Black Toenail Sign in MELAS Syndrome

doi:10.1016/j.pediatrneurol.2017.06.017

Pediatric Neurology

Volume 75, October 2017, Pages 61-65

https://doi.org/10.1016/j.pediatrneurol.2017.06.017 Get rights and content

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 sequences that resemble black toenails. We aimed to characterize the imaging features and the natural history of MELAS-related gyral necrosis.

Materials and Methods

Databases at two children's hospitals were searched for brain magnetic resonance imaging studies of individuals with MELAS. Examinations with motion artifact and those lacking T2/FLAIR sequences were excluded. The location, the cumulative number, and the maximum transverse diameter of necrotic gyral lesions were assessed using T2-weighted images and T2/FLAIR sequences. Wilcoxon signed-rank test was employed to evaluate the relationship between disease duration and the number of necrotic lesions.

Results

One hundred twenty-four examinations from patients with 14 unique MELAS patients (16 ± 3 years) were evaluated. Six of the eight patients who 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).

Conclusions

The black toenail sign signifying gyral necrosis is a common imaging feature in individuals with MELAS syndrome. The extent of gyral necrosis correlates with disease duration.

Introduction

Mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS) syndrome is a mitochondrial disorder causing progressive brain injury and neurological dysfunction in the form of recurrent strokelike 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 strokelike 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, 7, 8, 9, 10, 11, 12 The cortex and juxtacortical white matter are generally involved, but lesions do not tend to respect large arterial territories.6, 7, 10, 11, 12, 13, 14 Acute brain lesions are characterized by regional cortical or subcortical swelling and edema, which may either resolve or evolve into a permanent brain injury.5, 15, 16, 17 Chronically injured parenchyma shows magnetic resonance (MR) 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, 19, 20, 21, 22 Necrosis manifests signal suppression on T2-fluid attenuation inversion recovery (T2/FLAIR) sequences, with the degree of hypointensity corresponding to the degree of necrosis as the signal approaches the 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.

Section snippets

Materials and Methods

This retrospective study was performed after an 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 15-year span. In each case, the electronic medical record was reviewed to verify the diagnosis and to document the disease duration. Examinations lacking T2-FLAIR sequences and studies with substantial motion artifact were excluded. Studies were performed on either 1.5

Results

A total of 124 examinations from 14 unique MELAS patients (nine female, five male), with a mean age of 16 ± 3 years (range 6 to 22 years) met the inclusion criteria (Table). All patients except one had imaging at different time points with the number of follow-up studies ranging from two to 27 (two to 11-year follow-up interval). The most common clinical indications for the examinations were stroke (41 of 124), seizure (38 of 124), and headache (13 of 124). All 14 patients had a genetic

Discussion

Gyral necrosis is a common finding in MELAS syndrome. Moreover, the number of necrotic lesions correlates with the disease duration and tends 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 signals surrounded by a hyperintense signal.

Neuronal loss, necrosis, and gliosis in the involved cortex and white matter, with cortical laminar

Conclusions

The black toenail sign signifying gyral necrosis is a common imaging feature in MELAS syndrome. Gyral necrosis extent correlates with disease duration.

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Most of the cortical cystic lesions of the present patients were linear, just like a 'double line' and were observed from 1 to 18 years after onset. In only one patient (No. 20), the cortical cystic lesion showed a beaded appearance which resembled the 'black toenail' sign reported by Matthew et al [16]. However, their results differ from our present findings.
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In some cases, particularly those with recurrent SLLs, SLLs end up as permanent structural lesions. These include white matter lesions (WMLs), cysts, LCN, also known as pseudolaminar necrosis, cortical or subcortical, focal atrophy, or the “toenail sign” [1,21]. LCN is characterised by gyriform T1-hyperintensity in the chronic stage [4,7,21].
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SLLs are the hallmark of MELAS but occasionally occur in other MIDs. SLLs are best identified on multimodal, cerebral MRI. SLLs may present as uni−/multilocular, symmetric/asymmetric, cortical/subcortical, supra−/infratentorial condition, initially resembling a cytotoxic edema and later a vasogenic edema, or a variable mix between them. SLLs run through an acute and a chronic stage. The acute stage is characterised by a progressively expanding lesion over days, weeks, or months, showing up as increasing hyperintensity on T2/FLAIR, DWI, and PWI and by hyperperfusion, that does not conform to a vascular territory. ADC maps are initially hypointens to become hyperintens during the course. More rarely, a variable mixture of hyper- and hypointensities may be found. The chronic stage is characterised by hypoperfusion, gadolinium enhancement, and regression of hyperintensities to various endpoints. SLLs originate from an initial cortical lesion due to focal metabolic breakdown, which either remains stable or expands within the cortex or to subcortical areas. Some SLLs show spontaneous reversibility (fleeing cortical lesions) suggesting that neuronal/glial damage does not reach the threshold of irreversible cell death.
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Original ArticleBlack Toenail Sign in MELAS Syndrome

Abstract

Background

Materials and Methods

Results

Conclusions

Introduction

Section snippets

Materials and Methods

Results

Discussion

Conclusions

Neuromuscul Disord

Biochim Biophys Acta

J Neurol Sci

Pediatr Neurol

Brain Dev

Clin Neurol Neurosurg

A mutation in the tRNA leu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies

Nature

MELAS. GeneReviews® [Internet]

Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome

Ann Neurol

Imaging of MELAS

Curr Pain Headache Rep

Neuroimaging characteristics in mitochondrial encephalopathies associated with the m.3243A>G MTTL1 mutation

J Neurol

When should MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) be the diagnosis?

Arq Neuropsiquiatr

Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype

Neurology

Mitochondrial disorders: analysis of their clinical and imaging characteristics

AJNR Am J Neuroradiol

Original Article
Black Toenail Sign in MELAS Syndrome