28.1 Clinical Features and Laboratory Investigations
Leigh syndrome, also called subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder mainly occurring in infancy and childhood. The disease often starts before 1 year of age and leads to death in months or years. Juvenile and adult-onset forms have also been described. In most cases the disease has an autosomal recessive inheritance; in some cases inheritance is maternal or X-linked. Both sexes are affected, but among infants there is a 3:2 male predominance. The course can be acute, subacute, episodic, or chronically progressive. Generally, the later the onset, the slower the progression of the disease.
Although Leigh syndrome is a multisystem disorder, the clinical picture is dominated by signs of CNS dysfunction. In patients with neonatal and infantile onset, frequent signs are respiratory problems (irregular respiration, apnea, sighing, and hyperventilation), ocular abnormalities (strabismus, bizarre eye movements, external ophthalmoplegia, ptosis, optic atrophy, nystagmus, loss of vision, impaired pupillary reaction, retinal pigmentary degeneration), hypoto-nia, pyramidal signs (spastic paresis, hyperreflexia, extensor plantar reflexes), weakness, easy fatigability, and feeding problems (anorexia, difficulty in swallowing or sucking, vomiting, weight loss, and retarded growth). Episodes of lethargy, seizures, deafness, renal tubular dysfunction, and cardiac problems (car-diomyopathy and disturbances of cardiac rhythm with periods of tachycardia and bradycardia) may also be present. The same problems are frequent in later-onset forms of the disease, in addition to mental and motor retardation or deterioration, exercise intolerance, cerebellar signs (ataxia, dysarthria), and extrapyramidal signs (rigidity, hypokinesia, chorea, athetosis, myoclonus, tremor, ballismus). Sometimes there are signs of a peripheral polyneuropathy. In cases of acute onset, coma and convulsions, sometimes status epilepticus, may dominate the clinical picture. Causes of death are neurogenic disturbances of respiration, status epilepticus, sudden coma, pneumonia, hyperpyrexia, and cardiac problems.
quinone oxidoreductase) deficiency, complex II (suc-cinate dehydrogenase, succinate:ubiquinone oxido-reductase) deficiency, complex IV (cytochrome c oxidase) deficiency, and defects in subunit 6 of ATP synthase (complex V). Most of these defects may also lead to extensive leukoencephalopathy. A few patients with Leigh syndrome harbor a point mutation in the tRNA gene encoding lysine, usually associated with MERRF (myoclonus epilepsy and ragged red fibers), or have a mitochondrial DNA depletion.
Pyruvate dehydrogenase complex deficiency results in a wide spectrum of neurological disorders. Patients may have a neonatal or early-infantile-onset severe encephalopathy with profound lactic acidosis and early death. Some patients have a neurodegenerative course of the disease with an infantile or childhood onset and milder lactic acidosis (often typical of Leigh encephalopathy). At the mild end of the spectrum patients have mild, intermittent ataxia and normal intelligence. In patients with pyruvate dehydro-genase complex deficiency, worsening may be provoked by infections. Peripheral neuropathy has been reported in patients with a Leigh-like presentation and patients with intermittent ataxia. Patients with a neonatal presentation often have dysmorphic features, including a broad nasal bridge, upturned nose, micrognathia, low-set and posteriorly rotated ears, short fingers and arms, simian creases, hypospadias, and anteriorly placed anus. Most patients have a defect in the Eia subunit of the pyruvate dehydrogenase complex, with an X-linked mode of inheritance. Females can also be symptomatic, depending on the pattern of X inactivation. In fact, the number of affected females is approximately equal to the number of affected males, consistent with a high rate of manifestations of the disease in heterozygous females. Male patients tend to have a more severe phe-notype, but symptomatic females may also have a neonatal-onset devastating encephalopathy. Most defects in the Eia gene seem to originate in the germline.
Isolated complex I deficiency most often leads to clinical symptoms in the neonatal or infantile period or early childhood, but onset may also be later. There are a great variety of clinical presentations. Often complex I deficiency is a multisystem disorder with fatal outcome. Up to 50 % of patients with complex I deficiency present with Leigh syndrome or Leigh-like disease. Other commonly observed phenotypes are cardiomyopathy, fatal infantile lactic acidosis, macro-
cephaly with leukoencephalopathy, unspecified encephalopathy, and myopathy.
Complex II deficiency may lead to Leigh syndrome, diffuse leukoencephalopathy, late-onset ataxia and optic atrophy, myopathy with exercise intolerance, and isolated cardiomyopathy.
Cytochrome-c oxidase deficiency is associated with a wide range of clinical phenotypes including Leigh syndrome, leukoencephalopathy, unspecified en-cephalopathy, fatal infantile lactic acidosis, hyper-trophic cardiomyopathy and myopathy, isolated my-opathy, reversible cytochrome-c oxidase deficiency confined to skeletal muscle, motor neuron disease, spinocerebellar syndrome, myoglobinuria, hepatic failure, ketoacidotic coma, and renal tubulopathy.
Mutations in the mitochondrial gene encoding subunit 6 of ATP synthase are associated with two main phenotypes: the NARP syndrome (NARP standing for neurogenic weakness, ataxia, and retinitis pigmentosa, or neuropathy, ataxia, and retinitis pigmentosa) and maternally inherited Leigh syndrome. Other clinical features of NARP include mental retardation, dementia, seizures, behavioral problems, sen-sorineural deafness, and proximal muscle weakness. The severity of the phenotype is correlated with the load of the heteroplasmic mutation. Symptoms usually appear when mutant mitochondrial DNA exceeds 60 %; retinal-dystrophy-related visual loss is the most prevalent symptom in the 60-75% range of mutant mitochondrial DNA; full-blown NARP syndrome usually occurs at between 75% and 90% heteroplas-my; whereas Leigh syndrome usually occurs at mutant mitochondrial DNA levels above 90%. In a few patients retinal dysfunction occurs at mutant loads even lower than 60 % and manifests in an age-related fashion. Mutant loads tend to increase from mother to child, most frequently with a very rapid "leap" toward mutant homoplasmy. In some families, the mutation can only be demonstrated in the patient and not in the mother, other children, or maternal relatives, suggesting the possibility of a de novo mutation during oogenesis or after fertilization, or a germline mutation in the mother.
Laboratory investigations in Leigh syndrome reveal blood levels of lactate and pyruvate to be typically but not invariably elevated. In CSF, lactate and pyruvate are usually elevated. CSF protein is increased in about half of the patients. EEG shows normal findings or nonspecific abnormalities including diffuse or focal slowing and epileptic phenomena. EMG is either normal or shows signs of denervation or signs of a myopathy. Nerve conduction velocity is either normal or reduced. On biochemical analysis of intact mitochondria in muscle biopsy tissue, variable defects are encountered. Analysis of mitochondrial DNA may reveal mutations, whereas in some other cases defects in nuclear genes are encountered.
Since Leigh syndrome is a serious condition, prenatal diagnosis is important for families. In most cases of pyruvate dehydrogenase complex deficiency, the defect is in the Eia subunit and the condition is X-linked. Mutation analysis is the preferred method for prenatal diagnosis. Affected male fetuses are likely to have a phenotype similar to that of previous affected male siblings. The problem is that the clinical presentation of an affected female cannot be predicted, since there is no way of assessing the X chromosome inactivation pattern in the fetal brain. In all mitochondrial defects with an autosomal recessive mode of inheritance, DNA-based prenatal diagnosis is possible as soon as the basic defect is known in the family. Prenatal diagnosis may also be considered if the complex I deficiency is expressed in both skeletal muscle and skin fibroblasts to rule out tissue specificity and if no mitochondrial DNA defects have been established or suspected. The situation is much more complicated for mitochondrial DNA mutations. The mother carrying a mitochondrial DNA mutation conveys the mutation to all her offspring. The clinical phenotype of these children is mainly determined by the load of mutated mitochondrial DNA in different tissues. As a consequence of the heteroplasmy, a chorionic villus sample may not be representative of the level of mutant mitochondrial DNA in the embryo. In addition, the level of mutant mitochondrial DNA may be different for different tissues within the embryo and change over time. A reliable prediction of the phenotype is therefore impossible. The mutations in the ATP synthase 6 gene are an exception. The distribution of mutant load among tissues is generally uniform in patients, lacking the skewed segregation seen in other mitochondrial DNA mutations, and there is a good genotype-phenotype correlation. These factors make it possible to provide reliable genetic counseling and prenatal diagnosis.
The brunt of histopathological abnormalities in Leigh syndrome is borne by the central gray matter. The most consistent site of lesions is the brain stem gray matter. The lesions are usually bilateral, although not necessarily symmetrical. They are sharply delineated and not confined to the gray matter structures but often spread into the white matter. Preferential sites of affection are the periaqueductal region and brain stem tegmentum,posterior colliculi,substantia nigra, floor of the fourth ventricle, red nuclei, inferior olivary nuclei, dentate nuclei, putamen, caudate nucleus, and globus pallidus. Thalamus, hypothalamus, and subthalamic nuclei may also be involved, but less often. In the spinal cord, lesions are mainly located in the anterior horns, dorsal columns, and pyramidal tracts. Lesions rarely occur in the cerebral or cerebellar cortex or mammillary bodies. Exceptional cases with predominant cerebral and cerebellar cortical damage have been described. Microscopic examination of the lesions shows a marked sponginess with loosening and rarefaction of the neuropil. There is a characteristic intense capillary proliferation. Astrocy-tosis and microglial proliferation are present and macrophages may occur. Nerve cells are remarkably well preserved, although there may be some nerve cell loss. The spongy lesions contain numerous vacuoles, enclosed by single or double membranes. Myelin splitting may contribute to the vacuolation. Cavita-tion and tissue collapse is the end result in most severe lesions.
In the majority of the cases the white matter is well preserved, but sometimes there is also extensive involvement of cerebral and cerebellar white matter, often with sparing of the corpus callosum and internal capsule. The white matter abnormalities are characterized by sponginess, deficient myelin formation, myelin loss, abundant presence of lipid-laden macrophages, marked capillary proliferation, prominent gliosis, and eventually also axonal loss. In all areas there is a gradient of damage, so that myelin sheaths and dendrites degenerate before axons and cell bodies do. In some patients the affected white matter is partially cystic, sometimes even extensively cavitated. The optic nerves and tracts are often affected by demyelination and gliosis.
In patients with a neonatal-onset encephalopathy related to pyruvate dehydrogenase complex deficiency, neuropathological findings are dominated by signs of dysgenesis of the CNS, with agenesis of the corpus callosum, dilatation of the ventricular system, dysplasia and ectopia of the inferior olivary nuclei, dysplasia of the dentate nuclei, absence or hypoplasia of the medullary pyramids, periventricular neuronal heterotopias, and delayed or deficient myelination. Degenerative findings, which may also be present, include gliosis and cystic degeneration of the white matter and vascular proliferation in the white matter and striatum. In patients with pyruvate dehydrogenase complex deficiency and intermittent ataxia, neu-ropathological findings consist of atrophy of cerebel-lar structures.
28.3 Pathogenetic Considerations
Leigh syndrome is caused by a number of inborn errors of energy metabolism. Frequent causes are pyru-vate dehydrogenase complex deficiency, complex I
(NADH coenzyme Q reductase) deficiency, complex II (succinate dehydrogenase) deficiency, complex IV (cytochrome-c oxidase) deficiency, and subunit 6 of ATP synthase (complex V) deficiency. Rarely, patients with Leigh syndrome harbor a point mutation in the tRNA gene encoding lysine, usually associated with MERRF (myoclonus epilepsy and ragged red fibers), or mitochondrial DNA depletion.
The pyruvate dehydrogenase multienzyme complex catalyzes the thiamine-dependent oxidative de-carboxylation of pyruvate to acetyl CoA in the mitochondrial matrix. The complex contains three catalytic components: pyruvate dehydrogenase (Ei), di-hydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase (E3); two regulatory components, E1-kinase and E1-phosphatase; and protein X, a dihy-drolipoamide dehydrogenase binding protein, necessary for proper interaction between the E2 and E3 components. The E1 subunit is a heterotetramer composed of two a and two b subunits. The E1 subunit contains a thiamin pyrophosphate binding site that is shared by the a and b subunits. The gene for the E1a subunit, PDHA1, is located on the X chromosome. There is an autosomal counterpart located on chromosome 4. The E1p subunit gene, PDHB, is located on chromosome 3. The E2 subunit is encoded by a gene on chromosome 3. The gene for the E3 subunit, PHE3, is located on chromosome 7. The gene for protein X, PDX1, is located on chromosome 11. Pyruvate dehydrogenase deficiencies are most often associated with mutations in the gene that encodes the E1a subunit of the complex. Primary defects in the other genes encoding other subunits of the complex are very rare. Consequently, transmission of pyruvate dehydroge-nase deficiency occurs most often in an X-linked fashion, but sometimes in an autosomal recessive fashion.
Complex I (NADH coenzyme Q reductase, NADH: ubiquinone oxidoreductase) represents the largest complex of the mitochondrial electron transfer chain and consists of at least 35 nuclear-encoded subunits (NDUFV1-3, NDUFA1-10, NDUFAB1, NDUFB1-10, NDUFS1-8,NDUFC1-2,and a 17.2-kDa subunit),and 7 mitochondrial-encoded subunits (ND1-6, ND4L). The overall function of the complex is to pass electrons from NADH to ubiquinone while pumping hydrogen ions out of the mitochondrial matrix into the inner membrane space. Complex I deficiency has an autosomal recessive or maternal mode of inheritance.
Complex II, or succinate:ubiquinone oxidoreduc-tase,consists of a flavoprotein and an iron-sulfur protein, which together constitute the soluble enzyme succinate dehydrogenase. In addition, there are two membrane-anchored proteins. It catalyzes the oxidation of succinate to fumarate in the Krebs cycle and carries electrons to the ubiquinone pool of the respiratory chain. All four subunits of the complex are en coded by nuclear DNA. Complex II deficiencies have an autosomal recessive mode of inheritance.
Complex IV, or cytochrome-c oxidase, catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen. It is composed of 13 subunits, 10 of which are encoded by nuclear genes and 3 by mitochondrial genes. The catalytic core of the complex consists of the proteins COX I, COX II, and COX III, encoded by the mitochondrial genes COI, COII, and COIII, respectively. Heteroplasmic mutations in these three genes have been found in cytochrome c deficiency. Additionally, mutations in the mitochondrial tRNA gene for tryptophan and the tRNA gene for isoleucine may underlie a selective cytochrome-c oxidase deficiency. In these rare patients with a mutation in mitochondrial DNA, the disease has a maternal mode of inheritance. Autosomal recessive inheritance is much more common for cytochrome-c oxidase deficiency. Despite intensive studies, mutations have not been identified in any of the 10 nuclear-encoded genes in patients with an autosomal recessive cytochrome-c oxidase deficiency. In order to assemble a functional cytochrome-c oxidase complex, additional nuclear-encoded proteins, assembly factors, are necessary, including SURF1, SCO1, SCO2, COXIO, COX11, COX15, and COX17. Mutations in SURF1, SCO1, SCO2, COXIO, and COX15 have been identified in patients with cytochrome-c oxidase deficiency. The genetic defect in the majority of the patients with cytochrome-c oxidase deficiency is still unknown. Mutations in SURF1 most often lead to Leigh syndrome, but may also lead to a severe leukoen-cephalopathy. Mutations in COX10 have been described in association with leukoencephalopathy and tubulopathy. However, mutations in SURF1 and COX10 may also be associated with other phenotypes. Recently, mutations in the gene LRPPRC have been found in patients with cytochrome-c oxidase deficiency and Leigh syndrome (the so-called French-Canadian subtype). The precise function of LRPPRC protein is presently not known.
Defects in subunit 6 of ATP synthase (complex V of the respiratory chain) are most frequently caused by the T8993G mutation in the mitochondrial DNA. The same mutation is associated with NARP. Defective catalytic properties of the enzyme complex may result from an impairment of the proton transport or from impaired coupling of proton translocation with ATP synthesis. There is a clear-cut reduction in the rate of ATP synthesis in patient cells with a high load of mutant mitochondrial DNA. The T8993C mutation is observed less frequently and seems to be associated with a somewhat less severe phenotype and a less severe reduction in the rate of ATP synthesis. The T9176C and T8851C mutation in the same gene have also been found in some patients with Leigh syn drome. These mutations have a maternal mode of inheritance.
A few patients with Leigh syndrome were found to harbor a point mutation in the mitochondrial tRNA gene for lysine,A8344G or G8363A, usually associated with MERRF (myoclonus epilepsy and ragged red fibers).
All defects underlying Leigh syndrome affect energy metabolism. There is a striking clinical and morphological similarity between Leigh syndrome and thiamine deficiency (beriberi). Thiamine is part of the pyruvate dehydrogenase, ketoglutarate dehydro-genase, and branched-chain keto acid dehydrogenase complexes, and deficiency leads to a disturbance in oxidation of pyruvate and consequently to energy failure. The only histopathological differences between thiamine deficiency and Leigh syndrome are that in thiamine deficiency the mammillary bodies are mostly involved and the substantia nigra is not, whereas in Leigh syndrome it is the substantia nigra that is often involved and the mammillary bodies rarely are. These differences, however, are not absolute.
Therapeutic success is limited in Leigh syndrome. An important problem is that most of the brain damage is irreversible. Supportive care is important. Other possible therapeutic strategies include the removal of toxic metabolites, administration of artificial electron acceptors, administration of cofactors, administration of radical scavengers, and dietary interventions.
L-carnitine supplementation may have a nonspecific beneficial effect, in particular if toxic organic acid intermediates are present. Dichloroacetate has been used to lower blood and CSF lactate levels. Variable favorable results have been reported following the use of riboflavin (vitamin B2), nicotinamide, coenzyme Qi0, vitamin C and menadione (vitamin K3) in respiratory chain defects.
Thiamine treatment is effective in some patients with pyruvate dehydrogenase complex deficiency. The most rational therapeutic strategy in pyruvate dehydrogenase complex deficiency is the use of a ke-togenic diet. Oxidation of fatty acids and ketone bodies provides alternative sources of acetyl-CoA not derived from pyruvate. This acetyl-CoA enters the citric acid cycle, thus bypassing the block at the level of pyruvate dehydrogenase. Dichloroacetate, a structural analogue of pyruvate, inhibits E1 kinase, thereby keeping any residual E1 in its active, dephosphorylat-ed, form. Despite these therapeutic interventions, the outcome in patients with serious neurological disease is generally poor.
Irrespective of the underlying defect, the most commonly reported abnormalities on CT and MRI in Leigh syndrome involve the basal nuclei and brain stem (Figs. 28.1, 28.3, 28.9, 28.10, 28.14-28.16). The putamen and caudate nucleus are the most frequently affected, but the globus pallidus, subthalamic nucleus, dentate nucleus, substantia nigra, tegmentum of the pons, periaqueductal gray, red nucleus, the medulla, and other brain stem structures are also frequently involved. The colliculi, thalamus, hypothalamus, and cortex are less often involved. Although the lesions are often symmetrical, they may also be asymmetrical. These lesions may be swollen during the acute stage, may improve and become smaller, or may develop into focal atrophy or cystic lesions. During the acute stage, contrast enhancement may be present. Generalized cerebral and cerebellar atrophy has also been reported, and some of these patients develop secondary subdural effusions. Depending on the onset of the clinical symptomatology, myelination may be delayed or totally deficient.
Incidentally, focal or, more often, diffuse white matter abnormalities are seen on MRI, involving the cerebral white matter and often also the cerebellar white matter (Figs. 28.4-28.8 and 28.10-28.13). In some patients, the white matter disease is most prominent in the subcortical white matter; in some patients the white matter disease is mainly periven-tricular with sparing of the U fibers, whereas in other patients the cerebral white matter abnormalities are diffuse. Small cysts (or, in some patients, large cysts) may develop within the abnormal white matter (Figs. 28.4-28.6, 28.8, 28.10, 28.12, and 28.13) and their presence is particularly suggestive of a mito-chondrial disease. The cysts are generally well delineated. This is in contrast with the diffuse melting away pattern of cystic degeneration usually seen in vanishing white matter disease. Foci of contrast enhancement within the abnormal white matter is another feature suggestive of a mitochondrial disorder and is, for instance, not seen in vanishing white matter disease (Figs. 28.5, 28.6, and 28.13). The concomitant presence of Leigh-like gray matter lesions is also suggestive of a mitochondrial disease.
The reported white matter abnormalities for each basic defect are specified below:
Pyruvate dehydrogenase complex deficiency is incidentally associated with diffuse leukoencephalo-pathy. Patients with neonatal presentation of pyru-vate dehydrogenase complex deficiency usually have a distinct MRI pattern (Fig. 28.2) with signs of dysgenesis of the brain,including hypoplasia or agenesis of the corpus callosum and highly dilated lateral ventricles and third ventricle with a normal fourth ventricle. The cerebellum may be small with a cystic space behind it. In other neonates, these dysgenetic changes are not seen, but the white matter has an abnormal and swollen appearance and there may be multiple subependymal cysts. In patients with episodic cere-bellar ataxia, cerebellar atrophy may be seen.
Patients with isolated complex I deficiency may present with extensive cerebral leukoencephalopathy with initial swelling of the abnormal white matter and followed by macrocystic degeneration (Figs. 28.4 and 28.5). Focal areas of contrast uptake may be present (Figs. 28.5). A periventricular rim of white matter is sometimes spared. The corpus callosum is often involved, usually most seriously in its posterior part (Figs. 28.5). The cerebral or cerebellar cortex may be abnormal in signal with subsequent development of cortical atrophy (Fig. 28.5). There may also be lesions in the basal ganglia, thalamus, cerebellum, and brain stem. In other patients there are cerebral white matter abnormalities but they are less impressive and not cystic.
In complex II deficiency extensive cerebral white matter abnormalities may occur in the presence or absence of basal ganglia and thalamus lesions (Figs. 28.6-28.8). The U fibers tend to be spared. The corpus callosum may be involved in the process, often more seriously in its posterior part (Figs. 28.6 and 28.7). Focal areas of contrast enhancement may be present (Fig. 28.6). The abnormal white matter may be partially cystic (Figs. 28.6 and 28.8). Additional brain stem white and gray matter lesions may be present. The cerebellar white matter may also be involved.
In cytochrome-c oxidase deficiency, diffuse or less extensive leukoencephalopathy has been reported involving cerebral white matter (Figs. 28.10-28.13). The corpus callosum may also be involved (Figs. 28.10, 28.12, and 28.13). The internal capsule, cerebellar white matter, and U fibers are more variably affected. The abnormal white matter may contain small cysts (Figs. 28.10,28.12, and 28.13), sometimes many cysts. The basal ganglia, thalamus, subthalamic nucleus, dentate nucleus, and brain stem may be normal or contain lesions (Figs. 28.10 and 28.11).After contrast, focal enhancement may be seen, probably occurring in necrotic lesions (Fig. 28.13).
In Leigh syndrome and NARP related to a mutation in the mitochondrial gene encoding the ATP syn-thase 6 subunit, leukoencephalopathy has not been reported.
Proton MRS of the brain usually reveals elevated lactate in the brain of patients with Leigh syndrome, most prominently in lesion areas. In diffuse cerebral white matter abnormalities with cystic degeneration, the presence of highly elevated lactate is an argument in favor of an underlying mitochondrial defect and against vanishing white matter disease. In pyruvate dehydrogenase complex deficiency, additionally ele-
Fig.28.1. An 8-year-old boy with pyruvate dehydrogenase of the corpus callosum,globus pallidus,substantia nigra,and complex deficiency and episodic neurological deterioration dentate nucleus. The globus pallidus lesions are a typical fea-with Leigh-like features.There are lesions in the posterior part ture of pyruvate dehydrogenase complex deficiency
Fig.28.1. An 8-year-old boy with pyruvate dehydrogenase of the corpus callosum,globus pallidus,substantia nigra,and complex deficiency and episodic neurological deterioration dentate nucleus. The globus pallidus lesions are a typical fea-with Leigh-like features.There are lesions in the posterior part ture of pyruvate dehydrogenase complex deficiency vated pyruvate may be detectable at 2.37 ppm. In succinate dehydrogenase deficiency, highly elevated succinate is seen within the abnormal white matter in addition to the elevated lactate. Succinate is represented by a resonance at 2.40 ppm. More details and illustrations are found in Chap. 108.
Fig. 28.3. A 3-year-old boy with isolated complex I deficiency, related to mutations in the NDUFS7 subunit, and a Leigh-like presentation.The T2-weighted (first and second row) and FLAIR images (third row) show lesions in the medial thalamus, midbrain (including the periaqueductal gray), dentate nucleus, and medulla.Sagittal T1-weighted images (fourth row) without (left) and with contrast (middle and right) show enhancement of small spots within the areas of abnormal signal
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