TheNeuropsychological Features of Mitochondrial
Myopathies and Encephalomyopathies
L. D. Kartsounis, PhD; D. D. Troung, MD; J. A. Morgan-Hughes, FRCP; A. E. Harding, FRCP
\s=b\ Detailed
testing of higher cerebral func-
tion was performed in 36 patients with mito-
chondrial myopathies and encephalomyo-
pathies. Fourteen of these patients were
thoughtto be cognitively impaired on clinical
grounds. The assessments included tests of
general intellectual ability and focal tests of
memory, language, and perception. Twenty-
one (58%) of the 36 patients who were tested
had evidence of general intellectual deterio-
ration, with focal cognitive deficits of vari-
able degree. Of the remaining 15 patients in
whom there was no evidence of general intel-
lectual decline, five displayed focal cognitive
deficits. In only 10 patients was there evi-
dence of cerebral dysfunction. The range
and extent of cognitive deficits in mitochon-
drial myopathies are greater than predicted
by their clinical presentations.
(Arch Neurol. 1992;49:158-160)
rp he mitochondrial myopathies and en-
are a diverse
cephalomyopathies
group of disorders that share the com¬
mon feature of mitochondrial morpho¬
logical abnormalities in skeletal muscle
biopsy specimens. Their clinical presen¬
tation is very variable and involves the
central nervous system in about 30% of
adult patients.lJ Syndromes of encepha-
lomyopathy include the (1) Kearns-
Sayre syndrome of ophthalmoplegia,
retinopathy, and heart block3; (2) myo¬
clonus epilepsy with ragged red fibers4;
and (3) mitochondrial encephalopathy,
lactic acidosis, and strokelike episodes.'5
However, there is often an overlap be¬
tween these syndromes, and not all
Accepted for publication July 11, 1991.
From the Department of Clinical Neuropsycho-
logy (Dr Kartsounis) and University Department of
Clinical Neurology (Drs Truong, Morgan-Hughes,
and Harding), National Hospitals for Neurology
and Neurosurgery and Institute of Neurology,
London, United Kingdom.
Reprints not available.
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cases of mitochondrial encephalomyo-
'
pathy can be classified in this way. Al¬
though dementia has been reported in
mitochondrial disorders, the neuropsy¬
chological correlates of these conditions
are poorly defined. Cognitive impair¬
ments are usually referred to either in
global and nonspecific terms, including
dementia, or only general levels of IQs
are given in individual case studies.
This study attempts to delineate the
neuropsychological deficits in patients
with mitochondrial myopathies, both in
terms of general intellectual decline and
specific focal cognitive impairments.
PATIENTS AND METHODS
The medical records of 72 consecutive pa¬
tients with mitochondrial myopathy who
were investigated at the National Hospitals
for Neurology and Neurosurgery, London,
United Kingdom, between the years 1969
and 1989, were reviewed. Mitochondrial my¬
opathy was defined by the presence of 4% or
more of muscle fibers showing peripheral mi¬
tochondrial accumulations by using the succi-
nate dehydrogenase stain.1 Patient num¬
bers, used here, are as given in previous
publications.1(' Thirty-six of these patients
had undergone neuropsychological assess¬
ment. With the exception of one patient who
was first studied in 1973 and subsequently
reassessed in 1985, all of the patients were
examined within the years 1978 through
1987; eight of them were examined on more
than one occasion.
The neuropsychological examinations
aimed to ascertain whether, and to what ex¬
tent, the patients had impairment of higher
cerebral function. This was assessed by mea¬
sures of general intellectual deterioration
and deficits on focal cognitive tests. Indexes
of general intellectual deterioration were cal¬
culated by analyzing discrepancies between
estimates of premorbid IQ, optimal level of
general ability, and IQ measures at the time
of assessment. In 23 patients, optimal levels
of functioning were estimated on the basis of
their sight-reading vocabulary by using the
National Adult Reading Test' or the Schonell
Reading Test.8"* In the remaining 13 pa¬
tients, this method could not be used, be¬
cause either they had severe visual impair¬
ment or their reading skills were impaired
or
had neverdeveloped satisfactorily. In these
cases, optimal levels of functioning were esti¬
mated on the basis of educational or other
developmental attainments, such as degree
of independence.
The IQ measures of current general ability
were obtained by using the Wechsler Adult
Intelligence Scale10 or, in the case of one
patient, the Wechsler Intelligence Scale for
Children-revised.11 A discrepancy of 10 or
more IQ points between estimated optimal
levels of ability and performance on general
intelligence tests was considered to indicate
significant intellectual deterioration. Dis¬
crepancies between 10 and 15 IQ points were
defined as indicating a mild degree of deterio¬
ration, those between 15 and 30 IQ points
were thought to indicate a moderate degree
of deterioration, and for discrepancies of 30
or more IQ points, deterioration was consid¬
ered to be severe. Patients with long-stand¬
ing intellectual difficulties and/or those in
whom accurate measures of optimal abilities
could not be obtained were defined as im¬
paired if their IQs fell below the 10th percen¬
tile. Specifically, they were considered to be
mildly impaired if their IQs were at a border¬
line level and severely impaired if their IQs
were in the mentally retarded range. One
patient's IQ was within the lower limits of the
low-average range, but he was considered to
be mildly impaired since his best score on
other cognitive tests suggested a higher de¬
gree of optimal general ability.
Measures of focal higher cerebral impair¬
ments were obtained by using tests of memo¬
ry, language, and perception. These included
verbal and visual recognition memory
tests,12 recognition tests that employed col¬
ored pictures (E. K. Warrington, FRS, oral
communication, 1989), tests of sentence com¬
prehension and object naming,13'14 and tests
of visual perception with regard to fragment¬
ed letters and/or unusual views.151B Patients
who scored below the 10th percentile for
their age group or showed a significant dis¬
crepancy between their performance in focal
tests and overall level of intelligence (IQ)
 Table 1.—Clinical, Neuropsychological, Imaging, and EEG Data on 36 Patients
(encephalomyopathies and myopath¬
With Mitochondrial Myopathies and Encephalopathies*
ies); the data are summarized in Table 2.
About two thirds of the patients had
Cognitive Impairment impairment of higher cerebral function,
Neuro¬ Focal
ranging from mild to severe in degree.
Patient/
Features Clinical psychological lût Deficits EEG CT Scan Cognitive deficits were only predicted
in two thirds of these on clinical
Myopathies
1/OM 107 Normal grounds. Thirteen patients showed a
2/OMR No None Mem Abnormal Normal
moderate to severe degree of general
4/MR No None 100 Normal Normal intellectual deterioration, including
6/M Normal Normal three from the myopathy group, and a
26/OMR No None 84 Normal Normal further eight had mild cognitive impair¬
30/OMR No None 122 Normal Normal ment. Only two of the 22 patients with
No Normal Normal central nervous system involvement did
34/OM
No 117 Normal Normal not show any type of cognitive impair¬
39/OM
44/OMR No Moderate 90 Normal ment, both of whom had the Kearns-
45/OM No Severe 73 (V) Abnormal Sayre syndrome. Almost all of the pa¬
48/OM No None 119 Normal Normal tients with moderate or severe general
68/OMR No None 83 Abnormal Normal intellectual deterioration had, in addi¬
71/M No Moderate Mem Abnormal Normal tion, specific focal cognitive deficits of
93/OM Normal language, memory, and perception, and
Encephalopathies
four of the eight patients with a mild
8/ORAMcCh 72 degree of general intellectual deteriora¬
9/OAS Yes Severe UNT L, Mem, Abnormal Abnormal tion presented with one or two focal
10/ANChDf Severe UNT L, Mem, Normal Abnormal deficits. One third of the patients with¬
11 / MADy Yes Moderate 80 P, Mem Abnormal out evidence of general intellectual de¬
12/OADfMc No None 111 Abnormal Normal terioration had one focal cognitive defi¬
16/OMRDfA No None 92 (V) Abnormal cit. Thus, from the total group, only 10
17/OMRDfAC No None 87 Abnormal of 36 patients had normal higher cere¬
18/OMRDfAC No None 98 (V) Mem Abnormal Abnormal bral function.
19/OMRAC Yes Mild 90 (V) Abnormal Abnormal The majority of the 26 patients with
20/MANDf Yes Moderate 84 L, Mem, Abnormal generalized and/or focal cognitive defi¬
21/MRODfAt Yes Severe 52 (V) L, Mem, Abnormal Abnormal cits had abnormalities on computed
22/MRANMcDf Yes Severe 55 L, Mem, Abnormal Abnormal tomographic scans (17 of 23 scanned)
32/OMAMc No None 105 Mem Abnormal Abnormal and/or on electroencephalograms (18 of
49/OnDyAt Yes Severe UNT L, Mem, Abnormal Abnormal 21 studied). All of the patients with se¬
50/MRAMc Yes Severe UNT L, Mem, Abnormal Abnormal vere cognitive deficits had cerebral at¬
67/OMRDfAC None 95 (R) Abnormal rophy. Two patients without cognitive
76/OMADf Yes Mild 99 Mem Abnormal Abnormal deficits had abnormal computed tomo¬
78/RSA Yes Mild 81 Abnormal Abnormal graphic scans, and one had an abnormal
79/MDfA No Mild 83 Mem, Abnormal electroencephalogram.
80/OMAN No Mild 93 Normal Among the patients with encephalo¬
82/OMRA Yes Severe 43 L, Mem, Abnormal Abnormal myopathies, there were three who had
86/SN* Yes Severe UNT L, Mem, Abnormal Abnormal had strokelike episodes. These patients
*EEG indicates electroencephalographlc; CT, computed tomographic; O, ophthalmoplegia; M, limb muscle all demonstrated severe generalized in¬
weakness; B, retmopathy; Mem, memory; P, perception; L, language; A, ataxia; Me, myoclonus; Ch, chorea; S, tellectual deterioration, and they had
seizures; UNT, untestable; N, neuropathy; Df, deafness; On, optic neuropathy; Dy, dystonia; and C, cardiac con¬ severe focal cognitive dysfunction.
duction defect. Patient numbers are given as in the reports of Petty et al' and Holt et al.6 Patients 1, 2, 17-19, When considering all of the patients, a
26, 30, 34, 48, 67, and 68 had deletions of muscle mitochondrial DNA,6 patient 12 had the myoclonus epilepsy
with ragged red fibers mutation, and patients 20, 21, 39, 76, 78, 79, and 86 had the mitochondrial encephal¬ total number of 43 focal cognitive defi¬
opathy, lactic acidosis, and strokelike episodes mutation.22 cits were recorded in 22 patients (Table
tFull-scale IQs are given, except for V (verbal only) and R (based on Raven's colored matrices). 2). Twelve of them reflected language
^Denotes strokelike episodes.
difficulties, 15 reflected perceptual im¬
pairment, and 16 reflected memory
impairment.
were considered to have specific cognitive range, 13 to 63 years) at the time of their
deficits. Individuals with marked impair¬ COMMENT
last assessment. Twenty-three of these
ment of visual acuity were not assessed on
visual memory tests; memory deficits that patients had clinical evidence of central This study indicates that the inci¬
are mentioned in Table 1 and below are de¬
nervous system involvement; thus, dence of cognitive dysfunction in mito¬
fined irrespective of modality (verbal or visu¬ they were defined as having encephalo- chondrial myopathies and encephalo¬
al). Similarly, these patients were not as¬ myopathies, and 14 were thought to be myopathies is 50% higher than that
sessed for visual perceptual function or were cognitively impaired on clinical predicted by routine clinical assess¬
examined only on tests that are not depen¬ grounds. The neurological features of ment. Computed tomographic (eg, cere¬
dent on high acuity. most of these patients were reported by bral atrophy or focal areas of low attenu¬
RESULTS Petty and colleagues. ' Table 1 shows the ation) and/or electroencephalographlc
degree of general intellectual deteriora¬ (eg, diffuse slow-wave or paroxysmal
Eighteen of the patients who were tion and the incidence of focal deficits in activity) abnormalities were more sen¬
studied were male and 18 were female, all of the patients, and also with regard sitive indicators of impaired cognition
with a mean age of 34.8 years (age to the two broad diagnostic categories than a clinical impression of dementia.

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Table 2.—General Cognitive Function and Focal Cognitive Deficits in 36 Patients
With Mitochondrial Myopathies and Encephalomyopathies
No. of patients with myopathies ( = 14)
Generalized cognitive deterioration
(with focal deficits)_9 (1)_2 (1)_2 (2)_1
Focal deficits per patient
No. of patients with encephalomyopathies (n
Generalized cognitive deterioration
(with focal deficits)_6 (4)_6 (3)_2 (2)_8(8)
Focal deficits per patient 1 1-2
No. of patients (N =
36)
Generalized cognitive deterioration
(with focal deficits)_15
Focal deficits per patient 1 1-2
Not surprisingly, cognitive impairment
appeared to be particularly common in
patients with mitochondrial encepha¬
lopathy, lactic acidosis, and strokelike
episodes.
The pattern of focal deficits in these
patients did not indicate that any specif¬
ic higher cerebral function is more sus¬
ceptible to impairment than others in
mitochondrial encephalomyopathies.
However, a comprehensive analysis of
all possible focal deficits, such as frontal
lobe dysfunction, was not undertaken
here, with the focus being on aspects
of language, memory, and visual per¬
ception.
The pathological substrate for higher
cerebral dysfunction in these disorders
is not clear. Although patients with mi¬
tochondrial encephalopathy, lactic aci¬
dosis, and strokelike episodes may dem¬
onstrate focal cortical lesions with the
pathological features of infarction,17 and
many other patients have radiological
evidence of cerebral atrophy, pathologi¬
cal involvement of the cortex in dement¬
ed patients with most mitochondrial en¬
cephalomyopathies is striking by its
absence, and there is also rarely evi¬
dence of mitochondrial abnormalities in
the brain.17"19 The latter observation
probably relates to difficulties in obtain¬
ing tissue suitable for electron micros¬
copy and to the possibility that there are
differences in morphological reactions
between brain and muscle mitochon¬
dria. K Despite the lack of microscopic
cortical pathology, in these patients, ev¬
idence for abnormal cerebral metabo¬
lism has been provided by positron
emission tomography. Frackowiak and
colleagues2" showed uncoupling of glu¬
cose and oxygen metabolism in patients
with mitochondrial myopathies and ma¬
jor central nervous system involvement
(patients 10, 11, 20, and 22 in this
study), implying aerobic glycolysis to
lactate and/or other intermediary me¬
tabolites as a result of the underlying
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None Mild Moderate Severe
(1)
111 3 2. DiMauro S, Bonilla E, Zeviani M, Nakagawa
=
22)
2-3 3
(5)_8 (4)_4 (4)_9 (9)
2-3 3 red fibres (mitochondrial abnormalities): disease
respiratory chain defect being ex¬
pressed in the brain. Depression of oxy¬
gen metabolism was correlated with de¬
gree of dementia, as estimated by the
Wechsler Adult Intelligence Scale.
Berkovic and coworkers1* reported
rather different positron emission to¬
mography data from studies of patients
with myoclonus epilepsy with ragged
red fibers. Both glucose and oxygen me¬
tabolism were reduced with preserva¬
tion of blood flow. The authors suggest¬
ed that, in myoclonus epilepsy with
ragged red fibers, cortical neurons do
not increase anaerobic glycolysis but
adjust to a chronically low oxidative
rate, resulting in reduced generation of
adenosine triphosphate. It may be that
the pattern of cerebral hypometabolism
depends on the underlying genetic de¬
fect, which is known to be heteroge¬
neous21,22 (Table 1); the neuropsychologi¬
cal consequences are likely to be similar.
There is a need for caution in inter¬
preting the findings ofthe present study
in general. Only 36 of the whole series of
72 patients with mitochondrial myo¬
pathies were assessed neuropsychologi-
cally. The majority of patients who were
not referred for neuropsychological as¬
sessment (and therefore have not been
included in this study) probably repre¬
sent those who did not appear to be
cognitively impaired on routine clinical
examination. This means that the pro¬
portion of patients with mitochondrial
myopathy who show higher cerebral
dysfunction is probably overestimated
here. Patients who have severe forms of
intellectual impairments may also be
overrepresented. Nevertheless, even
sampling, the
in the context of biased
present study suggests that cognitive
deficits are more widespread among pa¬
tients with these disorders than hither¬
to assumed.
We wish to thank the Brain Research Trust,
London, United Kingdom, for financial support.
We thank D. Baxter, PhD; M. Jackson, PhD; A.
Costello, MSc; and P. McKenna, BSc, for perform¬
ing some of the neuropsychological examinations.
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