I. Introduction Peritumoral brain edema (PTBE), which is mostly seen in gliomas, meningiomas and metastases, is a common clinical problem in neurosurgery and directly affects the diagnosis, treatment and prognosis of tumors. This paper aims to deepen the understanding of neurosurgeons about PTBE in the nervous system, clarify the basic principles of diagnosis and treatment of PTBE, and provide practical and standardized drug treatment recommendations. Definition, risk and mechanism of PTBE 1. Definition PTBE refers to the increased water content in the neural tissue surrounding the tumor associated with central nervous system tumors. Tumors that can cause PTBE mainly include: metastases, gliomas and meningiomas. Most researchers believe that FFBE belongs to vasogenic edema, while cytotoxic factors also play a role in the occurrence of PTBE. 2.Harm Clinical data show that PTBE can affect the tumor revealing during surgery, increase the difficulty of tumor removal, can cause or aggravate neurological dysfunction, and can also cause or aggravate the increase of intracranial pressure. Therefore, PTBE is closely related to the patient’s symptoms and signs, the difficulty of surgery and the occurrence of postoperative complications. The degree of PTBE not only aggravates the tumor’s occupying effect and the degree of neurological deficits, but can also reflect the degree of malignancy of glioma. PTBE can loosen the tissue around the tumor, reduce the resistance of local structures, facilitate the movement of cellular matrix and adhesion molecules associated with invasion, and promote the growth and spread of the tumor. Proteins exuded from brain edema can provide substrate and space for tumor growth and promote tumor cell spreading, leading to highly aggressive tumors. Tumor cell infiltration often occurs within the peritumoral edema area, which may be one of the reasons for recurrence after surgery. The mechanism of FFBE has not been fully elucidated so far, but most scholars believe that it is related to the increase of capillary permeability in the tumor or perineural neural tissue, which leads to the increase of extracellular water content and cerebral edema due to the pressure gradient inside and outside the blood vessels and leakage of plasma into the brain interstitium. It is easy to accumulate water, which can spread along the nerve fibers. It has been demonstrated that PTBE can accumulate at a rate of 14-78 ml/d, but can balance edema formation and absorption through edema absorption mechanisms. Absorption mechanisms include the passage of edema fluid through the ventricular canal into the ventricles or absorption through local capillaries, and leaking protein can be absorbed through astrocytes and microglia. The blood-brain barrier plays a key role in the development of PTBE. Meningioma is an intracranial extracerebral tumor, with the arachnoid membrane, subarachnoid space, soft meninges and cerebral cortex between the tumor and the white matter of the brain. The arachnoid and soft meninges have good permeability to water molecules, but have a blocking effect on large molecules, such as protein components of vasogenic edema fluid; meanwhile, the cerebral cortex is composed of closely interwoven cells, which has the function of blocking the diffusion of vasogenic edema, so its PTBE generation mechanism has some special characteristics. The relevant theories are mainly as follows: (1) Mechanical causes: tumor compresses adjacent brain tissues, leading to brain tissue ischemia, or tumor compresses large draining veins or venous sinuses, etc., and poor venous return leads to PTBE production. (2) Edema-related factor production: such as the release of VEGF. (3) Others: disruption of blood-brain barrier due to hemodynamic reasons, underdevelopment of tumor draining veins, source of tumor blood supply, such as tumor blood supply from both meningeal and intracerebral arteries, higher edema index (E1), tumor invasion into brain tissue, etc. Among them, invasion of brain tissue is the key to PTBE formation in meningioma and an important cause of recurrence after meningioma surgery. Diagnosis of PTBE 1. Clinical manifestations Since PTBE can further aggravate the original occupying effect of tumor, PTBE involving functional brain area can appear or aggravate the corresponding signs and symptoms of neurological deficiency, and can form or aggravate intracranial hypertension. PTBE located around the cerebrospinal fluid pathway may also cause obstruction of the cerebrospinal fluid circulation pathway and secondary obstructive hydrocephalus, resulting in acute intracranial hypertension and, in severe cases, brain herniation. The clinical manifestations of PTBE are non-specific and mainly include: (1) focal neurological deficits: limb movement and/or sensory deficits, speech difficulties, and cranial nerve damage. Epilepsy and altered mental status may also be present. (2) Increased intracranial pressure: headache, vomiting, fundus optic papillary edema, impaired consciousness, altered vital signs such as elevated blood pressure, etc. In severe cases, brain herniation formation may be induced. It should be noted that PTBE located in the posterior cranial fossa can cause severe symptoms and signs of increased intracranial pressure or even formation of obstructive hydrocephalus and brain herniation with mild edema, which often requires emergency treatment. Since PTBE lacks specific manifestations, it is difficult to distinguish it from the symptoms caused by the tumor itself, so its diagnosis mainly relies on imaging examination. Cranial CT: The earliest method used to diagnose PTBE, and it is still one of the main examination means to diagnose PTBE. It mainly shows the hypodense area around the tumor. Magnetic resonance imaging (MRI): MRI is the most reliable method for evaluating PTBE. PTBE is demonstrated on conventional MRI as non-enhancing T1WI low or equal signal and T2WI high signal areas around the tumor. In terms of showing the extent and scope of PTBE, plain T2WI combined with enhanced T1WI is significantly better than CT scan and MRI plain T1WI. injection of enhancer can clearly show the demarcation interface between PTBE and tumor (i.e., the inner edge of the edema zone). However, compared with T2WI, FLAIR imaging technique (i.e. water suppression imaging technique, also known as black water series) is more advantageous for showing the tumor boundary and the extent of edema, and thus is often used as a standard for quantitative assessment of cerebral edema. 3.Imaging grading Currently, EI is often used to grade PTBE, which is classified into no edema, mild edema, moderate edema and severe edema according to the size of EI value. The EI is calculated as follows: EI = edema plus volume of tumor / volume of tumor. When El=1, no edema; when El=1~1,5, mild edema; when EI=1,5-3, moderate edema; when EI>3, severe edema. IV. Pharmacological treatment of PTBE 1. Meaning and objectives (1) Create favorable timing for intracranial surgery. Intracranial tumor is the root cause of PTBE, and resection of tumor is the fundamental method to treat PTBE. In patients with PTBE, the difficulty of surgical resection of tumor increases because the edematous tissue is not conducive to reveal the tumor in the intraoperative surgical field; meanwhile, the hospitalization time of patients with PTBE is significantly prolonged. Therefore, effective preoperative control of PTBE will create a more favorable time for surgery and improve the success rate of surgery. (2) Reduce postoperative complications and improve the survival rate of patients. 4%-23% of patients with PTBE die after surgery, and the incidence of postoperative intracranial hematoma and intracranial hypertension is also significantly higher. Some studies have shown that patients with concomitant PTBE have a higher recurrence rate after surgery, and the more severe the edema, the greater the likelihood of patient recurrence. (3) Reduction of intracranial pressure. Patients with moderate to severe PTBE have a higher rate of increased intracranial pressure such as headache, vomiting, and fundus edema than patients without FTBE¨8I, so enhanced treatment of PTBE is beneficial in reducing the risk of patients developing increased intracranial pressure. (4) Reduce the signs and symptoms of neurological deficits in patients. The incidence of epilepsy and limb sensorimotor disorders is significantly higher in patients with moderate to severe PTBE than in patients without PTBE; Vignes et al. showed that patients with meningioma with PTBE had more severe neurological symptoms, and epilepsy occurred in about 30% of patients; reducing PTBE helps to reduce the incidence of epilepsy. Glucocorticoids have been used for the treatment of PTBE since 1960, and because glucocorticoids are more effective in treating edema in the area of blood-brain barrier disruption, the European Academy of Neuro-Oncology (EANO) Guidelines for the Treatment of PTBE in 2003 recommended glucocorticoids as the only first-line treatment for PTBE. Based on previous clinical studies and authoritative foreign guidelines, we recommend the use of glucocorticoids for PTBE in patients with one of the following conditions: (1) perioperative applications in PTBE patients; (2) PTBE patients with signs and symptoms of severe neurological deficits; (3) PTBE patients with concomitant intracranial hypertension; (4) other patients with imaging evidence clearly indicating the presence of PTBE. Glucocorticoids should be used with caution or contraindicated in patients with the following conditions: (1) hyperadrenocorticism (Cushing’s syndrome): excessive plasma cortisol production due to excessive ACTH secretion by the pituitary gland or tumor; (2) active tuberculosis, infections that are difficult to control with drugs such as chickenpox, measles, mumps, etc. In these patients, hormone therapy should not be used without effective control of the infection; (3) active tuberculosis, infections that are difficult to control with drugs, such as chickenpox, measles, mumps, etc. (3) Active peptic ulcers: hormones can lead to enlargement and deepening of the ulcer area, bleeding and perforation in serious cases; (4) Diabetic patients whose blood sugar is difficult to control. Commonly used glucocorticoids are: methylprednisolone, dexamethasone, prednisone, hydrocortisone. Methylprednisolone and dexamethasone have less sodium retention and other salt corticosteroid-like effects compared to other glucocorticoids, so they are more suitable as therapeutic drugs for PTBE. The receptor affinity of different glucocorticoids differs, and hormones with high receptor affinity have faster onset of action and are more likely to achieve therapeutic goals. A study showed that the difference in efficiency between methylprednisolone and dexamethasone in the treatment of PTBE was not statistically significant, but the apparent efficiency was better than that of dexamethasone (P<0.05). In addition, methylprednisolone has higher lipophilicity and can cross the blood-brain barrier more quickly. After 1-10 min of intravenous injection, it can penetrate the blood-brain barrier and enter the brain tissue, while dexamethasone without c-cylinder methyl penetrates the blood-brain barrier and takes significantly longer than methylprednisolone to enter the brain tissue. Therefore, we recommend methylprednisolone for severe PTBE patients who need rapid edema reduction. In addition, because the fluorine group of dexamethasone C. increases the anti-inflammatory efficacy while also increasing the inhibition of the hypothalamic and pituitary-adrenocortical (HPA) axis (for up to 48 h), one should be alert to adverse effects associated with HPA inhibition when discontinuing the drug. Methylprednisolone, on the other hand, has a weak inhibitory effect on HPA and is less likely to cause withdrawal syndrome. Therefore, we tend to recommend methylprednisolone when high doses of hormones are needed. There is no widely accepted principle for the application of glucocorticoids in the field of neuro-oncology. We believe that the principle of glucocorticoid treatment for PTBE should be to balance efficacy and safety, and to achieve and maintain satisfactory efficacy while keeping the duration of application as short as possible. The first-line drugs commonly used in the treatment of PTBE are: methylprednisolone and dexamethasone. The specific regimens are as follows: (1) Dexamethasone and methylprednisolone should be preferred because of their small salt corticosteroid-like effects. Methylprednisolone is recommended when the patient has ionic disorders or edema that requires high dose application. (2) Start with low doses and adjust gradually as needed. Referring to the EANO protocol, we recommend: A. The starting dose of dexamethasone for intravenous use is 15 mg/d, which can be increased to 25 ms/d when the conventional dose is ineffective, and discontinued after 14 d. The daily dose can be given in 2-4 divided doses. Hormone toxicity begins to increase at doses above 25 mg/d. In patients with common edema, doses exceeding 25 mg/d are not recommended. b. The initial dose of methylprednisolone is 80 mg/d for 48 h. If signs and symptoms do not resolve, the dose can be increased to 160 mg/d (80 mg, 2 doses/d) intravenously. If the symptoms are severe with large edema (PTBE index is moderate or severe), 160 mg/d (80 mg, 2 times/d) can be applied directly intravenously. Due to the side effects of hormones, caution should be exercised when applying doses above 160 mg/d. Although there are reports of application up to 500 raged (shock dose), the course of treatment should be shortened as much as possible, generally not exceeding 3 d, and the side effects of hormones should be closely monitored. (3) If the effect is satisfactory after 7 d treatment, the hormone dosage should be reduced. a. For patients with mostly resected tumors, more limited edema and no symptoms and signs, glucocorticoids should be discontinued within 2-3 weeks. Patients with <21 d of medication. Withdrawal symptoms are less common. Reduce the dose by 50% every 3-4 days. If clinical symptoms worsen, the dose can be restored to the previous dose. b. For patients with partially resected or unresected tumors with PTBE, glucocorticoids need to be reduced more slowly, by 25% every 8 days. c. Glucocorticoid therapy can be gradually stopped when the patient's symptoms and signs are in remission after surgery; if the PTBE symptoms and signs recur or do not remit after surgery, the drug can be continued, but should be maintained at the lowest dose if the treatment is effective. However, the lowest dose should be maintained if the treatment is effective. It is worth noting that the relationship between hormone dosage and PTBE classification is uncertain at present. In the future, after obtaining reliable clinical evidence-based medical evidence, the hormone treatment plan may be further optimized according to the characteristics and degree of PTBE. 4. Adverse reactions and treatment Some adverse reactions may occur with glucocorticoid therapy, which are usually dose-dependent. During the treatment period, patients' plasma protein, blood glucose and potassium should be routinely monitored, and attention should be paid to control the dose and course of glucocorticoids. Especially when the patient's serum protein is below 25 g/L, the occurrence of adverse events should be highly alerted. In addition, the prolonged application of dexamethasone may inhibit the HPA axis, leading to the decline of adrenocortical function and adverse stress reactions in patients. 5. Hormone reduction and withdrawal Glucocorticoid withdrawal can produce hormone withdrawal syndrome, which is a series of symptoms caused by the suppression of HPA axis leading to insufficient adrenal gland function, mainly manifested as headache, drowsiness, hypothermia, muscle pain, etc. Sometimes it can lead to joint pain and affect walking; in serious cases, disorders of vital signs such as hypotension may occur. Withdrawal syndrome is usually seen when hormone application is rapidly stopped, especially in long-term high-dose application. HPA axis suppression is related to the dose and duration of drug use, and the recovery period of adrenal function varies from a few days to a year depending on individual patients. Patients on short-term hormone therapy can be rapidly discontinued. In patients with long-term hormone use, to avoid withdrawal syndrome, the drug should be discontinued gradually, usually by reducing the dose by 50% every 4 days. In patients with severe cerebral edema, rapid discontinuation may worsen the symptoms, usually by 25% every 8 days, and can be maintained by long-term application of low-dose dexamethasone (1-2 mg/d). Continuous application of high doses (e.g., methylprednisolone 500 mg/d) of hormones is neither necessary nor safe for patients, and generally such high doses should not be used for more than 3 d. If high doses for 3 d are ineffective, the hormones can be discontinued directly. For patients with higher starting doses, the interval between hormone reductions can be shortened, and when the reduction is close to the physiological level (equivalent to 30 mg/d of cortisone), the rate of reduction needs to be slowed down. Patients whose condition continues to deteriorate after stopping the drug can apply hormone for a long time. 6. Treatment of patients with PTBE combined with increased intracranial pressure Although the mechanisms of action are different, glucocorticoids and osmotic dehydration agents are both effective in reducing intracranial pressure. It should be noted that PTBE and intracranial hypertension are two completely independent concepts: patients with severe PTBE do not necessarily have combined intracranial hypertension, and vice versa. Likewise, the clinical benefit of treating PTBE is not only in the form of a reduction in intracranial pressure. In the 1980s, mannitol was considered to be used together with glucocorticoids for the treatment of PTBE, and osmotic dehydration drugs such as mannitol remain important for symptomatic relief of patients with intracranial tumors in combination with increased intracranial pressure, especially in cases of critical intracranial hypertension. However, "increased permeability of the blood-brain barrier" is the determining factor in the development of PTBE. Therefore, the key to treat PTBE is to restore and reconstruct the blood-brain barrier and keep the blood-brain barrier permeability stable. Hypertonic drugs can reduce the water content in intracranial tissues rapidly by increasing intravascular osmotic pressure, thus reducing the volume of intracranial tissues and achieving the effect of reducing intracranial pressure. However, when "the permeability of the blood-brain barrier increases", the reduction of intracranial pressure by hypertonic drugs does not improve the PTBE tissue. On the contrary, due to the disruption of the blood-brain barrier, hypertonic drugs penetrate into the brain parenchyma in the PTBE area, which may lead to increased local edema and "rebound phenomenon". To date, there is no reliable evidence-based evidence on the efficacy of osmotic dehydrating drugs such as mannitol for PTBE itself. Therefore, for the treatment of patients with severe PTBE combined with increased intracranial pressure, osmotic dehydrating drugs such as mannitol should be used in combination with adequate amounts of glucocorticoids. V. Summary PTBE is one of the common problems in neurosurgery, which is closely related to the treatment of intracranial tumors and should be paid attention to by all physicians. Glucocorticosteroids are the first choice for PTBE treatment, and methylprednisolone or dexamethasone are commonly used clinically, and their efficacy has been confirmed. In clinical practice, attention should be paid to the rational use of glucocorticoids to reduce the occurrence of side effects. This paper draws on the relevant consensus of foreign experts in the treatment of PTBE and combines the clinical experience of domestic experts, which was finally reached after thorough discussion. The purpose of this paper is to guide neurosurgeons to further reduce the harm of PTBE through comprehensive prevention and treatment, and to improve the efficacy and prognosis of patients with intracranial tumors.