24.1 Clinical Features and Laboratory Investigations
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes constitute the MELAS acronym. The disease shows maternal inheritance with considerable intrafamilial variation in expression of the disease. The age at onset varies between 3 months and 40 years, but in most cases first signs and symptoms occur before adulthood. Early development is normal in the majority of patients. The first manifestations of disease usually belong to the group of general features of encephalomyopathies. Growth disturbance and epileptic seizures are the most frequent first symptoms. The disease is progressive with increasing symptomatology. Learning disabilities, cognitive regression, exercise intolerance, and limb weakness are frequent manifestations of the disease. The myopathic features are rarely very prominent in MELAS. Stroke-like episodes are rarely early signs of the disease but have occurred before the age of 40 years in almost all patients. The stroke-like events give rise to both reversible and permanent neurological deficits. Hemiparesis and hemianopia or cortical blindness are seen most frequently. Seizures are common during the strokes. Episodic migrainous headaches with nausea and vomiting are common and often precede the stroke-like episodes. In some patients focal seizures progress to epilepsia partialis continua. All patients eventually develop cognitive impairment. In those with early-onset neurological impairment, development is generally delayed from early on in life, whereas in patients with later-onset impairment, the rapidity of disease progression and the number of cerebral infarcts have a direct impact on the presence and severity of cognitive impairment. Sensorineural hearing loss is frequent. Delayed puberty, infertility, and hypothalamic hypogonadism may be present. Diabetes mellitus, growth hormone deficiency, hypothyroidism, hypoparathyroidism, and hyperaldosteronism may occur. Less frequent findings, noted in less than half of the patients, include myoclonus, cerebellar ataxia, episodic coma, peripheral neuropathy, pigmentary retinopathy, oph-thalmoplegia, ptosis, optic atrophy, hypertrophic cardiomyopathy, electrocardiographic evidence of pre-excitation, cardiac conduction block, and nephropathy. In relatives of typical MELAS patients a "partial" syndrome may be seen instead of the full blown MELAS picture. Short stature, sensorineural hearing loss, mild myopathy, cardiomyopathy, diabetes mellitus, and seizures without stroke or learning problems may be the only clinical manifestation of disease.
Some MELAS patients have manifestations which are typical of other mitochondrial syndromes. Patients with MELAS-MERFF overlap have myoclonic epilepsy and the associated EEG features in combination with clinical symptoms seen in MELAS, including stroke-like episodes. LHON-MELAS overlap leads to features typical of Leber hereditary optic neuropathy and stroke-like episodes.
On laboratory examination, most patients have lactic acidosis, although in some resting serum lactate is normal. CSF lactate is often also elevated. CSF protein is often found to be elevated. EMG may show a myopathic pattern. There may be neurophysiological evidence of a mixed axonal and demyelinating sen-sorimotor neuropathy. Some patients have ECG abnormalities with evidence of cardiomyopathy, Wolff-Parkinson-White abnormality, or conduction block. In most patients ragged red fibers are found on muscle biopsy.
Antenatal diagnosis is very difficult in defects of mitochondrial DNA. Because of heteroplasmy, a chorionic villus sample may not be representative of the level of mutant mitochondrial DNA in the embryo and it is therefore difficult to predict the future phe-notype.
On light microscopic examination of muscle biopsies, application of the modified Gomori trichrome stain often reveals the presence of ragged red fibers. With this stain the abnormal fibers demonstrate a mottled and irregular appearance with red-staining peripheral and intermyofibrillar zones. Histochemistry for oxidative enzymes, such as NADH dehydrogenase, succinate dehydrogenase, and cytochrome c oxidase, may yield abnormal staining patterns. On electron microscopy, the ragged red fibers display large aggregates of mitochondria, generally under the sarcolem-ma, but also between myofibrils. The mitochondria are frequently abnormal in size and structure. The mitochondrial cristae are often increased in number and irregularly oriented. The mitochondria may con tain different abnormal inclusions such as crystalline or paracrystalline structures or globular bodies.
Postmortem examination of the brain of deceased MELAS patients often reveals atrophy on external examination. The cerebellum, too, may have an atrophic aspect. Major blood vessels are normal. Microscopic examination reveals areas of extensive cortical laminar necrosis, usually in the occipital and posterior temporal areas. The cortical lesions usually have an asymmetrical distribution and are not related to vascular supply areas. The three deepest cortical layers are affected most severely. The gyral crests and sulcal depths are equally affected. The severity of the cortical damage varies from fractional neuronal loss to microcystic destruction. Gliosis is present. The cortical damage may have a spongiform aspect. In the area of cortical damage, there is a proliferation of capillaries. The lesions vary in age, the patient often having lesions of different ages. The adjacent subcortical white matter is involved with loss of myelin and presence of fibrous gliosis. The white matter damage may be spongiform. The periventricular white matter is usually not involved. However, diffuse white matter gliosis and atrophy may also be found. Calcium deposits are frequently present in the globus pallidus, less frequently in the caudate nucleus, lateral thalamus, dentate nucleus,subthalamic nucleus,substantia nigra, and red nucleus. The calcium granules are mostly deposited in and around capillary and small arterial walls. Otherwise the basal nuclei are intact and no neuronal loss is seen. Within the cerebellum pathological changes consist of some variable loss of Purkinje cells and granule cells. The dendrites of Purkinje cells may show remarkable segmented swelling, which is called cactus. On electron microscopy, accumulation of mitochondria, neurofilaments, and membrane complex is seen in the region of cactus formation. Brain stem and spinal cord may also contain spongiform lesions. Electron microscopy reveals abnormal accumulation of mitochondria in endothelial and smooth muscle cells of small arteries. The major cerebral arteries are normal.
Two heteroplasmic point mutations have been discovered in most cases of MELAS. In 80 % of the patients a mutation is present in nucleotide 3243 of mitochondrial DNA, which affects a nucleotide position in the dihydrouridine loop of the tRNA specific to leucine (UUR codon) (tRNAleu(UUR)). In addition, 7.5% of the patients have another mutation in the same tRNAleu(UUR) gene at nucleotide 3271. The remainder of MELAS patients have other point mutations in the mitochondrial DNA; few have a deletion within the mitochondrial DNA. The 3243 mutation has also been found in patients with chronic progressive external ophthalmoplegia and other neurological complaints, but without stroke-like episodes.
In MELAS, an isolated defect of complex I or combined defects in complexes I, III, and IV are found in muscle mitochondria. The presence of a mutant tRNA disturbs the mitochondrial gene translation machinery and leads to a decrease in all mitochondrially encoded proteins. The mechanism by which the tRNAleu(UUR) gene mutation interferes with protein synthesis remains unclear, but defects in tRNAleu(UUR) function, rRNA to mRNA ratio, impaired incorporation of leucine into mitochondrial translation products, and defects in rRNA processing are viable alternatives.
Among MELAS patients and their maternal relatives there is a clear relationship between percentage of mutant mitochondrial DNA and severity of disease. This is clearer for the level of mutant mitochondrial DNA in muscle than for that in blood. Asymptomatic relatives have the lowest percentage, oligo-symptomatic relatives an intermediate percentage, and MELAS patients the highest. Among patients it has been found that the higher the percentage of mutant DNA is, the earlier the symptoms of stroke-like attacks appear.
The cause of the large cerebral lesions is a matter of debate. One hypothesis is that the relationship between mitochondrial dysfunction and cerebral pathology is explained by a mitochondrial vasculopa-thy of small arteries, observed in the "infarcted" areas. There is a marked increase in number of mitochondria in endothelial cells, smooth muscle cells, and pericytes of arterioles. The mitochondria are abnormal and enlarged. These vascular abnormalities may result in decreased blood supply. However, in SPECT and PET scan studies, evidence of patency of blood vessels is found in the acute stage of the infarct with the presence of a well-preserved blood flow. SPECT studies have repeatedly shown focal hyperper-fusion before and during the stroke in MELAS and focal hypoperfusion in the chronic, atrophic stage. Hence, it is more probable that the metabolic demands exceed the potential of energy provision by the disturbed oxidative phosphorylation, leading to cell damage and edema.
Various therapeutic strategies have been used in MELAS. In particular, administration of cofactors is often employed in an attempt to ameliorate the course of disease. Riboflavin is a precursor of both flavin monophosphate and flavin adenine dinucleotide (FAD), which are part of NADH-coenzyme Q reductase (complex I) and of complex II. Nicotinamide is a precursor of NAD. Coenzyme Q10 is given to substitute and supplement for endogenous coenzyme Q. Idebenone, a quinone compound similar to coenzyme Q10, has the theoretical advantage of crossing the blood-brain barrier. Vitamin C and vitamin K3 (menadione) are given to bridge a defect in the electron transport chain, as they accept and transport electrons. These drugs are given alone or in varying combinations. In patients with MELAS variable improvement has been reported, ranging from none to remarkable, but evidence for a consistent beneficial effect is lacking. Dichloroacetate inhibits the pyruvate dehydrogenase specific kinase, thereby activating the pyruvate dehydrogenase complex and reducing lactate levels. Oral creatine supplementation has been reported to lead to clinical improvement in incidental patients. Intravenous administration of L-arginine during acute stroke has also been reported to lead to improvement.
Symptomatic treatment of the neurological handicap, epilepsy, and endocrine dysfunction is important.
In MELAS CT often shows the presence of calcium deposits in the globus pallidus and caudate nucleus (Fig. 24.1). Sometimes the calcium deposits are more extensive and also affect the putamen and thalamus. During the acute phase of stroke-like episodes, one or more large hypodense areas are seen. The areas are swollen. They have, as a rule,an asymmetric distribution.
In MRI the calcium deposits in the basal nuclei are more difficult to see (Fig. 24.1). MRI shows the precise distribution of the lesions occurring during the stroke-like episodes. From MRI it is clear that the cortex is often more severely involved than the underlying white matter and that the periventricular white matter is most often preserved (Figs. 24.1 and 24.2). It is also the cortex that enhances after contrast injection (Fig. 24.1). The lesions are variable in size,some-times small, often large, sometimes single, often mul-tiple,and usually asymmetrical (Fig. 24.2). The distribution of the lesions does not follow vascular supply or vascular border zones. The occipital and posterior temporal areas are preferentially involved (Figs. 24.1 and 24.2). Other areas that may be involved are the thalamus, basal ganglia, and brain stem. Diffuse cere-bellar involvement has also been described. In the acute stage the lesions are often swollen. The lesions may increase in size over days. In the course of a few weeks, the lesions may either resolve or leave behind an area of atrophy and altered signal intensity, in particular in the cortex (Fig. 24.2). Over the years MRI may show "migrating infarcts" that leave their traces in progressive atrophy with enlargement of the ventricular system and subarachnoid spaces (Fig. 24.2). Cerebellar atrophy may be prominent.
Different MRI techniques can be of advantage in MELAS. Gradient-echo techniques are more sensitive to calcium than other techniques. FLAIR images are superior in showing small cortical lesions (Fig. 24.2). These lesions may arise without associated clinical symptoms of stroke. Diffusion-weighted imaging and mapping ADC values are of particular interest during the acute stages of a stroke-like episode (Figs. 24.3 and 24.4). The results reported so far are conflicting. A study with sequential imaging from day 3 up to day 25 shows that lesions in the acute phase may show normal or elevated ADC values in MELAS (Yoneda et al. 1999). Normal or elevated ADC values have also been reported in several other,less systematic studies. This, of course, is contrary to what is seen in ischemic infarctions. However,we and others (Wang et al. 2003) have found strongly reduced ADC values in acute lesions, suggesting cytotoxic edema. It remains unclear why ADC values are raised in the acute lesion in some patients with MELAS. It has been suggested that it is because of the presence of vasogenic edema, but this explanation seems too simple. There is evidence for hyperperfusion in acute MELAS lesions. Both this hy-perperfusion with more prominent presence of blood in the voxels and the disruption of the blood-brain barrier may affect the ADC measurements. Perhaps the conflicting findings described are also reflected in the observation that some of the lesions in MELAS disappear after a couple of weeks,whereas others persist or result in focal atrophy. It seems a reasonable assumption that there are differences between subtypes of MELAS lesions,reflected in differences in MR measurements. A more systematic MR approach, follow-up, and analysis could probably better document these differences.
Cerebral angiography, xenon-enhanced computed tomography, and SPECT demonstrate patency of vessels in MELAS and, in fact, vasodilation. The regional cerebral blood flow is increased in the area of an acute lesion (hyperperfusion). This has been documented in SPECT studies with 99mTc-ethyl cysteinate
Fig. 24.1. A 21-year-old female patient with MELAS and the 3243 mitochondrial DNA mutation. Note the calcium deposits in the globus pallidus on CT (second row, /eft).The globus pallidus has a low signal on T2-weighted SE images. There is a large lesion in the left temporo-occipital region, involving the cortex and to a lesser extent the subcortical white matter. A small lesion in the body of the caudate nucleus is seen on the right. After contrast administration (third and fourth row) it is mainly the affected cortex that enhances
Fig. 24.2. A male patient with MELAS and the 3243 mitochondrial DNA mutation underwent MRI at the ages of 9 years (first row), 11 years (second and third rows), 12.5 years (fourth row), and 15.5 years (fifth row). At 9 years, he had seizures and some learning problems, but was otherwise normal. At 11 years, he had seizures and migrainous headaches and was evidently dementing. He had not had any stroke-like episodes. The MRI showed multiple small cortical lesions and generalized cerebral atrophy.The FLAIR images (thirdrow) were much better at showing the cortical lesions.At the age of 12.5 years he had an episode of dysphasia and right-sided hemiplegia and hemi-anopia.The MRI showed a large lesion in the left temporo-oc-cipital region,involving both cortex and white matter. In addi-tion,multiple old,small cortical lesions were seen.At 15.5 years the patient had serious dementia and dysphasia. MRI showed marked generalized cerebral atrophy as well as focal atrophy of the previously infarcted region
Fig. 24.2. A male patient with MELAS and the 3243 mitochondrial DNA mutation underwent MRI at the ages of 9 years (first row), 11 years (second and third rows), 12.5 years (fourth row), and 15.5 years (fifth row). At 9 years, he had seizures and some learning problems, but was otherwise normal. At 11 years, he had seizures and migrainous headaches and was evidently dementing. He had not had any stroke-like episodes. The MRI showed multiple small cortical lesions and generalized cerebral atrophy.The FLAIR images (thirdrow) were much better at showing the cortical lesions.At the age of 12.5 years he had an episode of dysphasia and right-sided hemiplegia and hemi-anopia.The MRI showed a large lesion in the left temporo-oc-cipital region,involving both cortex and white matter. In addi-tion,multiple old,small cortical lesions were seen.At 15.5 years the patient had serious dementia and dysphasia. MRI showed marked generalized cerebral atrophy as well as focal atrophy of the previously infarcted region dimer (ECD) and 99mTc-D,L-hexamethylpropylene-amine oxime (HMPAO). The increased uptake of these substances in the lesion area also suggests a breakdown of the blood-brain barrier. Unfortunately, perfusion studies have not been performed systematically in a large group of MELAS patients, and no reports are available concerning MR perfusion studies of acute lesions. Especially, no data are available linking perfusion studies with ADC maps.
Proton MRS shows low N-acetylaspartate in acute lesions and highly elevated lactate. The decrease in N-acetylaspartate is at least partially reversible, and in the chronic stage lactate is usually normal or only mildly elevated. Elevated lactate may also be seen in areas that are not clearly abnormal on MR images,but the elevation is usually much more striking in acute and subacute lesions.
The obvious task for MR is to help distinguish between ischemic infarctions and the infarct-like lesions in MELAS. In the younger group it may be important to differentiate the infarct-like lesions of MELAS from the ischemic infarctions in the early phases of moyamoya disease. The distribution of lesions in patients with moyamoya syndrome can be the same as in MELAS. The abnormal vessels in moyamoya syndrome, usually already seen on conventional MR images, but more clearly on MR angio-graphy, will suggest the latter diagnosis. MELAS also has to be differentiated from vasculitic disorders presenting with multiple infarctions. In a case of predominantly temporal location of the acute lesion, herpes simplex encephalitis may be suspected. The raised serum lactate suggests mitochondrial dysfunction rather than herpes encephalitis, and the calcium deposits which are often present in the basal ganglia in MELAS patients may also help in differentiation. Other multifocal infectious and inflammatory lesions should be considered as well. Single and multiple large areas of abnormal signal intensity in the cortex and white matter are also seen in urea cycle defects. In MRS, however, findings are very different, with raised lactate in MELAS and raised glutamine in urea cycle defects. Assessment of blood lactate and ammonia levels shows a similar difference.
Fig. 24.3. Conventional and diffusion-weighted MRI of the patient in Fig. 24.2 at the age of 12.5 years.To be more precise, the stroke-like episode started with dysphasia,followed after 6 days by development of right-sided hemiplegia and hemi-anopia.The MRI was obtained 12 days after the onset of the episode. Displayed are T2-weighted SE images (first row), trace diffusion-weighted images with a b value of 1000 (second row), and ADC maps (third row).The T2-weighted images show the
Fig. 24.3. Conventional and diffusion-weighted MRI of the patient in Fig. 24.2 at the age of 12.5 years.To be more precise, the stroke-like episode started with dysphasia,followed after 6 days by development of right-sided hemiplegia and hemi-anopia.The MRI was obtained 12 days after the onset of the episode. Displayed are T2-weighted SE images (first row), trace diffusion-weighted images with a b value of 1000 (second row), and ADC maps (third row).The T2-weighted images show the extent of the lesion.The diffusion-weighted images show high signal in the lesion with an area of lower signal in the occipital white matter.The ADC maps show that the temporal lesion has a high ADC, whereas most of the occipital lesion has a low ADC.The difference in ADC may be related to the different age of the lesions. It could also be that the temporal lesion is more edematous, as suggested by the T2-weighted image
Fig. 24.4. Conventional and diffusion-weighted MRI of a 13-year-old MELAS patient with the 3243 mitochondrial DNA mutation. The MRI was obtained 3 days after the onset of right-sided hemianopia.The FLAIR image (left) shows a large
Fig. 24.4. Conventional and diffusion-weighted MRI of a 13-year-old MELAS patient with the 3243 mitochondrial DNA mutation. The MRI was obtained 3 days after the onset of right-sided hemianopia.The FLAIR image (left) shows a large occipital lesion. On the trace diffusion-weighted image with a b value of 1000 (middle) the lesion has a high signal, whereas the lesion has a low signal on the ADC map (right).The measured ADC is very low
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