Headache as Complication of Cancer

Clinical history suggesting a brain tumor headache

Cancer patient with a new headache or a change in

headache pattern

Unrelenting crescendo headache

Headache resistant to all medical interventions

Pain location invariant

Characteristics of brain tumor headaches

Frequent symptoms

Intermittent headaches

Headache building up and resolving in hours

Pain of pressure-like/ tightening/ dull aching quality

Moderate to severe intensity

Bilateral pain

Ipsilateral headaches in hemispheric tumors, with laterality usually being predictive for ipsilateral tumor location

Less frequent symptoms

Morning headaches

Daily headaches

Progressive headaches

Constant pain

Headaches worsening with bending over or with Valsalva’s maneuver

Headaches waking patients from sleep or interfering with falling asleep

Association with nausea and vomiting

Accompanying sign and symptoms

Diffuse weakness

Anorexia

Malaise

Hyperreflexia

Positive Babinski

Papilledema

Cognitive changes

Depression

Fatigue

Personality changes

Seizures

Although brain tumor headaches are usually nonspecific in character, they are usually accompanied by other symptoms suggesting either a focal lesion or increased intracranial pressure . Typically, either tension-type or migraine-like headaches are predominant, though a smaller subset of patient will have a mix of headache types. In a prospective study of 111 patients with brain tumors, the “classic” brain tumor type headache occurred in a meager 17% of patients. 67% patients of this subtype of “classic” brain tumor headaches had evidence of increased intracranial pressure . Headaches were worse in the morning in 36%, worse with bending over in 32%, worse with Valsalva in 23% and woke patients from sleep or interfered with falling sleep in 32% of the patients with headache. Nausea and vomiting associated with headaches were present in 48% patients. The headache was the worst symptom in only 45% patients [3]. In patients with a known history of brain tumor, the development of a headache late in the clinical course may signify the possibility of a change in the tumor structure or tumor recurrence.

Headache location may have a localizing value. Patients with unilateral headache without increased intracranial pressure is likely to have an ipsilateral location of the brain tumor. A frontal headache is the least valuable in localizing a brain tumor. Occipital headaches are associated with posterior fossa and infratentorial tumors. Patients with supratentorial tumors have headaches that more often correspond to the side of tumor than patients with infratentorial tumors. It has also been reported that headaches are more common with infratentorial tumors than supratentorial ones [1–3, 5].

The third edition of the International Classification of Headache Disorders (ICHD-3) has extensively described the diagnostic criteria of classification of headaches due to intracranial neoplasms [6]. While it is useful to have a description and classification of the brain tumor headache, a strict use of this guideline is not recommended as it places emphasis on the “classic” brain tumor headache. According to ICHD-3, the characteristic headache attributed to intracranial neoplasm is a headache that is usually progressive, worse in the morning and aggravated by Valsalva maneuvers, caused by one or more space-occupying intracranial tumors. Evidence of causation should be demonstrated by at least two of the following three criteria: headache has developed in a temporal relationship to the tumor or had led to its discovery; headache has significantly worsened in parallel with the worsening of tumor or headache has improved in parallel with the successful treatment of the tumor; and headache has at least one of the following characteristics-progressive, worse in the morning or after daytime napping, aggravated by Valsalva maneuver. When a patient develops headache for the first time or has a new headache type, and develops a brain tumor in unison, the headache should be attributed to the intracranial tumor, even when the headache character is a migraine, tension-type headache, or a cluster headache. On the other hand, when the patient has a history of a primary headache, which becomes worse in a close temporal relationship to the occurrence of an intracranial neoplasm, it is challenging to say if the intracranial neoplasm is the etiology of the worsened headache. There may be three possible explanations: the finding is coincidental, this is an aggravation of primary headache, or it represents a new headache, causally related to the intracranial neoplasm.

Pathophysiology of the Brain Tumor Headaches (Table 8.2 )

In people with a predisposition to headaches, brain tumor headaches may present similarly to primary headaches. This can lead to delay in tumor diagnosis, particularly when headache is the presenting or an isolated symptom. It also suggests that the primary and tumor-associated headaches may have a mutually shared biology. Progressive headache is more common in high grade tumor and secreting pituitary adenomas . Slow growing tumors are less likely to cause headaches [5, 7].

Table 8.2

Causes of headache in cancer patients

Tumor-related causes
Acute	Intratumoral hemorrhage Acute venous sinus thrombosis CSF obstruction with resulting increase in intracranial pressure Pressure wave headache
Chronic	Persistent or new tumor growth New metastatic lesion involving skull, meninges, brain, skull base, sinuses, orbits, etc. Invasion of tumor into calvarium, skull base, meninges, leptomeninges. Increased intracranial pressure with midline shift causing traction on veins, arteries, nerves, etc.
Nontumor-related causes
Treatment-related causes	Hormones (e.g., tamoxifen) Differentiation agents (retinoic acids) Antibiotics Reverse transcriptase inhibitors (e.g., AZT, DDI) Conventional agents (e.g., l-asparaginase, procarbazine, nitrosoureas, fludarabine, fazarabine, gallium nitrate) Cytokines (e.g., tumor necrosis factor, OKT3, interferons, interleukins, levamisole, GM-CSF) Intrathecal therapy (e.g., methotrexate, Ara-C)
Radiotherapy	Acute radiation encephalopathy Subacute demyelinating encephalopathy Cerebral radiation necrosis SMART syndrome
Supportive therapies	Corticosteroids, cimetidine, ondansetron, narcotics (withdrawal), metoclopramide, anticoagulants (intratumoral hemorrhage), dipyridamole, ibuprofen (aseptic meningitis)
Surgery	Hemorrhage, vascular injury, perioperative stroke, cerebrospinal fluid leak
Other causes of headache
Acute	Cerebral infarcts Fever Infection (abscess, meningitis) Metabolic (hypoxemia, hypercarbia, and hypoglycemia)
Chronic	Referred pain from extracranial structures (cervical metastases, lung tumors, etc.) Post lumbar-puncture headache

Courtesy of Robert Cavaliere, MD, author of a chapter on this subject in the previous edition of this book, in which this table appeared [49]

It is important to understand that increased intracranial pressure is not essential to the development of the brain tumor headache. Headaches in brain tumors may be caused by traction or compression of the pain-sensitive structures, release of potential signal substances, or neuroendocrine abnormalities. A direct mass effect or inflammation of intracranial and extracranial structures such as cranial nerves, vasculature, dura, periosteum, etc., can contribute to the headache. The pain-sensitive extracranial tissues include the galea, fascia, arteries, and the scalp muscles and the periosteum along the inferior, frontal, temporal, and occipital skull base. Intracranially, the pain-sensitive structures are the dura at the skull base and near the major venous sinuses, the tentorium cerebelli, cranial nerves V, IX, X, XI, and the proximal trunks of the main dural arteries. Pain-insensitive structures include the cranial bones, extracranial diploic and emissary veins, cerebral and cerebellar parenchyma, choroid plexus, the ependymal lining of the ventricles, pia-arachnoid, arachnoid granulation, and most of the dura covering the cerebral convexities [8]. Experimental observations suggest that stimulation of pain-sensitive structures on or above the superior surface of the tentorium resulted in pain transmitted by CN V located in the anterior half of the head. Stimulation of the pain-sensitive intracranial structures on or below the inferior surface of the tentorium resulted in pain over the posterior half of the head via CN IX and X and the upper three cervical nerves. Since lesions of remotely separated structures can cause headache in identical areas, the use of tumor location as a localizing tool can be challenging [9].

Cerebrospinal fluid (CSF) obstruction due to a mass lesion may cause increased intracranial pressure (ICP) and can stretch the pain-sensitive structures. Rapid distention or drainage of the ventricular system can produce diffuse headache due to traction on the cortical veins entering the dural sinuses. Third ventricular distention can cause a headache due to stretch of the arteries of the circle of Willis. Tumors may also produce signal substances like nitric oxide synthase, calcitonin gene-related peptide, tumor necrosis factor alpha, vasoactive intestinal peptide, tachykinin (substance P), and prostaglandin endoperoxide synthase, which may cause headaches [1]; however, this finding has not been well substantiated. Neuroendocrine abnormalities have been postulated as a cause of headache in patients with pituitary tumors. Patients with prolactinomas have a higher incidence of headache than those with growth hormone-related pituitary tumor, implicating a potentially greater role for the dopamine-prolactin axis in pain.

Brain Tumor Headache Associated with Increased Intracranial Pressure (Table 8.2 )

Approximately 86–95% of patients with increased intracranial pressure have headaches [5]. These headaches can be distinguished from other types of brain tumor headaches due to their severity, association with nausea or vomiting and resistance to common analgesics, rather than their quality or location. Etiologies for the development of increased intracranial pressure include intracranial mass effect due to tumor, cerebral edema, intratumoral hemorrhage, obstructive hydrocephalus, communicating hydrocephalus, and leptomeningeal spread of the tumor. The presence of increased intracranial pressure may slightly decrease the localizing value of ipsilateral headaches. Traction and displacement of periventricular pain-sensitive structures in obstructive hydrocephalus may be the mechanism of the headache pain. The common signs and symptoms associated with increased intracranial pressure are headache, nausea, vomiting, lethargy, papilledema, visual obscuration, diplopia, tinnitus, and somnolence.

The description of headaches associated with plateau waves is worth mentioning. Plateau waves, first described by Lundberg in 1960, are episodic increase in ICP that arise from rapid cerebrovascular vasodilatation that can cause stereotypical paroxysmal neurological symptoms like headache, blurred vision, diplopia, imbalance, and fainting spells. Impaired intracranial compliance is a prerequisite in the development of plateau waves. In the patient with a brain tumor, the intracranial compliance may be decreased due to the mass effect of the tumor or development of hydrocephalus [10, 11].

Plateau wave headache is also known as pressure wave headache or paroxysmal headache . This headache is usually severe in intensity and builds to peak intensity in seconds. The duration of the symptoms may be minutes or a few hours and the episode terminates quickly. Headache is frequently associated with plateau waves, but this phenomenon may be challenging to diagnose due to the patient’s impaired mental status and inability to describe their symptoms during this paroxysmal spell. These episodes may frequently be misdiagnosed as seizures. Awareness of this phenomenon of plateau waves is important as it may herald impending herniation [8].

Headaches in Pituitary Tumors

With the recent widespread use of sensitive imaging for head trauma, chronic sinusitis and headache, it is quite common for the clinician to find an unexpected sellar lesion. If the patient has a headache, then the question becomes whether the headache is related to the sellar lesion. Intrasellar tumors commonly manifest with headaches, which are often disabling. The reported incidence of headache associated with pituitary adenomas varies from 33 to 72% [2, 12].

A prospective study on 84 patients presenting with pituitary tumors classified patients’ headaches using the International Headache Society diagnostic criteria [13]. Headaches were found to be chronic migraines (46%), episodic migraines (30%), primary stabbing headache (27%), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT; 5%), cluster headache (4%), hemicrania continua (1%), and non-specific in 7% of patients. Half of the patients had a family history of headaches. It was posited that migraine patients have an increased sensitivity to changes in the internal or external milieu and that the development of pituitary tumors may have lowered the threshold for migraine attacks in this predisposed population. Migraines were found in a higher frequency in prolactinomas and growth hormone-secreting tumors, suggesting that functional activity may be an important trigger. Cluster headaches and SUNCT were overrepresented in pituitary disease.

Of the patients who underwent surgical treatment, 49% reported an improvement in headaches. Treatment with radiotherapy had a poor response in terms of headache alleviation. 64% of acromegalics who were treated with somatostatin analogues had improvement in their headaches. This suggests a shared biology between tumor activity and headache. Somatostatin analogues are known to interfere with the opioidergic system, which may explain an improvement in headache [14, 15]. Octretotide may be useful in the acute treatment of cluster headache [16]. Patients responded unpredictably to treatment with dopamine agonists; some had an improvement in their headaches while others had an exacerbation. It was hypothesized that an improvement in headache could be due to reduction in tumor size in large prolactinomas. The dopamine-prolactin axis plays an important role in several primary headaches like migraines and cluster headaches. Conversely, dopamine agonists may act on the trigeminovascular system, causing headache exacerbation [13, 17–19].

It has been suggested that the headache in pituitary tumors is related to dural traction on pain-sensitive structures, tumor size and cavernous sinus invasion. The expansion of pituitary tumor within the sella turcica stimulates the afferent fibers innervating the dura, causing pain. Invasion of the cavernous sinus by the pituitary tumor causes pain as the cavernous sinus contains the ophthalmic branch of the trigeminal nerve and the internal carotid artery, both of which are pain-sensitive structures. Another cause of headache in pituitary tumor may be the presence of tumor activity and neuroendocrinological signaling alteration. This is supported by the fact that headache can be present in small tumors and can be improved or worsened by endocrine treatment. Regarding the role of cavernous sinus invasion and tumor size in the causation of headaches, studies have reported conflicting results. While two studies found no association between cavernous sinus invasion, pituitary volume and headache, another prospective study in pituitary adenoma showed a positive association between the presence of headache with tumor size and cavernous sinus invasion [20–22]. Given the contradictory findings, further studies are needed to explain the mechanism of headache in pituitary tumors.

Headache in Systemic Cancer (Table 8.2 )

In the patient with a systemic cancer, headache is a common complaint. It is usually not a harbinger of an ominous intracranial pathology but nonetheless warrants careful clinical assessment. Patients with systemic cancer, like the general population, commonly suffer from migraine, tension headaches, and other primary headaches. Any change in the patient’s preexisting headache, crescendo headaches, headaches unresponsive to treatment, vomiting, lethargy, or abnormal neurological exam should raise suspicion of a secondary cause of headache due to intracranial pathology. A study examining 97 patients with an undiagnosed headache in the setting of systemic cancer found that 61% did not have a structural cause of headache. The majority of these patients with a non-structural cause of headache had migraine, tension headache, or headache due to systemic illness like fever or sepsis. 39% of patients had a structural cause of headache. The common structural causes of headache were cerebral metastases , skull base metastasis, or intracranial hemorrhage. Rare structural causes of headaches included leptomeningeal metastases, upper cervical spine metastasis, and primary brain tumor [23].

Patients with systemic cancers, especially breast cancer, lung cancer, and melanoma, may develop leptomeningeal spread of the tumor. Leptomeningeal disease frequently presents with headache. Usually, other multifocal neurological signs like cranial nerve palsy, evidence of spinal dysfunction, radiculopathies, or acute mental status change accompany the headache. The spread of tumor to the base of brain, arachnoid villi and reactive fibrosis may impede or block the CSF flow pathways leading to the development of hydrocephalus and increased intracranial pressure. The etiology of headache in leptomeningeal carcinomatosis may include hydrocephalus, increased ICP or cranial nerve infiltration.

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