MELAS

MELAS is a mitochondrial disorder characterized by myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. ^[1] Muscle biopsy typically reveals ragged-red fibers or abnormal mitochondria. This syndrome is associated with a mitochondrial tRNA mutation at base pair 3243 in approximately 80% of cases and a mutation at base pair 3271 in approximately 10% of cases. ^[2] In most cases, the stroke-like episodes occur before age forty. The etiology of the stroke-like episodes is unclear, although both impaired oxidative metabolism and ischemia may play a role. ^[3-5] We report detailed neuroimaging studies, including MRI, xenon (Xe)/CT, and MR spectroscopy, along with neuropathologic findings in a MELAS patient who suffered her first stroke-like episode at age forty-four.

Case report.

The patient had her first neurologic symptoms at 27 years of age when she experienced gradual onset of weakness in the upper and lower extremities. Her neurologic examination revealed moderate proximal muscle weakness consistent with a myopathy, and laboratory evaluation revealed a lactic acidosis with venous values ranging from 30 to 100 mmol/l (normal, 0.7 to 2.1). Her strength returned to near-normal levels over the next 12 months.

At age 42, bilateral sensorineural hearing loss was noted. At age 44, she was admitted to the Stanford Stroke Service because of headache, nausea, vomiting, and visual disturbance. Her neurologic examination was significant for severe cognitive deficits: she exhibited both alexia without agraphia and dysnomia, was disoriented to place and year, and was unable to perform simple calculations. She also had a dense left homonymous hemianopia. Motor examination revealed 4/5 strength in the biceps and triceps bilaterally, 4+/5 iliopsoas strength bilaterally, and 4+/5 strength in the anterior tibialis bilaterally. A brain MRI demonstrated abnormal T₂-weighted signal in the right posterior temporal and occipital lobes (Figure 1) that did not conform to a vascular territory. A four-vessel cerebral angiogram was normal. An EEG revealed bilateral slowing, although it was somewhat worse in the right hemisphere.

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Figure 1. T₂-weighted images from an MR examination obtained during the patient's first hospitalization. Two axial slices show signal hyperintensity in the posterior aspect of the right temporal lobe and the right occipital lobes. The hyperintensity is confined to the cortical regions.

During this hospitalization, lactic acid values ranged from 6.8 to 11.0 mmol/L. Pyruvate was 0.130 mmol/L. A muscle biopsy revealed ragged-red fibers. The abnormal fibers stained positively for succinic acid dehydrogenase, cytochrome C oxidase (COX), and adenylate deaminase. These fibers also showed a granular staining pattern with NADH, and Oil Red O staining revealed increased lipid content. Electron microscopy confirmed the presence of large, subsarcolemmal aggregates of abnormal mitochondria that were significantly enlarged and abnormally shaped. Crystalline inclusions were present within the mitochondrial matrix, and several of the mitochondria contained abnormal cristae in a whorled pattern. Although these findings are characteristic of mitochondrial myopathies in general, the findings of COX-positive ragged-red fibers is characteristic of MELAS. DNA analysis of muscle was positive for the tRNA^Leu (UUR) mutation (A[arrow right]G) at base pair 3243 (S. DiMauro unpublished data). A Xe/CT of the head performed 4 days after the MRI showed decreased cerebrovascular reserve in the frontal and occipital lobes following acetazolamide challenge (Figure 2). Cortical cerebral blood flow (CBF) values were obtained using contiguous 2-cm regions of interest. CBF was 90.3 ml/min/100 g in the left frontal lobe at baseline and decreased to 36.3 ml/min/100 g after acetazolamide challenge. CBF in the right frontal watershed territory was 48.4 ml/min/100 g at baseline and 34.4 ml/min/100 g after acetazolamide challenge. CBF in the occipital lobes was 62.6 ml/min/100 g (right) and 85.6 ml/min/100 g (left) at baseline; after acetazolamide challenge, flows were 35.1 ml/min/100 g (right) and 49.7 ml/min/100 g (left).

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Figure 2. Axial cerebral blood flow maps from xenon/CT. These maps are from the same anatomic levels. Flows are color-coded, with high flows shown in red and low flows in blue. Panel A represents the baseline xenon/CT examination and panel B represents the cerebral blood flow map obtained after acetazolamide challenge test. Following acetazolamide challenge test, there is a decrease in the cortical cerebral blood flow in the occipital lobes (right > left) and a decrease in the cerebral blood flow in the frontal lobes bilaterally. These changes are consistent with a lack of cerebrovascular reserve in these regions.

By hospital discharge, the patient's homonymous hemianopia had resolved, but she had only mild improvement in cognitive function. Two weeks later the patient was readmitted to Stanford with left arm weakness and suicidal ideations. During this admission she developed simple partial seizures involving the left upper extremity. A repeat brain MRI showed that the regions of abnormal signal seen 3 weeks previously had resolved, but there were new regions of abnormal T₂-weighted signal in the right parietal and anterior temporal lobes (Figure 3). She was started on coenzyme Q 60 mg/d, vitamin K₃ 50 mg/d, thiamine 200 mg/d, and vitamin B₆ 100 mg/d and was transferred to the psychiatric service because of paranoid delusions and severe anxiety. A follow-up examination 4 months later revealed improved language function, but she continued to have marked difficulty performing simple calculations and following complex commands. The extreme paranoia and delusions had resolved.

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Figure 3. T₂-weighted axial images from an MR examination obtained during the patient's second hospitalization (21 days after the first examination). Two axial slices shown are at the same anatomic levels as those in Figure 1. The hyperintensity previously seen in the posterior temporal lobe and occipital lobes has resolved, but new areas of hyperintensity can be noted in the anterior portion of the temporal and parietal lobes.

Approximately 1 year from onset of the stroke-like episodes, a repeat brain MRI revealed selective enlargement of the occipital and temporal horns of the right lateral ventricle and mild sulcal widening in the regions of the temporal and occipital lobes compatible with mild atrophy. MR spectroscopic measurements of cerebral lactate were performed using the techniques described by Adalsteinsson et al. ^[6] These studies revealed increased lactate in both occipital lobes (right > left) and temporal lobes. There was no decrease in N-acetylaspartate or increase in lipids (Figure 4). Clinically, during this period the patient was experiencing an increase in focal seizure activity. The areas of increased brain lactate did not correspond to the focality of her seizures.

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Figure 4. MR spectroscopic imaging results (water, N-acetyl aspartate [NAA], lipid, and lactate images) from two axial brain slices. The spectroscopic images were collected with the following sequences: TR = 2 sec; TE = 136 msec; TI = 170 msec; 3.4-cc voxels; acquisition time = 17 minutes. The 16 x 16 images have been interpolated to 256 x 256 and overlayed with an edge-detected version of the water image to provide an anatomic reference. Elevated lactate is visible in the occipital, parietal, and frontal regions.

The patient died at age 45 at home after experiencing an increase in seizure activity that day. The cause of death was unclear. Only brain was obtained for pathologic examination.

Her medical history was significant for Wolff-Parkinson-White syndrome, functional bowel syndrome, and hypercholesterolemia.

The patient's maternal family history was significant for a similar clinical syndrome in several individuals. The patient's mother had a history of bilateral hearing loss and a left-hemisphere "stroke" in her forties. She also developed generalized tonic-clonic seizures at age 51 and had severe psychiatric problems and was admitted to a chronic care psychiatric hospital. She died at age 53 of an acute bowel obstruction.

The patient's maternal grandmother died at age sixty four. She had suffered a stroke and was known to exhibit bizarre behavior. A maternal great aunt died at age 45; she had experienced episodes of unconsciousness and psychotic behavior. She also had diabetes. Another maternal aunt suffered from severe depression, and her daughter experienced psychiatric problems and died at an early age.

Discussion.

The pathophysiologic mechanisms that mediate the stroke-like episodes in MELAS are not well understood, but there are several hypotheses, including energy failure secondary to impaired oxidative metabolism and brain ischemia related to vascular abnormalities. Lactic acidemia in MELAS results from impaired oxidative metabolism secondary to defects in the electron transport chain. Cerebral angiography performed in these patients has either been normal or shown focal areas of capillary blush or early venous filling. ^[1,3] The few autopsies that analyzed cerebral vessels in MELAS patients have noted an increased number of mitochondria within smooth muscle cells of pial arterioles and small arteries. ^[7,8] Ohama et al ^[7] postulated that there was an impairment in autoregulation in these patients secondary to a mitochondrial angiopathy. Kishi et al ^[3] reported hypertrophy of endothelial cells and increased mitochondria in the subendothelial space and narrowing of capillary lumens.

There are only a few reports of CBF in MELAS patients. In two cases, sup 123 I-SPECT revealed areas of both increased and decreased tracer accumulation; the investigators attributed these differences to metabolic changes. ^[9] Only one previously reported case has been evaluated with the Xe/CT technique. ^[10] This patient, studied 3 hours after the development of a right homonymous hemianopia, showed increased regional CBF in the region that corresponded to the occipital lobe lucency on CT; the investigators attributed this finding to vasodilation secondary to metabolic acidosis. ^[10] Gropen et al ^[11] used¹³³ Xe to evaluate CBF in a patient with MELAS and lesions in the parietal, temporal, and occipital lobes 15 days, 26 days, 4 months, and 8 months after the event. They found hyperemia in both the infarcted and the noninfarcted areas as late as 8 months after the event. Testing vasomotor response with inhalation of 4% CO₂, they found an abnormal response after CO₂ inhalation 26 days after the event in the infarcted region but a normal response on follow-up examinations. ^[11]

The Xe/CT study in our patient revealed decreased vascular reserve in the right occipital lobe coinciding with the hyperintensity visualized on MRI. There were also areas of decreased flow in the left frontal and occipital lobes that did not have corresponding hyperintensity on the T₂-weighted MRI. The left-hemisphere abnormalities may explain the patient's significant language difficulties. These findings differ from those of the studies described above ^[10,11] in that we did not find hyperemia in regions corresponding to the abnormal MRI signal, although some areas did reveal high normal or hyperemic flows. This could relate to the timing of the study in relation to the other reported cases and suggests that the abnormal areas in our patient were either ischemic or metabolically inactive. The blood flow changes after acetazolamide challenge may have been secondary to impaired autoregulation or to metabolic changes secondary to impaired oxidative metabolism.

Prior MR spectroscopy findings in MELAS cases involved a small number of patients. ^[12,13] These reports document areas of increased lactate accumulation coinciding with abnormal T₂-weighted MRI hyperintensities during an acute exacerbation of neurologic symptoms. Barkovich et al ^[12] reported one patient with lactate elevation in a brain region that was unremarkable on T₁- and T₂-weighted MRI.

The most common histopathologic features seen in the brain in MELAS include multifocal necrosis, mineral deposits, neuronal degeneration, and spongy degeneration. ^[14] The topographic distribution of the necrotic foci in this patient is typical of that of many other MELAS cases, with the most affected areas being the crests of the cerebral gyri. The proportion of mutant mitochondrial tRNA in neurons has not corresponded to focal brain pathology. ^[15] Increased numbers of structurally abnormal mitochondria may be present in the endothelial and smooth muscle cells of blood vessels. These changes are most commonly seen in the walls of pial arteries and small intraparenchymal arteries. ^[4] Large numbers of abnormal mitochondria may also be present in choroid plexus epithelial cells. ^[16]

In summary, our patient had MRI findings typical of those described in other MELAS patients, including T₂ hyperintensities in the temporal/parietal and occipital lobes, primarily involving cortex, with resolution of the abnormalities and atrophy. ^[12,17-19] The CBF study revealed areas of decreased cerebrovascular reserve in areas coinciding with MRI lesions as well as in areas with normal MRI signal. The MR spectroscopic studies revealed increased lactate in the occipital lobes 1 year after the stroke-like episode. The finding of abnormal mitochondria in the endothelial cells and smooth muscle cells of blood vessels may explain the mechanism of the stroke-like episodes in MELAS. Our hypothesis is that the impaired metabolic activity of the endothelial cells and smooth muscle cells of the blood vessels impairs autoregulatory mechanisms as previously suggested by Ohama et al. ^[7] Acutely, this may result in the edema that is visualized as the increased T₂-weighted signal on MRIs that may resolve without residual infarction. Over time, the inability to respond to metabolic demands in the affected areas secondary to impaired autoregulation may result in ischemic injury, with resultant cortical loss and the subsequent atrophy visualized with CT and MRI.