What is the diagnosis and management for a 2-year-old child with T2 hyperintense lesions in the basal ganglia and dentate nuclei on Magnetic Resonance Imaging (MRI)?

T2 Hyperintense Lesions in Basal Ganglia and Dentate Nuclei in a 2-Year-Old

Primary Diagnostic Consideration

The most likely diagnosis is neurodegeneration with brain iron accumulation (NBIA), specifically pantothenate kinase-associated neurodegeneration (PKAN), which classically presents in the first decade with T2 hyperintensity in the basal ganglia, though the dentate nuclei involvement is less typical for PKAN and raises consideration for other NBIA subtypes or metabolic disorders. 1, 2

Differential Diagnosis by Pattern

NBIA Subtypes (Most Common in This Age Group)

• PKAN (NBIA Type 1) is the most common NBIA subtype, presenting in the first decade with progressive gait disturbances, dystonia, dysarthria, and spasticity 1
• The hallmark MRI finding is the "eye-of-the-tiger sign" - T2 hyperintensity within the anteromedial globus pallidus surrounded by T2 hypointensity from iron deposition 1, 2
• Critical caveat: Only 20% of PKAN cases show dentate nuclei hypointensity on FSE sequences, making isolated dentate involvement atypical 2
• Infantile neuroaxonal dystrophy (INAD) involves globus pallidus, substantia nigra, AND dentate nuclei on T2* sequences, making this a stronger consideration when dentate nuclei are prominently involved 2

Metabolic Disorders

• L-2-hydroxyglutaric aciduria presents with subcortical white matter changes, hyperintensity of basal ganglia AND dentate nuclei, developmental delay, ataxia, and tremor 3
• This diagnosis is critical to identify as it is potentially treatable and can present with sudden unexpected death in infancy 3
• Mitochondrial disorders (particularly T8993G mtDNA mutation) present with Leigh-like syndrome showing basal ganglia hyperintensity, often with infantile spasms, hyperlactatorrhachia (>3 mmol/L), hypotonia, and dystonia by end of first year 4

Histiocytic Disorders

• Langerhans cell histiocytosis (LCH) shows symmetrical T2 hyperintense signals in cerebellar gray matter, pons, basal ganglia, and globus pallidus 1
• This pattern can be asymptomatic or associated with progressive neurologic decline, termed "neurodegenerative histiocytosis" 1

Infectious/Inflammatory Causes

• Japanese B encephalitis typically involves thalamus and basal ganglia with T2 hyperintensity 1
• Enterovirus can spread posteriorly to involve cerebellar dentate nuclei or superiorly to involve thalami and basal ganglia 1
• These require urgent consideration if fever, acute illness, or CSF pleocytosis present 1

Diagnostic Algorithm

Immediate Clinical Assessment

• Neurological examination: Look for dystonia, spasticity, gait disturbances, pyramidal tract signs, ataxia, tremor, hypotonia 1, 3
• Developmental history: Assess for regression versus static delay versus progressive decline 3, 4
• Seizure history: Infantile spasms suggest mitochondrial disorder 4
• Acute versus chronic presentation: Fever and acute illness mandate infectious workup 1

Laboratory Evaluation

• CSF analysis with lactate measurement: Hyperlactatorrhachia (>3 mmol/L) strongly suggests mitochondrial disorder 4
• Serum lactate, pyruvate, amino acids, organic acids: Essential metabolic workup 5
• Urine organic acids: Screen for L-2-hydroxyglutaric aciduria 3
• If infectious suspected: CSF microscopy, viral PCR panel, bacterial cultures 1

Advanced MRI Sequences

• T2 gradient echo or susceptibility-weighted imaging (SWI)*: Superior for detecting iron deposition and distinguishing NBIA subtypes 1, 2
• Diffusion tensor imaging: Identifies axonal pathfinding disorders and microscopic architecture abnormalities 1
• Look for specific patterns:
  • Eye-of-the-tiger sign = PKAN 1, 2
  • Dentate + globus pallidus + putamen with cavitation = neuroferritinopathy 2
  • Uniform basal ganglia + thalami without cavitation = aceruloplasminemia 2
  • Dentate + globus pallidus + substantia nigra on T2* = INAD 2

Genetic Testing

• PANK2 gene sequencing if eye-of-the-tiger sign present 1
• L2HGDH gene sequencing if organic acid screen suggests L-2-hydroxyglutaric aciduria 3
• Mitochondrial DNA analysis (T8993G mutation) if infantile spasms and elevated lactate 4

Management Approach

Acute Phase

• If infectious etiology suspected: Start IV aciclovir 500mg/m² every 8 hours within 6 hours of admission while awaiting CSF results 1
• Seizure management: If infantile spasms present, vigabatrin or corticosteroids are first-line 4
• Supportive care: Physical therapy for spasticity, speech therapy for dysarthria, nutritional support for feeding difficulties 5

Chronic Management

• L-2-hydroxyglutaric aciduria: Potentially treatable - urgent metabolic consultation required 3
• NBIA disorders: Primarily supportive with physical/occupational therapy, dystonia management, nutritional support 1
• Mitochondrial disorders: Avoid mitochondrial toxins, consider coenzyme Q10 supplementation, manage complications 4

Critical Pitfalls to Avoid

• Do not assume normal aging iron deposition in a 2-year-old - pathologic iron accumulation in basal ganglia at this age always requires investigation 1
• Do not miss treatable causes: L-2-hydroxyglutaric aciduria and infectious etiologies require urgent specific therapy 1, 3
• Do not rely on standard T2 FSE sequences alone - T2* or SWI sequences are essential for detecting subtle iron deposition and distinguishing NBIA subtypes 2
• Do not overlook dentate nuclei involvement - this finding narrows the differential significantly and makes INAD, L-2-hydroxyglutaric aciduria, or enterovirus more likely than classic PKAN 2, 3
• Do not delay CSF analysis if any acute features present - infectious causes require immediate treatment 1

Follow-Up Monitoring

• Repeat MRI if symptoms progress or new neurological deficits appear, as static injuries should be non-progressive 5
• Monitor for complications: Eye protection if facial nerve involvement, screening for endocrinopathy in histiocytic disorders, cardiac monitoring in mitochondrial disease 1, 5, 4