J Neurol (1991) 238 : 83-86

Journal of

Neurology
© Springer-Verlag1991

Stroke-like episodes in familial mitochondrial encephalomyopathy:
clinical and biochemical aspects
M. S. D a m i a n 1, H. R e i c h m a n n 2, H.-J. Schiitz 1, W. D o r n d o r f 1, and W. Schachenmayr 3
1Neurologische Universit~itsklinik, Am Steg 14, W-6300 Giessen, Federal Republic of Germany
2Neurologische Universit~tsklinik, Josef-Schneider-Strasse 11, W-8700 Wtirzburg, Federal Republic of Germany
3Institut far Neuropathologie, Arndtstrasse 16, W-6300 Giessen, Federal Republic of Germany
Received March 19, 1990 / Received in revised form September 27, 1990 / Accepted October 15, 1990

Summary. Acute episodes of focal neurological dysfunction are a well-recognized complication of the mitochondrial encephalomyopathies. Because of rapid remission, biochemical tests and other diagnostic procedures
are mostly performed after the acute phase. We report
the case of a patient suffering from mitochondrial disease manifesting primarily with seizures, progressive
deafness and dementia, who experienced multiple strokelike episodes. Other members of the family with evidence of mitochondrial dysfunction are presented briefly. E E G and biochemical findings in the acute stage are
correlated with clinical symptoms, showing characteristics distinct from the chronic illness. The possible involvement of dietary factors in the provocation of strokelike episodes is discussed and regulation of glucose intake suggested as a strategy in the prevention of strokelike episodes.
Key words: Lactic acidosis - Mitochondrial myopathy Mitochondrial encephalopathy - Stroke-like episodes Myoclonus epilepsy

Introduction
Defects of mitochondrial metabolism have been recognized in numerous disorders affecting the nervous system as well as other organs [3]. Clinical syndromes observed in adults include the Kearns-Sayre syndrome [7]
and the syndromes of myoclonus epilepsy with raggedred fibres ( M E R R F ) [6] as well as mitochondrial myopathy, encephalopathy, lactic acidaemia and stroke-like
episodes ( M E L A S ) [11]. However, the underlying defects of mitochondrial metabolism are heterogeneous,
and symptoms vary considerably [3, 12]. The pathogenetic mechanisms in acute "stroke-like" episodes are
not yet clear. Various hypotheses such as cardiac embolism secondary to cardiomyopathy [1], anoxia secondary to cerebral mitochondrial dysfunction [8, 9] or capilOffprint requests to: W. Dorndorf

lary occlusion caused by endothelial swelling [10] have
been proposed.
In this paper, the case of a patient with symptoms of
both M E R R F and M E L A S is discussed in detail. No further family members had stroke-like episodes or myoclonus epilepsy, but hearing loss, mental and growth
retardation, pigmentary retinopathy, lactic acidosis and
diabetes mellitus were observed.
Figure 1 shows a pedigree of the family under study.
Table 1 summarizes the clinical features of affected
members. Patient 2 is discussed in detail.

Case report
The female patient's birth and childhood were normal. Progressive
deafness was noted when aged 23 years. During the same period a
personality change with apathy, moodiness and restless sleep
developed. Myoclonic jerks provocable by bright light were first
observed at 30; tonic-clonic seizures brought her to neurological
attention.
Evaluation in 1985 (at age 32) revealed mild intellectual impairment, severe sensorineural hearing loss and a discrete rightsided hemiparesis with generally sluggish reflexes. Electroencephalography (EEG) 5 days after the last tonic-clonic seizure
showed discrete generalized slowing with left temporo-parietal accentuation and intermittent bursts of sharp waves. The cerebrospinal fluid (CSF) lactate was 6.17mmol/1 (normal: <l.9mmol/1).

I
1I
1
lit

lV
3

4

5

Fig. 1. Pedigree of the family under study. (3 Female, [] male,
0, • affected, ~ deceased, ¢, ~ miscarriage, 1 - 5 patient no.
(Table 1)

84
Table 1. Clinical features. ©, Not observed:
© + , discrete; +, mild; + +, moderate:
+ + + , severe: GR, growth retardation;
LAC, lactic acidotic coma; DM, diabetes
mellitus; ME, myoclonus epilepsy: A, ataxia

Case no.

Age/sex
Lactic acidemia
Stroke-like episodes
Dementia/retardation
Myopathy
Pigmentary retinopathy
Deafness
Other

Fig. 2a, b. Light microscopy findings of muscle biopsy with raggedred fibres, a Red stained "ragged-red fibre" in trichrome stain
(Goldner), paraffin section, × 350. b Typical coarse granular aspect of a centrally situated so-called ragged-red fibre. H & E .
frozen section, × 420

Computed tomography (CT) showed a large, contrast-enhancing
left temporal hypodensity. Magnetic resonance imaging (MRI)
confirmed the lesion and revealed multifocal signal changes with
irregular e n h a n c e m e n t after gadolinium-DTPA. Electrocardiograms (ECG), echocardiography and cerebral angiography were
normal.
On follow-up the right-sided weakness had resolved and the
background E E G pattern was normal, but bilateral irregular 3-5
Hz spike-wave and poly-spike-wave complexes were prominent.
CT demonstrated progressive cerebral atrophy. The patient continued to have frequent myoclonic jerks and occasional tonicclonic fits.

1

2

3

4

5

57/f
+++
©
©+
++
©
++
GR, DM,
A

35/f
++
+++
++
+
©
+++
GR, DM,
ME, A

18/f
++
©
+
©
+
©
GR

14/m
+
©
+
©
©
©+
GR

6/f
+++
©
+
O
+
O
GR, LAC,
ME

Fig. 3. Electron microscopic aspect of an atrophic muscle fibre
with subsarcolemmal accumulation of normally sized mitochondria
and a few admixed membrane whorls. × 16000

In December 1987 she suffered acute confusion and loss of vision. Gait was now ataxic, but a visual disturbance was not demonstrable on admission. Pigmentary retinopathy was absent. The
E E G showed a background rhythm of 4 - 6 H z without signs of
myoclonic epilepsy. CSF lactate was again increased (6.1 ram©l/l).
Confusion remitted spontaneously in 48 h, leaving deafness, mild
ataxia and moderate intellectual impairment. A repeat E E G after
discharge was without generalized slowing; the poly-spike-wave
pattern had returned. Seizures were controlled with sodium valproate.
Electromyography demonstrated discrete myopathic changes.
A biopsy specimen from the left deltoid muscle showed approximately 5% ragged-red fibres (Fig. 2) and increased lipid storage on
oil-red staining. NADH-tetrazolium reductase revealed only occasional small dark fibres and a few type 1 fibres with ballooned un-

85
Table 2. Respiratory chain activity and muscle carnitine concentrations
Case no. (as in Fig. 1)

Controls

2

3

4

5

N A D H dehydrogenase
NADH-cytochrome c reductase
Succinate dehydrogenase
Succinate-cytochrome c reductase
Cytochrome c oxidase

71.0
5.33
1.93
1.91
4.7

54
7.3
2.6
3.3
2.5

78
12
3.6
4.5
3.4

65
13
3.5
3.7
1.8

48.0 + 9.4 units/gmuscle
3.2 + 1.53 units/gmuscle
2.4 _+ 1.1 units/gmuscle
1.64 _+ 0.62 units/g muscle
2.8 + 1.0 units/gmuscle

Musclecarnitine (total)
Musclecarnitine (free)

16.1
12.1

12.73
8.64

17.7
16.9

17.7
14.2

20.0 _+ 7.6
17.4 -- 7.0

Serum
Lactate
mmol/I

nmol/mgprotein
nmol/mgprotein

lOOg Glucose

It /

X~x"

x-~_

__

3-

21-

confusion

,# . . . . .
//,
ld 2d 3(:1 /-.d 5d 8d

EEG

(Hz)
rhythm8!1

~ X

10 12 1/. 16 18 20 2~2 2'/. 2

/~

6

i

8

ffl

!

i

i

i

Fig. 4. Effect of glucose tolerance test: 100g oral
glucose after a fasting lactate value of 3.1 mmol/l
led to clinical deterioration approximately 2 h
later. This lasted 6 h accompanied by an increase
of serum lactate levels and slowing of the E E G
pattern. Reversal of symptoms was paralleled by
E E G acceleration and decrease in lactate

ld 2d 3d /.n 5d

stained areas below an intensely stained subsarcolemmal rim. Acid
phosphatase activity was seen in some fibres, indicating a degenerative process. Accumulations of mitochondria without paracrystalline inclusions were seen on electron microscopy (Fig. 3). A
standard bicycle exertion test showed an excessive increase in lactate (8.8 mmol/1 after 15 min at 30 W) despite suboptimal cooperation. Serum lactate was at rest constantly elevated (2.5-4.0 mmol/1;
normal: < 2.2mmolB). Biochemical evaluation of the respiratory
chain by spectrophotometric methods [14] failed to identify a specific enzyme defect (a cytochrome c oxidase defect has since been
demonstrated in her daughter, case 5). Table 2 shows the evaluation of respiratory chain enzyme activity in four members of the
family. Serum and muscle carnitine concentrations were normal.
In January 1989 the patient suffered acute confusion and cortical blindness. The next day, a left hemianopia remained; she had
dystonic posturing of the left hand. CSF lactate was 5.81 mmol/1;
serum lactate 2 days after admission was 2.9 mmol/1. MRI demonstrated an extensive area of pathological signal in the right occipital region. Transcranial Doppler ultrasound (TCD) was normal, as
was repeat ECG. The symptoms resolved in several days.
The patient was readmnitted on 2 February 1989 after sudden
onset of right-sided weakness. There was a spastic right hemiparesis; the E E G showed severe generalized slowing ( l - 4 H z
background pattern). Serum lactate was 4.9 mmol/1. The next day,
the hemiparesis had resolved, but serum lactate was still 4.4mmol/l.
At home again, she suffered several generalized tonic-clonic
seizures; serum lactate reached 10.18mmol/1. The E E G again
showed severe generalized slowing but no poly-spike-wave pattern. Seizures ceased on the day of admission and the serum lactate 24h later had returned to 2.2mmol/1. Follow-up E E G revealed moderate slowing (5-6Hz), the poly-spike-wave pattern

returned. A connection between increased glucose intake and clinical deterioration was suspected (see below), and dietary treatment commenced. No further stroke-like episodes have occurred
since.
Clinical course, E E G changes and serum lactate levels suggested a metabolic influence outside the hospital no longer in
effect during hospitalization. The patient's husband was questioned
as to recent dietary habits. Having been informed of her defect in
energy metabolism, he had supplemented her diet with dextrose
and honey, amounting to approximately 200 g additional glucose/
day.
The correlation between glucose challenge, metabolic upset
and acute clinical deterioration was again suggested by a glucose
tolerance test performed because of elevated serum glucose levels
(Fig.4). Serum lactate levels reached 4.6mmol/1 and were still
over 4.0 mmol/l 10 h after glucose loading (blood glucose 126 mg/
dl).
Clinical deterioration with confusion, restlessness, hyperaggressire behaviour and impaired vision was noted, remitting after 10 h.
Average preprandial values of less than 3 mmol/1 were regained.
Marked generalized slowing (3Hz) improved to a background
E E G rhythm of 5 - 6 H z . Repeated pre- and postprandial serum
lactate studies on a standard 2000 kcal diet at rest and after clinical
stabilization showed almost normal early morning values with a
slight postprandial rise in lactate.

Discussion
T h e p a t i e n t b e l o n g s to a f a m i l y s u f f e r i n g f r o m a
mitochondrial disease with considerable clinical variety.

86
M a t e r n a l inheritance must be considered, but a dominant pattern with incomplete p e n e t r a n c e cannot be ruled
out. All affected m e m b e r s share m e n t a l and growth
retardation, and all have elevated rest and exertion
s e r u m lactate. O u r patient was the only one to have had
stroke-like episodes at the time of this study. The diabetes mellitus of patients 1 and 2 needs further study.
Investigation ruled out an a u t o i m m u n e type I diabetes,
and a c o n n e c t i o n with mitochondrial disease is suspected.
O t h e r authors have o b s e r v e d an increased incidence
of diabetes in mitochondrial disease [15].
Slow deterioration was p u n c t u a t e d by focal episodes
with g o o d remission. T h e E E G pattern of poly-spikewave complexes in the interval c h a n g e d to generalized
slowing during stroke-like episodes. A f t e r several episodes, h o w e v e r , m o d e r a t e slowing remained. A c u t e
deterioration was a c c o m p a i n e d by excessive lactate
levels.
A chronic disorder of cerebral m e t a b o l i s m was recently d e m o n s t r a t e d in mitochondrial disease by positron emission t o m o g r a p h y [5]. A relationship b e t w e e n
stroke-like episodes and cerebral embolism [1] appears
unlikely, as E C G , cerebral angiography, E E G and T C D
were normal. O u r observations suggest a direct metabolic cause of acute CNS dysfunction [8]. T h e E E G pattern
of severe generalized slowing also suggests generalized
dysfunction m o r e than embolic cerebrovascular occlusion. S e r u m lactate was excessively elevated during the
acute phase of stroke-like episodes and rapidly decreased after hospitalization, remaining m o d e r a t e l y elevated. B o t h generalized E E G slowing and excessive
serum lactate were seen without preceding fits (e.g. the
admissions D e c e m b e r 1987, J a n u a r y 1989 and 2 February 1989).
A c u t e metabolic crises with s u d d e n clinical deterioration and E E G changes a p p e a r to have b e e n induced by a
c a r b o h y d r a t e - s u p p l e m e n t e d diet, as has been o b s e r v e d
in p y r u v a t e d e h y d r o g e n a s e deficiency [2]. O t h e r authors
have r e p o r t e d exercise or fasting inducing acute sympt o m s [3]. W e suggest an o v e r l o a d of metabolites preceding the defect in e n e r g y m e t a b o l i s m as a p a t h o g e n e t i c
m e c h a n i s m s u p e r i m p o s e d on chronic deficiency of endproduct. Lactic acidaemia seems to be an indicator of
metabolic insufficiency and m a y be caused by glucose
challenge. E l e v a t e d blood lactate in the bicycle exertion
test is unlikely to have a m a j o r influence on the cerebral
lactate c o n c e n t r a t i o n . As lactate crosses the blood-brain
barrier slowly, alterations of v e n o u s and CSF lactate
c o n c e n t r a t i o n s are not parallel [13]. Glucose, however,
would influence b o t h cerebral and peripheral m e t a b o lism. Co-existing diabetes mellitus would increase serum
glucose elevation on dietary challenge, thus facilitating
metabolic d e c o m p e n s a t i o n .
T h e r a p e u t i c strategies can also include dietary measures [4] regulating c a r b o h y d r a t e supply as an adjunct
to e n z y m e substitution [16] to prevent acute "strokelike" events. N o further stroke-like episodes have occurred in our patient since a diet with decreased carbo-

hydrate and increased percentage of fat was instituted 18
m o n t h s ago, and her general condition remains stable,
although M R I shows slightly progressive cerebral atrophy.

Acknowledgements. Dr. T. Biittner kindly reviewed the electroencephalograms of this patient. We also thank Mrs. E. Part for
work on the text.

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