What is the cause of multiple punctate lesions of T2 signal hyperintensities in the periventricular and subcortical white matter on an MRI (Magnetic Resonance Imaging)?

Differential Diagnosis of Multiple Punctate T2 Hyperintensities in Periventricular and Subcortical White Matter

The most common cause of multiple punctate T2 hyperintensities in periventricular and subcortical white matter is age-related cerebral small vessel disease (ischemic microvascular disease), particularly when lesions are small (<3 mm), non-enhancing, and located in deep white matter regions. 1

Primary Diagnostic Consideration: Cerebral Small Vessel Disease

Ischemic small vessel disease should be your first consideration when:

• Lesions are small (0.3-0.6 cm) and multiple 1
• Distribution involves both subcortical/deep white matter AND periventricular regions 1
• Lesions do NOT directly abut the lateral ventricles (separated by normal-appearing white matter) 2
• Pattern is symmetric rather than asymmetric 2
• Patient has vascular risk factors (hypertension, diabetes, age >50 years) 1
• No restricted diffusion on DWI (excludes acute ischemia) 1
• No contrast enhancement (excludes active inflammation) 1

The pathophysiology involves arteriolosclerosis causing demyelination, astrocytic gliosis, and eventual axonal loss in periventricular white matter 3.

Critical Red Flags Requiring Alternative Diagnoses

Multiple Sclerosis (MS) - Consider When:

MS becomes the primary diagnosis if lesions meet ALL of the following criteria:

• Lesions are ≥3 mm in longest axis 2, 1
• Ovoid/round shape with sharp borders 2
• Directly abutting the lateral ventricles without intervening white matter 2
• Perpendicular orientation to corpus callosum ("Dawson's fingers") 2
• Asymmetric distribution 2
• Involve U-fibers (juxtacortical lesions) 2
• Patient age <50 years without vascular risk factors 1
• Presence of gadolinium enhancement (nodular or ring pattern in acute lesions) 2

MS diagnostic criteria require lesions in at least 2 of 4 characteristic regions: periventricular (≥3 lesions), juxtacortical (≥1), infratentorial (≥1), or spinal cord 4

CADASIL - Consider When:

• Bilateral lesions involving anterior temporal pole, external capsule, basal ganglia, and/or pons 1, 5
• Patient has migraine with aura, early-onset stroke (<60 years), or early cognitive decline 5
• Autosomal dominant family history of migraine, stroke, or dementia 5

Neuromyelitis Optica Spectrum Disorder (NMOSD) - Consider When:

• Long lesions parallel to corpus callosum (not perpendicular) 2
• Periaqueductal or periependymal lesions surrounding lateral ventricles 2
• Cloud-like, poorly marginated lesions in corpus callosum 2
• Longitudinally extensive transverse myelitis (≥3 vertebral segments) 4

Progressive Multifocal Leukoencephalopathy (PML) - Consider When:

• Large lesions (>3 cm) with subcortical location affecting U-fibers 2
• Ill-defined borders toward white matter, sharp borders toward cortex 2
• Punctate or miliary enhancement pattern 2
• Patient on immunosuppression (especially natalizumab) 2
• Subacute progressive clinical course over weeks 2

Susac Syndrome - Consider When:

• Multifocal, rounded "snowball" lesions centrally located in corpus callosum 2, 6

Common Diagnostic Pitfalls to Avoid

Do NOT misclassify lesions as periventricular MS lesions when:

• They are separated from ventricular surface by normal white matter 2
• They are <3 mm in size 2, 1
• They show linear plate-like hyperintensities parallel to lateral ventricles ("periventricular banding") 2
• They are symmetric in distribution 2

Do NOT pursue extensive MS workup when:

• Patient is >50 years with vascular risk factors 1
• Lesions lack characteristic MS morphology and distribution 1
• No clinical symptoms suggesting demyelinating disease 1

Recommended Diagnostic Algorithm

Step 1: Assess Lesion Characteristics

• Size: <3 mm favors small vessel disease; ≥3 mm allows MS consideration 2, 1
• Location: Directly abutting ventricles favors MS; separated from ventricles favors small vessel disease 2
• Shape: Ovoid/perpendicular favors MS; punctate/symmetric favors small vessel disease 2
• Enhancement: Present favors MS/inflammation; absent favors small vessel disease 1

Step 2: Clinical Context

• Age and vascular risk factors: >50 years with hypertension/diabetes strongly favors small vessel disease 1
• Symptoms: Acute neurologic deficits favor MS; asymptomatic or chronic cognitive decline favors small vessel disease 2, 1
• Immunosuppression status: Consider PML if present 2

Step 3: Additional Testing (Only if MS or Other Inflammatory Disease Suspected)

• Complete neuraxis MRI with gadolinium (brain and cervical/thoracic spine) 4
• CSF analysis for oligoclonal bands, IgG index 4
• Aquaporin-4 and MOG antibodies if NMOSD suspected 4
• JCV DNA in CSF if PML suspected 2, 4

Step 4: Follow-up Strategy

• Small vessel disease: Monitor vascular risk factors; repeat imaging only if new symptoms develop 1
• MS suspected: Follow-up MRI in 3-6 months to assess for new lesions in characteristic locations 1