How should I work up and manage a young patient with unexplained parkinsonism, dystonia, spasticity, and cognitive decline suggestive of neurodegeneration with brain iron accumulation?

Workup and Management of Suspected Neurodegeneration with Brain Iron Accumulation

MRI brain without contrast is the essential first-line imaging study, specifically looking for the pathognomonic "eye-of-the-tiger sign" (T2 hyperintensity within the anteromedial globus pallidus surrounded by T2 hypointensity from iron deposition), though this finding may not be present in all cases and can change or disappear over time. 1

Initial Diagnostic Imaging

MRI is the optimal imaging modality because of its superior soft-tissue characterization and sensitivity to iron deposition compared to CT 1:

• Order brain MRI with high-spatial-resolution 3D anatomical imaging, diffusion-weighted imaging (DWI), and susceptibility-weighted imaging (SWI) to better characterize iron deposition, evaluate for white matter lesions, assess for microbleeds, and distinguish calcium from iron 2
• Look specifically for T2 hypointensity in the globus pallidus and substantia nigra indicating iron accumulation 1
• Assess for blurring of borders between substantia nigra and red nucleus 1
• Evaluate for sparing of white matter and cortex, which is characteristic of NBIA type 1 1
• Consider IV contrast in the initial evaluation to exclude inflammatory etiologies that may mimic NBIA 1

CT has limited utility but may be helpful to distinguish calcium from iron deposition when MRI findings are ambiguous, as both can appear similar on MRI 1, 2

Critical Laboratory Workup

Immediately obtain serum ceruloplasmin, 24-hour urinary copper, and arrange slit-lamp examination for Kayser-Fleischer rings to evaluate for Wilson's disease, which can present with similar movement disorders and basal ganglia abnormalities 2, 3:

• Wilson's disease can present with tremor, dystonia, parkinsonian features, drooling, and oropharyngeal dystonia 3
• If diagnosis remains unclear, obtain hepatic copper content (>250 μg/g dry weight is diagnostic) 2

Check serum ferritin and thyroid function tests as part of the secondary causes workup 3

Clinical Phenotyping

The clinical presentation helps narrow the differential among NBIA subtypes 4, 5, 6, 7:

NBIA Type 1 (Pantothenate Kinase-Associated Neurodegeneration/PKAN) - the most common subtype:

• Typically presents in the first decade with slowly progressive gait disturbances, dystonia, dysarthria, spasticity, and pyramidal tract signs 1
• Annual incidence of 1/1,000 1
• Autosomal recessive inheritance 1

Document the following clinical features systematically 4, 5, 6, 7:

• Movement disorder characteristics: dystonia, parkinsonism, chorea 4, 6
• Pyramidal signs: spasticity, hyperreflexia 4, 6
• Speech abnormalities: dysarthria 4, 6
• Cognitive function: degree of decline, psychomotor retardation 4, 6
• Ocular abnormalities: retinal degeneration 4, 6
• Gait pattern: observe carefully for parkinsonian, ataxic, or mixed patterns 8

Genetic Testing Strategy

Once imaging confirms iron accumulation in basal ganglia, proceed with genetic testing targeting the 10 established NBIA genes 6, 7, 9:

• Primary genes to test: PANK2 (most common), PLA2G6, WDR45, C19orf12 4, 7, 9
• Secondary genes: COASY, FA2H, ATP13A2, FTL, CP, DCAF17 7, 9
• Use next-generation sequencing panels for comprehensive evaluation 7
• Note that a significant percentage of patients remain without genetic diagnosis despite testing, suggesting undiscovered NBIA genes 7

Advanced Imaging Considerations

Diffusion tensor imaging may show increased fractional anisotropy in both globus pallidus and substantia nigra in NBIA patients, though this is not routinely necessary for diagnosis 1

Nuclear medicine studies (HMPAO SPECT, FDG-PET, MR spectroscopy, fMRI) have no established role in the initial evaluation of suspected NBIA 1

Management Approach

Treatment remains largely symptomatic, but emerging disease-modifying therapies warrant consideration 4, 5:

Iron Chelation Therapy

• Deferiprone has been studied in PKAN with radiological improvement showing reduction of iron load in basal ganglia and a trend toward slowing disease progression 4
• Consider in confirmed PKAN cases, though evidence remains limited 4

Symptomatic Management

• Dystonia: botulinum toxin injections, anticholinergics, baclofen 5
• Spasticity: baclofen, tizanidine, physical therapy 5
• Parkinsonism: trial of levodopa/carbidopa, though response is typically poor 5

Investigational Therapies

• Fosmetpantotenate (alternative substrate for PKAN) did not show significant benefit in recent randomized controlled trial, leading to early termination 4
• 4'-phosphopantetheine showed promising results in animal models with ongoing clinical studies 4
• Deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLA2G6-associated neurodegeneration (PLAN) 4

Critical Pitfalls to Avoid

Do not rely solely on the "eye-of-the-tiger sign" - it may not be present in all NBIA cases and can change or disappear over time 1

Do not miss Wilson's disease - this is a treatable cause of similar symptoms and must be excluded in every young patient with movement disorders and basal ganglia abnormalities 2, 3

Do not assume normal aging-related iron accumulation - NBIA shows excess, pathologic iron deposition beyond normal age-related changes 1

Do not expect enhancement or restricted diffusion in areas of iron deposition on MRI, as these are not features of NBIA 1

Monitoring and Follow-Up

Arrange follow-up imaging in 6-12 months and serial neurological examinations to detect emerging symptoms and monitor disease progression 2

Multidisciplinary care is essential involving neurology, genetics, physical therapy, occupational therapy, and speech therapy to optimize quality of life 5, 6