Brain Magnetic Resonance Imaging Findings in Patients With Mitochondrial Cytopathies FREE

Diagnosis of mitochondrial cytopathy (MC) is based on the identification of classic phenotypes, laboratory findings,¹ and tissue identification of ragged red muscle fibers through modified Gomori staining.² However, when doubt persists, evaluation of mitochondrial DNA (mtDNA) is mandatory for complete characterization.³ The MCs are a heterogeneous group of clinical entities,⁴ some of which have classic phenotypes.⁵ Structural rearrangements, including single or multiple deletions, duplications, or point mutations of the mtDNA, sometimes combined with defective nuclear DNA, are responsible for the numerous clinical and ancillary manifestations. Symptoms and clinical findings are due to impaired adenosine triphosphate production. The cardiovascular, nervous, and musculoskeletal systems are the ones most frequently involved.^{1 ,3} The description of the genetic abnormalities in MC is beyond the scope of this report but may be found elsewhere.^{1 ,6}

During the 1980s, computed tomography was the most common form of imaging performed for patients presenting with MC. Computed tomography showed nonspecific findings such as white matter and basal ganglia hypodensity, calcification of cortex and basal ganglia, and atrophy of the pons and cerebellum.⁷ However, recurrent brain insults that resembled strokes were identified as a characteristic finding in mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS syndrome).⁸ Magnetic resonance imaging (MRI) has been reported to be helpful in the diagnosis of MC.^{9 - 11}

The aim of this study was to correlate the most common brain MRI findings reported in patients with MC with the clinical findings in 4 different MC subgroups.

The 21 cases described in this report were prospectively followed up in our institution between March 1997 and February 2002. Patients were referred by the physician in charge to confirm or rule out the diagnosis, which was based on the previously reported clinical criteria.¹ All cases fulfilled the following criteria: elevated serum levels of lactate, creatine kinase, and lactate dehydrogenase; elevated cerebrospinal fluid levels of lactate, lactate dehydrogenase, and proteins; and the presence of ragged red fibers in muscle biopsy specimens; and all cases had one of the following classic phenotypes: (1) chronic progressive external ophthalmoplegia (CPEO), external ophthalmoplegia combined with ragged red fibers and proximal myopathy without any other systemic manifestations¹² ; (2) Kearns-Sayre syndrome (KSS), consisting of the classic triad of chronic external ophthalmoplegia, heart block, and pigmentary retinopathy, with cerebellar ataxia and elevated cerebrospinal fluid protein levels (>100 mg/dL) considered optional findings¹³ ; (3) mitochondrial neurogastrointestinal encephalopathy (MNGIE), comprising leukoencephalopathy, chronic progressive external ophthalmoplegia, polyneuropathy, and chronic intestinal pseudo-obstruction¹⁴ ; and (4) myoclonic epilepsy with ragged red fiber myopathy (MERRF), consisting of myoclonic epilepsy, myoclonic ataxia, dementia, and the presence of ragged red fibers in the muscle biopsy specimen.¹⁵ Doubt persisted for 4 patients who fulfilled the above criteria, and for these patients mtDNA analysis was performed. In two of these patients we detected the presence of KSS and CPEO was ruled out, and in another case we ruled out KSS and identified MERRF. In the fourth patient MNGIE was diagnosed through the mtDNA analysis.

Brain MRI abnormalities in our patients included the most common brain MRI findings previously reported in patients with MC, as follows: supratentorial cortical atrophy (SCA)⁹ ; supratentorial subcortical atrophy (SSCA)⁶ ; cerebellar atrophy (CbA)^{9 ,16} ; widespread white matter hyperintensity (WSWH) on T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences^{16 - 18} ; cortical hyperintensity on T2-weighted images and FLAIR sequences,^{19 - 20} basal ganglia hyperintensity (BGH) on T1-weighted images²¹ ; and small hyperintense patchy lesions in the subcortical white matter (HPSCWM) on T2-weighted images and FLAIR sequences.²²

All examinations were performed in a 1.5-T magnetic resonance unit (Edge model; Picker Instruments Inc, Cleveland, Ohio). Sequence acquisitions included sagittal T1-weighted images (300-600/30 ms); axial T1- and T2-weighted images (3000-6000/90 ms); axial proton density–weighted images (3000-6000/30 ms) and FLAIR sequences (10 000/140 ms; inversion time, 2200 ms); and axial and coronal T1-weighted images with intravenous gadolinium.²³ The MRI images were evaluated by a panel of 3 neuroradiologists, and, to establish a diagnosis, at least two of them had to agree.

Continuous variables were reported as means with SDs. For nonnormal distributions, medians and interquartile ranges were used. Categorical and dichotomous variables were reported as absolute and relative frequencies. Stochastic significance was tested using the χ² test for categorical variables, and the binomial test was used for dichotomous variables using SPSS 10. The cutoff significance level was α = .05.

An initial exploration with the χ² test was performed using all the variables for the studied population. For this evaluation all the different types of MC were considered a single entity. Next, using the binomial test, a subgroup analysis was performed in which the relative frequencies of the variables in each subgroup were compared with their respective frequencies in the entire study population.

In all, 28 patients with suspected MC were initially recruited. Seven were eliminated, in 4 cases because no biopsy specimen was available and in the other 3 because brain MRI was not performed. Twenty-one patients were therefore included, 12 women (57%) and 9 men (43%) (male-female ratio, 0.75:1.0) with a mean ± SD age of 32.7 ± 12.7 years. The diagnostic subgroup distribution was as follows: CPEO, n = 7; KSS, n = 7; MNGIE, n = 6; and MERRF, n = 1. Demographic and clinical characteristics are shown in Table 1. The mean period from symptom onset to brain MRI was 185.0 months (range, 16.7-393.9 months; SD, 119.8 months).

All patients except one (20/21 [95%]) had at least one abnormality on brain MRI. Two patients, one with CPEO and the other with KSS, had concomitant brain MRI abnormalities. The patient with CPEO had SCA and HPSCWM while the patient with KSS had SCA and cortical hyperintensity (Table 2). Patients in all subgroups presented with SCA, WSWH, and CbA, except for the patient with MERRF, who presented with SCA and WSWH.

The most common brain MRI abnormalities were WSWH (19/21 [90%]), SCA (18/21 [86%]), and CbA (13/21 [62%]). Widespread white matter hyperintensity was identified on T2-weighted images and FLAIR sequences, while SCA and CbA were shown on T1-weighted images, T2-weighted images, and FLAIR sequences. Using the χ² test, WSWH (Figure 1) and SCA (Figure 2) were each correlated significantly with MC (P < .001 and P = .001, respectively) (Table 2).

On abnormal brain MRIs, subgroup analysis using the binomial test showed significant correlations between the absence of BGH (Figure 3) and KSS (P < .001) and between the presence of SCA (Figure 4) and MNGIE (P = .005). There was no significant relationship between brain MRI abnormalities and CPEO. Because only one patient had MERRF, no statistical results were available for this subgroup.

In the present series of 21 patients, we observed 4 different mitochondrial phenotypes and their corresponding brain MRI findings. In the patients who presented with MC, WSWH, and SCA, the brain MRI findings were statistically significant. Patients with KSS exhibited a significant relationship with the absence of BGH, and in patients with MNGIE the presence of SCA was a significant brain MRI finding. The other brain MRI findings, such as SSCA, CbA, and HPSCWM, were not significantly related to any MC subgroup. In agreement with our results, Valanne et al¹⁸ reported that brain MRI may be helpful in the diagnosis of classic MC, although their MRI findings were not specific.

In 6 (75%) of 8 cases, Wray et al⁹ found brain MRI abnormalities in patients with MC who had neurological symptoms, whereas patients with no such symptoms had either cortical atrophy or no findings on brain MRI. Sciacco et al¹⁰ confirmed that patients with full-blown neurological symptoms had various brain MRI abnormalities. According to Kapeller et al,¹¹ the progression of neurological symptoms was associated with the spread or increased extension of these abnormalities. The most common MRI finding reported in KSS is supratentorial and infratentorial atrophy, in agreement with the results of the present study.²⁴

Brainstem MRI abnormalities were identified by several authors in a few cases.^{25 - 26} Kapeller et al¹¹ reported abnormalities in glossopharyngeal nuclei in a patient with dysphagia, and Chu et al²⁵ reported brainstem hyperintensity in two patients. On the other hand, CbA was frequently identified in patients with KSS.²⁵ These abnormalities were not found in our patients, probably because they are uncommon abnormalities. However, this disparity might be due to ethnic or geographic variations.²⁷

Our study had 3 methodological limitations. First, our population was small because the diseases studied are relatively infrequent. Second, our brain MRI data displayed great variability, probably because of the long evolution of the disease and the presence of clinical neurological symptoms in all our patients. Third, our study did not have control cases. Recent publications show that diffusion-weighted MRI and magnetic resonance spectroscopy can help in the diagnosis of MC.^{11 - 20} Thus, Oppenheim et al²⁸ reported a case of MELAS that exhibited multiple hyperintense lesions in FLAIR sequences, with a normal to slightly increased apparent diffusion coefficient. While strokelike episodes showed both hyperintensity on T2-weighted images and an increased apparent diffusion coefficient, acute stroke showed hyperintensity on T2-weighted images and a significant reduction in apparent diffusion coefficient.²⁹ A study should be carried out using apparent diffusion coefficient sequences as well as magnetic resonance spectroscopy to confirm their usefulness before their widespread application is recommended.

In the present study we found that the presence of WSWH and SCA on brain MRI may help to establish the diagnosis of MC. Kearns-Sayre syndrome was correlated significantly with the absence of BGH, and MNGIE was correlated significantly with the presence of SCA. Brain MRI has an important part to play in the workup of MC by confirming or strongly suggesting the diagnosis and by possibly identifying a subgroup of MC.

Correspondence: Héctor Manuel Barragán-Campos, MD, MSc, Service de Neuroradiologie du Professeur Jacques Chiras, Groupe Hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l’hôpital, 75651 Paris, CEDEX 13, France (hector.barragan@psl.ap-hop-paris.fr).

Accepted for Publication: October 8, 2004.

Author Contributions:Study concept and design: Barragán-Campos, Barrera-Ramírez, Argote-Greene, Sánchez-Guerrero, Estañol, and Chiras. Acquisition of data: Barragán-Campos, Vallée, Lô, Barrera-Ramírez, and Guillevin. Analysis and interpretation of data: Barragán-Campos and Sánchez-Guerrero. Drafting of the manuscript: Lô, Barrera-Ramírez, Argote-Greene, and Guillevin. Critical revision of the manuscript for important intellectual content: Barragán-Campos, Vallée, Sánchez-Guerrero, Estañol, and Chiras. Statistical analysis: Barragán-Campos, Vallée. Administrative, technical, and material support: Barragán-Campos, Lô, Barrera-Ramírez, Argote-Greene, Sánchez-Guerrero, and Estañol. Study supervision: Sánchez-Guerrero, Estañol, Guillevin, and Chiras.

Funding/Support: This study was supported by grants from the Secretaría de Salud and from the Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico City, Mexico. Dr Barragán-Campos was awarded a scholarship by CONACYT to study for a master’s degree in medical sciences at the Universidad Nacional Autónoma de México, Mexico City, from March 2000 through February 2002. Dr Sánchez-Guerrero received a research grant from CONACYT.

Acknowledgment: We are grateful to María del Carmén Ávila-Casado, MD, PhD, Department of Pathology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico, who performed all the biopsies for this study; to Arturo Orea, MD, Department of Cardiology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, who was in charge of evaluating the electrocardiograms; and to Miriam Vázquez-Acevedo, QFB, and Diego González-Halpen, PhD, Institute of Cellular Physiology, Universidad Nacional Autónoma de México, Mexico City, for their invaluable help in the mitochondrial DNA analysis.