Abstract
Article abstract The authors performed a serial study of a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome (MELAS) who presented with diffusion-weighted MRI (DWI). DWI demonstrated a higher apparent diffusion coefficient in the lesion than in the control region during the acute stage of stroke. Vasogenic edema is present in stroke-like episodes in MELAS.
The pathogenic mechanism for the stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is unclear. Electron and light microscopic examinations of brain autopsy tissue from a MELAS patient revealed “mitochondrial angiopathy” characterized by increased numbers of enlarged mitochondria in the endothelial cells of intracerebral small vessels.1 From a pathologic study of brain autopsy tissue of a MELAS patient, it has been shown that most stroke regions extend over vascular territories.2 Cerebral angiography failed to demonstrate any embolic or stenotic lesion,3 suggesting that the underlying pathogenic mechanism for the stroke-like episodes is different than ischemic infarction. MR diffusion-weighted imaging (DWI) can detect proton mobility in brain tissue and can discriminate between vasogenic edema and cytotoxic edema in the stroke region of acute ischemic infarction.4 We performed serial DWI in the stroke region of a patient with MELAS.
Case report.
A 10-year-old boy with a history of recurrent strokes, migraine headaches, vomiting, and visual disturbance since 9 years of age was admitted to Fukui Pref. Saiseikai Hospital in September 1998. After leukocyte DNA examination revealed an A-to-G transition mutation at the nucleotide position 3243 in the tRNALeu(UUR) gene of mitochondrial DNA, he was diagnosed with MELAS. After IV administration of dexamethasone (12 mg/day), migraine headache and visual disturbance markedly improved. Between strokes, he presented with mild myoclonic jerks affecting the arms and legs and mild truncal ataxia.
In December 1998, at 10 years of age, he was admitted to Fukui Medical University Hospital for a follow-up examination. The light microscopic study of the skeletal muscle biopsy specimen revealed ragged-red fibers and strongly SDH-stained vessels, both of which were compatible with the pathologic findings in MELAS. We performed a MRI study including DWI. In January 1999, 5 days after discharge from the hospital, he experienced a migraine headache with scintillating scotoma in the left visual field again and was immediately readmitted to the hospital (day 1). Neurologic examination showed mild truncal ataxia, left homonymous hemianopsia, and myoclonic jerks affecting the arms and legs. Brain MRI (T2-weighted image [T2WI]) showed a recently formed focal high-intensity signal in the right occipital lobe (figure 1B). An electroencephalogram showed slow background activity mixed with high-amplitude and slow-wave bursts. The total protein in cerebrospinal fluid was normal without pleocytosis. Lactate in cerebrospinal fluid was markedly increased (41.4 mg/dL; normal control, 9 to 25 mg/dL). He had been treated with IM administration of dexamethasone (4 mg/day) for a week, and migraine and hemianopsia markedly improved. Two days after the administration of dexamethasone had ceased (day 8), he experienced a mild headache and scotoma on day 9 and began taking medication again on day 10. His symptoms disappeared in a few days.
Figure 1. The T2-weighted image (A–C) and apparent diffusion coefficient (ADC) maps (D–F) of the stroke region at several time points in a MELAS patient. (A and D) The period in which the patient had no stroke (day 0). (B and E) Two days after the stroke onset. (C and F) Twenty-four days after the stroke onset in which his visual disturbance disappeared. Arrows indicate the stroke region. Notice that the intensity of ADC in the stroke region is increased in the acute stage of stroke.
MRI studies.
Brain MRI was performed on hospital days 3, 10, 17, and 25. Brain MRI also was performed 14 days before the stroke onset (day 0). The patient was examined with a GE Signa 1.5-T MR unit by standard spin-echo (SE) sequences for T1-weighted images, fast SE sequences for T2-WI, fast fluid-attenuated inversion-recovery (FLAIR) images, and diffusion-weighted SE images. MR angiography of the circle of Willis and its major branches also was performed. Diffusion imaging was performed using a multislice, single-shot, SE planar sequence. The imaging measurements were TE = 3200 milliseconds, matrix size 250 × 256, fields of view 220 mm, with a 5-mm slice thickness. Diffusion gradients were applied in each of the x, y, and z directions with four b values ranging between 0 and 1000 seconds/minute2. Maps of apparent diffusion coefficient (ADC) were created by signals obtained from images with four b values according to the method previously described.4 Average ADC (ADCav) was calculated as ADCav = 1/3(ADCx + ADCy + ADCz). To quantitate changes in ADCav independent of tissue and gradient orientations, relative ADCav (ipsilateral/contralateral of ADCav) was calculated according to the method previously described.5
MRI findings and ADC maps.
Two days after the onset of the stroke, MRI showed a focus with increased T2 signal in the right occipital lobe (see figure 1B) compared with the signal in the same region in the period without stroke (day 0) (figure 1A). On day 25 (figure 1C), his visual disturbance disappeared. MR angiography of brain vessels on day 3 demonstrated no significant stenosis or spasms in the circle of Willis or its major branches. ADC maps showed increased intensities of ADC in the stroke region on day 3 (figure 1E) compared with those on days 0 (figure 1D) and 25 (figure 1F). As shown in figure 2, the ADCav ratio of the stroke region relative to the contralateral control side (rADC) reached a peak (1.52) on day 3 and gradually decreased on days 10 (1.32) and 17 (1.25); then, on day 25, it reached the level (1.02) equal to before the onset of the stroke (1.08). The level of lactate remained high (34.5 mg/dL) even after the abnormal signals on T2WI and DWI had disappeared.
Figure 2. Plot of the time course of the relative apparent diffusion coefficient (rADC). Notice that the rADC increased 2 days after the stroke onset and decreased gradually for 24 days after onset.
Discussion.
Conventional MRI techniques, such as T2WI or FLAIR, cannot distinguish cytotoxic edema from vasogenic edema in the stroke region. DWI, a recent advance in the MRI technique, can detect proton mobility in brain tissue and determine whether the edema during the acute stage of an ischemic infarction is vasogenic or cytotoxic in origin.4 In general, in acute ischemic infarctions, intracellular diffusion of protons is restricted or reduced, corresponding to low signals on ADC maps.4 We applied this MRI technique in a MELAS patient to investigate whether vasogenic or cytotoxic edema is involved during the acute stage of stroke-like episodes. In this MELAS patient, the ADC maps and rADC ratios of the stroke region, compared with the control side, demonstrated a higher proton mobility, which corresponded to the high signals on ADC maps (see figures 1E and 2⇑). This is contrary to the time course of rADC in acute ischemic infarction. Schlaug et al. demonstrated that a significant reduction of rADC lasts for at least 4 days from stroke onset, and an increasing trend from reduction through pseudonormalization to elevation of rADC occurred on day 7.4 From the duration of rADC in our MELAS patient, high mobility of protons in the stroke region strongly suggests that vasogenic, as opposed to cytotoxic, edema is a predominant feature in the stroke region.
Such a vasogenic edema has been described in “reversible posterior leukoencephalopathy,” which was seen in patients with hypertensive encephalopathy or eclampsia, and vasogenic edema was detected by DWI.6,7 Enhanced lesions have been reported in the stroke regions in MELAS on brain MRI or CT, and a breakdown of the blood–brain barrier has been speculated.8 The high mobility of protons in the stroke region that was detected by DWI in this case strongly supports the idea that there is increased permeability in the blood–brain barrier, presumably based on mitochondrial respiratory failure in the cerebral artery endothelium.
- Received May 10, 1999.
- Accepted August 10, 1999.
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