J Inherit Metab Dis DOI 10.1007/s10545-013-9643-x

REVIEW

Cognitive dysfunction and depression in Fabry disease: a systematic review Fay E. Bolsover & Elaine Murphy & Lisa Cipolotti & David J. Werring & Robin H. Lachmann

Received: 28 May 2013 / Revised: 11 July 2013 / Accepted: 15 July 2013 # SSIEM and Springer Science+Business Media Dordrecht 2013

Abstract Background Fabry disease, an X-linked lysosomal storage disorder, leads to multi-organ dysfunction, including cerebrovascular disease and psychological disorders. However, the prevalence and pattern of associated cognitive dysfunction is not well understood. Objectives To investigate whether there is reliable evidence for neuropsychological impairment in patients with Fabry disease and which cognitive domains are affected. To estimate the prevalence of and factors associated with depression in patients with Fabry disease. Method Qualitative systematic review of the literature of studies conducting neuropsychological assessment or measuring the prevalence of depression in adults with Fabry disease using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines where appropriate. Results There is some evidence for neuropsychological impairment in Fabry disease in executive functioning, information processing speed and attention, with preservation of: general intellectual functioning, memory, naming, perceptual functioning and global cognitive functioning. Prevalence rates of depression in Fabry disease ranged from 15 % to 62 %, with

Communicated by: Carla E. Hollak F. E. Bolsover : E. Murphy : R. H. Lachmann (*) Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, 8-11 Queen Square, Internal Mailbox 92, London WC1N 3BG UK e-mail: [email protected] L. Cipolotti Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG UK D. J. Werring Stroke Research Group, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG UK

the largest study to date reporting a prevalence rate of 46 %. The most common factor associated with depression was neuropathic pain, both directly and indirectly by affecting social and adaptive functioning. Conclusion Our review suggests that Fabry disease may be associated with a characteristic pattern of cognitive deficits and a high prevalence of psychological disorders such as depression but highlights the limited available data. Exploring the nature of cognitive impairment in Fabry disease using standardised neuropsychological assessment, brain imaging and measures of depression is an important task for future research.

Introduction Fabry disease (OMIM 301500) results from deficiency of the enzyme α-galactosidase A, leading to progressive accumulation of glycosphingolipids in tissues including renal, cardiac, ocular, skin and nervous systems. It is inherited as an X-linked trait, with an estimated incidence of between 1 in 40,000 to 1 in 117,000 male live births (Meikle et al 1999). Many female heterozygote carriers also present with clinically significant disease (Sadek et al 2004). We were interested in how this multisystem disease with prominent neurological features affected neuropsychological function. Nervous system involvement Peripheral nervous system disease commonly manifests as small fibre neuropathy, characterised by acute pain, including acroparesthesia (burning and tingling pain in the extremities) and episodes of ‘Fabry crises’ (severe pain in the extremities that may transfer to other areas of the body), often in response to physical exercise, fever, stress and changes in temperature (Burlina 2010). Autonomic nervous system disease may manifest with gastrointestinal symptoms similar to irritable bowel syndrome and hypohidrosis (inability to sweat) (Burlina 2010).

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Central nervous system disease may lead to cerebrovascular events. Ischemic stroke and transient ischemic attacks may occur, and white matter lesions are commonly seen on MRI, even in asymptomatic patients (Mehta and Ginsberg 2005). These appear as signal hyperintensities on T2 weighted images, and are commonly found in the periventricular and deep white matter, as well as the brainstem, cerebellum, and basal ganglia (Assareh et al 2011; Fellgiebel et al 2006). Even in patients with few white matter lesions, diffusion weighted imaging has demonstrated periventricular white matter pathology, suggesting important clinical utility for this measure (Fellgiebel et al 2007). Depression Psychological difficulties are common in Fabry disease, in particular depression, with 46 % of patients reported to have clinically significant depression (Cole et al 2007). Patients with Fabry disease have also been found to score significantly worse than a general population sample on measures of both depression and anxiety, placing them in the lowest quarter of the population for mental health, according to published statistics (Jenkinson 2000; Miners et al 2002). Significantly decreased health related quality of life has also been reported in Fabry disease, compared to both the general population and patients with other chronic diseases, including another lysosomal storage disorder (Gold et al 2002). Further psychiatric manifestations in patients with Fabry disease have also been documented, albeit rarely, particularly acute psychotic symptoms and personality and behavioural changes (Crosbie et al 2009; Gairing et al 2011; Laney et al 2010; Liston et al 1973). However, it is currently unclear whether depression arises due to difficulties in coping with the severe and variable symptoms such as neuropathic pain, or whether it is a result of the cerebrovascular disease commonly found in Fabry disease (Gairing et al 2011; Grewal 1993; Muller 2006). Cerebrovascular disease has been found to be associated with affective functioning - not only has the frequency and severity of white matter disease been found to relate to depression, but white matter lesions have been found to directly predict depression severity (Brown et al 1992; Herrman et al 2008; Lee et al 2012). Neuropsychology Periventricular and deep white matter lesions have been found to be associated with cognitive impairment (particularly deficits in attention, executive functioning and information processing speed) in older adults, patients with mild cognitive impairment and ischemic stroke patients (Delano-Wood et al 2008; Herrman et al 2008; Jokinen et al 2005). Severity of depression, which is common in Fabry disease, has been found to be related to impairment in both information processing

speed and executive functioning (Fossati et al 2002; Sexton et al 2012; Smith et al 2012). Despite the well known incidence of cerebrovascular disease and depression, to the best of our knowledge very few studies have systematically investigated the neuropsychological profile of patients with Fabry disease. The aim of this review was to undertake a systematic search of all published studies of neuropsychological functioning and of depression in adults with Fabry disease in order to try to answer the following questions: 1. Is there currently reliable evidence in the literature for neuropsychological impairment in patients with Fabry disease? 2. Which cognitive functions have been found to be impaired in Fabry disease? 3. What is the estimated prevalence of depression in Fabry disease? 4. Which factors appear to be associated with depression in Fabry disease?

Method The following methods were used to identify relevant papers published up to a cut off date of 15th November 2012. A search was conducted using the following electronic databases: Pub Med, Science Direct and NHS Evidence (incorporating AMED, BNI, CINAHL, Embase, Health Business Elite, HMIC, Medline and PsycInfo). The search terms (“fabry disease OR fabry’s disease OR anderson-fabry disease”) were combined with (“neuropsychology” OR “psychology” OR “psychiatry” OR “cognition” OR “depression”). Reference lists of relevant papers were examined to identify any additional relevant papers. The literature search yielded a total of 122 papers. The titles and abstracts were examined by the first author to see if the article was related to the topic of the literature review. When it was not clear from the title and/or abstract whether the study met inclusion criteria, the article was obtained in full. Full papers were obtained for 39 articles, of which 21 met the inclusion criteria - 11 investigating neuropsychological functioning and ten exploring depression in Fabry disease, with two papers investigating both neuropsychological functioning and depression in Fabry disease. The study selection process, including numbers of studies identified, screened, included and excluded are shown in Fig. 1. Due to the small number of relevant papers, all types of study design conducting neuropsychological assessment in patients with Fabry disease were included, including case studies, descriptive studies and conference abstracts. For the same reason, papers containing non-standardised neuropsychological tests or where the neuropsychological tests used were not stated were also included. Papers containing adult patients

J Inherit Metab Dis Fig. 1 Studies identified, screened, included and excluded for this review

103 records identified through database screening

19 additional records identified through other sources

104 records after duplicates removed

104 records screened

67 records excluded

39 full-text articles assessed for eligibility

21 studies included in qualitative synthesis

11 neuropsychology studies (2 also investigated depression)

(over 18 years) as well as child patients were included; however papers containing only child patients (less than 18 years) were excluded due to the different neuropsychological tests used resulting in a lack of comparability with adult studies. For studies measuring the prevalence of depression in Fabry disease, case studies were excluded due to the requirement to calculate prevalence values. Data were extracted from the studies and searched for the following variables: study design, participant numbers and characteristics including concomitant disorders, neuropsychological measures, cognitive domains impaired and preserved, depression measures, depression prevalence and factors associated with depression. The neuropsychological assessment usually assesses a variety of cognitive domains such as general intellectual functioning, memory, language, perception and executive functioning. Different cognitive tests are used to assess different cognitive domains. The main neuropsychological domains of functioning, the tests used in the investigation of patients with Fabry disease and examples of likely manifestations of impairment in everyday life are described in Table 1.

Results Neuropsychology The key characteristics and findings of the six included neuropsychological group studies are presented in Table 2.

18 full-text articles excluded as follows: No neuropsychological or depression measures N=7 Review paper N=7 Foreign language N=1 Children N=1 Depression case report N=2

10 depression studies

The existing data (in Table 2) suggests that patients with Fabry disease may be unimpaired in general intellectual functioning, memory, naming, perceptual functioning and global cognitive functioning (Elstein et al 2012; Longato et al 2011; Low et al 2007; Schermuly et al 2011; Segal et al 2010). In contrast, the existing data (in Table 2) suggests that patients with Fabry disease may be impaired in: executive functioning assessed by two standardised tests, the Stroop test and the Trail Making test part B, information processing speed and attention (Elstein et al 2012; Longato et al 2011; Segal et al 2010; Schermuly et al 2011). Five case studies documenting neuropsychological impairment have also been described. Two case studies have presented patients with Fabry disease and psychiatric disease (Gairing et al 2011; Muller et al 2006). Muller et al (2006) found their 38 year old female patient with Fabry disease and major depressive disorder to be unimpaired on all measures. However, Gairing et al (2011) reported their 21 year old female patient with Fabry disease and psychotic symptoms to be impaired on measures of information processing speed and attention, and executive functioning assessed using the Trail Making Test, with preservation of memory and intact performance on other measures of executive functioning, including verbal fluency. In addition, three case studies have presented patients with Fabry disease and severe cerebrovascular disease likely to result from Fabry disease, including symptomatic stroke or vascular dementia, (Mendez et al 1997; Mohanraj et al 2002; Yamadera et al 2009). Two of these patients were found to have impairment in either general

J Inherit Metab Dis Table 1 Neuropsychological domains of functioning, measures used and likely impairments Neuropsychological domain

Measures used

Example of likely manifestation of impairment

Current intellectual functioning—producing intelligence quotient (IQ) scores.

Wechsler Adult Intelligence Scale (WAIS) III Wechsler Adult Intelligence Scale—Revised (WAIS-R) Hamburg-Wechsler Intelligence Test for adults (HAWIE) – 112 Multiple Choice Vocabulary Test (MWT)

General deterioration in cognition and therefore level of competence in everyday functioning. Subtests cover different domains and may highlight a particular area of impairment requiring further investigation.

Pre-morbid intellectual functioning—usually assessed with tests tapping cognitive functions that are known to be resistant to brain damage and correlate with general intelligence in the normal population. Memory (verbal recall memory)—the learning Rey Auditory Verbal Learning Test (RAVLT) and recall of verbal information. California Verbal Learning Test (CVLT) (German version VLMT) Memory (visual recall memory)—the learning Wechsler Memory Scale—Revised (WMS-R) and recall of visual information. Rey-Osterreith Complex Figure (ROCF) Benton Visual Retention Test (BVRT) Memory (verbal working memory)—the Wechsler Memory Scale - Revised (WMS-R) immediate recall of small amounts of verbal digit span subtest information. Wisconsin Card Sorting Test (WCST) (adapted version CKV) Memory (visual working memory)—the Wechsler Memory Scale - Revised (WMS-R) immediate recall of small amounts of visual block span subtest information. Executive functioning—a range of processes Wisconsin Card Sorting Test (WCST) (adapted including: switching of attention requiring version CKV) cognitive flexibility, inhibition of pre-potent Trail Making Test (TMT) Part B responses and updating of working memory Stroop test representations - with different tests thought to Digit span backwards test tap different aspects of executive function. Executive functioning—verbal fluency Letter fluency – FAS words phonemic (letter) fluency and semantic Category fluency – Animals (category) fluency. Information processing speed—the ability to Connect the number test (ZVT) quickly and efficiently respond to stimuli. Trail Making Test (TMT) Part A Stroop test WAIS III Digit Symbol Coding subtest Attention (sustained) - the ability to maintain Digit span forwards test concentration over a period of time. Span of visual memory test Test of Attentional Performance (TAP) Continuous Performance Test (CPT) Attention (divided) - the ability to respond to Auditory Consonant Trigrams (ACT) test more than one task at once. Test of Attentional Performance (TAP)

Not applicable—measure of estimated premorbid functioning.

Forgetting conversations, instructions or appointments. Losing objects such as keys or a wallet/purse.

The inability to listen to and write down telephone numbers or to do mental arithmetic.

The inability to count change by looking at and remembering the different types of coins. Difficulties may be with planning, problem solving, initiating actions, suppressing responses or switching between tasks.

The inability to initiate verbal responses and to implement novel strategies. Feeling generally slowed down, the inability to keep track, such as missing parts of conversations. The inability to maintain concentration, for example in order to read or follow conversations.

The inability to do two tasks at the same time, for example walking or driving while having a conversation. Attention (selective) - the ability to focus on one Frankfurt Attention Inventory (FAIR) The inability to ignore distractions in order to stimulus while suppressing awareness of other Test of Attentional Performance (TAP) concentrate on a task, for example reading or stimuli. writing while in a noisy environment. Naming—the ability to name a range of objects of Kave Naming Test (KNT) The inability to remember the name of everyday varying frequency/familiarity. Boston Naming Test (BNT) objects, particularly lower frequency or less familiar objects. Perceptual functioning—the ability to integrate Neuropsychiatry Unit Cognitive Screen The inability to make sense of visual information perceptual information. (NUCOG) visuospatial subtest—involving may lead to, for example, mistaking one object geometric figure reproduction, demonstrating for another, the inability to recognise objects, actions, left–right orientation, neglect and or bumping into objects. calculation. Global cognitive functioning—assesses various Mini Mental State Examination (MMSE) Problems in various areas including reasoning functions in order to produce an overall Neuropsychiatry Unit Cognitive Screen and comprehension, and to act purposefully in cognitive score. (NUCOG) order to complete tasks.

Type of study

Group study (assessing global cognitive functioning)

Low et al (2007)

21 P 46 C

16

9

6

25 P 20 C

N

Not stated.

Not stated.

5–18 (Mild)

2–37 (Mild-Moderate)

Disease severity assessed by Mainz Severity Score Index (MSSI)

FD patients: 19 m, age Not stated. (M=40.4; SD=11.9; range=20–62) and 2 f. aged 20 and 56. Controls: no information provided.

9 f and 7 m, age (M=29).

7 f and 2 m, age (M=51.4).

FD patients: 15 f. 10 m, age (M=36.5; range=21–56), Controls: 11 f. 9 m, age (M=36.8; range 20–56). 4 f (aged 36, 41, 48 and 63) and 2 m (aged 25 and 35).

Participant characteristics (where provided)

P patients, C controls, f female, m male, M Mean, SD standard deviation; Measures – see Table 1

Segal et al (2010)

Group study (Conference abstract) Group study

Longato et al (2011)

Fellgiebel et al Group study (2012) & Schermuly et al (2011) Elstein et al Group study (2012)

Author and date

Cognitive domains impaired

RAVLT, WMS-R, TAP, TMT Attention and executive Part A, TMT Part B, and functioning (became nonWCST. significant after controlling for depression severity). Mindstreams computerised Information processing speed cognitive assessment was found to be system (NeuroTrax Corp., the most affected domain. NJ)—global cognitive score and subtests: memory, executive function, visuospatial, verbal, attention, information processing speed and motor skills. Not stated. Attention, information processing speed and executive functioning. WAIS III, ROCF, RAVLT, Attention, information KNT, Digit Span (forwards processing speed and and backwards), CPT, TMT executive functioning (on Part A, Stroop test, WAIS some measures). III Digit Symbol Coding, TMT Part B, Letter fluency and Maze test. MMSE and NUCOG Language (NUCOG). (overall score and subtests: attention, memory, visuoconstructional, executive and language).

Measures used

Table 2 Findings of group studies conducting neuropsychological assessment of cognitive functioning in Fabry disease

Global cognitive function (MMSE) and overall cognitive function, attention, memory, visuoconstructional and executive functioning (NUCOG).

Intelligence, memory, executive functioning (on some measures) and naming.

Memory and perceptual functioning.

Memory, executive functioning, visuospatial functioning, verbal skills, attention and motor skills were found to be less affected.

Memory and information processing speed.

Cognitive domains preserved

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intellectual functioning or global cognitive function, therefore affecting performance on tests of other focal cognitive domains including memory, naming, executive functioning including verbal fluency, information processing speed and attention (Mendez et al 1997; Mohanraj et al 2002). Depression The key characteristics and prevalence values of the 12 included depression studies are presented in Table 3. Prevalence estimates of depression in Fabry disease range from 15 % to 62 %, with the largest study to date (n=184) reporting a prevalence rate of 46 % (Cole et al 2007; Grewal 1993; Wang et al 2007). Of a sample of patients with Fabry disease (n=16), 62.5 % were found to be affected by some form of psychopathology, including depression (Segal et al 2010). The most common factor found to be associated with depression in Fabry disease is pain (Cole et al 2007; Crosbie et al 2009; Grewal 1993; Laaksonen et al 2008). Thus the severe painful neuropathy and pain crises that are common manifestations of Fabry disease may be associated with depression and psychiatric disorder. Chronic pain may also be indirectly associated with depression by affecting other factors found to be associated with depression, such as relationship status, employment and income, and poorer adaptive functioning (social and relationship functioning and occupational success) (Cole et al 2007; Laney et al 2010).

Discussion The aims of this review were to review the evidence in the literature for neuropsychological impairment in patients with Fabry disease and to determine which domains of functioning were most affected, as well as to explore the prevalence of depression and factors associated with depression in patients with Fabry disease. We identified 11 studies using neuropsychological measures to investigate cognitive functioning in Fabry disease and ten studies measuring depression in Fabry disease. Neuropsychology The literature suggests that in patients with Fabry disease there may be preservation of general intellectual functioning, memory, naming, perceptual functioning and global cognitive functioning, in the absence of severe cerebrovascular events such as stroke or dementia. Although results sometimes appear inconclusive, there does appear to be evidence of impairment in patients with Fabry disease in executive functioning (assessed using the Stroop and Trail Making tests), information processing speed and attention. However, the available mixed evidence suggests that these may be mild in nature, representing subtle

underfunctioning on some tests, rather than severe impairment in specific domains. Furthermore, the unreliable nature of the existing literature requires further research evidence to support these findings. The finding of some evidence of impairment on tests of executive functioning and information processing speed may provide support to the theory of impairment in these domains associated with both white matter pathology and depression in other populations, however further research evidence is required to substantiate these findings (Fossati et al 2002; Herrman et al 2008; Jokinen et al 2005; Sexton et al 2012; Smith et al 2012). However, it may be noted that no association has been reported between neuropsychological and neuroimaging parameters (particularly total white matter lesion volume) in patients with Fabry disease, after controlling for age and depression severity (Schermuly et al 2011). Using the same cohort of patients with Fabry disease, it has also been suggested that despite cerebral atrophy, neural plasticity may lead to functional compensation (Fellgiebel et al 2012). Significantly decreased bilateral hippocampal volumes have been reported in patients compared to controls, despite preservation of memory performance (Fellgiebel et al 2012). The finding of preservation of memory function despite hippocampal atrophy suggests functional compensation in this group of Fabry disease patients, leading to a lack of association between neuropsychological and neuroimaging parameters. Further research is therefore needed to investigate the association between neuropsychological functioning and neuroimaging parameters in Fabry disease. There are a number of concomitant disease processes likely to affect cognitive functioning in Fabry disease, including severe cerebrovascular disease such as stroke or dementia and psychological difficulties such as depression. Two studies reported cognitive functioning in Fabry disease and severe cerebrovascular disease including symptomatic stroke or vascular dementia, affecting patients’ general intellectual functioning or global cognitive function and thus affecting performance on tests of other cognitive domains (Mendez et al 1997; Mohanraj et al 2002). It is suggested that Fabry disease may be associated with vascular dementia due to cerebrovascular ischemic disease, which may therefore be an important consideration in future investigation of neuropsychological functioning in Fabry disease (Mendez et al 1997). It is likely that patients from other cohorts included in this review will also have had severe cerebrovascular disease, particularly symptomatic stroke, for example one group reported 20 % (n=5) of their sample of patients with Fabry disease to have suffered from a cerebrovascular event (Schermuly et al 2011). However, in this study, and the other group studies, the effect of cerebrovascular events on cognition was not specifically investigated. It appears that the presence of severe cerebrovascular disease such as symptomatic stroke or vascular dementia may be a prerequisite for severe neuropsychological

28

33

12

33

60

98

59

4

25

Crosbie et al (2009)

Grewal (1993)

Laaksonen et al (2008)

Laney et al (2010)

MacDermot et al (2001a)

MacDermot et al (2001b)

Miners et al (2002)

Sadek et al (2004)

Schermuly et al (2011)

Gender:15 f and 10 m Age: M=36.5 (Range 21–56)

Gender: 4 f Age: M=49

Gender: 59 m Age: M=37.2 (38/59 patients completed measure)

Gender: 98 m Age: M=34.8

Gender: 60 f Age: M=44.9

Gender: 6 m Age at diagnosis: M=29.3 (Range 23–37) (6/33 patients discussed) Gender: 12 f Age: M=45.5 (Range 17–63) (9/12 patients completed measure) Gender: 18 f and 15 m Age: M=40 (Range 18–59)

Gender: 12 f and 16 m Age: 18–30=32.1 %, 31– 45=28.6 %, 46–60=39.3 %.

184 Gender: 110 f and 74 m Age: M=44 (Range 18–76) (181/184 patients completed measure)

Cole et al (2007)

Prevalence of depression

Relationship status (being separated/divorced/widowed), employment (being unemployed/sick/disabled), income (being difficult/very difficult on income), the extent to which symptoms interfere with life (quite a bit or extremely), having acroparesthesia, angiokeratoma, anhidrosis or cardiac symptoms. Symptom severity and severity of pain.

Factors found to be associated with depression

Performance on a measure of executive functioning (but not overall cognitive function), scores on a questionnaire assessing positive and negative symptoms and psychopathology and mental health assessed using a health related quality of life questionnaire.

Not measured.

Not measured.

Not measured.

Not measured.

Poorer adaptive functioning (social and relationship functioning and occupational success).

Age, elevated scores for unspecific somatic symptoms, neuropathic pain assessed using a pain questionnaire and decreased intraepidermal nerve fibre intensity.

15 % (5/33) patients found to suffer from All patients with depression also found to have painful depression, with 6 % (2/33) having neuropathy and crises. committed suicide

60.7 % (17/28) patients had an elevated score on the depression scale

Author created 22.2 % (2/9) patients indicated severe questionnaire to evaluate depressive symptoms and 33.3 % (3/9) depressive symptoms indicated moderate depressive symptoms Achenbach adult self report 58 % (19/33) patients were in the questionnaire and borderline to clinical range of Achenbach adult depression behaviour checklist questionnaire Fabry disease specific, self- 33 % (20/60) women reported feeling report questionnaires depressed or anxious some of the time, with 5 % (3/60) reporting feeling suicidal most or all of the time Fabry disease specific, self- 20 % (20/98) men had scores within the report questionnaires clinically probable diagnosis range for anxiety and depression Anxiety/depression domain 36.8 % (14/38) patients scored in the of the EQ-5D health moderate range and 13.2 % (5/38) related quality of life scored in the severe range for anxiety/ questionnaire depression Hamilton Depression All patients (4/4) presented with severe Rating Scale (HAM-D) depression on the HAM-D, suicidal ideation and met DSM IV criteria for major depression Hamilton Depression 60 % (15/25) patients found to have Rating Scale (HAM-D) depressive symptoms

Minnesota Multiphasic Personality Inventory (MMPI-2) depression scale Retrospective review of medical records of 33 patients

Centre for Epidemiological 46 % (83/181) clinically significant Studies Depression Scale depression (CES-D)

Participant characteristics (where Depression measure provided)

N

Author & date

Table 3 Group studies investigating the prevalence of depression in Fabry disease

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62.5 % (10/16) of adult patients affected Higher number of average clinical findings and significant by psychopathology, with 25 % (4/16) overall cognitive impairment. patients found to have major depressive disorder 62 % (21/34), reported either symptoms Not measured. of depression or treatment with antidepressants

impairment associated with decline in general intellectual functioning or global cognitive function in patients with Fabry disease. One group study (n=15) reported 62.5 % of patients with Fabry disease to have psychiatric involvement such as depression, with patients with psychiatric findings being more likely to have cognitive impairment, highlighting the effect of psychiatric symptoms on cognitive functioning in Fabry disease (Segal et al 2010). Another group study found that poor performance on one executive function task (the WCST) no longer remained significant after controlling for depression severity, further highlighting the effect of depression on neuropsychological functioning (Schermuly et al 2011). Such a test requires sustained attention to novel stimuli, placing demands on motivation, which may be compromised in depression. However, the attention tonic alertness measure did remain significant even after controlling for depression severity, and cognitive performance in depressed and non-depressed patients was not found to be significantly different, suggesting that results were not solely due to depression (Schermuly et al 2011). In future studies, the specific investigation of the effects of severe cerebrovascular disease and depression may provide valuable insight into their effect on cognitive functioning in Fabry disease. Depression

f female, m male, M Mean

44 Wang et al (2007)

Gender: 44 f Age: M=46.1 (34 patients responded to depression questions)

Schedule for Affective Disorders and Schizophrenia (SADS) questionnaire Patient self-report 16 Segal et al (2010)

Gender: 9 f and 7 m Age: M=29

N Author & date

Table 3 (continued)

Participant characteristics (where Depression measure provided)

Prevalence of depression

Factors found to be associated with depression

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The literature suggests varying rates of depression prevalence in Fabry disease, with the largest study to date finding a prevalence rate of 46 %, of which 28 % were found to have severe clinical depression, and of these, 72 % were undiagnosed (Cole et al 2007). Depression in Fabry disease has been reported to be directly associated with chronic pain (Grewal 1993). Cole et al (2007) found four factors to be predictive of increased risk of depression in patients with Fabry disease. Two of these were factors related to depression in the general population, relationship status and financial status, with patients who were single or divorced/widowed more likely to have depression than those who were married or cohabiting, and patients reporting current financial difficulty more likely to have depression than those who did not. The other two factors were more directly related to patients’ illness. Firstly, having an additional chronic illness as well as Fabry disease increased risk of depression. However, the strongest predictor of depression was the degree to which Fabry disease symptoms interfered with life, with both pain symptoms and inability to sweat (anhidrosis) being found to strongly predict depression. It is of note that cerebrovascular symptoms were not found to strongly predict depression. However, chronic pain and depression may also be indirectly associated by affecting social and occupational functioning.

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Laney et al (2010) found an association between poorer adaptive (social, relationship and occupational) functioning and depression, but interestingly found no direct association between poorer adaptive functioning and either pain or disease severity. This suggests that depression or low mood may be a mediating variable in that it affects the way that a person copes with or adjusts to chronic pain or severe disease symptoms. Research into chronic pain in multiple sclerosis provides support for a biopsychosocial model in which psychosocial factors common in depression such as catastrophising, that is viewing situations as considerably worse than they actually are, may be important in understanding a person’s adjustment to pain (Osborne et al 2007). Further research is therefore needed to investigate these specific psychosocial factors affecting pain and depression in Fabry disease. Thus, the literature appears to suggest that depression is a reflection of the severity and variability of the symptoms of Fabry disease, rather than organic in nature and speculatively associated with white matter pathology. This theory is supported by the findings of no association between depression and white matter lesion load, and no association between depression severity and cerebrovascular symptoms (Cole et al 2007; Schermuly et al 2011).

may be a useful indicator of likely areas of impairment; however they cannot be seen as providing evidence of impairment due to no inferential statistics being provided. Case reports may also be very useful as they allow in depth examination of one patient’s functioning; however there are also a number of limitations of these studies, in particular that they are uncontrolled.

Methodological limitations

Future research

Only two detailed group studies conducting neuropsychological assessment have been published, limiting conclusions that can be drawn from the literature (largely comprising single case reports and descriptive studies). Both of these group studies have a number of limitations, making it difficult to infer preservation or impairment of cognitive function. One group study did not measure either current or pre-morbid intellectual functioning, limiting assessment of cognitive decline, and another lacked both a measure of pre-morbid intellectual functioning and a control group (Schermuly et al 2011; Segal et al 2010). One study also used a sample in which one third of patients with Fabry disease were children and teenagers, making it difficult to generalise the findings to the population as a whole (Segal et al 2010). Only three group studies provided data on disease severity and where provided this was in the mild or mild to moderate range. Indeed, the differences between studies in both age and disease severity are likely to contribute to the mixed findings in the literature. However, these studies also have several strengths. They assessed neuropsychological functioning in larger groups of patients with Fabry disease, and used standardised neuropsychological tests known to be sensitive to subtle impairments in functioning (Schermuly et al 2011; Segal et al 2010). One study used only broad cognitive screening tests, however these may not be detailed enough to detect subtle neuropsychological impairment in Fabry disease (Low et al 2007). The other types of study included in this review were either descriptive in nature or case study reports. Descriptive studies

It is an important task for future research to investigate cognitive functioning in Fabry disease using standardised neuropsychological tests of both current and pre-morbid functioning known to be sensitive to subtle impairment and covering all of the main domains of cognition; in a larger sample of adult Fabry disease patients and a matched control group, representative of the whole adult patient age range. Exploring the nature of cognitive impairment in Fabry disease by investigating the relationship between cognitive functioning and both affective disorders such as depression and cerebrovascular disease such as white matter lesions represents a significant but important challenge for future research.

Clinical implications There are several implications of the findings of this review for clinical practice, particularly regarding appropriate referral to psychological services. Due to the suggestion of mild neuropsychological impairment in Fabry disease, routine neuropsychological assessment using tests sensitive to subtle impairments may be necessary to identify and monitor cognitive decline, and to ensure that management strategies are in place to minimise the impact of cognitive impairment on everyday functioning. Due to the known prevalence of depression in Fabry disease, routine depression and suicide risk assessments by a healthcare professional should also form an important part of routine clinical care, in order to ensure that it is diagnosed and treated.

Conclusion The evidence regarding the prevalence, severity and extent of neuropsychological impairment in Fabry disease is currently limited. Nevertheless, existing data suggests that there may be some subtle impairment in executive functioning, information processing speed and attention, and preservation of general intellectual functioning, memory, naming, perceptual functioning and global cognitive functioning. However, in patients with Fabry disease and severe cerebrovascular disease such as stroke or dementia, there appears to be evidence of severe neuropsychological impairment due to decline in patients’

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general intellectual functioning or global cognitive function. Further research using standardised neuropsychological measures, brain imaging and measures of depression in a larger sample of patients with Fabry disease and matched controls is important to better understand the nature, clinical impact and underlying mechanisms of cognitive dysfunction in this disorder.

Conflict of interest Fay Bolsover has been supported by an educational grant from Shire Pharmaceuticals. Elaine Murphy has received educational grants and honoraria from Shire Pharmaceuticals and Genzyme. Lisa Cipolotti declares that she has no conflict of interest. David Werring receives research support from the Stroke Association and the British Heart Foundation. Part of this work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. Robin Lachmann has received educational grants and honoraria from Shire Pharmaceuticals and Genzyme.

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