T h e n e w e ng l a n d j o u r na l o f m e dic i n e case records of the massachusetts general hospital Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor Case 28-2008: An 8-Day-Old Infant with Congenital Deafness, Lethargy, and Hypothermia Kevin J. Staley, M.D., Katherine B. Sims, M.D., P. Ellen Grant, M.D., and E. Tessa Hedley-Whyte, M.D. Pr e sen tat ion of C a se From the Departments of Pediatric Neurology (K.J.S., K.B.S.), Radiology (Pediatric Division) (P.E.G.), and Neuropathology (E.T.H.-W.), Massachusetts General Hospital; and the Departments of Neurology (K.J.S., K.B.S.), Radiology (P.E.G.), and Pathology (E.T.H.-W.), Harvard Medical School. N Engl J Med 2008;359:1156-67. Copyright © 2008 Massachusetts Medical Society. 1156 Dr. Sarah M. Barnett (Neurology): An 8-day-old boy was admitted to the neonatal intensive care unit of this hospital because of weakness and lethargy. The patient was born after a full-term gestation to a 26-year-old primigravida at a birthing center. The mother had received prenatal care with normal screening laboratory tests, including a positive test result for antibody to rubella and negative test results for group B streptococcus, rapid plasma reagin, hepatitis C, and human immunodeficiency virus. The prenatal course was uncomplicated; the mother had no fever or other symptoms of infection, and there was no change in fetal movement in the days before delivery. The birth weight was 3 kg, the length 49.5 cm, and the head circumference 33 cm. The Apgar scores were 6 at 1 minute and 7 at 5 minutes. Immediately after birth, there were signs of respiratory distress, including grunting and flaring, and the infant was admitted to another hospital. On examination, the temperature was 36.8°C, the pulse 128 beats per minute, the respiratory rate 44 breaths per minute with grunting, and the oxygen saturation 97% while the patient was breathing ambient air. A systolic ejection murmur (grade 2 out of 6) was heard; hypospadias and a hydrocele in the right scrotum were noted, and ecchymosis was present on the left thumb. The remainder of the examination was normal. Newborn screening for metabolic abnormalities was normal; other laboratory-test results are shown in Table 1. An electrocardiogram revealed a normal sinus rhythm. The respiratory distress resolved. Brain-stem auditory evoked responses were abnormal bilaterally. An appointment was made for additional audiology testing, and the patient was discharged home on the fourth hospital day with follow-up later that day with his pediatrician. During the next 5 days, he breast-fed well and was appropriately interactive. Two days before admission, additional outpatient auditory testing confirmed the presence of bilateral congenital sensorineural deafness. On the day before admission, the patient was seen by his pediatrician at noon and appeared well. In the midafternoon, he became disinterested in breast-feeding n engl j med 359;11 www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital Table 1. Results of Laboratory Tests.* Reference Range, Newborns† 1 Day before Admission, at Other Hospital On Admission Hematocrit (%) 42.0–66.0 49.5 37.4 40.1 Hemoglobin (g/dl) 13.5–21.5 11.9 12.3 White cells (per mm3) 5000–21,000 9600 10,200 9700 Neutrophils (%) 30–48 55 50 47 Lymphocytes (%) 40–81 30 34 32 Monocytes (%) 4–11 15 21 Band forms (%) 0–10 1 1 150,000–450,000 173,000 81,000 Variable Nucleated red cells (per 100 white cells) Platelets (per mm3) Reticulocytes (%) Erythrocyte count (per mm3) 2nd Hospital Day 1 0.5–2.5 2.2 3,900,000–6,300,000 4,490,000 Mean corpuscular volume (μm3) 88–126 Glucose (mg/dl) 60–100 93 Total protein (g/dl)‡ 5.9–7.5 5.2 Albumin (g/dl)‡ 3.4–4.8 3.2 Calcium (mg/dl) 8.5–10.5 10.0 Ionic calcium (mmol/liter) 1.14–1.30 1.29 Alkaline phosphatase (U/liter) 15–350 163 Aspartate aminotransferase (U/liter) 47–150 32 Alanine aminotransferase (U/liter) 10–55 18 Lactate (mmol/liter) 0.5–2.2 1.1 Pyruvate (mmol/liter) 0.08–0.16 0.09 83 99 111 9.4 * To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to millimoles per liter, multiply by 0.250. † Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital for newborns and infants are estimates derived from a combination of published normal ranges and internal data for these age groups. ‡ The reference range was obtained from the first hospital where the patient was admitted. and was lethargic, with intermittent grunting. The rectal temperature was 34.4°C. He was taken to the emergency department of the other hospital. On examination, he was listless and hypotonic and cried with painful stimuli. The pulse and blood pressure were normal; the temperature was 34.7°C, and the oxygen saturation was more than 95% while the patient was breathing ambient air. Specimens of blood and urine were sent for culture; other laboratory-test results are shown in Table 1. Chest radiographs and an electrocardiogram were normal. A lumbar puncture was performed; the cerebrospinal fluid was bloody and did not clear. Ampicillin, gentamicin, n engl j med 359;11 and fluids were administered intravenously. The temperature rose to 36.1°C with external warming. Early the next morning, he was transferred by ambulance to this hospital and was admitted. Additional history was obtained; during the admission immediately after his birth, he had been placed on an adult bed and had fallen to the floor unobserved, where he was found crying, with no evidence of bruising. There were no allergies to medications and no family history of congenital deafness, coagulopathy, or bleeding diathesis. His parents were unrelated and of European descent and in good health. His mother’s blood type was O Rh-positive. www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. 1157 T h e n e w e ng l a n d j o u r na l o f m e dic i n e On examination, the infant had no dysmorphic features. The temperature was 36.3°C, with an external heating source, the pulse 154 beats per minute, and the blood pressure 100/65 mm Hg. The respiratory rate was 33 breaths per minute, with intermittent grunting and stridor; the oxygen saturation was 97% while the patient was breathing ambient air. The weight was 2.925 kg, and the head circumference 35.5 cm. The skin was pink, with no lesions. His eyes were closed, a rooting reflex was present, and there was minimal spontaneous movement. The frontal fontanelle was tense, and the posterior fontanelle full but not bulging; the sutures were well approximated. The findings on laboratory testing of coagulation measures, serum electrolytes, bilirubin, and renal function were normal; other laboratory-test results are shown in Table 1. Computed tomography (CT) of the brain showed ventriculomegaly with intraventricular hemorrhage, along with hemorrhage and edema involving the cerebral and cerebellar white matter bilaterally, the deep gray nuclei, and the pons. Culture of the urine for cytomegalovirus was negative. Ampicillin and gentamicin were continued; acyclovir was added intravenously, and one dose of hydralazine was administered. Flexible laryngoscopy revealed normal vocal-cord motion for most but not all breaths. There was no evidence of laryngomalacia. Approximately 8 hours after arrival, examination by a neurologist revealed marked bulging of the anterior fontanelle, although there was no resistance to flexion of the neck. Breathing was irregular and labored. The eyes were tightly closed; there was no conjunctival injection or discharge. The left pupil was 3 mm in diameter, and the right 1.5 mm. The eyes were deviated leftward and did not move beyond the midline with oculocephalic maneuvers. The arms and legs had increased extensor tone, which increased with body stimulation. The toes were upgoing bilaterally. Midazolam and morphine were administered; the trachea was intubated, and mechanical ventilation was begun for respiratory distress and increased work of breathing. A right transfontanelle ventricular tap was performed at the bedside, with aspiration of 5 ml of bloody cerebrospinal fluid, which did not appear to be under increased pressure. After the procedure, the fontanelles became soft, the eyes were divergent, and the tone in the limbs decreased, with resolution of extensor posturing. Results of laboratory analysis of the cerebrospinal 1158 n engl j med 359;11 fluid are shown in Table 2. Phenobarbital was begun. Fifteen hours after admission, magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) revealed symmetrical, bilateral low signal on T2-weighted images in all deep gray nuclei and the centrum semiovale, consistent with recent hemorrhage, intraventricular extension, and ventriculomegaly. Petechial hemorrhage was present in the pons and dentate nuclei. Increased T2-weighted signal was present throughout the supratentorial and infratentorial white matter, indicating diffuse edema. The findings on MRA were normal, and no dural venous sinus thrombosis was present. Ophthalmologic examination disclosed mild bilateral subconjunctival and intraretinal hemorrhages, with no retinitis or vitritis. Analysis of arterial blood gases was normal. On the second hospital day, ventriculostomy was performed in the operating room, and a catheter was placed in the right occipital ventricle with a subcutaneous reservoir for ventricular subgaleal shunting. Routine analysis of the urine was normal; other laboratory-test results are shown in Tables 1 and 2. Intravenous thiamine (at a dose of 5 mg daily) was begun. Spontaneous activity, even with lightened sedation, was minimal, with poor respiratory effort. The following day, ultrasonography of the brain revealed extensive white-matter edema and hemorrhage, ventriculomegaly, intraventricular hemorrhage, and edema and ischemic changes in the deep gray nuclei. On the fourth hospital day, repeated MRI and magnetic resonance spectroscopy (MRS) revealed evolution of the severe diffuse injury with additional volume loss. An electroencephalogram, obtained while the patient was receiving phenobarbital, revealed generalized delta waves and some theta slowing, with no evidence of seizures. Noxious stimulation produced no reaction. On the fifth hospital day, at the request of the parents, mechanical ventilation was stopped, and comfort measures were administered. The patient died several hours later. An autopsy was performed. Differ en t i a l Di agnosis Dr. Kevin J. Staley: An acute encephalopathy developed in this patient at 8 days of age. This is a difficult clinical situation because of the urgency with which treatable disorders must be identified from a broad list of potential causes. The initial www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital Table 2. Analysis of Cerebrospinal Fluid.* Variable Reference Range, Newborns† On Admission Color 2nd Hospital Day Colorless Amber Pink Turbidity Clear Slight Moderate Xanthochromia None Yes Yes Red cells (per mm3) None 9920 16,278 White cells (per mm3) 0–30 18 23 Neutrophils (%) 0 6 2 Lymphocytes (%) 0 50 83 Monocytes (%) 0 44 8 Macrophages (%) 0 6 Unclassified cells (%)‡ 1 Comments Yellow crystals present Protein (mg/dl) 5–55 503 350 Glucose (mg/dl) 50–75 35 34 Varicella–zoster virus on nucleic acid testing Negative Cytomegalovirus DNA on nucleic acid testing Negative Herpes simplex virus DNA on nucleic acid testing Negative Lactate (mmol/liter) 0.5–2.2 Pyruvate (mg/dl) 0.50–1.70 Gram stain 2.9 1.23 No organisms seen Acid-fast stain No organisms seen Negative Culture Sterile Sterile * To convert the values for glucose to millimoles per liter, multiply by 0.05551. PCR denotes polymerase chain reaction. † Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital for newborns and infants are estimates derived from a combination of published normal ranges and internal data for these age groups. ‡ Unclassified cells included a cluster of large, immature cells with indistinct borders, suggestive of germinal matrix cells. differential diagnosis includes disorders related to trauma, infection, epilepsy, toxins, hypoxia–ische­ mia, and metabolism. Potential clues include an unwitnessed fall shortly after birth, sensorineural deafness, and hypothermia without other signs of shock. Trauma Trauma is an important consideration in an afebrile infant presenting with acute changes in mental status, particularly in light of the history of an unwitnessed fall. The increase in head circumference from 33 to 35.5 cm in the 8 days before admission and the tense anterior fontanelle could be the consequence of traumatic intracranial bleeding. Retinal hemorrhage is strongly associated with traumatic brain injury and at this age is unlikely to be related to delivery.1 The cerebrospinal fluid n engl j med 359;11 was bloody and did not clear, and the xanthochromia indicates bleeding at least several hours before the lumbar puncture.2 Although basilar skull fractures can cause hearing loss, trauma is not a likely cause of this infant’s bilateral sensory deafness.3 Radiologic examinations are the best means to evaluate closed head injuries associated with reduced levels of consciousness. May we review the imaging studies? Dr. P. Ellen Grant: The initial CT demonstrated intraventricular hemorrhage with ventriculomegaly and multifocal, symmetrical hemorrhage and edema of the deep gray nuclei, cerebral white matter, cerebellar white matter, and pons, with sparing of the subcortical white matter (Fig. 1). The cerebral sulci were effaced, and the sutures were widened, consistent with severe cerebral www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. 1159 T h e n e w e ng l a n d j o u r na l o f m e dic i n e A B C Figure 1. CT of the Brain. Initial noncontrast CT shows marked ventriculomegaly, diffuse edema, and split sutures. At the level of the midcerebellum, hemorrhage is seen in the pons and dentate nuclei (Panel A, arrows). At the level of the deep gray-matter RETAKE 1st Staley AUTHOR ICM nuclei (Panel B), hemorrhage is seen primarily in the caudate heads (arrows) and lateral lentiform nuclei (arrow2nd REG F 1a-c FIGURE heads). At the level of the lateral ventricular bodies (Panel C), hemorrhage is present primarily in the corona radiata 3rd CASE TITLE bilaterally (arrows). Revised EMail Enon ARTIST: mst FILL Line H/T Combo 4-C H/T SIZE 33p9 whelming swelling. MRI 15 hours after admission confirmed AUTHOR, PLEASE NOTE: infections in infancy. However, hypoFigurewith has been redrawnthermia and type has been due toreset. infection is usually associated with the presence of recent hemorrhage, more Please check carefully. extensive petechial hemorrhage in the deep gray shock,5 and there were few such signs in this nuclei, pons, and dentate nucleiJOB: and involvement infant.ISSUE: Other9-11-08 vital signs were normal, no sugges35911 of the inferior vermis (Fig. 2). The findings on tive findings were reported from the initial physMRA were normal. The features of the blood prod- ical examination, and the initial laboratory evalucts (dark on T2-weighted images and isointense uations did not reveal evidence of multisystem to slightly bright on T1-weighted images) sug- involvement. gested that the hemorrhage was approximately Bacterial meningitis in this age group is most 2 to 4 days old. MRI on the third day revealed frequently due to group B streptococci, Escherichia no new hemorrhage. The severe, diffuse swelling coli, or Listeria monocytogenes.6 Although there was was resolving, and the ventricles had decreased no nuchal rigidity on the initial physical examinain size. However, apart from the cortex and sub- tion, its absence does not exclude meningeal ircortical white matter, the brain remained abnor- ritation in very young infants. The cell counts in mally bright on T2-weighted images in areas not the blood and cerebrospinal fluid are not suggesinvolved by hemorrhage. tive of bacterial infection, particularly an advanced In summary, the images show a devastating infection causing this degree of encephalopathy. brain injury with diffuse edema and hemorrhage. The MRI findings of symmetric injury to deep The most striking aspect of the pattern of involve- nuclei and brain-stem structures are not suggesment is its symmetry. tive of meningitis, in which the cerebral cortex is Dr. Staley: The imaging studies demonstrate in- most frequently compromised, presumably due to tracranial hemorrhage, but there are no skull frac- its greater proximity to the inflamed meninges.7 tures; there is no evidence of subdural or subarach- Although perforating arteries supplying deep brain noid bleeding; there are no signal changes on MRI structures are occasionally compromised in mensuggestive of shear injury,4 and the symmetry and ingitis, the extent and symmetry of the lesions in location of the hemorrhages would be very un- this patient do not suggest such a cause. usual for trauma. Congenital infections present in the perinatal period, and two of these, rubella and cytomegalic Infection virus, are associated with congenital sensorineural Infections are important treatable causes of acute deafness. This infant did not have microcephaly, encephalopathy in infancy. Although this infant systemic involvement, intracranial calcifications, was afebrile, hypothermia is frequent in over- or retinopathy, making congenital infection un1160 n engl j med 359;11 www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital A B C Figure 2. Axial T2-Weighted Fast Spin–Echo Images from Initial MRI, Showing Marked Ventriculomegaly and Intraventricular Hemorrhage, with Severe Cerebral Edema. At the level of the midcerebellum (Panel A), hemorrhage is present in the posterior pons and dentate nuclei (outRETAKE 1st AUTHOR Staley lined by arrows) on a background ofICM markedly edematous pons and cerebellum (high T2 signal). At the level of the 2nd REG F FIGURE 2a-c deep gray nuclei (Panel B), hemorrhage is seen to involve all deep gray-matter structures (outlined by arrows) on a 3rd CASE TITLE background of marked edema (high T2 signal). At the level of the lateral ventricular Revised bodies (Panel C), multiple reEMail Line 4-C gions of hemorrhage are present (arrows). SIZE Enon ARTIST: mst FILL H/T Combo H/T 33p9 AUTHOR, PLEASE NOTE: Figure has been redrawndecline and type has reset. status, although they generinbeen mental likely, and polymerase-chain-reaction (PCR) assay Please check carefully. ally present in the immediate perinatal period 9 and rarely 9-11-08this degree of encephalopathy. ISSUE: cause Although hemorrhage and edema are common acute sequelae of strokes, the distribution of injuries observed in this infant are not consistent with arterial compromise, and there was no evidence of venous thrombosis on magnetic resonance venography. A global hypoxic–ischemic injury can present with encephalopathy and symmetric hemorrhagic injury to the basal ganglia, thalamus, and brain stem.10 An unwitSeizures, Toxins, and Cerebrovascular nessed asphyxial event or arrhythmia could lead Accidents to such a presentation but is much less likely in Seizures are a common cause of acute alterations the absence of evidence of injury to other organ in consciousness. The tonic eye deviation and pos- systems. turing observed in this infant raise the possibility of seizures, although the infant responded more Metabolic Disorders clearly to ventricular drainage than to anticonvul- Metabolic causes of acute encephalopathy in insant therapy. The cerebrospinal fluid, imaging fancy include disordered metabolism of organic studies, and electroencephalography indicate that acids, amino acids, ammonia, and glucose, as well epilepsy is not the primary problem in this case. as peroxisomal and mitochondrial disorders. OrToxic causes of acute encephalopathy are an im- ganic acidemias present with vomiting and sysportant initial consideration, although ingestion temic acidosis and can thus be ruled out in this of a central nervous system depressant as a cause patient. Amino acidemias and urea-cycle defects is unlikely in light of the evidence of hemorrhage, can present acutely with seizures and encephaland ingestion of an anticoagulant is unlikely in opathy in the case of a catabolic stress that inthe absence of systemic bleeding and with nor- creases protein breakdown, such as an intercurrent infection. However, the brain injuries shown mal coagulation studies. Strokes are relatively common in the perina- on CT and MRI are not consistent with these tal period and frequently present with an isolated causes. Defects of gluconeogenesis, such as galacand maternal antibody testing ruled out these diagnoses. Acquired enteroviral8 and 35911simplex JOB:herpes viral infections can present with isolated central nervous system disease in this age group, although enteroviral infections in the absence of systemic disease are not associated with such severe hemorrhagic complications, and the negative PCR results on the cerebrospinal fluid analysis substantially reduce the probability of a herpes simplex infection. n engl j med 359;11 www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. 1161 T h e n e w e ng l a n d j o u r na l o f m e dic i n e tosemia, could present with hypoglycemia and secondary encephalopathy and brain injury. However, galactosemia presents with vomiting, acidosis, and jaundice, and the newborn screening for this disease was negative. Peroxisomal disorders, such as Zellweger’s syndrome and infantile adrenoleukodystrophy, which are due to mutations in genes required for metabolism of fatty acids and result in an accumulation of lipids in the nervous system, can present with encephalopathy, but this condition is manifested at the time of birth; in addition, dysmorphic features and hepatomegaly are common, and these disorders are not associated with cerebral hemorrhage. Mitochondrial Disorders Mitochondrial disorders often present with acute decompensation with overwhelming lactic acidosis and shock or with encephalopathy alone in the neonatal period and early infancy.11 The elevated lactate levels in the cerebrospinal fluid but not in the blood in this patient suggest a mitochondrial disorder expressed predominantly in the brain. In contrast to the other disorders considered thus far, the MRI findings are strongly suggestive of a mitochondrial disorder. Leigh’s syndrome, also known as subacute necrotizing encephalopathy, presents in infancy with symmetrical injuries to the basal ganglia and thalamus, deep white matter, brain stem, cerebellum, and spinal cord, with relative sparing of the cerebral cortex,12,13 precisely the distribution of injury in this case. Although this infant’s presentation is hardly subacute, in early infancy Leigh’s syndrome frequently presents as an acute encephalopathy. Furthermore, the disease process probably began before admission; the observed increase in head circumference would not occur immediately after an acute hemorrhage. An increase in head circumference has been reported in early infantile presentations of Leigh’s syndrome14,15 and indicates that the subacute descriptor is appropriate. The sudden onset of this infant’s symptoms may have been due to cumulative damage to brain-stem structures or to an acute increase in intracranial pressure because of bleeding. Cerebral hemorrhage, which was prominent in this infant even before the platelet count fell, is uncommon in Leigh’s syndrome16 but is common in a related disorder, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke). 1162 n engl j med 359;11 However, there was no systemic lactic acidosis; the symmetry and exclusively subcortical location of the injury would be unusual for MELAS, and that disorder almost always presents in older children and young adults. Hemorrhages in the thalamus, midbrain, and retina are common in Wernicke’s encephalopathy,17 which is due to a thiamineresponsive reduction in the activity of enzymes such as pyruvate dehydrogenase that are necessary for carbohydrate oxidation; congenital deficiency of pyruvate dehydrogenase is a frequent cause of Leigh’s syndrome.18 Wernicke’s encephalopathy19 and the mitochondrial encephalopathies of infancy20 may present with hypothermia without other evidence of shock, presumably due to hypothalamic injury. This infant had hearing loss, which is common in mitochondrial cytopathies.21 Although such hearing loss is not typically congenital, its presence in an infant with encepha­ lopathy may be an important clue to the diagnosis of a mitochondrial cytopathy.22 The MRS in this case suggests increased brain lactate, but this could not be definitively demonstrated. Although elevated lactate in the cerebrospinal fluid strongly suggest a disorder of oxidative phosphorylation, the clinical response to a ventricular tap suggests that this patient probably had reduced cerebral perfusion at some time, and it is also possible that the elevated lactate on MRS and in the cerebrospinal fluid reflected compromised tissue perfusion or mitochondrial dysfunction associated with hemorrhage23 rather than a primary mitochondrial disorder. In summary, it is likely that this infant with acute encephalopathy and hypothermia, increasing head circumference, extensive symmetric injury to deep gray-matter structures, elevated lactate in the cerebrospinal fluid, and sensorineural hearing loss had a mitochondrial encephalopathy. The distribution of injuries is strongly suggestive of Leigh’s syndrome, although the amount of hemorrhage is unusual. When lesions have atypical characteristics, the term “Leigh-like syndrome” is used,18 and that diagnosis seems most appropriate in this case. Dr. Eric S. Rosenberg (Pathology): Dr. Caviness, can you give us your impressions when you took care of the patient? Dr. Verne S. Caviness, Jr. (Neurology): Dr. Barnett and I saw this child with Dr. Sanjay Aurora and his team early in the morning of the first hospi- www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital tal day. Our immediate clinical diagnosis was lifethreatening intracranial hypertension due to hemorrhage, a neurosurgical emergency. Within a few minutes, the child was intubated and a ventricular tap was performed. The vital signs rectified, the decerebrate state relaxed, and the fontanelles relaxed. That afternoon, MRI showed the remarkable pattern described above, which essentially excluded virtually all diagnoses but a mitochondrial disorder. Cl inic a l Di agnosis Mitochondrial encephalopathy with intracranial hemorrhage. Dr . K e v in J. S ta l e y ’s Di agnosis Leigh-like syndrome of mitochondrial encephalopathy. Pathol o gic a l Discussion Dr. E. Tessa Hedley-Whyte: On examination of the brain at autopsy, the weight was normal; there was symmetrical, bilateral hemorrhagic necrosis of the basal ganglia, thalami, brain-stem gray matter, cerebellar dentate nucleus, spinal-cord gray matter, and cerebral and cerebellar white matter (Fig. 3A). Subependymal hemorrhage had ruptured into the lateral ventricles. The symmetrical distribution of the hemorrhagic necrosis is characteristic of Leigh’s syndrome, but the degree of hemorrhage is very unusual. Microscopically, the areas of necrosis contained macrophages with focal preservation of neurons (Fig. 3B) and vascular changes, including markedly thickened vessels with prominent endothelial cells and smaller capillaries with very prominent endothelial cells (Fig. 3B, inset). Vascular proliferation is characteristic of Leigh’s syndrome but was not as marked in this patient as it often is. In the deep white matter, there were areas of sharply delineated necrosis surrounded by macrophages, reactive gliosis, and mineralization, consistent with periventricular leukomalacia,24 a finding often seen in severely ill infants (Fig. 3C). Vascular thrombi and perivascular inflammation were minimal. The distribution and characteristics of the gray-matter injury are typical of Leigh’s syndrome. The remainder of the autopsy revealed a patent n engl j med 359;11 foramen ovale and ductus arteriosus, slight hy­po­ spa­dias, an accessory spleen, and evidence of stress, including renal cortical concretions, hepatic extramedullary erythropoiesis, and atrophy of adipose tissue. The mitochondria in the heart were abnormally large with abnormal cristae, suggestive of a mitochondrial cytopathy (Fig. 3D). The mitochondria in the liver were normal. A muscle biopsy that was performed for biochemical and histochemical analysis a few hours before the patient’s death had normal staining for NADH dehydrogenase, cytochrome oxidase, and succinate dehydrogenase. Electron microscopy showed a few enlarged mitochondria with complex cristae and double layers of membrane, suggestive but not diagnostic of a mitochondrial cytopathy (Fig. 3E). Although the degree of hemorrhage is most unusual, the findings overall are consistent with Leigh’s syndrome, an entity originally described by Denis Leigh, who drew attention to the resemblance of the lesions to those of adult Wernicke’s disease.25 The diagnosis of acute necrotizing encephalopathy should also be considered, but this disorder usually follows a febrile illness and is characterized by symmetrical hemorrhagic lesions that particularly affect the thalamus and less often affect the basal ganglia.26,27 Leigh’s syndrome is a phenotype defined by the presence of hemorrhagic necrosis in the deep graymatter structures of the brain, brain stem, and spinal cord, as seen in this patient. The disease is caused by abnormalities in mitochondrial energy metabolism that affect the vascular endothelium, presumably resulting in ischemia; mutations in genes that are associated with these pathways are found in some patients.18 As with most mitochondrial cytopathies, the reason for the specific distribution of the lesions is not known. Even in a family with the same mitochondrial genetic defect, one sibling can have Leigh’s syndrome while another has a different neurodegenerative disease.28 Dr. Katherine B. Sims: The mitochondrion has both mitochondrial and nuclear genetic input into its structure and function,29-32 and defects in both have been associated with Leigh’s syndrome.33-37 The disease is most commonly associated with defects in complex IV (cytochrome oxidase), complex I, or the pyruvate dehydrogenase pathway (Table 3). The muscle biopsy was tested for abnormalities in the electron transport chain at the Center for Inherited Disorders of Energy Metabo- www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. 1163 T h e n e w e ng l a n d j o u r na l o f m e dic i n e A B C D E Figure 3. Pathological Findings. Coronal sections of the formalin-fixed cerebral hemispheres (Panel A, top) and horizontal slices of the brain stem and spinal cord (Panel A, bottom) show symmetric, bilateral hemorrhagic necrosis of the basal ganglia, thalami, RETAKE The 1stcerebral and cerebellar white brain-stem gray matter, cerebellar dentate nucleus, and spinal cord gray matter. Staley AUTHOR ICM 2nd matter is gray and sunken. The distribution of the necrosis is typical of Leigh’s syndrome. There is blood in the latREG F FIGURE 3a-e CASE eral ventricles, which suggests subependymal into3rd the lateral ventricle. Microscopic TITLEmatrix hemorrhage with rupture Revised EMailpallidus and basal nucleus examination of sections of the globus Meynert (Panel B, hematoxylin and eosin) Line of 4-C SIZE Enon shows a necrotic background with sparing of the neurons inH/T the globus ARTIST: mst H/T pallidus and basal nucleus of Meynert 33p9 endothelial proliferation (arrow) in FILL with Leigh’s syndrome. Combo (arrows). These findings are consistent The inset shows small blood vessels of the basal ganglia. A vessel in the deep periventricular white matter (Panel C, hematoxylin and AUTHOR, PLEASE NOTE: has been and redrawn andare type has been reset. defined necrosis (arrowheads) eosin) is surrounded by a lymphocyticFigure cuff (arrow), there areas of sharply Please check carefully. with peripheral mineralization and reactive gliosis, findings consistent with periventricular leukomalacia. An electron micrograph of the heart at autopsy (Panel D) shows that the mitochondria are more variable in size than norJOB: 35911 ISSUE: 9-11-08 mal, and some have unusual, curved cristae (arrows). An electron micrograph of the muscle-biopsy specimen (Panel E) shows that the mitochondria in some myofibers are enlarged and elongated, with complex cristae (arrows), a feature that suggests a mitochondrial disorder (fixed in glutaraldehyde–osmium and embedded in epoxy in Panels D and E). lism at Case Western Reserve University School of Medicine in Cleveland. There was decreased citrate synthase activity, suggesting a decreased number of mitochondria, and deficiencies were found in multiple electron-transport-chain enzymes: complexes I, II, and IV. An elevation in the levels of long-chain acetylcarnitines was present, suggesting secondary dysfunction in fatty acid oxidation 1164 n engl j med 359;11 in the context of oxidative–phosphorylation abnormalities. Pyruvate dehydrogenase deficiency was ruled out by the normal pyruvate level in the cerebrospinal fluid and the presence of multiple deficiencies in the electron transport chain. The finding in this case of a deficiency of complex II in addition to complexes I and IV is unusual. Complex II has four structural subunits, www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital none of which are encoded in the mitochondrial DNA (mtDNA). The presence of multiple deficiencies in the electron transport chain, including complex II, together with the lack of a family history supporting maternal inheritance, would make a primary mtDNA-encoded defect unlikely. To better characterize this disorder and to offer genetic risk assessment for the family, molecular diagnostic studies were pursued. No mutations in mtDNA, including those associated with lactic acidosis and stroke (MELAS; mtDNA 3243, tRNALeu), mitochondrial encephalopathy with ragged red fibers (MERRF; mtDNA 8344, tRNALys), and neuropathy, ataxia, and retinitis pigmentosa (NARP; mtDNA 8993, ATPase 6), were found on full mtDNA screening by microarray analysis. Analysis for mtDNA deletion and duplication in muscle was normal. Testing for mtDNA depletion in muscle was not performed, since nuclear factors that underlie the stability of mtDNA may cause multiple complex deficiencies in the electron transport chain,38 but complex II would not be expected to be deficient, as it was in this patient. Genes encoding nuclear DNA (nDNA) that are associated with structural complex defects in the electron transport chain have been identified, but all result in dysfunction in a single complex. Nonstructural nDNA genes that are important in a variety of mitochondrial functions have been described, some of which have been associated with Leigh’s syndrome (Table 3).39-41 Testing for these abnormalities is not widely available and was not pursued. Testing that was performed at Boston Children’s Hospital Genetics Laboratory was negative for abnormalities in SLC26A4 (Pendred’s syndrome), mitochondrial hearing loss gene GJB6 (connexin 30), GJB2 (connexin 26), and hearing loss–associated mtDNA mutations at nucleotide positions 8296, 8344, 8356, and 8363 (tRNALys) and 7445, 7472, 7510, 7511, and 7512 (tRNASer). In summary, the diagnosis of Leigh’s syndrome is supported by the clinical and neuroimaging abnormalities, the gross and microscopic pathological findings, and the presence of multiple deficiencies in the electron transport chain in muscle. No specific molecular diagnosis was made, as is the case in 20 to 50% of cases of Leigh’s syndrome, since the majority of nDNA-encoded proteins that are important in mitochondrial function, structure, replication, segregation, and stability have n engl j med 359;11 Table 3. Common Abnormalities Associated with Leigh’s Syndrome, with Related Genes, ETC Deficiency or Protein Function, and Clinical Phenotype.* Abnormality Enzyme deficiency ETC complex IV (cytochrome oxidase) deficiency (most common) ETC complex I (NADH dehydrogenase coenzyme Q reductase) deficiency Pyruvate dehydrogenase deficiency Known genetic defect mtDNA-encoded mutations ETC complex V (ATPase 6; mtDNA 8993, 9176) deficiency ETC complex I (ND6) deficiency tRNALys, Leu (mtDNA 8344, 3243) mutations (rare) nDNA-encoded mitochondrial structural components NDUFV1, complex I; leukodystrophy, myoclonic epilepsy, Leigh’s syndrome NDUFV2, complex I; Leigh’s syndrome NDUFS1, complex I; Leigh’s syndrome NDUFS2, complex I; cardiomyopathy, encephalopathy NDUFS4, complex I; failure to thrive, hypotonia, Leigh-like syndrome NDUFS6, complex I; Leigh’s syndrome, adult myopathy NDUFS7, complex I; Leigh’s syndrome NDUFS8, complex I; Leigh’s syndrome Flavoprotein, complex II; Leigh’s syndrome or hereditary paraganglioma nDNA-encoded mitochondrial assembly, stability, oxidative–phosphorylation factors SURF1, cytochrome oxidase assembler; Leigh’s syndrome SCO1, cytochrome oxidase assembler, Cu+2; infantile encephalopathy SCO2, cytochrome oxidase assembler, Cu+2; infantile cardiomyopathy COX10, cytochrome oxidase assembler; infantile encephalopathy ANT1, nucleotide pool; autosomal dominant progressive external ophthalmoplegia Thymidine phosphorylase, nucleotide pool; mitochondrial neuroastrointestinal encephalopathy * Cu+2 denotes copper ion, ETC electron transport chain, mtDNA mitochondrial DNA, nDNA nuclear DNA, and tRNA transfer RNA. not been identified. Since no mtDNA mutation was identified, the abnormality is presumed to be in nDNA, so that the genetic risk of having an affected infant is substantially less than 100% for subsequent pregnancies in this mother. However, we do not know whether a sporadic mutation occurred in the patient or whether it is an inherited disorder, and thus we cannot further predict the genetic risk for future pregnancies. Dr. Sanjay Aurora (Neonatology): This child’s parents were very young, and this was their first child. The sudden devastation was very difficult emotionally for both them and the medical team to witness. When the likely diagnosis and grim prognosis became apparent, we spent a long time discussing the prognosis with them, so that they could come to the decision to end life support. Subsequently, the parents have participated actively in the genetic testing described by Dr. Sims. www.nejm.org september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. 1165 T h e n e w e ng l a n d j o u r na l o f m e dic i n e A nat omic a l Di agnosis Leigh’s syndrome, intraventricular hemorrhage, and periventricular leukomalacia. Dr. Staley reports holding a patent for the treatment of neonatal seizures with bumetanide, which is not licensed and is not associated with revenue; and Dr. Hedley-Whyte, having an equity interest in Becton Dickinson. No other potential conflict of interest relevant to this article was reported. References 1. Kaur B, Taylor D. Fundus hemor- rhages in infancy. Surv Ophthalmol 1992; 37:1-17. 2. Graves P, Sidman R. Xanthochromia is not pathognomonic for subarachnoid hemorrhage. Acad Emerg Med 2004;11: 131-5. 3. Zimmerman WD, Ganzel TM, Windmill IM, Nazar GB, Phillips M. Peripheral hearing loss following head trauma in children. Laryngoscope 1993;103:8791. 4. Zimmerman RA, Bilaniuk LT. Pediatric head trauma. Neuroimaging Clin N Am 1994;4:349-66. 5. Dagan R, Gorodischer R. Infections in hypothermic infants younger than 3 months old. Am J Dis Child 1984;138: 483-5. 6. Dawson KG, Emerson JC, Burns JL. Fifteen years of experience with bacterial meningitis. Pediatr Infect Dis J 1999;18: 816-22. 7. Jan W, Zimmerman RA, Bilaniuk LT, Hunter JV, Simon EM, Haselgrove J. Diffusion-weighted imaging in acute bacterial meningitis in infancy. Neuroradiology 2003;45:634-9. 8. Rorabaugh ML, Berlin LE, Heldrich F, et al. Aseptic meningitis in infants younger than 2 years of age: acute illness and neurologic complications. Pediatrics 1993;92:206-11. 9. Nelson KB. Perinatal ischemic stroke. Stroke 2007;38:Suppl:742-5. 10. Kreusser KL, Schmidt RE, Shackelford GD, Volpe JJ. Value of ultrasound for identification of acute hemorrhagic necrosis of thalamus and basal ganglia in an asphyxiated term infant. Ann Neurol 1984;16:361-3. 11. Debray FG, Lambert M, Chevalier I, et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 2007; 119:722-33. 12. Barkovich AJ, Good WV, Koch TK, Berg BO. Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol 1993;14: 1119-37. 13. Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders. AJNR Am J Neuroradiol 1998; 19:369-77. 1166 14. Feillet F, Mousson B, Grignon Y, Leonard JV, Vidailhet M. Necrotizing encephalopathy and macrocephaly with mitochondrial complex I deficiency. Pediatr Neurol 1999;20:305-8. 15. Dionisi-Vici C, Ruitenbeek W, Fariello G, et al. New familial mitochondrial encephalopathy with macrocephaly, cardiomyopathy, and complex I deficiency. Ann Neurol 1997;42:661-5. 16. van Erven PM, Cillessen JP, Eekhoff EM, et al. Leigh syndrome, a mitochondrial encephalo(myo)pathy: a review of the literature. Clin Neurol Neurosurg 1987;89:217-30. 17. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome: a clinical and pathological study of 245 patients, 82 with post-mortem examinations. Philadelphia: F.A. Davis, 1971. 18. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343-51. 19. Philip G, Smith JF. Hypothermia and Wernicke’s encephalopathy. Lancet 1973; 2:122-4. 20. McFarland R, Kirby DM, Fowler KJ, et al. De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol 2004; 55:58-64. 21. MITOMAP. a human mitochondrial genome database. 2007. (Accessed August 18, 2008, at http://www.mitomap. org.) 22. Jackson MJ, Schaefer JA, Johnson MA, Morris AA, Turnbull DM, Bindoff LA. Presentation and clinical investigation of mitochondrial respiratory chain disease: a study of 51 patients. Brain 1995;118:339-57. 23. Kim-Han JS, Kopp SJ, Dugan LL, Diringer MN. Perihematomal mitochondrial dysfunction after intracerebral hemorrhage. Stroke 2006;37:2457-62. [Erratum, Stroke 2006;37:3057.] 24. Banker BQ, Larroche JC. Periventricular leukomalacia of infancy: a form of neonatal anoxic encephalopathy. Arch Neurol 1962;7:386-410. 25. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951;14:216-21. 26. Wong AM, Simon EM, Zimmerman n engl j med 359;11 www.nejm.org RA, Wang H-S, Toh C-H, Ng S-H. Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome. AJNR Am J Neuroradiol 2006;27:1919-23. 27. Neilson DE, Eiben RM, Waniewski S, et al. Autosomal dominant acute necrotizing encephalopathy. Neurology 2003;61: 226-30. 28. Case Records of the Massachusetts General Hospital (Case 30-1992). N Engl J Med 1992;327:261-8. 29. Cohen BH. Mitochondrial cytopathies: a primer. Pittsburgh: United Mitochondrial Disease Foundation, 2000. (Accessed August 18, 2008, at http:// www.umdf.org.) 30. DiMauro S, Davidzon G. Mitochondrial DNA and disease. Ann Med 2005; 37:222-32. 31. Haas RH, Parikh S, Falk MJ, et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 2007;120:1326-33. 32. Schatz G. Mitochondria: beyond oxidative phosphorylation. Biochim Biophys Acta 1995;1271:123-6. 33. Antonicka J, Leary SC, Guercin GH, et al. Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet 2003;12:2693-702. 34. Bénit P, Slama A, Cartault F, et al. Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet 2004;41:14-7. 35. Loeffen J, Smeitink J, Triepels R, et al. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet 1998;63:1598608. 36. Matthews PM, Marchington DR, Squier M, Land J, Brown RM, Brown GK. Molecular genetic characterization of an X-linked form of Leigh’s syndrome. Ann Neurol 1993;33:652-5. 37. Zhu Z, Yao J, Johns T, et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 1998;20: 337-43. 38. DiMauro S, Hirano M, Schon EA, eds. Mitochondrial medicine. Abingdon, United Kingdom: Informa Healthcare, 2006. september 11, 2008 The New England Journal of Medicine Downloaded from nejm.org at GEORGE MASON UNIVERSITY on April 26, 2013. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital 39. Coenen MJH, Antonicka H, Ugalde C, et al. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N Engl J Med 2004;351:2080-6. 40. Horváth R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry 2006;77:74-6. 41. Ugalde C, Hinttale R, Timal S, et al. Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh syndrome. Mol Genet Metab 2007;90:10-4. Copyright © 2008 Massachusetts Medical Society. 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