Background     Evaluating headaches in patients with serious illness presents a diagnostic dilemma as many patients already have “red flags” related to their underlying illness (1). While most headaches will reflect a primary headache disorder, seriously ill patients have a significantly higher risk for life-threatening headache etiologies than the general population. Therefore, in this Fast Fact, we suggest that all seriously-ill adult patients with a new or changing headache be considered for prompt evaluation.

Classification     Primary headache disorders (e.g., migraine, tension, and medication overuse) typically have no underlying secondary cause and are “benign” in the sense that they are not life-threatening. Secondary headaches result from another condition and sometimes are life-threatening. We suggest clinicians frame their consideration of secondary headaches around three broad categories: structural, vascular, and infection (Table) (2).

Classification and Diagnostic Approach to Secondary Headache 

Category	Examples	Red Flags	Diagnostic Considerations	Potential Treatments
Structural	TumorCerebral Edema	Altered mental statusFocal neurologic deficitSeizureHistory of malignancy	MRI with contrast	CorticosteroidsSurgical decompressionRadiation therapy
Vascular	StrokeIntracerebralhemorrhage (SAH, SDH, IPH)Vertebral or carotid artery dissectionVenous thrombosisPRESRCVSGiant Cell Arteritis	Age >50 yearsSudden onset: “Thunderclap”Focal neurologic deficitAltered mental statusRecent traumaAnticoagulation Temporal artery tendernessBlurred vision	AngiographyMRI without contrastCoagulation profileLumbar punctureESR & CRP	ThrombolysisThrombectomySurgical evacuation or decompressionBlood pressure managementCorticosteroids
Infection	MeningitisEncephalitisAbscess	FeverImmunocompromisedRecent CNS surgery or instrumentation	Blood CultureCRPRapid HIV testLumbar PunctureMRI with contrast	DexamethasoneAntibioticsHardware removal

Abbreviations: SAH, subarachnoid hemorrhage; IPH, intraparenchymal hemorrhage; SDH, subdural hematoma; PRES, Posterior Reversible Encephalopathy Syndrome; RCVS, Reversible Cerebral Vasoconstriction Syndrome; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein 

Special Considerations

• Cancer – New or worsening headache in patients with solid tumors, especially lung, melanoma, breast, or colon cancer should elicit concern for metastatic disease (3,4). Additional red flags in this population include progressive and indolent headache (>8 weeks), associated nausea/vomiting, and focal neurologic deficits. Clinical signs may lack specificity however, therefore brain MRI with contrast should be considered in all patients with cancer and new or changing headache (5,6). Headaches due to neoplastic meningitis (leptomeningeal metastases) should also be considered. We refer readers to Fast Fact #135 for further detail and diagnostic considerations.
• Anticoagulation – Intracerebral hemorrhage (ICH) remains a devastating complication of anticoagulation therapy, with an annual rate for patients taking warfarin of 0.3-0.6%, and 0.1-0.2% for those on newer oral anticoagulants (7). Vomiting, and more ominously, decreased consciousness that appears and progresses quickly (i.e., hours) should prompt immediate concern.
• Age – Risk of a life-threatening secondary HA is 10 times higher in those 65 years and older (8). In one series of patients with new-onset headache, 15% of those 65 years or older had a secondary headache compared with 1.6% of patients younger than 65 years (9).

Determining Diagnostic Course of Action     As new or changing headaches are more likely to represent life-threatening complications in seriously-ill patients than the general population, they should prompt clinicians to consider urgent evaluation. The decision to pursue diagnostic testing, however, is dependent on a patient’s prognosis, location, and overall goals of care. For patients with shorter prognoses and care goals focused on comfort, deferring diagnostic work-up in lieu of aggressive symptom management might be the right decision. On the other hand, for patients with longer prognoses, diagnostic work-up could be worthwhile, even for some with comfort-focused goals of care, since some underlying causes are quite treatable.

References

1. Levin M. Approach to the workup and management of headache in the emergency department and inpatient settings. Semin Neurol. 2015; 35:667-674.
2. Filler L, Akhter M, & Nimlos P. Evaluation and management of the emergency department headache. Semin Neurol. 2019; 39:20-26.
3. Argyriouu AA, Chroni E, Polychronopoulos P, et al. Headache characteristics and brain metastases prediction in cancer patients. European Journal of Cancer Care. 2006; 15:90-95. 
4. Delattre JY, Krol G, Thaler HT, & Posner JB. Distribution of brain metastases. Archives of Neruology. 1988; 45: 741-744.
5. Goldlust SA, Graber JJ, Bossert DF, & Avial EK. Headache in patients with cancer. Curr Pain Headache Rep. 2010; 14:455-464.
6. Chou, DE. Secondary Headache Syndromes. Continuum (Minneap, MN). 2018; 24(4, Headache):1179-1191.
7. Steiner T, Weitz JI, & Veltkamp R. Anticoagulant-associated intracranial hemorrhage in the era of reversal agents. Stroke. 2017; 48:1432-1437.
8. Starling AJ. Diagnosis and management of headache in older adults. Mayo Clin Proc. 2018; 93(2):252-262.
9. Pascual J & Berciano J. Experience in the diagnosis of headaches that start in elderly people. J Neurol Neurosurg Psychiatry. 1994; 57(10):1255-1257.

Authors’ Affiliations: University of Pittsburgh School of Medicine, Pittsburgh, PA (JY, LK, RA). University of Michigan School of Medicine, Ann Arbor, MI (CS).

Conflicts of Interest: The authors have declared no conflicts of interest. 

Version History:  Originally edited by Drew A Rosielle; first electronically published in October 2019