What are the differential diagnoses for a unilateral headache?

Differential Diagnosis of Unilateral (One-Sided) Headache

When evaluating a patient with strictly unilateral headache, you must first rule out secondary causes, as side-locked headache is itself a red flag—approximately one-third of these patients have secondary headaches or neuralgias requiring urgent intervention 1, 2.

Primary vs Secondary Distribution

Research from specialized headache clinics shows that among patients with side-locked headaches 2, 3:

• Primary headaches: 58-67%
• Secondary headaches: 14-18%
• Cranial neuropathies/facial pain: 16%

Most Common Diagnoses (in order of frequency)

Primary Headaches

Trigeminal Autonomic Cephalalgias (TACs) - Most Common Overall (52%)

1. Cluster Headache (38% of all unilateral headaches) 2

   • Severe orbital/periorbital pain
   • 15-180 minutes duration
   • Ipsilateral autonomic features (lacrimation, conjunctival injection, nasal congestion)
   • Restlessness during attacks
   • Mean onset age: 32 years

2. Hemicrania Continua (8%) 2

   • Continuous unilateral pain with exacerbations
   • Absolute response to indomethacin (diagnostic)
   • Autonomic features during exacerbations
   • Mean onset age: 47-58 years

3. Paroxysmal Hemicrania (4%) 2

   • Brief attacks (2-30 minutes)
   • Multiple daily attacks (>5/day)
   • Absolute response to indomethacin
   • Mean onset age: 47-58 years

4. SUNCT/SUNA (3%) 2, 4

   • Very brief attacks (5-240 seconds)
   • Extremely frequent (multiple per hour)
   • Conjunctival injection and tearing (SUNCT) or other autonomic symptoms (SUNA)
   • Lamotrigine most effective prophylaxis

Migraine (11-15%) 5, 2, 3

• Unilateral location is one of four key characteristics 5
• Pulsating quality
• 4-72 hours duration
• Moderate-severe intensity
• Nausea/vomiting, photophobia/phonophobia
• Mean onset age: 22 years
• Can be with or without aura

Other Primary Headaches

• Cervicogenic headache (9%) 2: Pain starting in neck, spreading to fronto-orbital area; side-locked unilaterality 6
• Nummular headache (6%) 2: Coin-shaped area of pain on scalp
• Primary stabbing headache (1%) 2: Brief jabs of pain

Secondary Headaches (14-18% - MUST RULE OUT FIRST)

Critical Red Flags Requiring Immediate Imaging 5:

1. Thunderclap headache → Subarachnoid hemorrhage

   • CT head without contrast first (98% sensitivity) 7
   • If negative and high suspicion: CTA for aneurysm
   • MRI with FLAIR/SWI sequences if CT negative

2. Arterial dissection (carotid/vertebral)

   • Sudden severe unilateral pain
   • Horner syndrome
   • MRI/MRA most sensitive 7

3. Venous sinus thrombosis

   • Progressive headache
   • Risk factors: mastoiditis, oral contraceptives
   • MRV indicated 7

4. Intracranial mass/space-occupying lesion

   • Progressive headache
   • Worse with Valsalva
   • Neurological deficits
   • MRI brain with contrast

5. Pseudotumor cerebri (PTCS)

   • Papilledema
   • Visual changes
   • MRI brain + MRV 7

6. Meningitis/Encephalitis

   • Fever, neck stiffness
   • Altered consciousness
   • Consider anti-MOG antibody-associated encephalitis in young adults with persistent unilateral pulsatile headache 8

7. Temporal arteritis (age >50 years)

   • New onset headache
   • Jaw claudication, vision changes
   • ESR/CRP, temporal artery biopsy

Other Secondary Causes:

• Head trauma → subdural hematoma
• Sinusitis, dental pathology
• TMJ disorders
• Glaucoma

Algorithmic Approach

Step 1: Screen for Red Flags 5, 1

• Thunderclap onset
• Age >50 years (new onset)
• Progressive worsening
• Fever/systemic symptoms
• Neurological deficits
• Trauma history
• Positional component
• If ANY red flag present → Neuroimaging mandatory

Step 2: Characterize Pain Pattern

Duration of Individual Attacks:

• Seconds (5-240s) → SUNCT/SUNA
• Minutes (2-30 min, >5/day) → Paroxysmal hemicrania
• 15-180 minutes → Cluster headache
• Continuous with exacerbations → Hemicrania continua
• 4-72 hours → Migraine

Autonomic Features:

• Present and prominent → TACs (cluster, paroxysmal hemicrania, SUNCT/SUNA)
• Absent or mild → Consider migraine, cervicogenic

Behavior During Attack:

• Restless/agitated → Cluster headache
• Still/quiet → Migraine

Step 3: Consider Age at Onset 2

• 20s: Migraine (mean 22 years)
• 30s: Cluster headache (mean 32 years)
• 40s-50s: Cervicogenic, nummular, hemicrania continua, paroxysmal hemicrania (mean 47-58 years)
• >55 years: Higher likelihood of secondary headache

Step 4: Indomethacin Trial

For suspected hemicrania continua or paroxysmal hemicrania:

• Indomethacin 75 mg BID for 3 days 9
• Complete response is diagnostic for indomethacin-responsive headaches
• Achieved full remission in 25% of unclassified unilateral headaches 9

Step 5: Neuroimaging Strategy

• All patients with side-locked headache should be considered for imaging 1, 9
• MRI brain with contrast is preferred over CT for most non-emergent evaluations
• Imaging revealed causally related lesions in 13% of unilateral headache patients 9

Key Clinical Pitfalls

1. Don't assume migraine just because it's common - In side-locked headaches, TACs (especially cluster) are actually more frequent than migraine 2

2. Secondary headaches increase with age - Maintain higher suspicion in older patients 3

3. Cervicogenic headache is the most common secondary cause - Always examine neck and consider cervical spine pathology 3

4. Up to 31% of unilateral headaches cannot be classified by ICHD criteria 9 - Don't force a diagnosis; consider specialist referral

5. Aura symptoms can mimic TIA - Key difference: aura spreads gradually over ≥5 minutes; TIA has sudden simultaneous onset 5

6. 61% of side-locked headaches meet criteria for chronic daily headache 3 - Consider medication overuse headache if ≥15 headache days/month with regular acute medication use