In a 73-year-old woman with a CT showing enlargement of the splenium of the corpus callosum and surrounding white‑matter edema, what are the differential diagnoses and what further imaging should be obtained?

Differential Diagnosis of Splenial Enlargement with White Matter Edema in a 73-Year-Old Woman

Proceed immediately with brain MRI with and without gadolinium contrast, as CT is insufficiently specific for characterizing white matter pathology and determining the underlying etiology of splenial involvement. 1

Immediate Next Step: MRI Protocol

Order brain MRI with the following essential sequences: 1

• 3D T1 volumetric imaging to assess for callosal atrophy and structural changes 1
• FLAIR and T2-weighted sequences to characterize white matter lesions 1, 2
• Diffusion-weighted imaging (DWI) with ADC maps to distinguish acute cytotoxic edema from chronic changes and identify restricted diffusion patterns 1, 3
• Gradient echo or susceptibility-weighted imaging to detect microbleeds or calcifications 2
• Gadolinium contrast to identify enhancement patterns that distinguish inflammatory, infectious, or neoplastic processes 1

Primary Differential Diagnoses

1. Posterior Reversible Encephalopathy Syndrome (PRES)

PRES is a critical consideration given the acute presentation with splenial involvement and vasogenic edema. 4

• Look for acute onset of symptoms including altered mental status, seizures, headache, or visual disturbances 4
• Assess for precipitating factors: severe hypertension, renal failure, immunosuppressive medications, eclampsia, or autoimmune conditions 4
• MRI typically shows vasogenic edema (bright on T2/FLAIR, facilitated diffusion on DWI) predominantly in posterior circulation territories 4
• Splenial involvement occurs but is usually accompanied by other posterior white matter changes 4

2. Reversible Splenial Lesion Syndrome (RESLES)

This represents a distinct clinicoradiological entity with favorable prognosis. 5

• Associated with infections, metabolic disturbances (hypoglycemia, hypernatremia), antiepileptic drug withdrawal, or high-altitude cerebral edema 5, 6
• Clinical presentation is typically encephalopathy or encephalitis-like 5
• MRI shows isolated oval lesion in the splenium, hyperintense on T2/FLAIR, non-enhancing 5, 6
• Cytotoxic edema pattern (restricted diffusion) is characteristic except in high-altitude cases 5
• Complete resolution within weeks to months is the rule 5, 6

3. CSF1R-Related Leukoencephalopathy

Consider this progressive microgliopathy, particularly if frontoparietal white matter lesions are present beyond the splenium. 7

• Mean age of onset is 40-43 years, but can present in the 70s 7
• Key MRI findings include frontoparietal white matter lesions, callosal thinning (29% of cases), and persistent foci of restricted diffusion lasting months to years 7, 1
• Hallmark CT finding is white matter calcifications, which should be specifically assessed 7
• Look for progressive cognitive impairment, behavioral changes, or motor symptoms 7
• Diffusion restriction persists far longer than in typical ischemic or inflammatory conditions 7

4. Demyelinating Disease (Multiple Sclerosis or Acute Disseminated Encephalomyelitis)

Demyelination can involve the splenium but typically shows characteristic patterns. 7

• MS lesions are ≥3 mm, ovoid/round, oriented perpendicular to ventricles 7
• Callosal lesions in MS are typically at the inferior callosal-septal interface, not causing enlargement 7
• Look for additional periventricular, juxtacortical, or infratentorial lesions 7
• Gadolinium enhancement suggests active demyelination 7
• Red flag: Long lesions parallel to the corpus callosum suggest neuromyelitis optica spectrum disorder rather than MS 7

5. Infectious Encephalitis

Viral or autoimmune encephalitis can cause splenial involvement with edema. 5, 4

• Assess for fever, altered mental status, seizures, or CSF pleocytosis 5
• MRI may show enhancement with gadolinium in infectious cases 3
• Herpes simplex encephalitis typically involves temporal lobes but can have callosal extension 4
• Consider autoimmune encephalitis (anti-NMDA, anti-LGI1) with limbic and extralimbic involvement 4

6. Cerebral Small Vessel Disease with Callosal Involvement

In a 73-year-old, vascular disease is common but isolated splenial enlargement is atypical. 2

• Typical findings are lesions <0.6 cm, non-enhancing, without diffusion restriction 2
• Assess for vascular risk factors: hypertension, diabetes, hyperlipidemia, smoking 1, 2
• Look for additional deep white matter and periventricular lesions, lacunar infarcts, or microbleeds 2
• Isolated splenial enlargement argues against pure vascular etiology 4

Critical Clinical Information to Obtain

Gather the following history to narrow the differential: 1

• Temporal profile: Acute (hours-days) versus subacute (weeks) versus chronic (months) onset 1
• Medication history: Antiepileptic drugs (even without epilepsy), immunosuppressants, chemotherapy 5, 3
• Recent infections: Viral illness, gastroenteritis, respiratory infection 5, 6
• Metabolic disturbances: Recent hypoglycemia, electrolyte abnormalities, renal or hepatic dysfunction 5
• Blood pressure: Current and historical hypertension control 2
• Family history: Early-onset dementia, stroke, or known white matter disorders 1
• Cognitive trajectory: Acute confusion versus progressive decline 7

Common Pitfalls to Avoid

Do not rely on CT alone for definitive diagnosis, as it lacks the specificity needed to distinguish between etiologies and cannot adequately characterize white matter disease 7, 1

Do not assume benign age-related changes in a 73-year-old with splenial enlargement and edema, as this is pathological and requires explanation 1

Do not miss white matter calcifications on CT, as these are highly specific for CSF1R-related leukoencephalopathy and should prompt genetic testing if other features are consistent 7

Do not overlook medication-induced causes, particularly antiepileptic drugs, which can cause reversible splenial lesions even in non-epileptic patients 3

Do not dismiss the diagnosis if family history is negative, as many CSF1R cases are sporadic due to de novo mutations or mosaicism 7