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Neuropsychological findings in patients with Unverricht–Lundborg disease
Epilepsy & Behavior 14 (2009) 545–549
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Neuropsychological findings in patients with Unverricht–Lundborg disease Edoardo Ferlazzo a,*, Antonella Gagliano b, Tiziana Calarese b, Adriana Magaudda c, Pasquale Striano d, Lara Cortese c, Clemente Cedro c, Virgilie Laguitton e, Placido Bramanti a, Marilena Carbonaro f, Addolorata Albachiara f, Nina Fragassi f, Domenico Italiano a, Edoardo Sessa a, Antonietta Coppola f, Pierre Genton e a
IRCCS Centro Neurolesi ‘‘Bonino Pulejo”, Messina, Italy Department of Child Neurology and Psychiatry, University of Messina, Messina, Italy Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina, Messina, Italy d Muscular and Neurodegenerative Diseases Unit, ‘‘G. Gaslini” Institute, University of Genoa, Genoa, Italy e Centre Saint-Paul, Hôpital Henri Gastaut, Marseille, France f Epilepsy Centre, Department of Neurological Sciences, Federico II University, Naples, Italy b c
a r t i c l e
i n f o
Article history: Received 29 December 2008 Accepted 10 January 2009 Available online 29 January 2009 Keywords: Neuropsychology Unverricht–Lundborg disease Progressive myoclonus epilepsy
a b s t r a c t The aims of this study were to clarify if patients with Unverricht–Lundborg disease (ULD) have adequate cognitive functioning and to delineate their neuropsychological profile. We evaluated 20 patients with ULD and 20 healthy, matched controls. Mean age of the patients was 35 years, and mean duration of disease, 22 years. Patients underwent a neuropsychological battery exploring intelligence, executive functions, visuospatial and verbal memory, depression, and anxiety. Eleven of 20 subjects with ULD had mild to moderate cognitive impairment. Compared with controls, patients with ULD had lower scores on all short-term memory and executive function tasks. Linear regression analysis disclosed significant associations between impaired performance on some memory tests and duration of disease and between severity of myoclonus and performance on most executive function tests. In conclusion, most patients with ULD seem to be impaired with respect to cognitive abilities. Longitudinal prospective studies are needed to confirm and further expand our findings. Ó 2009 Elsevier Inc. All rights reserved.
1. Introduction Unverricht–Lundborg disease (ULD) is the most common, less severe form of progressive myoclonus epilepsy (PME). Although it occurs worldwide, its prevalence is higher in some geographic areas (Finland, Mediterranean region, Reunion Island) and in areas with a high rate of consanguinity (Maghreb). Age at onset is usually between 8 and 15 years. Clinically, ULD is characterized by the association of action myoclonus, rare generalized tonic–clonic or clonic–tonic–clonic seizures, and mild ataxia. Its evolution is characterized by stabilization of action myoclonus, which usually worsens only during the first 5 years of disease, and reduction or disappearance of seizures, with a permanent disability variable according to the severity of the myoclonus [1]. The disease is autosomal recessive inherited and is usually caused by a mutation [mainly an expansion of a dodecamer (CCCCGCCCCGCG) repeat or point mutation] in the promoter region of cystatin B gene, mapping on 21q2221q22 [2,3]. Recently, three pedigrees with ULD phe* Corresponding author. Fax: +39 0903656749. E-mail address: [email protected] (E. Ferlazzo). 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.01.001
notype presenting at a relatively earlier age, with a mutation in PRICKLE1, were described [4,5]. A progressive cognitive decline of about 10 points in total IQ every 10 years of disease was initially reported in patients with ULD of Finnish origin, with lower performance on the Arithmetic and Digit Span subtests of the Wechsler scales [6]. Subsequently, the same authors [7] revealed a normal cognitive level in most of their subjects with ULD, justifying the discrepancy with their previous findings with the use high phenytoin (PHT) doses in their patients. Indeed, no significant cognitive decline was observed in patients from the Mediterranean region [1,8–10] who did not receive PHT. Chew et al. [11] reported mild to severe intellectual dysfunction in three of seven subjects with ULD; moreover, memory impairment was observed in the patients. However, a detailed description of neuropsychological tests was lacking, and only IQ levels were reported. The aims of this study were to clarify whether people with ULD show an adequate cognitive profile, as previously suggested by the literature, and to better describe their neuropsychological profile using a wide battery of tests to explore memory and executive functions. In addition, we evaluated affective sphere (anxiety and depression) and its correlation with cognitive parameters.
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2. Methods 2.1. Subjects Twenty subjects (13 males, 7 females) diagnosed with genetically confirmed ULD and regularly followed in three European epilepsy centers (Centre for Diagnosis and Care of Epilepsy, Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina, Italy; Epilepsy Centre, Federico II University, Naples, Italy; Centre Saint-Paul, Hôpital Henri Gastaut, Marseille, France) were evaluated. Mean age was 35 years (range: 16–52), mean schooling 9.8 years (range: 5–16), and mean duration of disease 22 years (range: 6–33). A control group of 20 healthy subjects matched for sex (14 males, 6 females), age (average: 34.4 ± 13.1 years), and schooling (mean: 8.8 years) were also evaluated. To determine the severity of the myoclonus, on the same day the neuropsychological battery was administered, patients were assessed with Section 4 of the Unified Myoclonus Rating Scale (UMRS), which is used to evaluate action myoclonus (normal score: 0) [12]. 2.2. Neuropsychological assessment Patients and control subjects were administered a comprehensive test battery exploring intelligence (Wechsler Adult Intelligence Scale—Revised (WAIS-R) [13]), executive functions (Stroop Color–Word Interference Test or Stroop test [14], Wisconsin Card Sorting Test (WCST) [15], Verbal Fluency Test for letters and categories [16]), and visuospatial and verbal memory (Corsi Test [17], Rey Auditory Verbal Learning Test (RAVLT) [18]). Affective sphere was explored with the Hamilton Rating Scale for Anxiety (HAMA) [19] and Hamilton Rating Scale for Depression (HAM-D) [20]. The tests were administered by skilled neuropsychologists (T.C., L.C., V.L., M.C., A.A., N.F.) working in the epilepsy centers.
(Nos. 10, 11, 13). Action myoclonus varied from mild (UMRS <30) (Nos. 4, 5, 10, 13, 15, 20) to moderate/severe (UMRS >30), and severity varied even among siblings (Table 1). All patients were taking from three to five antiepileptic drugs (AEDs). Considering our patients with ULD as a whole, cognitive functions were impaired; the mean Total IQ score was just below 70, mean Verbal IQ and Performance IQ scores overlapped (Table 2), and performance on all WAIS subtests was below average (10 points) (see Supplemental material, Fig. 3). However, analysis of the IQ scores of each patient revealed broad variability in cognitive level, ranging from normal to moderate impairment (Table 3); 15 of 20 patients had Total IQ scores between 55 and 85. With respect to the WAIS subtests, patients with ULD obtained lower scores on Digit Span, Arithmetic, Digit Symbol, and Block Design, whereas their performance on Object Assembly, Vocabulary, Information, and Picture Completion was less impaired (Supplemental material, Fig. 3). When compared with controls on performance on memory and executive function tests, patients with ULD obtained statistically significantly lower scores on all tasks (Figs. 1 and 2). Only in three patients was major depression diagnosed. On the HAM-D, 13 of 20 patients with ULD obtained scores higher than the cutoff value (11), indicating the presence of depression, usually of mild intensity in most patients (11 of 20 patients) (Supplemental material, Table 4). Only two patients reported anxiety symptoms (Supplemental material, Table 5). Linear regression analysis revealed a significant association between severity of myoclonus and two WAIS subtests: Digit Symbol and Similarities (Supplemental material, Table 6). There was also a significant association between two tests from the memory set and duration of disease (Supplemental material, Table 7). Myoclonus severity was significantly associated with most of the tests in the executive function set (Supplemental material, Table 8). Finally, there was no significant association between the two affective variables and all neuropsychological tests (Supplemental material, Tables 6–8).
2.3. Statistical analyses 4. Discussion Data were analyzed with Statistical Package for the Social Sciences software (SPSS, Chicago, IL, USA) for Windows, Version 11.0. IQ scores (Total, Verbal, and Performance) and scores on each WAIS subtest were considered. Means and SD of these values were calculated. Other neuropsychological tests were grouped into two sets on the basis of the most explored neuropsychological functions, that is, memory and executive functions. The memory set comprised two verbal short-term memory tasks (Forward Digit Span and Backward Digit Span), two visuospatial short-term memory tasks (Forward Corsi and Backward Corsi), and two RAVLT subtests (Recognition and Delay). The second set, executive functions, comprised the Verbal Fluency Test (phonological and categorical), the Stroop test (interferential score), and the WCST. Scores on all neuropsychological tests, after transformation into Z scores, were compared with those of the control group using the Mann–Whitney test (Figs. 1 and 2). Two clinical variables (duration of disease, severity of myoclonus) and two psychoaffective variables (anxiety, depression) were considered. Linear regression analysis was performed with these four variables as independent, and IQ, executive function, and memory test scores as dependent variables. Differences were considered statistically significant at P < 0.05. 3. Results Table 1 summarizes the clinical and demographic characteristics of our ULD subjects. Nine patients were of French origin, and 11 were Italian. Four of five multiplex families had two affected siblings (Nos. 2, 3; 4, 5; 8, 9; 12, 15), whereas one family had three
Our study is the first to broadly explore neuropsychological profile in a large sample of people with ULD. With respect to general cognitive level, our patients had overall impairment of global cognitive functioning, with below-average Verbal IQ, Performance IQ, and Total IQ scores. Our data corroborate and further expand recent findings by Chew et al. [11], who reported a mean Verbal IQ of 79 and Performance IQ of 68 in seven subjects with ULD. The presence of a large variability in the level of mental functioning, ranging from normal (10%), to borderline (35%), to mild impairment (40%), to moderate impairment (15%), emerges from our data. Most likely, the WAIS does not adequately determine the cognitive level of patients with ULD. Indeed, action myoclonus may interfere with performance on some tasks, especially those in which a time limit and precision weigh heavily on the final result. Nevertheless, in our series, the only WAIS subtests that seem to be influenced by myoclonus severity are Digit Symbol and Similarities and, therefore, it is unlikely that Total IQ was significantly lowered by motor impairment. Moreover, mean Performance IQ, which could be influenced by motor abilities, was not lower than mean Verbal IQ in the subjects with ULD. Among the WAIS subtests, the subjects with ULD performed worse on Digit Span, Arithmetic, Digit Symbol, and Block Design. These findings overlap with the results of the only previous study of patients with ULD in which there was accurate analysis of WAIS subtests [6]; in that study, the subjects were most impaired in the skills assessed with the Arithmetic and Digit Span subtests. Ability on the Arithmetic subtest is strictly related to attention and concentration and requires
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E. Ferlazzo et al. / Epilepsy & Behavior 14 (2009) 545–549 1 0.8
ULD Controls
0.6 0.4 0.2 Z scores 0 -0.2 -0.4 -0.6 -0.8 -1
Forward Digit Span
Backward Digit Span
Forward Corsi
Backward Corsi
Rey Delay
Rey Recognition
Fig. 1. Comparison of performance of patients with ULD and controls on tests in the memory set.
1 0.8
ULD Controls
0.6 0.4 0.2 Z scores 0 -0.2 -0.4 -0.6 -0.8 -1
Phonological fluency
Semantic fluency
Stroop interference
WCST Categories
WCST Perseverations
Fig. 2. Comparison of performance of patients with ULD and controls on tests in the executive function set.
Table 1 Demographic and clinical features of 20 patients with ULD. Patient No. (sex)
Age (years)
Age at disease onset (years)
Geographic origin
Schooling (years)
Myoclonus severity (UMRS score)
AEDsa
1 (M) 2 (F) 3 (F) 4 (M) 5 (M) 6 (F) 7 (F) 8 (M) 9 (M) 10 (F) 11 (M) 12 (F) 13 (M) 14 (M) 15 (M) 16 (M) 17 (M) 18 (M) 19 (M) 20 (F)
40 16 16 52 38 28 26 39 47 40 45 19 36 21 17 46 36 45 49 46
10 11 10 17 12 8 9 14 15 11 12 9 14 12 12 16 15 17 16 16
France France France France France France France France France Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy
15 15 5 16 16 5 16 6 8 13 13 8 13 13 9 5 5 5 5 5
60 62 55 21 15 53 60 45 50 20 62 50 13 15 20 55 45 40 45 50
VPA, PIR, CLN VPA, CLN, LEV, ZNS VPA, CLN, LEV CLN, VPA, TPM, LEV VPA, LEV LEV, PIR, TPM, CLN VPA, CLN, LEV, PIR VPA, PIR VPA, CLN VPA, CLN VPA, CLN, LEV VPA, CLN, LEV VPA, CLN, LEV VPA, CLN, LEV VPA, CLN, LEV VPA, CLN, LEV, PB VPA, ACZ, CLN, LEV, BRI VPA, CLN, LEV, ZNS VPA, CLN, LEV, ZNS VPA, CLN, LEV, ZNS
a
ACZ, acetazolamide; BRI, brivaracetam; CLN, clonazepam; LEV, levetiracetam; PIR, piracetam; PB, phenobarbital; TPM, topiramate; VPA, valproate; ZNS, zonisamide.
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Table 2 Mean (SD) WAIS scores of the 20 patients with ULD. Total IQ Verbal IQ Performance IQ
67.9 (12.6) 71.1 (11.1) 69.4 (15.2)
Table 3 Total IQ scores of the subjects with ULD. TIQ
Number of patients
Cognitive level
>85 >70 but <85 >55 but <70 >40 but <55
2 7 8 3
Normal Borderline Mild impairment Moderate impairment
active organization and manipulation of events [21,22]. According to some authors [23], working memory plays a crucial role in this task. Working memory is also required in the Digit Span task, which presupposes encoding of the information, data recall, sequence conception, and vocalization of the information. Although this test is considered quite specific for attention [22,24], it is important to emphasize that inverted repetition is strictly supported by working memory [25]. So, short-term memory and attention can be identified as the main functions impaired in our ULD series. The low performance of patients with ULD on the Digit Symbol subtest should be considered less relevant, as it presupposes good control of fine motor abilities, which obviously are impaired by action myoclonus; indeed, linear regression analysis revealed a significant association between severity of myoclonus and performance on the Digit Symbol subtest. Moreover, because this subtest is a time-limited task, the slowness of subjects with ULD could be another unfavorable factor. However, it cannot be excluded that, to a certain extent, low performance on this task may be due to a coexistent deficit in working memory, which is essential in maintaining the code [24,26]. The low performance on the Block Design subtest can partially be explained by the motor impairment of patients with patients; this test presupposes the manipulation of small cubes and is also time limited. However, executive functions are also required to carry out this task, and this is in keeping with the low performance of our patients on all other frontal tests. On the contrary, it seems that long-term memory represents a less impaired cognitive domain, as patients performed better on the Information subtest, in which subjects must retrieve previously learned information. Visual perception and visuospatial reasoning also seem to be less impaired; indeed, patients performed better on the two WAIS subtests Picture Completion and Object Assembly, although the latter requires high motor involvement and is time limited. Both subtests involve reasoning on complex perceptive tasks, attention to detail, and ability to represent and mentally manipulate forms and object spatial features. Therefore, a final profile can be drawn that is characterized by relative preservation of logic, visual perceptive ability, and permanent learning ability, with impairment of short-term memory, especially verbal working memory, and attention. It is noteworthy that the patients with ULD performed poorly on all tests of memory and executive function. Controls performed better on all the tasks, further corroborating the hypothesis of global impairment in almost all neuropsychological domains. We should point out that patients with ULD also performed poorly on tasks that do not require motor abilities or in which these are less relevant, as in the Corsi test, where the patient can only establish the correct cube position. A progressive impairment of memory may be supposed on the basis of the significant association between duration of disease and Forward Corsi test, further corroborating the hypothesis of progressive impairment in short-term visuospatial memory. How-
ever, no significant correlation was observed between duration of disease and IQ scores. Moreover, the only WAIS subtest that was significantly associated with duration of disease was Vocabulary; this finding cannot be considered strong evidence of a progressive decline in the ability to recall from memory and to reorganize verbal information. These findings differ from those of Koskiniemi [6], who reported a progressive cognitive decline over years; however, the use of high-dose PHT may partially explain this difference. The associations that emerged between severity of myoclonus and performance on most executive function tests strongly suggest that patients with more severe myoclonus are also more severely impaired in frontal functions; the WAIS subtest Similiarities, which evaluates organization of data according to functional relationships, was also significantly correlated with severity of myoclonus. Therefore, the executive abilities of patients with ULD seem to worsen along with their motor abilities. We may argue that in patients with ULD, in parallel with an impairment of neuronal networks subserving motor control, there is dysfunction of cognitive networks involving mainly the frontal lobe. The connection that emerged between severity of myoclonus and the Forward Corsi test suggests that memory networks also may parallel the dysfunction of motor control networks. It must be stressed that a strong difference in myoclonus severity and cognitive functioning was found even among siblings, confirming that the size of the dodecameric expansion in the promoter region of the cystatin B gene (identical in siblings) is not correlated with severity of disease [27]. Therefore, it is very likely that other genetic or environmental factors contribute to the clinical manifestation of this condition. The importance of affective disorder in the cognitive functioning of patients with ULD has been stressed by some authors [10,11]. In a previous study on 11 patients of Mediterranean origin, fluctuation was observed in cognitive performance over the years and was ascribed to the significant interference of psychiatric symptoms with cognitive performance [10]. Indeed, depression, anxiety, and emotional liability were observed in 40% of their patients with ULD. Chew et al. [11] confirmed this observation, reporting that six of their seven subjects with ULD had psychiatric disorders, in particular depression. However, only 3 (15%) of our 20 patients had moderate to severe depression that could significantly impact cognitive functioning; therefore, the impact of depressive mood does not seem as relevant in our series. It must be also emphasized that only a very small percentage (10%) of our patients had symptoms of anxiety. Furthermore, linear regression analysis did not reveal a significant correlation between the psychoaffective domain and cognitive impairment in our patients. Pooled together, our findings downsize the impact of affective disorders on cognition in our patients with ULD. In the present study, we considered four main potentially interfering variables (myoclonus severity, duration of disease, anxiety status, and depressive symptoms); we did not include other variables such as seizure occurrence, EEG abnormalities, and AEDs. Indeed, it is known that, in patients with ULD, seizures are often rare, and overall, they become much less frequent after 10 years [1]. Also, EEG abnormalities, in particular generalized spike or polyspike and wave discharges, tend to decrease over time after an average of 15 years of disease [28]. Our patients underwent neuropsychological evaluation after an average disease duration of 22 years (75% after 15 years of disease), so it is very unlikely that seizures or EEG changes influenced the final neuropsychological scores. With respect to the potential influence of AEDs on neuropsychological findings, all patients were on polytherapy. Nineteen of 20 patients were on valproate, which is not known to cause a significant decline in neuropsychological performance [29]. Sixteen patients were on levetiracetam, which usually has no cognitive side effects as assessed in animal and human studies [30,31]. Eighteen patients were on clonazepam (CLN). Although CLN rarely
E. Ferlazzo et al. / Epilepsy & Behavior 14 (2009) 545–549
provokes sedation and behavioral problems, its cognitive side effects have not been systematically studied [32]. In a study of 23 patients with chronic epilepsy who underwent CLN withdrawal, no significant change in cognitive function, mood, or behavior was noted when the drug was discontinued [33]. Two patients (Nos. 4 and 6) were on topiramate, a drug that may affect cognition, in particular word fluency, list learning, and Verbal IQ [34]. Finally, only one patient (No. 16) was on phenobarbital, which can induce such cognitive impairments as motor slowness, memory disturbances, loss of concentration, and mental slowness [34]. None of our patients ever received PHT, a drug with well-known cognitive side effects [34]; its use in Finnish patients with ULD was associated with worsening of myoclonus and impairment of intellectual functioning. As all patients were on polytherapy, a cumulative neurotoxic side effect cannot be excluded [35]. However, the cognitive impairment in our patients was so severe that it is unlikely to be related to only the cognitive effects of AEDs. Our findings realistically reflect the cognitive outcome of these patients for whom pharmacological polytherapy is essential. In addition to motor troubles and possible coexistent psychoaffective problems, the cognitive abilities of subjects with ULDs are impaired. Patients with more severe myoclonus also seem to have more severe impairment of frontal functions. Our findings strongly emphasize that people with ULD should periodically undergo neuropsychological assessment to evaluate impairment of their cognitive functions. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.yebeh.2009.01.001. References [1] Magaudda A, Ferlazzo E, Nguyen VH, Genton P. Unverricht–Lundborg disease, a condition with self-limited progression: long-term follow-up of 20 patients. Epilepsia 2006;47:860–6. [2] Lehesjoki AE, Koskiniemi M, Sistonen P, Miao J, Hästbacka J, de la Chapelle A. Localization of a gene for progressive myoclonus epilepsy to chromosome 21q22. Proc Natl Acad Sci USA 1991;88:3696–9. [3] Pennacchio LA, Lehesjoki AE, Stone NE, et al. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 1996;271:1731–4. [4] Berkovic SF, Mazarib A, Walid S, et al. A new clinical and molecular form of Unverricht–Lundborg disease localized by homozygosity mapping. Brain 2005;128:652–8. [5] Bassuk AG, Wallace RH, Buhr A, et al. A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy– ataxia syndrome. Am J Hum Genet 2008;83:572–81. [6] Koskiniemi M. Psychological findings in progressive myoclonus epilepsy without Lafora bodies. Epilepsia 1974;15:537–45. [7] Lehesjoki AE, Koskiniemi M. Progressive myoclonus epilepsy of Unverricht– Lundborg type. Epilepsia 1999;40(Suppl. 3):23–8. [8] Tassinari CA, Michelucci R, Genton P, Pellisier GF, Roger J. Dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome): a condition unrelated to mitochondrial encephalomyopathies. J Neurol Neurosurg Psychiatry 1989;52:262–5.
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Neuropsychological findings in patients with Unverricht–Lundborg disease Edoardo Ferlazzo a,*, Antonella Gagliano b, Tiziana Calarese b, Adriana Magaudda c, Pasquale Striano d, Lara Cortese c, Clemente Cedro c, Virgilie Laguitton e, Placido Bramanti a, Marilena Carbonaro f, Addolorata Albachiara f, Nina Fragassi f, Domenico Italiano a, Edoardo Sessa a, Antonietta Coppola f, Pierre Genton e a
IRCCS Centro Neurolesi ‘‘Bonino Pulejo”, Messina, Italy Department of Child Neurology and Psychiatry, University of Messina, Messina, Italy Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina, Messina, Italy d Muscular and Neurodegenerative Diseases Unit, ‘‘G. Gaslini” Institute, University of Genoa, Genoa, Italy e Centre Saint-Paul, Hôpital Henri Gastaut, Marseille, France f Epilepsy Centre, Department of Neurological Sciences, Federico II University, Naples, Italy b c
a r t i c l e
i n f o
Article history: Received 29 December 2008 Accepted 10 January 2009 Available online 29 January 2009 Keywords: Neuropsychology Unverricht–Lundborg disease Progressive myoclonus epilepsy
a b s t r a c t The aims of this study were to clarify if patients with Unverricht–Lundborg disease (ULD) have adequate cognitive functioning and to delineate their neuropsychological profile. We evaluated 20 patients with ULD and 20 healthy, matched controls. Mean age of the patients was 35 years, and mean duration of disease, 22 years. Patients underwent a neuropsychological battery exploring intelligence, executive functions, visuospatial and verbal memory, depression, and anxiety. Eleven of 20 subjects with ULD had mild to moderate cognitive impairment. Compared with controls, patients with ULD had lower scores on all short-term memory and executive function tasks. Linear regression analysis disclosed significant associations between impaired performance on some memory tests and duration of disease and between severity of myoclonus and performance on most executive function tests. In conclusion, most patients with ULD seem to be impaired with respect to cognitive abilities. Longitudinal prospective studies are needed to confirm and further expand our findings. Ó 2009 Elsevier Inc. All rights reserved.
1. Introduction Unverricht–Lundborg disease (ULD) is the most common, less severe form of progressive myoclonus epilepsy (PME). Although it occurs worldwide, its prevalence is higher in some geographic areas (Finland, Mediterranean region, Reunion Island) and in areas with a high rate of consanguinity (Maghreb). Age at onset is usually between 8 and 15 years. Clinically, ULD is characterized by the association of action myoclonus, rare generalized tonic–clonic or clonic–tonic–clonic seizures, and mild ataxia. Its evolution is characterized by stabilization of action myoclonus, which usually worsens only during the first 5 years of disease, and reduction or disappearance of seizures, with a permanent disability variable according to the severity of the myoclonus [1]. The disease is autosomal recessive inherited and is usually caused by a mutation [mainly an expansion of a dodecamer (CCCCGCCCCGCG) repeat or point mutation] in the promoter region of cystatin B gene, mapping on 21q2221q22 [2,3]. Recently, three pedigrees with ULD phe* Corresponding author. Fax: +39 0903656749. E-mail address: [email protected] (E. Ferlazzo). 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.01.001
notype presenting at a relatively earlier age, with a mutation in PRICKLE1, were described [4,5]. A progressive cognitive decline of about 10 points in total IQ every 10 years of disease was initially reported in patients with ULD of Finnish origin, with lower performance on the Arithmetic and Digit Span subtests of the Wechsler scales [6]. Subsequently, the same authors [7] revealed a normal cognitive level in most of their subjects with ULD, justifying the discrepancy with their previous findings with the use high phenytoin (PHT) doses in their patients. Indeed, no significant cognitive decline was observed in patients from the Mediterranean region [1,8–10] who did not receive PHT. Chew et al. [11] reported mild to severe intellectual dysfunction in three of seven subjects with ULD; moreover, memory impairment was observed in the patients. However, a detailed description of neuropsychological tests was lacking, and only IQ levels were reported. The aims of this study were to clarify whether people with ULD show an adequate cognitive profile, as previously suggested by the literature, and to better describe their neuropsychological profile using a wide battery of tests to explore memory and executive functions. In addition, we evaluated affective sphere (anxiety and depression) and its correlation with cognitive parameters.
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2. Methods 2.1. Subjects Twenty subjects (13 males, 7 females) diagnosed with genetically confirmed ULD and regularly followed in three European epilepsy centers (Centre for Diagnosis and Care of Epilepsy, Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina, Italy; Epilepsy Centre, Federico II University, Naples, Italy; Centre Saint-Paul, Hôpital Henri Gastaut, Marseille, France) were evaluated. Mean age was 35 years (range: 16–52), mean schooling 9.8 years (range: 5–16), and mean duration of disease 22 years (range: 6–33). A control group of 20 healthy subjects matched for sex (14 males, 6 females), age (average: 34.4 ± 13.1 years), and schooling (mean: 8.8 years) were also evaluated. To determine the severity of the myoclonus, on the same day the neuropsychological battery was administered, patients were assessed with Section 4 of the Unified Myoclonus Rating Scale (UMRS), which is used to evaluate action myoclonus (normal score: 0) [12]. 2.2. Neuropsychological assessment Patients and control subjects were administered a comprehensive test battery exploring intelligence (Wechsler Adult Intelligence Scale—Revised (WAIS-R) [13]), executive functions (Stroop Color–Word Interference Test or Stroop test [14], Wisconsin Card Sorting Test (WCST) [15], Verbal Fluency Test for letters and categories [16]), and visuospatial and verbal memory (Corsi Test [17], Rey Auditory Verbal Learning Test (RAVLT) [18]). Affective sphere was explored with the Hamilton Rating Scale for Anxiety (HAMA) [19] and Hamilton Rating Scale for Depression (HAM-D) [20]. The tests were administered by skilled neuropsychologists (T.C., L.C., V.L., M.C., A.A., N.F.) working in the epilepsy centers.
(Nos. 10, 11, 13). Action myoclonus varied from mild (UMRS <30) (Nos. 4, 5, 10, 13, 15, 20) to moderate/severe (UMRS >30), and severity varied even among siblings (Table 1). All patients were taking from three to five antiepileptic drugs (AEDs). Considering our patients with ULD as a whole, cognitive functions were impaired; the mean Total IQ score was just below 70, mean Verbal IQ and Performance IQ scores overlapped (Table 2), and performance on all WAIS subtests was below average (10 points) (see Supplemental material, Fig. 3). However, analysis of the IQ scores of each patient revealed broad variability in cognitive level, ranging from normal to moderate impairment (Table 3); 15 of 20 patients had Total IQ scores between 55 and 85. With respect to the WAIS subtests, patients with ULD obtained lower scores on Digit Span, Arithmetic, Digit Symbol, and Block Design, whereas their performance on Object Assembly, Vocabulary, Information, and Picture Completion was less impaired (Supplemental material, Fig. 3). When compared with controls on performance on memory and executive function tests, patients with ULD obtained statistically significantly lower scores on all tasks (Figs. 1 and 2). Only in three patients was major depression diagnosed. On the HAM-D, 13 of 20 patients with ULD obtained scores higher than the cutoff value (11), indicating the presence of depression, usually of mild intensity in most patients (11 of 20 patients) (Supplemental material, Table 4). Only two patients reported anxiety symptoms (Supplemental material, Table 5). Linear regression analysis revealed a significant association between severity of myoclonus and two WAIS subtests: Digit Symbol and Similarities (Supplemental material, Table 6). There was also a significant association between two tests from the memory set and duration of disease (Supplemental material, Table 7). Myoclonus severity was significantly associated with most of the tests in the executive function set (Supplemental material, Table 8). Finally, there was no significant association between the two affective variables and all neuropsychological tests (Supplemental material, Tables 6–8).
2.3. Statistical analyses 4. Discussion Data were analyzed with Statistical Package for the Social Sciences software (SPSS, Chicago, IL, USA) for Windows, Version 11.0. IQ scores (Total, Verbal, and Performance) and scores on each WAIS subtest were considered. Means and SD of these values were calculated. Other neuropsychological tests were grouped into two sets on the basis of the most explored neuropsychological functions, that is, memory and executive functions. The memory set comprised two verbal short-term memory tasks (Forward Digit Span and Backward Digit Span), two visuospatial short-term memory tasks (Forward Corsi and Backward Corsi), and two RAVLT subtests (Recognition and Delay). The second set, executive functions, comprised the Verbal Fluency Test (phonological and categorical), the Stroop test (interferential score), and the WCST. Scores on all neuropsychological tests, after transformation into Z scores, were compared with those of the control group using the Mann–Whitney test (Figs. 1 and 2). Two clinical variables (duration of disease, severity of myoclonus) and two psychoaffective variables (anxiety, depression) were considered. Linear regression analysis was performed with these four variables as independent, and IQ, executive function, and memory test scores as dependent variables. Differences were considered statistically significant at P < 0.05. 3. Results Table 1 summarizes the clinical and demographic characteristics of our ULD subjects. Nine patients were of French origin, and 11 were Italian. Four of five multiplex families had two affected siblings (Nos. 2, 3; 4, 5; 8, 9; 12, 15), whereas one family had three
Our study is the first to broadly explore neuropsychological profile in a large sample of people with ULD. With respect to general cognitive level, our patients had overall impairment of global cognitive functioning, with below-average Verbal IQ, Performance IQ, and Total IQ scores. Our data corroborate and further expand recent findings by Chew et al. [11], who reported a mean Verbal IQ of 79 and Performance IQ of 68 in seven subjects with ULD. The presence of a large variability in the level of mental functioning, ranging from normal (10%), to borderline (35%), to mild impairment (40%), to moderate impairment (15%), emerges from our data. Most likely, the WAIS does not adequately determine the cognitive level of patients with ULD. Indeed, action myoclonus may interfere with performance on some tasks, especially those in which a time limit and precision weigh heavily on the final result. Nevertheless, in our series, the only WAIS subtests that seem to be influenced by myoclonus severity are Digit Symbol and Similarities and, therefore, it is unlikely that Total IQ was significantly lowered by motor impairment. Moreover, mean Performance IQ, which could be influenced by motor abilities, was not lower than mean Verbal IQ in the subjects with ULD. Among the WAIS subtests, the subjects with ULD performed worse on Digit Span, Arithmetic, Digit Symbol, and Block Design. These findings overlap with the results of the only previous study of patients with ULD in which there was accurate analysis of WAIS subtests [6]; in that study, the subjects were most impaired in the skills assessed with the Arithmetic and Digit Span subtests. Ability on the Arithmetic subtest is strictly related to attention and concentration and requires
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ULD Controls
0.6 0.4 0.2 Z scores 0 -0.2 -0.4 -0.6 -0.8 -1
Forward Digit Span
Backward Digit Span
Forward Corsi
Backward Corsi
Rey Delay
Rey Recognition
Fig. 1. Comparison of performance of patients with ULD and controls on tests in the memory set.
1 0.8
ULD Controls
0.6 0.4 0.2 Z scores 0 -0.2 -0.4 -0.6 -0.8 -1
Phonological fluency
Semantic fluency
Stroop interference
WCST Categories
WCST Perseverations
Fig. 2. Comparison of performance of patients with ULD and controls on tests in the executive function set.
Table 1 Demographic and clinical features of 20 patients with ULD. Patient No. (sex)
Age (years)
Age at disease onset (years)
Geographic origin
Schooling (years)
Myoclonus severity (UMRS score)
AEDsa
1 (M) 2 (F) 3 (F) 4 (M) 5 (M) 6 (F) 7 (F) 8 (M) 9 (M) 10 (F) 11 (M) 12 (F) 13 (M) 14 (M) 15 (M) 16 (M) 17 (M) 18 (M) 19 (M) 20 (F)
40 16 16 52 38 28 26 39 47 40 45 19 36 21 17 46 36 45 49 46
10 11 10 17 12 8 9 14 15 11 12 9 14 12 12 16 15 17 16 16
France France France France France France France France France Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy
15 15 5 16 16 5 16 6 8 13 13 8 13 13 9 5 5 5 5 5
60 62 55 21 15 53 60 45 50 20 62 50 13 15 20 55 45 40 45 50
VPA, PIR, CLN VPA, CLN, LEV, ZNS VPA, CLN, LEV CLN, VPA, TPM, LEV VPA, LEV LEV, PIR, TPM, CLN VPA, CLN, LEV, PIR VPA, PIR VPA, CLN VPA, CLN VPA, CLN, LEV VPA, CLN, LEV VPA, CLN, LEV VPA, CLN, LEV VPA, CLN, LEV VPA, CLN, LEV, PB VPA, ACZ, CLN, LEV, BRI VPA, CLN, LEV, ZNS VPA, CLN, LEV, ZNS VPA, CLN, LEV, ZNS
a
ACZ, acetazolamide; BRI, brivaracetam; CLN, clonazepam; LEV, levetiracetam; PIR, piracetam; PB, phenobarbital; TPM, topiramate; VPA, valproate; ZNS, zonisamide.
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Table 2 Mean (SD) WAIS scores of the 20 patients with ULD. Total IQ Verbal IQ Performance IQ
67.9 (12.6) 71.1 (11.1) 69.4 (15.2)
Table 3 Total IQ scores of the subjects with ULD. TIQ
Number of patients
Cognitive level
>85 >70 but <85 >55 but <70 >40 but <55
2 7 8 3
Normal Borderline Mild impairment Moderate impairment
active organization and manipulation of events [21,22]. According to some authors [23], working memory plays a crucial role in this task. Working memory is also required in the Digit Span task, which presupposes encoding of the information, data recall, sequence conception, and vocalization of the information. Although this test is considered quite specific for attention [22,24], it is important to emphasize that inverted repetition is strictly supported by working memory [25]. So, short-term memory and attention can be identified as the main functions impaired in our ULD series. The low performance of patients with ULD on the Digit Symbol subtest should be considered less relevant, as it presupposes good control of fine motor abilities, which obviously are impaired by action myoclonus; indeed, linear regression analysis revealed a significant association between severity of myoclonus and performance on the Digit Symbol subtest. Moreover, because this subtest is a time-limited task, the slowness of subjects with ULD could be another unfavorable factor. However, it cannot be excluded that, to a certain extent, low performance on this task may be due to a coexistent deficit in working memory, which is essential in maintaining the code [24,26]. The low performance on the Block Design subtest can partially be explained by the motor impairment of patients with patients; this test presupposes the manipulation of small cubes and is also time limited. However, executive functions are also required to carry out this task, and this is in keeping with the low performance of our patients on all other frontal tests. On the contrary, it seems that long-term memory represents a less impaired cognitive domain, as patients performed better on the Information subtest, in which subjects must retrieve previously learned information. Visual perception and visuospatial reasoning also seem to be less impaired; indeed, patients performed better on the two WAIS subtests Picture Completion and Object Assembly, although the latter requires high motor involvement and is time limited. Both subtests involve reasoning on complex perceptive tasks, attention to detail, and ability to represent and mentally manipulate forms and object spatial features. Therefore, a final profile can be drawn that is characterized by relative preservation of logic, visual perceptive ability, and permanent learning ability, with impairment of short-term memory, especially verbal working memory, and attention. It is noteworthy that the patients with ULD performed poorly on all tests of memory and executive function. Controls performed better on all the tasks, further corroborating the hypothesis of global impairment in almost all neuropsychological domains. We should point out that patients with ULD also performed poorly on tasks that do not require motor abilities or in which these are less relevant, as in the Corsi test, where the patient can only establish the correct cube position. A progressive impairment of memory may be supposed on the basis of the significant association between duration of disease and Forward Corsi test, further corroborating the hypothesis of progressive impairment in short-term visuospatial memory. How-
ever, no significant correlation was observed between duration of disease and IQ scores. Moreover, the only WAIS subtest that was significantly associated with duration of disease was Vocabulary; this finding cannot be considered strong evidence of a progressive decline in the ability to recall from memory and to reorganize verbal information. These findings differ from those of Koskiniemi [6], who reported a progressive cognitive decline over years; however, the use of high-dose PHT may partially explain this difference. The associations that emerged between severity of myoclonus and performance on most executive function tests strongly suggest that patients with more severe myoclonus are also more severely impaired in frontal functions; the WAIS subtest Similiarities, which evaluates organization of data according to functional relationships, was also significantly correlated with severity of myoclonus. Therefore, the executive abilities of patients with ULD seem to worsen along with their motor abilities. We may argue that in patients with ULD, in parallel with an impairment of neuronal networks subserving motor control, there is dysfunction of cognitive networks involving mainly the frontal lobe. The connection that emerged between severity of myoclonus and the Forward Corsi test suggests that memory networks also may parallel the dysfunction of motor control networks. It must be stressed that a strong difference in myoclonus severity and cognitive functioning was found even among siblings, confirming that the size of the dodecameric expansion in the promoter region of the cystatin B gene (identical in siblings) is not correlated with severity of disease [27]. Therefore, it is very likely that other genetic or environmental factors contribute to the clinical manifestation of this condition. The importance of affective disorder in the cognitive functioning of patients with ULD has been stressed by some authors [10,11]. In a previous study on 11 patients of Mediterranean origin, fluctuation was observed in cognitive performance over the years and was ascribed to the significant interference of psychiatric symptoms with cognitive performance [10]. Indeed, depression, anxiety, and emotional liability were observed in 40% of their patients with ULD. Chew et al. [11] confirmed this observation, reporting that six of their seven subjects with ULD had psychiatric disorders, in particular depression. However, only 3 (15%) of our 20 patients had moderate to severe depression that could significantly impact cognitive functioning; therefore, the impact of depressive mood does not seem as relevant in our series. It must be also emphasized that only a very small percentage (10%) of our patients had symptoms of anxiety. Furthermore, linear regression analysis did not reveal a significant correlation between the psychoaffective domain and cognitive impairment in our patients. Pooled together, our findings downsize the impact of affective disorders on cognition in our patients with ULD. In the present study, we considered four main potentially interfering variables (myoclonus severity, duration of disease, anxiety status, and depressive symptoms); we did not include other variables such as seizure occurrence, EEG abnormalities, and AEDs. Indeed, it is known that, in patients with ULD, seizures are often rare, and overall, they become much less frequent after 10 years [1]. Also, EEG abnormalities, in particular generalized spike or polyspike and wave discharges, tend to decrease over time after an average of 15 years of disease [28]. Our patients underwent neuropsychological evaluation after an average disease duration of 22 years (75% after 15 years of disease), so it is very unlikely that seizures or EEG changes influenced the final neuropsychological scores. With respect to the potential influence of AEDs on neuropsychological findings, all patients were on polytherapy. Nineteen of 20 patients were on valproate, which is not known to cause a significant decline in neuropsychological performance [29]. Sixteen patients were on levetiracetam, which usually has no cognitive side effects as assessed in animal and human studies [30,31]. Eighteen patients were on clonazepam (CLN). Although CLN rarely
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provokes sedation and behavioral problems, its cognitive side effects have not been systematically studied [32]. In a study of 23 patients with chronic epilepsy who underwent CLN withdrawal, no significant change in cognitive function, mood, or behavior was noted when the drug was discontinued [33]. Two patients (Nos. 4 and 6) were on topiramate, a drug that may affect cognition, in particular word fluency, list learning, and Verbal IQ [34]. Finally, only one patient (No. 16) was on phenobarbital, which can induce such cognitive impairments as motor slowness, memory disturbances, loss of concentration, and mental slowness [34]. None of our patients ever received PHT, a drug with well-known cognitive side effects [34]; its use in Finnish patients with ULD was associated with worsening of myoclonus and impairment of intellectual functioning. As all patients were on polytherapy, a cumulative neurotoxic side effect cannot be excluded [35]. However, the cognitive impairment in our patients was so severe that it is unlikely to be related to only the cognitive effects of AEDs. Our findings realistically reflect the cognitive outcome of these patients for whom pharmacological polytherapy is essential. In addition to motor troubles and possible coexistent psychoaffective problems, the cognitive abilities of subjects with ULDs are impaired. Patients with more severe myoclonus also seem to have more severe impairment of frontal functions. Our findings strongly emphasize that people with ULD should periodically undergo neuropsychological assessment to evaluate impairment of their cognitive functions. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.yebeh.2009.01.001. References [1] Magaudda A, Ferlazzo E, Nguyen VH, Genton P. Unverricht–Lundborg disease, a condition with self-limited progression: long-term follow-up of 20 patients. Epilepsia 2006;47:860–6. [2] Lehesjoki AE, Koskiniemi M, Sistonen P, Miao J, Hästbacka J, de la Chapelle A. Localization of a gene for progressive myoclonus epilepsy to chromosome 21q22. Proc Natl Acad Sci USA 1991;88:3696–9. [3] Pennacchio LA, Lehesjoki AE, Stone NE, et al. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 1996;271:1731–4. [4] Berkovic SF, Mazarib A, Walid S, et al. A new clinical and molecular form of Unverricht–Lundborg disease localized by homozygosity mapping. Brain 2005;128:652–8. [5] Bassuk AG, Wallace RH, Buhr A, et al. A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy– ataxia syndrome. Am J Hum Genet 2008;83:572–81. [6] Koskiniemi M. Psychological findings in progressive myoclonus epilepsy without Lafora bodies. Epilepsia 1974;15:537–45. [7] Lehesjoki AE, Koskiniemi M. Progressive myoclonus epilepsy of Unverricht– Lundborg type. Epilepsia 1999;40(Suppl. 3):23–8. [8] Tassinari CA, Michelucci R, Genton P, Pellisier GF, Roger J. Dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome): a condition unrelated to mitochondrial encephalomyopathies. J Neurol Neurosurg Psychiatry 1989;52:262–5.
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