- Email: [email protected]
Black Toenail Sign in MELAS Syndrome
Accepted Manuscript Title: Black Toenail Sign in MELAS Syndrome Author: Matthew T. Whitehead, Michael Wien, Bonmyong Lee, Nancy Bass, Andrea Gropman PII: DOI: Reference:
S0887-8994(17)30566-0 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.017 PNU 9187
To appear in:
Pediatric Neurology
Received date: Revised date: Accepted date:
28-5-2017 26-6-2017 29-6-2017
Please cite this article as: Matthew T. Whitehead, Michael Wien, Bonmyong Lee, Nancy Bass, Andrea Gropman, Black Toenail Sign in MELAS Syndrome, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Black Toenail Sign in MELAS Syndrome
Matthew T. Whitehead, M.D. (1,2), Michael Wien, M.D. (3,4), Bonmyong Lee, M.D. (5), Nancy Bass, M.D. (3,4), Andrea Gropman, M.D. (6)
(1) Department of Neuroradiology, Children’s National Medical Center, Washington, DC, 20010, USA (2) George Washington University School of Medicine, Washington, DC, 20037, USA (3) Rainbow Babies and Children’s Hospital - University Hospital Cleveland Medical Center, Cleveland, OH, 44106, USA (4) Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA (5) Johns Hopkins Medical Institute, Baltimore, MD, 21224, USA (6) Department of Neurology, Children’s National Medical Center, Washington, DC, 20010, USA
Correspondence: Matthew T. Whitehead, M.D. Children’s National Medical Center Department of Radiology 111 Michigan Ave. NW Washington, DC 20010 Phone: 202-476-2497 Email: [email protected]
Funding information: None Manuscript type: Original research
Page 1 of 14
2 Presentation information: NA Abbreviation Key: FLAIR = fluid attenuation inversion recovery; FSPGR = fast spoiled gradient echo
Disclosures: MTW: None MW: None BL: None NB: None AG: None
ABSTRACT Background: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder often causing progressive brain injury that is not confined to large arterial territories. Severe insults ultimately lead to gyral necrosis affecting the cortex and juxtacortical white matter; the neuroimaging correlate is partial gyral signal suppression on T2/FLAIR, resembling black toenails. We aim to characterize the imaging features and natural history of MELAS related gyral necrosis. Materials and Methods: Databases at two children’s hospitals were searched for brain MRIs from MELAS patients. Exams with motion artifact and those lacking T2/FLAIR sequences were excluded. Location, cumulative number, and maximum transverse diameter of necrotic gyral lesions were assessed using T2WI and T2/FLAIR sequences.
Page 2 of 14
3 Wilcoxon signed-rank test was employed to evaluate the relationship between disease duration and number of necrotic lesions. Results: One hundred twenty-four exams from 14 unique MELAS patients (16 +/- 3 years) were evaluated. Six of the 8 patients that developed brain lesions also developed gyral necroses (mean 13, range 0 to 44). Necrotic lesions varied in maximal diameter from 4 to 25 mm. Cumulative necrotic lesions correlated with disease duration (p<0.001). Conclusion: The black toenail sign signifying gyral necrosis is a common imaging feature in MELAS syndrome. Gyral necrosis extent correlates with disease duration. Keywords: MELAS, mitochondria, FLAIR, gyrus, necrosis
Introduction: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder causing progressive brain injury and neurological dysfunction in the form of recurrent stroke-like episodes and/or seizures in most patients. The most common mitochondrial gene defect causing MELAS is mt.3243A>G, which is present in roughly 80% [1, 2]. In addition to MELAS gene mutations, diagnostic criteria include encephalopathy (early stroke-like events or seizures), headache with vomiting, cortical vision loss, lactic acidosis, and focal brain lesions [3, 4, 5].
Progressive posterior predominant cerebral lesions are typical in MELAS [6-12]. The cortex and juxtacortical white matter are generally involved, but lesions do not tend to respect large arterial territories [6, 7, 10-14]. Acute brain lesions are characterized by
Page 3 of 14
4 regional cortical/subcortical swelling and edema, which may either resolve or evolve into permanent brain injury over time [5, 15-17]. Chronically injured parenchyma shows magnetic resonance signal changes representing encephalomalacia and gliosis, and in severe insults, coagulative necrosis. Neuronal loss, gliosis, and necrosis in the involved cortex and white matter have been confirmed histologically [11, 12, 18-22]. Necrosis manifests signal suppression on T2/Fluid attenuation inversion recovery (T2/FLAIR) magnetic resonance (MR) sequences, with the degree of hypointensity corresponding to the degree of necrosis as the signal approaches cerebrospinal fluid, the signal for which the FLAIR inversion pulse is targeted. This hypointense T2/FLAIR signal localizes to the deep gyral cortex and juxtacortical white matter, resembling toes with black nails. In this study, we aim to characterize the imaging features and natural history of MELAS related gyral necrosis.
Materials and Methods: This retrospective study was performed after Institutional Review Board approval. The imaging databases from two academic children’s hospitals were queried for all brain MRs from patients with MELAS syndrome performed over a fifteen-year span. In each case, the electronic medical record was reviewed to verify the diagnosis and document disease duration. Exams lacking T2/FLAIR sequence(s) and studies with substantial motion artifact were excluded. Studies were performed on either 1.5 Tesla (n=89) or 3.0 Tesla (n=35) MR scanners (General Electric, Milwaukee, WI or Siemens, Erlangen, Germany). Axial T2 weighted-images (T2WI) and axial T2/FLAIR images were reviewed in each case. The T2/FLAIR sequence parameters were as follows: Inversion time (TI) 2200-
Page 4 of 14
5 2250 msec, repetition time (TR) 9000-10000 msec, echo time (TE) 94-150 msec, 4-5 mm slice thickness, 0 mm slice spacing.
Location, cumulative number, and maximum transverse diameter of necrotic gyral lesions were assessed using T2WI and T2/FLAIR sequences. Necrotic lesions were defined as focal lesions with increased signal on T2WI and at least some degree of signal suppression on T2/FLAIR sequences.
Studies were reviewed in consensus by two pediatric neuroradiologists (MTW and MW). Although the diagnosis was known, the readers were blinded to the imaging report and clinical data during the review. Data collection and Statistics Data was stored in a Microsoft Excel spreadsheet (Excel 2011, Microsoft, Redmond, WA). Wilcoxon signed-rank test was employed to evaluate the relationship between disease duration and number of necrotic lesions. P values < 0.05 were considered significant.
Results: A total of 124 exams from 14 unique MELAS patients (9 female, 5 male), with a mean age of 16 ± 3 years (range 6 to 22 years) met inclusion criteria (Table 1). All patients except one had imaging at different time points with the number of follow-up studies ranging from 2 to 27 (2 to 11 year follow-up interval). The most common clinical indications for the examinations were stroke (41/124), seizure (38/124), and headache
Page 5 of 14
6 (13/124). All 14 patients had genetic confirmation of MELAS syndrome: 12 had the m.3243 A>G gene mutation and 2 had a m.3721 T>C mutation.
Eight of fourteen MELAS patients ultimately developed focal brain lesions. In all affected patients that had follow-up exams, permanent brain lesions accrued over time. Six of the 8 patients that developed brain lesions also developed gyral necroses affecting the cortex and juxtacortical white matter (mean 13, range 0 to 44) (Figs 1 and 2). Necrotic lesions varied in maximal diameter from 4 to 25 mm. At the outset, all necrotic lesions predominantly involved posterior cerebral lobes in each patient with the following order of regional prevalence: parietal (n=4), posterior temporal (n=4), occipital (n=3), frontal (n=1). Later, new anterior temporal and frontal necroses occurred in half of these patients (3/6). Five of 6 patients with gyral necroses had early scans prior to the onset of chronic brain lesions. Necrotic lesions did not develop in any of these patients prior to 10 months after the first known symptoms (mean= 3 years 7 months; range =11 months to 6 years 3 months). Cumulative necrotic lesions correlated with disease duration (p<0.001).
Discussion: Gyral necrosis is a common finding in MELAS syndrome. Moreover, the number of necrotic lesions correlates with disease duration, and tend to start in the posterior cerebrum without regard to large arterial territories. These gyral necroses resemble the appearance of black toenails on T2/FLAIR sequences: deep cortical/juxtacortical hypointense signal surrounded by hyperintense signal.
Page 6 of 14
7 Neuronal loss, necrosis, and gliosis in the involved cortex and white matter, with cortical laminar necrosis pronounced in gyral crests have been histologically demonstrated in MELAS [11, 12, 18-22]. Cortical laminar necrosis may be found in other mitochondrial disorders as well, but is most common in MELAS syndrome [23]. Lizuka and colleagues described cortical laminar necrosis in 60% of their MELAS cohort [24]. We found gyral necroses collectively representing chronic cortical laminar necrosis and juxtacortical white matter necrosis in 43% of our patients.
Necrosis is the end result of destructive changes in the involved brain parenchyma [25]. Hypoxia, ischemia, substrate insufficiency, toxin accumulation, and energy depletion are among the various insults that can cause necrosis given sufficient duration and severity [22-25]. It is also noteworthy that abnormal mitochondria accumulate in the small brain vessels indicating a vasculogenic contribution to MELAS pathology [12, 26-29]. Although the etiology of gyral necrosis in MELAS has not been firmly established, it appears that a number of these factors in combination are predisposing. For example, blood flow through small vessels can be diminished secondary to vascular obstruction or dysfunction leading to hypoxic/ischemic injury, decreased substrate delivery, and decreased toxin removal. Superimposed neuronal excitation can cause further energy depletion, especially during seizure activity.
Although MELAS related gyral necroses do not occur acutely, they commonly develop over time. On brain magnetic resonance imaging (MRI), these manifest as one or more cortical/juxtacortical gyral lesions not confined to a single vascular territory that are
Page 7 of 14
8 hyperintense on T2WI and have partial signal suppression on T2/FLAIR sequences, resembling the appearance of black toenails. This characteristic pattern can help confirm the diagnosis of MELAS, and may be particularly helpful in more clinically challenging cases.
This study is limited by a small sample size, lack of histopathologic information, and its retrospective nature. It is likely that the degree and extent of brain necroses are underestimated here, as there are inherent limits to tissue resolution on MR imaging. Larger studies with correlative pathology findings will be required to confirm and expand on our data.
Conclusions: The black toenail sign signifying gyral necrosis is a common imaging feature in MELAS syndrome. Gyral necrosis extent correlates with disease duration.
References: 1. Goto T, Nonaka I, Harai S (1990) A mutation in the tRNA leu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348: 651-653 2. DiMauro S, Hirano M (2001) MELAS. GeneReviews® [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK1233/. Updated 21 Nov 2013
Page 8 of 14
9 3. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP (1984). Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 16(4): 481-8 4. Hirano, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, DiMauro S, Rowland LP (1992) MELAS: an original case and clinical criteria for diagnosis. Neuromuscul Disord 2: 125–135 5. Yatsuga S, Povalko N, Nishioka J, et al (2012) MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta 1820: 619–624 6. Malhotra K, Liebeskind DS (2016) Imaging of MELAS. Curr Pain Headache Rep 20(9): 54 7. Tschampa HJ, Urbach H, Greschus S, Kunz WS, Kornblum C (2013) Neuroimaging characteristics in mitochondrial encephalopathies associated with the m.3243A>G MTTL1 mutation. J Neurol 260(4): 1071-80 8. Lorenzoni PJ, Werneck LC, Kay CS, Silvado CE, Scola RH (2015) When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis? Arq Neuropsiquiatr 73(11): 959-67 9. Kaufmann P, Engelstad K, Wei Y, et al (2011) Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology 77(22): 1965-71 10. Barkovich AJ, Good WV, Koch TK, Berg BO (1993) Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol 14: 1119– 1137 11. Hiromichi I, Mori K, Kagami S (2011) Neuroimaging of stroke-like episodes in MELAS. Brain Dev 33(4):283-288
Page 9 of 14
10 12. Betts J, Jaros E, Perry RH, Schaefer AM, Taylor RW, Abdel-All Z, et al (2006) Molecular neuropathology of MELAS: level of heteroplasmy in individual neurons and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol 32:359-373 13. Friedman SD, Shaw DW, Ishak G, Gropman AL, Saneto RP (2010) The use of neuroimaging in the diagnosis of mitochondrial disease. Dev Disabil Res Rev 16(2): 12935 14. Matthews PM, Tampieri D, Berkovic SF, et al (1991) Magnetic resonance imaging shows specific abnormalities in the MELAS syndrome. Neurology 41: 1043–1046 15. Kim JH, Lim MK, Jeon TY, et al (2011) Diffusion and perfusion characteristics of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode) in thirteen patients. Korean J Radiol 12(1): 15-24 16. Li R, Xiao HF, Lyu JH, JJ Wang D, Ma L, Lou X (2016) Differential diagnosis of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) and ischemic stroke using 3D pseudocontinuous arterial spin labeling. J Magn Reson Imaging. [Epub ahead of print] 17. Wang Z, Xiao J, Xie S, Zhao D, et al (2012) MR evaluation of cerebral oxygen metabolism and blood flow in stroke-like episodes of MELAS. J Neurol Sci 323(1-2): 173-7 18. Lizuka T, Sakai F (2005) Pathogenesis of stroke-like episodes in MELAS: analysis of neurovascular cellular mechanisms. Curr Neurovasc Res 2:29-45 19. Hamazaki S, Okada S, Kusaka H, Fujii T, Okuno T, Kashu I, Midorikawa O (1989) Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Report of an autopsy. Acta Pathol Jpn 39(9):599-606
Page 10 of 14
11 20. Fujii T, Okuno T, Ito M, Motoh K, Hamazaki S, Okada S, Kusaka H, Mikawa H (1990) CT, MRI, and autopsy findings in brain of a patient with MELAS. Pediatr Neurol 6(4):253-6 21. Terauchi A, Tamagawa K, Morimatsu Y, Kobayashi M, Sano T, Yoda S (1996) An autopsy case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) with a point mutation of mitochondrial DNA. Brain Dev 18(3):224-9 22. Valanne L, Paetau A, Suomalainen A, Ketonen L, Pihko H (1996) Laminar cortical necrosis in MELAS syndrome: MR and neuropathological observations. Neuropediatrics 27(3):154-60 23. Finsterer J (2009) Laminar cortical necrosis in mitochondrial disorders. Clin Neurol Neurosurg 111(8):655-8 24. Lizuka T, Sakai F, Ide T, Miyakawa S, Sato M, Yoshii S (2007) . J Neurol Sci 257(12):126-38 25. van der Knaap MS1, Smit LS, Nauta JJ, Lafeber HN, Valk J (1993) Cortical laminar abnormalities--occurrence and clinical significance. Neuropediatrics 24(3):143-8 26. Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T (1987) Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol 74(3): 226-33 27. Mizukami K, Sasaki M, Suzuki T, et al (1992) Central nervous system changes in mitochondrial encephalomyopathy: light and electron microscopic study. Acta Neuropathol 83(4): 449-52
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12 28. Gilchrist JM, Sikirica M, Stopa E, Shanske S (1996) Adult-onset MELAS. Evidence for involvement of neurons as well as cerebral vasculature in strokelike episodes. Stroke 27(8): 1420-3 29. Sparaco M, Simonati A, Cavallaro T, et al (2003) MELAS: clinical phenotype and morphological brain abnormalities. Acta Neuropathol 106(3): 202-12
Page 12 of 14
13 Fig 1: Brain MR images from a 14 year-old female with MELAS syndrome and new onset seizures. Axial T2WI (TR/TE msec, 5020/107)(a) and axial T2/FLAIR image (IT/TR/TE msec, 2200/9002/135)(b) depict normal brain volume and normal corticomedullary distinction without focal lesions.
Fig 2: Brain MR images from the same female MELAS patient from Fig 1, now 22 years old. Axial T2WI (TR/TE msec, 3350/160)(a) and axial T2/FLAIR image (IT/TR/TE msec, 2200/10000/124)(b) show that brain volume has decreased, and multifocal cortical/subcortical lesions have developed in both cerebral hemispheres, without regard to large arterial territories. Lesions are hyperintense on T2WI (a) and many demonstrate partial signal suppression on T2/FLAIR resembling black toenails (arrows, b), representing gyral necroses.
Page 13 of 14
14 Table 1: Patient Scans FU Sex (yrs)
Gene
Clinical
Lesions Toenail Location Sign
1
27
6
M m.3243 A>G Sz, Stroke, HA
+
+
P,T,O
2
20
4
F m.3243 A>G Sz, Stroke, HA
+
+
P,T,O,F
3
20
7
F m.3243 A>G Sz, Stroke, HA
+
+
P,T,O,F
4
10
6
F m.3243 A>G Sz, Stroke, HA
-
-
-
5
5
6
F m.3243 A>G Sz, Stroke, HA
+
+
T,O,F
6
1
NA
F m.3243 A>G
-
-
-
7
8
6
F m.3243 A>G Sz, Stroke, HA
+
+
T,O
8
4
NA
F
+
-
-
9
8
11
F m.3243 A>G Sz, Stroke, HA
+
+
P
10
2
4
M m.3721 T>C
Stroke
-
-
-
11
4
7
F m.3243 A>G
Sz
-
-
-
12
2
2
M m.3243 A>G
Sz
-
-
-
13
6
7
M m.3243 A>G Sz, Stroke, HA
-
-
-
14
7
2
M m.3243 A>G Sz, Stroke, HA
+
-
-
m.3721 T>C
Stroke
Stroke
Table showing total number of brain MRI scans, follow-up imaging time range, gender, genetic defects, the most common clinical symptoms at the time of imaging, and the presence (+) or absence (-) of brain lesions, the toenail sign representing gyral necrosis, and gyral necrosis location for each analyzed MELAS patient. NA=not applicable, FU= follow-up, yrs= years, Sz=seizures, HA=headache, P=parietal, T=temporal, O=occipital, F=frontal.
Page 14 of 14
S0887-8994(17)30566-0 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.017 PNU 9187
To appear in:
Pediatric Neurology
Received date: Revised date: Accepted date:
28-5-2017 26-6-2017 29-6-2017
Please cite this article as: Matthew T. Whitehead, Michael Wien, Bonmyong Lee, Nancy Bass, Andrea Gropman, Black Toenail Sign in MELAS Syndrome, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Black Toenail Sign in MELAS Syndrome
Matthew T. Whitehead, M.D. (1,2), Michael Wien, M.D. (3,4), Bonmyong Lee, M.D. (5), Nancy Bass, M.D. (3,4), Andrea Gropman, M.D. (6)
(1) Department of Neuroradiology, Children’s National Medical Center, Washington, DC, 20010, USA (2) George Washington University School of Medicine, Washington, DC, 20037, USA (3) Rainbow Babies and Children’s Hospital - University Hospital Cleveland Medical Center, Cleveland, OH, 44106, USA (4) Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA (5) Johns Hopkins Medical Institute, Baltimore, MD, 21224, USA (6) Department of Neurology, Children’s National Medical Center, Washington, DC, 20010, USA
Correspondence: Matthew T. Whitehead, M.D. Children’s National Medical Center Department of Radiology 111 Michigan Ave. NW Washington, DC 20010 Phone: 202-476-2497 Email: [email protected]
Funding information: None Manuscript type: Original research
Page 1 of 14
2 Presentation information: NA Abbreviation Key: FLAIR = fluid attenuation inversion recovery; FSPGR = fast spoiled gradient echo
Disclosures: MTW: None MW: None BL: None NB: None AG: None
ABSTRACT Background: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder often causing progressive brain injury that is not confined to large arterial territories. Severe insults ultimately lead to gyral necrosis affecting the cortex and juxtacortical white matter; the neuroimaging correlate is partial gyral signal suppression on T2/FLAIR, resembling black toenails. We aim to characterize the imaging features and natural history of MELAS related gyral necrosis. Materials and Methods: Databases at two children’s hospitals were searched for brain MRIs from MELAS patients. Exams with motion artifact and those lacking T2/FLAIR sequences were excluded. Location, cumulative number, and maximum transverse diameter of necrotic gyral lesions were assessed using T2WI and T2/FLAIR sequences.
Page 2 of 14
3 Wilcoxon signed-rank test was employed to evaluate the relationship between disease duration and number of necrotic lesions. Results: One hundred twenty-four exams from 14 unique MELAS patients (16 +/- 3 years) were evaluated. Six of the 8 patients that developed brain lesions also developed gyral necroses (mean 13, range 0 to 44). Necrotic lesions varied in maximal diameter from 4 to 25 mm. Cumulative necrotic lesions correlated with disease duration (p<0.001). Conclusion: The black toenail sign signifying gyral necrosis is a common imaging feature in MELAS syndrome. Gyral necrosis extent correlates with disease duration. Keywords: MELAS, mitochondria, FLAIR, gyrus, necrosis
Introduction: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder causing progressive brain injury and neurological dysfunction in the form of recurrent stroke-like episodes and/or seizures in most patients. The most common mitochondrial gene defect causing MELAS is mt.3243A>G, which is present in roughly 80% [1, 2]. In addition to MELAS gene mutations, diagnostic criteria include encephalopathy (early stroke-like events or seizures), headache with vomiting, cortical vision loss, lactic acidosis, and focal brain lesions [3, 4, 5].
Progressive posterior predominant cerebral lesions are typical in MELAS [6-12]. The cortex and juxtacortical white matter are generally involved, but lesions do not tend to respect large arterial territories [6, 7, 10-14]. Acute brain lesions are characterized by
Page 3 of 14
4 regional cortical/subcortical swelling and edema, which may either resolve or evolve into permanent brain injury over time [5, 15-17]. Chronically injured parenchyma shows magnetic resonance signal changes representing encephalomalacia and gliosis, and in severe insults, coagulative necrosis. Neuronal loss, gliosis, and necrosis in the involved cortex and white matter have been confirmed histologically [11, 12, 18-22]. Necrosis manifests signal suppression on T2/Fluid attenuation inversion recovery (T2/FLAIR) magnetic resonance (MR) sequences, with the degree of hypointensity corresponding to the degree of necrosis as the signal approaches cerebrospinal fluid, the signal for which the FLAIR inversion pulse is targeted. This hypointense T2/FLAIR signal localizes to the deep gyral cortex and juxtacortical white matter, resembling toes with black nails. In this study, we aim to characterize the imaging features and natural history of MELAS related gyral necrosis.
Materials and Methods: This retrospective study was performed after Institutional Review Board approval. The imaging databases from two academic children’s hospitals were queried for all brain MRs from patients with MELAS syndrome performed over a fifteen-year span. In each case, the electronic medical record was reviewed to verify the diagnosis and document disease duration. Exams lacking T2/FLAIR sequence(s) and studies with substantial motion artifact were excluded. Studies were performed on either 1.5 Tesla (n=89) or 3.0 Tesla (n=35) MR scanners (General Electric, Milwaukee, WI or Siemens, Erlangen, Germany). Axial T2 weighted-images (T2WI) and axial T2/FLAIR images were reviewed in each case. The T2/FLAIR sequence parameters were as follows: Inversion time (TI) 2200-
Page 4 of 14
5 2250 msec, repetition time (TR) 9000-10000 msec, echo time (TE) 94-150 msec, 4-5 mm slice thickness, 0 mm slice spacing.
Location, cumulative number, and maximum transverse diameter of necrotic gyral lesions were assessed using T2WI and T2/FLAIR sequences. Necrotic lesions were defined as focal lesions with increased signal on T2WI and at least some degree of signal suppression on T2/FLAIR sequences.
Studies were reviewed in consensus by two pediatric neuroradiologists (MTW and MW). Although the diagnosis was known, the readers were blinded to the imaging report and clinical data during the review. Data collection and Statistics Data was stored in a Microsoft Excel spreadsheet (Excel 2011, Microsoft, Redmond, WA). Wilcoxon signed-rank test was employed to evaluate the relationship between disease duration and number of necrotic lesions. P values < 0.05 were considered significant.
Results: A total of 124 exams from 14 unique MELAS patients (9 female, 5 male), with a mean age of 16 ± 3 years (range 6 to 22 years) met inclusion criteria (Table 1). All patients except one had imaging at different time points with the number of follow-up studies ranging from 2 to 27 (2 to 11 year follow-up interval). The most common clinical indications for the examinations were stroke (41/124), seizure (38/124), and headache
Page 5 of 14
6 (13/124). All 14 patients had genetic confirmation of MELAS syndrome: 12 had the m.3243 A>G gene mutation and 2 had a m.3721 T>C mutation.
Eight of fourteen MELAS patients ultimately developed focal brain lesions. In all affected patients that had follow-up exams, permanent brain lesions accrued over time. Six of the 8 patients that developed brain lesions also developed gyral necroses affecting the cortex and juxtacortical white matter (mean 13, range 0 to 44) (Figs 1 and 2). Necrotic lesions varied in maximal diameter from 4 to 25 mm. At the outset, all necrotic lesions predominantly involved posterior cerebral lobes in each patient with the following order of regional prevalence: parietal (n=4), posterior temporal (n=4), occipital (n=3), frontal (n=1). Later, new anterior temporal and frontal necroses occurred in half of these patients (3/6). Five of 6 patients with gyral necroses had early scans prior to the onset of chronic brain lesions. Necrotic lesions did not develop in any of these patients prior to 10 months after the first known symptoms (mean= 3 years 7 months; range =11 months to 6 years 3 months). Cumulative necrotic lesions correlated with disease duration (p<0.001).
Discussion: Gyral necrosis is a common finding in MELAS syndrome. Moreover, the number of necrotic lesions correlates with disease duration, and tend to start in the posterior cerebrum without regard to large arterial territories. These gyral necroses resemble the appearance of black toenails on T2/FLAIR sequences: deep cortical/juxtacortical hypointense signal surrounded by hyperintense signal.
Page 6 of 14
7 Neuronal loss, necrosis, and gliosis in the involved cortex and white matter, with cortical laminar necrosis pronounced in gyral crests have been histologically demonstrated in MELAS [11, 12, 18-22]. Cortical laminar necrosis may be found in other mitochondrial disorders as well, but is most common in MELAS syndrome [23]. Lizuka and colleagues described cortical laminar necrosis in 60% of their MELAS cohort [24]. We found gyral necroses collectively representing chronic cortical laminar necrosis and juxtacortical white matter necrosis in 43% of our patients.
Necrosis is the end result of destructive changes in the involved brain parenchyma [25]. Hypoxia, ischemia, substrate insufficiency, toxin accumulation, and energy depletion are among the various insults that can cause necrosis given sufficient duration and severity [22-25]. It is also noteworthy that abnormal mitochondria accumulate in the small brain vessels indicating a vasculogenic contribution to MELAS pathology [12, 26-29]. Although the etiology of gyral necrosis in MELAS has not been firmly established, it appears that a number of these factors in combination are predisposing. For example, blood flow through small vessels can be diminished secondary to vascular obstruction or dysfunction leading to hypoxic/ischemic injury, decreased substrate delivery, and decreased toxin removal. Superimposed neuronal excitation can cause further energy depletion, especially during seizure activity.
Although MELAS related gyral necroses do not occur acutely, they commonly develop over time. On brain magnetic resonance imaging (MRI), these manifest as one or more cortical/juxtacortical gyral lesions not confined to a single vascular territory that are
Page 7 of 14
8 hyperintense on T2WI and have partial signal suppression on T2/FLAIR sequences, resembling the appearance of black toenails. This characteristic pattern can help confirm the diagnosis of MELAS, and may be particularly helpful in more clinically challenging cases.
This study is limited by a small sample size, lack of histopathologic information, and its retrospective nature. It is likely that the degree and extent of brain necroses are underestimated here, as there are inherent limits to tissue resolution on MR imaging. Larger studies with correlative pathology findings will be required to confirm and expand on our data.
Conclusions: The black toenail sign signifying gyral necrosis is a common imaging feature in MELAS syndrome. Gyral necrosis extent correlates with disease duration.
References: 1. Goto T, Nonaka I, Harai S (1990) A mutation in the tRNA leu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348: 651-653 2. DiMauro S, Hirano M (2001) MELAS. GeneReviews® [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK1233/. Updated 21 Nov 2013
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9 3. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP (1984). Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 16(4): 481-8 4. Hirano, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, DiMauro S, Rowland LP (1992) MELAS: an original case and clinical criteria for diagnosis. Neuromuscul Disord 2: 125–135 5. Yatsuga S, Povalko N, Nishioka J, et al (2012) MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta 1820: 619–624 6. Malhotra K, Liebeskind DS (2016) Imaging of MELAS. Curr Pain Headache Rep 20(9): 54 7. Tschampa HJ, Urbach H, Greschus S, Kunz WS, Kornblum C (2013) Neuroimaging characteristics in mitochondrial encephalopathies associated with the m.3243A>G MTTL1 mutation. J Neurol 260(4): 1071-80 8. Lorenzoni PJ, Werneck LC, Kay CS, Silvado CE, Scola RH (2015) When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis? Arq Neuropsiquiatr 73(11): 959-67 9. Kaufmann P, Engelstad K, Wei Y, et al (2011) Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology 77(22): 1965-71 10. Barkovich AJ, Good WV, Koch TK, Berg BO (1993) Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol 14: 1119– 1137 11. Hiromichi I, Mori K, Kagami S (2011) Neuroimaging of stroke-like episodes in MELAS. Brain Dev 33(4):283-288
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10 12. Betts J, Jaros E, Perry RH, Schaefer AM, Taylor RW, Abdel-All Z, et al (2006) Molecular neuropathology of MELAS: level of heteroplasmy in individual neurons and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol 32:359-373 13. Friedman SD, Shaw DW, Ishak G, Gropman AL, Saneto RP (2010) The use of neuroimaging in the diagnosis of mitochondrial disease. Dev Disabil Res Rev 16(2): 12935 14. Matthews PM, Tampieri D, Berkovic SF, et al (1991) Magnetic resonance imaging shows specific abnormalities in the MELAS syndrome. Neurology 41: 1043–1046 15. Kim JH, Lim MK, Jeon TY, et al (2011) Diffusion and perfusion characteristics of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode) in thirteen patients. Korean J Radiol 12(1): 15-24 16. Li R, Xiao HF, Lyu JH, JJ Wang D, Ma L, Lou X (2016) Differential diagnosis of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) and ischemic stroke using 3D pseudocontinuous arterial spin labeling. J Magn Reson Imaging. [Epub ahead of print] 17. Wang Z, Xiao J, Xie S, Zhao D, et al (2012) MR evaluation of cerebral oxygen metabolism and blood flow in stroke-like episodes of MELAS. J Neurol Sci 323(1-2): 173-7 18. Lizuka T, Sakai F (2005) Pathogenesis of stroke-like episodes in MELAS: analysis of neurovascular cellular mechanisms. Curr Neurovasc Res 2:29-45 19. Hamazaki S, Okada S, Kusaka H, Fujii T, Okuno T, Kashu I, Midorikawa O (1989) Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Report of an autopsy. Acta Pathol Jpn 39(9):599-606
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11 20. Fujii T, Okuno T, Ito M, Motoh K, Hamazaki S, Okada S, Kusaka H, Mikawa H (1990) CT, MRI, and autopsy findings in brain of a patient with MELAS. Pediatr Neurol 6(4):253-6 21. Terauchi A, Tamagawa K, Morimatsu Y, Kobayashi M, Sano T, Yoda S (1996) An autopsy case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) with a point mutation of mitochondrial DNA. Brain Dev 18(3):224-9 22. Valanne L, Paetau A, Suomalainen A, Ketonen L, Pihko H (1996) Laminar cortical necrosis in MELAS syndrome: MR and neuropathological observations. Neuropediatrics 27(3):154-60 23. Finsterer J (2009) Laminar cortical necrosis in mitochondrial disorders. Clin Neurol Neurosurg 111(8):655-8 24. Lizuka T, Sakai F, Ide T, Miyakawa S, Sato M, Yoshii S (2007) . J Neurol Sci 257(12):126-38 25. van der Knaap MS1, Smit LS, Nauta JJ, Lafeber HN, Valk J (1993) Cortical laminar abnormalities--occurrence and clinical significance. Neuropediatrics 24(3):143-8 26. Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T (1987) Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol 74(3): 226-33 27. Mizukami K, Sasaki M, Suzuki T, et al (1992) Central nervous system changes in mitochondrial encephalomyopathy: light and electron microscopic study. Acta Neuropathol 83(4): 449-52
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12 28. Gilchrist JM, Sikirica M, Stopa E, Shanske S (1996) Adult-onset MELAS. Evidence for involvement of neurons as well as cerebral vasculature in strokelike episodes. Stroke 27(8): 1420-3 29. Sparaco M, Simonati A, Cavallaro T, et al (2003) MELAS: clinical phenotype and morphological brain abnormalities. Acta Neuropathol 106(3): 202-12
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13 Fig 1: Brain MR images from a 14 year-old female with MELAS syndrome and new onset seizures. Axial T2WI (TR/TE msec, 5020/107)(a) and axial T2/FLAIR image (IT/TR/TE msec, 2200/9002/135)(b) depict normal brain volume and normal corticomedullary distinction without focal lesions.
Fig 2: Brain MR images from the same female MELAS patient from Fig 1, now 22 years old. Axial T2WI (TR/TE msec, 3350/160)(a) and axial T2/FLAIR image (IT/TR/TE msec, 2200/10000/124)(b) show that brain volume has decreased, and multifocal cortical/subcortical lesions have developed in both cerebral hemispheres, without regard to large arterial territories. Lesions are hyperintense on T2WI (a) and many demonstrate partial signal suppression on T2/FLAIR resembling black toenails (arrows, b), representing gyral necroses.
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14 Table 1: Patient Scans FU Sex (yrs)
Gene
Clinical
Lesions Toenail Location Sign
1
27
6
M m.3243 A>G Sz, Stroke, HA
+
+
P,T,O
2
20
4
F m.3243 A>G Sz, Stroke, HA
+
+
P,T,O,F
3
20
7
F m.3243 A>G Sz, Stroke, HA
+
+
P,T,O,F
4
10
6
F m.3243 A>G Sz, Stroke, HA
-
-
-
5
5
6
F m.3243 A>G Sz, Stroke, HA
+
+
T,O,F
6
1
NA
F m.3243 A>G
-
-
-
7
8
6
F m.3243 A>G Sz, Stroke, HA
+
+
T,O
8
4
NA
F
+
-
-
9
8
11
F m.3243 A>G Sz, Stroke, HA
+
+
P
10
2
4
M m.3721 T>C
Stroke
-
-
-
11
4
7
F m.3243 A>G
Sz
-
-
-
12
2
2
M m.3243 A>G
Sz
-
-
-
13
6
7
M m.3243 A>G Sz, Stroke, HA
-
-
-
14
7
2
M m.3243 A>G Sz, Stroke, HA
+
-
-
m.3721 T>C
Stroke
Stroke
Table showing total number of brain MRI scans, follow-up imaging time range, gender, genetic defects, the most common clinical symptoms at the time of imaging, and the presence (+) or absence (-) of brain lesions, the toenail sign representing gyral necrosis, and gyral necrosis location for each analyzed MELAS patient. NA=not applicable, FU= follow-up, yrs= years, Sz=seizures, HA=headache, P=parietal, T=temporal, O=occipital, F=frontal.
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