Association between epilepsy and psychiatric disorders in adults with intellectual disabilities: systematic review and meta-analysis

Basma Akrout Brizard; Bharati Limbu; Carolina Baeza-Velasco; Shoumitro Deb

doi:10.1192/bjo.2021.55

Association between epilepsy and psychiatric disorders in adults with intellectual disabilities: systematic review and meta-analysis

Published online by Cambridge University Press: 03 May 2021

Basma Akrout Brizard

Bharati Limbu ,

Carolina Baeza-Velasco and

Shoumitro Deb

Show author details

Basma Akrout Brizard: Affiliation:
Université de Paris, Laboratory of Psychopathology and Health Processes, F-92100 Boulogne Billancourt, France
Bharati Limbu: Affiliation:
Department of Brain Sciences, Faculty of Medicine, Imperial College London, UK
Carolina Baeza-Velasco: Affiliation:
Laboratory of Psychopathology and Health Processes, Université de Paris, France; and Department of Emergency Psychiatry and Acute Care, CHU Montpellier, France
Shoumitro Deb*: Affiliation:
Division of Psychiatry, Department of Brain Sciences, Faculty of Medicine, Imperial College London, UK
*: Correspondence: Shoumitro Deb. Email: s.deb@imperial.ac.uk

Article contents

Abstract
Background
Aims
Method
Results
Conclusions
Method
Results
Discussion
Data availability
References

Rights & Permissions

Abstract

Background

Psychiatric disorders, such as depression and anxiety, are commonly associated with epilepsy in the general population, but the relationship between psychiatric disorders and epilepsy among adults with intellectual disabilities is unclear.

Aims

To conduct a systematic review and meta-analysis to assess whether epilepsy is associated with an increased rate of psychiatric disorders in adults with intellectual disabilities.

Method

We included literature published between 1985 and 2020 from four databases, and hand-searched six relevant journals. We assessed risk of bias by using SIGN 50 and the Cochrane risk of bias tool. Several meta-analyses were carried out.

Results

We included 29 papers involving data on 9594 adults with intellectual disabilities, 3180 of whom had epilepsy and 6414 did not. Of the 11 controlled studies that compared the overall rate of psychiatric disorders between the epilepsy and non-epilepsy groups, seven did not show any significant inter-group difference. Meta-analysis was possible on pooled data from seven controlled studies, which did not show any significant inter-group difference in the overall rate of psychiatric disorders. The rates of psychotic disorders, depressive disorders and anxiety disorders were significantly higher in the non-epilepsy control groups compared with the epilepsy group, with effect sizes of 0.29, 0.47 and 0.58, respectively. Epilepsy-related factors did not show any definite association with psychiatric disorders.

Conclusions

It is difficult to pool data from such heterogeneous studies and draw any definitive conclusion because most studies lacked an appropriately matched control group, which will be required for future studies.

Keywords

Intellectual disabilities epilepsy psychiatric disorders systematic review meta-analysis

Type: Review
Information: BJPsych Open , Volume 7 , Issue 3 , May 2021 , e95

DOI: https://doi.org/10.1192/bjo.2021.55 [Opens in a new window]
Creative Commons: This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright: Copyright © The Author(s), 2021. Published by Cambridge University Press on behalf of the Royal College of Psychiatrists

Intellectual disabilities are a group of aetiologically diverse conditions originating during the developmental period, characterised by significantly below-average intellectual functioning and adaptive behaviour that are approximately two or more standard deviations below the mean, based on appropriately normed, individually administered standardised tests.¹

Epilepsy in adults with intellectual disabilies

The prevalence of epilepsy is much higher in adults with intellectual disabilities (>25%) than in the general population (1%).^{Reference Deb2} Compared with the general population, epilepsy among adults with intellectual disabilities is not only more prevalent, but often manifests as multiple seizure types, starts at an early age, is of longer duration and is more treatment-resistant (around 30% in the general population compared with >70% in people with intellectual disabilities).^{Reference Shankar, Watkins, Alexander, Devapriam, Dolman and Hari3} Diagnosing epilepsy and seizure types can be difficult in this population. For example, stereotypy, cardiac syncope and non-epileptic attack disorders may all mimic epileptic seizures. On the other hand, absence and partial seizures may be particularly challenging to detect in this population.^{Reference Deb, Jacobson, Mulick and Rojahn4} Thus, both a false positive and a false negative diagnosis are possible.^{Reference Deb, Jacobson, Mulick and Rojahn4} Also, people with intellectual disabilities are more prone to die from sudden unexpected death in epilepsy.^{Reference Shankar, Eyeoyibo, Scheepers, Dolman, Watkins and Attavar5}

Epilepsy and psychiatric disorders in the general population

Studies in the general population found an increased rate of psychiatric disorders in adults with epilepsy. For example, the prevalence of mood and anxiety disorders is reported to be 20–30%, whereas psychoses are estimated to be 2–7% in the general population with epilepsy.^{Reference Lin, Mula and Hermann6} These figures are higher than the point prevalence of 17% of mood and anxiety disorders and 1–2% of psychoses observed among the general population who do not have a diagnosis of epilepsy.^{Reference McManus, Bebbington, Jenkins and Brugha7} The affective disorders tend to be present at all stages of epilepsy, whereas psychosis is particularly prevalent in the post-ictal phase.

Psychiatric disorders in intellectual disabilities

If problem (challenging) behaviour and autism spectrum disorder (ASD) are included, the overall rate of mental ill health seems higher in adults with intellectual disabilities (40.9%)^{Reference Cooper, Smiley, Morrison, Williamson and Allan8} than in the general population (16%).^{Reference Meltzer, Gill, Petticrew and Hinds9} However, excluding the diagnosis of ASD and problem behaviour, the rate of overall functional psychiatric disorders (14.5%)^{Reference Cooper, Smiley, Morrison, Williamson and Allan8,Reference Deb, Thomas and Bright10} is similar to that in the general population (16%).^{Reference Meltzer, Gill, Petticrew and Hinds9} The point prevalence of psychosis including schizophrenia is significantly higher in adults with intellectual disabilities (3.4–4.4%)^{Reference Deb, Thomas and Bright10–Reference White, Chant, Edwards, Townsend and Waghorn12} compared with adults without intellectual disabilities (1%).^{Reference Meltzer, Gill, Petticrew and Hinds9,Reference Sartorius, Ustün, Lecrubier and Wittchen13} Although depressive symptoms are reported in 16.5% of adults with intellectual disabilities, the rate of major depressive disorder seems similar in both adults with intellectual disabilities (2.2–8%)^{Reference Cooper, Smiley, Morrison, Williamson and Allan8,Reference Deb, Thomas and Bright10,Reference White, Chant, Edwards, Townsend and Waghorn12} and adults without intellectual disabilities (2.1%).^{Reference Meltzer, Gill, Petticrew and Hinds9} The rate of anxiety disorder seems higher in adults with intellectual disabilities (14%)^{Reference White, Chant, Edwards, Townsend and Waghorn12} than in the general population (10%).^{Reference Sartorius, Ustün, Lecrubier and Wittchen13} However, diagnosis of psychiatric disorders could be difficult in many adults with intellectual disabilities, particularly those who have a severe and profound intellectual disability and cannot communicate their thoughts and feelings to others.^{Reference Deb, Matthews, Holt and Bouras14} Therefore, both a false positive and a false negative diagnosis are possible.

The need for this systematic review

The question of whether there is an association between epilepsy and psychiatric disorders in adults with intellectual disabilities remains unanswered. We found only one systematic review of neuropsychiatric conditions in people with intellectual disabilities^{Reference van Ool, Snoeijen-Schouwenaars, Schelhaas, Tan, Aldenkamp and Hendriksen15} that included 15 studies, but only two of these are specifically on psychiatric disorders per se, and the rest are mostly on problem behaviour. Also, the previous review included participants of all ages and did not present data separately on adults, which is the focus of the current review. We have already published a systematic review with meta-analysis specifically on the relationship between epilepsy and problem behaviour in adults with intellectual disabilities.^{Reference Deb, Akrout Brizard and Limbu16} As there is currently no published systematic review and meta-analysis available specifically on the association between psychiatric disorders and epilepsy in adults with intellectual disabilities, we have carried out a systematic review and meta-analysis on studies that explored this relationship. We have concentrated on studies of adults with intellectual disabilities only, as the issues concerning children with intellectual disabilities are different from those of adults.

Method

Search strategy

Protocol and search strategy were based on the International Prospective Register of Systematic Reviews (PROSPERO) guidelines¹⁷ and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist.^{Reference Moher, Shamseer, Clarke, Ghersi, Liberati and Petticrew18} The study was registered with PROSPERO, under registration number CRD42020178083.

Four electronic databases were searched for relevant studies: EMBASE, PsycINFO, PubMed and DARE. The electronic search focused on articles published in English and French, between 1 January 1985 and 31 May 2020. Hand-searching for relevant articles was carried out in the past 10 years of issues, from January 2000 to June 2020, in the following journals: Seizure, Epilepsia, Epilepsy & Behavior, Journal of Intellectual Disability Research, Journal of Applied Research in Intellectual Disabilities and Research in Developmental Disabilities. Only quantitative studies were searched.

Search terms

Each database was searched using terms for intellectual disability, epilepsy and psychiatric disorders.

Terms for intellectual disabilities were: ‘Intellectual disability’ OR ‘Learning disability’ OR ‘Learning disorder’ OR ‘Learning difficulties’ OR ‘Mental disabilities’ OR ‘Neurodevelopmental disorders’ OR ‘NDD’ OR ‘ID’ OR ‘LD’ OR ‘Mental retardation’ OR ‘Mental handicap’ OR ‘Mental deficiency’.

The following search terms were used to cover psychiatric disorders: ‘Psychiatric illness’ OR ‘Psychiatric disorders’ OR ‘Schizophrenia’ OR ‘Psychosis’ OR ‘Depression’ OR ‘Major depressive disorder’ OR ‘Bipolar disorder’ OR ‘Mania’ OR ‘Hypomania’ OR ‘Anxiety disorders’ OR ‘Anxiety’ OR ‘Obsessive-Compulsive Disorder’ OR ‘OCD’ OR ‘Phobia’ OR ‘Phobic disorders’ OR ‘Personality disorder’ OR ‘Dementia’.

Terms for epilepsy were: ‘Epilepsy’ OR ‘Epilepsy syndrome’ OR ‘Seizures’ OR ‘Seizure disorders’ OR ‘Epileptic seizures’ OR ‘AED’ OR ‘Anti-epileptic drugs’.

Criteria for selecting studies for this review

A list of eligibility criteria, based on PROSPERO guidelines¹⁷ and Cochrane Handbook for Systematic Reviews of Interventions,^{Reference Lefebvre, Glanville, Briscoe, Littlewood, Marshall, Metzendorf, Higgins, Thomas, Chandler, Cumpston, Li, Page and Welch19} was adapted. The eligibility criteria for the review were (a) an epilepsy and intellectual disabilities group compared with a non-epilepsy group of adults with intellectual disabilities alone (if the study did not have a non-epilepsy control group, the study had to provide information on psychiatric disorders, epilepsy-related factors and anti-epileptic drug regimen); (b) all participants had intellectual disabilities; (c) all participants were defined as adults by the authors and (d) a minimum sample size of ten participants.

Types of studies

This review included studies with different designs. Both randomised and non-randomised studies, and both controlled and non-controlled observational or cross-sectional studies, were included. Controlled studies with both matched and non-matched control groups were included.

We included studies that compared the overall rate of psychiatric disorders, as well as different types of psychiatric disorders in adults with intellectual disabilities and epilepsy, with a group of adults with intellectual disabilities without epilepsy within the same cohort.

We also included studies that included participants with intellectual disabilities and epilepsy, but no participants with intellectual disabilities without epilepsy. These studies allowed assessment of the association of psychiatric disorders with epilepsy-related variables.

Studies were included regardless of the method used to assess the rate of any psychiatric disorders and specific psychiatric disorders, such as affective disorders, psychosis, anxiety disorders, personality disorders and dementia. In that, studies reporting data with standardised assessment tools, case notes, symptom checklists and semi-structured interviews administered by clinicians or trained professionals were included.

Types of participants

All participants were adults aged ≥16 years, had intellectual disabilities (all levels of severity) and had various types of psychiatric disorders. This review focuses on data on psychiatric disorders and does not present data on problem behaviour, as a separate systematic review has been published recently on the association between epilepsy and challenging (problem) behaviour in adults with intellectual disabilities.^{Reference Deb, Akrout Brizard and Limbu16}

Ethical approval was not required for this study because no individual patient-related data were collected or analysed.

Secondary outcome

Comparison between epilepsy and non-epilepsy groups was carried out for different types of psychiatric disorders (psychotic disorders, depressive disorders, anxiety disorders, personality disorders and dementia). To identify the role of different epilepsy-related factors in the development of psychiatric disorders, data on subgroup comparisons according to types of seizures, frequency of seizures and drug regimen (e.g. polypharmacy versus mono-pharmacy) were collected.

Selection process

After completion of each database search, references were recorded on Zotero reference management software version 5.0.77 for Windows (Corporation for Digital Scholarship, George Mason University, US; see https://www.zotero.org/download/).²⁰ Titles were searched for key terms. Non-human studies, studies involving children and people without intellectual disabilities were removed. Duplicates were identified by Zotero, and removed manually by the first author (B.A.B.). Independent screening of the remaining abstracts was carried out by B.A.B. and B.L., using pre-piloted eligibility criteria. The review authors were blind to each other's scores. Discrepancies identified were reviewed and discussed until resolution of differences by consensus. Full texts were gathered for the studies that met the inclusion criteria or the ones marked as uncertain. The full texts were then reviewed and assessed by both reviewers (B.A.B. and B.L.), using the same eligibility checklist that was used for screening abstracts.

The selection process is reported in a PRISMA flow diagram (see Fig. 1). It was not necessary for a third review author (S.D.) to arbitrate.

Fig. 1 Preferred Reporting Items for Systematic Review and Meta-Analysis flow chart of the study selection process.

Data extraction

Data from studies meeting eligibility criteria were extracted by both reviewers (B.A.B. and B.L.), using a standardised data extraction proforma adapted from the Cochrane Handbook for Systematic Reviews of Interventions (see Supplementary Appendix 1 available at https://doi.org/10.1192/bjo.2021.55).^{Reference Higgins, Thomas, Chandler, Cumpston, Li and Welch21} The third review author (S.D.) checked the collected data for accuracy. Data extraction started on 8 July 2020. We have presented data separately on the more recently published studies since 2010 because definitions of epilepsy, intellectual disabilities and psychiatric disorders have changed in the past decade.

Meta-analysis

We used RevMan version 5.3 for Windows 10 (The Cochrane collaboration, London, UK; see https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman/revman-5-download) meta-analysis software for the random-effects model. The random-effects model was used because of differing study designs.

As most studies presented prevalence rates among different groups but a few others presented the mean and s.d., we only included studies presenting prevalence rates of psychiatric disorders in each group (epilepsy versus non-epilepsy group) for meta-analysis. A forest plot was constructed for comparison, for which we reported the pooled odds ratio, 95% confidence interval and a P-value. The statistical significance level was set at P < 0.05. Heterogeneity was tested with χ ² and I ² values. Heterogeneity was considered minimal when under 40% and substantial when over 50%, according to guidelines from the Cochrane Handbook for Systematic Reviews of Interventions.^{Reference Higgins, Thomas, Chandler, Cumpston, Li and Welch21} Sensitivity analysis was carried out when heterogeneity was considered substantial.

Risk of bias assessment

The Scottish Intercollegiate Guideline Network (SIGN 50) checklist^{Reference Harbour and Forsyth22} was used to assess the quality of the 29 included studies. Additionally, the risk of bias for 25 controlled studies was assessed by the Cochrane risk of bias tool.^{Reference Sterne, Savović, Page, Elbers, Blencowe and Boutron23}

Confidence in the cumulative estimate

We assessed publication bias with a funnel plot and Egger's test, and assessed the included studies for consistency and precision. We excluded any studies deemed of low quality. We assessed the quality of the systematic review by using A Measurement Tool to Assess Systematic Reviews 2nd edition (AMSTAR-2) criteria (see Supplementary Appendix 2).^{Reference Shea, Reeves, Wells, Thuku, Hamel and Moran24}

Results

Search findings

A total of 2594 articles were screened based on titles. After screening with the eligibility criteria, 2539 articles were excluded. The remaining 55 abstracts were in English, and no studies in French were selected for abstract screening. We screened 55 abstracts with the eligibility criteria, and excluded 11 citations.

With an additional six citations detected through hand-searching and cross-referencing, a total of 50 full texts were screened with the eligibility criteria. Of these, 29 articles met the eligibility criteria and were ultimately included in the systematic review (see Fig. 1). A list of excluded articles with the reason for exclusion is presented in Supplementary Appendix 3.

Included studies

Twenty-nine papers were included in our systematic review. Three articles published data on the same cohort but different outcome measures. Six studies included participants >16 years of age, three studies included participants >17 years of age and three stated that the participants were adults. We have included all these studies, as authors defined the study population as adults, and age cut-off for defining adulthood varies from country to country. for legal and administrative purposes. Of the 29 studies, 11 were controlled studies of comparison of the overall rate of psychiatric disorders (two of which were matched), and 14 were controlled studies that presented data on specific psychiatric disorders between epilepsy and non-epilepsy groups. Four studies included only participants with intellectual disabilities and epilepsy, and did not have a control group. Table 1 presents data from studies that compared data on the overall rate of psychiatric disorders in adults with intellectual disabilities and epilepsy and adults with intellectual disabilities who did not have epilepsy. In two studies,^{Reference Deb and Hunter25,Reference Matthews, Weston, Baxter, Felce and Kerr26} the groups were matched, and the number of participants remained the same in the epilepsy and non-epilepsy groups. In the remaining nine studies, the two groups of adults with intellectual disabilities with and without epilepsy were not matched. ^{Reference Deb, Thomas and Bright10,Reference Arshad, Winterhalder, Underwood, Kelesidi, Chaplin and Kravariti27–Reference Mantry, Cooper, Smiley, Morrison, Allan and Williamson34} In the unmatched studies, the prevalence of psychiatric disorders was collected in a larger sample of adults with intellectual disabilities, only a proportion of whom (around 27%) had epilepsy. The rates of psychiatric disorders were compared between adults with intellectual disabilities with and without epilepsy within the same sample, but the two groups were not matched.

Table 1 The rates of psychiatric disorders in adults with intellectual disabilities and with and without epilepsy

WAIS, Wechsler Adult Intelligence Scale, WAIS-R, Wechsler Adult Intelligence Scale – Revised; PAA, Profile of Abilities and Adjustment Schedule; PSE, Present State Examination; PIMRA, Psychopathology Instrument for Mentally Retarded Adults; PAS-ADD, Psychiatric Assessment Schedule for Adults with Developmental Disabilities; EEG, electroencephalogram.

Table 2 presents data on the rates of different types of psychiatric disorders with comparisons between epilepsy and non-epilepsy groups of adults with intellectual disabilities. Table 3 includes data on epilepsy-related factors associated with psychiatric disorders in adults with intellectual disabilities and epilepsy. Table 4 presents data separately on the studies published in the past decade (2010 onward).

Table 2 Types of psychiatric disorders in adults with intellectual disabilities and epilepsy

PAS-ADD, Psychiatric Assessment Schedule for Adults with Developmental Disabilities; PPS-LD, Psychopathology Schedule for Adults with Learning Disabilities; PAA, Profile of Abilities and Adjustment Schedule; PSE, Present State Examination; OCD, obsessive–compulsive disorder; WAIS, Wechsler Adult Intelligence Scale, WAIS-R, Wechsler Adult Intelligence Scale – Revised; SAP, Standardized Assessment of Personality; T-L PBI, Temporal Lobe Personality Behaviour Inventory; ILAE, International League Against Epilepsy; TSI, Test for Severe Impairment; DSMSE, Down Syndrome Mental Status Examination.

Table 3 Psychiatric disorders according to different epilepsy variables

SAP, Standardized Assessment of Personality; T-L PBI, Temporal-Lobe Personality Behaviour Inventory; ILAE, International League Against Epilepsy; EEG, electroencephalogram.

Table 4 Overall and specific psychiatric disorders in publications from 2010 onward

DASH-II, Diagnostic Assessment for the Severely Handicapped-II; MANCOVA, multivariate analysis of covariance; ANCOVA, analysis of covariance; ADAMS, Anxiety, Depression, And Mood Scale; GAS-ID, Glasgow Anxiety Scale for People with an Intellectual Disability; HADS-A, Hospital Anxiety and Depression Scale, Anxiety Subscale; PAS-ADD, Psychiatric Assessment Schedule for Adults with Developmental Disabilities; ILAE, International League Against Epilepsy; ASD-CA, Autism Spectrum Disorders-Comorbidity for Adults version; MANOVA, multivariate analysis of variance; OCD, obsessive–compulsive disorder.

Of the included studies, 20 were in the UK, four were in Ireland, two were in the USA, two were in the Netherlands and one was in Denmark.

The studies present data from a total sample of 9594 adults with intellectual disabilities, which included 3180 with epilepsy and 6414 without epilepsy.

Diagnosis

Intellectual disabilities

Included studies used different methods to diagnose intellectual disabilities and evaluate severity. Six studies^{Reference Cooper, Smiley, Morrison, Allan, Williamson and Finlayson11,Reference Deb and Hunter25,Reference Espie, Watkins, Curtice, Espie, Duncan and Ryan30,Reference Deb and Hunter35–Reference Snoeijen-Schouwenaars, van Ool, Tan, Aldenkamp, Schelhaas and Hendriksen37} used standardised evaluation of intellectual disabilities with various psychometric tests, such as Wechsler Adult Intelligence Scale^{Reference Wechsler38} and Vineland Adaptive Behaviour Scales.^{Reference Sparrow, Balla and Cicchetti39,Reference Sparrow, Balla and Cicchetti40} Six studies referred to ICD criteria for intellectual disabilities diagnosis, with one study^{Reference Lund32} referring to the eighth edition,⁴¹ one study^{Reference Deb42} referring to the ninth edition⁴³ and four studies^{Reference Arshad, Winterhalder, Underwood, Kelesidi, Chaplin and Kravariti27,Reference Dunham, Kinnear, Allan, Smiley and Cooper29,Reference McGrother, Bhaumik, Thorp, Hauck, Branford and Watson33,Reference Tyrrell, Cosgrave, McCarron, McPherson, Calvert and Kelly44} referring to the tenth edition.⁴⁵ One study^{Reference Smith and Matson46} used the DSM-IV-TR⁴⁷ to diagnose intellectual disabilities.

Epilepsy

Epilepsy diagnosis was based on Gunn and Fenton's 1969 operational definition^{Reference Gunn and Fenton48} in four studies.^{Reference Deb and Hunter25,Reference Deb and Hunter35,Reference Deb42,Reference Reid and Ballinger49} Five studies^{Reference Snoeijen-Schouwenaars, van Ool, Tan, Aldenkamp, Schelhaas and Hendriksen37,Reference Tyrrell, Cosgrave, McCarron, McPherson, Calvert and Kelly44,Reference Smith and Matson46,Reference Deb and Joyce50,Reference Tyrrell, Cosgrave, McLaughlin and Lawlor51} referred to the International League Against Epilepsy criteria.^{52,Reference Fisher, Acevedo, Arzimanoglou, Bogacz, Cross and Elger53}

Psychiatric disorders

The methods used to define and assess psychiatric disorders differed across the selected studies. Seven studies used a retrospective design and collected data from case notes.^{Reference Deb and Joyce50,Reference Collacott54–Reference Turkistani59} Four studies^{Reference Arshad, Winterhalder, Underwood, Kelesidi, Chaplin and Kravariti27,Reference Cowley, Holt, Bouras, Sturmey, Newton and Costello28,Reference Deb and Joyce50,Reference Turkistani59} assessed psychiatric disorders based on ICD-10 criteria,⁴⁵ and two other studies^{Reference Deb and Hunter25,Reference Deb42} used the DSM-III-R.⁶⁰

Of the studies that used validated instruments, three^{Reference Cooper, Smiley, Morrison, Allan, Williamson and Finlayson11,Reference Espie, Watkins, Curtice, Espie, Duncan and Ryan30,Reference Reid, Smiley and Cooper36} used the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist (PAS-ADD)^{Reference Moss, Prosser, Costello, Simpson, Patel and Rowe61} and one^{Reference Turky, Felce, Jones and Kerr62} used the short version of the tool (mini PAS-ADD).^{Reference Prosser, Moss, Costello, Simpson, Patel and Rowe63} Only one study^{Reference Deb, Thomas and Bright10} used a stringent epidemiological methodology by using a three-stage process for diagnosis. In stage 1, the authors screened the sample with the mini PAS-ADD interview.^{Reference Prosser, Moss, Costello, Simpson, Patel and Rowe63} Those who met caseness criteria according to the mini PAS-ADD interview^{Reference Prosser, Moss, Costello, Simpson, Patel and Rowe63} were further interviewed in stage 2, using the full PAS-ADD interview.^{Reference Moss, Patel, Prosser, Goldberg, Simpson and Rowe64} In stage 3, information from the full PAS-ADD interview was used to make a psychiatric diagnosis according to the ICD-10 criteria.^{Reference Smith and Matson46} One study each used the Diagnostic Assessment for the Severely Handicapped-II,^{Reference Fitzgerald, Matson and Barker31,Reference Sevin, Matson, Williams and Kirkpatrick-Sanchez65} the Psychopathology Instrument for Mentally Retarded Adults^{Reference Matthews, Weston, Baxter, Felce and Kerr26,Reference Matson, Kazdin and Senatore66} and the Autism Spectrum Disorders-Comorbidity for Adults.^{Reference Smith and Matson46,Reference Matson, Terlonge and Gonzalez67}

Two studies^{Reference Deb and Hunter35,Reference Reid and Ballinger49} used the Standardized Assessment of Personality^{Reference Mann, Jenkins, Cutting and Cowen68} to evaluate personality disorders, and two studies^{Reference Tyrrell, Cosgrave, McCarron, McPherson, Calvert and Kelly44,Reference Tyrrell, Cosgrave, McLaughlin and Lawlor51} used the Test for Severe Impairment^{Reference Albert and Cohen69} and the Down's Syndrome Mental Status Examination^{Reference Haxby70} to evaluate dementia. To evaluate anxiety and depressive disorders, two studies^{Reference Snoeijen-Schouwenaars, van Ool, Tan, Aldenkamp, Schelhaas and Hendriksen37,Reference Hermans and Evenhuis71} used the Anxiety, Depression, And Mood Scale,^{Reference Esbensen, Rojahn, Aman and Ruedrich72} with one study^{Reference Hermans and Evenhuis71} also using the PAS-ADD interview^{Reference Moss, Patel, Prosser, Goldberg, Simpson and Rowe64} for diagnosis of anxiety disorders.

Statistical methods used

Descriptive statistics, χ ²-test, logistic regression analysis and univariate and multivariate regression analyses were used.

Outcome

The overall rate of psychiatric disorders

We identified 11 controlled studies that compared the rate of psychiatric disorder in epilepsy and non-epilepsy groups, seven^{Reference Deb, Thomas and Bright10,Reference Matthews, Weston, Baxter, Felce and Kerr26,Reference Dunham, Kinnear, Allan, Smiley and Cooper29–Reference Lund32,Reference Mantry, Cooper, Smiley, Morrison, Allan and Williamson34} of which showed no significant inter-group difference between epilepsy and non-epilepsy groups. Two studies^{Reference Deb and Hunter25,Reference Cowley, Holt, Bouras, Sturmey, Newton and Costello28} showed a significantly higher rate of psychiatric disorders in the non-epilepsy group. One study^{Reference McGrother, Bhaumik, Thorp, Hauck, Branford and Watson33} reported a significantly higher rate of psychiatric disorders in the epilepsy group, and another showed a higher rate of psychological symptoms (as opposed to psychiatric disorders) in the epilepsy group compared with the non-epilepsy control group^{Reference McGrother, Bhaumik, Thorp, Hauck, Branford and Watson33} (see Tables 1 and 4). The findings of the studies published since 2010 (see Table 4) are similar to those that were published before 2010.

Rates of different types of psychiatric disorders

Tables 2 and 4 present data from 18 studies that reported rates of different types of psychiatric disorders.

Regarding psychotic disorders, two studies^{Reference Cooper, Smiley, Morrison, Allan, Williamson and Finlayson11,Reference Pawar and Akuffo57} showed significantly lower rates of psychosis in the epilepsy group compared with the non-epilepsy control group, whereas two studies^{Reference Turkistani59,Reference Turky, Felce, Jones and Kerr62} did not find a significant inter-group difference in the rate of psychosis and psychotic symptom scores. Two studies^{Reference Arshad, Winterhalder, Underwood, Kelesidi, Chaplin and Kravariti27,Reference Cowley, Holt, Bouras, Sturmey, Newton and Costello28} showed a significantly lower rate of schizophrenic spectrum disorders in the epilepsy group compared with the non-epilepsy group. One study^{Reference Deb and Hunter25} found a non-statistically significant higher rate of schizophrenia in the epilepsy group compared with the non-epilepsy control group.

Concerning depressive disorders, four studies^{Reference Deb and Hunter25,Reference Arshad, Winterhalder, Underwood, Kelesidi, Chaplin and Kravariti27,Reference Pawar and Akuffo57,Reference Turkistani59} showed lower rates of depression in the epilepsy group compared with the non-epilepsy controls, whereas two studies showed significantly higher scores of depressive symptoms in the epilepsy group.^{Reference Smith and Matson46,Reference Turky, Felce, Jones and Kerr62}

Concerning anxiety disorders, two studies showed higher rates in the epilepsy group compared with the non-epilepsy group. In the first study,^{Reference Deb and Hunter25} the difference was not statistically significant, and in the second study,^{Reference Pawar and Akuffo57} statistical significance was not reported. One study^{Reference Arshad, Winterhalder, Underwood, Kelesidi, Chaplin and Kravariti27} showed lower rates in the epilepsy group compared with the non-epilepsy control group. Three studies^{Reference McGrother, Bhaumik, Thorp, Hauck, Branford and Watson33,Reference Reid, Smiley and Cooper36,Reference Turky, Felce, Jones and Kerr62} showed no statistically significant inter-group difference in anxiety disorders between epilepsy and non-epilepsy groups.

As for dementia, four studies^{Reference Tyrrell, Cosgrave, McCarron, McPherson, Calvert and Kelly44,Reference Tyrrell, Cosgrave, McLaughlin and Lawlor51,Reference Collacott54,Reference McCarron, McCallion, Reilly and Mulryan56} found a statistically significant association between dementia and epilepsy. All these studies included participants with Down syndrome. One study^{Reference McCarron, Gill, McCallion and Begley55} reported specifically on the rate of Alzheimer's disease, and found that epilepsy is significantly more common in those with Alzheimer's disease compared with those without the condition. Three other studies^{Reference Deb and Hunter25,Reference Arshad, Winterhalder, Underwood, Kelesidi, Chaplin and Kravariti27,Reference Turky, Felce, Jones and Kerr62} presented data related to dementia, but not specifically on participants with Down syndrome. In these studies, inter-group differences were not significant.

Regarding personality disorders, two studies^{Reference Deb and Hunter35,Reference Reid and Ballinger49} showed no significant difference between the epilepsy group and non-epilepsy control group, and one study^{Reference Arshad, Winterhalder, Underwood, Kelesidi, Chaplin and Kravariti27} showed lower rates of personality disorders in adults with intellectual disabilities and epilepsy compared with the non-epilepsy group; the significance level was not reported.

Association between psychiatric disorders and epilepsy-related variables

Association between overall and/or specific types of psychiatric disorders and epilepsy-related variables has been reported in various studies (see Tables 3 and 4).

Four studies investigated the relationship between seizure types such as focal versus generalised seizures, and rates of psychiatric disorders. None reported a significant association.^{Reference Lund32,Reference Snoeijen-Schouwenaars, van Ool, Tan, Aldenkamp, Schelhaas and Hendriksen37,Reference Deb and Joyce50,Reference Ring, Zia, Lindeman and Himlok58}

On the other hand, epileptic activity was significantly associated with overall psychiatric disorders in two studies.^{Reference Deb and Hunter25,Reference Espie, Watkins, Curtice, Espie, Duncan and Ryan30} One study^{Reference Lund32} showed a significantly higher rate of psychiatric disorders in the active epilepsy group (seizure in the past 12 months) than the non-epilepsy control group. Active epilepsy, characterised by having at least one seizure in the past 3 months^{Reference Ring, Zia, Lindeman and Himlok58} or at least one seizure in the past 12 months,^{Reference Deb and Hunter35} was respectively associated with lower rates of psychosis and depressive disorders in one study,^{Reference Ring, Zia, Lindeman and Himlok58} and with higher rates of personality disorders in another study.^{Reference Deb and Hunter35}

Two studies investigated electroencephalogram (EEG) activities associated with overall psychiatric disorders. One study showed higher rates of psychiatric disorders in those whose EEG showed epileptiform changes compared with those whose EEG did not show epileptiform changes,^{Reference Deb and Joyce50} and one study^{Reference Deb42} showed lower rates of psychiatric disorders in those whose EEG showed epileptiform changes compared with those whose EEG showed excessive background slowing activity. One study showed significantly higher rates of personality disorders in those whose EEG showed epileptiform changes compared with those whose EEG showed excessive background slowing.^{Reference Deb42}

Regarding seizure frequency, one study^{Reference Deb and Hunter25} found significantly lower rates of psychiatric disorders in those with frequent seizures compared with a control group of adults with intellectual disabilities alone (no epilepsy). One study^{Reference Turkistani59} showed a significant positive association between seizure frequency and depression, and one study^{Reference Snoeijen-Schouwenaars, van Ool, Tan, Aldenkamp, Schelhaas and Hendriksen37} found that lower levels of anxiety were significantly associated with a high seizure frequency in adults with intellectual disabilities.

One study^{Reference Espie, Watkins, Curtice, Espie, Duncan and Ryan30} reported a significant association between psychiatric disorders and seizure severity.

Polypharmacy of anti-epileptic medications was significantly associated with less psychiatric disorders compared with the intellectual disabilities only control group,^{Reference Deb and Hunter25} with a higher score of personality disorders^{Reference Deb and Hunter35} and lower levels of anxiety^{Reference Snoeijen-Schouwenaars, van Ool, Tan, Aldenkamp, Schelhaas and Hendriksen37} compared with those receiving mono-therapy of anti-epileptic medication.

Psychiatric disorders and the level of intellectual disabilities

Higher rates of psychiatric disorders were found in adults with mild-to-moderate intellectual disabilities compared with adults with severe-to-profound intellectual disabilities in four studies.^{Reference Deb and Hunter25,Reference Lund32,Reference Reid, Smiley and Cooper36,Reference Deb and Joyce50} The same association was found when investigating psychotic disorders in two studies.^{Reference Deb and Hunter25,Reference Ring, Zia, Lindeman and Himlok58} Concerning depressive disorders, one study^{Reference Ring, Zia, Lindeman and Himlok58} showed lower rates in those with mild intellectual disabilities compared with severe intellectual disabilities in the group of participants with non-active epilepsy. Another study^{Reference Snoeijen-Schouwenaars, van Ool, Tan, Aldenkamp, Schelhaas and Hendriksen37} found that depressive symptoms were associated with more severe levels of intellectual disabilities, but found no association between anxiety symptoms and severity of intellectual disabilities. However, one study^{Reference Reid, Smiley and Cooper36} showed that anxiety symptoms were more frequent in adults with mild intellectual disabilities compared with adults with severe intellectual disabilities.

Meta-analysis

For overall psychiatric disorders, relevant data for meta-analysis were available from only eight out of the 11 controlled studies. Using a random-effects meta-analysis, pooled odds ratio data from these eight studies showed no significant inter-group difference (P = 0.09), but the heterogeneity level was high (I ² = 76%, P < 0.01) (see Fig. 2). After the sensitivity check, we have removed data from one study that produced the highest level of heterogeneity and a high risk of bias according to the Cochrane risk of bias tool. This reduced heterogeneity to a borderline moderate level (I ²= 51%, P = 0.06). The final meta-analysis from the pooled data from seven studies shows a pooled odds ratio of 1.18 (95% CI 0.86–1.61, P = 0.06), using the random-effects model (see Fig. 3). This finding suggests the absence of a statistically significant difference in the rate of overall psychiatric disorders between the epilepsy and non-epilepsy control groups.