The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Case Records of the Massachusetts General Hospital TABLE 1. FINDINGS ON LUMBAR PUNCTURE. 25 MO Weekly Clinicopathological Exercises FOUNDED BY RICHARD C. CABOT R O B E R T E . S C U L L Y , M. D. , Editor E U G E N E J . M A R K , M. D. , Associate Editor W I L L I A M F . M C N E E L Y , M. D. , Associate Editor S A L L Y H . E B E L I N G , Assistant Editor Case 39-1998 VARIABLE Appearance of fluid Glucose (mg/dl)* Protein (mg/dl) IgG Oligoclonal IgG bands Myelin basic protein Cells (per mm3) Red White 21 MO BEFORE BEFORE ADMISSION ADMISSION ON ADMISSION Normal Normal Absent Normal 50 Clear, colorless 60 55 0 0 181 1 0 0 *To convert the value for glucose to millimoles per liter, multiply by 0.05551. PRESENTATION OF CASE A 13-year-old right-handed girl was admitted to the hospital because of a relapsing–remitting neurologic disorder. She had had a normal childhood, although she was awkward at running, bicycle riding, and gymnastics. Twenty-six months before admission, she had an acute febrile episode with otitis, pharyngitis, headache, drowsiness, imbalance, and confusion. A magnetic resonance imaging (MRI) examination of the brain showed signal abnormalities in both occipital lobes. A computed tomographic (CT) scan of the brain revealed radiolucent areas in both occipital lobes. The following month, the girl had a grand mal seizure, followed by cortical blindness for 18 hours, with slow resolution. A lumbar puncture was performed (Table 1). Visual evoked responses were absent at that time but were present on a subsequent test. Brain-stem auditory evoked responses were abnormal on the left side. Phenytoin was administered. Shortly thereafter, the patient was seen at this hospital. Examination showed 20/50 vision, with extinction of the left visual field. The patient had great difficulty recognizing objects. A right pronator drift and right Babinski sign were present. Three months later, the patient’s right arm and leg became limp and clumsy for a period of 36 hours. One week thereafter, sensation became altered in the left hand, which twitched for a prolonged interval, even during sleep. The right hand twitched constantly and functioned poorly for the next three days. Twentyone months before admission, a cranial CT scan (Fig. 1) showed slight improvement in the occipital abnormalities and a new lesion in the left frontoparietal region. An MRI study confirmed the CT findings. The findings on left carotid and vertebral an1914 · Figure 1. Cranial CT Scan Obtained 21 Months before Admission. An axial image at the level of the lateral ventricles shows hypodensities and a mass effect in the posterior left frontal and parietal lobes (arrow). Dec em b er 2 4 , 19 9 8 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L Figure 2. Axial T2-Weighted MRI Scan Obtained 13 Months before Admission. Abnormal signal and atrophy are evident in the left occipital lobe and right frontal and parietal opercula (arrows). Figure 3. Axial T2-Weighted MRI Scan Obtained Just before the Diagnostic Procedure Was Performed. An additional atrophic abnormality is evident in the left occipital lobe medial to the left atrium (arrow). giographic examination were normal. A lumbar puncture was performed (Table 1). Audiometric examination showed bilateral high-frequency loss, and the patient soon required hearing aids. Prednisone and clonazepam were administered because of dysfunction of the right hand. Clonazepam was tolerated poorly and several months later was replaced by carbamazepine. The dose of prednisone was tapered over a period of several months. Thirteen months before admission, the patient had increasing difficulty with word finding, pronunciation, and handwriting, with questionable worsening in her balance and gait. An MRI study (Fig. 2) revealed atrophic changes in the left frontoparietal abnormalities and new abnormalities in the right frontal and temporal lobes. One month later, examination of a muscle-biopsy specimen showed normal findings. A six-week course of corticosteroids was begun, with apparent improvement in the patient’s speech, writing, and memory thereafter. An MRI examination performed nine months before admis- sion showed new lesions in the right temporal and occipital lobes. During the next nine months, several “viral” illnesses were associated with dizziness and increasing impairment of writing and word finding. The patient experienced focal motor seizures on several occasions despite the administration of phenobarbital and carbamazepine. There had been an annual average decrease of 10 points in her Wechsler intelligence score during the preceding three years. She was admitted to the hospital. Three maternal siblings had died in childhood: an older brother never walked and died at two years of age of “Schilder’s disease,” with no autopsy performed; another brother died in infancy of “a high fever”; and a sister died of “malnutrition” at four years of age. Both the mother and a maternal uncle had hearing loss. A paternal uncle died at 31 years of age in status epilepticus, which was ascribed to poor compliance with medication; a paternal aunt was never able to sit up and died at 4 years of age; Vol ume 33 9 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. Numb e r 26 · 1915 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne and another paternal aunt had paraplegia and died in childhood. The patient’s brother and sister were normal. The temperature was 37.4°C, the pulse was 88, and the respirations were 90. The blood pressure was 110/70 mm Hg. On physical examination, the patient’s facial features were coarsened. Her retinas were normal. On neurologic examination, she was alert, appropriate, and oriented. She could not repeat a two-sentence story, even on the fifth attempt. She had difficulty adding and reading. Visual acuity was 20/20 in the left eye and 20/28 in the right eye. The visual fields were full; no afferent defect was detected. Hearing was reduced, especially in the left ear; the remaining cranial-nerve functions were intact. Muscle strength was normal, without drift. Stereognosis was reduced bilaterally, and graphesthesia was poor on the right side and fair on the left; sensation was intact. The deep-tendon reflexes were ++. Rapid alternating movements and fine finger movements were slow in the right hand; the Romberg test was negative, and a finger-to-nose test was performed well. Tandem walking was fair, forward and backward. Heel-toshin testing showed slight ataxia bilaterally. The urine was normal. A lumbar puncture was performed (Table 1). An electroencephalographic study showed a slow background alpha frequency at 7 Hz and continuous, irregular slowing in the left hemisphere at 35 to 75 µV while the patient was awake. There were spikes and sharp waves in the same region, more frequently during sleep, with occasional brief bursts of generalized, irregular spike-wave activity. Visual evoked potentials and brain-stem auditory evoked potentials were normal. A cranial MRI examination (Fig. 3) showed new signal abnormalities in the inferior right temporal lobe and medial left occipital lobe. The previously described abnormalities showed signal changes associated with atrophy. A diagnostic procedure was performed. DIFFERENTIAL DIAGNOSIS DR. JOHN F. DASHE*: This patient’s neurologic disorder included abnormal cognition and bilateral visual, motor, sensory, and cerebellar disturbances. The first question is whether the radiographic findings are those of a demyelinating or cerebrovascular disorder. The lesions of demyelinating diseases characteristically involve paraventricular white matter and the brain stem. Lesions of cerebrovascular disease involve the cortex, white matter, or both, and their distribution can reflect specific mechanisms of infarction. May we review the neuroimaging studies? *Director, Stroke Service, Beth Israel Deaconess Medical Center, Boston; instructor in neurology, Harvard Medical School. 1916 · DR. R. GILBERTO GONZALEZ: The initial MRI scan, obtained 26 months before admission, shows signal abnormalities involving gray matter and white matter in the left parieto-occipital region and similar signal abnormalities involving principally gray matter in both occipital lobes. The findings on CT scan confirmed these abnormalities. A CT scan obtained 21 months before admission (Fig. 1) reveals a new abnormality involving the posterior left frontal and parietal cortex, with some improvement in the occipital lesions. An MRI scan obtained shortly thereafter confirmed the new cortical abnormality, with minimal involvement of the white matter, and showed an abnormality involving the right parietal cortex. The occipital-lobe abnormalities were associated with atrophy. An MRI scan obtained 13 months before admission (Fig. 2) reveals new lesions in the right frontal and temporal lobes. Previously observed abnormalities show atrophy. On images obtained four months later, new lesions in the right temporal and occipital lobes and old lesions with atrophy are evident. The last MRI study, performed just before the diagnostic procedure (Fig. 3), shows a new lesion in the left occipital lobe. DR. DASHE: The relapsing–remitting course and the family history suggest a central nervous system demyelinating disorder. Schilder’s disease, a severe form of multiple sclerosis, can present with cortical blindness and bilateral occipital lesions.1,2 However, common manifestations of multiple sclerosis, such as abnormalities of eye movement and an afferent pupillary defect, with pleocytosis, band forms, and increased IgG levels in the cerebrospinal fluid, are absent in this patient. Finally, her lesions involve primarily the cortex, unlike demyelinating lesions. The centrum semiovale, the typical location of large plaque-like lesions in Schilder’s disease,3 is mostly spared. Therefore, I shall rule out primary demyelinating disease of the central nervous system. Diseases presenting with strokes or stroke-like episodes are important considerations in this case. Strokes in children are more heterogeneous than those in adults and include several general categories of disorders (Tables 2 and 3). Unlike most embolic infarcts, this patient’s lesions, as observed on the CT and MRI scans, tend to cross the boundaries of the major arterial territories. They do not correspond, however, to borderzone infarcts, which are commonly attributed to systemic hypoperfusion or stenosis of a large artery. The lesions also do not resemble small, deep, subcortical lacunar infarcts. Therefore, it is difficult to ascribe these lesions to embolism, low perfusion, or occlusive disease of large or small vessels. Cerebral vasculitis could explain the fluctuating course with recurrent “infarcts” in this patient, but there is no evidence of central nervous system or systemic inflammatory disease, and the normal angio- Dec em b er 2 4 , 19 9 8 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L TABLE 2. DISORDERS CAUSING STROKES OR STROKE-LIKE EPISODES IN CHILDREN. Disorders of blood vessels or blood Embolism Premature atherosclerosis Vasculitis Noninflammatory forms of vasculopathy Congenital and acquired heart disease Hypercoagulable states Metabolic diseases TABLE 3. METABOLIC DISEASES ASSOCIATED WITH STROKES OR STROKE-LIKE EPISODES. Fabry’s disease Homocystinuria Organic-acid disorders Methylmalonicacidemia Propionicacidemia Isovalericacidemia Glutaricaciduria, types I and II Ornithine transcarbamylase deficiency Carbohydrate-deficient glycoprotein syndromes Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) graphic findings do not support the diagnosis of vasculitis or another vasculopathy of the intracranial arteries known as moyamoya disease.4 Cerebral venous thrombosis can cause infarction, seizures, and headache.5 In this case, the clinical episode at the age of 10 years was accompanied by otitis, which can predispose a patient to cerebral venous thrombosis. However, cerebral venous thrombosis has a low rate of recurrence in the absence of a prothrombotic state. Also, venous infarction is often hemorrhagic and typically causes increased intracranial pressure, which was absent in this case. In Hashimoto’s encephalitis, thyroid-related autoantibodies cause encephalopathy with a relapsing course.6 Although a vasculitic mechanism has been postulated, the cerebral angiographic findings are typically normal. The CT findings are also normal, making the diagnosis unlikely in this case. A striking feature of this case is that the recurrent stroke-like episodes and seizures often occurred with fever and infection, strongly suggesting a metabolic or systemic disorder. Several metabolic diseases are associated with strokes or stroke-like episodes (Table 3). Fabry’s disease is an inherited X-linked lipid-storage disorder characterized by the appearance of angiokeratomas along body creases, especially in the abdomen and groin. Heterozygous female carriers can be symptomatic and usually have a characteristic corneal opacity.7 Ischemic symptoms are often related to the vertebrobasilar circulation,8,9 but multifo- cal occlusive disease of small arteries can occur elsewhere as well.7 Fabry’s disease is an unlikely diagnosis in this case, however. Typical features of the disorder include acroparesthesias, acquired anhidrosis, crises of pain, abdominal cramps, recurrent nausea and vomiting, skin lesions, and radiologic evidence of focal, deep white-matter infarcts, intracerebral hemorrhage, and tortuous ectatic vertebral and basilar arteries, all of which were absent in this case. Homocystinuria can be ruled out in this case because of the absence of characteristic features such as bilateral ectopia lentis, retinal detachment, cataracts, and skeletal changes, including osteoporosis, vertebral collapse, and pectus excavatum. Organic-acid disorders occur because of defects in mitochondrial metabolism, resulting in impairment of oxidative metabolism. Acute or subacute encephalopathy in the neonatal period or infancy is a common presentation, often with hyperammonemia. The clinical spectrum is broad, however, and includes progressive psychomotor retardation and seizures. Certain organic-acid disorders have been associated with stroke-like episodes, including methylmalonicacidemia, propionicacidemia, isovalericacidemia, and two forms of glutaricaciduria (types I and II).10,11 However, the clinical features of these disorders, which include an extrapyramidal syndrome characterized by dystonia and tremor and pyramidal-tract signs such as spastic quadriparesis, were absent in this case.12 Neuroimaging shows predominant involvement of basal ganglia in cases with stroke,13,14 and diffuse, deep white-matter involvement is typical.15 Ornithine transcarbamylase deficiency, the most common urea-cycle defect, is an X-linked disorder. The spectrum of severity of symptoms in heterozygous female carriers is broad: some have no symptoms, and some have severe symptoms. Recurrent stroke-like episodes occur in rare cases; stroke and seizures can be triggered by intercurrent infection and increased metabolic demand. Hyperammonemic episodes can lead to cerebral edema and increased intracranial pressure. The sequelae of severe hyperammonemic episodes include cortical blindness, which is usually transient. The clinical features of this case do not suggest ornithine transcarbamylase deficiency, especially since it usually develops in the neonatal period. However, the disorder can develop later16; therefore, it cannot be excluded from the differential diagnosis without knowledge of serum ammonia levels, serum and urinary urea-cycle metabolite levels, and blood gas values during symptomatic episodes. The carbohydrate-deficient glycoprotein syndromes result in abnormal glycosylation of glycoproteins.17,18 These syndromes usually become apparent during the early neonatal period, with failure to thrive and multisystem organ failure involving especially the liver and heart. In addition to the neonatal onset, Vol ume 33 9 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. Numb e r 26 · 1917 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne many clinical features of carbohydrate-deficient glycoprotein syndromes, including lower-motor-neuron impairment of the legs more than the arms, subcutaneous fat pads, strabismus, and retinitis pigmentosa, are inconsistent with the findings in this case. Neuroimaging studies typically show enlargement of the cisterna magna, with brain-stem and cerebellar hypoplasia,19 features that were absent in this case. The mitochondrial encephalomyopathies are a heterogeneous group of disorders that can cause central nervous system and neuromuscular disease.20-22 Brain tissue and muscle are particularly vulnerable, although any tissue in the body can be affected. Of the clinically defined subtypes, only one has both seizures and stroke-like episodes as prominent features: the syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).23 The hallmark of this syndrome is the occurrence of strokelike episodes that result in hemiparesis, hemianopia, or cortical blindness. Focal or generalized seizures, recurrent migraine-like headaches, vomiting, short stature, hearing loss, and muscle weakness are common. The syndrome usually develops during childhood and has a relapsing and remitting course, with stroke-like episodes separated by periods of variable resolution, that results in progressive neurologic dysfunction and dementia. Neuroimaging studies in patients with MELAS demonstrate radiolucent areas on CT scans and areas of hyperintense signal on T2-weighted MRI scans. These lesions predominantly involve the cortex and subcortical white matter, may cross the boundaries of the major arterial territories, and are more common in parieto-occipital regions than in other regions. Some investigators 24 have described these lesions as “transient” or “migratory,” because as the initial lesions resolve, new, often adjacent, lesions appear. Matthews et al.25 reported a pattern of abnormalities on T2-weighted MRI scans from four patients that may be specific for the diagnosis of MELAS: multifocal areas of hyperintense signal confined to the cerebral and cerebellar cortex and the immediately adjacent white matter. Some lesions involved only deep cortical layers, suggesting cortical laminar necrosis. Deep white matter was spared, except in one case, in which the corpus callosum was involved. In other studies, neuroimaging has shown infarction of basal ganglia that is either isolated or associated with cortical lesions 26 or, less often, with lesions involving white matter more than gray matter.27 In some patients with this syndrome, serial scanning has shown older brain lesions that have undergone atrophy.24 The atrophic foci may correspond to regions of spongy degeneration with microcyst formation and focal areas of encephalomalacia of the cortical mantle, which have been found at autopsy.23 In one patient, areas of low density on a CT scan 1918 · and hyperintense signal on a T2-weighted MRI scan were correlated with postmortem findings of regions of extensive but discontinuous laminar necrosis bordered by gliotic tissue throughout the cerebral cortexes.28 Calcifications in the basal ganglia are common on CT scans from patients with this disorder.29 The impaired mitochondrial function in MELAS has been associated with point mutations in mitochondrial DNA, suggesting a maternal pattern of inheritance, since virtually all mitochondrial DNA is derived from the oocyte at fertilization. In 80 to 90 percent of patients with MELAS, there is a substitution of G for A in a mitochondrial-DNA–encoded transfer RNA, tRNALeu(UUR), at base pair 3243. Other point mutations have also been identified. Determining inheritance on the basis of clinical features alone in a patient with MELAS can be difficult because of the extraordinary phenotypic variability. For example, the point mutation at position 3243 that is linked to MELAS has also been linked to progressive external ophthalmoplegia and the Kearns–Sayre syndrome,30 as well as to another phenotype of maternally inherited diabetes and deafness.31 This variability probably results from the unusual nature of mitochondrial DNA. Whereas nuclear DNA genes are represented by two alleles, there are multiple mitochondria in most cells, and each mitochondrion may contain multiple genomes. Mitochondria are distributed randomly among daughter cells at the time of cell division. A mutation in mitochondrial DNA may affect only some genomes, and the cell or tissue may then contain both a normal and a mutant population of genomes (heteroplasmy). Therefore, the proportion of mutant mitochondrial DNA may vary considerably among different tissues in one person and among different members of the same pedigree. If the proportion of mutant mitochondrial DNA exceeds a critical level, mitochondrial dysfunction occurs in the affected organ or tissue. Determining inheritance by genetic analysis is more useful. In one study, the family history was compatible with maternal inheritance in 14 of 16 pedigrees (88 percent), according to molecular genetic analysis of the mutation at base pair 3243.32 The proportion of mutant mitochondrial DNA in muscle was higher in the patients with MELAS than in family members with few or no symptoms. A cardinal feature of MELAS and some other mitochondrial encephalomyopathies is the presence of “ragged-red fibers” in muscle-biopsy specimens. These fibers correspond to areas of mitochondrial proliferation. The ragged-red features are seen with the Gomori trichrome stain, but this stain has less sensitivity and specificity for the detection of mitochondrial proliferation than a succinate dehydrogenase stain. In patients with MELAS, ragged-red fibers are also stained by cytochrome c oxidase, whereas in patients with most other mitochondrial disorders, Decem b er 2 4 , 19 9 8 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L the fibers are not stained by cytochrome c oxidase. Blood vessels are also strongly reactive to succinate dehydrogenase in muscle-biopsy specimens from patients with MELAS.33 Strict criteria have been proposed for the clinical diagnosis of MELAS.34 Three invariant criteria are stroke-like episodes before 40 years of age; encephalopathy characterized by seizures, dementia, or both; and lactic acidosis, ragged-red fibers, or both. The diagnosis is established if at least two of the following additional criteria are met: normal early development, recurrent headache, and recurrent vomiting. Some patients have a partial syndrome. In the case under discussion, all the clinical and radiologic features are consistent with the diagnosis, but the third invariant criterion — the presence of lactic acidosis, ragged-red fibers, or both — is not met. We are told that the results of a muscle biopsy performed when the patient was 12 years old were normal, but we do not know what stains were used. Ragged-red fibers can be missed, especially if a succinate dehydrogenase stain is not used, and the absence of ragged-red fibers does not rule out a mitochondrial disorder. In one study, ragged-red fibers were absent in 3 of 22 patients with MELAS (14 percent).32 In this case, the slightly elevated cerebrospinal fluid protein level, normal angiographic findings, and background slowing on the electroencephalogram,35 although nonspecific, are additional findings compatible with the diagnosis of MELAS. It is troubling that there is no history of recurrent migraine-like headaches, nausea, or vomiting in this case, since in one study, these features were present in 90 percent or more of 31 patients with MELAS.34 Exercise intolerance was found in all 31 patients in the same study, and it may have been present in this case, since the patient is described as awkward on exercise. The patient’s short stature, growth retardation, and hearing loss are compatible with the diagnosis of MELAS. Although maternal and paternal relatives had neurologic disease, the patient’s mother and maternal uncle had hearing loss, which is common among relatives with few symptoms who carry the point mutation at base pair 3243 of the tRNALeu(UUR) gene.32 The family history is therefore consistent with maternal inheritance of mitochondrial disease in this case. The probable mechanisms underlying the strokelike events vary among the metabolic disorders I have discussed (Table 3). Fabry’s disease and homocystinuria are associated with thrombosis. In the carbohydrate-deficient glycoprotein syndromes, there is evidence of abnormal coagulation.36 The concept of “metabolic stroke,” proposed to explain the focal lesions in patients with methylmalonicacidemia,13 postulates that an accumulation of toxic metabolites causes infarction in the absence of hypoxia or vascular insufficiency. The pathogenesis of the stroke-like episodes in patients with MELAS remains controversial.21 In this disorder, metabolic stroke suggests a mismatch between perfusion and metabolism. Perfusion and substrate delivery are intact, but defects in the electron-transport chain cause decreased production of ATP. The resulting energy failure, perhaps exacerbated by increased metabolic demand during intercurrent infection or seizure, causes neuronal death. An alternative vascular mechanism that has been postulated to cause stroke-like events in patients with MELAS is the impairment of autoregulation of cerebral blood flow caused by energy failure in vascular endothelium and smooth muscle,33,37 but this explanation is not consistent with the typically normal results of angiography. In conclusion, I favor the diagnosis of MELAS. The diagnostic procedure was probably either a repeated muscle biopsy or genetic analysis. Measurement of serum or cerebrospinal fluid lactate levels might also have provided diagnostic clues. CLINICAL DIAGNOSIS Syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). DR. JOHN F. DASHE’S DIAGNOSIS Syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PATHOLOGICAL DISCUSSION DR. PHILIP J. BOYER: The diagnostic procedure was another muscle biopsy, which was performed 11 years ago. Examination of the specimen revealed slight variation in fiber size and occasional raggedred fibers. Ultrastructural examination showed a focal increase in subsarcolemmal mitochondria (Fig. 4A) and occasional mitochondria containing whorled cristae (Fig. 4B). No paracrystalline inclusions were identified. These changes suggested a mitochondrial disease. The abnormalities associated with mitochondrial disease include an increased number of mitochondria, ragged-red fibers, elongation of fibers, abnormalities of the matrix and cristae, and intramitochondrial paracrystalline inclusions. Since none of these abnormalities are diagnostic of a specific clinical syndrome, respiratory-chain defect, or mitochondrial-DNA mutation,38 additional biochemical testing or genetic characterization may be indicated. The sensitivity of muscle biopsy in most syndromes associated with mitochondrial DNA is fairly high. In a study of specimens from 40 patients with a clinical diagnosis of MELAS, 36 had ragged-red fibers, which accounted for 1 to 20 percent of all fibers.39 Ragged-red fibers and other mitochondrial changes may also be seen in otherwise normal older persons40,41 or may be associated with drug therapy 42 or inflammatory myopathies.41,43 DR. MIA M. MACCOLLIN: The patient continued Vol ume 33 9 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. Numb e r 26 · 1919 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne A Figure 5. Coronal Section of Cerebral Hemisphere Showing Numerous Cortical Defects with Narrowing and Focal Cavitation of the Cortical Ribbon (Arrows). B Figure 4. Diagnostic Muscle-Biopsy Specimen. Panel A shows subsarcolemmal accumulation of mitochondria in scattered myofibers (nitrotetrazolium blue and nicotinamide adenine dinucleotide, reduced form, ¬460). The electron micrograph in Panel B shows occasional mitochondria with whorled cristae. The bar represents 0.3 µm. 1920 · to have seizures that were difficult to control, accompanied by a decline in cognition, hearing, vision, and balance. By the age of 20 years, she could no longer walk. MRI scans obtained during her adolescence and young adulthood revealed additional stroke-like lesions. Endocrinopathies, including hypothyroidism, inappropriate release of antidiuretic hormone, and diabetes developed in her late teens. The last of several episodes of respiratory distress and cardiovascular instability culminated in fatal sepsis and multiorgan failure at the age of 23 years. A molecular analysis of the mitochondrial genome in peripheral-blood leukocytes revealed the substitution of G for A at base pair 3243. Analysis of the mitochondrial-DNA genomes in skeletal muscle and cerebellum showed that 88 percent of the mitochondrial DNA was mutant. DR. BOYER: The changes in the central nervous system found at autopsy were typical of the spectrum of abnormalities seen in MELAS.44,45 The brain weighed only 791 g (normal range, 1200 to 1400), with mild-to-moderate cerebral atrophy. There were multiple minute, bilateral cortical and subcortical Dec em b er 2 4 , 19 9 8 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L A A B Figure 6. Specimen of Cerebral Cortex (Luxol Fast Blue–Hematoxylin and Eosin). Panel A shows focal disruption (arrow) of the cortical architecture affecting the entire cortex or only the deep cortical layers, with pallor of the underlying white matter (¬30). Panel B shows loss of neurons with moderate gliosis and isolated, normalappearing neurons (arrow) (¬240). B defects and scattered, predominantly cortical lesions as large as 2.5 cm by 2 cm by 0.8 cm (Fig. 5). Some lesions disrupted the architecture of the deep cortical layers; others disrupted that of the entire cortex (Fig. 6). The lesions were restricted to the neocortex and entorhinal cortex, involved gyri as well as sulci, and were found in all vascular territories. Although cortical lesions involved all lobes, the temporal lobes, the posterior insula (including the parietal and temporal opercula), and the occipital lobes were particularly affected. All the cortical lesions appeared to Figure 7. Electron Micrographs of a Meningeal Vessel. Panel A shows vacuoles representing dilated mitochondria in vascular smooth-muscle cells (arrows). The bar represents 4.35 µm. Panel B shows the vacuoles at a higher magnification. The bar represents 0.93 µm. Vol ume 33 9 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. Numb e r 26 · 1921 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne be months or years old. The histologic features of the lesions were most consistent with the occurrence of hypoxic–ischemic injury. Mild-to-moderate hyalinization of subarachnoid and superficial cortical blood vessels was present. The smooth muscle and, to a lesser extent, endothelial cells contained numerous mitochondria (Fig. 7) that appeared as small vacuoles on light microscopy. The name “mitochondrial angiopathy” has been proposed for this vascular abnormality in patients with MELAS.46 The cerebral white matter was pale and gliotic, especially adjacent to the cortical lesions. Examination of the cerebellum showed slight, patchy loss of Purkinje cells. The brain stem, including the cranial-nerve nuclei, was unaffected except for wallerian degeneration of the left corticospinal tract. Myelin was decreased in the medial portions of the posterior columns of the spinal cord. Fibers in the psoas and quadriceps muscles varied somewhat in size, with granular aggregates in scattered fibers (Fig. 8A), representing massive accumulations of normal-appearing mitochondria (Fig. 8B). No ragged-red fibers were seen. Only the fibers with the granular aggregates were negative for cytochrome c oxidase. Changes in the peripheral nerves included mildto-moderate loss of axons in the femoral nerve and severe loss of axons in the sural nerve, with occasional clusters of regenerating fibers. Axon loss in peripheral nerves has been documented in other patients with MELAS.47 A ANATOMICAL DIAGNOSIS * * Syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). REFERENCES * B Figure 8. Skeletal-Muscle Specimen Obtained at Autopsy When the Patient Was 23 Years Old. Panel A shows mild-to-moderate variation in fiber size, with scattered fibers containing granular aggregates (arrows) (trichrome stain, ¬280). The electron micrograph in Panel B shows aggregates composed of clusters of mitochondria and aggregates of myofibrillary protein (asterisks). The bar represents 2.13 µm. 1922 · 1. Lana-Peixoto MA, dos Santos EC. Schilder’s myelinoclastic diffuse sclerosis. J Clin Neuroophthalmol 1989;9:236-41. 2. Sedwick LA, Klingele TG, Burde RM, Fulling KH, Gado MH. Schilder’s (1912) disease: total cerebral blindness due to acute demyelination. Arch Neurol 1986;43:85-7. 3. Poser CM, Goutieres F, Carpentier MA, Aicardi J. Schilder’s myelinoclastic diffuse sclerosis. Pediatrics 1986;77:107-12. 4. Adams HP, Davis P. Moya-moya syndrome. In: Bogousslavsky J, Caplan LR, eds. Stroke syndromes. New York: Cambridge University Press, 1995: 405-11. 5. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin 1992; 10:87-111. 6. Shaw PJ, Walls TJ, Newman PK, Cleland PG, Cartlidge NE. Hashimoto’s encephalopathy: a steroid-responsive disorder associated with high anti-thyroid antibody titers — report of 5 cases. Neurology 1991;41:22833. 7. Kolodny EH. Fabry disease. In: Bogousslavsky J, Caplan LR, eds. Stroke syndromes. New York: Cambridge University Press, 1995:453-9. 8. Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s disease. Ann Neurol 1996;40:8-17. 9. Case Records of the Massachusetts General Hospital (Case 2-1984). N Engl J Med 1984;310:106-14. 10. Vallee L, Fontaine M, Nuyts JP, et al. Stroke, hemiparesis and deficient mitochondrial beta-oxidation. Eur J Pediatr 1994;153:598-603. 11. Brismar J, Ozand PT. CT and MR of the brain in glutaric acidemia type I: a review of 59 published cases and a report of 5 new patients. AJNR Am J Neuroradiol 1995;16:675-83. 12. Hoffmann GF, Gibson KM, Trefz FK, Nyhan WL, Bremer HJ, Rating Dec em b er 2 4 , 19 9 8 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L D. Neurological manifestations of organic acid disorders. Eur J Pediatr 1994;153:Suppl 1:S94-S100. 13. Heidenreich R, Natowicz M, Hainline BE, et al. Acute extrapyramidal syndrome in methylmalonic acidemia: “metabolic stroke” involving the globus pallidus. J Pediatr 1988;113:1022-7. 14. Korf B, Wallman JK, Levy HL. Bilateral lucency of the globus pallidus complicating methylmalonic acidemia. Ann Neurol 1986;20:364-6. 15. Gebarski SS, Gabrielsen TO, Knake JE, Latack JT. Cerebral CT findings in methylmalonic acid propionic acidemias. AJNR Am J Neuroradiol 1983;4:955-7. 16. Brusilow SW. Inborn errors of urea synthesis: paradigm of hyperammonemic encephalopathy. In: Berg BO, ed. Principles of child neurology. New York: McGraw-Hill, 1996:979-95. 17. Hagberg BA, Blennow G, Kristiansson B, Stibler H. 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Nicoll JA, Moss TH, Love S, Campbell MJ, Schutt WH. Clinical and autopsy findings in two cases of MELAS presenting with stroke-like episodes but without clinical myopathy. Clin Neuropathol 1993;12:38-43. ©1998, Massachusetts Medical Society. 35-MILLIMETER SLIDES FOR THE CASE RECORDS Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a medical teaching exercise or reference material is eligible to receive 35-mm slides, with identifying legends, of the pertinent x-ray films, electrocardiograms, gross specimens, and photomicrographs of each case. The slides are 2 in. by 2 in., for use with a standard 35-mm projector. These slides, which illustrate the current cases in the Journal, are mailed from the Department of Pathology to correspond to the week of publication and may be retained by the subscriber. Each year approximately 250 slides from 40 cases are sent to each subscriber. The cost of the subscription is $450 per year. Application forms for the next subscription year, which begins in January, may be obtained from Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone [617] 7264369). Slides from individual cases may be obtained at a cost of $35 per case. Vol ume 33 9 The New England Journal of Medicine Downloaded from nejm.org on August 12, 2015. For personal use only. No other uses without permission. Copyright © 1998 Massachusetts Medical Society. All rights reserved. Numb e r 26 · 1923