A Calcified Brain - Lieberman's...
Transcript of A Calcified Brain - Lieberman's...
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
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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
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Gillian Lieberman, MD
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MRI head (T2 Flair w/+) after the stroke like episodes
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Gillian Lieberman, MD
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MRI head (T2 Flair w/+) after the stroke like episodes
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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
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Gillian Lieberman, MD
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MRI head (T2 Flair w/+) after the stroke like episodes
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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
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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
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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
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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.
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Gillian Lieberman, MD
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Yuanfan Yang
Gillian Lieberman, MD