Brain, Vol. 126, No. 5, 1231-1240,
May 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg101
Executive and visuospatial deficits in patients with chronic progressive external ophthalmoplegia and Kearns–Sayre syndrome
1 Department of Psychiatry and 2 Department of Neurology, University of Bonn, Germany
Correspondence to: PD Dr Michael Wagner, Neuropsychology Laboratory, Department of Psychiatry, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany E-mail: michael.wagner{at}ukb.uni-bonn.de*These two authors contributed equally to this work
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Summary |
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Although neuropsychological deficits have been reported in mitochondrial cytopathies, patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns–Sayre syndrome (KSS) have not been studied systematically using a comprehensive test battery. The aim of our study was to assess the range and extent of putative cognitive dysfunction in 22 patients with CPEO or KSS, and to compare cognitive performance of patients with healthy control subjects matched for age, sex and years of education. Genetic analysis of skeletal muscle tissue from 22 patients with CPEO or KSS included screening for mitochondrial DNA (mtDNA) point mutations (3243/8344) and mtDNA deletions. All patients were examined by a neuropsychological test battery covering verbal skills, verbal and visual memory, visuo-spatial perception, visual construction, attention, abstraction and flexibility, and Quality of Life. Molecular genetic analysis of mtDNA revealed single large-scale deletions in 15 out of 22 patients and the tRNA (Leu) A3243G point mutation in two out of 22 patients. In five out of 22 patients none of the frequently encountered mtDNA mutations could be detected. Neuropsychological testing did not reveal general intellectual deterioration, but specific cognitive deficits, particularly in visual construction, attention and abstraction/flexibility. Subgroup analysis of 15 patients with mtDNA deletions showed similar results when compared with the full group. In our series of patients with CPEO or KSS neuropsychological testing did not reveal signs that would suggest general intellectual decline or dementia, but provided evidence of specific focal neuropsychological deficits, suggesting particular impairment of visuospatial perception associated to parieto-occipital lobes and executive deficits associated to the prefrontal cortex.
Keywords: mitochondrial disorders; neuropsychological deficits; executive functions; chronic progressive external ophthalmoplegia; Kearns–Sayre syndrome
Abbreviations: CPEO = chronic progressive external ophthalmoplegia; KSS = Kearns–Sayre syndrome; MELAS = mitochondrial encephalopathy, lactic acidosis and stroke-like episodes; mtDNA = mitochondrial DNA; RCFT = Rey-Osterrieth Complexe Figure Test; WAIS-R = Wechsler Adult Intelligence Scale—Revised; WCST = Wisconsin Card Sorting Test
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Introduction |
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Mitochondrial cytopathies comprise a heterogenous group of multisystemic disorders usually involving the skeletal muscle. Further organ involvement, particularly CNS involvement, is common (Howell, 1999
). Tissues with high energy demands, such as skeletal muscle, CNS and retina, seem to be more severely affected and clinical symptoms depend on the extent of different organ affection (Holt et al., 1989).
The common underlying pathomechanism of these clinically, biochemically and genetically highly variable diseases is a defect of oxidative phosphorylation resulting in energy depletion of the cells. Since brain energetics depend heavily on oxidative metabolism, the CNS is particularly susceptible to mitochondrial dysfunction (DiMauro and Moraes, 1993; Madsen et al., 1998). Furthermore, different brain regions seem to have different tolerance thresholds for metabolic dysfunction (Sparaco et al., 1993).
Symptoms of CNS dysfunction such as cognitive impairment or dementia have been described in several disease manifestations, e.g. myoclonus epilepsy with ragged red fibres, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), Kearns–Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia with or without additional features (CPEO/CPEO plus). In those clinical syndromes structural abnormalities of the brain including atrophy, white matter lesions and basal ganglia calcification have been demonstrated (Sue et al., 1998; Valanne et al., 1998; Chu et al., 1999), whereas limited and conflicting data exist on functional aspects of regional cerebral energy metabolism in mitochondrial cytopathies (De Volder et al., 1988; Frackowiak et al., 1988; Berkovic et al., 1989; Eleff et al., 1990; Matthews et al., 1991; Barbiroli et al., 1993; Molnar et al., 2000; Rango et al., 2001). There is evidence for cerebral metabolic impairment even in patients without obvious CNS symptoms (Molnar et al., 2000; Rango et al., 2001). In contrast to extensive research on morphological or metabolic aspects of brain affection, comparatively little is known regarding neuropsychological capabilities in mitochondrial diseases. Previous reports on neuropsychological deficits in mitochondrial cytopathies showed equivocal results with respect to both general intellectual capabilities and focal cognitive functions (Kartsounis et al., 1992; Lang et al., 1995; Turconi et al., 1999). This may partly be due to the inclusion of patients with MELAS and myoclonus epilepsy with ragged red fibres, where seizures could result in cognitive deficits. So far patients with CPEO or KSS have not been studied systematically using both a comprehensive neuropsychological test battery and a group of healthy controls. This renders conclusions regarding specific impairments difficult (Spreen and Strauss, 1998). Furthermore, although examination of frontal lobes may be of particular relevance due to their high metabolic demand (Roland et al., 1985, 1987), executive functions have not been assessed in detail to date. The aim of the present study was to examine the range and extent of putative cognitive dysfunction in 22 clinically, biochemically and genetically well-defined patients with CPEO or KSS using a neuropsychological test battery covering a broad range of focal cognitive skills with particular respect to frontal lobe functions.
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Patients and methods |
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Patients
The clinical and genetic data on 22 patients (CPEO/KSS: 16/6; male/female: 7/15; mean age: 48 ± 15 years) consecutively seen in the Department of Neurology, University of Bonn, between September 1999 and May 2000 is presented in Table 1. The results of our patients were compared with those of 20 healthy control subjects, matched for age, sex and level of education (Table 2). Inclusion criteria for KSS were: (i) progressive external ophthalmoplegia; (ii) age at onset <20 years; (iii) pigmentary retinopathy; and (iv) cardiac conduction block and/or cerebellar ataxia. All CPEO patients presented with bilateral ptosis, progressive external ophthalmoplegia and further skeletal muscle/organ involvement (CPEO plus; Table 1). Diagnosis of mitochondrial disease was made by means of clinical, laboratory, histological, histochemical, biochemical and genetic investigations following generally accepted criteria and methods (Morgan-Hughes, 1994
). None of the participants of our study had a history of head injury, alcohol or substance abuse, psychiatric diseases, epileptic seizures or stroke-like episodes, and none presented with further disorders that might affect CNS functions.
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Molecular genetic analysis of skeletal muscle tissue derived from diagnostic open muscle biopsy was performed as described previously (Schroeder et al., 2000
). Ophthalmological investigation prior to neuropsychological testing showed that all patients were free from visual impairment that would markedly interfere with testing. In no case was ptosis distinct enough to restrict upper visual fields. According to the Declaration of Helsinki, all patients and controls gave their written informed consent. The Ethics Committee of The University of Bonn approved the study protocol.
Neuropsychological test battery
All patients underwent a neuropsychological assessment using a battery of well established tests. Neuropsychological testing comprised vocabulary, verbal comprehension, visuo-construction, attention, abstraction/flexibility as well as verbal and visual memory tasks (Spreen and Strauss, 1998). In addition, Quality of Life aspects were assessed. Each cognitive function was further evaluated by one to four subtests. Timed and untimed tests were presented in alternation, and visual and verbal memory tests were arranged not to interfere with each other. The test session lasted 2.5–3 h for patients and 2 h for controls. All subjects used eyeglasses if needed.
Verbal skills and language
Verbal skills and language scores were assessed by the raw scores of the following tests: (i) Wechsler Adult Intelligence Scale—Revised (WAIS-R) Information; (ii) WAIS-R Comprehension; (iii) Vocabulary Test (WST; Schmidt and Metzler, 1992); and (iv) Token Test (aphasia screening; De Renzi and Vignolo, 1962).
Visual perception
To ensure intact basic visual functioning, all subjects were investigated with the ‘screening test’ and the ‘position discrimination test’ from the Visual Object and Space Perception Battery (Warrington and James, 1991).
Visuo-construction
To assess visuo-construction, the Rey-Osterrieth Complexe Figure Test (RCFT) and the Block Design Test of the WAIS-R were used. Scoring for the RCFT was done according to the Taylor and Binder schemes for accuracy and organization, respectively (Binder, 1982; Taylor, 1998).
Attention
Attentional functions were assessed by use of the following tests: (i) Digit Symbol Test of the WAIS-R to test visuomotor coordination. (ii) Number Connection Test (ZVT) to test perceptual speed/visual scanning (Oswald and Roth, 1987). The ZVT is similar to the Trail Making Test A, but subsequent numbers are within close vicinity to each other (<0.5° of visual angle), thus test performance was not compromised by ophthalmoparesis. (iii) Concentration Endurance Test (d2) to test sustained attention and visual scanning (Brickenkamp, 1981). (iv) Continous Performance Test (CPT) to test vigilance (modification of Kathmann et al., 1996). The sensitivity index P(
) and the mean of reaction latencies were analysed.
Abstraction/flexibility
The following tests were used: (i) short version of the Wisconsin Card Sorting Test (WCST) with 64 response cards—scoring was done according to Heaton criteria (Heaton et al., 1991); and (ii) Lexical fluency (finding words beginning with F, K. R).
Verbal memory
Verbal memory functions were evaluated by use of a German version of the Rey Auditory Verbal Learning Test (Helmstaedter and Durwen, 1990).
Visual memory
Visual memory functions were assessed by use of the RCFT. We used the Taylor scoring system for accuracy and the Binder scheme for organization to produce a quantitative score for the accuracy of drawing and the organizational strategy indicating executive aspects of memory (Binder, 1982; Taylor, 1998).
Quality of Life
Health-related Quality of Life was evaluated by use of the SF-36 (Medical Outcomes Study Short-Form 36-Item Health Survey, German version; Bullinger and Kirchberger, 1998).
Statistical analysis
To assess overall differences between groups, MANOVA (multivariate analysis of variance) with test scores as dependent variables and subject group as between-group factor was used. Secondly, t-tests were carried out for each subtest score, or 
2 tests if required. To assess the frequency and extent of clinically relevant neuropsychological deficits, each test score of the patient group was compared with the respective norm group. Measurements in patients who scored below the 10th percentile of performance were considered abnormal. 2 tests were conducted to compare the patient subgroups (CPEO versus KSS) with regard to the number of abnormal test results. To investigate a potential relationship between the extent of cognitive performance deficits and age at onset, disease duration or grade of heteroplasmy, Pearson correlations were calculated. Raw scores of the Quality of Life questionnaire were converted to Z-scores based on normative data of the German SF-36. For data analysis, a commercial computer program (SPSS 10.0, PC statistic) was used.
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Results |
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Genetic analysis
Molecular genetic studies revealed heteroplasmic single large-scale mitochondrial DNA (mtDNA) deletions in 15 patients with a deletion size ranging from 3.5 to 7 kB. The degree of heteroplasmy identified by Southern blot analysis varied from 5 to 85% (Table 1). The tRNA (Leu) A3243G point mutation was found in two CPEO patients, whereas in five patients (CPEO/KSS: 4/1) none of the frequently encountered mtDNA mutations [mtDNA rearrangements; tRNA (Leu) A3243G and tRNA (Lys) A8344G point mutations] could be detected. Direct sequencing of the whole mitochondrial genome in these five patients is currently underway. All five patients fulfilled the clinical criteria for CPEO/KSS and showed typical histological features of a mitochondrial myopathy in skeletal muscle tissue (ragged red fibres; modified Gomori trichrome stain; cytochrome c oxidase-negative fibres/cytochrome c oxidase stain).
Visual acuity
Visual acuity was 0.4 or better in all patients (Table 1). Patients did not differ significantly from controls in both visual screening tests.
Neuropsychological data
Neuropsychological profile of CPEO/KSS patients versus healthy controls
As expected, MANOVA revealed a significant difference between CPEO/KSS patients and controls [F(1,39) = 2.306; P = 0.044]. Patients showed relative performance deficits in several domains, particularly in visuo-construction, attention and flexibility tasks. Raw test scores for patients and controls and the results of univariate statistical analyses are shown in Table 2.
Frequency of clinically relevant neuropsychological deficits in CPEO/KSS patients versus respective norm group
Twenty out of 22 patients scored below the 10th percentile of performance in one or more tests. The percentage of patients with clinically relevant neuropsychological deficits is shown in Fig. 1. Marked deficits were particularly seen in subtests for visuo-construction, attention and flexibility.
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CPEO versus KSS patients
Twenty-four percent of all tests and subtests in CPEO patients showed pathological results. In comparison, abnormal results were seen in 31% all of tests in KSS patients. This difference between groups was not significant [
2(1) = 2.05; P < 0.900] indicating that patients with KSS did not differ from CPEO with respect to their neuropsychological performance.
Cognitive impairment in relation to genetic and clinical findings
To evaluate the extent of cognitive impairment, abnormal test results in one or two subtests were considered as mild, in three to five subtests as moderate and in more than five subtests as severe impairment. There was neither a significant correlation between the extent of cognitive impairment and grade of heteroplasmy (r = 0.10; P = 0.316) or disease duration (r = 0.05; P = 0.833), nor between cognitive dysfunctioning and age at onset (r = 0.13; P = 0.580).
In the analyses above all patients fulfilling the clinical criteria for CPEO or KSS were compared with normal controls. Genetic analyses revealed no mtDNA deletion in five patients and a mtDNA A3243G point mutation in two further patients. Both patients carrying the mtDNA A3243G point mutation showed the clinical picture of CPEO and not MELAS syndrome. In order to examine the degree and pattern of cognitive dysfunction in a homogenous group with mtDNA deletions, the analyses were repeated excluding the five patients without mtDNA deletions and the two patients with point mutations. The resulting homogenous patient sample (n = 15) was well matched with the group of healthy controls with regard to age, sex and education (P > 0.5 for all comparisons). The neuropsychological results were highly similar to those reported in Table 2 for the full sample of clinically defined cases, except for three variables where the group difference no longer reached the P = 0.05 level of significance [WCST perseverative errors, P = 0.068; RCFT initial organization, P = 0.071 and organization after 3 min, P = 0.073 (Binder scheme)].
In Fig. 1 the proportion of the 15 patients carrying a mtDNA deletion who were cognitively impaired (i.e. performing below the 10th percentile of published test norms) is presented. The number of test results in the impaired range is about two to five times higher than can be expected to occur as a result of normal variation.
One of the two patients carrying the mtDNA A3243G point mutation had marked deficits in immediate verbal recall, attention and category abstraction, despite an average to above average level of intelligence [verbal intelligence quotient (IQ) 114]. The other patient (verbal IQ 99) showed clinically relevant deficits in visual construction, delayed visual recall and attention.
Quality of Life
Regarding the evaluation of Quality of Life, patients differed from the healthy norm population in the following SF-36 scales: (i) limitations in physical activities due to health problems; (ii) limitations in common role activities due to physical health problems; (iii) perception of general health; and (iv) vitality. However, subjective assessment of ‘general mental health’ (well being) and ‘limitations in social activities due to physical or emotional problems’ did not differ significantly from the healthy norm population.
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Discussion |
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To our knowledge, this is the first neuropsychological investigation of CPEO and KSS patients employing an age-, sex- and education-matched healthy control group, which allows detection of even subtle deficits and assessment of deficit profiles.
In our series of 22 patients with CPEO or KSS, neuropsychological testing did not reveal anything to suggest general intellectual deterioration or dementia when compared with healthy controls. Verbal and visual long-term memory were largely unaffected. In contrast, a rather specific pattern of focal cognitive impairment emerged with executive, visuo-constructional and attentional functions being particularly affected. The pattern and the extent of deficits was not dependent on the inclusion of two patients with mtDNA point mutations. When the analyses were restricted to the 15 patients with mtDNA deletions, sizeable deficits in several cognitive domains were found in 20–50% of the patients (Fig. 1).
Evaluation of executive functions in CPEO/KSS patients showed a significant increase of perseverative errors in the WCST, whereas the number of non-perseverative errors did not differ from healthy controls. A particularly increased number of perseverative errors in the WCST has been observed in patients with prefrontal lesions (Anderson et al., 1991). Together with our finding of markedly reduced verbal fluency, the pattern of deficits is consistent with compromised frontal lobe functioning in CPEO and KSS patients. Previous neuropsychological studies on patients with various mitochondrial disorders have not examined executive functions in detail, except for a single report on a patient with MELAS, who, similar to our results, demonstrated no dementia but marked focal impairment in executive and visuo-constructive functions that were progressive in a detailed neuropsychological 4-year follow-up study (Sartor et al., 2002).
Assessment of attentional functions included measuring of sustained attention (vigilance), controlled search and selective attention. CPEO and KSS patients displayed pronounced deficits in all speeded tasks requiring visual target search and visuomotoric coordination, indicating impairment of psychomotor functions and cognitive processing speed in our group of patients. In contrast, vigilance was only slightly reduced in patients and simple reaction time was normal. It seems unlikely that the detected deficits were mainly due to ophthalmoplegia, since the selected tasks involved scanning only across a narrow field of foveal vision.
Visual processing and visual construction were markedly impaired in our patient group, as evident from impairments in Block Design testing and in copying the Rey figure (RCFT). Interestingly, group differences were most marked when scoring the organizational strategy (Binder, 1982) of the subjects copying the Rey figure. Thus, the deficits may in part result from a piecemeal approach to processing visual tasks.
Verbal and visual long-term memory appeared to be largely intact in our series of patients. While patients had significantly reduced immediate recall scores, delayed recall and recognition of learned words did not differ from controls. Similarly, when relating the recall of the Rey figure (RCFT) to the amount drawn initially (which is useful to disentangle storage and retrieval deficits from perceptual and encoding deficits; Spreen and Strauss, 1998), recall (accuracy) was not impaired in the patient group.
Assessment of verbal comprehension and vocabulary resulted in unexpected findings. While all patients passed the Token Test, significantly reduced scores were found in a lexical decision type vocabulary task and in the WAIS-R Information test. These tests are usually considered to reflect ‘premorbid’ intellectual capacity. The difference between groups was equivalent to 
10 IQ points. This raises the question of whether, despite using educational-matched controls, differences in general cognitive capacity might underlie the domain-specific deficits described above. To rule out improper matching, we dropped five patients with a verbal IQ below 79 (leaving 17 patients with a mean IQ of 98.8, SD 9.1) and three controls with a verbal IQ above 120 from the analysis (leaving 17 controls with a mean IQ of 102.6, SD 7.6), resulting in subsamples matched with regard to verbal IQ [t(32) = 1.35, n.s.]. When univariate analyses were rerun, all focal cognitive deficits described above were confirmed (P < 0.05). Thus, the somewhat lower verbal intelligence in our patient sample cannot account for specific neuropsychological deficits.
To assess neuropsychological performance of patients with respect to clinical relevance, patients’ results were compared with published normative data for each test. Patients demonstrated abnormal test scores (below the 10th percentile) in 24 and 31% (CPEO or KSS, respectively) of all tests, particularly in visuo-construction, attention and flexibility tasks. There were no significant differences between KSS and CPEO patients, which may represent a clinical spectrum rather than separate disease entities.
Assessment of health-related Quality of Life gave no evidence of depression in our group of patients. However, patients reported being seriously impaired in everyday life situations, and loss of ‘energy’ and exhaustion were characteristic within the patient group. On the other hand, mental health status did not differ from the healthy normative population.
The range and extent of cognitive deficits were not correlated with the age at onset of symptoms and the duration of disease in our patient group. Our findings, therefore, do not support the hypothesis that long-standing ophthalmoplegia might be responsible for visuo-spatial impairment or attentional dysfunction due to neuronal plasticity of the CNS (Shepherd et al., 1986; Recanzone et al., 1993; Turconi et al., 1999).
The grade of heteroplasmy in skeletal muscle tissue did not correlate with neuropsychological performance in our patients with mtDNA mutations. According to our results, the percentage of mutant mtDNA in skeletal muscle tissue does not seem to be a useful predictor for cognitive capabilities in KSS and CPEO patients. These results are consistent with the literature, where the proportion of mutant mtDNA has been shown to vary widely between different tissues in KSS, and the grade of heteroplasmy in skeletal muscle tissue did not predict organ and CNS involvement in mitochondrial disorders (Shanske et al., 1990; Reichmann et al., 1996).
Our results are partially in line with previous findings of Turconi et al. (1999), who in various mitochondrial disorders found distinct cognitive deficits in visuo-constructive skills, visuo-spatial perception and working memory, but no dementia. Executive functions were not assessed by Turconi et al. (1999). Two other studies on mitochondrial disorders showed equivocal results regarding global intellectual capabilities and focal cognitive decline, thus denying a specific pattern of higher cerebral dysfunction (Kartsounis et al., 1992; Lang et al., 1995). In contrast to our findings, patients with Friedreich’s ataxia, a mitochondrial disorder primarily affecting the mitochondrial iron metabolism, did not demonstrate major frontal lobe-related cognitive decline in neuropsychological evaluation with special respect to executive functions (White et al., 2000). However, our data provide evidence for a specific pattern of focal cognitive deficits predominantly affecting visuo-construction, attention and abstraction/flexibility tasks when compared with a matched healthy control group, as well as with the respective norm group of each test setting. Deficits may be due to parieto-occipital lobe dysfunction and to impairment of supervisory attentional control associated to the prefrontal cortex, respectively. Our data do not suggest dementia to be a predominant finding in CPEO and KSS patients, since memory impairment was uncommon in our patient group and there was no uniform pattern of cognitive decline. However, it is important to note that our observations represent a snapshot in time in the chronic progressive course of the disease.
The aetiology of focal neuropsychological deficits in our patients remains unclear. There are a number of reports on brain tissue examinations in mitochondrial cytopathies that compared the proportion of mutant mtDNA in different brain areas in postmortem analyses (Shanske et al., 1990; Amemiya et al., 2000). Findings have unequivocally demonstrated the highest percentages of mutant mtDNA in frontal lobes, followed by parietal, occipital and temporal lobes and the cerebellum. Since the vulnerability to respiratory chain dysfunction varies profoundly in different tissues according to their energy demand, high metabolism of the frontal cortex (Roland et al., 1985, 1987) may result in a specific susceptibility of frontal lobes to mitochondrial dysfunction. Accumulation of mutant mtDNA in frontal lobes resulting in impairment of energy supply could explain distinct deficits in executive functions in our series of patients with genetically proven mtDNA mutations. However, the role and pathology of frontal cortices in patients with mitochondrial disorders and executive deficits is still highly speculative. To investigate potential correlations between brain metabolism and cognitive function in mitochondrial cytopathies, further studies including functional MRI, single photon emission computed tomography or PET will be useful.
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Acknowledgements |
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Simone Bosbach works now at the Max Planck Institute for Psychological Research, Munich, Germany.
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