Case 36-2005 — A 61-Year-Old Woman with Seizure, Disturbed Gait, and Altered Mental Status
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《新英格兰医药杂志》
Presentation of Case
Dr. Ronan Walsh (Department of Neurology, Brigham and Women's Hospital): A 61-year-old left-handed woman was admitted to the neurology service of this hospital because of a seizure and altered mental status.
On the morning of admission, her husband awoke at 4 a.m. to find her thrashing in bed, with rhythmic movements of all four extremities, for two to five minutes. She subsequently appeared groggy but alert, with a facial droop, garbled speech, and an inability to follow verbal commands. Emergency-medical-services personnel were called and she was brought to the emergency department of this hospital and admitted to the neurology service.
The patient had been in good health, with the exception of mild hypertension for which she took no medications. She worked in retail sales, had smoked until she was 35 years of age, and rarely drank alcohol. She was married with four sons, had no siblings, and had no family history of stroke or other neurologic illness.
Her vital signs were normal except for a blood pressure of 180/76 mm Hg. The weight was 73 kg and the height 150 cm. The general physical examination revealed no abnormalities. On neurologic examination, the patient was alert and pleasant but did not follow commands or know the date. When speaking, she made frequent phonemic paraphasic errors and perseverated. She could write but not speak the names of objects on the National Institutes of Health stroke cards and could not repeat spoken words. She read with paraphasic errors and did not follow written commands. Motor examination revealed no pronator drift and full strength in the arms and legs. There was decreased blink reflex in response to threat on the right. Her extraocular movements were full. A sensory examination was limited by her aphasia. Reflexes were 2+ throughout, with the left toe going downward on plantar-reflex testing and the right equivocal. The gait was slightly wide-based but steady with good stride. The serum levels of electrolytes, calcium, phosphorus, and magnesium were normal, as were the results of renal-function tests. The cerebrospinal fluid protein and glucose levels were normal, and the cell counts showed no abnormalities. Other laboratory-test results are shown in Table 1.
Table 1. Laboratory-Test Results.
Phenytoin was administered intravenously. A urinary tract infection was confirmed and treated with levofloxacin. Computed tomographic (CT) scanning of the brain revealed a focus of low attenuation in the left temporal lobe. Magnetic resonance imaging (MRI) disclosed a corresponding region of bright signal in the left temporal lobe on T2-weighted and diffusion-weighted imaging. An electroencephalogram revealed periodic lateralizing epileptiform discharges in the left hemisphere with marked asymmetry in the form of low-amplitude delta and theta waves on the left. A biopsy of the left temporal-lobe lesion was performed on the fourth hospital day. An examination of the biopsy specimen disclosed features that were consistent with ischemic changes.
The patient's speech gradually improved but remained severely impaired. She was discharged to a rehabilitation facility on the 16th hospital day. Over the course of the next two months, she was able to perform most activities of daily living, but language difficulty and confusion persisted. She was readmitted for a repeated brain biopsy, two months later, which showed features identical to the first.
For the next six months, she remained aphasic and confused, and she had difficulty recognizing family members. She read and wrote at a second-grade level. No further seizure activity occurred. Over a two-day period, worsening aphasia and confusion developed, and she was again brought to the emergency room and admitted to the hospital. The results of the neurologic examination were unchanged from the first admission.
A repeated brain MRI revealed a new, right-sided, temporo-occipital lesion that was bright on T2-weighted and diffusion-weighted imaging. Electroencephalography revealed right-sided parieto-occipital periodic lateralizing epileptiform discharges, two separate bursts of activity consistent with focal electrographic seizures, and generalized slowing. The phenytoin level was 8 μg per milliliter. Intravenous phenytoin (0.5 g) was given and clonazepam was begun. The levels of cerebrospinal fluid protein and glucose and the cell counts were normal. Other laboratory-test results are shown in Table 1. The patient was treated for a confirmed urinary tract infection. A biopsy specimen of the left deltoid muscle obtained on the third hospital day (of the readmission) showed mild myofiber atrophy and occasional fibers with abnormal NADH–tetrazolium reductase (NADH-TR) staining. Testing of a blood specimen for mitochondrial DNA mutations was negative for the seven most common mutations. The patient was discharged on the fifth hospital day with her language functioning having returned to baseline levels.
Approximately six weeks after discharge she began to have difficulty hearing, worse on the left side than on the right. Two weeks later, she had an episode of tremulousness in the left hand and was readmitted to the hospital. A new enhancing lesion in the right temporal lobe was seen on MRI. Her symptoms resolved, and she was discharged after three days. Over the course of the next five months, her speech fluency and comprehension deteriorated. She had increasing difficulty with oral intake, frequently regurgitated food and pills, and lost 23 kg. Her gait became unsteady, and she could walk only with assistance. She was readmitted to the hospital.
The patient's vital signs were normal. On neurologic examination, she was alert but could not answer questions or follow verbal commands. Her gait was shuffling, with small steps, and she required the assistance of one person. The phenytoin level was elevated at 25.8 μg per milliliter (normal, 5 to 20); phenytoin was withheld and her gait gradually improved. During the hospital stay she showed some paranoid behavior and seemed to have hallucinations or illusions, which improved after treatment with quietapine. Thiamine, biotin, coenzyme Q10, folate, riboflavin, vitamin C, and vitamin E were added to the patient's treatment. Auditory evoked responses in the brain stem confirmed dysfunction in the peripheral hearing system, worse on the left side than on the right side.
A gastrostomy tube was inserted on the 15th hospital day, and a diagnostic procedure was performed.
Differential Diagnosis
Dr. Bradford C. Dickerson: This 61-year-old woman had an acute neurologic syndrome that began with a seizure and was followed by residual aphasia, which was accompanied by right visual-field loss. This set of focal neurologic deficits localizes the lesion to the left temporo-occipital region. Hypertension was the only obvious element of the medical history that predisposed the patient to neurologic disease. At the time of her initial presentation, the differential diagnosis was broad, including cerebrovascular, neoplastic, infectious, inflammatory, and metabolic processes. Given the absence of a history of a prodrome (such as a headache, subtle neurologic symptoms, or systemic illness) or predisposing conditions (such as autoimmune disease or alcoholism), a cerebrovascular insult was high on the list of diagnostic possibilities.
Although the development of seizures soon after that of ischemic cerebral infarcts was described more than 100 years ago,1 seizure is the presenting feature in only 2 to 33 percent of ischemic strokes.2 However, seizures are common as a presenting feature of other cerebrovascular diseases, including lobar intracerebral hemorrhage,3 cerebral venous sinus thrombosis,4 and hypertensive encephalopathy.5 A neuroimaging study is an essential and urgent component of the workup of a patient who presents to the hospital in this manner; the interpretation of the study will heavily influence management of the acute syndrome.
May we review the neuroimaging studies?
Dr. P. Ellen Grant: The MRI obtained on the patient's first admission (Figure 1A) shows increased T2-weighted signal in both gray and white matter of the left temporal lobe, indicating increased free water, which results in a local mass effect effacing the sulci. On the T1-weighted images obtained after the administration of contrast material, there is a small region of cortical enhancement, indicating breakdown of the blood–brain barrier (Figure 1B). On diffusion-weighted imaging, there are areas of abnormally bright signal in the left temporal lobe (Figure 1C), which indicates increased T2-weighted signal, decreased diffusion, or both. The corresponding apparent-diffusion-coefficient map (Figure 1D) indicates that the rate of diffusion in the affected cortex is only mildly decreased (10 to 15 percent), whereas the subcortical white matter has increased diffusion (approximately twice the normal rate).
Figure 1. Magnetic Resonance Images from the First Admission.
An axial fluid-attenuated inversion recovery image (Panel A) shows increased signal and sulcal effacement involving a large portion of the left temporal lobe (arrows). The signal in this region was low on T1-weighted imaging and after the administration of contrast material (Panel B); there was a small region of cortical enhancement (arrow). Diffusion-weighted imaging is used to examine the properties of the free water to determine whether the water molecules are moving at a slower rate than normal, as in metabolic dysfunction or failure, or at a faster rate than normal, as in vasogenic edema. Bright signal on diffusion-weighted imaging can be due to increased T2-weighted signal, decreased diffusion, or both. The diffusion-weighted image (Panel C) shows increased cortical signal in the anterior left temporal lobe (arrows). The corresponding apparent-diffusion-coefficient maps are used to determine whether the bright diffusion-weighted-imaging signal is due to decreased diffusion or increased T2-weighted signal. Each pixel value on the apparent-diffusion-coefficient map is the rate of water diffusion in that pixel. On the apparent-diffusion-coefficient map (Panel D), the cortical regions have diffusion that is normal to only slightly decreased (10 to 15 percent), as compared with the normal contralateral cortex. The subcortical white matter in the anterior left temporal lobe (arrows) has increased diffusion (approximately twice the normal rate).
Decreased diffusion occurs when there is failure or impairment of the sodium–potassium pump. When there is complete failure, necrosis ensues and the apparent-diffusion-coefficient values are typically decreased by 60 to 80 percent. In this case, the cortical apparent-diffusion-coefficient values are mildly decreased — suggesting that either a small fraction of cells is undergoing necrosis or the sodium–potassium pump is partially impaired. Increased diffusion occurs in vasogenic edema, and thus the edema is probably affecting the subcortical white matter. Magnetic resonance spectroscopy showed almost complete loss of N-acetylaspartate, choline, and creatine, but with a markedly elevated lactate peak. The perfusion study showed symmetric blood volume and blood flow without a clear defect in the left temporal lobe, which would be atypical in acute stroke. The mean transit times were normal.
Eight months later, the left temporal-lobe abnormality had evolved into an area of encephalomalacia, but there was now a right temporo-occipital abnormality similar in appearance to the left temporal-lobe lesion at presentation. The lesion was bright on diffusion-weighted imaging, and the apparent diffusion coefficient indicated that diffusion was only approximately 10 percent decreased. Therefore, much of the bright signal seen on diffusion-weighted imaging was due to increased T2-weighted signal and only a small amount was due to a decrease in the apparent diffusion coefficient.
Four days later, this lesion had enlarged in size (Figure 2A and Figure 2B), and on the apparent-diffusion-coefficient map, increased diffusion was evident in the subcortical white matter, probably owing to vasogenic edema (Figure 2C). The diffusion in the cortex was normal to approximately 10 to 15 percent decreased. Perfusion-weighted imaging, as before, showed no focal deficit, but there was mildly increased cerebral blood flow and decreased mean transit time. A proton magnetic resonance spectrograph in the affected regions (Figure 2D) showed reduction of all normal metabolites and a large lactate peak indicative of cell loss and anaerobic metabolism.
Figure 2. Magnetic Resonance Images from Day 4 of the Third Admission, Eight Months after the Initial Seizure.
In the images from the third admission, the left temporal tip is normal, but the remainder of the left temporal region has progressed to cystic encephalomalacia and gliosis with volume loss (Panels A, B, and C, arrows). A new region of abnormality is seen in the cortex of the right posterior temporal region on the T2-weighted image (arrowheads, Panel A), with abnormal increased T2-weighted signal caused by increased fluid, and with a mild local mass effect; this has increased in size since the day of admission, and increased T2-weighted signal is evident in the subcortical white matter. There is a corresponding region of abnormally bright cortical signal on diffusion-weighted imaging (arrowheads, Panel B) that has also increased in size in the interval since the study was performed at the patient's first admission. The apparent-diffusion-coefficient map (Panel C) shows normal to slightly decreased cortical apparent-diffusion coefficient values and increased apparent-diffusion coefficient in the subcortical region (arrowheads). Magnetic resonance spectroscopy (Panel D) shows a large lactate peak and decreased N-acetylaspartate (NAA), choline (cho), and creatine (cr).
What disorders present acutely as bright lesions involving cortex and white matter with T2-weighted imaging and diffusion-weighted imaging? In an acute stroke, the lesion apparent-diffusion-coefficient values are typically markedly reduced, whereas here the apparent-diffusion-coefficient values were elevated in the white matter. Also in acute stroke, there is typically a perfusion deficit in the area of the abnormality on diffusion-weighted imaging, whereas here there was no perfusion defect. Occasionally status epilepticus can cause increased diffusion-weighted imaging, but typically only the cortex is involved and there is at most only minimal cortical edema without mass effect. In status epilepticus, ipsilateral thalamic involvement is often seen, probably owing to involvement of cortical thalamic loops. Therefore, the imaging findings do not fit well either with a focal arterial ischemic event or with status epilepticus.
These asynchronous lesions, which presented acutely with cortical and subcortical edema with mildly decreased cortical apparent-diffusion-coefficient values and elevated white-matter apparent-diffusion-coefficient values, no perfusion deficit, and marked lactate elevation, are evidence of cortical injury, white-matter vasogenic edema, and anaerobic metabolism in the presence of maintained perfusion. These findings are strongly suggestive of a metabolic disorder.
Dr. Dickerson: During this patient's first hospitalization, the neuroimaging findings confirmed the clinical localization of the left temporo-occipital lesion, and its characteristics suggested focal metabolic dysfunction. In addition, the background electrophysiological rhythm in this region was slowed, and there was evidence of persistent cortical irritability. This neurologic syndrome occurred in the context of a urinary tract infection, and lumbar puncture revealed only elevated lactate levels, without evidence of a central nervous system infection or inflammatory response. The unusual constellation of findings prompted additional workup, including magnetic resonance spectroscopy — which provided evidence of derangement of cellular energy within the lesion — and, subsequently, brain biopsy.
Eight months later, an acute deterioration of neurologic function, again in the setting of urinary tract infection, was accompanied by similar findings on neuroimaging and electroencephalographic study and similar cerebrospinal fluid data. A muscle-biopsy specimen revealed biochemical abnormalities suggestive of mitochondrial myopathy, but typical morphologic features were not seen.
This patient's clinical course was one of progressive dementia, marked by intercurrent acute neurologic episodes and the serial development of multifocal brain lesions. Dysfunction occurred primarily in the left perisylvian network for language and in the occipito-temporal network for object recognition.6 This pattern is not typical of the common degenerative dementias, such as Alzheimer's disease, but would potentially be consistent with cerebrovascular dementia.7,8 The stepwise course of this patient's clinical decline was also consistent with vascular dementia,9 but the imaging characteristics of the lesions and their extreme electrophysiological irritability suggested that the disease mechanism was one of cellular energy failure rather than ischemia. Moreover, the development of the lesions in the setting of increased systemic metabolic demand due to urinary tract infection supported this hypothesis.
Finally, the additional clinical findings, including the patient's short stature and hearing loss; the laboratory findings of mildly elevated serum creatine kinase and elevated lactate in the serum, cerebrospinal fluid, and the brain lesions; and the presence of a myopathy with an oxidative metabolic abnormality all provided further signs suggesting a primary abnormality of mitochondrial function. Although this patient had no family history of such a condition and symptoms developed much later in life than is usual for patients with this disease, we suspected a diagnosis of mitochondrial encephalomyopathy — specifically, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (the MELAS syndrome).
Mitochondrial Encephalomyopathies
Mitochondrial encephalomyopathies are a diverse group of disorders that have been known since the 1960s; they are usually diseases of childhood and young adulthood.10 Since the first disease-related mitochondrial mutations were identified in 1988,11,12 more than 150 pathogenic mutations have been reported in patients with a variety of clinical disorders (www.mitomap.org). Most of these are maternally inherited and multisystemic, although some are sporadic and tissue-specific.13,14,15 Population-based studies suggest that mitochondrial disorders may be at least as common (prevalence, 1 in 8500 population) as other sporadic and inherited neurologic disorders, such as amyotrophic lateral sclerosis and Huntington's disease.16,17,18
The symptoms of mitochondrial disorders arise from dysfunction of tissue types that are thought to be vulnerable because of their high rate of oxidative metabolism, including tissue in the brain and peripheral nerves, skeletal and cardiac muscle, retina and organ of Corti, and the renal tubule.19 The index of suspicion for a mitochondrial disorder should be high when there is apparently unrelated symptomatic involvement of two or more tissues. In the proper context, the suspicion that an illness involves mitochondrial dysfunction should be raised when the individual or family history includes any of the following: short stature, migraine-like headaches, sensorineural hearing loss, progressive external ophthalmoplegia, axonal neuropathy, diabetes mellitus, hypertrophic cardiomyopathy, or renotubular acidosis.
Of the variety of clinical syndromes associated with mitochondrial dysfunction (Table 2),20 this patient's illness is best characterized as the MELAS syndrome.21 Previously established diagnostic criteria for the MELAS syndrome specified the presence of stroke-like episodes before the age of 40 years, encephalopathy with seizures or dementia, and either lactic acidosis or so-called ragged-red fibers (subsarcolemmal accumulation of red-staining material on muscle biopsy), along with at least two of the following: normal early development, recurrent headache, or recurrent vomiting.22,23 As data have accumulated on the breadth of phenotypes in patients harboring genetic mutations associated with the MELAS syndrome, some authorities have suggested an approach to the diagnostic workup that would broaden the identification of mitochondrial encephalomyopathy even when strict diagnostic criteria are not met.20 As was the case with the approach to this patient, the workup includes a detailed history and family history (with particular attention to potentially associated conditions described above), laboratory tests (especially measurement of serum and cerebrospinal fluid lactate and serum creatine kinase), MRI studies (including the specific sequences used in this case), exercise physiology, muscle biopsy for morphology and biochemistry, and molecular genetic screening.
Table 2. Clinical Features of Mitochondrial Diseases Associated with Mitochondrial DNA Mutations.
Although mitochondrial encephalomyopathy was the leading diagnosis, both health care providers and the patient's family were frustrated by the difficulty of obtaining a definitive tissue and genetic diagnosis. Genetic screening performed on the first muscle-biopsy specimen for the seven most common mitochondrial DNA mutations was negative.
The diagnostic procedure was a second muscle biopsy.
Clinical Diagnosis
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (the MELAS syndrome).
Dr. Bradford C. Dickerson's Diagnosis
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (the MELAS syndrome).
Pathological Discussion
Dr. Di Tian: Both of the muscle-biopsy specimens were taken from the right deltoid. The first showed mildly increased variation in myofiber size and rare myocytes with increased subsarcolemmal and cytoplasmic NADH–tetrazolium reductase enzyme activity. However, there was no subsarcolemmal accumulation of red-staining material (ragged-red fibers, which characterize mitochondrial myopathy) on trichrome staining. Stain for ATP revealed occasional small atrophic myofibers of both types without fiber-type grouping. Electron microscopical examination did not reveal morphologically abnormal mitochondria.
The second muscle-biopsy specimen showed moderately increased variation in myofiber size and some atrophic myocytes displaying coarse cytoplasmic and subsarcolemmal staining with hematoxylin and eosin (Figure 3A). These fibers contained subsarcolemmal accumulation of linear, irregular material that stained red, indicating ragged-red fibers (Figure 3B). Abnormal subsarcolemmal and cytoplasmic accumulations of mitochondria were also highlighted by NADH-TR (Figure 3C), succinyl dehydrogenase, and cytochrome c oxidase stains and on electron microscopy (Figure 3D). These morphologic features were highly suggestive of mitochondrial myopathy.
Figure 3. Biopsy Specimen of the Right Deltoid Muscle Showing Features of Mitochondrial Myopathy.
A myocyte shows clumped cytoplasmic staining on a hematoxylin-and-eosin stain (Panel A) and subsarcolemmal accumulation of red-staining material, so-called "ragged-red fibers," on a modified Gomori's trichrome stain (arrow, Panel B). NADH–tetrazolium reductase stain (Panel C) highlights markedly increased enzymatic activity (dark blue staining) in the subsarcolemmal compartment of some fibers. Electron microscopy reveals subsarcolemmal and interfibrillary accumulation of mitochondria. Some mitochondria (Panel D) are enlarged, with complex internal structure, and some contain abnormal electron-dense material.
Tissue was sent to Columbia University's laboratory for biochemical and genetic testing. Electron-transport-chain assays on both biopsy samples revealed a defect in complex I, with normal activities in complexes II, III, and IV. DNA sequencing disclosed a G13513A missense mutation in the ND5 mitochondrial gene, a subunit of complex I, resulting in alteration from aspartic acid to asparagine at amino acid residue 393 (D393 N), which is predicted to cause a secondary structural change.24,25 This mutation has been described in patients with various clinical phenotypes that are associated with mitochondrial dysfunction, including cases of both childhood and adult-onset MELAS syndrome,26,27,28,29 Leber's hereditary optic neuropathy and MELAS overlap syndromes,26,29 adult-onset encephalomyopathy with blindness,29 and Leigh or Leigh-like (atypical) syndrome with isolated complex I deficiency in childhood.24,30
Among the six reported patients with the MELAS syndrome and G13513A mutation, all had clinical features of the MELAS syndrome, including hearing loss, by their mid-40s — and most were in their second decade. The patient under discussion was in her early 60s at the onset of her illness, making her the oldest patient with the MELAS syndrome known to carry the G13513A mutation.
Discussion of Management
Dr. Dickerson: The patient was discharged home from her third admission on the 19th hospital day. The level of diagnostic specificity imparted by the results of the genetic testing, which were returned two months after the patient's discharge, provided relief to the patient's husband and sons and made possible both a discussion of the heritability of diseases associated with mutations in mitochondrial DNA and optimal planning for end-of-life care for the patient.
Therapeutic options for mitochondrial encephalomyopathies are currently limited.18,20 Symptomatic and palliative approaches include the treatment of seizures, hearing loss, ophthalmoplegia, diabetes, and cardiac-conduction block. The mainstay of treatment, which was used with this patient, is the use of metabolite and cofactor supplements, including coenzyme Q10 (an oxygen-radical scavenger) and L-carnitine (to restore secondarily lowered levels of free carnitine). Although there are few data to support the efficacy of these supplements, the risks are minimal. Exercise and physical therapy, once thought to be detrimental to patients with mitochondrial disorders, is now the subject of investigations, with recent evidence indicating that aerobic training increases work tolerance and oxidative capacity in patients with mitochondrial DNA mutations.31 Finally, new approaches to genetic therapy are being studied.
Over the course of several home visits, I worked with the patient's husband and sons and the hospice team to develop a palliative care program that included pain management and other symptom management, psychosocial support, and the coordination of services, including autopsy arrangements.32,33
Dr. Walsh: Over the eight months after discharge the patient continued to decline. She became almost mute and spent most of her time sleeping. She died at home two years after the onset of her illness.
Dr. Tian: The autopsy showed bronchopneumonia to be the immediate cause of death. The brain weighed 1070 g (normal, 1300 to 1400 g). The left temporal lobe, the left inferior parietal lobe, and the anterior aspect of the left occipital lobe, as well as the right inferior parietal lobe, were soft with yellowish discoloration (Figure 4A). These lesions were asymmetric and did not fall into the vascular territories or border zones of any major cerebral arteries. Coronal sections revealed laminar cortical necrosis in these areas (Figure 4B). Microscopical examination showed severe neuronal loss in the middle and deep cortical layers, with the accumulation of hemosiderin-laden macrophages and reactive astrocytes (Figure 4C). The underlying white matter was gliotic. Scattered foci of isolated cortical necrosis were present.
Figure 4. Autopsy Findings in the Brain.
A gross external photograph of the brain shows that the left temporal, parietal, and anterior occipital lobes are soft and yellow (arrows, Panel A). A coronal section of the left cerebral hemisphere shows laminar cortical disruption in the inferior parietal lobule and lateral temporal cortexes (arrows, Panel B). A low-magnification photomicrograph of the left superior and middle temporal gyri reveals laminated cortical disruption (arrows, Panel C). Marked neuronal loss, reactive gliosis, and the accumulation of hemosiderin-laden macrophages are seen on higher magnification (inset). Some cerebellar Purkinje cells have marked swelling of the proximal dendrites, the so-called "cactus dendrites" (arrows, Panel D). (Panels C and D, Luxol fast blue–hematoxylin and eosin stain).
Some cerebellar Purkinje cells had marked swelling of the proximal dendrites (Figure 4D), referred to as "cactus dendrites" by some authors,34 which have been described in patients with mitochondrial diseases. Arteriosclerosis and arteriolosclerosis and a small putamenal infarct were present, consistent with the patient's history of hypertension. The skeletal muscles demonstrated changes similar to those noted in her second muscle biopsy.
The postmortem findings of multifocal cortical laminar necrosis and isolated cortical necrosis are consistent with mitochondrial encephalomyopathy.
Dr. Nancy Lee Harris (Pathology): Dr. Holtzman, can you explain the peculiarities of mitochondrial DNA as they relate to this patient and her family?
Dr. David Holtzman: Mitochondria are present in the cytoplasm of the ovum and are thus all inherited from the mother. There are multiple DNA molecules in each mitochondrion and multiple mitochondria in each cell.35 The mitochondria are randomly sorted when daughter cells are formed. Thus, when a mitochondrial mutation is present, the mutation load in any given organ of any single person is highly variable — a condition known as heteroplasmy. It cannot be predicted whether the mutation load will reach a threshold for clinical expression. This random sorting of mitochondrial DNA and its mutations explains why no one in the patient's mother's family had a similar clinical phenotype and limits the value of genetic testing in other family members. Other factors, such as toxins and aging, also may affect the clinical expression.
Anatomical Diagnosis
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (the MELAS syndrome).
Source Information
From the Departments of Neurology (B.C.D., D.H.) and Pediatrics (D.H.), the Division of Pediatric Radiology, Department of Radiology (P.E.G.), and the Department of Pathology (D.T.), Massachusetts General Hospital; the Division of Cognitive and Behavioral Neurology, Department of Neurology, Brigham and Women's Hospital (B.C.D.); and the Departments of Neurology (B.C.D., D.H.), Pediatrics (D.H.), Radiology (P.E.G.), and Pathology (D.T.), Harvard Medical School — all in Boston.
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Dr. Ronan Walsh (Department of Neurology, Brigham and Women's Hospital): A 61-year-old left-handed woman was admitted to the neurology service of this hospital because of a seizure and altered mental status.
On the morning of admission, her husband awoke at 4 a.m. to find her thrashing in bed, with rhythmic movements of all four extremities, for two to five minutes. She subsequently appeared groggy but alert, with a facial droop, garbled speech, and an inability to follow verbal commands. Emergency-medical-services personnel were called and she was brought to the emergency department of this hospital and admitted to the neurology service.
The patient had been in good health, with the exception of mild hypertension for which she took no medications. She worked in retail sales, had smoked until she was 35 years of age, and rarely drank alcohol. She was married with four sons, had no siblings, and had no family history of stroke or other neurologic illness.
Her vital signs were normal except for a blood pressure of 180/76 mm Hg. The weight was 73 kg and the height 150 cm. The general physical examination revealed no abnormalities. On neurologic examination, the patient was alert and pleasant but did not follow commands or know the date. When speaking, she made frequent phonemic paraphasic errors and perseverated. She could write but not speak the names of objects on the National Institutes of Health stroke cards and could not repeat spoken words. She read with paraphasic errors and did not follow written commands. Motor examination revealed no pronator drift and full strength in the arms and legs. There was decreased blink reflex in response to threat on the right. Her extraocular movements were full. A sensory examination was limited by her aphasia. Reflexes were 2+ throughout, with the left toe going downward on plantar-reflex testing and the right equivocal. The gait was slightly wide-based but steady with good stride. The serum levels of electrolytes, calcium, phosphorus, and magnesium were normal, as were the results of renal-function tests. The cerebrospinal fluid protein and glucose levels were normal, and the cell counts showed no abnormalities. Other laboratory-test results are shown in Table 1.
Table 1. Laboratory-Test Results.
Phenytoin was administered intravenously. A urinary tract infection was confirmed and treated with levofloxacin. Computed tomographic (CT) scanning of the brain revealed a focus of low attenuation in the left temporal lobe. Magnetic resonance imaging (MRI) disclosed a corresponding region of bright signal in the left temporal lobe on T2-weighted and diffusion-weighted imaging. An electroencephalogram revealed periodic lateralizing epileptiform discharges in the left hemisphere with marked asymmetry in the form of low-amplitude delta and theta waves on the left. A biopsy of the left temporal-lobe lesion was performed on the fourth hospital day. An examination of the biopsy specimen disclosed features that were consistent with ischemic changes.
The patient's speech gradually improved but remained severely impaired. She was discharged to a rehabilitation facility on the 16th hospital day. Over the course of the next two months, she was able to perform most activities of daily living, but language difficulty and confusion persisted. She was readmitted for a repeated brain biopsy, two months later, which showed features identical to the first.
For the next six months, she remained aphasic and confused, and she had difficulty recognizing family members. She read and wrote at a second-grade level. No further seizure activity occurred. Over a two-day period, worsening aphasia and confusion developed, and she was again brought to the emergency room and admitted to the hospital. The results of the neurologic examination were unchanged from the first admission.
A repeated brain MRI revealed a new, right-sided, temporo-occipital lesion that was bright on T2-weighted and diffusion-weighted imaging. Electroencephalography revealed right-sided parieto-occipital periodic lateralizing epileptiform discharges, two separate bursts of activity consistent with focal electrographic seizures, and generalized slowing. The phenytoin level was 8 μg per milliliter. Intravenous phenytoin (0.5 g) was given and clonazepam was begun. The levels of cerebrospinal fluid protein and glucose and the cell counts were normal. Other laboratory-test results are shown in Table 1. The patient was treated for a confirmed urinary tract infection. A biopsy specimen of the left deltoid muscle obtained on the third hospital day (of the readmission) showed mild myofiber atrophy and occasional fibers with abnormal NADH–tetrazolium reductase (NADH-TR) staining. Testing of a blood specimen for mitochondrial DNA mutations was negative for the seven most common mutations. The patient was discharged on the fifth hospital day with her language functioning having returned to baseline levels.
Approximately six weeks after discharge she began to have difficulty hearing, worse on the left side than on the right. Two weeks later, she had an episode of tremulousness in the left hand and was readmitted to the hospital. A new enhancing lesion in the right temporal lobe was seen on MRI. Her symptoms resolved, and she was discharged after three days. Over the course of the next five months, her speech fluency and comprehension deteriorated. She had increasing difficulty with oral intake, frequently regurgitated food and pills, and lost 23 kg. Her gait became unsteady, and she could walk only with assistance. She was readmitted to the hospital.
The patient's vital signs were normal. On neurologic examination, she was alert but could not answer questions or follow verbal commands. Her gait was shuffling, with small steps, and she required the assistance of one person. The phenytoin level was elevated at 25.8 μg per milliliter (normal, 5 to 20); phenytoin was withheld and her gait gradually improved. During the hospital stay she showed some paranoid behavior and seemed to have hallucinations or illusions, which improved after treatment with quietapine. Thiamine, biotin, coenzyme Q10, folate, riboflavin, vitamin C, and vitamin E were added to the patient's treatment. Auditory evoked responses in the brain stem confirmed dysfunction in the peripheral hearing system, worse on the left side than on the right side.
A gastrostomy tube was inserted on the 15th hospital day, and a diagnostic procedure was performed.
Differential Diagnosis
Dr. Bradford C. Dickerson: This 61-year-old woman had an acute neurologic syndrome that began with a seizure and was followed by residual aphasia, which was accompanied by right visual-field loss. This set of focal neurologic deficits localizes the lesion to the left temporo-occipital region. Hypertension was the only obvious element of the medical history that predisposed the patient to neurologic disease. At the time of her initial presentation, the differential diagnosis was broad, including cerebrovascular, neoplastic, infectious, inflammatory, and metabolic processes. Given the absence of a history of a prodrome (such as a headache, subtle neurologic symptoms, or systemic illness) or predisposing conditions (such as autoimmune disease or alcoholism), a cerebrovascular insult was high on the list of diagnostic possibilities.
Although the development of seizures soon after that of ischemic cerebral infarcts was described more than 100 years ago,1 seizure is the presenting feature in only 2 to 33 percent of ischemic strokes.2 However, seizures are common as a presenting feature of other cerebrovascular diseases, including lobar intracerebral hemorrhage,3 cerebral venous sinus thrombosis,4 and hypertensive encephalopathy.5 A neuroimaging study is an essential and urgent component of the workup of a patient who presents to the hospital in this manner; the interpretation of the study will heavily influence management of the acute syndrome.
May we review the neuroimaging studies?
Dr. P. Ellen Grant: The MRI obtained on the patient's first admission (Figure 1A) shows increased T2-weighted signal in both gray and white matter of the left temporal lobe, indicating increased free water, which results in a local mass effect effacing the sulci. On the T1-weighted images obtained after the administration of contrast material, there is a small region of cortical enhancement, indicating breakdown of the blood–brain barrier (Figure 1B). On diffusion-weighted imaging, there are areas of abnormally bright signal in the left temporal lobe (Figure 1C), which indicates increased T2-weighted signal, decreased diffusion, or both. The corresponding apparent-diffusion-coefficient map (Figure 1D) indicates that the rate of diffusion in the affected cortex is only mildly decreased (10 to 15 percent), whereas the subcortical white matter has increased diffusion (approximately twice the normal rate).
Figure 1. Magnetic Resonance Images from the First Admission.
An axial fluid-attenuated inversion recovery image (Panel A) shows increased signal and sulcal effacement involving a large portion of the left temporal lobe (arrows). The signal in this region was low on T1-weighted imaging and after the administration of contrast material (Panel B); there was a small region of cortical enhancement (arrow). Diffusion-weighted imaging is used to examine the properties of the free water to determine whether the water molecules are moving at a slower rate than normal, as in metabolic dysfunction or failure, or at a faster rate than normal, as in vasogenic edema. Bright signal on diffusion-weighted imaging can be due to increased T2-weighted signal, decreased diffusion, or both. The diffusion-weighted image (Panel C) shows increased cortical signal in the anterior left temporal lobe (arrows). The corresponding apparent-diffusion-coefficient maps are used to determine whether the bright diffusion-weighted-imaging signal is due to decreased diffusion or increased T2-weighted signal. Each pixel value on the apparent-diffusion-coefficient map is the rate of water diffusion in that pixel. On the apparent-diffusion-coefficient map (Panel D), the cortical regions have diffusion that is normal to only slightly decreased (10 to 15 percent), as compared with the normal contralateral cortex. The subcortical white matter in the anterior left temporal lobe (arrows) has increased diffusion (approximately twice the normal rate).
Decreased diffusion occurs when there is failure or impairment of the sodium–potassium pump. When there is complete failure, necrosis ensues and the apparent-diffusion-coefficient values are typically decreased by 60 to 80 percent. In this case, the cortical apparent-diffusion-coefficient values are mildly decreased — suggesting that either a small fraction of cells is undergoing necrosis or the sodium–potassium pump is partially impaired. Increased diffusion occurs in vasogenic edema, and thus the edema is probably affecting the subcortical white matter. Magnetic resonance spectroscopy showed almost complete loss of N-acetylaspartate, choline, and creatine, but with a markedly elevated lactate peak. The perfusion study showed symmetric blood volume and blood flow without a clear defect in the left temporal lobe, which would be atypical in acute stroke. The mean transit times were normal.
Eight months later, the left temporal-lobe abnormality had evolved into an area of encephalomalacia, but there was now a right temporo-occipital abnormality similar in appearance to the left temporal-lobe lesion at presentation. The lesion was bright on diffusion-weighted imaging, and the apparent diffusion coefficient indicated that diffusion was only approximately 10 percent decreased. Therefore, much of the bright signal seen on diffusion-weighted imaging was due to increased T2-weighted signal and only a small amount was due to a decrease in the apparent diffusion coefficient.
Four days later, this lesion had enlarged in size (Figure 2A and Figure 2B), and on the apparent-diffusion-coefficient map, increased diffusion was evident in the subcortical white matter, probably owing to vasogenic edema (Figure 2C). The diffusion in the cortex was normal to approximately 10 to 15 percent decreased. Perfusion-weighted imaging, as before, showed no focal deficit, but there was mildly increased cerebral blood flow and decreased mean transit time. A proton magnetic resonance spectrograph in the affected regions (Figure 2D) showed reduction of all normal metabolites and a large lactate peak indicative of cell loss and anaerobic metabolism.
Figure 2. Magnetic Resonance Images from Day 4 of the Third Admission, Eight Months after the Initial Seizure.
In the images from the third admission, the left temporal tip is normal, but the remainder of the left temporal region has progressed to cystic encephalomalacia and gliosis with volume loss (Panels A, B, and C, arrows). A new region of abnormality is seen in the cortex of the right posterior temporal region on the T2-weighted image (arrowheads, Panel A), with abnormal increased T2-weighted signal caused by increased fluid, and with a mild local mass effect; this has increased in size since the day of admission, and increased T2-weighted signal is evident in the subcortical white matter. There is a corresponding region of abnormally bright cortical signal on diffusion-weighted imaging (arrowheads, Panel B) that has also increased in size in the interval since the study was performed at the patient's first admission. The apparent-diffusion-coefficient map (Panel C) shows normal to slightly decreased cortical apparent-diffusion coefficient values and increased apparent-diffusion coefficient in the subcortical region (arrowheads). Magnetic resonance spectroscopy (Panel D) shows a large lactate peak and decreased N-acetylaspartate (NAA), choline (cho), and creatine (cr).
What disorders present acutely as bright lesions involving cortex and white matter with T2-weighted imaging and diffusion-weighted imaging? In an acute stroke, the lesion apparent-diffusion-coefficient values are typically markedly reduced, whereas here the apparent-diffusion-coefficient values were elevated in the white matter. Also in acute stroke, there is typically a perfusion deficit in the area of the abnormality on diffusion-weighted imaging, whereas here there was no perfusion defect. Occasionally status epilepticus can cause increased diffusion-weighted imaging, but typically only the cortex is involved and there is at most only minimal cortical edema without mass effect. In status epilepticus, ipsilateral thalamic involvement is often seen, probably owing to involvement of cortical thalamic loops. Therefore, the imaging findings do not fit well either with a focal arterial ischemic event or with status epilepticus.
These asynchronous lesions, which presented acutely with cortical and subcortical edema with mildly decreased cortical apparent-diffusion-coefficient values and elevated white-matter apparent-diffusion-coefficient values, no perfusion deficit, and marked lactate elevation, are evidence of cortical injury, white-matter vasogenic edema, and anaerobic metabolism in the presence of maintained perfusion. These findings are strongly suggestive of a metabolic disorder.
Dr. Dickerson: During this patient's first hospitalization, the neuroimaging findings confirmed the clinical localization of the left temporo-occipital lesion, and its characteristics suggested focal metabolic dysfunction. In addition, the background electrophysiological rhythm in this region was slowed, and there was evidence of persistent cortical irritability. This neurologic syndrome occurred in the context of a urinary tract infection, and lumbar puncture revealed only elevated lactate levels, without evidence of a central nervous system infection or inflammatory response. The unusual constellation of findings prompted additional workup, including magnetic resonance spectroscopy — which provided evidence of derangement of cellular energy within the lesion — and, subsequently, brain biopsy.
Eight months later, an acute deterioration of neurologic function, again in the setting of urinary tract infection, was accompanied by similar findings on neuroimaging and electroencephalographic study and similar cerebrospinal fluid data. A muscle-biopsy specimen revealed biochemical abnormalities suggestive of mitochondrial myopathy, but typical morphologic features were not seen.
This patient's clinical course was one of progressive dementia, marked by intercurrent acute neurologic episodes and the serial development of multifocal brain lesions. Dysfunction occurred primarily in the left perisylvian network for language and in the occipito-temporal network for object recognition.6 This pattern is not typical of the common degenerative dementias, such as Alzheimer's disease, but would potentially be consistent with cerebrovascular dementia.7,8 The stepwise course of this patient's clinical decline was also consistent with vascular dementia,9 but the imaging characteristics of the lesions and their extreme electrophysiological irritability suggested that the disease mechanism was one of cellular energy failure rather than ischemia. Moreover, the development of the lesions in the setting of increased systemic metabolic demand due to urinary tract infection supported this hypothesis.
Finally, the additional clinical findings, including the patient's short stature and hearing loss; the laboratory findings of mildly elevated serum creatine kinase and elevated lactate in the serum, cerebrospinal fluid, and the brain lesions; and the presence of a myopathy with an oxidative metabolic abnormality all provided further signs suggesting a primary abnormality of mitochondrial function. Although this patient had no family history of such a condition and symptoms developed much later in life than is usual for patients with this disease, we suspected a diagnosis of mitochondrial encephalomyopathy — specifically, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (the MELAS syndrome).
Mitochondrial Encephalomyopathies
Mitochondrial encephalomyopathies are a diverse group of disorders that have been known since the 1960s; they are usually diseases of childhood and young adulthood.10 Since the first disease-related mitochondrial mutations were identified in 1988,11,12 more than 150 pathogenic mutations have been reported in patients with a variety of clinical disorders (www.mitomap.org). Most of these are maternally inherited and multisystemic, although some are sporadic and tissue-specific.13,14,15 Population-based studies suggest that mitochondrial disorders may be at least as common (prevalence, 1 in 8500 population) as other sporadic and inherited neurologic disorders, such as amyotrophic lateral sclerosis and Huntington's disease.16,17,18
The symptoms of mitochondrial disorders arise from dysfunction of tissue types that are thought to be vulnerable because of their high rate of oxidative metabolism, including tissue in the brain and peripheral nerves, skeletal and cardiac muscle, retina and organ of Corti, and the renal tubule.19 The index of suspicion for a mitochondrial disorder should be high when there is apparently unrelated symptomatic involvement of two or more tissues. In the proper context, the suspicion that an illness involves mitochondrial dysfunction should be raised when the individual or family history includes any of the following: short stature, migraine-like headaches, sensorineural hearing loss, progressive external ophthalmoplegia, axonal neuropathy, diabetes mellitus, hypertrophic cardiomyopathy, or renotubular acidosis.
Of the variety of clinical syndromes associated with mitochondrial dysfunction (Table 2),20 this patient's illness is best characterized as the MELAS syndrome.21 Previously established diagnostic criteria for the MELAS syndrome specified the presence of stroke-like episodes before the age of 40 years, encephalopathy with seizures or dementia, and either lactic acidosis or so-called ragged-red fibers (subsarcolemmal accumulation of red-staining material on muscle biopsy), along with at least two of the following: normal early development, recurrent headache, or recurrent vomiting.22,23 As data have accumulated on the breadth of phenotypes in patients harboring genetic mutations associated with the MELAS syndrome, some authorities have suggested an approach to the diagnostic workup that would broaden the identification of mitochondrial encephalomyopathy even when strict diagnostic criteria are not met.20 As was the case with the approach to this patient, the workup includes a detailed history and family history (with particular attention to potentially associated conditions described above), laboratory tests (especially measurement of serum and cerebrospinal fluid lactate and serum creatine kinase), MRI studies (including the specific sequences used in this case), exercise physiology, muscle biopsy for morphology and biochemistry, and molecular genetic screening.
Table 2. Clinical Features of Mitochondrial Diseases Associated with Mitochondrial DNA Mutations.
Although mitochondrial encephalomyopathy was the leading diagnosis, both health care providers and the patient's family were frustrated by the difficulty of obtaining a definitive tissue and genetic diagnosis. Genetic screening performed on the first muscle-biopsy specimen for the seven most common mitochondrial DNA mutations was negative.
The diagnostic procedure was a second muscle biopsy.
Clinical Diagnosis
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (the MELAS syndrome).
Dr. Bradford C. Dickerson's Diagnosis
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (the MELAS syndrome).
Pathological Discussion
Dr. Di Tian: Both of the muscle-biopsy specimens were taken from the right deltoid. The first showed mildly increased variation in myofiber size and rare myocytes with increased subsarcolemmal and cytoplasmic NADH–tetrazolium reductase enzyme activity. However, there was no subsarcolemmal accumulation of red-staining material (ragged-red fibers, which characterize mitochondrial myopathy) on trichrome staining. Stain for ATP revealed occasional small atrophic myofibers of both types without fiber-type grouping. Electron microscopical examination did not reveal morphologically abnormal mitochondria.
The second muscle-biopsy specimen showed moderately increased variation in myofiber size and some atrophic myocytes displaying coarse cytoplasmic and subsarcolemmal staining with hematoxylin and eosin (Figure 3A). These fibers contained subsarcolemmal accumulation of linear, irregular material that stained red, indicating ragged-red fibers (Figure 3B). Abnormal subsarcolemmal and cytoplasmic accumulations of mitochondria were also highlighted by NADH-TR (Figure 3C), succinyl dehydrogenase, and cytochrome c oxidase stains and on electron microscopy (Figure 3D). These morphologic features were highly suggestive of mitochondrial myopathy.
Figure 3. Biopsy Specimen of the Right Deltoid Muscle Showing Features of Mitochondrial Myopathy.
A myocyte shows clumped cytoplasmic staining on a hematoxylin-and-eosin stain (Panel A) and subsarcolemmal accumulation of red-staining material, so-called "ragged-red fibers," on a modified Gomori's trichrome stain (arrow, Panel B). NADH–tetrazolium reductase stain (Panel C) highlights markedly increased enzymatic activity (dark blue staining) in the subsarcolemmal compartment of some fibers. Electron microscopy reveals subsarcolemmal and interfibrillary accumulation of mitochondria. Some mitochondria (Panel D) are enlarged, with complex internal structure, and some contain abnormal electron-dense material.
Tissue was sent to Columbia University's laboratory for biochemical and genetic testing. Electron-transport-chain assays on both biopsy samples revealed a defect in complex I, with normal activities in complexes II, III, and IV. DNA sequencing disclosed a G13513A missense mutation in the ND5 mitochondrial gene, a subunit of complex I, resulting in alteration from aspartic acid to asparagine at amino acid residue 393 (D393 N), which is predicted to cause a secondary structural change.24,25 This mutation has been described in patients with various clinical phenotypes that are associated with mitochondrial dysfunction, including cases of both childhood and adult-onset MELAS syndrome,26,27,28,29 Leber's hereditary optic neuropathy and MELAS overlap syndromes,26,29 adult-onset encephalomyopathy with blindness,29 and Leigh or Leigh-like (atypical) syndrome with isolated complex I deficiency in childhood.24,30
Among the six reported patients with the MELAS syndrome and G13513A mutation, all had clinical features of the MELAS syndrome, including hearing loss, by their mid-40s — and most were in their second decade. The patient under discussion was in her early 60s at the onset of her illness, making her the oldest patient with the MELAS syndrome known to carry the G13513A mutation.
Discussion of Management
Dr. Dickerson: The patient was discharged home from her third admission on the 19th hospital day. The level of diagnostic specificity imparted by the results of the genetic testing, which were returned two months after the patient's discharge, provided relief to the patient's husband and sons and made possible both a discussion of the heritability of diseases associated with mutations in mitochondrial DNA and optimal planning for end-of-life care for the patient.
Therapeutic options for mitochondrial encephalomyopathies are currently limited.18,20 Symptomatic and palliative approaches include the treatment of seizures, hearing loss, ophthalmoplegia, diabetes, and cardiac-conduction block. The mainstay of treatment, which was used with this patient, is the use of metabolite and cofactor supplements, including coenzyme Q10 (an oxygen-radical scavenger) and L-carnitine (to restore secondarily lowered levels of free carnitine). Although there are few data to support the efficacy of these supplements, the risks are minimal. Exercise and physical therapy, once thought to be detrimental to patients with mitochondrial disorders, is now the subject of investigations, with recent evidence indicating that aerobic training increases work tolerance and oxidative capacity in patients with mitochondrial DNA mutations.31 Finally, new approaches to genetic therapy are being studied.
Over the course of several home visits, I worked with the patient's husband and sons and the hospice team to develop a palliative care program that included pain management and other symptom management, psychosocial support, and the coordination of services, including autopsy arrangements.32,33
Dr. Walsh: Over the eight months after discharge the patient continued to decline. She became almost mute and spent most of her time sleeping. She died at home two years after the onset of her illness.
Dr. Tian: The autopsy showed bronchopneumonia to be the immediate cause of death. The brain weighed 1070 g (normal, 1300 to 1400 g). The left temporal lobe, the left inferior parietal lobe, and the anterior aspect of the left occipital lobe, as well as the right inferior parietal lobe, were soft with yellowish discoloration (Figure 4A). These lesions were asymmetric and did not fall into the vascular territories or border zones of any major cerebral arteries. Coronal sections revealed laminar cortical necrosis in these areas (Figure 4B). Microscopical examination showed severe neuronal loss in the middle and deep cortical layers, with the accumulation of hemosiderin-laden macrophages and reactive astrocytes (Figure 4C). The underlying white matter was gliotic. Scattered foci of isolated cortical necrosis were present.
Figure 4. Autopsy Findings in the Brain.
A gross external photograph of the brain shows that the left temporal, parietal, and anterior occipital lobes are soft and yellow (arrows, Panel A). A coronal section of the left cerebral hemisphere shows laminar cortical disruption in the inferior parietal lobule and lateral temporal cortexes (arrows, Panel B). A low-magnification photomicrograph of the left superior and middle temporal gyri reveals laminated cortical disruption (arrows, Panel C). Marked neuronal loss, reactive gliosis, and the accumulation of hemosiderin-laden macrophages are seen on higher magnification (inset). Some cerebellar Purkinje cells have marked swelling of the proximal dendrites, the so-called "cactus dendrites" (arrows, Panel D). (Panels C and D, Luxol fast blue–hematoxylin and eosin stain).
Some cerebellar Purkinje cells had marked swelling of the proximal dendrites (Figure 4D), referred to as "cactus dendrites" by some authors,34 which have been described in patients with mitochondrial diseases. Arteriosclerosis and arteriolosclerosis and a small putamenal infarct were present, consistent with the patient's history of hypertension. The skeletal muscles demonstrated changes similar to those noted in her second muscle biopsy.
The postmortem findings of multifocal cortical laminar necrosis and isolated cortical necrosis are consistent with mitochondrial encephalomyopathy.
Dr. Nancy Lee Harris (Pathology): Dr. Holtzman, can you explain the peculiarities of mitochondrial DNA as they relate to this patient and her family?
Dr. David Holtzman: Mitochondria are present in the cytoplasm of the ovum and are thus all inherited from the mother. There are multiple DNA molecules in each mitochondrion and multiple mitochondria in each cell.35 The mitochondria are randomly sorted when daughter cells are formed. Thus, when a mitochondrial mutation is present, the mutation load in any given organ of any single person is highly variable — a condition known as heteroplasmy. It cannot be predicted whether the mutation load will reach a threshold for clinical expression. This random sorting of mitochondrial DNA and its mutations explains why no one in the patient's mother's family had a similar clinical phenotype and limits the value of genetic testing in other family members. Other factors, such as toxins and aging, also may affect the clinical expression.
Anatomical Diagnosis
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (the MELAS syndrome).
Source Information
From the Departments of Neurology (B.C.D., D.H.) and Pediatrics (D.H.), the Division of Pediatric Radiology, Department of Radiology (P.E.G.), and the Department of Pathology (D.T.), Massachusetts General Hospital; the Division of Cognitive and Behavioral Neurology, Department of Neurology, Brigham and Women's Hospital (B.C.D.); and the Departments of Neurology (B.C.D., D.H.), Pediatrics (D.H.), Radiology (P.E.G.), and Pathology (D.T.), Harvard Medical School — all in Boston.
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