Assessment and
Therapy Monitoring
of Leigh Disease by
MRI and Proton
Spectroscopy
Ingeborg Kr~igeloh-Mann, MD*,
Wolfgang Grodd, MD*,
Gerhard Niemann, MD*,
Gerhard Haas, MD*, and
Wim Ruitenbeek, PhD~
In a 2-year-old boy with Leigh disease, spasticity,
dysarthria, and optic atrophy gradually developed.
Computed tomography and magnetic resonance imaging disclosed progressive, symmetric basal ganglia
lesions. In muscle tissue, a defect of pyruvate dehydrogenase complex was found. Magnetic resonance volume selective proton spectroscopy (MRVS) of the basal
ganglia demonstrated an abnormal lactate peak. A
ketonemic diet coincided with clinical stabilization and
arrest of progressive brain lesions. Lactate could no
longer be demonstrated by MRVS. It reappeared with
a new brain lesion coinciding with discontinuation of
the diet. MRVS, therefore, appears to be a sensitive tool
to evaluate pathologic lactate production in metabolic
brain disease with disturbed energy metabolism and
allows noninvasive therapy monitoring.
Kr/igeloh-Mann I, Grodd W, Niemann G, Haas G,
Ruitenbeek W. Assessment and therapy monitoring of
keigh disease by MRI and proton spectroscopy. Pediatr
Neurol 1992;8:60-4.

regression, ataxia, dystonia, spasticity, visual deterioration) [1 ]. Metabolic acidosis is a frequent, but not constant,
laboratory finding [2]. Definite diagnosis of Leigh disease
has been based on pathologic findings which typically
demonstrate necrotizing lesions that are most commonly
found symmetrically in the tegmentum of the brainstem.
as well as the basal ganglia, thalamus, cerebellum, medulla, optic nerves, and posterior columns of the spinal cord
[3]. Computed tomography (CT) [4-61 and, with higher
sensitivity, magnetic resonance imaging (MRI)[2,7.81
detect these lesions and most authors [4-81 stress the importance of symmetric basal ganglia defects, especially of
the putamina. Deficiencies of specific mitochondrial enz y m e s - especially pyruvate dehydrogenase complex
(PDHc), pyruvate carboxylase, NADH dehydrogenase,
cytochrome c oxidase- have been demonstrated in fibreblasts, liver, muscle, and brain of patients with Leigh disease. The deficiencies in brain tissue were found only in
combination with evidence of defects in other organs [3,812]. An abnormality of PDHc is believed to be the most
consistent biochemical finding in Leigh disease [13]. Morphologic studies of Leigh disease have revealed mitochondrial abnormalities in brain and other organs of autopsied
cases [14]; the brain abnormalities are regarded as evidence that Leigh disease is a cerebral mitochondriopathy.
Previously, it was supposed that the metabolic defect in
Leigh disease may be restricted to brain [8,13] as normal
mitochondrial enzyme activity may be found in muscle
tissue and cultured skin fibroblasts despite elevated
cerebrospinal (CSF) lactate and pyruvate levels. We report
a boy whose clinical findings, CT and MRI studies, and
biochemical analyses of muscle tissue were suggestive of
mitochondrial encephalopathy with deficiency of the
PDHc. Further diagnostic support of a defect in the oxidative metabolism involving mainly the brain was given by
MRVS volume selective proton spectroscopy which demonstrated an abnormal peak of lactate in the region of the
most progressive lesions (heads of the caudate nucleus).

Case Report

Leigh disease is an autosomal recessive disease with
onset in infancy or early childhood. The onset usually is
insidious and the course intermittently progressive for
several years. Clinical manifestations vary considerably
and are nonspecific (i.e., feeding problems, psychomotor

This boy was the first child of nonconsanguineous parents After uneventful pre-, peri- and post-natal periods and normal early development until the age of 2 years, deterioration of motor functions slowly
developed. He exhibited staggering and walked stiffly on his toes.
Hand functions became clumsy and speech slurred. Mental development was normal. During the first 21/2 years of the disease, neurologic
examinations demonstrated a slightly progressive spasticity which was
greater in the lower than in the upper extremities (i.e., increased tone,
hyperactive tendon reflexes, extensor plantar responses) with dystonic
posturing and progressive dysarthria. This spastic tetraplegia was first
predominant on the left side and then gradually became symmetric
during the fifth year of life. One year later, his gait and speech stabi-

From the Departments of *Developmental Neurology and
tNeuroradiology; University of Tiibingen; Tiibingen, Germany;
qnstitute of Pediatrics; University Hospital of Nijmegen; Nijmegen,
The Netherlands.

Communications should be addressed to:
Dr. Kr~geloh-Mann; Universit~its-Kinderklinik; Frondsbergstrasse 23:
D 74 Ti.ibingen, Germany.
Received May 28, 1991; accepted September 23, 1991.

Introduction

60

PEDIATRIC NEUROLOGY

Vol. 8 No. 1

CT2

CT1

$

,~MRI1
$

MRS1
MRI3

MRI2

$

MRS2
MRI4

$

MRS3
MRIS

$

$

MRS4
MRI6

$

biopsy

$

neurology: deterioration
|

2

l

l

l

l

l

i

l

3

l

l

stabilization
l

l

|

l

l

l

l

l

l

4

l

l

i

l

i

l

5

l

l

l

l

6

yrs

Figure 1. Disease course with respect to neuroradiologic investigations and diet.

decreased to below the 3rd percentile during the fourth and fifth years
of life, then reached the 3rd percentile during the sixth year, leaving
the child's height below the 3rd percentile.

lized, he could walk again without falling, and dysarthria was less
pronounced. Height and weight were at the 3rd percentile and head
circumference the 25th percentile at age 21/2 years. Growth rate

A

B

Figure 2. (A) T~-weighted cranial images at 39 months of age (1, corresponding to MRI1 in Fig 1) disclosing bilateral defects of the putamina
and the caudate head on the right side, defects being hypointensive; at age 50 months (2, corresponding to MRI2) disclosing an increase in
volume of the left head of the caudate nucleus with decreased signal intensities; at age 56 months (3, corresponding to MRI3) disclosing a
decrease in volume of the left head of the caudate nucleus and a hyperintense area; at age 64 months (4, corresponding to MRI4) revealing no
additional tissue defects; at age 74 months (5, corresponding to MRI5) unchanged; at age 78 months (6, corresponding to MRI6) disclosing a
defect of the right caudate head. (B) T2-weighted images of the same examinations disclosing reversed signal intensities. The hyperintense
areas of the caudate head visualized on the Tl-weighted images are masked here which excludes remnants of blood and favors a paramagnetic
effect in the necrotic area.

Kr~geloh-Mann et al: Leigh Disease 61

Table 1. Serum lactate and pyruvate levels

Lactate (mmol/L)

2~/2

31/4

Age (years)
41&
5 IA

51/2

6 V2

Normal

2.2

1.4

1.7

1.7

[.8

1.2

~ 1.8

Pyruvate (gmol/L)

147

84

116

120

114

91

_.~ 120

Lactate/pyruvate
ratio

15

16

14.7

14.2

15.8

12.2

~ 15

At the age of 2½ years, normal results were demonstrated by neurophysiologic studies (i.e., electroencephalography, electromyography,
motor nerve conduction velocity studies), electrocardiography, echocardiography, and abdominal ultrasonography. Fundoscopy was normal,
but demonstrated bilateral partial optic atrophy without deterioration of
vision 2 years later and proved unchanged at the age of 6 years.
At 4 years of age, oral treatment with thiamine (500 mg daily) was
begun and continued for 6 months. A diet with increased saturated
short-chain fatty acids then was introduced in order to obtain ketohernia (i.e., diet consisted of 40% fat; Fig 1).
Differential Diagnosis. Normal values were found fur ceruloplasmin,
copper excretion, biotinidase, phytanic acid, and very long-chain fatty
acids, for lysosomal enzymes in leukocytes (arylsulfatase A, I~-galactosidase, 13-hexosaminidase A and B), and serum (13-glucuronidase, fucosidase, oc- and [$-mannosidase, ~-hexosaminidase A and B). CSF contained normal cell number, protein content, and protein immunoelectrophoretic pattern. Organic acids and amino acids in urine were normat; there was no excess of glutaric acid and 3-hydroxyglutaric acid.
Energy Metabolism. The serum lactate and pyruvate levels were
slightly elevated at the time of the first examination (age 2 ½ years;
Table 1) and returned to normal at the time of subsequent examinations. CSF lactate was elevated (3.0 mmol/L; normal: _<2.2 mmol/L).
Diet Control. Serum acetoacetate was low before diet administration
(53 ~tmol/L) and elevated on the diet (110 pmol/L); hydroxybutyrate
demonstrated the same changes (111 and 283 gmol/L, respectively).
Urine ketones remained normal or were at 5-10 mg/dl. At 61/2 years of
age, acetoacetate decreased to 67 pmol/L and hydroxybutyrate to 118
~tmol/L, which resulted from discontinuation of the diet by the child's
mother. During the diet, lactate response to glucose loading was normal
(lactate 1.8 mmol/L before loading and 2.0 mmol/L after 20 min). CSF
lactate was not controlled during the diet. Serum lactate and pyruvate

Table 2.

Activities of mitochondrial enzymes in muscle tissue
Patient

Control Range

Cytochrome c oxidase

97

73-284 *

Succinate: cyt c oxidoreductase

7.0

4.1 - 16 *

NADH: Q1 oxidoreductase

4.7

4.7-19 *

Pyruvate dehydrogenase
complex

1.2

2.8-6.2 *

Citrate synthetase

55

48-146 *

Carnitine, total

1.0

2.7-4.6 **

Carnitine, nonesterified

0.9

2.2-4.2 **

Creatine, total

2.6

> 15 **

* In mU/mg homogenate protein [2].
** In gmoles/gm wet weight [2].

62

PEDIATRIC NEUROLOGY

Vol. 8 No. 1

did not change significantly during the diet (Table 1). Serum cholesterol was 211 mg/dl before the diet and increased to 232 and 242
mg/dl during the diet (normal: 120-246 mg/dl).

Morphologic Studies
Histochemical studies of gastrocnemius muscle tissue at the age of
3 ½ years disclosed no abnormalities. Ultrastructural studies of muscle,
skin, and lymphocytes proved normal; sural nerve study demonstrated
slight signs of demyelination and some loss Of unmyetinated axons.

Biochemical Studies
Enzyme activities and caruitine content were determined as described
previously [15] in total homogenates prepared from frozen gastrocnemius muscle. The enzyme complexes of the respiratory chain, cytochrome c oxidase, succinate: cytochrome c oxidoreductase, NADH: Q1
oxidoreductase and the mitochondrial reference enzyme citrate synthetase had normal activities (Table 2); however, the activity of the PDHc
[16] was diminished to 43% of the lowest control value. Immunochemical investigation using anti-bovine heart PDHc antiserum did not
reveal a specific decrease in one of the proteins composing the Complex after SDS-polyacrylamide gel electrophoresis [16]. Diminished
values of muscle camitine were found, but the significance is obscure
because the reference compound creatine also had a very low concentratiun. Serum camitine level was normal (43 gmot/L; normal: 3555 ~tmol/L).

Neuroradiologic Investigations
Figure 1 demonstrates the time course of the disease with respect to
neuroradiologic investigations and diet.
Computed Tomography. CT was performed at 21/2 years of age (Siemens DRH scanner, 512 x 512 matrix), and demonstrated bilateral,
nearly symmetric, hypodense areas in the lenticular nucleus as well as
in the right head of the caudate nucleus without pathologic enhancement on contrast medium.
Magnetic Resonance Imaging. MRI was performed with a 1.5 T
Magnetom (Siemens; Figs 2A,2B). TI-weighted, multi-slice, single
spin-echo technique was used in sagittal, axial, and coronal orientation
with TR 600 msec, TE 15 msec, and 256 × 256 matrix: Axial and
coronal T2-weighted, multi-slice, double-echo sequences were obtained
(TR: 2,400 msec, TE: 120 msec).
MRI at 3 years, 3 months of age (MRI 1, Figs 1,2A,2B) demonstrated bilateral defects of the putamina and caudate head on the right
hemisphere, defects being hypointensive on Tl- and hypedntensive on
Ta-weighted images. In addition to these results, MRI at 4 years, 2
months of age (MRI 2, Figs 1,2A,2B) disclosed an increase in volume
of the left head of the caudate nucleus with abnormal signal intensities
(decreased in Tl- and increased in T2-weighted images).
At 4 years, 8 months of age, (MRI 3, Figs 1,2A,2B), the extent of the
abnormal areas was unchanged, the left head of the caudat¢ nucleus
had a decrease in volume and a hyperintense area on the Tl-weighted
images which was masked on the T2-weighted images.
At 5 years, 4 months of age (MRI 4, Figs 1,2A,2B), there were no
additional tissue defects. This finding was unchanged 10 months later

,

_

MRS l

VOl 8 ml
Tit 1500 m s

|

J

~

TE 1~ ms

t2.

10.

MRS 3

NAA

Lac

8.
B

4.

MRS 4

O.

,'.,

~'.,

2'.,

~'.,

Chem:J.col

~'.,

shift;

~'.s
/

,'.,

,'.,

ppm

Figure 3. MR volume selective proton spectroscopy with TE 135
msec of the left caudate head at 4 years, 8 months of age (MRVS1)
demonstrating normal peaks for choline (Ch), creatine/phosphocreatine (Cr/PCr), and N-acetyl-aspartate (NAA), and an abnormal
lactate (Lac) peak; at 6 years, 2 months of age (MRVS3) demonstrating no lactate; at age 61/2 years (MRVS4, right caudate head) disclosing a small lactate peak.
(MRI 5, Figs 1,2A,2B). At 61/2 years of age, the right caudate head
again disclosed abnormal signal intensities (MRI 6, Figs 1,2A,2B).
Magnetic Resonance Volume Selective Proton Spectroscopy. Volume
selection was achieved with a spin-echo technique, 2 spectra with 256
acquisitions, TR 1,500 msec and TE 135 and 270 msec were obtained
to ensure the identification of lactate. The voxel (2 x 2 × 2 cm) was
situated in the left head of the candate nucleus for MRVS 1-3 and in
the right head for MRVS 4. In addition to normal peaks of N-acetylaspartate (NAA), creatine/phosphocreatine and choline, there was a
peak of lactate at 4 years, 8 months of age. Lactate could no longer be
demonstrated at 5 years, 4 months of age and at 6 years, 2 months, but
could be seen again at the age of 61/2 years (Fig 3). This latter MRVS
control was performed because ketonemia could no longer be detected
due to discontinuation of the diet.
Discussion

Our patient presented with leg-dominated spasticity,
dystonia, and dysarthria, beginning at the age of 2 years.
Mental development was normal. Neurologic symptoms
were slowly progressive during the first 2 years. Since the
age of about 41/2 years, the child stabilized, with the institution of a diet with increased, saturated short-chain
fatty acids. This diet was chosen to replace, in part, pyruvate oxidation by oxidation of ketone bodies [17] because
no specific enzyme defect within the PDHc could be verified which could have been more specifically influenced
by thiamine or lipoic acid [18,19] and because a 6-month
trial of orally administered thiamine (500 mg daily) failed

to produce a clinical response (MRI even disclosed progression of lesions). Animal studies demonstrated better
utilization of ketone bodies to replace pyruvate oxidation
in brain of younger animals when compared to that of
mature ones [20]. There is evidence of positive effects in
clinical studies [17].
Cerebral CT and especially MRI disclosed bilateral
lesions of the putamina and pallidum, as well as progressive lesions of the head of the caudate nucleus affected
initially on the right side, then on the left, and then again
on the right. Clinically, the child initially exhibited a predominantly left-sided spastic tetraplegia which gradually
became symmetric; the second lesion of the right caudate
head did not produce a significant clinical correlate. The
findings of elevated CSF lactate, slightly elevated serum
lactate and pyruvate, and especially diminished activity of
the PDHc complex in muscle tissue all support a defect in
pyruvate oxidizing metabolism. These data together with
the clinical findings and course and neuroradiologic abnormalities strongly suggest the diagnosis of Leigh disease. The metabolic defect concerning energy metabolism
of the brain could further be supported by the detection of
lactate in the lesion demonstrated by MRVS volume selective proton spectroscopy which provides an additional tool
for noninvasive biochemical tissue analysis. Lactate concentration in brain tissue is normally below 1 mM and is
not clearly detectable by proton spectroscopy [21]. Our
patient demonstrated a distinct lactate peak at the first
spectroscopic examination which was performed at the
onset of the diet after a chronically progressive disease
course over 21/2 years. The lactate peak disappeared completely at the second and third MRVS 6 and 16 months
after the onset of the diet. It reappeared at age 61/2 years
when there was evidence of a new lesion which coincided
with discontinuation of the diet. There is still little knowledge about in vivo brain lactate in pathologic conditions.
One study reported that it could still be detected 4 days
after acute stroke in an adult [21]. There was no evidence
of lactate 4 days after neonatal asphyxia [22]. Detre et al.
reported elevated brain lactate, particularly in basal ganglia lesions, in an 11-month-old child with Leigh disease.
Grodd et al. demonstrated a clear lactate peak in basal
ganglia lesions of 2 other patients with Leigh disease, 3
and 18 months after acute neurologic deterioration [24].
The impact of the diet is debatable; Leigh disease may
have an episodic course where acute deterioration may be
followed by spontaneous recovery; however, it is noteworthy that after a long period of clinical deterioration and
progressive tissue destruction- demonstrated by cranial
MRI - clinical stabilization and normalization of the spectrum coincided with the application of a diet and reappeared when the diet was discontinued. The disappearance
of the lactate peak while this patient was on the diet may
be attributed to the successful diminution of pyruvate oxidation in brain tissue by an increase in the oxidation of
ketone bodies. Further case studies will be required to
validate these findings.

Kr/igeloh-Mann et al: Leigh Disease

63

The authors thank Mrs. Vera RiJhl-Ullrich for planning the diet.

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