non_invasive_aICP_Tumor
non_invasive_aICP_Tumor
Since decades, neurosurgeons and neurooncologists assumed that the mass effect of brain
 tumors with peritumoral edema or intratumoral hemorrhage might lead to increased ICP.
 Therefore, decisions on surgical procedures and medical treatments were made based on
 clinical and radiological findings suggesting increased ICP. But in fact, no measurement has
 ever confirmed increased ICP in brain tumor patients. From an ethical point of view, it is
 not justifiable to implant an intraparenchymal ICP probe within an invasive surgical
 procedure in a brain tumor patient unless the patient is comatose or present with rapid
 impairment of the level of consciousness. Therefore, with the new medical device for
 non-invasive ICP measurement presented in this study protocol, we will be able to measure
 absolute ICP values in patients with brain tumors.
Primary brain tumors in adults are less common than metastatic tumors. The most frequent are
 glioblastoma multiforme, metastases, anaplastic astrocytoma, meningioma, pituitary tumors and
 vestibular schwannoma. 70% of the tumors in adults are supratentorial. The most
 infratentorial tumors are metastases, schwannoma, meningioma, epidermoid, hemangioblastoma,
 and brainstem glioma. Causes of brain tumors are genetics, radiation, immunosuppression,
 viruses and chemotherapy.

 Clinically patients present with neurological deficits as hemiparesis, cranial nerve
 deficiency or signs of raised ICP such as headache, nausea, vomitus, vigilance disturbance.
 After clinical assessment, standard MRI with contrast agent is performed to visualize the
 size and structure of the tumor, contrast uptake, peritumoral edema (PTE), and other
 radiological findings. Depending on the tumor, size and location, the further procedure must
 be defined with either surgical resection, observation, other adjuvant therapies. Mostly, a
 histological diagnosis is needed to know the tumor biology and set supplementary treatment.

 In patients with brain tumors with mass effect and peritumoral edema with consecutive midline
 shift increased intracranial pressure (ICP) is usually considered. During the expansion of an
 intracranial mass lesion, there is initially a minimal increase in ICP, but as compensatory
 capacity is exhausted the volume pressure curve rapidly steepens, and by further expansion of
 the mass a distinct increase in ICP results.

 Supratentorial tumors can produce significant mass effect in the brain. In certain tumor
 types, especially metastases, high grade gliomas, and meningeomas significant peritumoral
 edema that lead to elevation of intracranial pressure might be associated. In cases of
 infratentorial tumors with or without edema earlier clinical decompensation with
 hydrocephalus, increased ICP and downward herniation are more often due to reduced space
 within the posterior fossa. Within the closed bony cranium, increase of volume, such as tumor
 with associated edema or hemorrhage, ischemia, occlusion of venous perfusion or hydrocephalus
 lead to an increase of ICP and secondary injury to the normal brain. PTE is caused by
 vasogenic edema in particular, but also cytotoxic edema, tumor-related-pressure, arterial
 blood supply, venous congestion and secretion of angiogenic factors such as vascular
 endothelial growth factor (VEGF). VEGF, Aquaporin-4 (AQP4), cyclooxygenase-2 (COX- 2), and
 nitric oxide (NO) induce dysfunction of tight junction proteins playing an important role in
 the formation of edema. Cerebral edema induced by brain tumor is characterized by an increase
 in the permeability of brain capillary endothelial cells and an increase in the brain water
 content. Peritumoral vasogenic edema as a result of blood-brain-barrier dysfunction within
 the tumor affects neurological function and quality of life, and may even cause
 life-threatening raised intracranial pressure.

 Cerebral blood flow (CBF) and the carbon dioxide (CO2) reactivity, are known to be reduced in
 patients with brain tumor, especially those with pronounced signs of intracranial
 hypertension.The study reported by Chang et al. showed, that the mean CBF of both hemispheres
 in each group was not significantly different from brain tumor patients with peritumoral
 edema to age-matched controls. Cerebrovascular reactivity (CVR) was preserved in patients
 with mild peritumoral edema but was significantly reduced in patients with moderate and
 severe peritumoral edema. Surgical removal of the tumor significantly improved the impaired
 CVR, although the mean CBF did not change.

 An earlier study on measurements of intratumoral and peritumoral blood flow as well as within
 the hemispheres indicated, very low flow values in the peritumoral edematous area. These
 findings suggest that the hypodense area surrounding brain tumor may actually represent tumor
 pressure ischemia.

 Certain risk factors for increased edema, such as age, sex, tumor size, neurological
 symptoms, seizures, location, histology, and contrast enhancement, have been identified. The
 extend of PTE has been demonstrated as a predictor of favorable overall survival time in
 patients with larger PTE in metastases, but on the contrary smaller PTE was a statistically
 significant predictor of longer survival in high-grade gliomas. On the other hand it has been
 shown, that postoperative complications were more frequent and duration of intensive care
 treatment was longer in patients with PTE. Outcome was significantly better in patients
 without PTE.

 Steroids are in use since 1960's and play a substantial role in the management of brain tumor
 and increased ICP associated with perilesional edema. Vasogenic edema responds very well to
 corticosteroids, although they have important side effects. Corticosteroids should be used in
 a low dose daily to avoid serious side effects such as myopathy, diabetes, hypertonia,
 osteoporosis, psychiatric alterations, skin thinning and an increased risk for some
 opportunistic infections.

 In the study of Skjoeth et al., brain tumor patients with a substantial amount of edema were
 included. The effect of steroids was monitored during 5 days by clinical examination and
 epidural ICP measurement. ICP reduction was found only in 4 of 13 patients, another 4
 patients with meningioma had a significant increase of ICP and none of them experienced
 clinical improvement.

 Cerebral swelling through the craniotomy can seriously threaten surgical access and increase
 the risk of cerebral ischemia with potential worsening of outcome. Rasmussen et al. observed
 that subdural ICP is the strongest predictor of intraoperative brain swelling. In addition
 midline shift, diagnosis of glioblastoma multiforme and metastasis were significant risk
 factors of intraoperative brain swelling. With an intraoperative ICP greater than 13 mmHg,
 supra- and infratentorial brain swelling occurred with 95% probability and at an ICP greater
 than 26 mmHg, severe brain swelling occurred with 95% probability.

 Cold et al. reported subdural ICP measurements in 29 patients during supra- and
 infratentorial craniotomies. The authors observed, that at subdural ICP < 6 mmHg
 intraoperative brain herniation never occurred. Patients with a subdural ICP greater than 7
 mmHg some brain herniation was documented in all cases, and if subdural ICP was greater than
 11 mmHg, pronounced brain swelling/herniation occurred in all patients. In a follow-up study,
 including patients receiving supratentorial craniotomy cerebral herniation did not occur at
 subdural ICP < 7 mmHg. On the other hand, at ICP >10 mmHg cerebral herniation occurred with
 high probability. These thresholds were independent of anesthetic agent used and the level of
 partial pressure of carbon dioxide (PCO2). Jorgensen et al. reported results of posterior
 fossa craniotomies where at an ICP < 10 mmHg, brain swelling/herniation rarely occurred,
 while at ICP ≥10 mmHg some degree of brain swelling/herniation was always present.
 Interestingly neurosurgeons' tactile estimation of dural tension correlated poorly with any
 tendency to brain swelling/herniation.

 Peritumoral edema is considered to decrease after surgical resection, but there are cases
 where the edema enlarges postoperatively. Ono and other authors presented cases with
 postoperative progressive edema. Correlating to this results, it has been proven, that
 postoperative sustained ICP elevation occurs and the rise in ICP occurred before any
 neurological deterioration was noticed. Similarly, studies showed, that edema increases after
 radiotherapy or radiosurgery.

 Although it is suspected that intracranial lesion with mass effect might cause increased ICP,
 there is no clinical evidence proven yet. Raised ICP can cause clinical manifestations and
 symptoms such as headache, nausea, vomiting, and neurological deficits. These signs, which
 are known as intracranial hypertension signs, are variable and have not been validated due to
 the lack of technological tools to measure ICP non-invasively. To date, only intra- and
 postoperative measurements of increased ICP have been shown with intraparenchymal ICP probes
 or intraventricular catheters.

 The inspection of the ocular fundus would be an option to detect papilledema as a sign of
 intracranial hypertension. Nevertheless, papilledema is considered to have a late onset since
 it takes some time to be developed and not all patients with brain tumors present with fundus
 abnormalities. Moreover, if the patient has a preexisting condition such as high blood
 pressure causing intracranial hypertension and chronic papilledema, it will be difficult to
 assess the changes.

 Currently, ICP can be measured and registered only using invasive techniques. The two ICP
 measurement methods available - intraventricular and intraparenchymal - require both a
 neurosurgical procedure, in order to implant the catheter and probes within the brain
 parenchyma and ventricles. Thus, these measures include themselves a risk for the subject.
 Infections and intracranial bleedings related to invasive ICP measurement techniques are
 considered frequent complications. In addition, invasive recording of ICP requires
 neurosurgical expertise and intensive care unit (ICU) facilities. Present review articles
 conclude that there is still a lack of non-invasive techniques for accurate measurement of
 the ICP.

 Intracranial pressure (ICP) measurement is clinically important in several pathophysiology
 conditions. Cerebrospinal fluid (CSF) pressure is the reference for the "gold standard"
 invasive ICP measured via a brain ventriculostomy or by lumbar puncture in patients with free
 CSF circulation. Elevated ICP is a critical indication for treatment of patients with acute
 neurologic condition, and the best approach to management is considered to be different
 depending on the underlying pathophysiology. ICP can only be measured using invasive methods
 in routine clinical practice. The most common application of ICP monitoring is in the
 management of patients with severe closed head injury or some other neurologic disorders.

 The concept of non-invasive ICP measurement has been discussed since the 1980s. Numerous
 methods for finding the objects or physiological characteristics of cerebrospinal system that
 would be related to the ICP and its monitoring have been postulated by many authors. Most of
 the proposed technologies were based on ultrasound and were capable of monitoring blood flow
 in intracranial or intraocular vessels, cranium diameter, or acoustic properties of the
 cranium. Broad research has extended into sonography of optic nerve sheath and its relation
 with elevated ICP. However, most of these correlation-based methods had the same problem -
 the need of individual patient specific calibration.

 Seeking to measure absolute ICP values, researchers from Kaunas University of Technology
 created a non-invasive method, which does not need a patient specific calibration. The method
 is based on direct comparison of ICP value with the value of pressure Pe that is externally
 applied to the tissues surrounding the eyeball. Intracranial segment of ophthalmic artery
 (OA) is used as a natural sensor of ICP and extracranial segment of OA is used as a sensor of
 Pe. A special two depth transcranial Doppler (TCD) device is used as a pressure balance
 indicator when ICP = Pe. Accuracy, precision, sensitivity, specificity, and diagnostic value
 of this method were proven with patients with mild neurological diseases. This device has not
 yet been used in clinical studies to investigate ICP in brain tumor patients. A study of our
 neurosurgical department to validate the accuracy of non-invasive ICP measurement compared to
 invasive measurement techniques is ongoing.

 Since decades, neurosurgeons and neurooncologists assumed, that the mass effect of brain
 tumors with peritumoral edema or intratumoral hemorrhage might lead to increased ICP.
 Therefore, decisions on surgical procedures and medical treatments were made based on
 clinical and radiological findings suggesting increased ICP. But in fact, no measurement has
 ever confirmed increased ICP in brain tumor patients. From an ethical point of view, it is
 not justifiable to implant an intraparenchymal ICP probe within an invasive surgical
 procedure in a brain tumor patient unless the patient is comatose or present with rapid
 impairment of the level of consciousness. Therefore, with the new medical device presented in
 this study protocol, we will be able to measure absolute ICP values in patients with brain
 tumors. The aim of the study is to correlate absolute ICP values with clinical and
 radiological (tumor size, midline shift and peritumoral edema) parameters which are defined
 as intracranial hypertension signs in brain tumor patients. The observations obtained in this
 study have important clinical implications to neurosurgeons, neurologists, and
 neurooncologists in order to define the timing of surgical procedures, medical treatments
 such as steroids and osmotic agents and indications for monitoring in the ICU.
Inclusion Criteria:

 -  Patient with diagnosed brain tumor with signs of mass effect, occlusive hydrocephalus,
 and/or perilesional brain edema on CT scan or magnetic resonance imaging (MRI).

 -  Clinical symptoms for intracranial hypertension such as headache, nausea, vomiting,
 neurological deficits, cognitive deficits, hemiparesis or cranial nerve deficits.

 -  Age: ≥ 18 years at admission

 -  Informed consent

 Exclusion Criteria:

 -  Patients with wounds, scars including the front orbital region.

 -  Patients with any known ocular condition that may be worsened by sustained eye
 pressure