What is the differential diagnosis for an 86-year-old woman with new intermittent confusion and aphasia that have become more frequent and longer in duration since Saturday, after acute stroke has been ruled out and routine laboratory studies are unremarkable?

Differential Diagnosis for Intermittent Confusion and Aphasia in an 86-Year-Old Woman

The most likely diagnoses to prioritize are non-convulsive seizures, transient ischemic attacks (TIAs) despite negative initial stroke workup, and early Alzheimer's disease or other neurodegenerative processes, with less common but critical considerations including autoimmune encephalitis and cortical spreading depression.

Algorithmic Approach to Differential Diagnosis

High-Priority Considerations (Life-Threatening or Rapidly Treatable)

1. Non-Convulsive Seizures

• The intermittent, episodic nature with increasing frequency and duration strongly suggests seizure activity 1
• Post-ictal aphasia can mimic stroke and persist for extended periods
• Critical next step: Obtain EEG immediately to assess for convulsive or non-convulsive seizure activity 1
• This is particularly important given the fluctuating course and progressive worsening

2. Recurrent TIAs or Stroke Mimics

• Even with negative initial ED evaluation, recurrent vascular events remain possible 2, 3
• Key imaging consideration: The initial ED workup may have missed early ischemic changes or small vessel disease
• MRI with diffusion-weighted imaging (DWI) is more sensitive than CT for acute ischemia and should be obtained if not already done 1
• Consider embolic sources: cardiac evaluation with echocardiography, telemetry monitoring, and vascular imaging of carotid/vertebral arteries 4

3. Autoimmune/Inflammatory Encephalitis

• Hashimoto's encephalopathy (SREAT) presents with episodic confusion, aphasia, and fluctuating neurological symptoms in elderly women 5
• Check thyroid antibodies, especially anti-TPO (anti-thyroid peroxidase), even if thyroid function tests are normal 5
• CSF analysis showing elevated protein supports this diagnosis
• This is critical because it responds dramatically to corticosteroids 5

Moderate-Priority Considerations

4. Early Alzheimer's Disease or Related Dementia

• The insidious onset over days (since Saturday) is somewhat rapid for typical AD, but language-variant presentations can occur 6
• Primary progressive aphasia variants can present with episodic worsening
• However, the acute onset and fluctuating course make this less likely as the primary diagnosis 6
• Consider this if other acute causes are excluded

5. Cortical Spreading Depression

• Can occur after any brain injury and mimics stroke or seizure 7
• Presents with episodic focal deficits including aphasia
• More likely if there's history of recent head trauma, migraine, or prior intracranial pathology 7
• Diagnosis of exclusion after ruling out stroke and seizures

6. Metabolic/Toxic Encephalopathy

• Despite "unremarkable" labs, specifically review:
  • Sodium (hyponatremia is common in elderly)
  • Glucose (both hypo- and hyperglycemia)
  • Calcium
  • Thiamine levels (Wernicke encephalopathy) 1
  • Medication review for anticholinergics, sedatives, narcotics, or recent changes 1
  • Urinalysis and chest X-ray to exclude occult infection 1

Lower-Priority but Important Considerations

7. Delirium from Systemic Causes

• Nursing home residence, cognitive impairment, hearing impairment, and stroke history are strong risk factors 1
• Look for precipitants: infection (UTI, pneumonia), hypoxia, cardiac events 1
• However, isolated aphasia without other delirium features makes this less likely

8. Intracranial Mass or Subdural Hematoma

• Less likely given negative ED evaluation, but episodic symptoms can occur 7
• If initial imaging was only non-contrast CT, consider MRI brain with and without contrast to evaluate for tumor, inflammatory lesions, or subtle hemorrhage 1

Recommended Immediate Workup

Neuroimaging:

• MRI brain with and without contrast if not already done—superior to CT for detecting acute ischemia, inflammatory processes, and subtle structural lesions 1
• Non-contrast head CT has only 11% yield for relevant findings in altered mental status, but MRI significantly increases diagnostic sensitivity 1

Electrophysiology:

• EEG (urgent) to rule out non-convulsive status epilepticus or seizure activity 1

Laboratory Studies:

• Anti-TPO antibodies (Hashimoto's encephalopathy) 5
• Comprehensive metabolic panel with specific attention to sodium
• Thiamine level
• ESR/CRP (inflammatory/vasculitic processes) 4
• Consider lumbar puncture if infectious or inflammatory encephalitis suspected 1

Vascular Evaluation:

• Carotid duplex ultrasound or CTA neck
• Echocardiogram (transthoracic, consider transesophageal if embolic source suspected)
• Continuous cardiac monitoring 4

Critical Pitfalls to Avoid

• Don't assume stroke is ruled out based on initial negative CT alone—MRI with DWI is far more sensitive 2
• Don't miss non-convulsive seizures—they require EEG for diagnosis and are easily mistaken for confusion 1
• Don't overlook autoimmune encephalitis—it's treatable with steroids but requires high clinical suspicion and specific antibody testing 5
• Don't attribute symptoms to "dementia" without excluding acute reversible causes in an 86-year-old with acute onset 6

The episodic and progressive nature of symptoms, combined with aphasia as a prominent feature, makes seizures and recurrent vascular events the most urgent diagnoses to pursue, followed by autoimmune encephalitis given its treatability.