What is the differential diagnosis (ddx) and management approach for an adult patient with a headache and no significant past medical history?

Headache Differential Diagnosis

In an adult with headache and no significant past medical history, first rule out life-threatening secondary causes using red flag criteria, then systematically differentiate between primary headache disorders—migraine, tension-type headache, and cluster headache—using ICHD-3 diagnostic criteria based on attack duration, pain characteristics, and associated symptoms.

Red Flags Requiring Immediate Investigation

Before considering primary headache disorders, exclude dangerous secondary causes. Red flags include 1, 2, 3, 4:

• Thunderclap headache ("worst headache of life")—suggests subarachnoid hemorrhage 2
• New-onset headache after age 50—consider giant cell arteritis or space-occupying lesion 2, 5
• Progressive worsening headache or headache awakening patient from sleep—suggests increased intracranial pressure or tumor 2
• Headache with Valsalva, cough, or exertion—indicates possible increased intracranial pressure 2, 3
• Focal neurological symptoms or signs—suggests stroke, TIA, or structural lesion 1, 2, 4
• Unexplained fever with neck stiffness—meningitis until proven otherwise 1, 2
• Recent head or neck trauma—consider subdural hematoma or carotid dissection 1, 3
• Altered consciousness, memory, or personality changes—suggests serious intracranial pathology 2

Neuroimaging Indications

MRI brain with and without contrast is the preferred modality for subacute presentations, offering higher resolution without ionizing radiation 1, 2. Use non-contrast CT head only if presenting within 6 hours of acute severe headache onset (sensitivity 95% on day 0 for subarachnoid hemorrhage) or for acute trauma 2.

Critical pitfall: Neuroimaging is NOT indicated for typical primary headache presentations without red flags—it exposes patients to unnecessary radiation and can reveal clinically insignificant abnormalities that trigger alarm and further unnecessary testing 1.

Primary Headache Differential Diagnosis

Migraine Without Aura

Suspect migraine when headache is unilateral, pulsating, moderate-to-severe, and accompanied by nausea/vomiting or photophobia plus phonophobia 1, 2. Requires at least 5 lifetime attacks meeting these criteria 1, 2:

• Duration: 4-72 hours when untreated 1, 2
• Pain characteristics (≥2 required): Unilateral location, pulsating quality, moderate-to-severe intensity, aggravation by routine physical activity 1, 2
• Associated symptoms (≥1 required): Nausea/vomiting OR both photophobia and phonophobia 1, 2
• Family history: Strong genetic component; prevalence higher among first-degree relatives 1, 2
• Typical onset: At or around puberty 1, 2

Migraine With Aura

Requires ≥2 attacks with fully reversible aura symptoms (visual, sensory, speech/language, motor, brainstem, or retinal) 1, 2. Key distinguishing features 1, 2:

• Aura characteristics: Gradual spread over ≥5 minutes, individual symptoms last 5-60 minutes, at least one unilateral symptom, aura accompanied by or followed by headache within 60 minutes 1, 2
• Critical distinction: Atypical aura is a red flag requiring neuroimaging to exclude stroke or TIA 1, 2

Chronic Migraine

Diagnose when headache occurs ≥15 days/month for >3 months, with ≥8 days meeting migraine criteria 1, 2. This is a distinct entity with substantially greater burden requiring different treatment than episodic migraine 2.

Tension-Type Headache

The only other common primary headache disorder, distinguished by 1, 2:

• Bilateral location (can be unilateral but typically bilateral) 1, 5
• Pressing or tightening quality (not pulsating) 1, 2
• Mild-to-moderate intensity 1, 2
• NOT aggravated by routine physical activity 1, 2
• Lacks migraine-associated symptoms: No nausea/vomiting, no photophobia/phonophobia, no autonomic features 1

Cluster Headache

Rare (0.1% prevalence) but highly characteristic, easily distinguished by 1, 6:

• Strictly unilateral orbital/periorbital/temporal pain 1, 6
• Severe or very severe intensity 1, 6
• Short duration: 15-180 minutes 1, 6
• Frequency: 1-8 attacks daily during cluster periods 6
• Ipsilateral autonomic symptoms: Conjunctival injection, lacrimation, nasal congestion, ptosis, miosis 1, 6
• Restlessness during attacks (patients pace rather than lie still as in migraine) 6

Critical pitfall: Do not assume all unilateral headaches are migraines—cluster headache requires completely different acute treatment (high-flow oxygen 100% at 12-15 L/min or subcutaneous sumatriptan) 2, 6.

Medication-Overuse Headache

A secondary headache disorder that commonly develops from treating migraine attacks, diagnosed when 1, 2:

• Headache ≥15 days/month in patient with pre-existing headache disorder 1, 2
• Regular overuse for >3 months: Non-opioid analgesics ≥15 days/month OR any other acute medication ≥10 days/month 1, 2

This perpetuates the headache cycle and requires medication withdrawal, not escalation 5, 7.

Diagnostic Tools

Validated Screening Questionnaires

• ID-Migraine (3-item): Sensitivity 0.81, specificity 0.75, positive predictive value 0.93 2
• Migraine Screen Questionnaire (5-item): Sensitivity 0.93, specificity 0.81, positive predictive value 0.83 2

Headache Diary

Essential for accurate diagnosis—reduces recall bias and allows systematic application of ICHD-3 criteria over multiple attacks 1, 2. Document frequency, duration, character, triggers, accompanying symptoms, and medication use 2.

Acute Treatment Considerations

For Migraine

• NSAIDs or acetaminophen: First-line for mild-to-moderate attacks 2
• Triptans: For moderate-to-severe attacks or when NSAIDs fail 2, 7
• Contraindications to triptans: Uncontrolled hypertension, coronary artery disease, Prinzmetal's angina, stroke/TIA history, Wolff-Parkinson-White syndrome 7
• Cardiovascular screening: Perform cardiovascular evaluation in triptan-naive patients with multiple CAD risk factors (age, diabetes, hypertension, smoking, obesity, strong family history) before prescribing 7

Critical FDA warning: Sumatriptan is NOT indicated for cluster headache prevention and safety/effectiveness have not been established for cluster headache 7.

For Cluster Headache

• High-flow oxygen (100% at 12-15 L/min): First-line acute treatment 2, 6
• Subcutaneous or intranasal triptans: Alternative acute treatment 2, 6
• Verapamil 360 mg/day: Prophylactic drug of choice 6

Referral Criteria

• Emergency admission: Any red flag present, patient unable to self-care without help 2
• Urgent neurology referral (within 48 hours): Suspected spontaneous intracranial hypotension 2
• Routine neurology referral (2-4 weeks): Suspected primary headache with uncertain diagnosis or first-line treatment failure 2
• Rheumatology referral: Suspected giant cell arteritis (ESR/CRP indicated, though ESR can be normal in 10-36% of cases) 2