*

*matrix-intraventricular hemorrhage.* J Magn Reson Imaging, 2018. **48**(5): p. 1199-1207.

[72] Klebe, D., et al., *Modulating the Immune Response Towards a Neuroregenerative Peri-injury Milieu After Cerebral Hemorrhage.* J Neuroimmune Pharmacol, 2015. **10**(4): p. 576-586.

[73] Chen, S., et al., *An update on inflammation in the acute phase of intracerebral hemorrhage.* Transl Stroke Res, 2015. **6**(1): p. 4-8.

[74] Yang, Y., et al., *Attenuation of acute stroke injury in rat brain by minocycline promotes blood-brain barrier remodeling and alternative microglia/macrophage activation during recovery.* J Neuroinflammation, 2015. **12**: p. 26.

[75] Tang, J., et al., *Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2.* Mol Neurobiol, 2016. **53**(3): p. 1935-1948.

[76] Feng, Z., et al., *Anti-inflammation conferred by stimulation of CD200R1 via Dok1 pathway in rat microglia after germinal matrix hemorrhage.* J Cereb Blood Flow Metab, 2019. **39**(1): p. 97-107.

[77] Karimy, J.K., et al., *Inflammationdependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.* Nat Med, 2017. **23**(8): p. 997-1003.

[78] Flores, J.J., et al., *PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats.* Neurobiol Dis, 2016. **87**: p. 124-133.

[79] Strahle, J., et al., *Mechanisms of hydrocephalus after neonatal and adult*  *intraventricular hemorrhage.* Transl Stroke Res, 2012. **3**(Suppl 1): p. 25-38.

[80] Klebe, D., et al., *Posthemorrhagic hydrocephalus development after germinal matrix hemorrhage: Established mechanisms and proposed pathways.* J Neurosci Res, 2020. **98**(1): p. 105-120.

[81] Manaenko, A., et al., *Inhibition of transforming growth factor-β attenuates brain injury and neurological deficits in a rat model of germinal matrix hemorrhage.* Stroke, 2014. **45**(3): p. 828-834.

[82] Ahn, S.Y., et al., *Mesenchymal stem cells prevent hydrocephalus after severe intraventricular hemorrhage.* Stroke, 2013. **44**(2): p. 497-504.

[83] Ding, Y., et al., *Astrogliosis inhibition attenuates hydrocephalus by increasing cerebrospinal fluid reabsorption through the glymphatic system after germinal matrix hemorrhage.* Exp Neurol, 2019. **320**: p. 113003.

[84] Liu, S.P., et al., *Secukinumab attenuates reactive astrogliosis via IL-17RA/(C/EBPβ)/SIRT1 pathway in a rat model of germinal matrix hemorrhage.* CNS Neurosci Ther, 2019. **25**(10): p. 1151-1161.

[85] Mukerji, A., V. Shah, and P.S. Shah, *Periventricular/Intraventricular Hemorrhage and Neurodevelopmental Outcomes: A Meta-analysis.* Pediatrics, 2015. **136**(6): p. 1132-1143.

[86] Reubsaet, P., et al., *The Impact of Low-Grade Germinal Matrix-Intraventricular Hemorrhage on Neurodevelopmental Outcome of Very Preterm Infants.* Neonatology, 2017. **112**(3): p. 203-210.

[87] Volpe, J.J., *Impaired Neurodevelopmental Outcome After Mild Germinal Matrix-Intraventricular Hemorrhage.* Pediatrics, 2015. **136**(6): p. 1185-1187.

[88] Tortora, D., et al., *The effects of mild germinal matrix-intraventricular haemorrhage on the developmental white matter microstructure of preterm neonates: a DTI study.* Eur Radiol, 2018. **28**(3): p. 1157-1166.

[89] Tortora, D., et al., *Regional impairment of cortical and deep gray matter perfusion in preterm neonates with low-grade germinal matrixintraventricular hemorrhage: an ASL study.* Neuroradiology, 2020. **62**(12): p. 1689-1699.

[90] Back, S.A., et al., *Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury.* J Neurosci, 2001. **21**(4): p. 1302-1312.

[91] Xu, G., et al., *Late development of the GABAergic system in the human cerebral cortex and white matter.* J Neuropathol Exp Neurol, 2011. **70**(10): p. 841-858.

### *Edited by Pınar Kuru Bektaşoğlu and Bora Gürer*

Cerebrospinal fluid is an essential, clear, and colorless liquid essential for maintaining homeostasis of the brain and neuronal functioning. Its secretion in adults ranges from 400 to 600 ml per day and it is renewed about four or five times daily. Cerebrospinal fluid is mainly reabsorbed from arachnoid granulations. Any disruption in this wellregulated system, such as overproduction, decreased absorption, or obstruction, could lead to hydrocephalus. This book contains essential knowledge about cerebrospinal fluid anatomy and physiology, pathologies related to cerebrospinal fluid, and treatment strategies for cerebrospinal fluid disorders.

Published in London, UK © 2022 IntechOpen © someone25 / iStock

Cerebrospinal Fluid

Cerebrospinal Fluid

*Edited by Pınar Kuru Bektaşoğlu* 

*and Bora Gürer*