Medical Care of Patients With Brain Tumors
CONTINUUM: Lifelong Learning in Neurology
Drappatz, Jan MD
Address correspondence to Dr Jan Drappatz, UPMC Cancer Pavilion, 5150 Centre Avenue, 5th Floor, Pittsburgh, PA 15232, email@example.com.
Relationship Disclosure: Dr Drappatz reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Drappatz reports no disclosure.
- case 1-1
- cerebral edema
- case 1-2
- thromboembolic complications
- case 1-3
- neurocognitive symptoms
- key points
Purpose of Review: Patients with brain tumors require close attention
to medical issues resulting from their disease or its therapy.
Effective medical management results in decreased morbidity and
mortality and improved quality of life. The most frequent
neurology-related issues that arise in these patients include seizures,
peritumoral edema, venous thromboembolism, fatigue, and cognitive
dysfunction. This article focuses on the most recent findings for the
management of the most relevant medical complications among patients
with brain tumors.
Recent Findings: Increasing evidence suggests that anticoagulation in
patients with thromboembolic complications is safe even when they are
receiving antiangiogenic therapy. There are also increasing data to
support the use of newer, non–enzyme-inducing antiepileptic drugs, which
have the advantage of lacking interactions with antineoplastic agents
and are as effective as their older counterparts at preventing seizures.
Relatively few studies have addressed the management of fatigue and
depression, and definitive recommendations cannot be made.
Summary: Corticosteroids to treat vasogenic edema should be used at
the minimum amount required to control symptoms and should be tapered as
quickly as possible. Anticonvulsants should be used only if patients
have had seizures. Non–enzyme-inducing antiepileptic drugs are preferred
to minimize interactions with concurrently administered chemotherapy.
Thromboembolic complications are common and are preferably treated with
low-molecular-weight heparins. Only patients with hemorrhagic
complications require an inferior vena cava filter. Cognitive deficits
are frequent in patients with brain tumors and include problems such as
poor short-term memory, distractibility, personality change, emotional
lability, loss of executive function, and decreased psychomotor speed.
Stimulants can help to improve these symptoms.
Seizures are a major cause of morbidity associated with brain
tumors. The incidence of seizures among patients with brain tumors
ranges from 30% to 70%. Patients with low-grade gliomas present more
frequently with seizures (60% to 85%) than those with high-grade gliomas
(20% to 40%) or brain metastases (15% to 20%)1–3 (Case 1-1). Cortical tumors are more epileptogenic than infratentorial, deep gray, or white matter lesions.
A 52-year-old woman an with unremarkable past medical history was
found collapsed in her home. She was oriented to her name only and did
not recognize her son. She was transferred by ambulance to a local
hospital where she regained only spotty recall of recent events. She was
noted to have a large bruise on her right forehead and a tongue bite.
Her workup included an MRI scan, which demonstrated a nonenhancing T2
hyperintense lesion in her temporal lobe approximately 9 cm by 4 cm in
size (Figure 1-1).
CSF examination was unrevealing. She was started on levetiracetam for
presumed seizure and has remained seizure free since. Biopsy of her
lesion several weeks later demonstrated a low-grade (World Health
Organization grade II) astrocytoma.
FIGURE 1-1. Axial fluid-attenuated inversion recovery MRI
demonstrating abnormal signal in the right anterior and medial right
temporal lobe without associated enhancement.
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Comment. Seizures are a common presenting symptom of a
brain tumor. For patients who present with seizures, long-term treatment
with a single non–enzyme-inducing antiepileptic is recommended.
underlying pathophysiology is not completely understood. Presumed
mechanisms include an imbalance between inhibitory and excitatory,
mainly glutamatergic, mechanisms; changes within peritumoral brain
tissue; and the relative deafferentation of cortical areas, known to
induce epileptogenic foci, which can be distant from the tumor location.4
Status epilepticus is not common but usually occurs at the time of
diagnosis or progression. It is associated with high mortality, similar
to status epilepticus from other causes.5,6
Prophylactic antiepileptic drugs (AEDs) are often used on the
basis of the individual preference of the treating physician rather than
clinical evidence. A meta-analysis of five randomized trials of 403
patients diagnosed with glial tumors, meningiomas, and brain metastases
found no benefit of anticonvulsant prophylaxis with phenobarbital,
phenytoin, or valproic acid among patients without history of seizures.7
A different meta-analysis exploring the potential benefit of AED
prophylaxis after supratentorial surgery favored the use of phenytoin to
prevent early seizures in patients with brain tumors undergoing
However, there was no evidence that phenytoin or carbamazepine reduced
the incidence of seizures later on compared with placebo or no
Known adverse effects with anticonvulsant therapy
include rash (including Stevens-Johnson syndrome), myelosuppression,
fatigue, ataxia, hepatotoxicity, osteomalacia, tremor, and cognitive
dysfunction. The incidence and severity of these side effects is higher
in patients with brain tumors than in other patients receiving
anticonvulsants,9–11 mandating changes in or discontinuation of AED therapy in a significant proportion of patients with brain tumors.9
Considering the lack of evidence supporting the use of
prophylactic anticonvulsants, an AAN practice parameter states that
prophylactic AEDs should not be administered routinely to patients with
newly diagnosed brain tumors (standard) and should be tapered and
discontinued in the first postoperative week in patients who have not
experienced a seizure (guideline).9
Despite these recommendations, 89% of adult patients with glioma in a
recent study received AEDs, even though only 32% presented with
Once a patient with a brain tumor has a seizure, long-term
treatment with AEDs is indicated because of the high risk of recurrence.
Even if complete seizure control cannot be achieved, AED therapy may
decrease seizure severity and frequency. The choice of anticonvulsant
should take into consideration the potential for drug-drug interactions
with antineoplastic agents.
oxcarbazepine, and phenobarbital are known as enzyme-inducing
antiepileptic drugs (EIAEDs) because they induce CYP450 enzymes, leading
to a reduction in the plasma levels of many antineoplastic drugs.
EIAEDs also interact with dexamethasone, which is used to treat
peritumoral edema. Dexamethasone induces CYP450 enzymes, potentially
lowering levels of AEDs metabolized by the cytochrome P450 system.
Conversely, the use of EIAEDs may result in the need to increase the
dose of dexamethasone to produce the same therapeutic effect.13
Valproic acid is a CYP450 inhibitor and reduces clearance of other
drugs metabolized by this pathway. Most of the newer agents (eg,
lacosamide, levetiracetam, gabapentin, pregabalin, lamotrigine,
topiramate, tiagabine, and zonisamide) do not induce the CYP450 system
and should be preferentially used in patients with brain tumors. Several
studies have demonstrated that monotherapy with levetiracetam is safe
and effective in treating and preventing seizures in patients with brain
The general principles for management of epilepsy apply to
patients with brain tumors. Patients should be treated with a single
agent at the lowest dose that effectively controls seizures.
Tables 1-1 and 1-2
list commonly used AEDs with their doses, side effects, and the US Food
and Drug Admin is tration (FDA)–approved indication. If the initial
drug does not work at the highest-tolerated dose, then patients should
be switched to monotherapy with a second drug. The use of multiple AEDs
should be reserved for refractory cases because side effects increase
with the number of AEDs used. Although the FDA has approved the
marketing of some AEDs for adjunctive use only, many of the non-EIAEDs
are frequently used as monotherapy.17
Few studies comparing the efficacy of different anticonvulsants exist.
The selection of the AED for an individual patient is usually made on
the basis of considerations of side effect profile, pharmacokinetic
properties, administration, and mode of action.
TABLE 1-1 Enzyme-Inducing Antiepileptic Drugs Used for Patients With Brain Tumors
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TABLE 1-2 Non-Enzyme-Inducing Antiepileptic Drugs Used for Patients With Brain Tumors
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Some AEDs have useful concomitant effects. Topiramate and zonisamide
can cause weight loss, and lamotrigine and valproic acid are mood
Antiepileptic Drug Interactions With Antineoplastic Agents
Many chemotherapy agents commonly used in patients with brain
tumors, such as cisplatin, carboplatin, carmustine, and methotrexate,
interact with AEDs such as phenytoin, reducing their bioavailability.
The mechanisms implied include impaired AED absorption, cytochrome P450
enzyme induction, and altered protein binding. EIAEDs in return
accelerate the metabolism of many chemotherapeutic agents, including
thiotepa, taxanes, and irinotecan,18,19
as well as many of the newer targeted molecular agents. Glucocorticoids
such as dexamethasone also induce the cytochrome P450 system. If given
with dexamethasone or prednisone, phenytoin concentrations should be
monitored closely, and the dose should be adjusted if necessary.
Temozolomide is not known to have interactions with anticonvulsants.
Valproic acid inhibits the glucuronidation of SN-38, the active
metabolite of irinotecan, leading to increased irinotecan levels.
Additionally, it has been shown to inhibit histone deacetylase, a target
of several therapeutic agents, such as vorinostat and panobinostat, in
development for gliomas and other cancers; its use in patients receiving
these drugs should therefore be avoided.20
Seizures in patients with brain tumors may occasionally be
refractory to medical management. Surgical treatment of brain
tumor–related epilepsy is generally indicated only in patients with
slow-growing tumors with a good prognosis. The best results are obtained
when the pathologic lesion and adjacent epileptogenic cortex are
The vasogenic edema that surrounds many brain tumors contributes
significantly to morbidity. Peritumoral edema results from disruption of
the blood-brain barrier, allowing protein-rich fluid to accumulate in
the extracellular space.22
Tumor-related disruption in the blood-brain barrier is caused by two
major mechanisms. Angiogenic factors such as vascular endothelial growth
factor (VEGF) and basic fibroblast growth factor (bFGF) lead to
development of abnormal tumor blood vessels characterized by absence of
tight endothelial cell junctions. The permeability of these vessels is
further increased through local production of VEGF, bFGF, glutamate, and
leukotrienes.22 Other molecules of importance are the aquaporins, matrix metalloproteinases, and angiopoietins.23
Vasogenic edema tends to spread more readily in the extracellular
space of white matter than in that of gray matter, possibly because of
lower resistance to flow within the white matter. Tumor-related edema
may disrupt synaptic transmission, alter neuronal excitability, and
contribute to headaches, seizures, focal neurologic deficits, and
drowsiness (Case 1-2). Furthermore, uncontrolled cerebral edema may result in fatal herniation.
A 32-year-old man with recurrent glioblastoma presented with
increasing confusion, word-finding difficulties, and vomiting. On
examination, he had a nonfluent aphasia with prominent reading
difficulties. His Mini-Mental State Examination (MMSE) score was 16 of
30. An MRI demonstrated an enlarging left hemispheric tumor with
extensive surrounding edema (Figure 1-2).
FIGURE 1-2. Fluid-attenuated inversion recovery T2-weighted MRI
demonstrating increased left hemispheric signal abnormality resulting in
mass effect and midline shift in a 32-year-old man with recurrent
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He was started on dexamethasone (10 mg bolus, followed by 8 mg twice
daily) and enrolled in a clinical trial with a novel vascular
endothelial growth factor (VEGF)–targeted agent. His symptoms improved
significantly within a week. When he returned to the clinic a week
later, his symptoms had nearly resolved. His MMSE score was 28.
Comment. Vasogenic edema accounts for significant
morbidity in patients with brain tumors. It responds quickly to
corticosteroids. VEGF-targeted agents have an increasing role in
treatment of tumor-related edema.
Diagnosis and Treatment
It can occasionally be difficult to differentiate neurologic
dysfunction caused by the tumor from neurologic dysfunction caused by
its associated edema. Edema is readily visible on both CT and MRI. On
CT, it causes an area of low signal. On MRI, the edematous brain has
increased T2 and fluid-attenuated inversion recovery signal (Figure 1-2).
Most patients with brain tumors and peritumoral edema can be adequately managed with corticosteroids.24
Reduction of intracranial pressure and improvement in neurologic
symptoms usually begins within hours. A decrease in capillary
permeability (ie, improvement in blood-brain barrier function) can be
identified within a few hours, and changes on diffusion-weighted MRI
indicating decreased edema are identifiable within 2 to 3 days.25
Systemic corticosteroids are indicated in all patients who are
symptomatic. Dexamethasone is the standard agent because its relative
lack of mineralocorticoid activity reduces the potential for fluid
retention, and it may be associated with a lower risk of infection and
cognitive impairment compared with other corticosteroids.26,27
The mechanism of action of corticosteroids for control of
vasogenic edema is not fully understood. Dexamethasone has recently been
shown to upregulate angiopoietin 1, a strong blood-brain
barrier–stabilizing factor, whereas it downregulates VEGF (a strong
Corticosteroids may also increase the clearance of peritumoral edema by
facilitating the transport of fluid into the ventricular system.
patients with severe symptoms, a commonly used dexamethasone regimen
consists of a 10-mg loading dose followed by 4 mg 4 times per day or 8
mg twice daily. Some evidence suggests that lower doses (1 mg to 2 mg 4
times per day) may be as effective as higher doses and less toxic in
patients without impending herniation.29
Although dexamethasone is often prescribed in four divided daily doses,
its biological half-life is sufficiently long to allow twice-daily
dosing, which is more convenient for patients and avoids the nocturnal
doses that contribute to insomnia. To minimize complications, the lowest
possible dose necessary to control peritumoral edema should be used.
Absorption of oral corticosteroids is excellent and is complete within
30 minutes of administration. IV dosing may be necessary if oral
absorption cannot be assured or if mental status is altered.24
Because adequate reduction in elevated intracranial pressure
resulting from peritumoral edema may take several days with steroid
therapy alone, patients with severe symptoms and impending herniation
may require additional measures until corticosteroids have had a chance
to take effect or until debulking surgery can be performed.30
These interventions include elevation of the head of the bed, fluid
restriction, hyperventilation, and administration of mannitol,
hypertonic saline, or diuretics.31–33
Osmotic therapy with mannitol is used for patients with severe brain
edema who cannot tolerate the 24 to 72 hours required for maximal
corticosteroid effect. The standard dosage is 1 g/kg (250 mL of 20%
Complications With Corticosteroid Use
Despite the beneficial effect of corticosteroids, they are associated with a large number of side effects (Tables 1-3 and 1-4).
Common adverse effects include insomnia, tremor, and hiccups; patients
should be warned in advance that they may occur. The characteristic
features of long-term steroid use include truncal obesity, moon facies,
buffalo hump, acne, purpura, and striae distensae. Three complications
of corticosteroids are of particular concern to patients with brain
tumors: gastrointestinal complications, steroid myopathy, and
opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP).
TABLE 1-3 Systemic Complications of Corticosteroids
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TABLE 1-4 Neurologic Complications of Corticosteroids
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Corticosteroids, especially when used in conjunction with nonsteroidal
anti-inflammatory drugs (NSAIDs), increase the risk of gastrointestinal
complications such as gastritis or peptic ulcer disease. Concurrent
anticoagulation therapy and a prior history of peptic ulcer disease are
other factors that can increase the likelihood of gastrointestinal
bleeding. The effectiveness of prophylactic therapy to prevent peptic
ulceration in patients with brain tumors is unknown. Prophylactic
therapy is probably unnecessary for most patients unless they are at
high risk for developing peptic ulceration (ie, previous peptic ulcer
disease, concurrent anticoagulation, NSAID therapy). When NSAIDs are
necessary, use of a selective COX-2 inhibitor may reduce the risk of
Perforation of the
gastrointestinal tract is a life-threatening complication of steroid
therapy. This is frequently difficult to diagnose because clinical
features of peritonitis can be masked by the corticosteroids.
Gastrointestinal perforation is of particular concern in patients who
are receiving concurrent VEGF-inhibitor therapy.34
The prevention of severe constipation may decrease the risk of
intestinal perforation. A high index of suspicion is important because
early diagnosis improves the outcome of this serious complication.
Steroid myopathy. Steroid-related myopathy
contributes significantly to morbidity in patients with brain tumors and
has an estimated incidence of up to 20%.35
The onset is usually subacute, occurring over several weeks, although
individual susceptibility varies considerably. Some patients become weak
after a low dose of steroids for a few weeks, whereas others never
develop myopathy despite receiving large doses of steroids for months or
years. Treatment of steroid myopathy is difficult. Ideally, steroids
should be discontinued, but if this is not feasible, the lowest possible
dose should be used. Recovery after discontinuation of steroid therapy
can be expected within 2 to 3 months but may be much slower if treatment
is continued, even at a reduced dose.
Opportunistic infections. PJP is a life-threatening opportunistic infection that occurs in immunocompromised hosts.36
Although PJP is relatively rare in patients with brain tumors (small
cohort studies estimate the incidence to be between 1.7% and 6.2%),
patients receiving corticosteroids or prolonged courses of daily
temozolomide are at increased risk for developing PJP.37–39 Patients are particularly at risk when steroids are tapered.
caring for patients with brain tumors who are receiving corticosteroids
should maintain a high index of suspicion for PJP. Although the
hallmark of PJP is fever and dyspnea with or without a prominent dry
cough, the presentation can be subtle and nonspecific. Thus, the
diagnosis should be considered in any patient developing respiratory
All patients with brain tumors receiving chronic
steroids or prolonged daily courses of temozolomide should receive
prophylactic therapy against PJP. Trimethoprim-sulfamethoxazole is
highly effective at preventing PJP when it is administered as a single
double-strength tablet (160 mg of trimethoprim plus 800 mg of
sulfamethoxazole) once daily 3 times a week during steroid
administration and for 1 month afterward. Aerosolized pentamidine,
dapsone, or atovaquone are alternatives that should be considered in
patients allergic to trimethoprim-sulfamethoxazole (Table 1-5).
TABLE 1-5 Prophylaxis of Pneumocystis jiroveci Pneumonia
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Candidiasis is the most common opportunistic infection secondary to
immunosuppression from steroids. Most candidal infections are
mucocutaneous or oropharyngeal and easily treated with nystatin,
clotrimazole, or topical antifungal agents. Occasionally, esophageal or
systemic candidiasis may occur and require systemic therapy with agents
such as fluconazole or itraconazole.
Other steroid side effects. Glucose
intolerance develops in 50% of patients who are treated with
corticosteroids for more than 1 month. In nearly half of these patients,
disturbances persist despite reduction or withdrawal of the drug.24
Glucocorticoid therapy commonly causes secondary osteoporosis, which usually presents with a fracture.40
Steroid-induced osteoporosis predominantly affects regions of the
skeleton that have abundant cancellous bone, such as the lumbar spine
and proximal femur.41
All patients should receive adequate calcium supplementation (1200 mg
per day in divided doses) and adequate vitamin D supplementation (800
units to 2000 units per day), but these precautions alone are not
sufficient to prevent fractures.41
Bisphosphonates are considered first-line therapy for the treatment of
glucocorticoid-induced osteoporosis and should be offered to patients at
highest risk (ie, postmenopausal women, patients who require steroids
for longer than 3 months).40,41
Neuropsychiatric disturbances range from insomnia to psychosis.
Sleep disturbance can be reduced by giving the bulk of the steroid dose
in the morning. Psychotic symptoms and agitation respond better to
dopamine antagonists than benzodiazepines.
Epidural lipomatosis is
a rare disorder in which excess adipose tissue is deposited within the
epidural space. It occurs in patients receiving chronic steroid
treatment and has been described in patients with brain tumors. It can
present as back pain, radiculopathy, or frank spinal cord compression.
Treatment is directed at decreasing the steroid dose, and in severe
cases multilevel decompressive laminectomy might become necessary to
alleviate the neurologic symptoms caused by spinal cord compression.
Longer-term corticosteroid use may result in glaucoma and cataract
formation, the severity of which corresponds to the dose and duration of
therapy. Corticosteroids can also cause hiccups. These can occasionally
be troublesome and require treatment with metoclopramide,
chlorpromazine, or baclofen.
Because of the multiple side effects
that occur with chronic use described above, steroids should be tapered
as soon as possible. Decreasing the dose by 25% every 4 to 5 days is a
In patients who have required corticosteroids for more than 2 weeks, a
“steroid withdrawal syndrome” may occur, characterized by arthralgias,
myalgias, and joint pain as well as symptoms that may be difficult to
dissociate from those of the brain tumor, such as headache, depression,
lethargy, and postural dizziness. Guidelines for managing adrenal
insufficiency, which usually occurs with longer-term use, are available
Novel Treatments for Cerebral Edema
Because VEGF plays an important role in the pathogenesis of
peritumoral edema, anti-VEGF monoclonal antibodies such as bevacizumab
or inhibitors of VEGF receptors may be helpful in reducing cerebral
edema.44–46 These classes of drugs may eventually prove to be more effective and less toxic alternatives to corticosteroids.
Epidemiology and Pathophysiology
Venous thromboembolism (VTE) is the second leading cause of death
in patients with cancer. The association between brain tumors and
thromboembolic disease is well known and contributes significantly to
morbidity and mortality (Case 1-3). The incidence of
deep vein thrombosis (DVT) or pulmonary embolism (PE) in patients with
brain tumors varies significantly among studies (3% to 60%).47 In patients with high-grade gliomas outside the perioperative period, the incidence is approximately 20% to 30%.47,48
This risk is generally greater in the postoperative period; in patients
older than 60 years; in patients with hemiplegia, glioblastoma
histology, and large tumor size; and in patients on chemotherapy and
hormonal therapy. In contrast to adults, children with brain tumors have
a low incidence of VTE. Timely diagnosis and initiation of therapy for
VTE is essential. Left untreated, nearly 50% of all patients with
symptomatic proximal DVTs will develop PE, with mortality rates of 10%
The VTE risk persists throughout the clinical course of these patients.
A prospective study of 77 patients with high-grade glioma reported a
21% risk of DVT at 12 months, which increased to 32% at 24 months.
A 64-year-old woman with glioblastoma presented for evaluation of
asymmetric right lower extremity edema and calf tenderness. On
examination, her right calf was swollen and tender. She had a resting
oxygenation saturation rate of 94% and a pulse of 90 beats/min. She had
been reporting mild shortness of breath with exertion for the past week.
d-Dimer level was elevated at 1200 ng/mL. A CT of her chest revealed
several subsegmental pulmonary emboli. She received low-molecular-weight
heparin (LMWH) and was discharged the next day.
Two weeks later,
she presented to the emergency department after being found slumped over
at her desk. She had right-sided hemiplegia and was aphasic. CT of the
brain demonstrated a 4-cm intratumoral hemorrhage. LMWH was
discontinued, and an inferior vena cava filter was placed.
Comment. Thromboembolic complications occur in up to
30% of patients with malignant brain tumors. If the patient has no prior
history of bleeding diathesis, the preferred treatment is LMWH. In
patients with prior hemorrhagic complications, an inferior vena cava
filter should be considered instead.
The pathogenesis of VTE in patients with brain tumors is not
completely understood. Normal brain tissue is a rich source of tissue
factor (TF), the cell surface receptor of factor VII/VIIa that plays a
central role in the initiation of the coagulation cascade. Higher-grade
tumors express higher levels of TF, leading to greater activation of the
coagulation cascade. The release of brain-derived TF and other
procoagulants and fibrinolytic inhibitors from the tumor and surrounding
cerebral tissue into the systemic circulation is thought to activate
the coagulation cascade and result in chronic disseminated intravascular
coagulation. Elevated levels of D-dimer, homocysteine, lipoprotein (a),
VEGF, tissue plasminogen activator, and plasminogen activator inhibitor
are found in patients with malignant gliomas and contribute to the
As antiangiogenic agents are increasingly
used in patients with brain tumors, a growing number of patients may be
at risk for both hemorrhagic and thrombotic complications.50
The use of bevacizumab, cediranib, vandetanib, XL 184, and other
VEGF-targeted agents is associated with small increases in thrombosis
Patients receiving thalidomide or derivatives such as lenalidomide have
a high risk of thromboembolism and likely should receive chronic
prophylaxis.52 Initial reports indicate that patients may be safely anticoagulated while on bevacizumab.53
Duplex ultrasonography in combination with clinical evaluation
generally provides an adequately precise and noninvasive approach to
diagnosing DVT. For proximal DVT, ultrasonography has a sensitivity of
89% to 96% and a specificity of 94% to 99%.54 However, for symptomatic calf DVT, the sensitivity drops to 73% to 93%,54 and for asymptomatic patients ultrasonography has a sensitivity of only 50%.54
Repeat ultrasound or venography may be required for patients who have
suspected calf vein DVT and a negative or technically inadequate
ultrasound. Contrast venography is still considered the criterion
standard to rule out the diagnosis of DVT, but it is rarely performed.
For patients with a low clinical suspicion of DVT, a normal D-dimer test
is sufficient to exclude DVT, and an ultrasound can be safely omitted
in these cases.
The diagnosis of PE involves a combination of
clinical assessment and imaging studies. For patients who have at least
an intermediate pretest probability of PE, imaging is necessary. From a
radiologic point of view, CT angiogram has become the de facto first
imaging test in clinical routine, as patients with a high-quality
negative CT angiogram do not require further examination or treatment
for suspected PE.55,56
Because of the high risk of developing VTE, patients with brain
tumors undergoing craniotomy require adequate prophylaxis. Methods of
VTE prophylaxis can be mechanical, pharmacologic (ie, unfractionated
heparin [UFH] or low-molecular-weight heparin [LMWH]), or a combination
of both. The optimal prophylactic regimen has not been established.
Mechanical methods include early ambulation, compression stockings,
electrical calf muscle stimulation, and intermittent external pneumatic
compression devices. Each of these helps to limit venous stasis and
enhance systemic fibrinolysis. Studies of mechanical prophylaxis in
neurosurgery patients have demonstrated up to a 50% reduction in VTE
compared with controls, with the greatest effect derived from the use of
pneumatic compression, although failure rates in some studies were as
high as 9.5%. Studies comparing pneumatic compression devices with
heparin in patients who have undergone craniotomy suggest that heparin
reduces the frequency of DVT and PE by 40% to 50%.57
However, the rate of major postoperative intracranial hemorrhage may
increase from its baseline of 1% to 3.9% to as high as 10.9% when
heparin is introduced.58,59
A meta-analysis of four trials of thromboprophylaxis in predominantly
patients with brain tumors found that LMWH and UFH reduced the risk of
VTE from 12.5% to 6.2% and carried only a 2% risk of major bleeding.60 Nonetheless, many neurosurgeons continue to associate LMWH with bleeding complications and use mechanical methods only.
high incidence of VTE in patients with malignant gliomas beyond the
perioperative period could potentially be reduced with prophylactic
anticoagulation, although whether this reduction would outweigh the
potential risks is unclear. A randomized placebo-controlled trial of
dalteparin (the PRODIGE study) was prematurely stopped because of poor
accrual. However, a trend of lower risk of VTE in the treatment group
with an increase in intracranial hemorrhage was observed. Survival was
similar in both groups.61 The role of prophylactic LMWH in patients with brain tumors remains uncertain.
The main objectives in the treatment of VTE are to prevent PE,
improve lower limb circulation, and resolve leg edema and associated
pain. UFH, and particularly LMWH, are widely used for the treatment of
VTE and for reducing the frequency of recurrent thromboembolic
complications. Meta-analyses comparing UFH and LMWH for the treatment of
DVT have shown better outcomes, with a reduction of major bleeding
complications, in patients treated with LMWH.
Only patients with
strict contraindications for therapeutic anticoagulation should be
treated with inferior vena cava (IVC) filters (Case 1-3).
IVC filters have a higher complication rate and are less effective in
preventing PE than anticoagulation. A retrospective study of patients
with brain tumors identified complications in up to 62% of patients
after IVC filter placement. These complications included
procedure-associated morbidity (ie, pneumothorax, infection, bleeding,
IVC wall damage) as well as thrombotic events, including a 12% risk of
recurrent PE, a 26% incidence of IVC thrombosis, and a 10% incidence of
In a case series reported by Schiff and DeAngelis, four out of 10
patients with brain metastases who received IVC filters had recurrent
The use of IVC filters should therefore be reserved for patients with
recent craniotomy, intracranial hemorrhage, frequent falls, poor
medication adherence, or prolonged thrombocytopenia from chemotherapy.
In patients with temporary contraindications, an IVC filter followed by
delayed anticoagulation may limit future thromboembolic complications.
studies have demonstrated the relative safety of properly monitored
anticoagulation in patients with primary and metastatic brain tumors,
and this topic has been reviewed extensively in the neurosurgical and
neuro-oncologic literature. The incidence of cerebral hemorrhage in
these studies was generally not significantly increased in
anticoagulated patients, and systemic bleeding was generally minor and
infrequent. When hemorrhagic complications occur, they are most common
in the context of supratherapeutic anticoagulation. Table 1-6 lists the anticoagulants that are most commonly used in the treatment of VTE.
TABLE 1-6 Agents Used in the Treatment of Venous Thromboembolism
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Until recently, the overwhelming majority of patients receiving
anticoagulation for VTE were treated initially with UFH or LMWHs and
then switched to warfarin. Because patients with brain tumors frequently
receive concurrent therapy with medications that interact with
warfarin, close monitoring of the international normalized ratio (INR)
is necessary. The use of LMWHs in lieu of warfarin avoids the
difficulties of fluctuating INRs due to the many drug-drug interactions
with warfarin. Although there is no evidence indicating that LMWHs are
safer or more effective than oral anticoagulant therapy in patients with
brain tumors, there is accumulating evidence that LMWHs are safer and
more effective in patients with cancer in general. In a randomized trial
of secondary prevention of VTE in patients with systemic cancer,
warfarin was associated with a higher frequency of bleeding than
enoxaparin; there were six deaths due to hemorrhage in the warfarin
group and none in the enoxaparin group.64
In the Comparison of Low Molecular Weight Heparin Versus Oral
Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients
With Venous Thromboembolism (CLOT) trial, dalteparin was more effective
than warfarin for the prevention of VTE in patients with cancer, and
bleeding complications were similar in each group. The study included 27
patients with brain tumors.65
At my institution, we favor LMWH over warfarin for secondary
prevention of VTE, although more evidence is certainly desirable before
applying this approach routinely in this patient population. Before
initiation of therapeutic anticoagulation, a head CT or MRI should be
performed to rule out recent intracranial bleeding. Evidence of recent
spontaneous bleeding is generally considered a contraindication to
anticoagulation. Anticoagulation should probably also be avoided in
patients with brain metastases from melanoma, choriocarcinoma, and renal
or thyroid cancer because these tumors are associated with an increased
rate of hemorrhage.
Current FDA-approved LMWHs for the treatment
of VTE include enoxaparin, dalteparin, tinzaparin, and nadroparin.
Stable patients with DVT and PE are usually treated with LMWH in the
outpatient setting. The duration of anticoagulation depends on the
persistence of the underlying hypercoagulable state. Because most
primary brain tumors and metastatic cancers are incurable,
anticoagulation is continued indefinitely in most of these patients.
When the underlying cause of the hypercoagulable state no longer exists,
anticoagulation can be discontinued after approximately 6 months.
with heparin-induced thrombocytopenia (HIT) must not receive heparin
products. In lieu of heparin, direct thrombin inhibitors such as
lepirudin, argatroban, or bivalirudin could be considered, although
little data exist to guide their use in patients with brain tumors.
Fondaparinux is a synthetic pentasaccharide that binds to antithrombin,
thereby indirectly selectively inhibiting factor Xa. Fondaparinux
demonstrated greater efficacy than LMWH in randomized clinical trials
and is FDA approved for the prevention and treatment of VTE. Because it
does not bind to platelets or platelet factor 4, it should not produce
HIT, and although it is not FDA approved for this indication, its use
might be considered in patients with brain tumors who have developed
The most serious complication of anticoagulation in patients
with brain tumors is intracranial hemorrhage. Any change in neurologic
symptoms or onset of headaches should prompt immediate brain imaging. If
hemorrhage is confirmed, anticoagulation will need to be reversed and a
neurosurgical consultation should be obtained. Protamine reverses UFH
completely. However, it incompletely reverses LMWH and has even less
effect on fondaparinux and the direct thrombin inhibitors. Vitamin K
reverses the effect of warfarin but requires hours to days to take
effect. Therefore, blood products such as fresh frozen plasma,
recombinant factor VIIa, or prothrombin complex concentrates should be
used as part of initial therapy.66–68 Recombinant factor VIIa may also reverse the anticoagulant effects of LMWHs, direct thrombin inhibitors, and fondaparinux.
At the time of diagnosis, cognitive impairment is already present
in many patients with brain tumors, and most will experience
distressing neurocognitive symptoms during their illness. These symptoms
include fatigue, depression, and cognitive impairment and contribute to
a marked reduction in quality of life.
Several studies assessing the quality of life in patients with
malignant gliomas found that fatigue was the most frequently reported
and troublesome of all symptoms. Fatigue tends to be more common in
patients with high-grade gliomas than those with lower-grade tumors and
is especially troublesome following treatment with radiation therapy
(RT). Anemia, AEDs, chemotherapy, depression, and adverse effects of
weight gain and other issues related to steroid use or steroid
withdrawal all contribute to fatigue.
It is important to exclude
hypothyroidism and hypocortisolism, reduce or eliminate AEDs, and treat
anemia and depression. Psychostimulants may play a role in the treatment
of brain tumor– related fatigue. The psychostimulants available include
methylphenidate, pemoline, dextroamphetamine, modafinil, and
armodafinil. These drugs are generally well tolerated in patients with
brain tumors. A pilot study of modafinil for treatment of
neurobehavioral dysfunction and fatigue in adult patients with brain
tumors showed improvement across cognitive, mood, and fatigue outcome
measures, and the drug was well tolerated.69
Cognitive deficits are common in patients with brain tumors and
include problems such as poor short-term memory, distractibility,
personality change, emotional lability, loss of executive function, and
decreased psychomotor speed. These symptoms can be tumor related and
exacerbated by chemotherapy and RT as well as AEDs and corticosteroids.70
Whole-brain RT alone or in combination with high-dose chemotherapy
results in greater cognitive decline than partial RT or high-dose
MRIs in these patients often demonstrate periventricular white matter
changes. The cognitive impairment may be associated with behavioral
disturbances and require psychiatric intervention and social service
support. Medications such as methylphenidate may be helpful in improving
motivation, attention, and neurologic functioning. A recent open-label
study of donepezil in postradiation patients suggested improvement in
attention, mood, and verbal memory, but the population was heterogeneous
and there was no control group.72 Cognitive rehabilitation programs are another intervention to address cognitive deficits in patients with brain tumors.
acetylcholinesterase inhibitors, and glutamate inhibitors such as
memantine, may also be helpful with memory loss. Atypical antipsychotics
such as quetiapine, risperidone, and olanzapine are often used to treat
psychotic symptoms, anger, agitation, and poor impulse control.
Patients with cognitive impairment, frontal gait disorder, and urinary
incontinence should be evaluated for the presence of communicating
hydrocephalus and may benefit from ventriculoperitoneal shunting.
Depression is a common symptom in patients with brain tumors.
Depression may be related to frontal lobe tumor location or medications
(dexamethasone and levetiracetam in particular), or it may be part of
the psychological response to the tumor diagnosis. Estimates of the
rates of depression vary among studies and depend on the assessment
method. In the Glioma Outcomes Project, physicians diagnosed depression
using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
criteria in 15% of the study participants in the early postoperative
period; however, a total of 93% of these patients reported symptoms of
Patients who are depressed should beconsidered for antidepressant
pharmacotherapy. The norepinephrine-dopamine reuptake inhibitor
bupropion is associated with lowering of the seizure threshold and
should be avoided in patients with brain tumors.
Seizures, cerebral edema, thromboembolic complications,
neurocognitive dysfunction, and depression are common challenges in
patients with brain tumors and account for significant morbidity and
mortality. Effective medical management of these complications can
significantly improve quality of life.
* For patients without a history of seizures who have not
undergone a neurosurgical procedure within 1 week, use of prophylactic
anticonvulsants is not recommended.
* For patients who have
experienced one or more seizures associated with a primary or metastatic
brain tumor, initial treatment with a single agent antiepileptic drug
* To avoid clinically significant drug-drug
interactions, monotherapy with a non–enzyme-inducing anticonvulsant such
as levetiracetam, lacosamide, or pregabalin is suggested since these
may be titrated very quickly to a clinically effective dose.
Steroids should be avoided in asymptomatic patients. Patients with
symptomatic peritumoral edema should receive the lowest necessary dose
* Appropriate attention should be paid to prevent or treat potential complications of glucocorticoid treatment.
* For patients at increased risk for peptic ulcer disease, a proton pump inhibitor should be considered.
* Any patient with a brain tumor receiving steroids or antiangiogenic
agents who experiences unexplained abdominal symptoms should be
evaluated for the possibility of bowel perforation.
myopathy is a significant contributor to functional decline in patients
with brain tumors, especially patients of older age.
* Patients receiving steroids for extended periods of time or prolonged courses of daily temozolomide require Pneumocystis jiroveci pneumonia prophylaxis.
* All patients receiving steroids should receive vitamin D and calcium
supplementation. Patients with the highest risk of osteoporosis should
* Small doses of dopamine antagonists are often effective for treating steroid-induced psychotic symptoms and agitation.
* Steroids should be tapered as quickly as tolerated to minimize the risk of complications.
* Bevacizumab and other potent vascular endothelial growth factor
(VEGF)–targeted agents have steroid-sparing properties. In patients
receiving a VEGF-targeted agent, steroids can often be tapered.
The risk of venous thromboembolism in patients with malignant glioma is
extraordinarily high and extends beyond the postoperative period.
Therefore, physicians should have a high level of suspicion, and any
patient with calf pain, leg swelling, or shortness of breath should be
evaluated for the presence of deep vein thrombosis or pulmonary
* Anticoagulation with low-molecular-weight heparins is
considered safe in patients receiving concurrent vascular endothelial
growth factor–targeted therapy.
* In patients with low clinical suspicion of deep vein thrombosis (DVT), a negative D-dimer test is sufficient to exclude DVT.
* Despite the high risk of thromboembolic complications, current data
provide evidence against the use of low-molecular-weight heparin in the
primary prophylaxis of venous thromboembolism beyond the postoperative
* The use of inferior vena cava filters should be
restricted to patients with prior history of hemorrhage in the
* Low-molecular-weight heparin is safer and more effective than oral anticoagulant therapy in patients with cancer.
* Stimulants are considered safe—even in patients with a history of
seizures—and should be considered to improve fatigue and cognitive
MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant
prophylaxis in patients with newly diagnosed brain tumors. Report of the
Quality Standards Subcommittee of the American Academy of Neurology.
Neurology 2000; 54 (10): 1886–1893.
14. Bahr O,
Hermisson M, Rona S, et al. Intravenous and oral levetiracetam in
patients with a suspected primary brain tumor and symptomatic seizures
undergoing neurosurgery: the HELLO trial [published online ahead of
print September 10, 2011]. Acta Neurochir (Wien) 2012;154(2):229–235.
Maschio M, Dinapoli L, Sperati F, et al. Levetiracetam monotherapy in
patients with brain tumor-related epilepsy: seizure control, safety, and
quality of life. J Neurooncol 2011; 104 (1): 205–214.
MD, Yung WK, Jaeckle KA, et al. Phase 1 trial of irinotecan (CPT-11) in
patients with recurrent malignant glioma: a North American Brain Tumor
Consortium study. Neuro Oncol 2004; 6 (1): 44–54.
Kotsarini C, Griffiths PD, Wilkinson ID, et al. A systematic review of
the literature on the effects of dexamethasone on the brain from in vivo
human-based studies: implications for physiological brain imaging of
patients with intracranial tumors. Neurosurgery 2010; 67 (6): 1799–1815;
TC, McDermott M, Robinson PD, et al. The role of steroids in the
management of brain metastases: a systematic review and evidence-based
clinical practice guideline. J Neurooncol 2010; 96 (1): 103–114.
R, Dietrich PY, Ostermann Kraljevic S, et al. Promising survival for
patients with newly diagnosed glioblastoma multiforme treated with
concomitant radiation plus temozolomide followed by adjuvant
temozolomide. J Clin Oncol 2002; 20 (5): 1375–1382.
MH, Johnson JR, Pazdur R. Food and Drug Administration drug approval
summary: temozolomide plus radiation therapy for the treatment of newly
diagnosed glioblastoma multiforme. Clin Cancer Res 2005; 11 (19 pt 1):
WS, Ley CD, Farrar CT, et al. Edema control by cediranib, a vascular
endothelial growth factor receptor-targeted kinase inhibitor, prolongs
survival despite persistent brain tumor growth in mice. J Clin Oncol
2009; 27 (15): 2542–2552.
Drappatz J, Wong ET, Schiff D, et al. A pilot safety study of
lenalidomide and radiotherapy for patients with newly diagnosed
glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2009; 73 (1):
AD, Bartolomeo J, Tanaka S, et al. Safety of concurrent bevacizumab
therapy and anticoagulation in glioma patients [published online ahead
of print June 26, 2011]. J Neurooncol 2012;106(1):121–125. doi:
Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus
compression stockings compared with compression stockings alone in the
prevention of venous thromboembolism after elective neurosurgery. N Engl
J Med 1998; 339 (2): 80–85.
Constantini S, Kornowski R, Pomeranz S, et al. Thromboembolic phenomena
in neurosurgical patients operated upon for primary and metastatic brain
tumors. Acta Neurochir (Wien) 1991; 109 (3–4): 93–97.
JR, Julian JA, Laperriere NJ, et al. PRODIGE: a randomized
placebo-controlled trial of dalteparin low-molecular-weight heparin
thromboprophylaxis in patients with newly diagnosed malignant glioma. J
Thromb Haemost 2010; 8 (9): 1959–1965.
G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight
heparin and warfarin for the secondary prevention of venous
thromboembolism in patients with cancer: a randomized controlled study.
Arch Intern Med 2002; 162 (15): 1729–1735.
AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a
coumarin for the prevention of recurrent venous thromboembolism in
patients with cancer. N Engl J Med 2003; 349 (2): 146–153.
Kaleita TA, Wellisch DK, Graham CA, et al. Pilot study of modafinil for
treatment of neurobehavioral dysfunction and fatigue in adult patients
with brain tumors [abstract]. J Clin Oncol 2006; 24 (18S): 1503.
EG, Rosdhal R, D’Agostino RB Jr, et al. Phase II study of donepezil in
irradiated brain tumor patients: effect on cognitive function, mood, and
quality of life. J Clin Oncol 2006; 24 (9): 1415–1420.