What is the differential diagnosis for a patient presenting with headache?

Differential Diagnosis for Headache

Primary vs. Secondary Classification

The first critical step is determining whether the headache is primary (no underlying pathology) or secondary (identifiable structural or biochemical cause), as this fundamentally changes management and urgency. 1, 2

Primary Headache Disorders

Primary headaches account for the majority of presentations and include four main categories:

• Migraine without aura: Recurrent moderate-to-severe unilateral pulsating headache lasting 4-72 hours, worsened by routine physical activity, with nausea/vomiting and/or photophobia plus phonophobia; requires at least 5 lifetime attacks meeting these criteria 1, 3

• Migraine with aura: Same features as migraine without aura plus recurrent visual, sensory, speech, or motor symptoms that develop gradually over ≥5 minutes and last <60 minutes, with headache following within 60 minutes 1

• Chronic migraine: ≥15 headache days per month for >3 months, with ≥8 days meeting migraine criteria; this represents a distinct entity with substantially greater disability than episodic migraine 4, 1

• Tension-type headache: Bilateral, mild-to-moderate pressing/tightening quality lasting variable duration; lacks nausea, photophobia, and phonophobia; not aggravated by routine physical activity; affects 38% of the population 1, 3

• Cluster headache: Strictly unilateral severe headache lasting 15-180 minutes with ipsilateral autonomic symptoms including lacrimation, conjunctival injection, nasal congestion, ptosis, or miosis 1

• Medication-overuse headache: ≥15 headache days per month with regular overuse of non-opioid analgesics ≥15 days/month or other acute medications ≥10 days/month for >3 months 1

Secondary Headache Disorders (Urgent Considerations)

Secondary causes require immediate identification as they may be life-threatening:

• Subarachnoid hemorrhage: Thunderclap headache ("worst headache of life"), may have altered taste; non-contrast CT has 95% sensitivity on day 0, declining to 74% by day 3 and 50% at 1 week 1, 5

• Meningitis: Headache with neck stiffness and unexplained fever 1, 6

• Brain tumor or space-occupying lesion: Progressive headache that awakens from sleep or worsens with Valsalva/cough 7, 1

• Giant cell arteritis: New-onset headache in patients >50 years with scalp tenderness and jaw claudication; ESR can be normal in 10-36% of cases 1, 8

• Stroke or TIA: Atypical aura with focal neurological symptoms 1

• Cerebral venous thrombosis: Increased intracranial pressure with headache, especially with risk factors like cancer or hypercoagulable states 7

• Spontaneous intracranial hypotension: Orthostatic headache that is absent/mild on waking, develops within 2 hours of upright posture, and improves >50% within 2 hours of lying flat 7, 1

• Pseudotumor cerebri syndrome: Particularly in overweight females with papilledema 7

• Cervicogenic headache: Provoked by cervical movement rather than posture 7

Red Flag Features Requiring Urgent Evaluation

Any of the following red flags mandate immediate neuroimaging or other urgent testing:

• New-onset headache in patients >50 years of age 7, 6, 5
• Thunderclap headache (sudden onset, "worst headache of life") 1, 6
• Headache worsened by Valsalva maneuver, cough, or exertion 7, 6, 5
• Headache that awakens patient from sleep 7, 1
• Focal neurological signs or symptoms 7, 1, 6
• Abnormal neurological examination findings 7, 6
• Papilledema on fundoscopy 7, 6
• Neck stiffness or limited neck flexion 1, 6
• Unexplained fever 1, 6
• Immunocompromised state or presence of cancer 6, 5
• Recent head or neck trauma 1, 5
• Altered consciousness, memory, or personality 1
• Witnessed loss of consciousness 1
• Progressive worsening headache 1, 5

Diagnostic Workup Algorithm

History Taking (Essential Elements)

• Temporal pattern: Age at onset (migraine typically begins at/around puberty), duration of episodes (migraine 4-72 hours, cluster 15-180 minutes), frequency (episodic vs. chronic ≥15 days/month) 1

• Pain characteristics: Location (unilateral vs. bilateral), quality (pulsating vs. pressing/tightening), severity (mild-to-moderate vs. moderate-to-severe) 1

• Aggravating/relieving factors: Routine physical activity worsens migraine but not tension-type; Valsalva/cough suggests secondary causes; lying flat improves orthostatic headache 7, 1

• Associated symptoms: Nausea/vomiting, photophobia, phonophobia (migraine); autonomic symptoms like lacrimation or nasal congestion (cluster); aura symptoms (visual/sensory disturbances lasting <60 minutes) 1

• Medication history: Document all acute and preventive medications to assess for medication-overuse headache 1

• Use headache diary: Document frequency, duration, character, triggers, accompanying symptoms, medication use, and blood glucose levels if diabetic; this reduces recall bias and increases diagnostic accuracy 1, 9

Physical Examination

• Complete neurological examination including fundoscopy to check for papilledema 7, 1
• Assess for neck stiffness or limited neck flexion 1, 6
• Check for scalp tenderness (giant cell arteritis) 1
• Evaluate for focal neurological deficits 7, 6

Screening Tools for Primary Headaches

• ID-Migraine questionnaire (3-item): Sensitivity 0.81, specificity 0.75, positive predictive value 0.93 1
• Migraine Screen Questionnaire (5-item): Sensitivity 0.93, specificity 0.81, positive predictive value 0.83 1

Neuroimaging Indications

The yield of neuroimaging in patients with headache and normal neurologic examination is quite low (brain tumors 0.8%, AVMs 0.2%, aneurysms 0.1%), but specific clinical scenarios mandate imaging: 8

• Non-contrast CT head: If presenting <6 hours from acute severe headache onset (subarachnoid hemorrhage suspected); also for acute trauma or abrupt-onset headache 1, 5

• MRI brain with and without contrast: Preferred modality for subacute presentations, suspected tumor/inflammatory process, or patients >50 years with new-onset headache; offers higher resolution without ionizing radiation 1, 9, 5

• Do NOT order neuroimaging: For typical primary headache presentations without red flags or abnormal examination findings 7

Laboratory Testing

• ESR/CRP: If temporal arteritis suspected (patients >50 years with new-onset headache); note ESR can be normal in 10-36% of giant cell arteritis cases 1, 8

• Morning TSH and free T4: If cold intolerance or lightheadedness present (hypothyroidism) 1

• Thyroid peroxidase (TPO) antibodies: If biochemical hypothyroidism confirmed 1

Lumbar Puncture Indications

• Suspected subarachnoid hemorrhage with negative CT (spectrophotometry for xanthochromia is 100% sensitive at 12 hours through 2 weeks, >70% at 3 weeks) 8
• Suspected meningitis or encephalitis 5
• Suspected spontaneous intracranial hypotension 5
• Suspected high or low CSF pressure syndromes 5

Additional Testing

• Dental panoramic radiographs: If dental pathology or sinusitis suspected 1

Common Pitfalls to Avoid

• Assuming chronic headache is always primary without considering secondary causes is dangerous; always reassess for red flags 7

• Ordering neuroimaging for typical primary headache presentations without red flags wastes resources and is not recommended 7

• Missing spontaneous intracranial hypotension because the orthostatic component may not always be obvious; specifically ask about positional changes 7

• Relying solely on patient recall for headache frequency without a headache diary leads to diagnostic inaccuracy; patients often underreport milder headaches 4, 1

• Assuming normal ESR rules out giant cell arteritis in patients >50 years with new-onset headache; ESR can be normal in 10-36% of cases 1, 8

• Missing medication-overuse headache by failing to document all acute medication use; this requires different management than primary headaches 1

Referral Guidelines

• Emergency admission: Any red flag present, patient unable to self-care without help 1

• Urgent neurology referral (within 48 hours): Suspected spontaneous intracranial hypotension, patient unable to self-care but has help 1

• Routine neurology referral (2-4 weeks): Suspected primary headache disorder, diagnosis uncertain, first-line treatments fail 1

• Urgent specialist referral (within 1 month): Diagnosis in doubt, first-line treatments fail, rapid clinical deterioration, serious complications 1

• Rheumatology referral: Suspected giant cell arteritis 1