Brain tumor headache

INTRODUCTION — Headache is one of the most common complaints encountered in clinical medicine. Though the vast majority of headaches are caused by primary headache disorders, more ominous etiologies, such as cerebral neoplasm or metastatic disease, may also be heralded by headache. This topic will review headache related to brain tumors. Other clinical aspects of brain tumors are discussed separately. (See "Overview of the clinical features and diagnosis of brain tumors in adults".)

The approach to evaluating headache in adults and children is reviewed elsewhere. (See "Evaluation of headache in adults" and "Headache in children: Approach to evaluation and general management strategies" and "Evaluation of the adult with nontraumatic headache in the emergency department" and "Emergency department approach to nontraumatic headache in children".)

MECHANISMS OF HEADACHE — Traction on the large blood vessels and dura as well as direct compression of cranial and cervical nerve fibers by the tumor itself are the likely mechanisms for headaches attributed to brain tumors [1-3]. Peripheral and central sensitization may also contribute [4]. Of note, the brain parenchyma is insensitive to pain. Structures that are sensitive to pain include the following [2,3]:

●The large arteries at the base of the brain and the first few centimeters of their immediate branches

●The meningeal arteries

●The large venous channels of the brain and dura

●Parts of the dura, including the tentorium and the diaphragma sellae

●Cranial nerves that carry pain fibers (V, VII, IX, X)

●Skin and subcutaneous tissue, muscle, vessels, and periosteum of the skull

Tumors and other mass lesions can cause headache by direct pressure on any of the above structures. Pain arising from the intracranial cavity is a form of visceral pain, and therefore referred to more superficial structures; it is not perceived as coming directly from the compressed region [5]. In general, unilateral lesions refer pain ipsilaterally, supratentorial lesions refer pain to the frontal regions, and posterior fossa masses refer pain to the occiput [5]. However, these associations have poor localizing value in clinical practice. As an example, in a study that evaluated 37 patients with infratentorial tumors, 73 percent of patients had headache in the frontal, temporal, and/or parietal regions, while nuchal and occipital pain occurred in only 27 percent [6].

Acute or severe headache from a brain tumor can potentially be caused by elevated intracranial pressure resulting from hydrocephalus, mass effect of the tumor itself, or hemorrhage into or around the tumor [7]. A tumor can distort or displace structures distant from its locale, resulting in referred pain that does not correspond with its location. In such cases of "distant traction," elevated intracranial pressure may be the cause of the headache [4]. However, the relationship between elevated intracranial pressure and headache in brain tumor remains uncertain [8].

EPIDEMIOLOGY — Headache at presentation is observed in approximately 20 percent of patients with brain tumor, and headache occurs during the course of the disease in 48 to 60 percent [9-11]. In one prospective cohort study of 507 patients, 54 percent of patients reported a preoperative headache, and at one and six months postoperatively, the prevalence was 43 and 30 percent, respectively [12]. In the same study, headache was more commonly seen in younger female patients with brain tumors. Several reports have noted that a prior history of headache is a probable risk factor for headache associated with brain tumor [11,13], though this may apply only to a longstanding primary headache history and not to a remote history [11].

The most frequent primary intracranial tumors are gliomas, meningiomas, and pituitary adenomas. The most frequent sources of metastatic tumors are lung and breast cancer, followed by malignant melanomas and carcinomas of the kidney and gastrointestinal tracts [14,15].

Though headache is a common symptom of brain tumor, it is infrequently seen in isolation, as described in the following sections. Furthermore, among all patients with headache who have normal neurologic examinations, the prevalence of intracranial neoplasm is exceedingly low [16]. By contrast, the prevalence of intracranial involvement is relatively high in patients with known systemic malignancy. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases".)

CLINICAL FEATURES — The features of brain tumor headache are generally nonspecific and vary widely with tumor location, size, and rate of growth [7,11,16]. The headache is usually bilateral but can be on the side of the tumor [15,17]. Supratentorial tumors impinging on structures innervated by the ophthalmic division of the trigeminal nerve may produce a frontotemporal headache, while posterior fossa tumors compressing the glossopharyngeal and vagus nerves can cause occipitonuchal pain. There is generally little radiation, except in posterior fossa tumors. Nausea and/or vomiting accompany the headache in 40 to 60 percent of adult patients [6,9,13]. Headache exacerbation with Valsalva, change in position, or exertion occurs in a substantial minority of patients.

The evidence regarding the phenotypes of brain tumor headache is inconsistent. In most series, tension-type headache is the most common phenotype in patients presenting with primary or metastatic brain tumors, accounting for 40 to 50 percent of all headaches [11,13,18,19]. Classic brain tumor headache, atypical migraine-type headache, and worsening of a preexisting headache are less common phenotypes.

Other studies have also reported tumors that produced migraine-like headaches with visual aura [20-23]. In addition, brain tumor headache can also mimic cough or exertional headache [24,25], stabbing headache [26], cluster headache [27-29], cluster variants such as short-lasting unilateral neuralgiform pain with conjunctival injection and tearing (SUNCT) [30], orthostatic headache [31], and chronic paroxysmal hemicrania [32]. Secondary trigeminal autonomic cephalgias appear to have a stronger association with pituitary tumors than other types of brain tumors [33,34].

Though headache is a common symptom of brain tumor, it is a relatively weak predictor on its own and is infrequently seen in isolation. In the majority of cases, brain tumor headache is associated with other neurologic symptoms such as seizures, fatigue, cognitive dysfunction, or focal weakness [35,36]. In pediatric patients with brain tumor, isolated headache at presentation has been reported in 0 to 1 percent [37,38]. Among adults, only 2 to 16 percent of patients with brain tumor present with headache alone [13,18,39-41]. Isolated headache of more than 10 weeks duration is seldom caused by brain tumor [40].

The classic "brain tumor triad," comprising nocturnal or early morning occurrence, nausea/vomiting, and severe nature, has not been borne out as a typical pattern in modern studies. In one series of 53 adults with brain tumor headache, this triad occurred in only nine patients (17 percent) [13]. Morning worsening of headache was observed in 19 (36 percent). The patients described most headaches as "moderate to severe," rather than severe. In children, the prevalence of nocturnal or morning headaches appears to be higher than in adults [37,42].

Tumor type and location — Tumor location and pathology may influence the presentation of the headache. Primary brain tumors and metastatic tumors are equally likely to cause headache [13,43,44]. In general, slow-growing supratentorial tumors, such as low-grade gliomas, cause headache less frequently than tumors with more rapid growth. With slower-growing tumors, seizures are more common than headaches [10]. Meningiomas are usually slowly progressive and cause headaches significantly less often than gliomas. Headache occurs in approximately one-third of patients with supratentorial meningiomas [13,17]. The meninges may also be involved in diffuse tumor infiltration (leptomeningeal carcinomatosis), which results in a generalized headache.

Tumors in the posterior fossa, such as medulloblastomas and ependymomas, cause headache in 60 to 83 percent of patients, and earlier in the clinical course than supratentorial ones [43-45]. Though a study of brainstem gliomas, excluding ependymomas, found only 44 percent of patients with headache [46], this lower figure might reflect the slower growth of low-grade gliomas or the presence of other symptoms that led to diagnosis before the onset of headache [8]. Within the posterior fossa, location seems to be a more important determinant of headache than tumor type, probably because posterior fossa lesions tend to obstruct cerebrospinal fluid pathways early and lead to increased intracranial pressure [5]. Headache is the first symptom of posterior fossa tumors in most cases, with the notable exception of cerebellopontine angle tumors. Many of those tumors are vestibular schwannomas, which usually present with hearing loss or tinnitus before the onset of headache. (See "Vestibular schwannoma (acoustic neuroma)".)

Tumors in the sellar and parasellar regions, usually pituitary adenomas and craniopharyngiomas, are usually heralded by the presence of visual or endocrine symptoms. Nevertheless, headache is a common accompaniment of pituitary tumors [47]. In one study of 63 patients with pituitary tumors, the prevalence of headache was 70 percent, but there was no relationship between headache features and pituitary volume [48]. In a longitudinal cohort study of 133 consecutive patients with pituitary lesions (mostly macroadenomas), the prevalence of headache was 63 percent, and the group with headache was more likely to be younger, female, and to have a prior history of headache [49]. In children, headache is usually the presenting complaint, as they are often unaware of the other symptoms.

Third ventricle tumors, such as colloid cysts, are associated with paroxysmal headaches. Patients report sudden onset of severe headache, which reflects blockage of the cerebrospinal fluid pathway by the tumor in a ball-valve mechanism. The headache can be worsened or relieved by changes in position. (See "Overview of thunderclap headache", section on 'Colloid cyst of the third ventricle'.)

DIAGNOSIS — Though only a small minority of patients with headache have brain tumor as the cause, it is crucial to recognize those headache characteristics that are associated with tumors. Because of the variable nature of headache among patients with brain tumor, the diagnosis of headache attributed to brain tumor should be considered in patients who complain of a headache with any of the following "red flags" [50-52]:

●Acute, new, usually severe headache or headache that has changed from previous patterns

●New headache onset in an adult, especially over 50 years of age

●Headache in older adults or in children

●Headache on exertion, onset at night, or onset at early morning

●Headache that is progressive in nature

●Headache associated with fever or other systemic symptoms

●Headache with meningismus

●Headache with new neurologic signs

●Precipitation of head pain with the Valsalva maneuver (by coughing, sneezing, or bending over)

In patients with any of the above complaints, further investigation with neuroimaging should be pursued.

Neuroimaging — Brain magnetic resonance imaging (MRI) with and without contrast is the optimal neuroimaging study for the evaluation of brain tumors. Although computed tomography (CT) is sufficient in showing a majority of neoplasms [53], the sensitivity and specificity of MRI exceeds that of CT imaging for most tumors, particularly for posterior fossa and dural-based abnormalities [54]. (See "Overview of the clinical features and diagnosis of brain tumors in adults", section on 'Neuroimaging features'.)

Diagnostic criteria — Proposed diagnostic criteria for headache attributed to intracranial neoplasm have been developed by the International Headache Society [55].

For headache attributed directly to neoplasm, the diagnostic criteria are as follows [55]:

●A) Any headache fulfilling criterion C (below)

●B) A space-occupying intracranial neoplasm has been demonstrated

●C) Evidence of causation demonstrated by at least two of the following:

•Headache has developed in temporal relation to the intracranial neoplasia, or led to its discovery

•Either or both of the following:

-Headache has significantly worsened in parallel with worsening of the neoplasm

-Headache has significantly improved in temporal relation to successful treatment of the neoplasm

•Headache has at least one of the following four characteristics:

-Progressive

-Worse in the morning and/or when lying down

-Aggravated by Valsalva-like maneuvers

-Accompanied by nausea and/or vomiting

●D) Not better accounted for by another International Classification of Headache Disorders, third edition (ICHD-3) diagnosis

These criteria are less restrictive than the corresponding criteria in the ICHD-2 [56], which required specific headache characteristics, and may result in decreased sensitivity. To offset this and improve the sensitivity of ICHD-3's criteria C, some have suggested adding a fourth sub-criterion, "any new kind of headache in oncologic patients with a cancer type prone to metastasis to the brain" [57].

Formal diagnostic criteria also exist in the ICHD-3 for headaches attributed to more specific tumors, including colloid cyst of the third ventricle, carcinomatous meningitis, and pituitary adenoma [55].

DIFFERENTIAL DIAGNOSIS — In addition to differentiating between tumor headaches and primary headache disorders, other etiologies must be considered in evaluating a patient with headache [8]. Other space-occupying lesions such as abscesses and subdural hematoma can present with a similar clinical picture to intracranial neoplasm, as can stroke and subarachnoid hemorrhage. The possibility of systemic disorders (ie, thyroid disease, hypertension, pheochromocytoma), temporal arteritis, and traumatic head injuries should be taken into account as well. Idiopathic intracranial hypertension (formerly referred to as pseudotumor cerebri or benign intracranial hypertension) presents with headache as well.

TREATMENT — The treatment of brain tumors is reviewed in detail elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases" and "Management of vasogenic edema in patients with primary and metastatic brain tumors" and "Overview of the management of central nervous system tumors in children" and "Management of known or presumed benign (WHO grade 1) meningioma" and "Systemic treatment of recurrent meningioma" and "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults" and "Radiation therapy for high-grade gliomas" and "Overview of the treatment of brain metastases" and "Management of glioblastoma in older adults".)

In general, the treatment of brain tumor headache depends on tumor type, the functional status of the patient, and the extent of disease progression [7]. Early on, glucocorticoids and simple analgesics often provide good symptom relief while the patient awaits definitive treatment. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors", section on 'Symptomatic treatment'.)

Depending on the patient's prognosis, tumor type, and tumor location, treatment of the tumor itself may involve chemotherapy, surgery, radiation therapy, or a combination of the above. However, in many patients with metastatic brain tumors, life expectancy is limited and treatment is palliative. Pain should be managed aggressively with simple analgesics, narcotics, and glucocorticoids. Consultation with a palliative care team is encouraged.

Tumor treatment itself may cause headache [4].

●Radiotherapy is associated with acute (within two weeks) and subacute (after one to six months) radiation encephalopathy, manifest by new or worsening headache, focal neurologic symptoms and signs, and nausea and vomiting. Nevertheless, acute encephalopathy with whole brain radiotherapy is rare with modern treatment techniques. (See "Acute complications of cranial irradiation", section on 'Standard fractionated radiation therapy'.)

●Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare and late complication of brain radiation and should be considered in patients with a prior history of central nervous system (CNS) radiotherapy who develop migraine-like headaches, focal neurologic deficits, and seizures. The syndrome may be associated with permanent sequelae. Characteristic brain magnetic resonance imaging (MRI) findings in SMART syndrome include unilateral hyperintense cortical signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences with gyriform enhancement (image 1) [58,59]. (See "Delayed complications of cranial irradiation", section on 'Migraine-like headache (SMART) syndrome'.)

●Chemotherapeutic agents may also induce headaches in patients with brain tumors. Temozolomide, which is commonly used to treat malignant gliomas, has been associated with headache in approximately 20 percent of patients [60]. In addition, intrathecal infusions of methotrexate and cytosine arabinoside can cause aseptic meningitis [60-62]. Antiemetics used in conjunction with chemotherapy, such as ondansetron and granisetron, are reported to cause headache in 14 to 39 percent of patients [63,64].

●Postcraniotomy headache is another potential complication of brain tumor treatment. One study found that the majority of patients who undergo craniotomy had headaches similar to tension-type headache or site-of-injury headache, most of which resolved [65]. Hemicrania continua-like headache has also been reported [66]. Surgery can also result in cerebrospinal fluid leakage and subsequent low pressure headache [67]. (See "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis".)

SUMMARY AND RECOMMENDATIONS

●Traction on the large blood vessels and dura as well as direct compression of cranial and cervical nerve fibers by the tumor itself are the likely mechanisms for headaches attributed to brain tumors. (See 'Mechanisms of headache' above.)

●Headache at presentation is observed in approximately 20 percent of patients with brain tumor, and headache occurs during the course of the disease in 48 to 60 percent. Though headache is a common symptom of brain tumor, it is infrequently seen in isolation. Furthermore, among all patients with headache who have normal neurologic examinations, the prevalence of intracranial neoplasm is very low. (See 'Epidemiology' above.)

●Though only a minority of patients with headaches have brain tumor, it is crucial to recognize those headache characteristics that may be more commonly associated with tumors. The features of brain tumor headache are generally nonspecific and vary widely with tumor location, size, and rate of growth. The headache is usually bilateral, but can be on the side of the tumor. Brain tumor headache often resembles tension-type headache, but may resemble migraine or a variety of other headache types. (See 'Clinical features' above.)

●Brain tumors should be considered in patients presenting with headaches associated with meningismus, focal neurologic signs, fever, or systemic symptoms. New-onset headaches in adults over age 50 should prompt further work-up as well. A prior history of headache does not rule out the possibility of brain tumor, and indeed, a change in headache pattern is a diagnostic "red flag." (See 'Diagnosis' above.)

●Brain magnetic resonance imaging (MRI) is the diagnostic test of choice in evaluating for brain tumor, especially if a posterior fossa or dural-based abnormality is suspected. (See 'Neuroimaging' above.)

●Treatment of brain tumor headache depends on tumor type, the patient's functional status, and the extent of disease progression. In cases where treatment is palliative, pain should be managed aggressively with simple analgesics, opioids, glucocorticoids, and the assistance of a palliative care team. (See 'Treatment' above.)