What is the next priority in managing a 66-year-old woman with hypertension who was switched from losartan/hydrochlorothiazide to metoprolol/chlorthalidone, presents with possible stroke, has a negative brain MRI, and persistent unilateral leg weakness and numbness?

Immediate Neurological Re-evaluation and Stroke Workup

Despite a negative brain MRI, persistent unilateral leg weakness and numbness in a 66-year-old woman with recent medication changes and elevated blood pressure demands urgent repeat neurological assessment and vascular imaging to exclude evolving stroke or transient ischemic attack, as a negative initial MRI does not definitively rule out acute ischemia, particularly within the first 24-48 hours.

Critical Next Steps

1. Immediate Neurological Assessment

• Perform a focused neurological examination documenting the exact distribution of weakness and numbness, testing strength in all muscle groups of the affected leg, assessing sensory modalities (light touch, pinprick, proprioception, vibration), and checking for upper motor neuron signs (hyperreflexia, Babinski sign) to localize the lesion 1
• Assess for other stroke symptoms including facial asymmetry, arm drift, speech abnormalities, visual field defects, gait disturbance, and coordination deficits that may have been missed or developed since the ER visit 2, 1
• Document the time course of symptom onset and progression, as symptoms persisting beyond 24 hours with negative imaging raise concern for evolving infarction or alternative diagnoses 2, 1

2. Urgent Vascular Imaging

• Obtain MRI with diffusion-weighted imaging (DWI) if not already performed, as DWI is more sensitive than standard MRI sequences for detecting acute ischemia, particularly in the first 24-48 hours when CT and conventional MRI may be falsely negative 2, 1
• Perform vascular imaging (MRA or CTA from aortic arch to vertex) to evaluate for large vessel occlusion, intracranial stenosis, or vertebrobasilar insufficiency that could explain persistent symptoms despite negative parenchymal imaging 2, 1
• Consider repeat imaging if initial MRI was performed very early (within 6-12 hours of symptom onset), as some infarcts may not be visible on initial imaging but become apparent on delayed studies 1

3. Blood Pressure Management in the Acute Setting

• Do NOT aggressively lower blood pressure in the acute phase if this represents an evolving ischemic stroke, as elevated BP may be a compensatory mechanism to maintain cerebral perfusion to ischemic tissue 2
• Restart antihypertensive therapy only after neurological stability is confirmed (typically after the first 24 hours), as the 2017 ACC/AHA guideline recommends restarting medications in patients with pre-existing hypertension who are neurologically stable 2
• Avoid blood pressure reduction unless SBP >220 mmHg or DBP >120 mmHg in the setting of acute ischemic stroke without thrombolysis, as lower thresholds may worsen outcomes 2
• Target SBP <140 mmHg for secondary prevention once acute stroke is excluded or the patient is stable beyond 24 hours, using thiazide diuretics, ACE inhibitors, or ARBs as first-line agents 2

Medication Review and Optimization

Evaluate the Recent Medication Change

• The switch from losartan/HCTZ 100/25 to metoprolol 50 and chlorthalidone 25 may have contributed to inadequate blood pressure control during the transition period, potentially precipitating the neurological event 2, 3, 4
• Chlorthalidone 25 mg is more potent than HCTZ 25 mg for blood pressure reduction (particularly nighttime and 24-hour ambulatory BP), but the loss of the ARB component (losartan 100 mg) may have resulted in net worse control during the changeover 5, 6
• Metoprolol monotherapy is inferior to ARB-based regimens for stroke prevention, as demonstrated in the LIFE study where losartan-based therapy reduced stroke risk by 25% compared to atenolol-based therapy 3, 4

Optimal Long-Term Regimen After Stabilization

• Resume an ARB or ACE inhibitor as the foundation of therapy, as these agents provide superior stroke risk reduction compared to beta-blockers in hypertensive patients 2, 3, 4
• Combine with chlorthalidone rather than HCTZ if a thiazide diuretic is indicated, given chlorthalidone's superior 24-hour blood pressure control and proven cardiovascular outcomes in landmark trials 2, 5
• Consider triple therapy (ARB + calcium channel blocker + chlorthalidone) if blood pressure remains >130/80 mmHg on dual therapy, as combination treatment is recommended for secondary stroke prevention 2
• Target blood pressure <130/80 mmHg for long-term secondary stroke prevention, though <140/90 mmHg is acceptable in elderly or frail patients 2

Differential Diagnosis Beyond Stroke

Alternative Neurological Causes

• Transient ischemic attack (TIA) with prolonged symptoms can occasionally present with deficits lasting >24 hours despite negative imaging, particularly in small vessel or posterior circulation events 2
• Hemiplegic migraine can mimic stroke with unilateral weakness and sensory symptoms, though this is less likely in a 66-year-old without prior migraine history 1
• Peripheral nerve or plexus lesion (e.g., lumbosacral radiculopathy, sciatic neuropathy) should be considered if weakness and numbness follow a dermatomal or peripheral nerve distribution rather than a central pattern 1
• Spinal cord pathology (e.g., cord compression, transverse myelitis) must be excluded if there are bilateral symptoms, sensory level, or bowel/bladder dysfunction 1

Metabolic and Systemic Causes

• Hypokalemia from diuretic therapy can cause muscle weakness, though this typically presents bilaterally and symmetrically; check serum potassium, especially given the recent addition of chlorthalidone 2, 5, 6
• Hypoglycemia or hyperglycemia can present with focal neurological deficits mimicking stroke; obtain fingerstick glucose immediately 1

Common Pitfalls to Avoid

• Do not dismiss persistent neurological symptoms based solely on negative initial imaging, as MRI sensitivity for acute stroke is time-dependent and some infarcts (particularly small lacunar or posterior circulation strokes) may not be visible on early scans 2, 1
• Do not rapidly lower blood pressure in the setting of possible acute stroke, as this can extend the infarct by reducing perfusion to the ischemic penumbra; permissive hypertension is appropriate until stroke is definitively excluded 2
• Do not attribute symptoms to "hypertensive emergency" without documented target organ damage, as the ER diagnosis of elevated BP causing symptoms is questionable given the negative MRI and lack of other end-organ findings 7
• Do not continue metoprolol as monotherapy for secondary stroke prevention, as beta-blockers are inferior to ARBs and ACE inhibitors for reducing recurrent stroke risk 2, 3, 4