Bilateral Basal Ganglia Calcification in a child with Mitochondrial

Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes

(MELAS)

Yuanfan Yang Peking Union Medical College, Tsinghua University

Exchange student at Harvard Medical School, BIDMC

Gillian Lieberman, MD

April, 2013

Yuanfan Yang,

Gillian Lieberman, MD

A Calcified Brain

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Yuanfan Yang

Gillian Lieberman, MD

Basal Ganglia

Deep Grey Structure between the

lateral ventricle and insular cortex:

Basal Ganglia

• caudate

• putamen

• globus pallidus

Thalamus

Core of the extrapyramidal system,

integrating extrapyramidal motor activity .

http://www.radnet.ucla.edu/sections/DINR/index.htm

Normal Basal Ganglia

There is a normal aging process in T2-weighted MR images, due to iron deposition.

Yuanfan Yang

Gillian Lieberman, MD

S.L. Harder et.al. Am J Neuroradiol 29:176–83. 2008.

Metabolism of the Basal Ganglia

• Dynamic metabolism, especially in children

• Rich in mitochondria (ATP), vascular supply(O2& Glucose),

neurotransmitters and trace metal

• Vulnerable to metabolic abnormalities

Chugani HT, et. al.Positron emission tomography study of human

brain functional development. Ann Neurol1987; 22:487-497. Chad R. Cohen,et. al., RadIology 134:97-99, 1980.

Yuanfan Yang

Gillian Lieberman, MD

Very rare in Children

Case report from PUMC Hospital

• A 13yo girl

• HPI: Presented to ER of a county hospital after 5 episodes

of epilepsy-like symptom.

• PMH: early development is normal. Failure to thrive after

5 years of age.

• Fatigability after running.

• Secondary sex development delay.

• recurrent migraine headaches associated with episodic

vomiting

• No childhood infection.

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Yuanfan Yang

Gillian Lieberman, MD

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CT scan Head: basal ganglia calcification

Image from a county hospital in China

Yuanfan Yang

Gillian Lieberman, MD

Common Causes of basal ganglia damage

Acute Causes:

• Hypoxia, CO poisoning, choke

• Hypoglycemia

• Vascular occlusion

--Unlikely considering the history

Chronic Causes?

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Yuanfan Yang

Gillian Lieberman, MD

Chronic causes of basal ganglia calcification

Yuanfan Yang

Gillian Lieberman, MD

Vincent B. Ho, et. al. Bilateral Basal Ganglia Lesions: Pediatric Differential Considerations. RadioGraphics 1993; 13:269-292

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Thorough Evaluation at PUMC Hospital

CT Scan Head

What is the possible relationship between basal

ganglia calcification and developmental retardation?

Image from PACS, PUMC Hospital

Patient transferred to

Peking Union Medical

College Hospital.

Basic biochemistry,

Electrolyte level was

normal.

No abnormality found in

Parathyroid function

Yuanfan Yang

Gillian Lieberman, MD

A thorough history taking and tests

revealed more information

• Mother was found to have neurosensory hearing loss at 28yo

• Mother had Ophthalmoplegia

• High lactate level in serum and CSF

• Pituitary hypoplasia

• GI discomfort (due to lactate acidemia)

• Myoclonus

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Yuanfan Yang

Gillian Lieberman, MD

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Gene Diagnosis

• m.3243 A → G confirmed the diagnosis of MELAS

• The mitochondrial gene codes a functional protein in complex I

of ETC

• Tissues with high energy requirements such as muscle and brain

are particularly vulnerable

• The mitochondrial mutation confer maternal inheritance pattern

of the mitochondrial encephalomyopathy

Yuanfan Yang

Gillian Lieberman, MD

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Maternal Inheritance Pattern of Mitochondrial disease

Yuanfan Yang

Gillian Lieberman, MD

Interest Region

MR Spectrometry reveals focused on Basal Ganglia

Image from PACS, PUMC Hospital

cholin

e C

reatine

NA

A

La

ctate

This technique may detect elevated brain lactate elevations. The lactate signal is

usually seen as a doublet at 1.3 ppm in H-MRS spectra changing its polarity,

depending on the TE applied.

Yuanfan Yang

Gillian Lieberman, MD

Pathophysiology of MELAS syndrome

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Douglas C. Wallace Science 283, 1482 (1999)

Yuanfan Yang

Gillian Lieberman, MD

Glucose is converted into Pyruvate in step 1 of oxidative phosphorylation

(Glycolysis), which happened outside the mitochondria, upstream of the ETC.

Electron transport chain, ETC

Douglas C. Wallace Science 283, 1482 (1999)

Pathophysiology of MELAS syndrome

Yuanfan Yang

Gillian Lieberman, MD

Abundant ATP is produced in the ETC,

which requires normal function of

complex I- complexV

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Douglas C. Wallace Science 283, 1482 (1999)

Pathophysiology of MELAS syndrome

Yuanfan Yang

Gillian Lieberman, MD

MELAS patients have a defect in complex I, so only glycolysis and citric-acid

cycle produce very limited ATP, affecting development and body activity.

Lactate accumulates as a by-product of anaerobic metabolism.

Mechanisms of Basal Ganglia Calcification

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M.F. Casanova, J.M. Araque. Psychiatry Research 121: 59–87. 2003

One hypothesis: may be due to iron accumulation from

regenerated defective mitochondria?

Yuanfan Yang

Gillian Lieberman, MD

MRI Scan Head while the patient was stable…

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T1 Flair T2 FRFSE

Image from PACS, PUMC Hospital

Slight white matter lesions and T2-hyperintense lesions in the basal ganglia

Yuanfan Yang

Gillian Lieberman, MD

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The patient experienced 2 major Stroke-like episode 1 month after the

diagnosis.

This is a characteristic of the disease, where symptom could present as

hemianopia, hemiparesis.

The occipital regions are the most usually affected in such situation.

But a MR angiography (Time of Flight) will demonstrate normal

bilateral posterior cerebellar arteries rulling out stroke.

MRI Scan Head while the patient had stroke like episodes…

Yuanfan Yang

Gillian Lieberman, MD

MRI head (T2 Flair w/+) after the stroke like episodes

Acute lesions appear as high

intensity areas on the T2-weighted

image

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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MRI head (T2 Flair w/+) after the stroke like episodes

Yuanfan Yang

Gillian Lieberman, MD

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Finding Frequency (%)

Reversible

Infarct -like focal

Lesion

Parieto-occipital 58%

96% Basal ganglia 28%

Temporal 10%

Generalized cerebral atrophy 38%

Focal cerebral atrophy 28%

Cerebellar atrophy 28%

White matter lesions (T2 high intensity) 24%

Ventricular dilation 10%

Reversible Infarct-like focal lesions in non-vascular territory, are part of the trade-marks

of MELAS, not finding these lesions makes the diagnosis of MELAS less likely.

Most common Imaging Findings

in MELAS syndrome

Rafael Rojas. Radiologic Features of Mitochondrial Mutations with Brain Involvement: Pictorial Review.

RSNA 04 Radiology Global Forum.

Yuanfan Yang

Gillian Lieberman, MD

A comparative case report from literature

Sheng-Horng Chung, et. al., Symmetric basal ganglia calcification in a 9-year-old child with MELAS. Neurology. 2005

After stroke-

like episodes

Yuanfan Yang

Gillian Lieberman, MD

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References

1. Douglas M. Sproule and Petra Kaufmann. Mitochondrial Encephalopathy, Lactic

2. Acidosis, and Strokelike Episodes. Ann. N.Y. Acad. Sci. 2008. 1142: 133–158.

3. Sheng-Horng Chung, et. al., Symmetric basal ganglia calcification in a 9-year-old child with

MELAS. Neurology. 2005. 65;E19

4. Vincent B. Ho, et. al. Bilateral Basal Ganglia Lesions: Pediatric Differential Considerations.

RadioGraphics 1993; 13:269-292

5. Amogh N. Hegde et. al. Differential Diagnosis for Bilateral Abnormalities of the Basal Ganglia and

Thalamus. RadioGraphics 2011; 31:5–30

6. MG HARRINGTON, et. al., The significance of the incidental finding of basal ganglia calcification

on computed tomography. Journal of Neurology, Neurosurgery, and Psychiatryl981 ;44:1168-1170

7. FENG Feng et. al. Preliminary proton MR spectroscopy study in patients with MELAS. Chin J Med

Imaging Technol，2006; 22:6

8. Chad R. Cohen,et. al., Calcification of the Basal Ganglia as Visualized by Computed Tomography.

RadIology 134:97-99, 1980.

9. James Barkovich, et. al. Mitochondrial Disorders: analysis of their clinical and imaging

characteristics. American Journal of Neuroradiology, 1993;14:1119-1137.

10. Douglas C. Wallace. Mitochondrial Diseases in Man and Mouse. Science. 1999; 283:1482. 11. http://www.radnet.ucla.edu/sections/DINR/index.htm 12. Taverni N, Pozzo GD, et al. Diagnosis and follow-up of mitochondrial encephalomyopathy: CT and

MR studies. J Comput Assist Tomogr 1988;12:696-697

Yuanfan Yang

Gillian Lieberman, MD

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13. Satoh M, et al. N-Isoprpyl-p- 123I iodoanphetamine SPECT in MELAS syndrome: Comparison with

CT and MR imaging. J Comput Assist Tomogr 1991;15:77-82

14. Hasuo K, et al. Computed tomography and angiography in MELAS: report of 3 cases. Neuroradiology

1987;29:393-397

15. Sue CM, et al. Neuroradiological features of six kindreds with MELAS tRNALeu A3243G point

mutation:implications for pathogenesis. J Neurol Neurosurg Psychiatry 1998; 65:233-240

16. Kim IO, et al. Mitochondrial myopathy-encephalopathy-lactic acidosis-and strokelike episodes

(MELAS) syndrome: CT and MR findings in seven children. AJR 1996;166:641-645

17. Matthews PM, et al. Magnetic resonance imaging shows specific abnormalities in the MELAS

syndrome. Neurology 1991;41:1043-1046

18. Valanne L, Ketonen L, et al. Neuroradiologic findings in children with mitochondrial disorders. AJNR

Am J Neuroradiol 19:369-377, 1998.

19. Valanne L, et al. Laminar cortical necrosis in MELAS syndrome: MR and neuropathological

observations. Neuropediatrics 1996;27:154-160

20. Majoie CB, et al. Mitochondrial encephalomyopathy: comparison of conventional MR imaging with

diffusion-weighted and diffusion-tensor imaging: case report. AJNR Am J Neuroradiol 2002;23:813-

816

21. Clark JM, et al. MELAS: clinical and pathologic correlations with MRI, Xenon/CT and MR

spectroscopy. Neurology 1996;46:223-227

22. Castillo M, et al. MELAS Syndrome: Imaging and proton MR Spectroscopic Findings.AJNR Am J

Neuroradiol 16:233-239, 1995

References

Yuanfan Yang

Gillian Lieberman, MD

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Acknowledgements

Thanks Dr. Rojars, Dr. Bhadelia and Dr. Mary Tenenbaum

for discussion with me and suggestions on the topic！

Thanks to the Endocrinology team of Peking Union Medical

College Hospital:

Dr. Jiang-Feng Mao, Dr. Zhi-Xin Wang, Dr. Jia-Jia Tian

Thanks Dr. Lieberman for kind comments and suggestions.

Yuanfan Yang

Gillian Lieberman, MD

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Yuanfan Yang

Gillian Lieberman, MD