Headache associated with intracranial neoplasms …

Ravi Uniyal MD DM

Headache & Pain

Updated 09.30.2024
Released 06.26.1995
Expires For CME 09.30.2027

Headache associated with intracranial neoplasms

Author: Ravi Uniyal MD DM

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Editor: Shuu-Jiun Wang MD

Headache associated with intracranial neoplasms

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Introduction

Overview

Headaches associated with intracranial neoplasms are common. This article discusses the epidemiology, pathogenesis, and clinical presentation of brain tumor-associated headaches. 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 headaches 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 (61; 49). 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 (47). 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 pressure or tightening or a throbbing or shooting pain (28; 66; 77; 90).

The headache pain is usually intermittent, moderate to severe in intensity, and progressive (28; 66; 77; 90). Only about a third of patients have nocturnal or morning headaches or both, and 20% report headache exacerbation by Valsalva maneuvers (28; 66; 90). Nausea and vomiting are reported in 18% to 60% of patients (28; 66; 77; 90).

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 (28; 66; 77; 90). Tension-type headaches were seen in 29% to 39% of patients (77; 90).

Overall, 62% of the children with brain tumors experienced chronic or frequent headache. Headache frequency was more common in children with infratentorial tumors (70%) than in children with supratentorial tumors (58%). Children with a brain tumor and headache had more 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 (18).

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 a study of 183 patients, all patients had developed other symptoms within 10 weeks (91; 77; 90). Headache was the most common symptom (62%) in patients presenting with brain metastases as the first indication of systemic cancer (40).

A study of 3291 children with brain tumors found that fewer than 1% had headache as their sole symptom, and fewer than 3% had no neurologic abnormality on examination (18). 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 (97).

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 (66). In contrast, Forsyth and colleagues found that all patients with unilateral headache had an ipsilateral tumor (28). Frontal headaches were the most unreliable in predicting tumor location and were most common (28; 90). The reported frequency of bilateral headaches ranged from 18% to 72% (28; 66). 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 (41).

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 (66; 77; 90).

Among pediatric headache patients, accompanying vomiting, neurologic signs, and association of seizure had an increased risk of intracranial neoplasm. Previous headache history had a decreased risk of intracranial neoplasm (80).

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 (35; 16).

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 (31; 10; 57).

Uncommon headache syndromes as a symptom of brain tumors. Headache is reported in 72% of pituitary tumors (53). 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 (54). Patients with prolactinomas and growth hormone-secreting tumors are reported to have more severe headaches than patients with nonsecreting tumors (53). 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 (95). Sometimes, the presence of a tumor in the cerebellopontine angle may be confusing, and the actual reason for the symptoms of trigeminal neuralgia may be the neurovascular conflict alone (88).

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 (37). 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 five of these died. Four additional patients presented with sudden unexplained death caused by a colloid cyst for an overall mortality of 12% (22). 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 two patients had a postural component (21). 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 (11; 89). Four of 42 patients (9.5%) with asymptomatic, nonfunctioning pituitary adenomas developed apoplexy over a 5-year observation period (05). Rarely, pituitary apoplexy proves fatal if unrecognized (81).

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 (76; 34; 86). The inflammation may be severe enough to cause death.

Although headaches are a common complaint in patients with pituitary lesions, the relationship between the symptom and underlying pathology remains unclear. With the exception of pituitary apoplexy, there is likely only a small subset of patients whose headaches result directly from pituitary disease, and this category has yet to be fully elucidated. Although in most cases, patient complaints can be attributed to a primary headache syndrome or other unrelated cause, the presence of endocrine dysfunction, recent visual changes, or new-onset trigeminal autonomic cephalalgia mandates further workup with imaging (23). Prospective evaluations indicate that risk factors for the development of headache in the setting of pituitary adenoma include highly proliferative tumors, cavernous sinus invasion, and personal or family history of headache. Migraine-like headaches are the predominant presentation. Unilateral headaches are often ipsilateral to the side of cavernous sinus invasion (87).

Prognosis and complications

In most cases, the prognosis of brain tumor-associated headache depends on the prognosis of the underlying tumor.

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 (70). From these experiments, they postulated six 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.
(7) ictal epileptic episode caused by intracranial tumor

Studies of an additional 67 patients with brain tumors concluded that local and distant traction on pain-sensitive structures, mass effect, and hydrocephalus caused most headaches (49).

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 (79). However, raised intracranial pressure induced by saline infusions caused headache in other studies (84). Headaches, dizziness, and alterations in consciousness and motor control triggered by standing are symptoms of plateau waves, which are acute elevations in intracranial pressure (94).

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 (53). 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 (54). It has been postulated that expression of somatostatin receptors coupled to the pain pathways may cause headaches (51), 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 (52; 59).

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; 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 (60).

Other possible mechanisms for headache in intracranial tumors include infarction or infection of tumor and treatment-related mechanisms (60; 83). Treatment-related headache mechanisms will be discussed later in this review.

In a case report of a patient with a hippocampal tumor, headache attacks occurred only during ictal activity monitored by electroencephalography (07). This finding suggested that ictal epileptic episode could cause headache in patients with intracranial neoplasm.

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% (28; 66; 20; 77; 90). 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 (18; 96).

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%) (18; 66; 96).

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 (28; 66). 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 (66; 53; 77; 90). 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 (28; 90). Schankin and associates reported an alteration of headache in 82.5% of patients with preexisting headache. Interestingly, 18% reported marked relief from their preexisting headache. Only 38% of patients without preexisting headache developed headache (77). Forty-nine percent of patients with headaches and pituitary tumors had a family history of a headache disorder (54).

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 (56), 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 (18).

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 (19). Emesis, headache duration of fewer than 10 weeks, and non-tension-type headache pain were independent predictors of metastases but had low specificity (19). 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 (04). 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% (03).

Differential diagnosis

Associated or underlying disorders

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 (60). Immunosuppression increases the risk of 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 (93; 08; 39). Patients may present with headache due to raised intracranial pressure or diffuse encephalopathy without focal signs (36). 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 (09; 62). Breast, lung, melanoma, leukemia, and lymphoma are the most common systemic tumors associated with leptomeningeal spread (39), 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 (02). Evans proposed the term “vagal cephalgia” to include headache or facial pain from vagal efferent stimulation from cancer or myocardial ischemia (25).

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 tumors in patients with new undifferentiated headache is low (0.15%) and is even less in those with headache that meets the criteria for a primary headache disorder (0.045%) (45). Briefly, patients with new or changed headache and new neurologic signs or systemic symptoms should be assessed for serious or life-threatening headache causes, including brain tumors (68). 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 (67; 66). Patients with a new diagnosis of trigeminal autonomic cephalalgia should be screened for pituitary or cavernous sinus lesions (47).

Headache due to treatment of brain tumors. Treatment-related causes of headache in brain tumor patients include postcraniotomy pain (27; 83), 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 agent-induced mechanisms (Table 1).

Table 1. Clinical Syndrome of CNS Toxicity of Anticancer Drugs That Cause Headaches

Clinical syndrome	Drugs
Reversible posterior leukoencephalopathy (PRES)	Cyclophosphamide, Ara-C, cis-paltinum, ifosfamide, vincristine, 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 (38). Persistent postcraniotomy headaches are uncommon in patients with supratentorial craniotomies (43; 30). In a series of 71 patients with craniotomy for aneurysms, 48% had craniofacial pain and functional jaw limitations 4 to 6 months after craniotomy (72). 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 (74). In another study, 64% of patients reported postoperative headache after acoustic neuroma surgery; this persisted in 55% (71).

Despite normalizing prolactin levels, dopamine agonists may worsen headaches (54). Patients treated with octreotide for acromegaly may develop rebound headache after initial response (54).

Temozolomide is an alkylating agent used for malignant gliomas and other brain tumors and is reported to cause headache in 25% of patients (58; 99). 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 (15).

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 (55). 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 (83).

Retinoids are associated with an increase in intracranial pressure (pseudotumor cerebri), and L-asparaginase agents may cause cerebral venous thrombosis. Both pseudotumor cerebri and cerebral venous thrombosis can cause headache (83).

Intrathecal chemotherapy can cause chemical meningitis in as many as 25% of patients (32; 83). 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 (24; 42).

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 (78). 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 (73). Radiotherapy can sometimes cause reversible splenial lesion syndrome, which usually presents with fever, headache, and neutropenia in cancer patients after treatment. MRI typically reveals a corpus callosum lesion, which resolves with antibiotics and G-CSF therapy (69).

Several reports of stroke-like migraine attacks after radiation therapy (SMART syndrome) occurring as a late complication of radiotherapy have been published (82; 12; 44; 06). 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 (82). 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. Some SMART syndrome cases progressed after onset of symptoms (13). The exact mechanism of SMART syndrome is not well known. Supposedly, the main pathophysiologic factors involve white matter necrosis, vascular endothelial damage, mitochondrial dysfunction, demyelination, and gliosis, all secondary to delayed irradiation injury (64). There is a case report of SMART syndrome in a patient with previous surgical removal of cerebellar medulloblastoma and radiation therapy 17 years ago. His magnetic angiography revealed multiple stenoses of distal vasculature on both middle and posterior cerebral arteries, with leptomeningeal enhancement in headache side. Multiple stenosis of vasculature and leptomeningeal enhancement reverse after 2 years. Therefore, “reversible cerebral vasoconstriction syndrome”-like vascular changes work in the pathogenesis of SMART syndrome (07).

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 (14), but in one study, only 41% had a significant improvement in headache after radiotherapy (98). Two prospective studies have suggested that improvement or stabilization of headache and lower requirements for corticosteroids were seen after whole-brain radiotherapy (98; 85). Surgical resection or stereotactic radiosurgery may provide additional benefit in patients with limited numbers of metastases and controlled systemic disease (65; 48; 75).

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 (63; 33). 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 (50). There are no published reports of its use in SMART syndrome, but it may potentially be helpful.

Headache in patients with pituitary tumors showed variable response to treatment. In a case series, 73.7% of patients improved headache after surgical removal of tumors (01). Another study showed that 49% reported headache improvement after surgical treatment, 36% had no change of headache, and 8% worsened. Of the patients who underwent radiotherapy, only 6.25% had headache improvement. The use of somatostatin analogs resulted in 54.6% with headache improvement and 45.4% no change. The use of dopamine agonists improved headache in 30% and with worsening or no change in 30% (54).

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 (28). 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 (92; 29). 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 (54). Surgery even for pituitary microadenomas may relieve headache in patients who have failed medical therapy (26).

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.

References

01: Abe T, Matsumoto K, Kuwazawa J, Toyoda I, Sasaki K. Headache associated with pituitary adenomas. Headache 1998;38(10):782-6. PMID 11279904
02: Abraham PJ, Capobianco DJ, Cheshire WP. Facial pain as the presenting symptom of lung carcinoma with normal chest radiograph. Headache 2003;43(5):499-504. PMID 12752757
03: Antunes NL. The spectrum of neurologic disease in children with systemic cancer. Pediatr Neurol 2001;25(3):227-35. PMID 11587878
04: Argyriou AA, Chroni E, Polychronopoulos P, et al. Headache characteristics and brain metastases prediction in cancer patients. Eur J Cancer Care (Engl) 2006;15:90-5. PMID 16441682
05: Arita K, Tominaga A, Sugiyama K, et al. Natural course of incidentally found nonfunctioning pituitary adenoma, with special reference to pituitary apoplexy during follow-up examination. J Neurosurg 2006;104(6):884-91. PMID 16776331
06: Armstrong AE, Gillan E, DiMario FJ Jr. SMART syndrome (stroke-like migraine attacks after radiation therapy) in adult and pediatric patients. J Child Neurol 2014;29(3):336-41. PMID 23364656
07: Bae SY, Lee BI, Kim SE, et al. Ictal epileptic headache in an elderly patient with a hippocampal tumor. J Clin Neurol 2018;14(1):120-2. PMID 29629548
08: Balm M, Hammack J. Leptomeningeal carcinomatosis. Presenting features and prognostic factors. Arch Neurol 1996;53(7):626-32. PMID 8929170
09: Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003;97(12):2972-7. PMID 12784331
10: Bhatti MT, Furman J, Gupta S, Tabandeh H, Monshizadeh R. Superficial temporal artery biopsy diagnostic for lung carcinoma. Am J Ophthalmol 2001;132(1):135-8. PMID 11438078
11: Biousse V, Newman NJ, Oyesiku NM. Precipitating factors in pituitary apoplexy. J Neurol Neurosurg Psychiatry 2001;71:542-5. PMID 11561045
12: Black DF, Bartleson JD, Bell ML, Lachance DH. SMART: stroke-like migraine attacks after radiation therapy. Cephalalgia 2006;26:1137-42. PMID 16919065
13: Bompaire F, Zinchenko L, Lahutte M, et al. SMART syndrome: Classic transient symptoms leading to an unusual unfavorable outcome. Rev Neurol (Paris) 2017;173(1-2):67-73. PMID 27919464
14: Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 1980;6(1):1-9. PMID 6154024
15: Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008;9(5):453-61. PMID 18452856
16: Capobianco DJ, Brazis PW, Rubino FA, Dalton JN. Occipital condyle syndrome. Headache 2002;42(2):142-6. PMID 12005291
17: Chamberlain MC, Sandy AD, Press GA. Leptomeningeal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. Neurology 1990;40(3 Pt 1):435-8. PMID 2314584
18: Childhood Brain Tumor Consortium. The epidemiology of headache among children with brain tumor. Headache in children with brain tumors. J Neurooncol 1991;10(1):31-46. PMID 2022972
19: Christiaans MH, Kelder JC, Arnoldus EP, Tijssen CC. Prediction of intracranial metastases in cancer patients with headache. Cancer 2002;94(7):2063-8. PMID 11932910
20: Davies E, Clarke C. Early symptoms of brain tumours. J Neurol Neurosurg Psychiatry 2004;75(8):1205-6. PMID 15258238
21: Desai KI, Nadkarni TD, Muzumdar DP, Goel AH. Surgical management of colloid cyst of the third ventricle--a study of 105 cases. Surg Neurol 2002;57(5):295-302; discussion 302-4. PMID 12128295
22: de Witt Hamer PC, Verstegen MJ, De Haan RJ, et al. High risk of acute deterioration in patients harboring symptomatic colloid cysts of the third ventricle. J Neurosurg 2002;96(6):1041-5. PMID 12066904
23: Donovan LE, Welch MR. Headaches in patients with pituitary tumors: a clinical conundrum. Curr Pain Headache Rep 2018;22(8):57. PMID 29974273
24: Einhorn LH, Nagy C, Werner K, Finn AL. Ondansetron: a new antiemetic for patients receiving cisplatin chemotherapy. J Clin Oncol 1990;8(4):731-5. PMID 2138214
25: Evans RW. Hemicrania continua-like headache due to nonmetastatic lung cancer- a vagal cephalgia. Headache 2007;47(9):1349-51. PMID 17927655
26: Fleseriu M, Yedinak C, Campbell C, Delashaw JB Jr. Significant headache improvement after transsphenoidal surgery in patients with small sellar lesions. J Neurosurg 2009;110:354-8. PMID 19012490
27: Flexman AM, Ng JL, Gelb AW. Acute and chronic pain following craniotomy. Curr Opin Anaesthesiol 2010;23(5):551-7. PMID 20717011
28: Forsyth PA, Posner JB. Headaches in patients with brain tumors: a study of 111 patients. Neurology 1993;43(9):1678-83. PMID 8414011
29: Gatzonis S, Mitsikostas DD, Ilias A, Zournas CH, Papageorgiou C. Two more secondary headaches mimicking chronic paroxysmal hemicrania. Is this the exception or the rule. Headache 1996;36(8):511-3. PMID 8824008
30: Gee JR, Ishaq Y, Vijayan N. Postcraniotomy headache. Headache 2003;43(3):276-8. PMID 12603648
31: Gironell A, Marti-Fabregas J, Bello J, Avila A. Non-Hodgkin's lymphoma as a new cause of non-thrombotic superior sagittal sinus occlusion. J Neurol Neurosurg Psychiatry 1997;63(1):121-2. PMID 9221985
32: Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 1999;5(11):3394-3402. PMID 10589750
33: Gofton TE, Graber J, Carver A. Identifying the palliative care needs of patients living with cerebral tumors and metastases: a retrospective analysis. J Neurooncol 2012;108(3):527-34. PMID 22467138
34: Gormley WB, Tomecek FJ, Qureshi N, Malik GM. Craniocerebral epidermoid and dermoid tumours: a review of 32 cases. Acta Neurochir (Wien) 1994;128(1-4):115-21. PMID 7847126
35: Greenberg HS, Deck MD, Vikram B, Chu FC, Posner JB. Metastasis to the base of the skull: clinical findings in 43 patients. Neurology 1981;31(5):530-7. PMID 6972014
36: Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999;25(2):103-19. PMID 10395835
37: Harris W. Paroxysmal and postural headaches from intraventricular cysts and tumors. Lancet 1944:654-5.
38: Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013;33(9):629-808. PMID 23771276
39: Jayson GC, Howell A. Carcinomatous meningitis in solid tumours. Ann Oncol 1996;7(8):773-86. PMID 8922190
40: Jin J, Zhou X, Liang X, et al. A study of patients with brain metastases as the initial manifestation of their systemic cancer in a Chinese population. J Neurooncol 2011;103(3):649-55. PMID 20978821
41: Kahn K, Finkel A. It is a tumor -- current review of headache and brain tumor. Curr Pain Headache Rep 2014;18(6):421. PMID 24760490
42: Kalaycio M, Mendez Z, Pohlman B, et al. Continuous-infusion granisetron compared to ondansetron for the prevention of nausea and vomiting after high-dose chemotherapy. J Cancer Res Clin Oncol 1998;124(5):265-9. PMID 9645457
43: Kaur A, Selwa L, Fromes G, Ross DA. Persistent headache after supratentorial craniotomy. Neurosurgery 2000;47(3):633-6. PMID 10981750
44: Kerklaan JP, Lycklama á Nijeholt GJ, Wiggenraad RG, Berghuis B, Postma TJ, Taphoorn MJ. SMART syndrome: a late reversible complication after radiation therapy for brain tumours. J Neurol 2011;258(6):1098-104. PMID 21373901
45: Kernick D, Stapley S, Goadsby PJ, Hamilton W. What happens to new-onset headache presented to primary care. A case-cohort study using electronic primary care records. Cephalalgia 2008;28(11):1188-95. PMID 18771496
46: Kirby S, Purdy RA. Headache associated with intracranial neoplasms. In: Olesen J, Goadsby PJ, Tfelt-Hansen P, Welch KM, Ramadan NM, editors. The headaches. 3rd ed. Lippincott Williams & Wilkins, 2005:949-57.
47: Kirby S, Purdy RA. Headaches and brain tumors. Neurol Clin 2014;32(2):423-32. PMID 24703537
48: Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45(2):427-34. PMID 10487566
49: Kunkle EC, Ray BS, Wolff HG. Studies on headache: the mechanism and significance of the headache associated with brain tumor. Bull NY Acad Med 1942;18:400-22.
50: Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 2011;79(5):1487-95. PMID 20399573
51: Levy MJ, Bejon P, Barakat M, Goadsby PJ, Meeran K. Acromegaly: a unique human headache model. Headache 2003;43(7):794-7. PMID 12890136
52: Levy MJ, Classey JD, Maneesri S, Meeran K, Powell M, Goadsby PJ. The association between calcitonin gene-related peptide (CGRP), substance P and headache in pituitary tumours. Pituitary 2004a;7(2):67-71. PMID 15761654
53: Levy MJ, Jager HR, Powell M, Matharu MS, Meeran K, Goadsby PJ. Pituitary volume and headache: size is not everything. Arch Neurol 2004b;61(5):721-5. PMID 15148150
54: Levy MJ, Matharu MS, Meeran K, Powell M, Goadsby PJ. The clinical characteristics of headache in patients with pituitary tumours. Brain 2005;128:1921-30. PMID 15888539
55: Lou E, Turner S, Sumrall A, et al. Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma. J Clin Oncol 2011;29(28):e739-42. PMID 21900098
56: Lowry JK, Snyder JJ, Lowry PW. Brain tumors in the elderly: recent trends in a Minnesota cohort study. Arch Neurol 1998;55(7):922-8. PMID 9678309
57: Matsumoto K, Ohta M, Takeshita I. Reversible non-thrombotic occlusion of the superior sagittal sinus caused by metastatic malignant lymphoma--case report. Neurol Med Chir (Tokyo) 2003;43(7):349-51. PMID 12924595
58: Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000;18(1):158-66. PMID 10623706
59: Nathoo S, Classey JD, Levy MJ, Meeran K, Powell M, Goadsby PJ. No relationship between vasoactive intestinal polypeptide expression and headache in pituitary tumours. Acta Neurol Scand 2005;111(5):317-22. PMID 15819711
60: Navi BB, Reichman JS, Berlin D, et al. Intracerebral and subarachnoid hemorrhage in patients with cancer. Neurology 2010;74:494-501. PMID 20142616
61: Northfield DW. Some observations on headache. Brain 1938;61:133-62.
62: Omuro AM, Kris MG, Miller VA, et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 2005;103(11):2344-8. PMID 15844174
63: Osoba D, Brada M, Prados MD, Yung WK. Effect of disease burden on health-related quality of life in patients with malignant gliomas. Neuro Oncol 2000;2(4):221-8. PMID 11265231
64: Ota Y, Liao E, Shah G, Srinivasan A, Capizzano AA. Comprehensive update and review of clinical and imaging features of SMART syndrome. AJNR Am J Neuroradiol 2023;44(6):626-33. PMID 37142432
65: Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322(8):494-500. PMID 2405271
66: Pfund Z, Szapary L, Jaszberenyi O, Nagy F, Czopf J. Headache in intracranial tumors. Cephalalgia 1999;19(9):787-90; discussion 765. PMID 10595287
67: Pladdet I, Boven E, Nauta J, Pinedo HM. Palliative care for brain metastases of solid tumour types. Neth J Med 1989;34(1-2):10-21. PMID 2464770
68: Purdy RA, Kirby S. Headaches and brain tumors. Neurol Clin North Am 2004;22:39-53. PMID 15062527
69: Qi X, Zou D, Zhang M, Wang H. Febrile neutropenia induced by adjuvant radiotherapy for a patient with breast cancer accompanied with reversible splenial lesion syndrome (RESLES, TypeI): a case report. BMC Neurol 2024;24(1):353. PMID 39300408
70: Ray BS, Wolff HG. Experimental studies on headache: pain-sensitive structures of the head and their significance. Arch Surg 1940;41:813-56.
71: Rimaaja T, Haanpaa M, Blomstedt G, Farkkila M. Headaches after acoustic neuroma surgery. Cephalalgia 2007;27(10):1128-35. PMID 17711494
72: Rocha-Filho PA, Fujarra FJ, Gherpelli JL, Rabello GD, de Siqueira JT. The long-term effect of craniotomy on temporalis muscle function. Oral Surg Oral Med Oral Pathol Radiol Endod 2007;104(5):e17-21. PMID 17764986
73: Rogers LR. Neurological complications of radiation. Continuum Lifelong Learning Neurolol 2012;18(2):343-54.
74: Ryzenman JM, Pensak ML, Tew JM Jr. Headache: A quality of life analysis in a cohort of 1,657 patients undergoing acoustic neuroma surgery, results from the acoustic neuroma association. Laryngoscope 2005;115(4):703-11. PMID 15805885
75: Sanghavi SN, Miranpuri SS, Chappell R, et al. Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys 2001;51(2):426-34. PMID 11567817
76: Satoh H, Uozumi T, Arita K, et al. Spontaneous rupture of craniopharyngioma cysts. A report of five cases and review of the literature. Surg Neurol 1993;40(5):414-9. PMID 8211660
77: Schankin CJ, Ferrari U, Reinisch VM, Birnbaum T, Goldbrunner R, Straube A. Characteristics of brain tumour-associated headache. Cephalalgia 2007;27(8):904-11. PMID 17635527
78: Schultheiss TE, Kun LE, Ang KK, Stephens LC. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 1995;31(5):1093-1112. PMID 7677836
79: Schumacher GA, Wolff HG. Experimental studies on headache. Arch Neuro Psychiatry 1941;45:199-214.
80: Sheridan DC, Waites B, Lezak B, et al. Clinical factors associated with pediatric brain neoplasms versus primary headache: A case-control analysis. Pediatr Emerg Care 2020;36(10):459-63. PMID 29135901
81: Shields LB, Balko MG, Hunsaker JC 3rd. Sudden and unexpected death from pituitary tumor apoplexy. J Forensic Sci 2012;57(1):262-6. PMID 21854388
82: Shuper A, Packer RJ, Vezina LG, et al. 'Complicated migraine-like episodes' in children following cranial irradiation and chemotherapy. Neurology 1995;45(10):1837-40. PMID 7477978
83: Soffietti R, Trevisan E, Rudà R. Neurologic complications of chemotherapy and other newer and experimental approaches. Handb Clin Neurol 2014;121:1199-218. PMID 24365412
84: Sorensen PS, Corbett JJ. High cerebral fluid pressure. In: Olesen J, Tfelt-Hansen P, Welch KM, editors. The headaches. 2nd ed. New York: Raven Press, 2000.
85: Steinmann D, Paelecke-Habermann Y, Geinitz H, et al. Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases. BMC Cancer 2012;12:283. PMID 22780988
86: Stendel R, Pietila TA, Lehmann K, et al. Ruptured intracranial dermoid cysts. Surg Neurol 2002;57(6):391-8; discussion 398. PMID 12176198
87: Suri H, Dougherty C. Clinical presentation and management of headache in pituitary tumors. Curr Pain Headache Rep 2018;22(8):55. PMID 29904889
88: Thirumalai Vasu S, Retnathankom A. Trigeminal neuralgia in patients with cerebellopontine angle tumors: should we always blame the tumor? A case report and review of literature. Scand J Pain 2022;23(1):213-6. PMID 36030402
89: Turgut M, Ozsunar Y, Başak S, Güney E, Kir E, Meteoğlu İ. Pituitary apoplexy: an overview of 186 cases published during the last century. Acta Neurochir (Wien) 2010;152(5):749-61. PMID 20140630
90: Valentinis L, Tuniz F, Valent F, et al. Headache attributed to intracranial tumours. Cephalalgia 2010;30(4):89-398. PMID 19673912
91: Vazquez-Barquero A, Ibanez FJ, Herrera S, Izquierdo JM, Berciano J, Pascual J. Isolated headache as the presenting clinical manifestation of intracranial tumors: a prospective study. Cephalalgia 1994;14(4):270-2. PMID 7954755
92: Vijayan N. Symptomatic chronic paroxysmal hemicrania. Cephalalgia 1992;12(2):111-3. PMID 1290485
93: Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49(4):759-72. PMID 6895713
94: Watling CJ, Cairncross JG. Acetazolamide therapy for symptomatic plateau waves in patients with brain tumors. Report of three cases. J Neurosurg 2002;97(1):224-6. PMID 12134920
95: Wilbrink LA, Ferrari MD, Kruit MC, Haan J. Neuroimaging in trigeminal autonomic cephalalgias: when, how, and of what. Curr Opin Neurol 2009;22(3):247-53. PMID 19434790
96: Wilne S, Collier J, Kennedy C, Koller K, Grundy R, Walker D. Presentation of childhood CNS tumours: a systematic review and meta-analysis. Lancet Oncol 2007;8(8):685-95. PMID 17644483
97: Wilne SH, Ferris RC, Nathwani A, Kennedy CR. The presenting features of brain tumours: a review of 200 cases. Arch Dis Child 2006;91:502-6. PMID 16547083
98: Wong J, Hird A, Zhang L, et al. Symptoms and quality of life in cancer patients with brain metastases following palliative radiotherapy. Int J Radiation Oncology Biol Phys 2009;75(4):25-1131. PMID 19231099
99: Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000;83(5):588-93. PMID 10944597

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ravi Uniyal MD DM

Dr. Uniyal of King George's Medical University has no relevant financial relationship to disclose.
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Editor

Shuu-Jiun Wang MD

Dr. Wang of the Brain Research Center, National Yang-Ming University, and the Neurological Institute, Taipei Veterans General Hospital, has no relevant financial relationships to disclose.
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Former Authors

Susan M Snodgrass MD
R Allan Purdy MD FACPC FACP FAHS
Sarah Kirby MD
Min Kyung Chu MD PhD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Headache associated with intracranial neoplasms

Differential Diagnosis

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

Also Relevant

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

Headache associated with intracranial neoplasms …

Headache associated with intracranial neoplasms

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Table 1. Clinical Syndrome of CNS Toxicity of Anticancer Drugs That Cause Headaches

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Start a Free Account
to access the full version.

Questions or Comment?

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Headache associated with intracranial neoplasms

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Table 1. Clinical Syndrome of CNS Toxicity of Anticancer Drugs That Cause Headaches

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Acupuncture

Migraine in childhood

Headache attributed to head trauma

Migraine: pathogenesis and pathophysiology

Tension-type headache

Benign paroxysmal vertigo

Vagal nerve stimulation for headaches

New daily persistent headache

This is an article preview.
Start a Free Account
to access the full version.