Al Jubeilan, R. Al Hashim, A. Kristjansson, S. Nicolas-Jilwan, M. Bilateral Lesions of The Basal Ganglia: Clues to Solve The Diagnostic Dilemma Al Jubeilan, R. Al Hashim, A. Kristjansson, S. Nicolas-Jilwan, M. Department of Radiology, Neuroradiology Division King Faisal Specialist Hospital & Research Center Riyadh, Saudia Arabia

DISCLOSURE There is no financial support from commercial sources or pecuniary interest that would pose a conflict of interest.

INTRODUCTION The term “basal ganglia” refers to the bilateral caudate and lentiform nuclei, the latter composed of putamen and globus pallidus. Their high metabolic activity explains their need for trace metals (Fe, Cu and Mn) as enzyme cofactors and consequently the predilection for these metals to accumulate in the basal ganglia when their metabolism is compromised. It also explains their vulnerability to various conditions in which blood/oxygen/energy levels are diminished and lead to their damage. A wide range of diseases may present as basal ganglia abnormalities. Magnetic resonance imaging (MRI) is the imaging modality of choice for evaluation.

On MRI , the caudate and lentiform nuclei follow the signal intensity of the cerebral cortex as they represent gray matter structures. In adults, the globus pallidus is slightly hypointense relative to the putamen as a result of iron deposition, which increases with age. Basal ganglia injury is much more frequently bilateral than unilateral.

In most cases, the imaging findings of bilateral basal ganglia injury are not specific and must be considered in the context of the clinical history and other diagnostic tests. Unfortunately, it is not uncommon for basal ganglia disease to remain without a specific diagnosis. We present a wide range of pediatric and adult brain disorders which cause bilateral basal ganglia lesions and where the pattern of abnormality or associated findings allow for a specific diagnosis to be made or at least are suggestive of a certain diagnosis. In cases where a disorder can have various imaging patterns, we present several patients with the same pathology to illustrate a wider spectrum of imaging features.

MATERIALS & METHODS We retrospectively selected brain MR examinations of 21 patients aged 5 weeks to 58 years performed on GE & SIEMENS MR scanners of 1.5 and 3 Tesla magnetic field strengths. The cases encompass a wide range of inherited and acquired pathologies where the pattern of abnormality of the basal ganglia and/or associated findings enable or at least suggest a specific diagnosis, as follows: A- Inherited Metabolic Disorders: Wilson disease, biotin responsive basal ganglia disease, 3 methyl glutaconic aciduria, L-2 hydroxyglutaric aciduria, Leigh disease, and MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes).

B- Acquired Metabolic Disorders: kernicterus and hepatic failure. C- Neurodegenerative Disorders: Parkinson disease, Woodhouse-Sakati syndrome and Pantothenate kinase-associated neurodegeneration (PKAN). D- Toxic Injuries: Secondary to cyclosporine and methanol in two patients. E- Inherited Myelin Disorders: Canavan disease, Krabbe disease and molybdenum cofactor deficiency.

CASES

A- Inherited Metabolic Disorders

22 year-old lady with Wilson Disease CASE 1 22 year-old lady with Wilson Disease

Bilateral T2/FLAIR hyperintense signal in the basal ganglia is accompanied by characteristic involvement of the ventrolateral thalami and midbrain. The typical midbrain abnormality is referred to as face of the panda sign as the signal abnormality surrounding red nuclei and substantia nigra gives this appearance. The splenium is also affected.

4 year-old boy with Biotin Responsive Basal Ganglia Disease CASE 2 4 year-old boy with Biotin Responsive Basal Ganglia Disease

Swollen & T2 hyperintense Thalami, Midbrain, Brainstem and Dentate nuclei with Diffusion Restriction Biotin responsive basal ganglia disease typically spares the globus pallidus and frequently involves thalami and midbrain in about 80% of cases. The dentate nuclei are involved in about 10% of cases.

11 year-old girl with Biotin Responsive Basal Ganglia Disease CASE 3 11 year-old girl with Biotin Responsive Basal Ganglia Disease

Symmetrical swelling and high T2 signal of bilateral putamina and caudate nuclei with small foci of cystic change representing necrosis. Typical sparing of the globus pallidus. The bilateral subcortical white matter involvement is common, seen in 80% of cases.

20 month-old with Biotin Responsive Basal Ganglia Disease CASE 4 20 month-old with Biotin Responsive Basal Ganglia Disease

Symmetrical swelling with ↑ T2 SI of the putamina and medial thalami along with asymmetrical involvement of the caudate nuclei

6 year-old boy with 3-Methyl-Glutaconic Aciduria CASE 5 6 year-old boy with 3-Methyl-Glutaconic Aciduria

Symmetrical ↑ T2 SI and atrophy of the caudate nuclei and putamina with small associated areas of restricted diffusion. Symmetrical sparing of an intermediate zone in the posterior putamina and associated cerebellar atrophy are very suggestive of this disorder.

8 year-old boy with L-2 Hydroxyglutaric Aciduria CASE 6 8 year-old boy with L-2 Hydroxyglutaric Aciduria

Symmetrical bilateral subcortical white matter high T2 signal is characteristic. There is involvement of the dentate nuclei. The basal ganglia are spared.

11 year-old girl with L-2 Hydroxyglutaric Aciduria CASE 7 11 year-old girl with L-2 Hydroxyglutaric Aciduria

Symmetrical mild swelling with ↑ T2 SI of the caudate and lentiform nuclei as well as ↑ FLAIR SI of the dentate nuclei and bilateral subcortical white matter signal abnormality.

8 year-old girl with Leigh Disease CASE 8 8 year-old girl with Leigh Disease

Symmetrical ↑ T2 SI of the thalami, periaqueductal grey matter, midbrain, brainstem and dentate nuclei In Leigh disease, there is frequent involvement of the midbrain, periaqueductal grey matter and brainstem variably associated with basal ganglia, thalami and dentate nuclei involvement.

2 year-old girl with Leigh Disease CASE 9 2 year-old girl with Leigh Disease

Bilateral ↑ T2 SI of the lentiform nuclei with diffusion restriction indicating acute injury. Notice the caudate nuclei and thalami are spared. Midbrain, brainstem and dentate nuclei were also normal.

3 year-old girl with Leigh Disease CASE 10 3 year-old girl with Leigh Disease

Symmetrical ↑ T2 SI of the substantia nigra, red nuclei, periaqueductal grey matter, medulla oblongata and dentate nuclei with diffusion restriction. Basal ganglia and thalami are spared.

7 year-old girl with MELAS CASE 11 7 year-old girl with MELAS

Swollen basal ganglia with T2 hyperintense signal and abnormal diffusion signal denoting acute injury Characteristic stroke-like cortical lesions which do not follow the distribution of vascular territories October 6, 2010

Same patient, one month later Chronic stage of basal ganglia injury with atrophy and small foci of cystic/necrotic change seen as foci of very dark T1 signal. The cortical lesions of MELAS are typically due to vasogenic edema. The high diffusion signal represents T2 shine through without low signal ADC correlate. This is an important differentiating feature from infarcts. November 7, 2010

B- Acquired Metabolic Disorders

5 month-old boy with Kernicterus CASE 12 5 month-old boy with Kernicterus

Subtle symmetrical ↑T2 SI of the globi pallidi. No T1 SI alteration, diffusion restriction or susceptibility. Bilateral T2 hyperintense signal of the globi pallidi is characteristic of kernicterus

58 year-old lady with Chronic Liver Disease CASE 13 58 year-old lady with Chronic Liver Disease

Symmetrical globi pallidi increased T1 signal intensity This is a characteristic feature, thought to be due to manganese deposition

C- Neurodegenerative Disorders

58 year-old lady with Parkinsonism CASE 14 58 year-old lady with Parkinsonism

Symmetrical globi pallidi signal alteration with peripheral rim of low SI on T2 and T2 gradient imaging and internal stripes of high SI on T1 and T2 giving the “Eye of The Tiger” sign This sign can be seen in, but is not specific of, Parkinson disease. It is an indicator of iron deposition in the globi pallidi.

37 year-old lady with Woodhouse-Sakati syndrome CASE 15 37 year-old lady with Woodhouse-Sakati syndrome

Typical prominent periventricular white matter T2 hyperintensity Bilateral iron deposition and calcification of the basal ganglia and thalami resulting in T2 hypointense and T1 hyperintense signal Typical prominent periventricular white matter T2 hyperintensity

CASE 16 10 year-old boy with PKAN (Pantothenate Kinase Associated Neurodegeneration)

Symmetrical bilateral globus pallidus↑T2 SI with ↓T1 SI Note the low DWI SI of the globi pallidi due to iron deposition susceptibility. Typical involvement of the globi pallidi with iron deposition, can cause eye of the tiger sign

D- Toxic Injuries

7 year-old boy with Cyclosporine Toxicity CASE 17 7 year-old boy with Cyclosporine Toxicity

Basal ganglia symmetrical high T2/ FLAIR SI with significant swelling and diffusion restriction

40 year-old lady with Methanol Intoxication CASE 18 40 year-old lady with Methanol Intoxication

Symmetrical bifrontal WM ↑T2 SI with volume loss (gliosis). Symmetrical ↑T2 SI of the putamina and to a lesser extent caudate nuclei with atrophy (chronic stage of injury). Symmetrical bifrontal WM ↑T2 SI with volume loss (gliosis). Bilateral injury of the putamina is characteristic of Methanol toxicity with swelling in the acute phase and atrophy at the chronic stage.

F- Inherited Myelin Disorders

2 year-old girl with Canavan Disease CASE 19 2 year-old girl with Canavan Disease

Symmetrical diffuse ↑T2 SI of the globi pallidi, ventral thalami, cerebral WM, pons and medulla oblongata with volume loss. Note the characteristic markedly elevated NAA peak.

3 year-old girl with Krabbe Disease CASE 20 3 year-old girl with Krabbe Disease

Symmetrical ↑T2 SI of the internal capsule posterior limbs and cerebral white matter most prominently involving the periventricular white matter The peripheral margin of the white matter signal abnormality shows restricted diffusion reflecting active myelin destruction while the deeper white matter abnormality might show cavitation reflecting established injury with cavitation. The basal ganglia can be involved, but are not in this case Head CT can show bilateral high density, most commonly of the thalami.

5 week-old boy with Molybdenum Co-factor Deficiency CASE 21 5 week-old boy with Molybdenum Co-factor Deficiency

Symmetrical basal ganglia and thalami ↑T2 SI with atrophy. Extensive bilateral white matter cyst-like cavitary areas of injury with scattered microbleeds. Symmetrical basal ganglia and thalami ↑T2 SI with atrophy.

SUMMARY We presented a wide range of disorders affecting the basal ganglia in an effort to emphasize that careful attention to the pattern of abnormality and associated findings, along with patient’s age and clinical presentation, frequently allow a specific diagnosis to be made.

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