Headache associated with intracranial neoplasms

By Min Kyung MD PhD (Dr. Chu of Hallym University College of Medicine has no relevant financial relationships to disclose.)
Originally released June 26, 1995; last updated August 14, 2017; expires August 14, 2020

Introduction

This article includes discussion of headache associated with intracranial neoplasms and stroke-like migraine attacks
after radiation (SMART) syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage,
and abbreviations.

Overview

Headaches associated with intracranial neoplasms are common. In this article, the epidemiology, pathogenesis, and
clinical presentation of brain tumor-associated headaches are discussed. In addition, uncommon headache syndromes
caused by brain tumors, headaches precipitated by the initial treatment of brain tumors, as well as headaches
occurring as late complications of brain tumor treatment are described. The approach to new headaches in patients
with known malignancies and the treatment of brain tumor headache are briefly discussed.

Historical note and terminology

Headache has been recognized as a common symptom of brain tumors for many years. In the 1940s, a series of
classic papers described the clinical characteristics and mechanisms of brain tumor-associated headache (Northfield
1938; Kunkle et al 1942). With improved neuroimaging and the resultant earlier diagnosis, the spectrum of tumor-
associated headache has expanded beyond these classical descriptions.

Clinical manifestations

Presentation and course

Features of brain tumor-associated headache. The classic brain tumor headache has been described as severe,
early morning, or nocturnal headache with nausea and vomiting (Kirby and Purdy 2014). In studies of unselected
tumors, the associated headache characteristics vary and there is no typical brain tumor-associated headache.
Headache pain ranges from a dull ache to a pressure or tightening or a throbbing or shooting pain (Forsyth and Posner
1993; Pfund et al 1999; Schankin et al 2007; Valentinis et al 2010).

The headache pain is usually intermittent, moderate to severe in intensity, and progressive (Forsyth and Posner 1993;
Pfund et al 1999; Schankin et al 2007; Valentinis et al 2010). Only about a third of patients have nocturnal or morning
headaches or both, and 20% report headache exacerbation by Valsalva maneuvers (Forsyth and Posner 1993; Pfund et
al 1999; Valentinis et al 2010). Nausea and vomiting are reported in 18% to 60% of patients (Forsyth and Posner 1993;
Pfund et al 1999; Schankin et al 2007; Valentinis et al 2010).

Headaches with features of primary headache disorders are found in a minority of patients. Migraine-type headaches
are reported in up to 15% of patients, and these usually have atypical features, including middle-age onset,
progressive pattern, association with Valsalva maneuver or lying down, nocturnal occurrence, and unresponsiveness to
analgesic treatment (Forsyth and Posner 1993; Pfund et al 1999; Schankin et al 2007; Valentinis et al 2010). Tension-
type headaches were seen in 29% to 39% of patients (Schankin et al 2007; Valentinis et al 2010).

Overall, 62% of the children with brain tumors experienced chronic or frequent headache. The frequency of headache
was more common in children with infratentorial tumors (70%) than children with supratentorial tumors (58%).
Children with a brain tumor and headache had a greater number of symptoms and neurologic signs, such as nausea or
vomiting, papilledema, or hypoactive tendon reflex. However upper extremity weakness, optic atrophy, and irritability
were less frequent (Childhood Brain Tumor Consortium 1991).
Isolated headache with no other symptoms may be the first manifestation of a brain tumor, but it is unusual for
patients not to develop other symptoms by diagnosis. In adults, only 2% to 8% of patients have isolated headache on
presentation, and in 1 study of 183 patients, all patients had developed other symptoms within 10 weeks (Vazquez-
Barquero et al 1994; Schankin et al 2007; Valentinis et al 2010). Headache was the most common symptom (62%) in
patients presenting with brain metastases as the first indication of a systemic cancer (Jin et al 2011).

A study of 3291 children with brain tumors found that less than 1% had headache as their sole symptom and less than
3% had no neurologic abnormality on examination (Childhood Brain Tumor Consortium 1991). In 2006, Wilne and
colleagues reported that 41% of 200 children with brain tumors had headache at presentation, and all 200 children
had other symptoms and signs (Wilne et al 2006).

Headache lateralization does not always predict tumor location. Pfund and colleagues found that headache
lateralization predicted tumor location in only one third of patients, and 12% of patients with unilateral headaches had
a contralateral tumor (Pfund et al 1999). In contrast, Forsyth and colleagues found that all patients with unilateral
headache had an ipsilateral tumor (Forsyth and Posner 1993). Frontal headaches were the most unreliable in
predicting tumor location and were most common (Forsyth and Posner 1993; Valentinis et al 2010). The reported
frequency of bilateral headaches ranged from 18% to 72% (Forsyth and Posner 1993; Pfund et al 1999). Laterality of
headache was predictive of tumor location with 82.8% of side-locked headache occurring ipsilateral to tumors. Among
strict bilateral headache, 53.3% had bihemispheric tumors, and 25% had midline tumors (Kahn and Finkel 2014).

The majority of patients with infratentorial tumors have supratentorial headaches only; but if occipital pain is present,
an infratentorial tumor is more likely. Skull-based tumors were more often associated with frontal headache (Pfund et
al 1999; Schankin et al 2007; Valentinis et al 2010).

Tumors of the skull base. Headache or head pain may be caused by metastatic disease in the base of the skull. Five
syndromes have been described:

(1) Orbital syndrome: blurred binocular vision followed by proptosis, diplopia, supraorbital, and eventually external
ophthalmoplegia.

(2) Parasellar syndrome: unilateral frontal headache, diplopia, ocular paresis, but no proptosis.

(3) Middle fossa or gasserian ganglion syndrome: pain, sensory change in the maxillary or mandibular division of the
fifth cranial nerve, and diplopia. Motor involvement of the mandibular branch or headache was less common.

(4) Jugular foramen syndrome: pain including glossopharyngeal neuralgia, hoarseness due to vocal cord paresis, and
palatal, tongue, or ipsilateral sternocleidomastoid or trapezius weakness or wasting.

(5) Occipital condyle syndrome: severe, localized, unilateral occipital pain; dysarthria or dysphagia due to unilateral
twelfth nerve palsy (Greenberg et al 1981; Capobianco et al 2002).

Headache or head pain has also been caused by occlusion of the superior sagittal sinus by lymphoma or other tumors
and by occlusion of the temporal artery by metastatic lung carcinoma (Gironell et al 1997; Bhatti et al 2001;
Matsumoto et al 2003).

Uncommon headache syndromes as a symptom of brain tumors. Headache is reported in 72% of pituitary
tumors (Levy et al 2004b). Trigeminal autonomic cephalalgias (TACS)-like headaches are reported more frequently
than expected. In a case series of 84 pituitary tumor patients with troublesome headache, 76% had chronic or episodic
migraine-like headache, 5% had short-lasting unilateral neuralgiform headache attacks with conjunctival injection and
tearing (SUNCT)-like headache, 4% had cluster-like headache, 1% had hemicrania continua-like, and 27% had primary
stabbing headache-like (Levy et al 2005). Patients with prolactinomas and growth hormone-secreting tumors are
reported to have more severe headaches than patients with nonsecreting tumors (Levy et al 2004b). Secondary
trigeminal autonomic cephalalgias are reported with other tumors as well as neurovascular and other lesions. They
may be indistinguishable from primary trigeminal autonomic cephalalgias, including their response to indomethacin
and other therapies (Wilbrink et al 2009).

Cerebrospinal fluid obstruction and cystic brain lesions. Harris described severe paroxysmal headache relieved by
changes in head position as the classic presentation of a colloid cyst (Harris 1944). These benign tumors are of
interest, as they may present with headache not associated with other symptoms and be unrecognized. Patients still
die from colloid cysts when they present with catastrophic acute deterioration due to blockage of the foramen of
Munroe by the pedunculated tumor. In a study of 78 symptomatic patients with newly diagnosed colloid cysts, 25
patients (32%) presented with acute deterioration, and 5 of these died. Four additional patients presented with sudden
unexplained death caused by a colloid cyst for an overall mortality of 12% (de Witt Hamer et al 2002). In a study of
105 cases of colloid cysts, the classic description of the associated headache was uncommon, as 92% of patients
reported generalized, intermittent headache, and only 2 patients had a postural component (Desai et al 2002).
Papilledema was found in 76% of patients, and ataxia, decreased vision, and urinary incontinence were present in 18%
to 27%.

Pituitary tumors. Pituitary apoplexy caused by infarction or hemorrhage into a pituitary tumor presents with acute
onset of intense headache associated with visual loss plus or minus ocular palsies, facial numbness, or somnolence
and pituitary insufficiency (Biousse et al 2001; Turgut et al 2010). Four of 42 patients (9.5%) with asymptomatic,
nonfunctioning, pituitary adenomas developed apoplexy over a 5-year observation period (Arita et al 2006). Rarely,
pituitary apoplexy proves fatal if unrecognized (Shields et al 2012).

Tumor cysts may rupture, spilling their contents into the cerebrospinal fluid. Craniopharyngioma, dermoid, and
epidermoid cyst ruptures have all been reported to cause headache due to the inflammatory meningeal reaction
caused by the irritating cyst contents (Satoh et al 1993; Gormley et al 1994; Stendel et al 2002). The inflammation
may be severe enough to cause death.

Prognosis and complications

The prognosis of brain tumor-associated headache depends on the prognosis of the underlying tumor in most cases.

Biological basis

Etiology and pathogenesis

The etiology of brain tumor-associated headache is multifactorial, including direct physical structural changes, tumor
secretions, and side effects of treatment.

In 1940, Ray and Wolff mapped the pain-sensitive structures of the head in a series of patients undergoing
craniotomies (Ray and Wolff 1940). From these experiments, they postulated 6 mechanisms of headache pain:

(1) traction on the veins draining into the large venous sinuses with resulting displacement;
(2) traction on the middle meningeal artery;
(3) traction on the major arteries at the base of the brain;
(4) direct pressure on cranial nerves with afferent pain fibers from the head;
(5) distension and dilation of the intracranial and extracranial arteries;
(6) inflammation in or around the pain sensitive structures of the head.

Studies of an additional 67 patients with brain tumors led to the conclusion that local and distant traction on pain-
sensitive structures, mass effect, and hydrocephalus caused most headaches (Kunkle et al 1942).

The evidence for raised intracranial pressure as a cause for headache is mixed. In migraineurs, raising cerebrospinal
fluid pressure abolished the headache induced by intravenous histamine (Schumacher and Wolff 1941). However,
raised intracranial pressure induced by saline infusions caused headache in other studies (Sorensen and Corbett
2000). Headaches, as well as dizziness and alterations in consciousness and motor control that are triggered by
standing, are symptoms of plateau waves, which are acute elevations in intracranial pressure (Watling and Cairncross
2002).

Not all brain tumor-associated headaches are caused by traction on pain-sensitive structures and mass effect. Patients
with pituitary tumors frequently have headaches, but Levy and colleagues reported no association between pituitary
volume and headache or between cavernous sinus invasion and headache (Levy et al 2004b). Headaches experienced
by patients with growth hormone-producing tumors may respond to treatment with somatostatin analogues. In
prolactinomas, dopamine agonists may either improve or exacerbate headache (Levy et al 2005). It has been
postulated that expression of somatostatin receptors coupled to the pain pathways may cause headaches (Levy et al
2003), but other studies by the same group have found no association between vasoactive intestinal polypeptide,
calcitonin gene-related peptide, and substance P expression and headache in pituitary tumors (Levy et al 2004a;
Nathoo et al 2005).

Headache is a common symptom of intracranial hemorrhage (ICH); however, hemorrhage into a brain tumor is an
infrequent cause of spontaneous intracranial hemorrhage (<10%). In a study of 208 cancer patients with intracranial
hemorrhage, 61% of them have bled into a brain tumor, and headache is a presenting symptom in 40%. Most
hemorrhages (77%) were in solid tumors, especially melanoma, lung cancer, breast cancer, and renal cell carcinoma.
Twenty-one percent of them were in primary brain tumors, especially glioblastoma and oligodendrogliomas (Navi et al
2010).

Other possible mechanisms for headache in intracranial tumors include infarction or infection of tumor and treatment-
related mechanisms (Navi et al 2010; Soffietti et al 2014). Treatment-related headache mechanism will be discussed
later in this review.

Epidemiology"

The prevalence of headache associated with brain tumors varies widely depending on the tumor's location and type
and the patient's age. Most studies report headache at presentation only.

In studies of unselected tumors in adults, headache prevalence ranges from 48% to 71% (Forsyth and Posner 1993;
Pfund et al 1999; Davies and Clarke 2004; Schankin et al 2007; Valentinis et al 2010). The prevalence has remained
relatively constant despite changes in neuroimaging techniques and greater availability. This suggests that headache
is an early symptom in adults with brain tumors. In contrast, headache was reported in only 33% of children in a meta-
analysis of later papers from 1991 to 2005 reporting signs and symptoms of childhood brain tumors at presentation
versus 62% in an earlier study (Childhood Brain Tumor Consortium 1991; Wilne et al 2007).

The prevalence of headache varied with tumor location: intraventricular and midline tumors (92% to 95% had
headache), infratentorial tumors (70% to 84%), and supratentorial tumors (55% to 60%) (Childhood Brain Tumor
Consortium 1991; Pfund et al 1999; Wilne et al 2007).

Factors that predict increased risk of headache in patients with brain tumor other than location include raised
intracranial pressure, degree of midline shift, and increasing edema (Forsyth and Posner 1993; Pfund et al 1999). The
relationship between tumor size and the likelihood of headache is uncertain. Similar to the results of Forsyth and
Posner, Valentinis and colleagues found that within similar pathologies, increased size was associated with increased
risk of headache, but others did not have similar findings (Pfund et al 1999; Levy et al 2004b; Schankin et al 2007;
Valentinis et al 2010). In my experience, when an individual patient has a brain tumor-associated headache, the
headache worsens as the tumor grows.

A prior history of headaches also predicts an increased risk of headache with a brain tumor (Forsyth and Posner 1993;
Valentinis et al 2010). Schankin and associates reported an alteration of headache in 82.5% of patients with
preexisting headache. Interestingly, 18% reported marked relief of their preexisting headache. Only 38% of patients
without preexisting headache developed headache (Schankin et al 2007). Forty-nine percent of patients with
headaches and pituitary tumors had a family history of a headache disorder (Levy et al 2005).

Both the elderly and the very young are less likely to present with headache. Only 8% of patients over the age of 75
had headache (Lowry et al 1998), compared with 44% of those 18 to 24 years of age. At least 72% of children aged 4
to 20 years had headache, but only 8% of those younger than 1 year had headache (Childhood Brain Tumor
Consortium 1991).

A new or changed headache experienced by a patient with a known systemic malignancy should be investigated. One
study reported intracranial metastases in 32.4% of 68 cancer patients with new or changed headache (Christiaans et
al 2002). Emesis, headache duration of less than 10 weeks, and non-tension-type headache pain were independent
predictors of metastases but had low specificity (Christiaans et al 2002). Argyriou and colleagues reported on 54
patients with new or changed headache, 54% of whom had intracranial metastases. In their series, emesis, bilateral
frontotemporal headache, pulsating quality, moderate-to-severe intensity, duration of 8 weeks or longer, gait
instability, and extensor plantar responses were independent predictors of brain metastases (Argyriou et al 2006). In
children with systemic cancer and new headache, only 12% of headaches were caused by brain metastases, and
primary brain tumors were found in 1% (Antunes 2001).

Prevention

Usually, headaches associated with brain tumors cannot be prevented, although they can be treated. The exception to
this is the change in surgical techniques used to reduce the frequency of headache after posterior fossa craniotomy.

Differential diagnosis

Approach to headache in cancer patients. All cancer patients with new headache should be assumed to have
brain metastases until proven otherwise. Cancer patients are also at risk for hemorrhage into a tumor as well as
venous sinus thrombosis and cerebral infarcts. In a series of 208 cancer patients with intracerebral hemorrhage, 61%
hemorrhaged into a brain tumor, most commonly melanoma, lung, breast, and renal cell carcinoma (Navi et al 2010).
Immunosuppression increases the risk for infection, including meningitis or opportunistic infections. Cancer patients
are not immune to the primary headache disorders.

Headaches have been reported by 30% to 40% of patients with leptomeningeal metastases, often associated with
multifocal neurologic signs and symptoms, as well as pain in a spinal, radicular, or meningeal pattern (Wasserstrom et
al 1982; Balm and Hammack 1996; Jayson and Howell 1996). Patients may present with headache due to raised
intracranial pressure or a diffuse encephalopathy without focal signs (Grossman and Krabak 1999). An increasing
incidence of CNS metastases, including leptomeningeal disease, has been noted in patients treated with gefitinib for
non-small cell lung cancer and trastuzumab for breast cancer (Bendell et al 2003; Omuro et al 2005). Breast, lung,
melanoma, leukemia, and lymphoma are the most common systemic tumors associated with leptomeningeal spread
(Jayson and Howell 1996), whereas ependymomas, medulloblastomas, pineal region tumors, and primary CNS
lymphomas are the most common primary brain tumors.

Abraham and colleagues reported a series of 33 patients with a nonmetastatic manifestation of lung cancer causing
severe unilateral ear, face, and temporal pain. It was thought to be caused by local tumor invasion of the vagus nerve
or compression by enlarged lymph nodes in the mediastinum (Abraham et al 2003). Evans proposed the term vagal
cephalgia to include headache or facial pain from vagal efferent stimulation from cancer or myocardial ischemia
(Evans 2007).

New headache in patients without known malignancy. The evaluation of new headache in patients without
known malignancy is beyond the scope of this review. The risk of brain tumor in patients with new undifferentiated
headache is low (0.15%) and is even less in those with headache that meets criteria for a primary headache disorder
(0.045%) (Kernick et al 2008). Briefly, patients with new or changed headache with new neurologic signs or systemic
symptoms should be assessed for serious or life-threatening causes of headache, including brain tumors (Purdy and
Kirby 2004). Older patients, those with progressive headache, emesis, meningismus, nocturnal or early morning
headache, and patients whose headache worsens with Valsalva maneuver or exertion should raise an increased index
of suspicion for a secondary cause for headache (Pladdet et al 1989; Pfund et al 1999). Patients with a new diagnosis
of a trigeminal autonomic cephalalgia should be screened for pituitary or cavernous sinus lesions (Kirby and Purdy
2014).

Headache due to treatment of brain tumors. Treatment-related causes of headache in brain tumor patients
include postcraniotomy pain (Flexman et al 2010; Soffietti et al 2014), other complications of surgery, radiotherapy,
chemotherapeutic agents, antiemetics, and corticosteroid withdrawal. Possible treatment-related mechanisms for
brain tumors include postcraniotomy headache, reversible leukoencephalopathy syndrome (PRES), pseudotumor
cerebri, cerebral venous thrombosis, chemical meningitis, and biological agents-induced mechanisms (Table 1).

Table 1. Clinical Syndrome of CNS Toxicity of Anticancer Drugs That Cause Headaches
Clinical syndrome Drugs
Reversible posterior Cyclophosphamide, Ara-C, cis-paltinum, ifosfamide, vincristine,
leukoencephalopathy (PRES) gemcitabine, bevacizumab
Pseudotumor cerebri Retinoids
Cerebral venous thrombosis L-asparaginase
Aseptic meningitis Methotrexate, Ara-C
Biological therapies Interferons, interleukins, tamoxifen
Persistent headache attributed craniotomy was listed in the third beta edition of the international classification of
headache disorders (code 5.5). It was renamed from chronic postcraniotomy headache in the second edition of the
international classification of headache disorders (Headache Classification Committee of the International Headache
Society 2013). Persistent postcraniotomy headaches are uncommon in patients with supratentorial craniotomies (Kaur
et al 2000; Gee et al 2003). In a series of 71 patients with craniotomy for aneurysms, 48% had craniofacial pain and
functional jaw limitations 4 to 6 months after craniotomy (Rocha-Filho et al 2007). Similar jaw and craniofacial pains
are common in brain tumor patients (personal observation).

Suboccipital craniotomies are associated with a much higher prevalence of postoperative headache. A survey of 1657
patients who had surgery for an acoustic neuroma found that a third had preoperative headache, 78% to 93% had
headache 3 months postoperatively, depending on the surgical approach, and 50% to 66% continued to have
headache 3 years postoperatively (Ryzenman et al 2005). In another study, 64% of patients reported postoperative
headache after acoustic neuroma surgery; this persisted in 55% (Rimaaja et al 2007).

Despite normalizing prolactin levels, dopamine agonists may worsen headaches (Levy et al 2005). Patients treated
with octreotide for acromegaly may develop rebound headache after initial response (Levy et al 2005).

Temozolomide is an alkylating agent used for malignant gliomas and other brain tumors and is reported to cause
headache in 25% of patients (Middleton et al 2000; Yung et al 2000). Pseudoprogression, which occurs when
temozolomide is used concurrently with radiotherapy for treatment of glioblastoma, presents with headache and
neurologic deterioration starting shortly after completion of radiotherapy. Imaging shows increased enhancement and
mass effect indistinguishable from recurrent tumor. Pseudoprogression usually responds to increased doses of
corticosteroids and likely represents an enhanced response to treatment as these patients have longer survival rates
than those who do not show pseudoprogression (Brandsma et al 2008).

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients treated with bevacizumab, which
is a monoclonal antibody that binds to vascular endothelial growth factor and is used to treat malignant gliomas (Lou
et al 2011). PRES has also been reported with other targeted therapies. Other chemotherapeutic agents including
cyclophosphamide, Ara-C, cis-platinum, ifosfamide, vincristine, and gemcitabine were reported to be associated with
PRES, which may cause headache (Soffietti et al 2014).

Retinoids are associated with an increase of intracranial pressure (pseudotumor cerebri), and L-asparaginase agents
may cause cerebral venous thrombosis. Both pseudotumor cerebri and cerebral venous thrombosis can cause
headache (Soffietti et al 2014).

Intrathecal chemotherapy can cause chemical meningitis in as many as 25% of patients (Glantz et al 1999; Soffietti et
al 2014). Corticosteroid withdrawal may precipitate headache despite no worsening of tumor-related cerebral edema.
Selective serotonin type-3 receptor antagonists, such as ondansetron, are used to control chemotherapy-related
nausea and may cause headache in 14% to 39% of patients (Einhorn et al 1990; Kalaycio et al 1998).

Radiotherapy to the brain may cause headaches at several different stages. An acute radiation encephalopathy with
headache may occur at the onset of therapy. At 1 to 6 months postradiotherapy, a subacute demyelinating radiation
encephalopathy may present with headache and worsening symptoms and signs (Schultheiss et al 1995). Imaging may
show increased cerebral edema and gadolinium enhancement that is indistinguishable from recurrent tumor on
standard CT or MRI. Delayed complications include cerebral radiation necrosis, which presents months to years after
radiation and presents with headache and other focal symptoms depending on the location of the lesion (Rogers
2012).

Several reports of stroke-like migraine attacks after radiation therapy (SMART syndrome) occurring as a late
complication of radiotherapy have been published (Shuper et al 1995; Black et al 2006; Kerklaan et al 2011; Armstrong
et al 2014). Initially reported by Shuper and colleagues, these patients have prolonged and usually reversible episodes
lasting hours to weeks of migraine-type headache and focal neurologic deficits, including seizures (Shuper et al 1995).
The episodes may start many years after radiotherapy. MRI often shows striking ribbon-like cortical enhancement of
the involved hemisphere, which resolves as the episode abates.

Diagnostic workup
There are many causes of new headache in cancer patients, including intracranial metastases, side effects of therapy,
hemorrhage, infarction, infection, and metabolic causes (Kirby and Purdy 2005). After a careful history and physical
examination, neuroimaging is essential in ruling out structural causes, such as metastases. MRI with gadolinium
enhancement is superior to CT scan in detecting parenchymal metastases or leptomeningeal disease, and MRA/MRV
sequences are better for detecting venous sinus thrombosis (Chamberlain et al 1990), whereas a CT scan may be
better for acute hemorrhage or base of skull lesions. If imaging studies are negative and the clinical picture is
compatible, lumbar puncture, measuring opening pressure, glucose, protein, and cell count in the CSF, as well as
cytological examination of the CSF may reveal leptomeningeal metastases. A significant false negative rate of 25% to
50% exists for both CSF cytology and MRI scans, so studies may need to be repeated (Wasserstrom et al 1982;
Grossman and Krabak 1999).

The workup of secondary trigeminal autonomic cephalalgias may be indistinguishable from primary trigeminal
autonomic cephalalgias, so neuroimaging should be considered to rule out secondary causes (Wilbrink et al 2009). The
workup of other new headache patients without known malignancy is beyond the scope of this review.

Management

Management of headache associated with brain tumor depends on the tumor pathology, location, associated
symptoms, and the patient's functional status. For headaches caused by raised intracranial pressure and mass effect
secondary to tumor-associated edema, corticosteroids such as dexamethasone often provide dramatic symptomatic
relief until more definitive therapy can be used. Potential complications of corticosteroids, such as avascular necrosis
of the hip, should be discussed with patients.

Patients with brain metastases are frequently treated with whole brain radiotherapy. In an early study of patients with
brain metastases, 82% had relief of headache with palliative radiotherapy (Borgelt et al 1980), but in one study, only
41% had a significant improvement in headache after radiotherapy (Wong et al 2009). Two prospective studies have
suggested that improvement or stabilization of headache and lower requirements for corticosteroids were seen after
whole-brain radiotherapy (Wong et al 2009; Steinmann et al 2012). Surgical resection or stereotactic radiosurgery may
provide additional benefit in patients with limited numbers of metastases and controlled systemic disease (Patchell et
al 1990; Kondziolka et al 1999; Sanghavi et al 2001).

Cerebral edema due to a primary brain tumor often responds to corticosteroids temporarily with good headache relief.
Headaches may also respond to simple analgesics, although antiplatelet agents should be avoided by patients using
corticosteroids or whose tumors have hemorrhaged. More definitive treatment depends on tumor pathology but may
include surgery, radiotherapy, and chemotherapy. In my experience, treatment of malignant gliomas usually relieves
headache but at recurrence, 26% to 52% of patients complain of headache (Osoba et al 2000; Gofton et al 2012).
Good palliative care should include adequate pain control using corticosteroids, and both simple analgesics and
narcotics as required. Headache management is only one part of the symptom burden of progressive tumors, and
palliative care support is essential for patients and their families.

Symptoms from radiation necrosis may respond to steroids, and surgery removing the necrotic tissue can be helpful.
Bevacizumab is a monoclonal antibody active against vascular endothelial growth factor. In a small randomized trial, it
was shown to be effective against radiation necrosis (Levin et al 2011). There are no published reports of its use in
SMART syndrome, but it may potentially be helpful.

Headache in patients with pituitary tumor showed variable response to treatment. In a case series, 73.7% of patients
improved headache after surgical removal of tumors (Abe et al 1998). Another study showed that 49% reported
headache improvement after surgical treatment, 36% had no change of headache, and 8% worsened. Of the patients
that underwent radiotherapy, only 6.25% had headache improvement. Use of somatostatin analogs resulted in 54.6%
with headache improvement and 45.4% no change. Use of dopamine agonists resulted in headache improvement in
30% and with worsening or no change in 30% (Levy et al 2005).

Headache management of patients who are likely to have a long survival may be more complex. Patients with previous
primary headache disorders are more likely to experience headache with a brain tumor (Forsyth and Posner 1993). It is
important to distinguish between headache caused by the brain tumor and headache from a primary headache
disorder so treatment can be tailored appropriately. Occasionally, a secondary headache disorder will respond to
therapies used for primary headache disorder (Vijayan 1992; Gatzonis et al 1996). Medical therapy for the tumor may
also relieve the associated headache, as may be seen with the use of octreotide for growth hormone-secreting
pituitary tumors and dopamine agonists for prolactinomas (Levy et al 2005). Surgery even for pituitary microadenomas
may relieve headache in patients who have failed medical therapy (Fleseriu et al 2009).

In summary, headaches associated with brain tumors can have many presentations, and a high index of suspicion is
warranted when patients with a known malignancy present with a new headache. Certain rare headache syndromes,
such as the trigeminal autonomic cephalalgias, appear to be more frequent in patients with brain tumors, and a
secondary cause for these syndromes should always be ruled out by appropriate imaging. It is important to recognize
that treatment of brain tumors may cause headache so as to avoid unnecessary investigations and patient anxiety.
Finally, given the shortened life expectancy of many patients with brain tumors, it is critical to optimize symptom
control quickly to maintain their quality of life.

Special considerations

Pregnancy

Headaches may be associated with brain tumors in pregnant as well as nonpregnant women. Management of these
headaches is subject to the same constraints as in pregnant women without brain tumors, where the risk to the fetus
must be balanced against the risk to the mother. Decisions about the timing of definitive treatment of the brain tumor
will depend on the woman's wishes, risk, and surgical judgment.

Anesthesia

The presence or absence of headache in isolation is unlikely to change anesthetic management during surgery for
brain tumors. However, the factors that make a patient more prone to brain tumor-associated headache, such as
raised intracranial pressure and mass effect, may change management during surgery. As in any surgery, good
postoperative pain control is necessary.

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Former authors

Susan M Snodgrass MD (original author), R Allan Purdy MD, and Sarah Kirby MD

ICD and OMIM codes

ICD codes

ICD-9:
Cluster headache syndrome: 346.2
Headache: 784.0
Migraine with aura: 346.0
Tension headache: 307.81

ICD-10:
Chronic post traumatic headache: G44.3
Cluster headache syndrome: G44.0
Drug induced headache, not elsewhere classified: G44.4
Headache: R51
Migraine with aura: G43.1
Tension-type headache: G44.2
Vascular headache not elsewhere classified: G44.1

Profile

Age range of presentation

0-01 month
01-23 months
02-05 years
06-12 years
13-18 years
19-44 years
45-64 years
65+ years

Sex preponderance

male=female

Family history

family history may be obtained

Heredity

heredity may be a factor

Population groups selectively affected

none selectively affected

Occupation groups selectively affected

none selectively affected

Differential diagnosis list

postcraniotomy pain
headache due to complications of surgery
headache due to radiotherapy
headache due to chemotherapeutic agents
headache due to antiemetics
headache due to corticosteroid withdrawal
headache due to Temozolomide
selective serotonin type-3 receptor antagonists (eg, ondansetron) used to control chemotherapy-related nausea

Other topics to consider

Brain metastases
Cerebrovascular complications of cancer
Cluster headache
Epidemiology of headache
Migraine
Neuroimaging of headache
Tension-type headache

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