Headache classification

Headache is a common type of recurrent pain and one of the most frequent symptoms in medicine. Although virtually everyone experiences some kind of headache in their lifetime, there are well-defined headache disorders (defined as recurrent attacks of a particular phenotype) that vary in incidence, prevalence, and duration (31).

Before 1988, the headache classification systems that were available did not have clear operational rules, and nomenclature varied widely. In 1988, the International Headache Society instituted a classification system that has become the standard for headache diagnosis as well as clinical research (15). The 2nd edition of the International Classification of Headache Disorders (ICHD-2) was released in September of 2004 (16), and the 3rd edition (ICHD-3 beta) was issued in July 2013 in beta form (17) and finalized and published as the 3rd edition (ICHD-3) in January 2018 (18). According to this system, headache is divided into 2 broad categories: primary headache disorders and secondary headache disorders. In secondary disorders, headache is attributed to another condition, such as a brain tumor, infection, or head injury; for the primary disorders, no specific cause can be found.

Headache is the fifth most common chief complaint in the emergency department in about 2% of patients, or 2 million visits annually in the United States (23). Internists and neurologists are often called to evaluate, or are consulted by, patients during a headache attack. The diagnosis of acute headache can be challenging and should proceed in an orderly fashion. Crucial elements include a thorough history, supplemented by general medical and neurologic examinations, and laboratory testing and neuroimaging of selected patients (30).

Approaching a patient with acute headache

An important first step in acute headache diagnosis is to distinguish a primary from a secondary headache. Most patients who have an acute headache have a primary headache disorder, but the probability of secondary headache increases in the emergency department or urgent medical setting.

Certain “red flags” suggest the possibility of secondary headache. Once these features are identified, the physician must conduct the workup indicated by the red flag (Table 1) and diagnose the secondary headache disorder if one is present.

Table 1. Red Flags in the Diagnosis of Headache

Table 2. Differential Diagnoses of Thunderclap Headache

Identifying secondary headache disorders

Herein we discuss common red flags, the differential diagnoses suggested by these red flags, and the appropriate investigation required by each one. It is important to emphasize that red flags indicate an increased probability of secondary headache. The presence of a red flag increases the need to perform further investigation, but the patient must be evaluated in the context of the overall clinical picture. Certain “comfort signs,” such as acknowledgement of a typical headache trigger, a family history of similar headache attacks, or the presence of typical signs and symptoms of a primary headache disorder may offset minor red flags. Some clinical scenarios may prompt the clinician to ascribe a secondary diagnosis erroneously, leading to incorrect treatment.

(1) Sudden onset of severe headache (thunderclap headache). The sudden onset of a severe (explosive) headache must be investigated. Although it is not the most common cause of thunderclap headache, subarachnoid hemorrhage is the most feared. Thunderclap headache is actually a poor predictor of subarachnoid hemorrhage (28). Other studies have identified the following features as predictive of subarachnoid hemorrhage: age greater than 40, witnessed loss of consciousness, neck stiffness, onset during exertion, vomiting, blood pressure greater than 160/100, and arrival by ambulance (28). All patients with thunderclap headache should have an expedient and exhaustive search for an underlying cause. These include serious intracranial vascular disorders, such as aneurysmal subarachnoid hemorrhage, intracerebral hemorrhage, cerebral venous (or sinus) thrombosis, arteriovenous malformation, arterial dissection (intra- and extracranial), CNS angiitis, pituitary apoplexy, and reversible cerebral vasoconstriction syndrome, which is increasingly recognized as a cause of recurrent thunderclap headache (34). Other organic causes of thunderclap headache are colloid cysts of the third ventricle, CSF hypotension, acute sinusitis (particularly with barotrauma), and meningoencephalitis (06).

A thunderclap headache evaluation should include head CT and a lumbar puncture if the CT is negative to evaluate for subarachnoid hemorrhage first and foremost. CT scan is most sensitive if performed within the first 6 hours of symptom onset; however, sensitivity falls as CT imaging is prolonged from initial symptom onset (02). If these studies are unrevealing, many clinicians will then order an MRA or CTA in effort to discover an aneurysm if suspicion remains high, especially within 12 hours of ictus. A mathematical analysis suggested that a follow-up lumbar puncture is highly cost-effective, but that CTA is questionable in this regard with no clearly defined utility (20).

If no aneurysm is revealed, or if a different etiology is highly suspected based on the presentation, other studies are warranted. When considering cerebral venous thrombosis, CT is often inadequate for diagnosing it, and MRV or CTV is necessary to exclude this entity. When pituitary apoplexy is suspected, dedicated views of the sella turcica should be requested. When reversible cerebral vasoconstriction syndrome is of concern, particularly with recurrent thunderclap headache, serial arterial imaging (be it MRA, CTA, or conventional angiography) may be required to detect it because it can be an intermittent phenomenon that also may not be visible on imaging performed early in the course.

When a patient with a thunderclap headache has a completely negative work-up, a diagnosis of primary thunderclap headache may be assigned.

(2) Worsening headache pattern. A worsening headache pattern must be interpreted in the context of a patient’s overall headache history. Headache of recent onset may indicate a mass lesion, such as a brain tumor, abscess, or subdural hematoma. Although mass lesions often present with focal neurologic deficits or papilledema, these features may be absent, particularly if the mass lesion is slow-growing or in a silent area. In this context, neuroimaging is mandatory.

When progression occurs in the context of a well-established primary disorder, 2 possibilities exist. Progression may represent the development of a new headache disorder (either primary or secondary) superimposed on a preexisting primary headache. Alternatively, progression may represent the transformation of a primary preexisting headache disorder. If these possibilities cannot be differentiated clinically, investigation is necessary.

Migraine and tension-type headache are well known to progress. Migraine may evolve to a condition known as chronic migraine, in which headache attacks (not necessarily migraine attacks) occur 15 or more days per month (or 180 or more days per year) with an average duration of 4 or more hours per day. Individuals with chronic migraine usually report a process of transformation over months or years, characterized by increasing headache frequency. Although chronic migraine affects 0.5% to 5% of the global population, it accounts for substantial healthcare resource utilization and overall cost (01).

Risk factors for the development of chronic migraine include high frequency of headache prior to transformation, obesity, stressful life events, alcohol overuse, hypothyroidism, viral infections, head trauma, snoring, and sleep disturbances. Overuse of acute medications is a substantial complicating factor and is now considered a sequela of comorbid phenomenon to chronic migraine (01).

A gradual progression of headache in a person with migraine who has readily identifiable exacerbating factors and a normal examination is most likely chronic migraine. Patients who have atypical clinical features or exacerbating factors that cannot be identified easily require further investigation.

(3) Headache with systemic illness or systemic symptoms. Many systemic disorders are associated with a prominent complaint of acute headache, including intracranial and extracranial infections (meningitis, encephalitis, Lyme disease, HIV, sinusitis), hypoxia and hypercapnia (high-altitude illness, diving, sleep apnea), dialysis, uncontrolled hypertension, hypotension, hypothyroidism, fasting, collagen vascular disorders, systemic arteritis, and carbon monoxide poisoning, among others (21).

Clues that the headache is associated with a systemic illness include systemic symptoms, such as fever, neck stiffness, cutaneous rash, fatigue, malaise, and arthralgias. A skin rash could suggest Lyme disease (erythema migrans), herpes zoster (vesicles distributed in a dermatomal pattern), or sarcoidosis (erythema nodosum). Other dermatologic disorders might suggest the presence of a systemic or localized disease, such as antiphospholipid antibody syndrome or Sneddon syndrome. A clinician should search for opportunistic infections (including toxoplasmosis and cryptococcal meningitis) and malignancy in patients who have AIDS or HIV risk factors. This also is true for patients who are immunocompromised.

When patients have cancer, brain and leptomeningeal metastasis should be considered. Depending on the clinical setting, blood work, neuroimaging, and CSF examination may be required.

(4) Headache with focal signs other than typical visual or sensory aura. Aura is most commonly associated with migraine but also may occur with other primary headache disorders (eg, chronic paroxysmal hemicrania, cluster headache, and tension-type headache) (18). Typical migraine aura is rarely associated with secondary causes.

Focal signs other than aura are divided into those that are transient and those that are permanent. Transient focal signs may be the manifestations of seizure, transient ischemic attack, and toxic-metabolic disorders. Permanent deficits (even those that are partial and difficult to detect unequivocally) may be caused by stroke, mass lesion, arteriovenous malformation, or collagen vascular disease. Appropriate workup includes neuroimaging, collagen vascular evaluation, and sometimes lumbar puncture.

Differentiating aura related to headache from a simple partial seizure may be difficult. Table 3 describes clinical clues that are useful in establishing this differentiation. If seizure is suspected, EEG and neuroimaging (in patients who have not been previously investigated) are required. Postictal headache might be of special importance, especially considering that migraine and epilepsy are comorbid (03).

Table 3. The Aura in Migraine and Epilepsy

(5) Headache triggered by cough, exertion, orgasm, or direct stimuli. The key issue in establishing this red flag is to identify the sudden development of a severe headache temporally related to a trigger. In other words, severe headache unequivocally triggered by cough, heavy exercise, or orgasm must be investigated. Postcoital headache, mild headache following exercise, and mild headache followed by cough do not seem to be associated with secondary headache disorders at a higher rate than headache not associated with red flags.

A headache triggered by straining, coughing, or sneezing suggests a hindbrain malformation, occipitocervical junction disorder (including Arnold-Chiari malformation), increased intracranial pressure, or vasospasm. With orgasmic headache, one must exclude subarachnoid hemorrhage, reversible cerebral vasoconstriction syndrome, and mass lesions (06).

Direct stimuli such as cold stimulus and external pressure may cause headache as well. The cold stimulus may be applied externally to the head, or it may be ingested or inhaled. External-pressure headache can be caused by compression and traction not severe enough to cause damage to the scalp but intense enough to activate central pain mechanisms through peripheral inputs (05).

(6) Headache during pregnancy or postpartum. Most headache that occurs during pregnancy or postpartum are migraine or tension-type headache. In a pregnant or postpartum woman with a history of migraine or tension-type headache, without atypical features and with a normal examination, investigation is usually not necessary. However, some women report new onset of severe headache with migraine features, or a worsening pattern of a previously diagnosed primary headache. In these cases, intracranial hypertension or hypotension, cortical vein or cranial sinus thrombosis, carotid dissection, reversible cerebral vasoconstriction syndrome, and pituitary apoplexy enter into the differential diagnosis, especially in the proper clinical context (26). These disorders are much more common in the third trimester or in the early postpartum period. Stroke is thought to be more common in late pregnancy and the early postpartum period. Neuroimaging, including MRI and MRA, is necessary to exclude such vascular disorders. The differential diagnosis also includes preeclampsia, a multi-system disorder with various forms. In addition to hypertension and proteinuria, tissue edema, thrombocytopenia, and abnormalities in liver function can occur. Preeclampsia appears to involve a strong maternal inflammatory response with broad systemic activity. Subsidiary investigation includes blood and urine testing (09).

(7) Positional headache. Orthostatic or reverse-orthostatic headache brings to mind dysregulation of cerebrospinal fluid pressure or volume. Though orthostatic headache is typically due to low pressure/volume, and reverse-orthostatic headache can be due to elevated pressure/volume, the opposite may also be true. In fact, elevated pressure/volume usually does not present with positional headache, but rather with visual obscurations, pulsatile tinnitus, and papilledema, with variable but commonly migrainous headache quality (22). The diagnosis of a low pressure/volume state is suggested not only by orthostatic headache, but also by “second-half-of-the-day headache.” Migraine features are common, and if significant hindbrain descent occurs, cerebellar and brainstem signs and symptoms may be present. MRI with gadolinium may show “brain sag,” pituitary engorgement, and pachymeningeal enhancement, and MRV may show the “venous distention sign” of a convex appearance to the transverse sinuses on sagittal view. Some orthostatic headache syndromes are due to slow, undetectable leaks or result from increased compliance of the lower lumbar CSF space without actual leak (08). Spinal CSF leaks, traditionally difficult to detect, are increasingly recognized as a cause of orthostatic headache, with some leaks having the etiology of a CSF-venous fistula (Schievenk et al 2021). Other orthostatic headache syndromes are not due to CSF pressure dysregulation at all, but rather to autonomic dysfunction in disorders such as orthostatic hypotension and postural orthostatic tachycardia syndrome (07). Another potential cause is cervicogenic headache, particularly in hypermobility syndrome and atlanto-axial instability syndrome. Finally, orthostatic headache may also be reflective of vestibular pathology, particularly in the presence of vertigo, nystagmus, and other positional triggers.

(8) Headache in the elderly. Headache in this age group should always be investigated for secondary cause, although primary headache syndromes do occur (eg, hypnic headache). Giant cell arteritis is an underdiagnosed and preventable cause of visual loss and stroke in the elderly. When giant cell arteritis is suspected (headache, constitutional signs and symptoms, jaw claudication, temporal artery tenderness, transient neurologic symptoms, etc.), empiric treatment with steroids is justified and mandatory while awaiting the results of laboratory investigations and biopsies of the temporal arteries. The workup must be guided by the clinical picture, but often includes a complete blood cell count with differentiation, sedimentation rate, C-reactive protein, and chemical profile (24). Headache in the elderly associated with activity may be an anginal equivalent, a rare disorder sometimes termed “cardiac cephalgia” (Ruiz-Ortiz et al 2020). Other common diagnostic considerations are cervicogenic headache from severe degenerative disease, metastatic cancer, and subdural hemorrhage; these are usually suggested by typical history and examination findings.

(9) Sinus symptoms and headache. The interplay of sinus symptoms and migraine is a complex relationship and can pose challenges in diagnosis and treatment (04). Congestion, rhinorrhea, aural fullness, and facial pain may occur in primary headache disorders (migraine, tension-type, and trigeminal autonomic cephalalgias), often leading to a misdiagnosis of “sinus headaches.” In 1 series, only 5% of suspected sinus headaches actually met criteria for this diagnosis (acute sinus infection with headache that resolves after appropriate antimicrobial therapy), leading to inappropriate treatment with antibiotics in a vast majority, sinus endoscopy in about a quarter, and even septoplasty in about 15% (13). A diagnosis that is not to be missed is sphenoid sinusitis, an elusive entity due to the general lack of obvious sinus symptoms. Fever and facial numbness are 2 key features suggesting the disorder, which are seen on neuroimaging. Undiagnosed, it can lead to significant morbidity.

(10) The eye and headache. Most ophthalmologic disorders in which a symptom of headache is common are readily diagnosed based on the obvious abnormal physical manifestations typical of these problems. However, these signs may be absent or easily overlooked, as in acute angle closure glaucoma; therefore, one must maintain clinical suspicion in order to arrive at the correct diagnosis. Some other examples of ocular disorders that may not have obvious physical abnormalities are dry eye, keratitis, uveitis, and trochleitis (14). Not all headache accompanied by abnormal physical appearance of the eye is ophthalmologic in nature, of course, with the trigeminal autonomic cephalgias being the best example (see below).

Diagnosing a primary headache disorder

In the absence of secondary causes or contributors, the clinician can proceed to diagnosing a primary headache disorder. If the headache is atypical or difficult to classify, the possibility of secondary headache should be reconsidered, although the modifying effect of any treatment should be kept in mind. Discussing the diagnostic criteria of primary headache disorders is beyond the scope of this article. The objective of this section is to propose a strategy to approach the primary headache disorders, after excluding secondary disorders.

If a patient has acute headache and secondary headache syndromes have been excluded, either by clinical history or appropriate investigation, the next step is to assign the primary headache diagnosis. Patients can be divided into those whose headache occurs at low-to-moderate frequency (fewer than 15 headache days per month) versus high frequency (15 or more headache days per month). Based on average duration of a typical untreated headache attack, the headache syndrome is classified as either short-duration (less than 4 hours a day) or long-duration (4 or more hours) (18).

Low-to-moderate frequency headache attacks of long duration

Low-to-moderate frequency headache attacks of long duration include episodic migraine and episodic tension-type headache. The main pain features of tension-type headache are bilateral location, non-pulsating quality, mild to moderate intensity, and lack of aggravation by routine physical activity. The pain is not accompanied by nausea or vomiting, although either photophobia or phonophobia (but not both) may occur (18). Even though episodic tension-type headache is the most prevalent primary headache disorder in the population, it is not a frequent reason for medical consultation.

Migraine is the most common acute headache disorder seen in the emergency department, by far more frequent than secondary headache syndromes (30). Migraine attacks in the acute care setting are usually severe, throbbing, and associated with nausea, photophobia, or phonophobia. If the attack is very severe, the patient may be prostrate and pale, sometimes vomiting. Although unilaterality of pain is a diagnostic criterion, pain is often bilateral. It is not necessary to investigate a typical attack. However, migraine-like attacks not responsive to treatment and requiring prolonged observation (longer than 12 hours) should be investigated further.

Presentations other than typical migraine with or without aura are more common in the emergency department than in other settings. Migraine with brainstem aura is a subtype characterized by at least 2 of the following aura symptoms, all fully reversible: dysarthria, vertigo, tinnitus, decreased hearing, double vision, ataxia, and decreased level of consciousness. The attack otherwise fulfills criteria for migraine (18).

Hemiplegic migraine is the first migraine syndrome to be linked to a specific set of genetic polymorphisms (10). This is migraine with aura, except that the aura includes motor weakness (hemiplegia) and may be more prolonged than 60 minutes (up to 24 hours). In familial hemiplegic migraine, at least 1 first-degree relative has had similar attacks (also meeting these criteria). Cerebellar ataxia occurs in 20% of familial hemiplegic migraine cases. Headache syndromes that otherwise meet these criteria but present without family history of the disorder are classified as sporadic hemiplegic migraine. Unless patients already have a diagnosis of hemiplegic migraine (and were, therefore, previously investigated), additional investigation is necessary.

Status migrainosus refers to an attack of migraine with a headache phase that lasts longer than 72 hours. The pain and associated symptoms are debilitating.

Persistent aura without infarction is diagnosed when aura symptoms, otherwise typical of past attacks, persist for more than 1 week, and investigation shows no evidence of infarction. It is an unusual but well-documented complication of migraine that is now included in the International Headache Society classification.

Migrainous infarction is an uncommon occurrence. One or more otherwise typical aura symptoms persist beyond 1 hour, and neuroimaging confirms ischemic infarction. Strictly applied, these criteria distinguish this disorder from other causes of stroke, which must be excluded. The neurologic deficit develops during the course of an apparently typical attack of migraine with aura and exactly mimics the aura of previous attacks, but it persists and is proven to be due to cerebral ischemia (18).

High-frequency headache attacks of long duration

High-frequency headache attacks of long duration include chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Medication overuse is common, being present in more than 80% of chronic migraine patients in subspecialty clinics but in only 30% of people with chronic headache in population studies (36). Patients with chronic migraine tend to seek care when they have a superimposed full-blown migraine (exacerbation). When a clear history is obtained, and the exam is unremarkable, investigation is not required.

New daily persistent headache is characterized by the abrupt onset of a chronic daily headache. It is classified as a primary headache disorder, although a viral prodrome may precede the onset, suggesting that some syndromes may actually be secondary despite the lack of an obvious demonstrable cause. When patients with acute headache first seek care with this syndrome, thorough investigation is necessary to exclude secondary disorders (38).

Hemicrania continua is commonly mistaken for chronic migraine. Both disorders are characterized by chronic unilateral pain with superimposed painful exacerbations. In hemicrania continua, the exacerbations are associated with ipsilateral autonomic features, such as conjunctival injection, lacrimation, and ptosis, though migraine features may be present as well. In chronic migraine, exacerbations are more typically accompanied by nausea, photophobia, and phonophobia, though autonomic features may occur. If the headache is longstanding, the patient may not remember how the problem began. Though pain fluctuates in hemicrania continua, it does not usually have the morning and end-of-dosing-interval pattern of exacerbations typical of chronic migraine. It is advisable to offer patients with unilateral chronic daily headache a therapeutic trial with indomethacin (doses of up to 225 mg/day for 3 to 4 days) prior to other intervention (29).

Headache attacks of shorter duration

High-frequency, short-duration headache syndromes include the trigeminal autonomic cephalgias (episodic and chronic cluster headache, episodic and chronic paroxysmal hemicrania), SUNCT (short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) and SUNA (short lasting unilateral neuralgiform headache attacks with autonomic features) syndromes, hypnic headache, and exertional headache.

The trigeminal autonomic cephalgias (TACs) are characterized by unilateral pain in the trigeminal distribution, with ipsilateral autonomic features (25). The most common disorder in this family is cluster headache. The pain of cluster headache is described variously as sharp, boring, drilling, knife-like, piercing, or stabbing, in contrast to the pulsating pain of migraine. It usually peaks in 10 to 15 minutes but remains excruciatingly intense for an average of 1 hour within a duration range of 15 to 180 minutes. During this pain, patients find it difficult to remain still, often exhibiting marked agitation and restlessness, and autonomic features are usually prominent. After an attack, the patient may be exhausted for some time. In episodic cluster, the disease is active periodically with at least 3 months between bouts. In the chronic form, remissions are shorter than 3 months or absent entirely (Suri and Allani 2021).

Like cluster headache, episodic and chronic paroxysmal hemicrania are characterized by unilateral attacks of trigeminal pain and autonomic features. The paroxysmal hemicranias have 3 main features that distinguish from cluster headache: (1) greater frequency (more than 5 per day); (2) shorter duration (2 to 30 minutes); (3) absolute response to therapeutic doses of indomethacin. The same distinction between episodic and chronic is made as with cluster headache. Paroxysmal hemicranias are relatively rare (11).

SUNCT is another rare primary headache. The diagnostic criteria describe high-frequency attacks (3 to 200 per day) of unilateral orbital, supraorbital, or temporal stabbing or pulsating pain, lasting 5 to 240 seconds and accompanied by ipsilateral conjunctival injection and lacrimation. The attacks are characteristically dramatic, with moderately severe pain, peaking in intensity within 3 seconds, and prominent tearing (11).

SUNA syndrome is similar to SUNCT. Attacks may last slightly longer and be less frequent. Either conjunctival injection or tearing may be present, but not both, and other autonomic features are more common (11). SUNCT and SUNA together comprise the short-lasting unilateral neuralgiform headache attacks (SUNHA) syndromes (18).

Hypnic headache is a primary headache disorder of the elderly, characterized by short-lived attacks (typically 30 minutes) of nocturnal head pain that awaken the patient at a consistent time each night, in many cases on more nights than not. It does not occur outside sleep. Hypnic headache is usually bilateral (although unilaterality does not exclude the diagnosis) and typically mild to moderate in intensity, different from the unilateral orbital or periorbital, knife-like, intense pain of cluster headache. Autonomic features are usually absent (35).

Headache triggered by cough, exertion, sexual activity, or external stimuli include the disorders named for these triggers. Especially in patients presenting in the emergency department, or during an attack, these headache syndromes may only be diagnosed after an exhaustive and methodical search for secondary causes. However, in a patient previously investigated or previously diagnosed, repeating the investigation is usually not necessary, and patients simply should be treated.

Conclusions

As previously discussed, the differential diagnosis of acute headache requires a systematic approach. In a 1990 review article, John Edmeads stated that even when a patient is quiet and calm, able and willing to present an orderly history, and easy to examine, the headache diagnosis may be difficult (12). However, during an attack, headache sufferers may not be completely cooperative, and, consequently, the quality of the information may be affected. We have herein presented an orderly approach to differential diagnosis. The precise criteria for each disorder are presented elsewhere (18). This outline should help neurologists move forward quickly and safely when assessing patients with acute headache.