Headache Labs and Next Steps: When to Test, What to Order, and How to Treat

How Common Are Headaches and Why Do They Happen?

Headache is one of the most frequent reasons adults seek medical care. The WHO estimates that roughly half of the global adult population has an active headache disorder, with tension-type headache (TTH) carrying a global prevalence of approximately 42% and migraine affecting about 14% 1. Understanding the mechanism behind a headache is the first step toward deciding whether labs or imaging are warranted.

Primary vs. Secondary Headaches

Primary headaches have no identifiable structural or systemic cause. The three most common are tension-type headache, migraine (with or without aura), and cluster headache. Together they account for well over 90% of all headache presentations in outpatient settings 2.

Secondary headaches arise from an identifiable underlying condition: subarachnoid hemorrhage (SAH), meningitis, giant cell arteritis (GCA), cerebral venous sinus thrombosis, carbon monoxide poisoning, or hypertensive crisis, among others. These are far less common but carry significant morbidity and mortality if missed.

Pathophysiology at a Glance

Pain-sensitive structures inside the skull include the large blood vessels, dural sinuses, and cranial nerves V, IX, and X. The brain parenchyma itself is not pain-sensitive. In migraine, cortical spreading depression triggers trigeminal activation and release of calcitonin gene-related peptide (CGRP), producing the characteristic throbbing unilateral pain 3. Tension-type headache likely involves peripheral sensitization of pericranial myofascial tissues and central sensitization over time 4.

Red Flags That Change the Workup Immediately

Not every headache is benign. The SNOOP4 mnemonic (Systemic illness, Neurological signs, Onset sudden, Older age, Prior headache change, Positional, Precipitated by Valsalva, Papilledema) was validated in a 2013 review published in Headache and helps clinicians identify headaches that need urgent investigation 5.

The Thunderclap Headache

A headache that reaches maximum intensity within 60 seconds of onset is a thunderclap headache until proven otherwise. SAH accounts for roughly 10% of thunderclap headaches presenting to the emergency department, but up to 25% of patients with SAH are initially misdiagnosed 6. Non-contrast CT head performed within 6 hours of onset detects SAH with a sensitivity approaching 98% 7. If CT is negative, lumbar puncture is required to measure opening pressure and look for xanthochromia or elevated red blood cells.

Neurological Signs and Meningismus

New headache with fever, neck stiffness, photophobia, or a petechial rash demands immediate evaluation for bacterial meningitis. The combination of fever, neck stiffness, and altered consciousness has a sensitivity of approximately 44% for bacterial meningitis, meaning absence of the full triad does not rule out the diagnosis 8. Lumbar puncture (after CT if any focal neurological signs are present) is the definitive diagnostic step.

Headache in Adults Over 50

New headache onset after age 50, particularly with temporal tenderness, jaw claudication, or an elevated erythrocyte sedimentation rate (ESR), raises concern for giant cell arteritis. The American College of Rheumatology criteria include an ESR above 50 mm/hr as one of five diagnostic features 9. Temporal artery biopsy remains the gold standard, but treatment with high-dose prednisone (40 to 60 mg/day) should begin immediately if GCA is suspected, before biopsy results return, to prevent irreversible vision loss.

Which Labs Should Be Ordered?

For most patients presenting with a classic primary headache pattern and a normal neurological exam, no laboratory testing is required. The American Headache Society and the American Academy of Neurology both caution against routine imaging or labs for uncomplicated migraine or tension-type headache 10.

When the clinical picture suggests a secondary cause, the following panels guide workup.

Basic Metabolic and Inflammatory Markers

• CBC with differential: Detects anemia (which can worsen migraine frequency), thrombocytopenia (relevant to anticoagulation decisions), and leukocytosis suggesting infection.
• CMP (complete metabolic panel): Screens for electrolyte disturbances, renal dysfunction, and hepatic disease. Hyponatremia, for example, can cause headache with altered mentation.
• ESR and CRP: Elevated in GCA, meningitis, and systemic vasculitis. An ESR above 50 mm/hr in a patient over 50 with new headache has a sensitivity of roughly 83% for GCA 11.
• Thyroid function (TSH): Both hypothyroidism and hyperthyroidism cause headache; TSH is a low-cost screening step when other features of thyroid disease are present.

Coagulation and Thrombophilia Screen

Cerebral venous sinus thrombosis (CVST) presents with progressive headache, often with papilledema, seizure, or focal deficits. D-dimer has a sensitivity of approximately 94% for CVST but low specificity; MRI venography is confirmatory 12. A thrombophilia screen (factor V Leiden, prothrombin G20210A, antiphospholipid antibodies, protein C and S) is appropriate when CVST is confirmed to guide duration of anticoagulation.

Toxicology and Carbon Monoxide

Headache affecting multiple household members simultaneously, particularly in winter or with a functioning gas appliance, warrants immediate carboxyhemoglobin measurement. Carbon monoxide poisoning produces a carboxyhemoglobin level above 10% in symptomatic patients 13. Treatment is 100% oxygen by non-rebreather mask; levels above 25% or with neurological symptoms require hyperbaric oxygen consideration.

Lumbar Puncture Findings to Know

| Condition | Opening Pressure | WBC | Glucose | Protein | Other | |---|---|---|---|---|---| | Bacterial meningitis | Elevated | >1,000 PMN | Low | High | Gram stain positive in ~60% | | Viral meningitis | Normal or mildly elevated | 10 to 500 lymphocytes | Normal | Mildly elevated | PCR for HSV | | SAH | Normal | Normal or bloody | Normal | Normal or elevated | Xanthochromia at 2 to 4 hr | | IIH | >25 cmH2O | Normal | Normal | Normal | Normal cytology | | Cryptococcal meningitis | Markedly elevated | Variable | Low | High | India ink, cryptococcal antigen |

Imaging: When and What to Order

Non-Contrast CT Head

Non-contrast CT is the first-line imaging modality for suspected hemorrhage, mass lesion, or acute hydrocephalus. For thunderclap headache presenting within 6 hours, its sensitivity for SAH is approximately 98%; that figure drops to around 90% beyond 12 hours from onset 7. CT does not reliably detect posterior fossa lesions, early ischemic infarcts, or leptomeningeal disease.

MRI Brain With and Without Contrast

MRI is preferred when the concern is for posterior fossa pathology, leptomeningeal enhancement, pituitary apoplexy, cerebral venous thrombosis, or intracranial hypotension. Gadolinium contrast allows detection of meningeal enhancement and parenchymal metastases missed on non-contrast sequences 14.

CT Angiography and MR Angiography

CT angiography (CTA) of the head and neck is ordered when an unruptured aneurysm, arteriovenous malformation, or cervical artery dissection is suspected. A 2019 systematic review found CTA sensitivity for aneurysms above 5 mm approaches 97%, though sensitivity drops to around 85% for aneurysms smaller than 3 mm 15.

Diagnosing Primary Headache Disorders

Migraine: ICHD-3 Criteria

The International Classification of Headache Disorders, 3rd edition (ICHD-3), requires at least 5 attacks lasting 4 to 72 hours, with at least 2 of the following: unilateral location, pulsating quality, moderate-to-severe intensity, or aggravation by routine physical activity, plus nausea or vomiting or photophobia and phonophobia 16. No biomarker confirms migraine. Diagnosis is purely clinical.

Tension-Type Headache

TTH is bilateral, pressing or tightening in quality, mild to moderate in intensity, and not aggravated by routine activity. Nausea is absent, and at most one of photophobia or phonophobia is present per ICHD-3 16. There are no diagnostic tests for TTH. Overuse of analgesics more than 10 to 15 days per month can transform episodic TTH into chronic daily headache.

Cluster Headache

Cluster headache attacks are strictly unilateral, periorbital or temporal, severe to excruciating in intensity, and last 15 to 180 minutes. At least one ipsilateral autonomic feature (lacrimation, conjunctival injection, rhinorrhea, ptosis, or miosis) must be present 16. Cluster headache is three times more common in men. MRI of the brain is recommended at initial diagnosis to exclude a secondary mimic such as a pituitary adenoma.

Evidence-Based Treatment Options

Acute Treatment of Migraine

The combination of a triptan plus an NSAID outperforms either agent alone. A randomized trial published in NEJM (N=900) found that sumatriptan 85 mg plus naproxen sodium 500 mg produced pain freedom at 2 hours in 26% of patients vs. 10% with placebo (P<0.001) 17. Triptans are contraindicated in patients with ischemic heart disease, uncontrolled hypertension, or prior stroke.

For moderate-to-severe migraine in the emergency department, intravenous prochlorperazine 10 mg plus diphenhydramine 25 mg provides more sustained pain relief than intravenous opioids and carries a lower risk of recurrence 18.

CGRP-Targeted Therapies

Monoclonal antibodies targeting CGRP or its receptor (erenumab, fremanezumab, galcanezumab, eptinezumab) are FDA-approved for migraine prevention. In the ARISE trial (N=577), erenumab 70 mg monthly reduced mean monthly migraine days by 2.9 days vs. 1.8 days for placebo at 12 weeks 19. These agents are appropriate when patients fail or cannot tolerate two oral preventive medications.

Acute Treatment of Cluster Headache

High-flow oxygen at 100%, 12 to 15 liters per minute by non-rebreather mask for 15 to 20 minutes aborts cluster attacks in approximately 78% of patients 20. Subcutaneous sumatriptan 6 mg is the fastest-acting pharmacological option, with attack termination within 15 minutes in roughly 74% of patients in placebo-controlled trials 21.

Preventive Therapy: When to Start and What to Use

Prevention is recommended when headaches occur 4 or more days per month, when acute medications are used more than 10 days per month, or when attacks are significantly disabling despite acute treatment. The American Academy of Neurology 2012 evidence-based guidelines rate the following as having level A evidence for migraine prevention: topiramate 50 to 100 mg/day, valproate 500 to 1,000 mg/day, propranolol 40 to 240 mg/day, and timolol 10 to 15 mg twice daily 22.

For patients with comorbid depression or insomnia, amitriptyline 10 to 75 mg at bedtime carries level B evidence and has the added benefit of treating both conditions simultaneously.

Non-Pharmacological Options

Biofeedback, cognitive behavioral therapy (CBT), and aerobic exercise each have grade A evidence from the Canadian Headache Society for reducing migraine frequency 23. A meta-analysis covering 55 trials found that relaxation training reduced migraine frequency by 37% relative to control conditions 24.

Special Populations and Situations

Headache in Pregnancy

Triptans are not FDA-approved during pregnancy. For acute attacks, acetaminophen 500 to 1,000 mg is first-line. Metoclopramide 10 mg IV is used in the inpatient setting and is generally considered compatible with pregnancy. Magnesium sulfate infusion (1 to 2 g IV over 15 minutes) has evidence for both acute treatment and prevention in pregnant patients with migraine 25. New-onset headache in the third trimester, particularly with hypertension and hyperreflexia, demands immediate evaluation for preeclampsia.

Medication Overuse Headache

Medication overuse headache (MOH) develops when acute headache treatments are used too frequently: triptans or combination analgesics more than 10 days per month, or simple analgesics more than 15 days per month for 3 or more months. Withdrawal is the definitive treatment. A Cochrane review found that structured outpatient withdrawal programs achieve headache day reduction in 50 to 70% of MOH patients at 6 months 26.

Post-Traumatic Headache

Headache is the most common symptom after mild traumatic brain injury, reported in up to 90% of concussion patients in the first week. The ICHD-3 classifies post-traumatic headache as acute (resolving within 3 months) or persistent (lasting beyond 3 months) 16. Treatment follows the phenotype: migraine-like post-traumatic headache responds to triptans and preventive agents used for primary migraine.

A Practical Decision Framework for the Clinician

The following stepwise approach applies to any new headache presentation:

1. Screen for red flags using SNOOP4. Any red flag present means urgent workup before reassurance.
2. Perform a full neurological exam. Any focal deficit, papilledema, or meningismus demands same-day imaging and possible LP.
3. Classify the headache as primary vs. Likely secondary based on history, exam, and onset pattern.
4. Order targeted labs only when a specific secondary cause is on the differential (ESR/CRP for GCA, CBC/CMP for systemic illness, toxicology for CO, coagulation panel for CVST).
5. Initiate appropriate acute therapy matched to headache phenotype.
6. Assess for preventive therapy eligibility at the same visit if frequency exceeds 4 days per month.
7. Reassess at 4 to 8 weeks. Treatment response and headache diary data guide next adjustments.