What is the differential diagnosis and management approach for a patient presenting with unilateral headache (HA)?

Differential Diagnosis for Unilateral Headache

The differential diagnosis for unilateral headache includes migraine without aura (most common primary cause), cluster headache (severe orbital pain with autonomic features), and critical secondary causes including giant cell arteritis (in patients >50 years), carotid dissection, and intracranial pathology—all of which require systematic exclusion based on specific clinical features and red flags. 1

Primary Headache Disorders

Migraine Without Aura

• Suspect migraine when the unilateral headache is pulsating, moderate-to-severe intensity, lasts 4-72 hours, and is accompanied by nausea/vomiting and/or photophobia and phonophobia. 1
• Patients typically prefer to lie still in a dark, quiet room during attacks. 2
• Diagnosis requires at least 5 lifetime attacks meeting these criteria. 3

Cluster Headache

• Characterized by severe unilateral orbital/periorbital pain lasting 15-180 minutes with ipsilateral autonomic symptoms (lacrimation, nasal congestion, ptosis, miosis) and restlessness during attacks. 1
• Attacks occur in clusters with a frequency of 1-8 attacks daily. 2
• The shorter duration (15-180 minutes vs. 4-72 hours for migraine) and prominent autonomic symptoms distinguish cluster headache from migraine. 2
• Patients pace or rock during attacks, contrasting with migraine patients who remain still. 2

Tension-Type Headache

• Typically bilateral but can present unilaterally with pressing/tightening quality, mild-to-moderate intensity, and absence of autonomic features. 1, 2

Critical Secondary Causes Requiring Urgent Exclusion

Giant Cell Arteritis (Age >50 Years)

• Urgently exclude in patients over 50 years old with new-onset unilateral temporal headache, characterized by continuous dull aching pain, jaw claudication, and systemic symptoms (fever, weight loss, elevated ESR/CRP). 1
• Missing this diagnosis risks permanent vision loss. 1

Carotid Dissection

• Presents with continuous unilateral pain and focal neurological deficits, incompatible with episodic attack patterns. 1

Intracranial Pathology

• Obtain neuroimaging (MRI brain preferred) when any red flags are present: focal neurological deficits, atypical headache pattern, progressive worsening, or abrupt-onset headache. 1

Diagnostic Approach Algorithm

Step 1: Characterize the Headache

• Duration: 15-180 minutes suggests cluster headache; 4-72 hours suggests migraine. 1, 2
• Quality: Pulsating favors migraine; severe stabbing/boring favors cluster. 1
• Location: Orbital/periorbital suggests cluster; hemicranial suggests migraine. 1
• Intensity: Severe excruciating pain suggests cluster; moderate-to-severe suggests migraine. 1

Step 2: Identify Associated Symptoms

• Autonomic symptoms (lacrimation, nasal congestion, ptosis, miosis) strongly suggest cluster headache. 1, 2
• Nausea/vomiting, photophobia, and phonophobia suggest migraine. 1, 3
• Restlessness during attacks suggests cluster; preference to lie still suggests migraine. 2

Step 3: Screen for Red Flags

• New-onset headache in patient >50 years (consider giant cell arteritis). 1
• Focal neurological deficits (obtain neuroimaging). 1
• Progressive worsening or abrupt-onset ("thunderclap"). 1
• Recent head or neck trauma. 4
• Headache brought on by Valsalva, cough, or exertion. 4
• Systemic signs (fever, weight loss) or cancer/HIV history. 4

Step 4: Consider Medication-Overuse Headache

• Ask about frequency of acute medication use—overuse of triptans, NSAIDs, or opioids for ≥10 days per month perpetuates the headache cycle and requires medication withdrawal. 1, 5

Management Based on Diagnosis

Migraine Without Aura

• Acute treatment: NSAIDs (ibuprofen, naproxen) or acetaminophen for mild-to-moderate attacks, limiting use to ≤2 days per week or maximum 10 days per month. 3
• If NSAIDs fail or pain is moderate-to-severe, prescribe triptans (sumatriptan, rizatriptan). 3
• Before prescribing triptans, screen for cardiovascular risk factors (hypertension, hypercholesterolemia, smoking, obesity, diabetes, family history of CAD) and consider cardiovascular evaluation if multiple risk factors are present. 2, 5
• Triptans are contraindicated in patients with CAD, Prinzmetal's angina, uncontrolled hypertension, history of stroke/TIA, or Wolff-Parkinson-White syndrome. 5
• Preventive therapy: Initiate if attacks occur frequently enough to impair quality of life or patient is at risk for medication-overuse headache. 3
• Options include propranolol, topiramate (the only agent with evidence in chronic migraine), CGRP monoclonal antibodies, or onabotulinumtoxinA. 6, 3

Cluster Headache

• Acute treatment: Subcutaneous sumatriptan 6 mg or 100% oxygen inhalation at 12 L/min are first-line therapies, with 70% achieving relief within 10 minutes. 2
• Intranasal zolmitriptan 10 mg is an alternative. 2
• Prophylactic treatment: Verapamil 360 mg/day is the drug of choice, with ECG monitoring for PR interval prolongation at higher doses. 2
• Consider oral corticosteroids or greater occipital nerve blockade as bridging therapy while verapamil takes effect. 2
• Galcanezumab for episodic cluster headache; lithium, topiramate, or divalproex sodium for chronic cases. 2

Common Pitfalls to Avoid

• Do not assume all unilateral headaches are migraines—cluster headache requires different acute (oxygen, subcutaneous sumatriptan) and preventive (verapamil) treatment strategies. 1
• Do not miss medication-overuse headache in patients with frequent headache days, as this perpetuates the cycle and requires withdrawal. 1
• Do not miss giant cell arteritis in patients over 50 with new-onset temporal headache—delayed diagnosis risks permanent vision loss. 1
• Do not prescribe triptans without screening for cardiovascular risk factors and contraindications. 2, 5

Referral Indications

• Emergency admission: Any red flag present, patient unable to self-care, or suspected spontaneous intracranial hypotension. 3
• Urgent neurology referral (within 48 hours): Suspected spontaneous intracranial hypotension. 3
• Routine neurology referral (2-4 weeks): Diagnosis uncertain after initial evaluation, first-line treatments fail, or suspected primary headache disorder requiring specialist management. 3