What is the differential diagnosis and recommended imaging workup for a patient with new onset headaches, anisocoria, fatigue, and blurry vision, considering potential conditions such as migraines, cluster headaches, subarachnoid hemorrhage, brain tumors, and multiple sclerosis?

New Onset Headaches with Anisocoria, Fatigue, and Blurry Vision

Immediate Priority: Rule Out Life-Threatening Causes

This constellation of symptoms—particularly the combination of new headache with anisocoria (pupillary asymmetry)—demands urgent neuroimaging to exclude compressive lesions, particularly posterior communicating artery aneurysm, subarachnoid hemorrhage, or brainstem pathology. 1

Critical Red Flags Present

Your patient exhibits multiple red flags that mandate immediate imaging workup:

• Anisocoria with headache: Suggests third nerve involvement from compression (aneurysm, tumor, herniation) or increased intracranial pressure 1
• New onset headache: Any new headache pattern requires exclusion of secondary causes 1, 2
• Blurry vision with headache: May indicate papilledema from increased intracranial pressure or optic nerve involvement 1
• Fatigue: Non-specific but concerning when combined with neurological signs 1

Differential Diagnosis (Prioritized by Urgency)

Life-Threatening Causes (Must Exclude First)

1. Subarachnoid hemorrhage (SAH): Anisocoria suggests third nerve compression from aneurysm, particularly posterior communicating artery 1
2. Brain tumor with mass effect: Can cause third nerve palsy and increased intracranial pressure 1
3. Cerebral venous thrombosis: Can present with headache, visual changes, and pupillary abnormalities 3, 4
4. Brainstem lesion: Demyelination, infarct, or hemorrhage affecting cranial nerve nuclei 5
5. Meningitis/encephalitis: Infection can cause cranial nerve palsies and headache 1, 6

Secondary Causes Requiring Investigation

1. Idiopathic intracranial hypertension (pseudotumor cerebri): Presents with headache, visual changes, and papilledema 1
2. Carotid or vertebral artery dissection: Can cause Horner's syndrome (mimicking anisocoria) with headache 7
3. Multiple sclerosis: Brainstem lesions can cause cranial nerve dysfunction and headache 5
4. Pituitary apoplexy: Sudden hemorrhage causing headache, visual changes, and cranial nerve palsies 6

Primary Headache Disorders (Diagnosis of Exclusion Only)

1. Migraine with aura: Can rarely cause transient anisocoria, but this is a diagnosis of exclusion after imaging 1, 7
2. Cluster headache: Causes ipsilateral autonomic symptoms but typically not true anisocoria 1

Recommended Imaging Workup Algorithm

Step 1: Immediate Non-Contrast CT Head

Obtain stat non-contrast CT head as the first imaging study 1, 6

• Rationale: Rapidly identifies acute hemorrhage, mass effect, hydrocephalus, and large masses 1
• Sensitivity for SAH: 95% if performed within 24 hours of onset, declining to 74% by day 3 1, 7
• Limitations: Poor sensitivity for small aneurysms, brainstem lesions, and subtle pathology 1

Step 2A: If CT Shows SAH or Mass Lesion

Proceed immediately to CTA head and neck 1

• For SAH: CTA has 97.2% sensitivity for aneurysms, though only 61% for aneurysms <3mm 1
• If CTA negative but high suspicion: Proceed to digital subtraction angiography (DSA) 1

Step 2B: If CT is Normal or Non-Diagnostic

Obtain urgent MRI brain with and without IV contrast plus MRA or MRV 1, 3, 4

MRI protocol must include:

• T1-weighted pre- and post-contrast sequences to evaluate for dural enhancement (spontaneous intracranial hypotension), meningeal disease, or tumor 3, 4
• T2/FLAIR sequences for demyelinating lesions, edema, or infarction 1, 5
• Diffusion-weighted imaging (DWI) for acute infarction 1
• Gradient echo (GRE) or susceptibility-weighted imaging (SWI) for microhemorrhages 1
• Dedicated orbital sequences if optic nerve pathology suspected 1

Add MRA head and neck to evaluate for:

• Unruptured aneurysms 1, 7
• Arterial dissection 7
• Vascular malformations 7

Add MRV if concern for cerebral venous thrombosis based on:

• Headache pattern (may worsen with recumbency) 4
• Presence of dural enhancement 3, 4

Step 3: If Initial Imaging Normal but High Clinical Suspicion

Consider lumbar puncture (LP) if performed >6 hours after headache onset 1

• Indication: Rule out SAH when CT negative and symptom onset >6 hours prior 1
• Technique: Spectrophotometric analysis for xanthochromia has 100% sensitivity and 95.2% specificity 1
• Timing: Xanthochromia remains detectable for weeks (100% at 2 weeks, >70% at 3 weeks, >40% at 4 weeks) 7
• Also evaluate: Opening pressure (elevated in idiopathic intracranial hypertension), cell count, protein, glucose, and culture if infection suspected 1

Step 4: Additional Testing Based on Clinical Context

If MRI shows dural enhancement:

• Consider spontaneous intracranial hypotension (CSF leak) 3, 4
• Obtain spine MRI to localize CSF leak 4
• Urgent MRV to exclude cerebral venous thrombosis complication 3, 4

If demyelinating lesions identified:

• Consider multiple sclerosis workup with cervical/thoracic spine MRI 5
• Lumbar puncture for oligoclonal bands and IgG index 5

If patient >50 years old with new headache:

• Check ESR and CRP to evaluate for temporal arteritis (though ESR can be normal in 10-36% of cases) 7
• Consider temporal artery biopsy if clinical suspicion high 7

Critical Management Points

Do Not Delay Imaging for Any of These Features:

• Pupil-involving third nerve palsy (anisocoria with ptosis/ophthalmoplegia): Aneurysm until proven otherwise 1
• Thunderclap headache: Peak intensity within 1 hour 1
• Headache with altered mental status: Even subtle changes 1, 4
• Progressive worsening over days to weeks: Suggests mass lesion or increasing intracranial pressure 1, 2
• Headache awakening patient from sleep: Red flag for secondary causes 2, 4

Common Pitfalls to Avoid:

1. Assuming anisocoria is benign physiologic anisocoria: When combined with new headache, this must be investigated 1
2. Relying on CT alone: CT misses 30% of lesions detected by MRI in neurological presentations 1
3. Performing LP too early after headache onset: Xanthochromia may not be present if LP done <6 hours after SAH 1
4. Missing subtle dural enhancement on MRI: Specifically request radiologist review for this finding if clinical suspicion for intracranial hypotension or venous thrombosis 3, 4
5. Attributing symptoms to migraine without imaging: Migraine is a diagnosis of exclusion in the setting of anisocoria 1, 2

Neurological Examination Priorities:

• Detailed pupillary examination: Document size in light and dark, direct and consensual responses, assess for relative afferent pupillary defect 1
• Extraocular movements: Third nerve palsy causes ptosis, "down and out" eye position, and impaired adduction/elevation/depression 1
• Fundoscopic examination: Look for papilledema (increased intracranial pressure) or optic atrophy 1
• Visual fields and acuity: Document any deficits 1
• Focal neurological signs: Any focal weakness, sensory changes, ataxia, or cranial nerve deficits 1, 2
• Neck stiffness: Suggests meningeal irritation from SAH or meningitis 1, 6

The presence of anisocoria with new headache is not compatible with a "wait and see" approach—this patient requires urgent neuroimaging today. 1