Brief Communications

tests, such as cerebral angiography, in the appropriate time. Bispectral
index monitoring can be used in severely comatose children for early
detection and confirmation of brain death. Nevertheless, further studies
are needed to determine the role of bispectral index monitoring in the
diagnosis and confirmation of brain death in children.
Çetin Okuyaz, MD
Department of Pediatrics
Mersin University Medical Faculty
Handan Birbiçer, MD
Nurcan Doruk, MD
Department of Anesthesiology and Reanimation
Mersin University Medical Faculty
Aytuǧ Atıcı, MD
Department of Pediatrics
Mersin University Medical Faculty
Mersin, Turkey
Received April 22, 2005. Received revised July 9, 2005. Accepted for publication July 24, 2005
Address correspondence to Dr Çetin Okuyaz, Adnan Menderes Bulv.
Eǧriçam Mah., Kasım Ekenler Sitesi. B blok. No: 23, Mersin, Turkey. Tel:
+90-324-3374300/1141; fax: +90-324-3263352; e-mail: okuyazc@
mersin.edu.tr.

References
1.

Schneider S, Ashwal S: Determination of brain death in infants and
children, in Swaiman K (ed): Pediatric Neurology, 3rd ed. Vol 2. St.
Louis, Mosby, 1999, 969–980.

2.

Report of Special Task Force: Guidelines for the determination of
brain death in children. American Academy of Pediatrics task force
on brain death in children. Pediatrics 1987;80:298–330.

3.

Wijdicks EF: The diagnosis of brain death. N Engl J Med 2001;344:
1215–1221.

4.

Okuyaz C, Gücüyener K, Karabacak N, et al: Tc-99m-HMPAO SPECT
in the diagnosis of brain death in children. Pediatr Int 2004;46:711–
714.

5.

Paolin A, Manualin A, Di Paola F, et al: Reliability in diagnosis of
brain death. Intensive Care Med 1995;21:657–662.

6.

Flashion R, Windsor A, Sigl J, et al: Recovery of consciousness after
thiopental or propofol. Anesthesiology 1997;86:613–619.

7.

Driessen JJ, Harbers JB, van Egmond J, et al: Evaluation of the
electroencephalographic bispectral index during fentanyl-midazolam
anesthesia for cardiac surgery. Does it predict haemodynamic
responses during endotracheal intubation and sternotomy? Eur J
Anasthesiol 1999;16:622–627.

8.

Liu J, Singh H, White PF: Electroencephalogram bispectral analysis
predicts the depth of midazolam induced sedation. Anesthesiology
1996;84:64–69.

9.

Glass PS, Bloom M, Kearce L, et al: Bispectral analysis measures
sedation and memory effects of propofol, midazolam, isoflurane and
alfentanyl in healthy volunteers. Anesthesiology 1997;86:836–847.

10.

Billard V, Gambus PL, Chamoun N, et al: A comparison of spectral
edge, delta power, and bispectral index as EEG measures of
alfentanyl, propofol, and midazolam drug effect. Clin Pharmacol
Ther 1997;61:45–58.

11.

Gan TJ, Glass PS, Windsor A, et al: Bispectral index monitoring
allows faster emergence and improved recovery from propofol,
alfentanil, and nitrous oxide anesthesia. Anesthesiology 1997;87:808–
815.

12.

De Deyne C, Struys M, Decruyenaere J, et al: Use of continuous
bispectral EEG monitoring to assess depth of sedation in ICU
patients. Intensive Care Med 1998;24:1294–1298.

13.

Simmons LE, Riker RR, Prato BS, et al: Assessing sedation during
intensive care unit mechanical ventilation with the bispectral index
and the sedation-agitated scale. Crit Care Med 1999;27:1499–1504.

14.

Watson BJ, Van Delft M, Evans JJ, et al: Bispectral index in coma
patients, abstract. J Neurosurg Anesthesiol 1996;8:1103.

801

15.

Gilbert TT, Wagner MR, Halukurike V, et al: Use of bispectral index
electroencephalogram monitoring to assess neurologic status in
unsedated, critically ill patients. Crit Care Med 2001;29:1996–2000.

16.

Hana AR, Inchoisa MA, Frost EAM: The bispectral index as a
predictor of outcome after head injury, abstract. 73rd Congress of the
International Anesthesia Research Society, 1999. Anesth Analg 1999;
88:S56.

17.

Vivien B, Paueron X, Le Cosquer P, et al: Detection of brain death
onset using the bispectral index in severely comatose patients.
Intensive Care Med 2002;28:419–425.

18.

Anez Simon C, Recasens Urbez J, Lorente Cogollos C, et al: The
bispectral electroencephalographic index (BIS) and brain death. Rev
Esp Anesthesiol Reanim 2000;47:422–423.

19.

Valero R, Gambus P, Zavala B, et al: BIS monitoring as an outcome
predictor in severely brain damaged nonsedated critically ill patients,
abstract. Eur J Anesthesiol 2001;18(Suppl 21):A245.

20.

American Electroencephalographic Society: Guideline three:
Minimum technical standards for EEG recording in suspected
cerebral death. J Clin Neurophysiol 1994;11:10–13.

21.

Shapiro BA: Bispectral index: Better information for sedation in the
intensive care unit? Crit Care Med 1999;27:672–678.

22.

Hsia SH, Wu CT, Wang HS, et al: The use of bispectral index to
monitor unconscious children. Pediatr Neurol 2004;31:20–23.

23.

Johansen JW, Sebel PS: Development and clinical application of
electroencephalographic bispectrum monitoring. Anesthesiology
2000;93:1136–1344.

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Bruhn J, Bouillon TW, Shafer SL: Electromyographic activity falsely
elevates the bispectral index. Anesthesiology 2000;92:1485–1487.

25.

Guerit JM: Unexpected myogenic contaminants observed in the
somatosensory evoked potentials recorded in one brain-dead patient.
Electroencephalogr Clin Neurophysiol 1986;64:21–26.

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Reilly EL, Kelley JT, Pena YM: Failure of Pavulon to consistently
provide adequate EMG attenuation for recording electrocerebral
inactivity. Clin Electroencephalogr 1985;16:72–76.

27.

Wee AS: Scalp EMG in brain death electroencephalogram. Acta
Neurol Scand 1986;74:128–131.

Proton Magnetic Resonance Spectroscopy and
Diffusion-Weighted Imaging in Isolated Sulfite
Oxidase Deficiency
ABSTRACT
Isolated sulfite oxidase deficiency is a rare autosomal recessive
disorder of the newborn that can be mistaken for neonatal
asphyxia. Diffusion-weighted imaging of the brain demonstrates
widespread diffusion restriction, and proton magnetic resonance
spectroscopy shows an elevated lactate level, a decrease in the
ratio of N-acetylaspartate to creatine, and a rise in the ratio of
choline to creatine. This precedes severe cystic encephalomalacia and suggests that the energy failure associated with neuronal
dysfunction and myelin disintegration occurs early in isolated
sulfite oxidase deficiency. (J Child Neurol 2006;21:801–805; DOI
10.2310/7010.2006.00174).

In the terminal reaction in the metabolism of sulfur-containing amino
acids, sulfite is oxidized to sulfate by sulfite oxidase, which requires
molybdenum as a cofactor.1
Deficiency of sulfite oxidase leads to seizures and severe neurologic
deterioration,1,2 although the neuropathogenesis remains unknown.
We report the findings of diffusion-weighted imaging and proton

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Journal of Child Neurology / Volume 21, Number 9, September 2006

Figure 1. Diffusion-weighted images and apparent diffusion coefficient maps on the fourth day of life. Restricted diffusion was seen in almost
the entire cortex and subcortical white matter, with posterior predominance, as well as in the lentiform nuclei, caudate, and small foci in the
thalami, with sparing of the ventrolateral thalamus. No signal abnormalities were seen in the anterior temporal lobes, cerebellum, and brain
stem.

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Brief Communications

magnetic resonance spectroscopy in a neonate with isolated sulfite
oxidase deficiency. The full clinical details of this patient were recently
reported.3

Case Report
After an uneventful pregnancy, a full-term baby boy was born with a
birthweight of 4.06 kg (75th–90th percentile), a length of 54.5 cm (97th
percentile), and a head circumference of 37.0 cm (75th percentile). He
required minimal resuscitation at delivery and had Apgar scores of 5 at 1
minute and 9 at 5 minutes. Toward the end of his first 24 hours of life, he
became tachypneic and irritable and had coarse breath sounds, and he
received intravenous antibiotics for presumed pneumonia. On the
following day, he fed very poorly, and by his third day of life, he was
noted to have respiratory distress and stridor during feedings. On
examination, he was hypotonic, with arching episodes. He also had a
high-pitched cry. On his fourth day of life, he had a seizure with right foot
cycling and tonic-clonic activity of the right upper extremity.
Electroencephalographic (EEG) recordings demonstrated diffuse, bilateral, hemispheric epileptiform discharges, predominantly over the
frontotemporal regions, right greater than left. The background showed
a marked burst suppression pattern. Initially, he did not respond to
phenobarbital, and phenytoin was added. He did not respond to a
pyridoxine trial and continued to have arching episodes. On ophthalmologic examination, the position of his lenses was normal.
A metabolic work-up revealed normal bicarbonate and ammonia
levels. Serum amino acids and urine organic acids were within normal
limits. Urine analysis revealed the presence of sulfites on his sixth day of
life. Plasma total homocysteine was undetectable, and urinary xanthine
and hypoxanthine levels were normal; these findings strongly suggested
the diagnosis of isolated sulfite oxidase deficiency instead of molybdenum cofactor deficiency. Mutation analysis of the sulfite oxidase gene
revealed a novel 4 basepair deletion that led to a frameshift mutation and
resulted in a prematurely truncated protein. Both of his parents were

803

heterozygous carriers for the same deletion.3 His parents were not known
to be consanguineous, and there was no family history of neurologic or
metabolic disorders. A diet low in sulfur amino acids (methionine and
cysteine) was started, and thiamine was administered. Over the course of
the next week, the arching episodes abated. An EEG at 2 weeks of life
showed no organized seizure activity, but the burst suppression pattern
continued.
An ophthalmologic examination at 11 months of age showed
bilateral mild nasal subluxation of the lenses. At 13 months of age, he
was microcephalic, with a head circumference of 41.5 cm (below the 3rd
percentile) and a length of 76 cm (50th percentile), and was severely
delayed in his development. He was hypertonic in all four limbs, with
brisk deep tendon reflexes, but his head control and truncal tone were
very poor. Repeated startle to loud noises and opisthotonic posturing
were noted. He was unable to roll over or sit up. He was not reaching out
for objects, and there was no meaningful vocalization.
Magnetic resonance imaging (MRI) was performed on a 1.5-Tesla
system (GE Signa, Madison, WI) on the fourth day of life and at 3K
months of age. It included sagittal T1-weighted (repetition time 5 500
milliseconds, echo time 5 10 milliseconds), axial T2-weighted (repetition
time 5 6025 milliseconds, echo time 5 102 milliseconds), threedimensional axial spoiled gradient recalled acquisition (repetition time
5 32 milliseconds, echo time = 8 milliseconds; 25 degrees flip angle), and
diffusion tensor imaging (repetition time 5 7500 milliseconds, echo time
5 118 milliseconds; field of view 40 3 20 cm; matrix 256 3 256; b value 0
and 1000 s/mm2; three signals acquired; six gradient directions). Our
diffusion sequence automatically processes and displays diffusionweighted images and apparent diffusion coefficient maps. Axial fast
fluid-attenuated inversion recovery (repetition time 5 10,000 milliseconds, echo time 5 140 milliseconds, inversion time: 2200 milliseconds)
images were obtained at the second examination.
Initial MRI findings obtained suggested an abnormal, possibly
ischemic, pattern, with diffuse loss of gray- and white-matter differentiation (Figure 1). Imaging at 3K months of age showed interval evolution of

Figure 2. Marked cystic encephalomalacia on fluid-attenuated inversion recovery images in the areas of former decreased diffusion on followup imaging at 3K months of age. Thinning of the corpus callosum and prominence of the ventricles, cisterns, and sulci consistent with diffuse
parenchymal loss were present.

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Journal of Child Neurology / Volume 21, Number 9, September 2006

decreased diffusion involving almost the entire cortex and subcortical
white matter, with relative sparing of the anterior temporal and
anterosuperior frontal lobes, which now showed marked encephalomalacia (Figure 2). No new foci of decreased diffusion were seen.
Single-voxel proton magnetic resonance spectroscopy was performed as part of the Probe spectroscopy package (repetition time 5
1500 milliseconds, echo time 5 144 milliseconds) on a GE 1.5-Tesla Signa
scanner on the fourth day of life. (The data were compared with those
from two age-matched control subjects who had normal MRIs that had
been obtained for evaluation of seizures.) Voxels with a size of 2 3 2 3 2
cm were placed in the deep gray nuclei (choline to creatine ratio 5 0.81
[control 0.55], N-acetylaspartate [NAA] to creatine ratio 5 0.89 [control
1.63], lactate to creatine ratio 5 5.46 [control 0.29]), centrum semiovale
(choline to creatine ratio 5 1.46 [control 0.50]), NAA to creatine ratio 5
0.96 [control 1.65], lactate to creatine ratio 5 9.13 [control 0.04]), and
parasagittal lobe (choline to creatine ratio 5 1.33 [control 0.55], NAA to
creatine ratio 5 0.75 [control 1.63], lactate to creatine ratio 5 10.16
[control 0.29]) (Figure 3). Follow-up magnetic resonance spectroscopy
at 3K months of age showed an interval decrease in all metabolite
ratios (NAA to creatine ratio 5 0.86, 0.96, and 0.48; choline to creatine
ratio 5 0.51, 0.63, and 0.68; lactate to creatine ratio 5 0.55, 0.47, and 1.44
in the deep gray nuclei, centrum semiovale, and parasagittal lobe,
respectively).

Discussion
Our neuroimaging findings offer insights into the possible pathophysiology of isolated sulfite oxidase deficiency. Diffusion-weighted imaging
showed early widespread decreased diffusion throughout the entire
cortex, subcortical white matter, and basal ganglia. Large lactate peaks
were seen in multiple regions. This was previously described in
molybdenum cofactor deficiency,4 the pathogenesis of which is believed
to be due to a secondary deficiency in sulfite oxidase. A decrease in the
NAA to creatine ratio and an elevation of the choline to creatine ratio
preceded severe cystic white-matter changes and volume loss in the basal
ganglia.
The radiographic picture of diffusion restriction and metabolic
abnormalities seen on magnetic resonance spectroscopy in our patient
is similar to that seen in neonatal hypoxic-ischemic encephalopathy.5
Whereas hypoxic-ischemic encephalopathy often results in injury to areas
of high metabolic demand or regions considered to be watershed zones,
isolated sulfite oxidase deficiency appears to affect the brain diffusely,
with relative sparing of the temporal lobe and thalamus. Further, the
caudate is rarely affected in hypoxic-ischemic encephalopathy, whereas it
is clearly involved in isolated sulfite oxidase deficiency. The decreased
T2-weighted signal in the white matter with blurring of the gray-matter–
white-matter junction throughout the brain and the significantly
decreased apparent diffusion coefficient measures in the
subcortical regions might be characteristic for isolated sulfite oxidase
deficiency.
The brains of deceased patients with isolated sulfite oxidase
deficiency are characterized by massive loss of neurons and axons, with
intense demyelination and glial proliferation leading to multiple discrete
cavitations in the deep cerebral white matter.1,2 Cystic and gliotic lesions
are also found in the basal ganglia, thalamus, and cerebellum.
Histopathologically, cortical lamination at the gyral apices is well
preserved, but gliosis and marked neuronal loss are observed in the sulci.
Our finding of decreased water diffusion suggests a disruption of
energy metabolism. In ischemia, it is thought that failure of the Na+/K+
adenosine triphosphatase leads to loss of ionic gradients and a net
translocation of water from the extracellular to the intracellular
compartment, where water mobility is relatively more restricted.6 Our
finding of increased lactate on proton magnetic resonance spectroscopy
might support this theory. Increased lactate is usually the result of
deranged energy metabolism and has been observed in ischemia,7 brain
tumors,8 mitochondrial diseases,9 and other conditions. Interestingly,
cerebrospinal fluid and serum lactate in our case were normal, indicative
of compartmentalized cerebral tissue injury. NAA is believed to be of
neuronal or axonal origin in mature brain,10 and its early decrease is most

Figure 3. Single-voxel proton magnetic resonance spectroscopy of
the cortical gray matter on the fourth day of life. Choline (Cho)
appears to be mildly elevated and N-acetylaspartate (NAA) abnormally low. A large lactate (Lac) doublet and some prominence of the
glutamate/glutamine region (Gl) is seen. Cr 5 creatine.
likely due to neuronal loss or dysfunction. The choline signal in proton
brain spectra is a composite signal consisting mainly of glycerophosphocholine, phosphocholine, and free choline itself, compounds that are
precursors and breakdown products of membranes. An elevation of the
choline signal is seen in active demyelination or an increased number of
glial cells.11
Refractory seizures and progressive neurologic deterioration in the
newborn should raise the suspicion of isolated sulfite oxidase deficiency.
The diagnosis can easily be distinguished from hypoxic-ischemic
encephalopathy by abnormally low plasma total homocysteine and the
presence of sulfites in urine. The findings in the present case indicate that
energy failure associated with neuronal dysfunction and myelin disintegration occurs early in isolated sulfite oxidase deficiency. Several
different pathways might be at work and warrant further investigation.

Acknowledgment
We are grateful to Eva Ratai, PhD, for her expert technical assistance in the
processing of magnetic resonance spectroscopic data.

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Florian Eichler, MD
Department of Neurology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
Wen-Hann Tan, MRCPCH
Genetics Training Program
Harvard Medical School
Boston, Massachusetts

Brief Communications

Vivian E. Shih, MD
Department of Neurology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
P. Ellen Grant, MD
Department of Radiology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
Kalpathy Krishnamoorthy, MD
Department of Neurology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts

805

myopathy. We describe a case of acute stroke owing to Barth
syndrome that required intra-arterial thrombolysis. This case
suggests that cardiovascular complications can be observed in
patients with Barth syndrome. Stroke prevention measures,
including the use of antithrombotic agents, might be warranted.
(J Child Neurol 2006;21:805–807; DOI 10.2310/7010.2006.00177).

Received May 12, 2005. Received revised August 4, 2005. Accepted for
publication August 17, 2005

Barth syndrome is a rare, inherited disorder with clinical features of
dilated cardiomyopathy, neutropenia, growth retardation, and skeletal
myopathy. Manifestations in the central nervous system have not been
reported, despite the theoretic risk of cardioembolic stroke. We describe
the first case of stroke associated with Barth syndrome, including a
discussion of intra-arterial thrombolysis and the prognostic implications
of this cerebrovascular complication.

This work was supported in part by the Mary L. Efron Fund at the
Massachusetts General Hospital.

Case Report

Address correspondence to Dr Kalpathy Krishnamoorthy; Department of
Neurology, Division of Child Neurology, Massachusetts General
Hospital, 55 Fruit Street, Boston, MA 02114. Tel: 617-726 3877; fax: 6177247860; e-mail: kkrishnamoorthy@partners.org.

References
1.

Johnson JL, Duran M: Molybdenum cofactor deficiency and isolated
sulfite oxidase deficiency, in Scriver CR, Sly WS, Childs B, et al (eds):
The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New
York, McGraw-Hill Professional, 2001, 3163–3177.

2.

Rupar CA, Gillett J, Gordon BA, et al: Isolated sulfite oxidase
deficiency. Neuropediatrics 1996;27:299–304.

3.

Tan WH, Eichler FS, Hoda S, et al: Isolated sulfite oxidase deficiency:
a case report with a novel mutation and review of the literature.
[published erratum appears in Pediatrics 2005;116:1615]. Pediatrics
2005;116:757–766.

4.

Takeoka M, Soman TB, Yoshii A, et al: Diffusion-weighted images in
neonatal cerebral hypoxic-ischemic injury. Pediatr Neurol 2002;26:
274–281.

5.

Salvan AM, Chabrol B, Lamourex S, et al: In vivo proton MR
spectroscopy in a case of molybdenum cofactor deficiency. Pediatr
Radiol 1999;29:846–848.

6.

Schaefer PW, Grant PE, Gonzalez RG: Diffusion-weighted MR
imaging of the brain. Radiology 2000;217:331–345.

7.

Barker PB, Gillard JH: Acute stroke: Evaluation with serial proton
magnetic resonance spectroscopic imaging. Radiology 1994;192:723–
732.

8.

Alger JR, Frank JA, Bizzi A, et al: Metabolism of human gliomas:
Assessment with H 1 MR spectroscopy and F-18 fluorodeoxyglucose
PET. Radiology 1990;177:633–641.

9.

Mathews PM, Andermann F, Arnold DL, et al: Proton MR spectroscopic characterization of differences in regional brain metabolic
abnormalities in mitochondrial encephalomyopathies. Neurology
1993;43:2484–2490.

10.

Birken DL, Oldendorf WH: N-acetyl-L-aspartic acid: A literature
review of a compound prominent in 1H-NMR spectroscopic studies of
brain. Neurosci Biobehav Rev 1989;13:23–31.

11.

Gill SS, Small RK, Thomas DG, et al: Brain metabolites as 1H NMR
markers of neuronal and glial disorders. NMR Biomed 1989;2:196–200.

An 18-year-old male with a well-documented personal and family history
of Barth syndrome experienced the sudden onset of headache and was
subsequently found on the floor of his apartment with dysarthria and
right hemiparesis. Prior to this episode, he had multiple syncopal
episodes and was treated with digoxin, lisinopril, and aspirin for dilated
cardiomyopathy. At emergency room presentation, his vital signs
included a blood pressure of 90/60 mm Hg and a heart rate of 108 bpm.
Neurologic examination revealed a dense right hemiparesis, right
hemisensory loss, and fluctuating aphasia, accounting for a National
Institutes of Health (NIH) Stroke Scale score of 20. Noncontrast
computed tomography revealed a hyperdense left middle cerebral artery.
Owing to his arrival at 3.5 hours from the time last known well,
intravenous tissue plasminogen activator was deferred. Hyperacute
magnetic resonance imaging (MRI) revealed thrombosis of the left
middle cerebral artery with restricted diffusion in a subcortical lesion
extending from the posterior limb of the internal capsule to the corona
radiata. Fluid-attenuated inversion recovery vascular hyperintensities
suggested slow collateral blood flow in the distal middle cerebral artery
and was corroborated with retrograde middle cerebral artery blood flow
via leptomeningeal collateral supply on emergent conventional angiography. Angiography demonstrated complete occlusion of the proximal
left middle cerebral artery just beyond its origin with robust collaterals
from the left anterior and posterior cerebral arteries (Figure 1A). Intraarterial thrombolysis with 12 mg of tissue plasminogen activator over 60
minutes failed to achieve recanalization. Mechanical thrombolysis using
serial passes of a 3.5 mm diameter Sentry balloon catheter (Boston
Scientific/Target, Fremont, CA) advanced over a Transend 0.010-inch
guidewire (Boston Scientific/Target) through the occluded M1 segment
resulted in complete recanalization at 7 hours (Figure 1B). Recanalization
was accompanied by simultaneous improvement in neurologic deficits in
the angiography suite, with only residual mild dysarthria and hemiparesis.
A subsequent transthoracic echocardiogram demonstrated a dilated left
ventricle with severe global systolic dysfunction and an ejection fraction
of 20%, without evidence of intracardiac thrombus. Despite postprocedural anticoagulation, he developed a 2.5 cm left ventricular thrombus
visualized on transesophageal echocardiography several weeks later.
Following multiple documented bouts of ventricular dysrhythmias, an
implantable cardioverter defibrillator was placed.

Discussion

Stroke Associated With Barth Syndrome
ABSTRACT
Barth syndrome is an inherited disorder characterized by dilated
cardiomyopathy, neutropenia, growth retardation, and skeletal

Barth syndrome is a rare (1 in 300,000 births) X- linked recessive disease
that is characterized by dilated cardiomyopathy, neutropenia, growth
retardation, and skeletal myopathy.1,2 A causative role for a mutation in
the G4.5 tafazzin gene has been demonstrated, which leads to defects in
cardiolipin.3 Affected individuals have a high rate of mortality during
infancy or early childhood from congestive cardiomyopathy or septicemia. Affected males often require digitalis, diuretics, and afterload
reduction agents as infants or toddlers but can be successfully weaned off

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