Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease

Abstract

Purpose and background: Mitochondrial diseases are a group of inherited disorders caused by a derangement of mitochondrial respiration. The clinical manifestations are heterogeneous, and the diagnosis is often based on information acquired from multiple levels of inquiry. MR spectroscopy has previously been shown to help detect an abnormal accumulation of lactate in brain parenchyma and CSF in association with mitochondrial disorders, but the frequency of detection is largely unknown. We sought to examine the frequency of detectable elevations of CNS lactate by proton MR spectroscopy in a population of children and young adults with suspected mitochondrial disease.

Methods: MR spectroscopy data evaluated for the presence or absence of abnormal brain or CSF lactate were compared with other clinical indicators of mitochondrial dysfunction for 29 patients with suspected mitochondrial disease during the years 1990 to 2000. Based on an independent review of the final diagnoses, the patients were divided into groups based on the probability of mitochondrial disorder.

Results: A total of 32 scans from 29 patients were reviewed. Of eight patients thought to have a definitive mitochondrial disorder on the basis of genetic, biochemical, or pathologic features, five were found to have abnormal brain or CSF lactate levels revealed by MR spectroscopy (for one patient in whom two images were acquired, one was negative and the other positive). Among the studies conducted using a multisection spectroscopic imaging technique, five of six showed elevated lactate in the brain parenchyma, six of six showed elevated lactate in the CSF, and five of six showed elevated lactate in both brain and CSF. Of 16 patients who were highly suspected of having mitochondrial disorders on the basis of clinical grounds alone but who were lacking genetic, biochemical, or pathologic confirmation, four had abnormal lactate levels shown by MR spectroscopy. Mitochondrial disorder was excluded for five patients, none of whom had CNS lactate shown by MR spectroscopy.

Conclusion: Detection of CNS lactate by MR spectroscopy is useful in the diagnosis of mitochondrial disease. In our series of patients with confirmed mitochondrial disease, a high level of lactate shown by MR spectroscopy correlated well with other markers of mitochondrial disease. As with all other means used to diagnose mitochondrial disorders, MR spectroscopy does not depict elevated lactate in all cases. Abnormal CNS concentrations of lactate may be undetected by MR spectroscopy because of differences in the type of mitochondrial disorder, timing, severity, or location of the affected tissues and the site of interrogation.

Fig 1.

Images from the case of a 31-year-old man with MELAS syndrome, which was documented by a point mutation in the mitochondrial tRNA (Leu). T2-weighted MR image (T2 MRI) (2600/80/1) shows a large focal hyperintensity in the left parietal region, predominantly affecting the gray matter. This area corresponds to elevated choline (Cho), decreased N-acetylaspartate (NAA), and markedly elevated lactate (Lac) on the multisection spectroscopic imaging metabolic maps. In addition, multisection spectroscopic images show globally elevated lactate, which is greatest in the left parietal strokelike lesion, next highest in the remaining gray matter (G.M.) and CSF, and lowest in the white matter. R., right; L., left.

Fig 2.

Images from the case of a 3-year-old male patient with MELAS-MERRF overlapping syndrome, which was documented by a point mutation. Initial multisection spectroscopic images show no definitive lactate signal intensity. Voxels placed in the right corona radiata (area 1), CSF (area 2), and periventricular white matter (areas 3 and 4) show no clear evidence of lactate doublet. Lipid contamination (*) in this region (1.1–1.4 ppm) may, however, obscure a small lactate peak. R., right; L., left; Cho, choline; Cr, creatine; NAA, N-acetylaspartate; W.M., white matter; T1 MRI, T1-weighted MR image; Lac, lactate.

Fig 3.

Images from the same case of MELAS-MERRF overlapping syndrome shown Figure 2, obtained 1 year later during a subsequent study. MR spectroscopic images show a lactate doublet in the CSF (lateral ventricles, areas 2 and 3) and periventricular white matter (areas 5 and 6), bilaterally. R., right; L., left; Cho, choline; Cr, creatine; NAA, N-acetylaspartate; W.M., white matter; T1 MRI, T1-weighted MR image; Lac, lactate.

Fig 4.

Images from the case of an 8-year-old female patient with complex I mitochondrial disease, which was diagnosed when the patient was older than 3 years. MR image shows extensive T1-hypointense and T2-hyperintense signal abnormalities in the periventricular regions, particularly in the frontal white matter, in addition to T2 hyperintensity involving the genu of the corpus callosum. MR spectroscopic images show a large lactate peak in the CSF (left lateral ventricle, area 2). A small lactate peak may occur in the frontal white matter lesion (area 1), although spectra are also partially contaminated by lipids (*).W. M., white matter; Lac, lactate; Cho, choline; Cr, creatine; NAA, N-acetylaspartate; G. M., gray matter; T1 MRI, T1-weighted MR image; FLAIR, fluid-attenuated inversion recovery.