Abstract
Purpose of Review
The diagnosis of brain tumors often leads to complications that are either related to the tumor itself or the tumor-directed and supportive therapies, increasing the burden on the patients’ quality of life and even survival. This article reviews the medical and neurological conditions that commonly complicate the disease course of brain tumors patients.
Recent Findings
Various mechanisms have been newly identified to be involved in the pathophysiology of seizures and brain edema and can help advance the treatment of such complications. There have also been new developments in the management of thromboembolic disease and cognitive impairment.
Summary
Medical and neurological complications are being identified more often in brain tumor patients with the improved survival provided by therapeutic advances. Early and proper identification and management of such complications are crucial for a better survival and quality of life.
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Introduction
The diagnosis of central nervous system (CNS) tumors carries a high risk of medical and neurological complications. While seizures and behavioral changes are mainly attributed to the direct effect of the tumor, thromboembolic events and strokes are indirect effects. In addition, tumor-directed and supportive therapies might lead to complications ranging from mild fatigue and nausea to severe infections and hematological and endocrinological disorders. This review will discuss the common neurological and medical complications that can be observed in brain tumor patients, highlighting their etiologies, diagnostic work-up, and management.
Tumor-Related Epilepsy
Seizures are common in patients with brain tumors. They affect up to 70% of patients during their disease course and are the presenting symptom in up to 40% [1]. They are the most common cause of non-elective emergency department visits and hospital admissions in patients with glioblastoma (GBM) [2]. A diagnosis of tumor-related epilepsy is entertained after a single seizure and leads to psychological distress and increased economic burden. Patients’ quality of life is also impaired with the subsequent loss of independence and concern of tumor progression with each recurrent seizure. The incidence of seizures is the lowest in CNS lymphoma and leptomeningeal disease and highest in low-grade tumors. It can reach 90–100% in developmental tumors such as dysembryoblastic neuroepithelial tumors and gangliogliomas [3, 4]. This can be attributed to their more common cortical location, frequently detected concurrent cortical dysplasia and other structural abnormalities, and a longer survival observed with these tumors [5]. In addition, isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas reduce alpha ketoglutarate to 2-hydroxyglutarate, which structurally resembles glutamate and can activate N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, leading to epileptogenesis [6]. A high expression of glutamate is often identified in the glioma peritumoral environment and has been ascribed to the enhanced activity of system Xc− cystine/glutamate transporter that imports cystine for the synthesis of glutathione in glioma cells and releases glutamate in return [7, 8]. This, in addition to chronic hypoxia that is often observed in brain tumors, contributes to neuronal hyperexcitability [9]. Recent evidence suggests the presence of abundant bidirectional synapses between neurons and glioma cells [10, 11]. Electrochemical signaling via these synapses, predominantly involving neuroligin-3, leads to activation of AMPA receptors and the PI3K-mTOR pathway, with subsequent proliferation of glioma tumor cells [10, 11]. Inhibition of AMPA receptors with anticonvulsants such as perampanel can inhibit both tumor growth as well as seizure activity [10]. On the other hand, seizure refractoriness has been associated with enhanced expression of multi-drug resistance protein 1 (MDR1) that restricts the penetration of lipophilic antiepileptic drugs (AED) [12].
The management of seizures varies widely. Many patients are prescribed prophylactic AED in the perioperative settings for 1–6 weeks according to a survey evaluating neurosurgical practice [13]. However, retrospective and prospective studies found increased toxicity with the use of perioperative prophylactic AED, without any advantage on the incidence of postoperative seizures [14,15,16,17]. Similar studies also failed to show benefit of prophylaxis in preventing the first seizure. Therefore, despite the high risk of seizures in brain tumor patients, the American Academy of Neurology (AAN) practice parameters, first published in 2000, recommended against the routine use of prophylactic AED and recommended tapering off AED within 1–2 postoperative weeks in patients who are medically stable and have no evidence of seizures [18]. More recently, the Society For Neuro-oncology (SNO) and European Association of Neuro-Oncology (EANO) practice guideline update on anticonvulsant prophylaxis in brain tumors also advises against the use of prophylactic anticonvulsants [19].
When treating seizures and choosing an appropriate AED, the patient’s medical comorbidities and the need for concomitant antineoplastic therapies and steroids should be taken into consideration, as some AED can interact with such therapies and reduce their efficacy. Malignant tumors in particular are often treated with chemotherapies and experimental therapies that are metabolized by the hepatic cytochrome P450 system, and concomitant enzyme-inducing AED (EIAED) should be avoided. Temozolomide, the most widely used alkylating agent in the treatment of primary brain tumors, is not affected by EIAED [20]. However, such AED, specifically phenytoin, phenobarbital, and carbamazepine, reduce the effectiveness of steroids and other chemotherapeutic agents used for the treatment of primary and metastatic brain tumors, like etoposide, methotrexate, and topoisomerase inhibitors [21]. On the other hand, valproic acid inhibits cytochrome 2C9, reducing the metabolism of some antineoplastic agents, enhancing their toxicities, as well as aggravating the tremors induced by concurrent steroids [20]. No AED has been found to be superior to another in controlling tumor-related seizures or improving seizure-free survival [19]. Valproic acid is a histone deacetylase inhibitor and was associated with improved survival in a subset of patients with GBM who received concurrent chemoradiation [22, 23]. However, this benefit was not observed in other studies, including one that pooled more than 1800 patients from 4 randomized clinical trials, nor was it observed in lower-grade gliomas [20, 23]. Levetiracetam also lacked a survival benefit. Although perampanel, a highly selective AMPA receptor antagonist, might be theoretically effective in disrupting the glioma-neuron synapses [24], studies showing such benefit are still lacking. Therefore, individualized choice of AED is advised, based on the type of seizures, concomitant therapies, patient’s medical comorbidities, and toxicity profiles of the AED, and should not be influenced by the tumor histology or grade nor the extent of surgical resection [25, 26]. Levetiracetam is the most widely administered AED due to its ease of use and well-tolerated adverse event profile [19]. However, it is associated with a non-dose-related risk of neuropsychiatric side effects [27]. The side effect profiles of commonly used AED are summarized in Table 1. Antiepileptic treatment is often a lifelong commitment. However, AED discontinuation can be considered in carefully selected patients who have a long-term seizure freedom and a low risk of tumor progression [28].
Tumor growth, tumor-associated brain edema, increased intracranial pressure, metabolic disorders, and other tumor-related factors can also precipitate seizures and should be appropriately managed to achieve an adequate seizure control.
Infectious Complications
Pneumocystis jirovecii pneumonia (PJP) is a rare, but potentially fatal infection that can affect brain tumor patients [29]. P. jirovecii is an organism colonizing the lower respiratory tract that is reactivated in immunosuppressive settings, typically lymphopenia, which is mainly observed during a long course of steroids and/or chemotherapy. The pneumonia has a slow gradual onset, and its diagnosis is often delayed. Any brain tumor patient who presents with unexplained fever or respiratory symptoms, in the setting of hypoxemia, lymphopenia, and/or steroid course of more than 4 weeks, should be expeditiously evaluated for PJP. Diagnosis is usually entertained with chest imaging showing bilateral ground-glass changes with apical predominance and peripheral sparing and with polymerase chain reaction (PCR) [30, 31]. Although aggressive treatment is usually effective, this infection can be fatal. However, prophylaxis has shown benefit in reducing the infection rate [32]. The greatest risk of infection is associated with prolonged use of steroids, both during the high-dose treatment and the tapering period [33]. In early studies of glioblastoma patients receiving concomitant temozolomide with radiation therapy, some patients developed PJP [34, 35]. PJP prophylaxis should be considered in patients receiving concomitant temozolomide or a steroid dose equivalent to dexamethasone of 4 mg or greater for more than 4 weeks [36]. The most frequent prophylactic regimen is trimethoprim-sulfamethoxazole. The recommended dose in adults is either once-daily dosing with single-strength (80/400 mg) or double-strength dose (160/800 mg), or a three-times-weekly dosing with the double-strength dose [36]. In case of prior allergy, second-line agents can be used (Table 2). Prophylaxis should continue until lymphocyte counts return to normal and the provoking therapy is discontinued.
Immunosuppression also subjects patients to increased risk of Candida infections. Oropharyngeal candidiasis is the most common manifestation. Local treatment with clotrimazole, miconazole, or nystatin swish and swallow for 7–14 days is recommended.
Brain abscesses can mimic primary and metastatic brain tumors both clinically and radiologically. Usually occurring in immunosuppressive settings, their risk is particularly elevated with neurosurgical interventions in the setting of steroid treatment. It has similar magnetic resonance imaging characteristics to GBM, with a contrast-enhancing rim and a necrotic center. The mean water diffusivity, measured with the apparent diffusion coefficient (ADC) sequence, is typically low in abscesses and high in tumor cysts [37, 38]. However, 5–21% of abscesses can have a high ADC value, and some necrotic GBM and cystic metastases can have a low ADC value, making the differentiation difficult [39, 40]. Dynamic susceptibility contrast-enhanced perfusion MRI may show lower cerebral blood volume in the enhancing rim of the abscess compared to brain tumors [41]. Treatment consists of an emergent surgical evacuation and intravenous antibiotics.
Peritumoral Edema
The blood–brain barrier (BBB) is often disrupted in CNS tumors, causing extravasation of plasma fluids and proteins, leading to vasogenic edema, increased intracranial pressure, and neurologic morbidity [42]. However, the amount of edema identified on brain imaging does not necessarily correlate with the patients’ symptoms. Vascular endothelial growth factor (VEGF), a proangiogenic peptide, is the main cause of increased vascular permeability. It is secreted by tumor and host stromal cells and upregulated in the setting of tissue hypoxia and acidosis, and with specific intrinsic genetic mutations [43, 44]. It stimulates the downregulation of intercellular molecules zonula occludens 1 and 2, leading to fragmentation and fenestrations in the CNS endothelial basement membrane [45,46,47]. Other factors implicated in the disruption of BBB are increased secretion of nitric oxide; increased expression of aquaporins 4 and 5, leukotriene C4, and cyclooxygenase 2 (COX-2); and downregulation of endothelial cell claudins [46, 48,49,50]. Radiation and some systemic chemotherapeutic agents may worsen the vasogenic edema.
Treatment of vasogenic edema should be initiated only if the patient is symptomatic and usually involves glucocorticoids such as dexamethasone. The use of steroids for that purpose was pioneered by Ingraham in 1952 in the postoperative settings and has been implemented in the management of brain metastases in 1957 and for gliomas in 1961 [51]. Steroids are lipid soluble molecules that bind to intracellular glucocorticoid receptors and lead to transcriptional changes affecting multiple pathways in the tumor and endothelial cells, including suppression of VEGF production, and enhanced expression of claudin and occluden proteins [52]. Radiologic improvement in the edema can be observed within 2 weeks of steroid initiation, but a clinical improvement is often noticed sooner. However, steroids reduce the ability of the contrast dye to cross the BBB, resulting in a reduced tumor enhancement, which should not be misinterpreted as tumor regression [53].
Dexamethasone is the preferred steroid given its potent glucocorticoid effect and limited mineralocorticoid activity, avoiding excessive fluid retention. It was initially used by Galicich in 1961 as an initial bolus of 10–40 mg, followed by a 4 mg intramuscular dose every 6 h [51]. However, although its plasma half-life is only 3–4 h, its biological half-life can last up to 54 h, and a single dose maintained a reduction of capillary permeability in a rat glioma model for more than 12 h [54]. Therefore, a once or twice daily administration leads to a similar clinical response as more frequent dosing schedules [55, 56]. Moreover, although higher initial doses correlate with improved clinical benefit, high maintenance doses have similar benefit as lower doses but are associated with more side effects. Improvement in performance status was similar in patients who received a 4 mg daily maintenance dose and those who had similar symptoms and received 8 or 16 mg daily doses in 2 randomized clinical trials [55]. An ASCO/SNO expert panel in 2019 recommended the use of steroids for symptom relief on a temporary basis. The recommended initial daily dose is 4–8 mg for mild symptoms, and 16 mg for moderate to severe symptoms [57]. Despite their undeniable temporary clinical benefit, their use is often associated with a myriad of complications. The most bothersome symptoms reported by patients are increased appetite, weight gain, anxiety, irritability, and insomnia [58]. Other reported side effects include tremor, dyspepsia, gastritis, avascular necrosis, purpura, epidermal lipomatosis, proximal myopathy, Cushing’s syndrome, osteoporosis, and increased risk of venous thromboembolism. The incidence of complications correlates with the treatment dose and duration and increases with hypoalbuminemia [59, 60]. As indicated earlier, prophylactic therapy for PJP should be considered in patients treated with steroids for more than 4 weeks [29, 61].
Corticosteroids may also have a deleterious effect on patient survival. Retrospective analysis of survival data from several datasets showed a worse outcome in GBM patients treated with steroids, even after adjustment for age, extent of surgical resection, performance status, and treatment modality [62, 63]. In addition, steroid-induced hyperglycemia has been independently associated with shorter survival in GBM patients, and the risk of death was positively correlated with the serum glucose level [64, 65]. The long-term use of dexamethasone also induces genetic alterations in the glioma cells, producing an anti-apoptotic effect and resistance to radiation [63]. The immunosuppressive effect of steroids increases the risk of infections, and doses as low as the equivalent of 10 mg of daily prednisone have been associated with lower response rates and survival in trials evaluating novel immunotherapies for brain tumors due to the proapoptotic and reduced functional capacity effects on the lymphocytes [66,67,68,69,70]. Therefore, the lowest clinically effective dose of steroids should be used, and a gradual taper is recommended once clinical improvement is observed. A clinical change from a reduced dose usually manifests after 72 h; hence, the dose should be preferably tapered every 3–5 days, over the course of 2–4 weeks. Taper can be challenging with long-term use due to the risk of adrenal insufficiency. A slower taper should then be considered with doses of dexamethasone of 1 mg or less daily, and transitioning to prednisolone or hydrocortisone if necessary [71].
Various alternative therapies have emerged for patients who experience intolerable side effects from steroids or cannot tolerate their taper. Antiangiogenic agents are the most widely used, especially bevacizumab, a humanized anti-VEGF antibody that is very effective in reducing vascular permeability and decreasing peritumoral edema. A higher rate of steroid reduction was observed in patients receiving bevacizumab in addition to the standard-of-care therapy for GBM and melanoma in multiple phase II and III trials [72,73,74]. VEGFR inhibitors such as cabozantinib can also reduce peritumoral edema [75, 76]. Other steroid-sparing agents include corticorelin acetate, a synthetic peptide formulation of the normal endogenous human corticotropin releasing factor, COX-2 inhibitors (celecoxib and rofecoxib), and extracts of Boswellia serrata. Corticorelin acetate helped reduce the steroid dose in patients with malignant tumors in a phase III trial [77], and COX-2 inhibitors showed some benefit in animal glioma models and one case of metastatic melanoma, whereas boswellic acids have so far only been beneficial in animal glioma models [78,79,80].
Vascular Complications
Venous thromboembolism (VTE) is common in cancer. The expression of tissue factor, podoplanin, plasminogen activation inhibitor 1, and phosphatidyl serine by the tumor cells and circulating tumor microparticles leads to direct platelet activation and aggregation [81,82,83]. On the other hand, indirect activation of platelets occurs in the setting of endothelial dysfunction induced by hypoxia in the tumor microenvironment, the release of damage-associated molecular patterns (DAMPs) by dying cancer cells, the enhanced release of neutrophil extracellular traps by circulating cancer-derived factors, and the metastatic cancer cell dissemination and intravasation into the blood vessels [84, 85]. The incidence of VTE is among the highest in glioma patients, particularly GBM, compared to other cancer patients, reaching a rate of 20–30%, and is associated with a shorter survival [86, 87]. The risk is particularly elevated in the postoperative settings and increases with age, body weight, immobility, and hemiparesis [88, 89]. It also increases with larger tumor size and smaller extent of surgical resection [89, 90]. Moreover, higher histological grade, intraluminal thrombosis on surgical pathology, and some intrinsic genetic alterations, like PTEN loss, EGFR amplification, and activation of the MAPK cascade, are associated with an upregulated tissue factor expression, and subsequently a higher risk of VTE, although the molecular predictors of VTE have not been consistently confirmed [91,92,93,94]. The use of platinum-based chemotherapy and antiangiogenic agents can also increase the risk of arterial and venous thromboses [95].
Since the risk of VTE is particularly common in the postoperative period, and thromboembolic events were responsible for 22% of readmissions in brain tumor patients within 30 days of surgery in a retrospective study, thromboprophylaxis should be considered in patients who undergo craniotomy in the absence of major contraindications [86]. Prophylaxis can be achieved mechanically with intermittent pneumatic compression devices and compression stockings, or chemically with unfractionated (UFH) or low-molecular-weight heparin (LMWH). While both methods reduce the risk of postoperative VTE, the combination of both modalities showed the most benefit without an increased risk of major hemorrhage [96, 97]. Chemical prophylaxis should start within 24 h after craniotomy and can be stopped after few days, or until the patient can ambulate. The role of long-term prophylactic anticoagulation is unclear. A phase III trial evaluating the role of prophylactic dalteparin following surgery was prematurely discontinued but showed a trend towards deceased VTE and higher risk of hemorrhage in the dalteparin arm [98].
Most malignant brain tumors are incurable and remain an active risk factor for VTE justifying the need for lifelong secondary thromboprophylaxis after a diagnosis of VTE. Increased risk of major bleeding is the main concern, particularly intracranial hemorrhage (ICH), that usually has a worse prognosis when occurring in the setting of anticoagulation [99]. Vitamin K antagonists (VKA) are not recommended for cancer-associated VTE due to their limited benefit in preventing recurrent events and the increased risk of major bleeding [100, 101]. LMWH products, such as enoxaparin, dalteparin, and tinzaparin, are generally safe in patients with malignant gliomas and brain metastases and are associated with a greater benefit in reducing the rate of recurrent VTE than VKA, with a similar to lower risk of bleed or death [102,103,104]. Intravenous UFH is recommended for sick patients with an acute progressive VTE event, and LMWH agents are used in stable patients who do not need hospitalization. However, their subcutaneous administration route is associated with increased rates of interruption or discontinuation compared to the oral VKA counterparts [105, 106]. The new direct oral anticoagulants (DOAC) have the advantage of ease of administration, fixed dose regimen, predictable pharmacology, and no need for routine monitoring. Dabigatran is a direct thrombin inhibitor, while rivaroxaban, apixaban, and edoxaban are direct factor Xa inhibitors. A retrospective review of 67 patients with primary brain tumors and 105 patients with brain metastases did not show an increased risk of ICH with edoxaban, rivaroxaban, or apixaban compared to enoxaparin [107]. Edoxaban was found non-inferior to dalteparin in the risk of recurrent VTE and major bleeding in a large open-label non-inferiority trial that included 1050 patients; only 74 of whom had primary or metastatic brain tumors [108]. Similarly, rivaroxaban and apixaban showed a greater benefit in the risk of VTE recurrence than dalteparin, with no increased risk of ICH in multi-center randomized trials [109,110,111]. However, these trials only included a small number of brain tumor patients. DOAC also showed lower VTE recurrence and ICH rates in patients with cancer when compared to VKA [112, 113]. However, while treatment with DOAC is often associated with a greater compliance, their use can be challenging in patients suffering from severe nausea and vomiting [114]. DOAC are also substrates of the cytochrome P450 3A4 and P-glycoprotein, raising the concern of drug-drug interactions with antiepileptic drugs and chemotherapeutic agents that share the same metabolic pathway. UFH or VKA are preferred in patients with chronic kidney disease. Individualized treatment regimens should be applied after a shared decision-making discussion between the physician and the patient, and DOAC can be used if there is a low risk of bleeding and lack of drug-drug interactions with any current systemic therapy [115]. The risk of CNS or intratumoral bleeding can be assessed by the PANWARDS score that was evaluated to predict the incidence of ICH in a large retrospective study and is used to predict the incidence of ICH among patients receiving VKA or DOAC for the treatment of atrial fibrillation [99].
Inferior vena cava (IVC) filters are a non-pharmacological alternative for the treatment of VTE. However, their use should be reserved for patients with a recent or active ICH, or other medical contraindications for pharmacological anticoagulation, as it has been associated with various complications, including recurrent DVT and PE, IVC filter thrombosis, and increased risk of short-term death [116, 117].
Intracranial hemorrhages can also occur spontaneously in brain tumor patients, particularly in oligodendrogliomas, high-grade gliomas, and metastases. They are mostly intratumoral and often occur at the time of progression or with the use of anticoagulation or antiangiogenic agents such as bevacizumab. However, the rate of clinically significant ICH remains low, even with the use of such agents [118,119,120,121].
Cerebral microbleeds (CM) are another common occurrence in CNS tumor patients. They are usually a complication of radiation and tend to increase with time. A retrospective review of pediatric brain tumor patients who had received cranial radiation identified whole brain radiation, older age at radiation, and concurrent bevacizumab use as predictors of CM, and the latency of their development was inversely correlated with the radiation dose [122]. They are believed to result from a radiation-induced vasculopathy with hyalinization and fibrinoid necrosis of vascular walls, leading to vascular proliferative lesions with high bleeding propensity [123, 124]. Although often identified incidentally, they can become symptomatic, manifesting mainly in cognitive dysfunction [125, 126].
Strokes are more common in brain tumor patients than the general population. They occur as a result of tumor resection and/or radiation-induced accelerated atherosclerosis and hypertrophy of the lamina intima of pial vessels, in the setting of a tumor-related hypercoagulable state [127]. The risk increases with antiangiogenic agents. They are often asymptomatic and identified incidentally on regular brain imaging, with no further work-up or management required. However, work-up for alternative etiologies can be considered in symptomatic strokes occurring outside of the radiation field. It is worth noting the lack of increased risk of cardioembolic strokes from a nonbacterial thrombotic endocarditis in brain tumors, unlike other malignancies [128]. Thrombolysis and intraarterial interventions are contraindicated due to the distinct pathophysiology of strokes in brain tumors and the theoretical higher risk of ICH [129, 130].
The syndrome of stroke-like migraine attacks after radiation therapy (SMART) is another latent complication of radiation. It was first described in children by Shuper in 1995, but its incidence has been increasing due to advances in treatment and improved survival [131]. It is characterized by recurrent transient reversible neurological dysfunction that can manifest by migrainous headaches, focal deficits that can last for days, and sometimes seizures [132, 133]. It usually develops years after exposure to a cumulative radiation dose equal or greater than 50 Gy [134]. Its pathophysiology is still unclear, but believed to result from radiation-induced vasculopathy and/or neuronal dysfunction [135, 136]. Brain MRI findings, when present, typically include thickened gyri in the affected areas and cortical enhancement that resolves after the acute event. No clear therapy has been identified yet. Valproic acid, topiramate, methylprednisolone, and verapamil are often used, but with variable evidence of effectiveness.
Endocrine Complications
Diabetes mellitus is a common endocrinologic comorbidity in patients with brain tumors, and it can be precipitated or worsened by high doses of steroids. Acute rises and drops in blood glucose can make the neurological symptoms and seizures worse, and persistent and chronic hyperglycemia is associated with a shorter survival in brain tumor patients [54,55,56]. Hence, a tight blood sugar control is recommended in all patients, particularly the ones with preexisting diabetes mellitus.
Syndrome of inappropriate secretion of antidiuretic hormone may be observed in brain tumor patients. The resulting hyponatremia leads to encephalopathy and seizures, along with worsening focal neurological symptoms. It should be cautiously treated with water restriction and salt supplementation.
Other endocrinopathies involving the hypothalamus-hypophysis-adrenal axis (HPAA) are also common in brain tumor patients and can occur in up to 30% of patients whose radiation field involves the hypothalamus and pituitary gland. They are typically chronic sequelae of childhood brain tumors and start few years after completion of the radiation course [138]. A large retrospective review of childhood brain tumor survivors documented growth hormone deficiency in 46.5% of patients [139]. Deficiencies in all the other HPAA hormones, especially thyroid stimulating hormone and thyroxine were also frequent. A higher radiation dose, a younger age at the time of radiation, hydrocephalus at the time of tumor diagnosis and suprasellar, and infratentorial tumor sites were identified as independent factors in developing deficiency in at least one HPAA domain [139, 140]. Neuroendocrinology expertise is advised in the treatment of these complications. Infertility is among the long-term complications of the HPAA dysfunction but can also result from the mass effect exerted by the tumor or from certain chemotherapies, and fertility risk and preservation counseling should be discussed with all patients of reproductive age prior to treatment [141].
Neurobehavioral Complications
During their disease course, brain tumor patients are at risk of developing multiple psychiatric, cognitive, and behavioral changes. Major depressive disorder is common at the time of diagnosis—it can affect up to 42% of patients and can get worse during the course of the illness; and every patient should be screened for it [142]. Diagnosis with incurable tumors and the loss of independence lead to a depressed mood. Depression is associated with cognitive and functional impairment and reduced quality of life. Antidepressants are safe to use and do not interact with most of the chemotherapeutic agents. However, bupropion should be avoided as it lowers the seizure threshold. Fluoxetine showed a survival advantage in GBM patients in a recent study, but randomized trials are needed to confirm such findings [143]. Non-pharmacologic approaches can also be considered.
Fatigue is also very common in brain tumors, affecting up to 70% of patients during the course of their illness [144]. Its incidence increases with tumor-directed therapy, particularly irradiation [145]. Psychostimulants such as methylphenidate, modafinil, and armodafinil failed to show a significant benefit in randomized trials [146, 147].
Irritability and personality changes can also be observed, particularly with frontal lobe tumors. Steroids can also affect patients’ mood and cause irritability, anxiety, psychosis, mania, and insomnia, and they should therefore be avoided in patients at risk of experiencing such symptoms. Levetiracetam is also a frequent cause of irritability and occasionally depression. Anxiolytics and antipsychotics can be considered for managing such symptoms.
Most patients experience cognitive decline. Frontal and temporal lobe tumors are particularly associated with impairment in attention, executive functioning, and information processing speed. These changes are more pronounced or can be induced by radiation therapy and chemotherapy [148]. Radiation-related cognitive decline is a progressive subcortical dementia [149]. It is more frequent with whole-brain radiation (WBRT) and starts during radiation and gets worse over time [150]. Short-term cognitive changes are mainly related to radiation-induced fatigue and increased intracranial pressure and can be reversible. However, the delayed effects of radiation, including demyelination and vasculopathy, impaired neural stem cell function, and neurogenesis, can lead to progressive and irreversible impairment in cognition, particularly in patients who receive radiation therapy at a young age, those with pre-existing vascular risk factors or treatment with chemotherapies such as methotrexate during or after irradiation [151,152,153,154]. The management of this complication is challenging. Administration of armodafinil concurrently with radiation failed to show benefit in a pilot study, while donepezil showed only a modest benefit in memory, motor speed, and dexterity in a small pilot study and a phase III randomized trial, and this benefit was mainly seen in patients with worse baseline cognitive function [146, 155, 156]. Non-pharmacological approaches, such as cognitive behavioral therapy and cognitive rehabilitation, may be helpful in selected patients [147]. Hippocampal avoidance whole brain radiation (HA-WBRT) helps preserve the radiosensitive, memory-specific neural stem cells of the hippocampus and has shown a reduced decline in memory and an improvement in quality of life compared to the standard WBRT [157, 158]. The addition of memantine was also associated with delayed cognitive decline and better scores on executive function, processing speed, and delayed recognition [159]. Therefore, focal radiation is preferred over WBRT, and hippocampal avoidance and memantine use are recommended whenever WBRT is necessary.
Conclusion
New advances in the management of brain tumors have improved survival and quality of life of patients, although at the expense of increased rate of medical and neurological complications. Any new symptoms or signs in brain tumor patients should be thoroughly evaluated and managed, as some can be life-threatening. The management of these complications often requires a collaboration of a multidisciplinary team of neuro-oncology, oncology, infectious diseases, neuro-endocrine, and vascular disciplines to achieve an adequate therapeutic control while preserving the patients’ quality of life and avoiding major adverse events.
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The editors would like to thank Dr. John Brust for taking the time to review this manuscript.
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Gilbert Youssef declares no potential conflicts of interest. Patrick Y. Wen has received research support from Agios, Astra Zeneca/Medimmune, Bayer, Celgene, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Oncoceutics, Vascular Biogenics, and VBI Vaccines. Dr. Wen also serves on the advisory board of Agios, Astra Zeneca, Bayer, Black Diamond, Boston Pharmaceuticals, Elevate Bio, Imvax, Karyopharm, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Vascular Biogenics, VBI Vaccines, Voyager, and QED.
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Youssef, G., Wen, P.Y. Medical and Neurological Management of Brain Tumor Complications. Curr Neurol Neurosci Rep 21, 53 (2021). https://doi.org/10.1007/s11910-021-01142-x
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DOI: https://doi.org/10.1007/s11910-021-01142-x