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The

n e w e ng l a n d j o u r na l

of

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 36.8C, 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

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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 (%)

42.066.0

49.5

37.4

40.1

Hemoglobin (g/dl)

13.521.5

11.9

12.3

Variable

White cells (per mm3)

2nd Hospital
Day

500021,000

9600

10,200

9700

Neutrophils (%)

3048

55

50

47

Lymphocytes (%)

4081

30

34

32

15

21

Monocytes (%)

411

Band forms (%)

010

150,000450,000

173,000

81,000

Nucleated red cells (per 100 white cells)


Platelets (per mm3)
Reticulocytes (%)
Erythrocyte count (per mm3)

1
0.52.5

2.2

3,900,0006,300,000

4,490,000

Mean corpuscular volume (m3)

88126

Glucose (mg/dl)

60100

93

Total protein (g/dl)

5.97.5

5.2

Albumin (g/dl)

3.44.8

3.2

8.510.5

10.0

Calcium (mg/dl)
Ionic calcium (mmol/liter)

83
99

111

9.4

1.141.30

1.29

Alkaline phosphatase (U/liter)

15350

163

Aspartate aminotransferase (U/liter)

47150

32

Alanine aminotransferase (U/liter)

1055

18

Lactate (mmol/liter)

0.52.2

1.1

Pyruvate (mmol/liter)

0.080.16

0.09

* 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 34.4C. 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 34.7C, 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,

and fluids were administered intravenously. The


temperature rose to 36.1C 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 mothers
blood type was O Rh-positive.

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On examination, the infant had no dysmorphic


features. The temperature was 36.3C, 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
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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

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case records of the massachusetts gener al hospital

Table 2. Analysis of Cerebrospinal Fluid.*


Reference Range,
Newborns

On Admission

Colorless

Amber

Pink

Clear

Slight

Moderate

None

Yes

Yes

None

9920

16,278

030

18

23

Neutrophils (%)

Lymphocytes (%)

50

83

Monocytes (%)

44

Macrophages (%)

Variable
Color
Turbidity
Xanthochromia
Red cells (per

mm3)

White cells (per mm3)

2nd Hospital Day

Unclassified cells (%)

Comments

Yellow crystals
present

Protein (mg/dl)

555

503

350

Glucose (mg/dl)

5075

35

34

Varicellazoster virus on nucleic acid testing

Negative

Cytomegalovirus DNA on nucleic acid testing

Negative

Herpes simplex virus DNA on nucleic acid testing


Lactate (mmol/liter)
Pyruvate (mg/dl)

Negative
0.52.2

2.9

0.501.70

Gram stain

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, hypoxiaische
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

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 infants 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

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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
FILL

ARTIST: mst

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

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case records of the massachusetts gener al hospital

Figure 2. Axial T2-Weighted Fast SpinEcho 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.
inbeen
mental
polymerase-chain-reaction
(PCR)
assay
Please check carefully.

status, although they generally 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 hypoxicischemic 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 galaclikely, and
and 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.

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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 Zellwegers 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. Leighs 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 infants presentation is hardly subacute, in
early infancy Leighs 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 Leighs
syndrome14,15 and indicates that the subacute descriptor is appropriate. The sudden onset of this
infants 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 Leighs syndrome16 but is common
in a related disorder, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke).

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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 Wernickes
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
Leighs syndrome.18 Wernickes 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 Leighs 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-

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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
Leighs 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 Leighs
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 Leighs
syndrome.
The remainder of the autopsy revealed a patent

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 patients 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
Leighs syndrome, an entity originally described by
Denis Leigh, who drew attention to the resemblance of the lesions to those of adult Wernickes
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
Leighs 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 Leighs 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 Leighs 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-

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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 Leighs 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 Leighs 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 glutaraldehydeosmium 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

in the context of oxidativephosphorylation 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,

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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
Leighs syndrome (Table 3).39-41 Testing for these
abnormalities is not widely available and was not
pursued. Testing that was performed at Boston
Childrens Hospital Genetics Laboratory was negative for abnormalities in SLC26A4 (Pendreds syndrome), mitochondrial hearing loss gene GJB6
(connexin 30), GJB2 (connexin 26), and hearing
lossassociated mtDNA mutations at nucleotide
positions 8296, 8344, 8356, and 8363 (tRNALys)
and 7445, 7472, 7510, 7511, and 7512 (tRNASer).
In summary, the diagnosis of Leighs 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 Leighs syndrome,
since the majority of nDNA-encoded proteins that
are important in mitochondrial function, structure, replication, segregation, and stability have

Table 3. Common Abnormalities Associated with Leighs 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, Leighs syndrome
NDUFV2, complex I; Leighs syndrome
NDUFS1, complex I; Leighs syndrome
NDUFS2, complex I; cardiomyopathy, encephalopathy
NDUFS4, complex I; failure to thrive, hypotonia, Leigh-like syndrome
NDUFS6, complex I; Leighs syndrome, adult myopathy
NDUFS7, complex I; Leighs syndrome
NDUFS8, complex I; Leighs syndrome
Flavoprotein, complex II; Leighs syndrome or hereditary paraganglioma
nDNA-encoded mitochondrial assembly, stability, oxidativephosphorylation
factors
SURF1, cytochrome oxidase assembler; Leighs 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 childs 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.

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A nat omic a l Di agnosis


Leighs syndrome, intraventricular hemorrhage,
and periventricular leukomalacia.

of

m e dic i n e

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.

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