A Systematic Review of the Neuropsychological Sequelae of People Diagnosed with Anti N-Methyl-D-Aspartate Receptor Encephalitis in the Acute and Chronic Phases

A Systematic Review of the Neuropsychological Sequelae of People Diagnosed with Anti... Abstract Objective A systematic review was conducted to investigate the emerging cognitive profile for people diagnosed with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. Method Ten papers met the review criteria including five neuropsychological case studies and five case series; three of the 10 studies used matched controls. The cognitive functioning of 54 participants (46 female: eight male) was studied. Paper quality assessment was undertaken and outcomes summarized. Neuropsychological results during the acute phase (≤12 months) and chronic phase (>12 months) were extracted and a narrative review of the papers’ findings undertaken. Results A range of neuropsychological test batteries were used across the studies, administered between one and four times. The review revealed difficulties with memory, particularly delayed verbal memory, and executive functioning. This may be consistent with the role of NMDA receptors in the limbic system, specifically the hippocampus, which are thought to be essential to aspects of learning and memory. Conclusions To date, there is a paucity of high quality neuropsychological and psychological research concerning the impact of anti-NMDAR encephalitis on cognitive function and psychosocial wellbeing, both of adults and particularly of those under 18 years. Significant limitations of the literature reviewed include lack of attention to pre-morbid functioning, insufficient rationale for neuropsychological battery choice, use of samples of convenience, and limited translation of neuropsychological findings into rehabilitation. Limitations of this review include exclusive focus on an adult population and the necessity of a narrative review given the methodological diversity in studies making up the evidence base. Anti-NMDAR, Encephalitis, Autoimmune, Neuropsychology, Cognitive functioning Introduction Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDAR) is a rare form of autoimmune encephalitis, officially categorized and named only in 2007 (Dalmau et al., 2007). It is an acute and often severe illness caused by the body’s antibodies attacking, predominantly, the NR1 subunit of the NMDA receptors in the brain (Dalmau et al., 2008). It is often associated with a teratoma tumor, frequently ovarian in women and possibly testicular in men (Irani et al., 2010). However, there are an increasing number of cases reported with no identifiable tumor (Lim et al., 2014). Women have been found to be significantly more affected than men (Finke et al., 2012). The illness typically initiates with prodomal influenza or viral type symptoms, such as headache, fever, and nausea (Dalmau, Lancaster, Martinez-Hernandez, Rosenfeld, & Balice-Gordon, 2011). Symptoms such as delusional thinking, mood disturbances and aggression then frequently develop (Kayser, Titulaer, Gresa-Arribas, & Dalmau, 2013). These symptoms mean that 77% of patients first present for assessment by a psychiatrist (Kuppuswamy, Takala & Sola, 2014) and that there is a risk of anti-NMDAR going undiagnosed (Lennox, Coles, & Vincent, 2012) or resulting in a protracted time to diagnosis. This is significant given that quicker diagnosis and treatment is thought to improve prognosis (Byrne, McCoy, Lynch, Webb, & King, 2014; Kuppuswamy et al., 2014). Following the initial phase, most patients proceed into a period of alternating between catatonia and agitation with symptoms such as decreased levels of consciousness, hypoventilation, autonomic instability, and oro-lingual-facial dyskinesias (involuntary repetitive movements of the mouth and face) (Dalmau et al., 2011; Iizuka, & Sakai, 2008; Titulaer et al., 2013). Loughan, Allen, Perna, and Malkin (2016) report that in around 50% of anti-NMDAR cases, MRI scans of the brain have been normal (Dalmau et al., 2011; Maneta & Garcia, 2014) and any abnormalities found are usually small/transient despite the severity and duration of symptoms (Dalmau et al., 2011). Dalmau and colleagues (2011) reported that single photon emission topography (SPECT) results have been variable, with some studies finding variable multifocal cortical and subcortical abnormalities, which change during the course of the disease (Llorens et al., 2010), and other studies finding no abnormalities (Iizuka & Sakai, 2008). Therefore, confirmation of the clinical diagnosis is typically determined via positive identification of NMDA antibodies in the cerebrospinal fluid and/or serum (Barry, Byrne, Barrett, Murphy, & Cotter, 2015; Gresa-Arribas et al., 2014). For all patients, management of anti-NMDAR consists of first-line immunotherapy, including corticosteroids, intravenous immunoglobulins, or plasma exchange (Chen et al., 2016; Dalmau et al., 2011). Teratomas are resected if identified (Irani et al., 2010). Some patients, such as those with a delayed diagnosis, will go on to have second-line immunotherapy, such as Rituximab (Dalmau et al., 2011). Incidence and prevalence rates of anti-NMDAR encephalitis have yet to be established. However, research so far suggests that most patients recover fully medically or have mild sequelae, although a minority die or remain severely disabled (Dalmau et al., 2008). In a longitudinal study of 501 patients, Titulaer and colleagues (2013) found that 81% had a favorable outcome and 9.5% of patients had died after a median follow-up of 24 months. Three independent factors were predictive of good outcome: the rapid commencement of immunotherapy; tumor resection if needed; and less severe symptoms (i.e. not needing intensive care unit support). Titulaer and colleagues (2013) found 12% of their patients relapsed within 24 months, particularly when there was no associated tumor or undetected/recurrent tumors. However, the authors also found relapses were less frequent when patients received second-line immunotherapy (Titulaer et al., 2013). With regards cognitive function, amnesia during the initial stages is often reported (Leypoldt et al., 2012; Titulaer et al., 2013). Dalmau and colleagues (2008) stated that, in their study of 100 patients with anti-NMDAR (91 women; mean age 23 years), 23 presented with short-term memory loss. Language is also affected, with a reduction of verbal output, some echolalia (often together with echopraxia), and in some cases mutism (Dalmau et al., 2011). However, clinicians suggest memory difficulties and other neurocognitive abnormalities can be overlooked due to the dominance of psychiatric symptoms (Parfene, Lipira, Gunning, & Gordon-Elliott, 2016) and speech difficulties, which interfere with the assessment of memory (Dalmau et al., 2008, 2011). Memory deficits are said to be consistent with the distribution and function of NMDARs in the brain, which are required for long-term potentiation in the hippocampus, thought to be the center for learning and memory (McKeon et al., 2016; Rezvani, 2006). Research into the long-term neurophysiological and structural consequences of anti-NMDAR is still lacking given the relative infancy of the disease categorization. Most research has been undertaken by Finke and colleagues (2012, 2013,,2016). Using resting state fMRI, Finke and colleagues (2013) found significantly reduced bilateral functional connectivity between the hippocampus and the anterior default mode network (aDMN). This was shown to be correlated with individual memory performance, despite normal routine clinical MRI and grey matter morphology. The DMN is found to be more active in resting, internally focused tasks and researchers suggest it is involved in episodic memory processing and imagination (Finke et al., 2013). These findings are consistent with the knowledge that the CA1 region of the hippocampus has the highest density of NMDARs in the brain (Finke et al., 2013). Whilst neuroimaging results are important in understanding the neurophysiological and structural impacts of anti-NMDAR, neuropsychological studies are needed to establish a cognitive profile and understand the impact of any cognitive difficulties on functioning and wellbeing. Although this research is starting to emerge, a systematic review of neuropsychological studies of anti-NMDAR has not yet been completed. The aim of this study is to systematically investigate current literature on neuropsychological sequelae, to evaluate its quality and to attempt to establish a cognitive profile for this clinical population, both in the acute (≤12 months) and chronic (>12 months) phases. Given previous research it is hypothesized that short-term memory difficulties, along with language difficulties, will be common in the acute phase of the illness (Dalmau et al., 2008, 2011; Parfene et al., 2016), and long-term memory difficulties in the chronic phase (Finke et al., 2013). Some difficulties related to the DMN, such as relating to others and imagination might also be present in the chronic phase given the research by Finke and colleagues (2013). Method In this review of the literature, a systematic approach was adopted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance (Moher, Liberati, Tetzlaff, Altman, & PRISMA Group, 2009). The following search string was used: anti-NMDAR OR Anti-N-Methyl-d-Aspartate AND encephalitis AND Neuropsycholog* OR cogniti*. Appropriate studies were identified using PsycINFO, MEDLINE, Scopus and Web of Science. The search was limited to the English language. Given that anti-NMDAR was only officially categorized in 2007, the period of 2007 to March 2017 was searched, accepting articles and reviews. Studies of children (under age 18, based on a typical UK research cut-off) were excluded, due to the specificities of neurodevelopmental level on cognitive functioning (Johnson, Blum, & Giedd, 2009). The search was devised to identify papers where the search terms appeared in the title, abstract or keywords. The abstracts identified in each of the four databases were downloaded into a reference manager and duplicates automatically removed. Titles and abstracts were screened and relevant papers’ full texts were downloaded. Reference sections were then hand searched for any further relevant papers. Fig. 1 shows the search process. Single case studies were included given the limited literature in this area. Fig. 1. View largeDownload slide Overview of searching and screening process PRISMA (Moher et al., 2009). Fig. 1. View largeDownload slide Overview of searching and screening process PRISMA (Moher et al., 2009). An Assessment of Methodological Quality An examination of existing standardized quality appraisal checklists was carried out including consideration of the Critical Appraisal Skills Programme (CASP, 2017) and the Scottish Intercollegiate Guidelines Network (SIGN, 2017). The case control study tools provided by both could be applied to the five studies that used a control group, but not to the remaining five. Moreover, both tools lacked questions to examine potentially confounding factors such as pain, mental health difficulties, pre-morbid functioning or effort; crucial information for attribution of the neuropsychological assessment outcomes to anti-NMDAR. Therefore, a checklist was developed for the purpose of this review. This was informed by the foregoing existing checklists and by guidance from: Evans (2010) on potential contra-indicators to neuropsychological testing validity; guidelines on psychometric testing (Psychologists Board New Zealand, 2015); information on single-case methodology in neuropsychology (Crawford, 2017) and guidance on reporting of medical case studies (Cohen, 2006; Green, Johnson, Long, Harkins, & Meeker, 2006; McCarthy, & Reilly, 2000). Each article was reviewed and given an overall score (possible maximum of 33; see Supplementary data 1) based upon which criteria were met. For ease of reference, articles are referred to as “Low” (0–11), “Medium” (12–22) or “High” (23–33) quality, depending on their score. Given the small number of papers meeting the inclusion criteria, no articles were excluded on the basis of their score on the quality checklist, rather, this was used to critically appraise the quality of current literature and provide recommendations for future research. Two independent raters piloted the quality of the assessment tool, any differences in scoring were discussed and the tool’s wording changed accordingly. An independent rater then formally reviewed a total of five articles, which demonstrated moderate inter-rater reliability (k = 0.72). All the scores were within the same category (Low, Medium, High), aside from Vahter and colleagues (2014), which the first author rated as “Low” quality and the second rater as “Medium” quality (one point difference). Data Extraction Data were extracted from the articles by the first author and divided into acute (≤12 months), and chronic cognitive deficits (>12 months). This was in an attempt to establish a cognitive profile, firstly for the “acute” neuropsychological phase of the illness, i.e., from the onset of the symptoms (the period when most treatment is commenced and completed), and secondly for the “chronic” phase, i.e., for any cognitive difficulties remaining once the systemic effects of the illness have receded. It should be noted there is currently little agreement as to the definition of “acute” and “chronic” periods and papers largely base this on medical and treatment criteria. McIvor and Moore (2017) refer to the acute stage as 4–6 weeks after symptom onset; post-acute stage as 2–6 months and the chronic stage as 6–13 months. However, time to treatment is under-reported across the 10 articles: patients may not start treatment until several months after symptom onset (Urakami, 2016); or it may be unknown (McKeon et al., 2016). Therefore, the “acute” phase for the purpose of this neuropsychological review was defined as 0–12 months on the premise that if patients were still recovering from the systemic effects of the illness, and if treatment was still being received, this would affect cognitive functioning. The terms “chronic” and “acute” were used as opposed to short and long- term to reduce confusion with short and long-term memory references. Results Search Results and Characteristics of Studies The search and screening process identified 10 eligible articles, including five case studies (one single case study, four with multiple) and five case series (four with a single case and one with multiple; Table 1). Three studies had matched controls and all participants neuropsychological test results were compared to normative samples. The data were derived from 54 participants diagnosed with anti-NMDAR from eight different countries. The time of “neuropsychological testing since diagnosis” varied considerably from eight days to 6 years (Table 1). Of note is the large timeframe in the “chronic” section, with “time tested since diagnosis” ranging from 12 to 72 months, both within and between articles. The results of the case series are presented in the results section and differences between participants’ scores across different time periods are discussed. How articles described “time tested since diagnosis” varied; seven articles described time since disease/symptom onset, one article described time since diagnosis and one reported time since treatment completion. Five of the studies carried out neuropsychological testing with participants who had medical treatment only, four with those who had treatment and rehabilitation and one with a participant who had no treatment or rehabilitation. Eight articles were rated as “Medium” quality, one “High” quality and one “Low” quality (Table 3). Consistent with the current evidence on epidemiology of anti-NMDAR (Titulaer et al., 2013), there were more female participants than males (46F:8M). Table 1. Table of study characteristics Study  Setting  Participant information  Treatment/Rehabilitation  Study or series & time assessed  Domains assessed  Cognitive deficits reported  Quality rating  Finke et al. (2012)  Participants recruited from the Department of Neurology, University Hospital, Germany.  8F,1M Mean age 28.4 years Range 21–44 Matched controls: 12 healthy participants without a history of neurological or psychiatric disorders who were matched for sex, age and educational level.  Five participants received first-line (immunotherapies including corticosteroids, intravenous immunoglobulin or both) during first 3 months of the disease, three participants received immunotherapy later in course of disease and one did not receive immunotherapy. One participant received second-line immunotherapy with methotrexate for 5 years. Two patients, ovarian teratomas were found and removed surgically. No rehabilitation.  Case study. Median 43 months after disease onset. Range 23–69 months.  Perceptual organization; attention; processing speed; verbal and non-verbal short-term memory; working memory, verbal and non-verbal episodic memory; executive functioning; general intellectual abilities.  Working memory, episodic memory, delay-dependent deficits in STM tasks; executive functioning; attention.  18 Med  Martin et al. (2012)  Participant sent for neuropsychological testing following admission to the Department of Neurology, at the Virgen del Rocío Hospital (Seville)  1F 35 years  Treatment with steroids, intravenous immunoglobulins, azathioprine, plasma exchange and cyclophosphamide. Four relapses despite of adequate treatment. Neurorehabilitation over a period of 6 years.  Case series. Tested at 6, 12, 72 months after disease onset.  Orientation; general cognitive functions; verbal and figural short- and long-term memory; frontal executive functions; language; visuospatial cognition; motor skills.  STM, anterograde, declarative memory; executive functioning; attention; visuoperceptive.  16 Med  Finke et al. (2013)  Participants were recruited in Germany and Austria between July 2011 and July 2012 and were referred to the outpatient clinic of the Department of Neurology of Charite Universit, Berlin for further counseling and treatment.  21F, 3M Mean age 27.9 years. Matched controls: 21F, 3M Mean age 28.0 years.  Immunotherapy reported, not specified. No rehabilitation. Neuropsychological battery completed after the acute phase.  Case study. Mean 33 months. Median 35 months. Range 9–72 months. Calculated by the first author from the reported time between first symptoms and imaging. Working on the assumption neuropsychological testing would have been performed around the same time.  Verbal memory; non-verbal short-term memory; working memory; verbal and non-verbal episodic memory; executive functioning; pre-morbid intelligence quotient; general intellectual abilities.  Working memory, verbal LTM; executive functioning.  14 Med  Marcos-Arribas et al. (2013)  Participant sent for neuropsychological testing following admission to the Neurology Department, Hospital Clínico San Carlos, Madrid, Spain  1F 24 years  Neuropsychological battery completed on admission. The participant underwent surgery within 7 days since admission and the diagnosis of mature ovarian teratoma was confirmed by pathology studies. Then nine alternate days sessions of plasmapheresis were then started. After 1 month the neuropsychological battery was repeated. No rehabilitation.  Tested at symptom onset & 1 month from symptom onset  Short-term memory; working memory; attention; semantic and episodic memories, visuospatial, praxical, thinking and language functions.  Short-term verbal & visual memory; retrograde amnesia of 2 months; attention.  14 Med  Vahter et al. (2014)  Participant sent for neuropsychological testing following admission to the Department of Neurology, West-Tallinn Central Hospital, Estonia.  1F 29 years  Immunotherapy with plasma exchange, intravenous IgG, followed later by cyclophosphamide. Neuropsychological testing throughout acute period. No rehabilitation.  Tested four times at symptom onset, 8 months, 12 months, 20 months after symptom onset.  Verbal memory; visuospatial memory; logical memory; executive functioning; information processing speed; verbal fluency; visuoconstructive abilities.  Long-term verbal memory; executive functioning; attention; language; visuoconstructive.  11 Low  Bach (2014)  Participants referred to the Specialist Acquired Brain Injury Unit Outreach Team (community rehabilitation team), London.  2F 24 & 23 years  Surgery (one participant) plasma exchange and course of intravenous immunoglobulin. Outreach Team for further management and rehabilitation.  Case study. Tested approximately 6 months after symptom onset. Determined from the narrative description of the cases.  Verbal memory; working memory; immediate memory; delayed memory; perceptual organization; verbal fluency; attention; executive functioning; processing speed.  Memory (long-term verbal memory), working memory, STM; executive functioning; attention; language; social cognition.  13 Med  Loughan et al. (2016)  Participant referred for neuropsychological evaluation, Department of Neurology, USA  1M 42 years  Plasmapheresis, IV steroids, Rituximab, Cyclophosphamide. Inpatient rehabilitation for 2 months. Neuropsychological testing completed once discharged.  Case study. Tested 6 months post-diagnosis.  Working memory; verbal fluency; global ability; attention; effort; executive functioning; verbal comprehension; perceptual reasoning; verbal memory; visual memory; immediate memory; delayed memory.  Verbal memory; executive functioning; attention; processing speed; language.  24 High  McKeon et al. (2016)  Participants recruited via Queensland-based physicians to Neuropsychology Research Unit, Australia.  6F, 1 M Mean age, 26.4 years Range 16–37 years Matched controls: 10F, 4M Mean age, 25.8 years Range, 16–38 years without significant psychiatric or neurological histories  Four participants (P2, P3, P6, P7) received immunotherapy within a month of symptom onset, and had not relapsed. The remaining three participants (P1, P4, P5) had lengthy psychiatric histories and comparatively poorer response to immunotherapy. No rehabilitation.  Case study. Tested: Mean 19 months (median 22.5 months; range 7–41 months). Calculated by the first author from estimated time between treatment completion & neuropsychological assessment and mean 23 months (median 20 months, range 4–35 months). As calculated from estimated time between treatment initiation & current assessment. Three participants had treatment ongoing at time of testing due to residual symptoms.  Episodic memory; semantic memory; language; auditory short-term memory; working memory; attention; processing speed; executive functioning  Verbal & visual episodic memory, verbal STM, working memory; executive functioning; attention; processing speed; visuospatial organization; social cognition  20 Med  Urakami (2016)  Participants undergoing rehabilitation at the National Rehabilitation Center for Persons with Disabilities, Japan.  5F, 1 M Mean age 33.3 years Range 20–47 years  Corticosteroids, intravenous immunotherapy (IVIg) and appropriate ovarian teratoma removal. Rehabilitation of 6 months approximately. Neuropsychological testing both before and after neurorehabilitation.  Case series. Tested twice. Mean 6 months after onset of symptoms (calculated by the first author from Table 1) and after rehabilitation (interval between start & end of rehab = mean 184.8 days).  Attention, verbal and non-verbal short-term and working memory, executive functioning; general intellectual abilities.  Working memory, verbal memory, visual memory; attention; processing speed.  14 Med  McIvor & Moore (2017)  Participant referred to Department of Clinical Neuropsychology, The Walton Center NHS Foundation Trust, Liverpool, UK.  1M 19 years  No treatment or rehabilitation. Spontaneous recovery assessed.  Case series. An untreated case tested three times over 30 months.  Delayed memory; immediate memory, visual memory; visual working memory; auditory memory; executive functioning; pre-morbid functioning.  STM, auditory memory, delayed memory.  19 Med  Study  Setting  Participant information  Treatment/Rehabilitation  Study or series & time assessed  Domains assessed  Cognitive deficits reported  Quality rating  Finke et al. (2012)  Participants recruited from the Department of Neurology, University Hospital, Germany.  8F,1M Mean age 28.4 years Range 21–44 Matched controls: 12 healthy participants without a history of neurological or psychiatric disorders who were matched for sex, age and educational level.  Five participants received first-line (immunotherapies including corticosteroids, intravenous immunoglobulin or both) during first 3 months of the disease, three participants received immunotherapy later in course of disease and one did not receive immunotherapy. One participant received second-line immunotherapy with methotrexate for 5 years. Two patients, ovarian teratomas were found and removed surgically. No rehabilitation.  Case study. Median 43 months after disease onset. Range 23–69 months.  Perceptual organization; attention; processing speed; verbal and non-verbal short-term memory; working memory, verbal and non-verbal episodic memory; executive functioning; general intellectual abilities.  Working memory, episodic memory, delay-dependent deficits in STM tasks; executive functioning; attention.  18 Med  Martin et al. (2012)  Participant sent for neuropsychological testing following admission to the Department of Neurology, at the Virgen del Rocío Hospital (Seville)  1F 35 years  Treatment with steroids, intravenous immunoglobulins, azathioprine, plasma exchange and cyclophosphamide. Four relapses despite of adequate treatment. Neurorehabilitation over a period of 6 years.  Case series. Tested at 6, 12, 72 months after disease onset.  Orientation; general cognitive functions; verbal and figural short- and long-term memory; frontal executive functions; language; visuospatial cognition; motor skills.  STM, anterograde, declarative memory; executive functioning; attention; visuoperceptive.  16 Med  Finke et al. (2013)  Participants were recruited in Germany and Austria between July 2011 and July 2012 and were referred to the outpatient clinic of the Department of Neurology of Charite Universit, Berlin for further counseling and treatment.  21F, 3M Mean age 27.9 years. Matched controls: 21F, 3M Mean age 28.0 years.  Immunotherapy reported, not specified. No rehabilitation. Neuropsychological battery completed after the acute phase.  Case study. Mean 33 months. Median 35 months. Range 9–72 months. Calculated by the first author from the reported time between first symptoms and imaging. Working on the assumption neuropsychological testing would have been performed around the same time.  Verbal memory; non-verbal short-term memory; working memory; verbal and non-verbal episodic memory; executive functioning; pre-morbid intelligence quotient; general intellectual abilities.  Working memory, verbal LTM; executive functioning.  14 Med  Marcos-Arribas et al. (2013)  Participant sent for neuropsychological testing following admission to the Neurology Department, Hospital Clínico San Carlos, Madrid, Spain  1F 24 years  Neuropsychological battery completed on admission. The participant underwent surgery within 7 days since admission and the diagnosis of mature ovarian teratoma was confirmed by pathology studies. Then nine alternate days sessions of plasmapheresis were then started. After 1 month the neuropsychological battery was repeated. No rehabilitation.  Tested at symptom onset & 1 month from symptom onset  Short-term memory; working memory; attention; semantic and episodic memories, visuospatial, praxical, thinking and language functions.  Short-term verbal & visual memory; retrograde amnesia of 2 months; attention.  14 Med  Vahter et al. (2014)  Participant sent for neuropsychological testing following admission to the Department of Neurology, West-Tallinn Central Hospital, Estonia.  1F 29 years  Immunotherapy with plasma exchange, intravenous IgG, followed later by cyclophosphamide. Neuropsychological testing throughout acute period. No rehabilitation.  Tested four times at symptom onset, 8 months, 12 months, 20 months after symptom onset.  Verbal memory; visuospatial memory; logical memory; executive functioning; information processing speed; verbal fluency; visuoconstructive abilities.  Long-term verbal memory; executive functioning; attention; language; visuoconstructive.  11 Low  Bach (2014)  Participants referred to the Specialist Acquired Brain Injury Unit Outreach Team (community rehabilitation team), London.  2F 24 & 23 years  Surgery (one participant) plasma exchange and course of intravenous immunoglobulin. Outreach Team for further management and rehabilitation.  Case study. Tested approximately 6 months after symptom onset. Determined from the narrative description of the cases.  Verbal memory; working memory; immediate memory; delayed memory; perceptual organization; verbal fluency; attention; executive functioning; processing speed.  Memory (long-term verbal memory), working memory, STM; executive functioning; attention; language; social cognition.  13 Med  Loughan et al. (2016)  Participant referred for neuropsychological evaluation, Department of Neurology, USA  1M 42 years  Plasmapheresis, IV steroids, Rituximab, Cyclophosphamide. Inpatient rehabilitation for 2 months. Neuropsychological testing completed once discharged.  Case study. Tested 6 months post-diagnosis.  Working memory; verbal fluency; global ability; attention; effort; executive functioning; verbal comprehension; perceptual reasoning; verbal memory; visual memory; immediate memory; delayed memory.  Verbal memory; executive functioning; attention; processing speed; language.  24 High  McKeon et al. (2016)  Participants recruited via Queensland-based physicians to Neuropsychology Research Unit, Australia.  6F, 1 M Mean age, 26.4 years Range 16–37 years Matched controls: 10F, 4M Mean age, 25.8 years Range, 16–38 years without significant psychiatric or neurological histories  Four participants (P2, P3, P6, P7) received immunotherapy within a month of symptom onset, and had not relapsed. The remaining three participants (P1, P4, P5) had lengthy psychiatric histories and comparatively poorer response to immunotherapy. No rehabilitation.  Case study. Tested: Mean 19 months (median 22.5 months; range 7–41 months). Calculated by the first author from estimated time between treatment completion & neuropsychological assessment and mean 23 months (median 20 months, range 4–35 months). As calculated from estimated time between treatment initiation & current assessment. Three participants had treatment ongoing at time of testing due to residual symptoms.  Episodic memory; semantic memory; language; auditory short-term memory; working memory; attention; processing speed; executive functioning  Verbal & visual episodic memory, verbal STM, working memory; executive functioning; attention; processing speed; visuospatial organization; social cognition  20 Med  Urakami (2016)  Participants undergoing rehabilitation at the National Rehabilitation Center for Persons with Disabilities, Japan.  5F, 1 M Mean age 33.3 years Range 20–47 years  Corticosteroids, intravenous immunotherapy (IVIg) and appropriate ovarian teratoma removal. Rehabilitation of 6 months approximately. Neuropsychological testing both before and after neurorehabilitation.  Case series. Tested twice. Mean 6 months after onset of symptoms (calculated by the first author from Table 1) and after rehabilitation (interval between start & end of rehab = mean 184.8 days).  Attention, verbal and non-verbal short-term and working memory, executive functioning; general intellectual abilities.  Working memory, verbal memory, visual memory; attention; processing speed.  14 Med  McIvor & Moore (2017)  Participant referred to Department of Clinical Neuropsychology, The Walton Center NHS Foundation Trust, Liverpool, UK.  1M 19 years  No treatment or rehabilitation. Spontaneous recovery assessed.  Case series. An untreated case tested three times over 30 months.  Delayed memory; immediate memory, visual memory; visual working memory; auditory memory; executive functioning; pre-morbid functioning.  STM, auditory memory, delayed memory.  19 Med  View Large Table 1. Table of study characteristics Study  Setting  Participant information  Treatment/Rehabilitation  Study or series & time assessed  Domains assessed  Cognitive deficits reported  Quality rating  Finke et al. (2012)  Participants recruited from the Department of Neurology, University Hospital, Germany.  8F,1M Mean age 28.4 years Range 21–44 Matched controls: 12 healthy participants without a history of neurological or psychiatric disorders who were matched for sex, age and educational level.  Five participants received first-line (immunotherapies including corticosteroids, intravenous immunoglobulin or both) during first 3 months of the disease, three participants received immunotherapy later in course of disease and one did not receive immunotherapy. One participant received second-line immunotherapy with methotrexate for 5 years. Two patients, ovarian teratomas were found and removed surgically. No rehabilitation.  Case study. Median 43 months after disease onset. Range 23–69 months.  Perceptual organization; attention; processing speed; verbal and non-verbal short-term memory; working memory, verbal and non-verbal episodic memory; executive functioning; general intellectual abilities.  Working memory, episodic memory, delay-dependent deficits in STM tasks; executive functioning; attention.  18 Med  Martin et al. (2012)  Participant sent for neuropsychological testing following admission to the Department of Neurology, at the Virgen del Rocío Hospital (Seville)  1F 35 years  Treatment with steroids, intravenous immunoglobulins, azathioprine, plasma exchange and cyclophosphamide. Four relapses despite of adequate treatment. Neurorehabilitation over a period of 6 years.  Case series. Tested at 6, 12, 72 months after disease onset.  Orientation; general cognitive functions; verbal and figural short- and long-term memory; frontal executive functions; language; visuospatial cognition; motor skills.  STM, anterograde, declarative memory; executive functioning; attention; visuoperceptive.  16 Med  Finke et al. (2013)  Participants were recruited in Germany and Austria between July 2011 and July 2012 and were referred to the outpatient clinic of the Department of Neurology of Charite Universit, Berlin for further counseling and treatment.  21F, 3M Mean age 27.9 years. Matched controls: 21F, 3M Mean age 28.0 years.  Immunotherapy reported, not specified. No rehabilitation. Neuropsychological battery completed after the acute phase.  Case study. Mean 33 months. Median 35 months. Range 9–72 months. Calculated by the first author from the reported time between first symptoms and imaging. Working on the assumption neuropsychological testing would have been performed around the same time.  Verbal memory; non-verbal short-term memory; working memory; verbal and non-verbal episodic memory; executive functioning; pre-morbid intelligence quotient; general intellectual abilities.  Working memory, verbal LTM; executive functioning.  14 Med  Marcos-Arribas et al. (2013)  Participant sent for neuropsychological testing following admission to the Neurology Department, Hospital Clínico San Carlos, Madrid, Spain  1F 24 years  Neuropsychological battery completed on admission. The participant underwent surgery within 7 days since admission and the diagnosis of mature ovarian teratoma was confirmed by pathology studies. Then nine alternate days sessions of plasmapheresis were then started. After 1 month the neuropsychological battery was repeated. No rehabilitation.  Tested at symptom onset & 1 month from symptom onset  Short-term memory; working memory; attention; semantic and episodic memories, visuospatial, praxical, thinking and language functions.  Short-term verbal & visual memory; retrograde amnesia of 2 months; attention.  14 Med  Vahter et al. (2014)  Participant sent for neuropsychological testing following admission to the Department of Neurology, West-Tallinn Central Hospital, Estonia.  1F 29 years  Immunotherapy with plasma exchange, intravenous IgG, followed later by cyclophosphamide. Neuropsychological testing throughout acute period. No rehabilitation.  Tested four times at symptom onset, 8 months, 12 months, 20 months after symptom onset.  Verbal memory; visuospatial memory; logical memory; executive functioning; information processing speed; verbal fluency; visuoconstructive abilities.  Long-term verbal memory; executive functioning; attention; language; visuoconstructive.  11 Low  Bach (2014)  Participants referred to the Specialist Acquired Brain Injury Unit Outreach Team (community rehabilitation team), London.  2F 24 & 23 years  Surgery (one participant) plasma exchange and course of intravenous immunoglobulin. Outreach Team for further management and rehabilitation.  Case study. Tested approximately 6 months after symptom onset. Determined from the narrative description of the cases.  Verbal memory; working memory; immediate memory; delayed memory; perceptual organization; verbal fluency; attention; executive functioning; processing speed.  Memory (long-term verbal memory), working memory, STM; executive functioning; attention; language; social cognition.  13 Med  Loughan et al. (2016)  Participant referred for neuropsychological evaluation, Department of Neurology, USA  1M 42 years  Plasmapheresis, IV steroids, Rituximab, Cyclophosphamide. Inpatient rehabilitation for 2 months. Neuropsychological testing completed once discharged.  Case study. Tested 6 months post-diagnosis.  Working memory; verbal fluency; global ability; attention; effort; executive functioning; verbal comprehension; perceptual reasoning; verbal memory; visual memory; immediate memory; delayed memory.  Verbal memory; executive functioning; attention; processing speed; language.  24 High  McKeon et al. (2016)  Participants recruited via Queensland-based physicians to Neuropsychology Research Unit, Australia.  6F, 1 M Mean age, 26.4 years Range 16–37 years Matched controls: 10F, 4M Mean age, 25.8 years Range, 16–38 years without significant psychiatric or neurological histories  Four participants (P2, P3, P6, P7) received immunotherapy within a month of symptom onset, and had not relapsed. The remaining three participants (P1, P4, P5) had lengthy psychiatric histories and comparatively poorer response to immunotherapy. No rehabilitation.  Case study. Tested: Mean 19 months (median 22.5 months; range 7–41 months). Calculated by the first author from estimated time between treatment completion & neuropsychological assessment and mean 23 months (median 20 months, range 4–35 months). As calculated from estimated time between treatment initiation & current assessment. Three participants had treatment ongoing at time of testing due to residual symptoms.  Episodic memory; semantic memory; language; auditory short-term memory; working memory; attention; processing speed; executive functioning  Verbal & visual episodic memory, verbal STM, working memory; executive functioning; attention; processing speed; visuospatial organization; social cognition  20 Med  Urakami (2016)  Participants undergoing rehabilitation at the National Rehabilitation Center for Persons with Disabilities, Japan.  5F, 1 M Mean age 33.3 years Range 20–47 years  Corticosteroids, intravenous immunotherapy (IVIg) and appropriate ovarian teratoma removal. Rehabilitation of 6 months approximately. Neuropsychological testing both before and after neurorehabilitation.  Case series. Tested twice. Mean 6 months after onset of symptoms (calculated by the first author from Table 1) and after rehabilitation (interval between start & end of rehab = mean 184.8 days).  Attention, verbal and non-verbal short-term and working memory, executive functioning; general intellectual abilities.  Working memory, verbal memory, visual memory; attention; processing speed.  14 Med  McIvor & Moore (2017)  Participant referred to Department of Clinical Neuropsychology, The Walton Center NHS Foundation Trust, Liverpool, UK.  1M 19 years  No treatment or rehabilitation. Spontaneous recovery assessed.  Case series. An untreated case tested three times over 30 months.  Delayed memory; immediate memory, visual memory; visual working memory; auditory memory; executive functioning; pre-morbid functioning.  STM, auditory memory, delayed memory.  19 Med  Study  Setting  Participant information  Treatment/Rehabilitation  Study or series & time assessed  Domains assessed  Cognitive deficits reported  Quality rating  Finke et al. (2012)  Participants recruited from the Department of Neurology, University Hospital, Germany.  8F,1M Mean age 28.4 years Range 21–44 Matched controls: 12 healthy participants without a history of neurological or psychiatric disorders who were matched for sex, age and educational level.  Five participants received first-line (immunotherapies including corticosteroids, intravenous immunoglobulin or both) during first 3 months of the disease, three participants received immunotherapy later in course of disease and one did not receive immunotherapy. One participant received second-line immunotherapy with methotrexate for 5 years. Two patients, ovarian teratomas were found and removed surgically. No rehabilitation.  Case study. Median 43 months after disease onset. Range 23–69 months.  Perceptual organization; attention; processing speed; verbal and non-verbal short-term memory; working memory, verbal and non-verbal episodic memory; executive functioning; general intellectual abilities.  Working memory, episodic memory, delay-dependent deficits in STM tasks; executive functioning; attention.  18 Med  Martin et al. (2012)  Participant sent for neuropsychological testing following admission to the Department of Neurology, at the Virgen del Rocío Hospital (Seville)  1F 35 years  Treatment with steroids, intravenous immunoglobulins, azathioprine, plasma exchange and cyclophosphamide. Four relapses despite of adequate treatment. Neurorehabilitation over a period of 6 years.  Case series. Tested at 6, 12, 72 months after disease onset.  Orientation; general cognitive functions; verbal and figural short- and long-term memory; frontal executive functions; language; visuospatial cognition; motor skills.  STM, anterograde, declarative memory; executive functioning; attention; visuoperceptive.  16 Med  Finke et al. (2013)  Participants were recruited in Germany and Austria between July 2011 and July 2012 and were referred to the outpatient clinic of the Department of Neurology of Charite Universit, Berlin for further counseling and treatment.  21F, 3M Mean age 27.9 years. Matched controls: 21F, 3M Mean age 28.0 years.  Immunotherapy reported, not specified. No rehabilitation. Neuropsychological battery completed after the acute phase.  Case study. Mean 33 months. Median 35 months. Range 9–72 months. Calculated by the first author from the reported time between first symptoms and imaging. Working on the assumption neuropsychological testing would have been performed around the same time.  Verbal memory; non-verbal short-term memory; working memory; verbal and non-verbal episodic memory; executive functioning; pre-morbid intelligence quotient; general intellectual abilities.  Working memory, verbal LTM; executive functioning.  14 Med  Marcos-Arribas et al. (2013)  Participant sent for neuropsychological testing following admission to the Neurology Department, Hospital Clínico San Carlos, Madrid, Spain  1F 24 years  Neuropsychological battery completed on admission. The participant underwent surgery within 7 days since admission and the diagnosis of mature ovarian teratoma was confirmed by pathology studies. Then nine alternate days sessions of plasmapheresis were then started. After 1 month the neuropsychological battery was repeated. No rehabilitation.  Tested at symptom onset & 1 month from symptom onset  Short-term memory; working memory; attention; semantic and episodic memories, visuospatial, praxical, thinking and language functions.  Short-term verbal & visual memory; retrograde amnesia of 2 months; attention.  14 Med  Vahter et al. (2014)  Participant sent for neuropsychological testing following admission to the Department of Neurology, West-Tallinn Central Hospital, Estonia.  1F 29 years  Immunotherapy with plasma exchange, intravenous IgG, followed later by cyclophosphamide. Neuropsychological testing throughout acute period. No rehabilitation.  Tested four times at symptom onset, 8 months, 12 months, 20 months after symptom onset.  Verbal memory; visuospatial memory; logical memory; executive functioning; information processing speed; verbal fluency; visuoconstructive abilities.  Long-term verbal memory; executive functioning; attention; language; visuoconstructive.  11 Low  Bach (2014)  Participants referred to the Specialist Acquired Brain Injury Unit Outreach Team (community rehabilitation team), London.  2F 24 & 23 years  Surgery (one participant) plasma exchange and course of intravenous immunoglobulin. Outreach Team for further management and rehabilitation.  Case study. Tested approximately 6 months after symptom onset. Determined from the narrative description of the cases.  Verbal memory; working memory; immediate memory; delayed memory; perceptual organization; verbal fluency; attention; executive functioning; processing speed.  Memory (long-term verbal memory), working memory, STM; executive functioning; attention; language; social cognition.  13 Med  Loughan et al. (2016)  Participant referred for neuropsychological evaluation, Department of Neurology, USA  1M 42 years  Plasmapheresis, IV steroids, Rituximab, Cyclophosphamide. Inpatient rehabilitation for 2 months. Neuropsychological testing completed once discharged.  Case study. Tested 6 months post-diagnosis.  Working memory; verbal fluency; global ability; attention; effort; executive functioning; verbal comprehension; perceptual reasoning; verbal memory; visual memory; immediate memory; delayed memory.  Verbal memory; executive functioning; attention; processing speed; language.  24 High  McKeon et al. (2016)  Participants recruited via Queensland-based physicians to Neuropsychology Research Unit, Australia.  6F, 1 M Mean age, 26.4 years Range 16–37 years Matched controls: 10F, 4M Mean age, 25.8 years Range, 16–38 years without significant psychiatric or neurological histories  Four participants (P2, P3, P6, P7) received immunotherapy within a month of symptom onset, and had not relapsed. The remaining three participants (P1, P4, P5) had lengthy psychiatric histories and comparatively poorer response to immunotherapy. No rehabilitation.  Case study. Tested: Mean 19 months (median 22.5 months; range 7–41 months). Calculated by the first author from estimated time between treatment completion & neuropsychological assessment and mean 23 months (median 20 months, range 4–35 months). As calculated from estimated time between treatment initiation & current assessment. Three participants had treatment ongoing at time of testing due to residual symptoms.  Episodic memory; semantic memory; language; auditory short-term memory; working memory; attention; processing speed; executive functioning  Verbal & visual episodic memory, verbal STM, working memory; executive functioning; attention; processing speed; visuospatial organization; social cognition  20 Med  Urakami (2016)  Participants undergoing rehabilitation at the National Rehabilitation Center for Persons with Disabilities, Japan.  5F, 1 M Mean age 33.3 years Range 20–47 years  Corticosteroids, intravenous immunotherapy (IVIg) and appropriate ovarian teratoma removal. Rehabilitation of 6 months approximately. Neuropsychological testing both before and after neurorehabilitation.  Case series. Tested twice. Mean 6 months after onset of symptoms (calculated by the first author from Table 1) and after rehabilitation (interval between start & end of rehab = mean 184.8 days).  Attention, verbal and non-verbal short-term and working memory, executive functioning; general intellectual abilities.  Working memory, verbal memory, visual memory; attention; processing speed.  14 Med  McIvor & Moore (2017)  Participant referred to Department of Clinical Neuropsychology, The Walton Center NHS Foundation Trust, Liverpool, UK.  1M 19 years  No treatment or rehabilitation. Spontaneous recovery assessed.  Case series. An untreated case tested three times over 30 months.  Delayed memory; immediate memory, visual memory; visual working memory; auditory memory; executive functioning; pre-morbid functioning.  STM, auditory memory, delayed memory.  19 Med  View Large The articles also varied in the numbers of participants tested and presence or absence of a control group (Table 1). Additionally, many different neuropsychological tests were used to measure cognitive functioning across studies (Table 2). Therefore, comparison of the articles was difficult and data synthesis was not appropriate. As such, a narrative synthesis of the results was undertaken. Five of the studies were case series, four of which assessed patients both during the acute and chronic phases, and as such the relevant results are discussed in the “acute” and “chronic” sections (Martín-Monzón, Trujillo-Pozo, & Romero, 2012; McIvor, & Moore, 2017; Urakami, 2016; Vahter et al., 2014). Bach (2014) reported three case studies, but only the two participants assessed with formal neuropsychological testing, within the first 12 months, were included in the ≤12-month analysis. The patient assessed at 30 months did not undergo formal neuropsychological testing; data reported derives from behavioral observations and clinical judgment. The main results are presented under different cognitive domains, based on Lezak (2012) and the DSM-5 approach to classifying neurocognitive disorders (Sachdev et al., 2014). This is also in keeping with general reporting of neuropsychological assessment by clinical neuropsychologists and should make for ease of reference in a clinical setting. Table 2. Tests used by each study Cognitive function  Tests used  Cognitive function  Tests used  Verbal memory    Attention & Processing Speed    Loughan et al. (2016)  RBANS: List learning & Recall Story Memory & Recall  Loughan et al. (2012)  TMT: Part A & B  Finke et al. (2012)  RAVLT  Finke et al. (2012)  TAP  Martín-Monzón et al. (2012)  WMS III: Logical Memory Selective Reminding test  Martín-Monzón et al. (2012)  TMT: Part A WAIS-III: Digit Symbol-Coding   Finke et al. (2013)  RAVLT  Finke et al. (2013)  None named  Marcos-Arribas et al. (2013)  WMS-III: Logical Memory I & II Verbal Paired Associates I & II Word Pairs I & II Letter-Number Sequencing  Marcos-Arribas et al. (2013)  WAIS-III: Digit Symbol-Coding  Bach (2014)  WMS-IV: Logical Memory I  Bach (2014)  TMT: Part A & B  Vahter et al. (2014)  WMS?: Verbal memory (assume all subtests) Buschke selective verbal memory, controlled long-term retrieval, long-term storage & later recall  Vahter et al. (2014)  TMT: Part A & B  McKeon et al. (2016)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McKeon et al. (2016)  Digit Span Forwards Visual Scanning Time Letter Sequencing Time Number Sequencing Time Motor Speed Time Color Naming Time Word Reading Time PRP Paradigm SART  Urakami (2016)  WMS-R (assume all verbal memory subtests)  Urakami (2016)  WAIS-III: Coding Symbol search  McIvor and Moore (2017)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McIvor and Moore (2017)  None  Cognitive function  Tests used  Cognitive function  Tests used  Visual memory    Executive function    Finke et al. (2012)  ROCFT: Copy, Delayed & Recall  Finke et al. (2012)  BADS Stroop Test Tower of London  Loughan et al. (2016)  RBANS: Figure Copy & Recall  Loughan et al. (2012)  D-KEFS  Martín-Monzón et al. (2012)  ROCFT: Immediate & Delayed recall WAIS-III: Design Immediate recall & Delayed recall   Martín-Monzón et al. (2012)  WAIS-III Matrix Reasoning TMT: Part B Stroop Colors and words Verbal fluency Wisconsin Categories  Marcos-Arribas et al. (2013)  ROCFT: Immediate & Delayed recall  Marcos-Arribas et al. (2013)  None  Finke et al. (2013)  None  Finke et al. (2013)  Stroop test Computerized go = no-go test Semantic fluency  Bach (2014)  None  Bach (2014)  BADS: Rule Shift Action program Key search Temporal Judgment Zoo map Modified six elements  Vahter et al. (2014)  Visual Spatial Memory: Immediate &Delayed recall  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  ROCFT: Immediate, Delayed & Recall  McKeon et al. (2016)  D-KEFS: TMT Tower Test Verbal Fluency Proverbs Test Inhibition Test (Stroop Test) Inhibition/Switching Test Hayling Test  Urakami (2016)  WMS-R: Visual memory (assume all subtests)  Urakami (2016)  None  McIvor and Moore (2017)  WMS-IV: Visual reproduction I & II  McIvor and Moore (2017)  D-KEFS: TMT Verbal Fluency Test  Cognitive function  Tests used  Cognitive function  Tests used  Working memory    Visuospatial ability    Loughan et al. (2016)  WAIS-IV: Digit Span Arithmetic  Loughan et al. (2012)  WAIS-IV: Block design RBANS: Figure Copy   Finke et al. (2012)  WAIS-IV: Digit Span Block Span  Finke et al. (2012)  ROCFT: Copy  Martín-Monzón et al. (2012)  WAIS-III: Digit Symbol Coding Digit Span backwards Letter Number Sequencing Arithmetic  Martín-Monzón et al. (2012)  Benton Visual Form Discrimination Test WAIS-III: Picture Completion  Marcos-Arribas et al. (2013)  WMS-III: Letter-Number Sequencing WAIS-III: Digit span  Marcos-Arribas et al. (2013)  ROCFT: Copy  Finke et al. (2013)  (WAIS?): Digit span backwards  Finke et al. (2013)  ROCFT: Copy  Bach (2014)  WAIS-IV: Digit Span  Bach (2014)  None  Vahter et al. (2014)  None  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  WAIS-IV: Digit Span  McKeon et al. (2016)  ROCFT: Copy  Urakami (2016)  WAIS-III & WMS-R (assume digit span, arithmetic, symbol & spatial span)  Urakami (2016)  WAIS-III (assume block design)  McIvor and Moore (2017)  WMS-IV: VWMI-Spatial Addition & Spatial Span  McIvor and Moore (2017)  None  Social Cognition  Bach (2014)  No tests; A 10 item questionnaire to assess ability to understand other’s mental states and general social cognition    McKeon et al. (2016)  Mind in the Eyes Test Advanced ToM Test Social Situations Test Emotion Attribution Task    Cognitive function  Tests used  Cognitive function  Tests used  Verbal memory    Attention & Processing Speed    Loughan et al. (2016)  RBANS: List learning & Recall Story Memory & Recall  Loughan et al. (2012)  TMT: Part A & B  Finke et al. (2012)  RAVLT  Finke et al. (2012)  TAP  Martín-Monzón et al. (2012)  WMS III: Logical Memory Selective Reminding test  Martín-Monzón et al. (2012)  TMT: Part A WAIS-III: Digit Symbol-Coding   Finke et al. (2013)  RAVLT  Finke et al. (2013)  None named  Marcos-Arribas et al. (2013)  WMS-III: Logical Memory I & II Verbal Paired Associates I & II Word Pairs I & II Letter-Number Sequencing  Marcos-Arribas et al. (2013)  WAIS-III: Digit Symbol-Coding  Bach (2014)  WMS-IV: Logical Memory I  Bach (2014)  TMT: Part A & B  Vahter et al. (2014)  WMS?: Verbal memory (assume all subtests) Buschke selective verbal memory, controlled long-term retrieval, long-term storage & later recall  Vahter et al. (2014)  TMT: Part A & B  McKeon et al. (2016)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McKeon et al. (2016)  Digit Span Forwards Visual Scanning Time Letter Sequencing Time Number Sequencing Time Motor Speed Time Color Naming Time Word Reading Time PRP Paradigm SART  Urakami (2016)  WMS-R (assume all verbal memory subtests)  Urakami (2016)  WAIS-III: Coding Symbol search  McIvor and Moore (2017)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McIvor and Moore (2017)  None  Cognitive function  Tests used  Cognitive function  Tests used  Visual memory    Executive function    Finke et al. (2012)  ROCFT: Copy, Delayed & Recall  Finke et al. (2012)  BADS Stroop Test Tower of London  Loughan et al. (2016)  RBANS: Figure Copy & Recall  Loughan et al. (2012)  D-KEFS  Martín-Monzón et al. (2012)  ROCFT: Immediate & Delayed recall WAIS-III: Design Immediate recall & Delayed recall   Martín-Monzón et al. (2012)  WAIS-III Matrix Reasoning TMT: Part B Stroop Colors and words Verbal fluency Wisconsin Categories  Marcos-Arribas et al. (2013)  ROCFT: Immediate & Delayed recall  Marcos-Arribas et al. (2013)  None  Finke et al. (2013)  None  Finke et al. (2013)  Stroop test Computerized go = no-go test Semantic fluency  Bach (2014)  None  Bach (2014)  BADS: Rule Shift Action program Key search Temporal Judgment Zoo map Modified six elements  Vahter et al. (2014)  Visual Spatial Memory: Immediate &Delayed recall  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  ROCFT: Immediate, Delayed & Recall  McKeon et al. (2016)  D-KEFS: TMT Tower Test Verbal Fluency Proverbs Test Inhibition Test (Stroop Test) Inhibition/Switching Test Hayling Test  Urakami (2016)  WMS-R: Visual memory (assume all subtests)  Urakami (2016)  None  McIvor and Moore (2017)  WMS-IV: Visual reproduction I & II  McIvor and Moore (2017)  D-KEFS: TMT Verbal Fluency Test  Cognitive function  Tests used  Cognitive function  Tests used  Working memory    Visuospatial ability    Loughan et al. (2016)  WAIS-IV: Digit Span Arithmetic  Loughan et al. (2012)  WAIS-IV: Block design RBANS: Figure Copy   Finke et al. (2012)  WAIS-IV: Digit Span Block Span  Finke et al. (2012)  ROCFT: Copy  Martín-Monzón et al. (2012)  WAIS-III: Digit Symbol Coding Digit Span backwards Letter Number Sequencing Arithmetic  Martín-Monzón et al. (2012)  Benton Visual Form Discrimination Test WAIS-III: Picture Completion  Marcos-Arribas et al. (2013)  WMS-III: Letter-Number Sequencing WAIS-III: Digit span  Marcos-Arribas et al. (2013)  ROCFT: Copy  Finke et al. (2013)  (WAIS?): Digit span backwards  Finke et al. (2013)  ROCFT: Copy  Bach (2014)  WAIS-IV: Digit Span  Bach (2014)  None  Vahter et al. (2014)  None  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  WAIS-IV: Digit Span  McKeon et al. (2016)  ROCFT: Copy  Urakami (2016)  WAIS-III & WMS-R (assume digit span, arithmetic, symbol & spatial span)  Urakami (2016)  WAIS-III (assume block design)  McIvor and Moore (2017)  WMS-IV: VWMI-Spatial Addition & Spatial Span  McIvor and Moore (2017)  None  Social Cognition  Bach (2014)  No tests; A 10 item questionnaire to assess ability to understand other’s mental states and general social cognition    McKeon et al. (2016)  Mind in the Eyes Test Advanced ToM Test Social Situations Test Emotion Attribution Task    WMS-R/III/IV = Weschler Memory Scale Revised/Third/Fourth Edition; WAIS III/IV = Weschler Adult Intelligence Scale Third/Fourth Edition; TMT = Trail Making Test; ROCFT = Rey-Osterrieth Complex Figure Test; RAVLT = Rey Auditory Verbal Learning Test; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; DT-VMI = Beery-Buktenica Developmental Test of Visual-Motor Integration; DTVP = Beery-Buktenica Developmental Test of Visual Perception; DKEFS = Delis-Kaplan Executive Function System; TOL = Tower of London test; BADS = Behavioral Assessment of the Dysexecutive Syndrome; TAP = Test battery for the assessment of attention. View Large Table 2. Tests used by each study Cognitive function  Tests used  Cognitive function  Tests used  Verbal memory    Attention & Processing Speed    Loughan et al. (2016)  RBANS: List learning & Recall Story Memory & Recall  Loughan et al. (2012)  TMT: Part A & B  Finke et al. (2012)  RAVLT  Finke et al. (2012)  TAP  Martín-Monzón et al. (2012)  WMS III: Logical Memory Selective Reminding test  Martín-Monzón et al. (2012)  TMT: Part A WAIS-III: Digit Symbol-Coding   Finke et al. (2013)  RAVLT  Finke et al. (2013)  None named  Marcos-Arribas et al. (2013)  WMS-III: Logical Memory I & II Verbal Paired Associates I & II Word Pairs I & II Letter-Number Sequencing  Marcos-Arribas et al. (2013)  WAIS-III: Digit Symbol-Coding  Bach (2014)  WMS-IV: Logical Memory I  Bach (2014)  TMT: Part A & B  Vahter et al. (2014)  WMS?: Verbal memory (assume all subtests) Buschke selective verbal memory, controlled long-term retrieval, long-term storage & later recall  Vahter et al. (2014)  TMT: Part A & B  McKeon et al. (2016)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McKeon et al. (2016)  Digit Span Forwards Visual Scanning Time Letter Sequencing Time Number Sequencing Time Motor Speed Time Color Naming Time Word Reading Time PRP Paradigm SART  Urakami (2016)  WMS-R (assume all verbal memory subtests)  Urakami (2016)  WAIS-III: Coding Symbol search  McIvor and Moore (2017)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McIvor and Moore (2017)  None  Cognitive function  Tests used  Cognitive function  Tests used  Visual memory    Executive function    Finke et al. (2012)  ROCFT: Copy, Delayed & Recall  Finke et al. (2012)  BADS Stroop Test Tower of London  Loughan et al. (2016)  RBANS: Figure Copy & Recall  Loughan et al. (2012)  D-KEFS  Martín-Monzón et al. (2012)  ROCFT: Immediate & Delayed recall WAIS-III: Design Immediate recall & Delayed recall   Martín-Monzón et al. (2012)  WAIS-III Matrix Reasoning TMT: Part B Stroop Colors and words Verbal fluency Wisconsin Categories  Marcos-Arribas et al. (2013)  ROCFT: Immediate & Delayed recall  Marcos-Arribas et al. (2013)  None  Finke et al. (2013)  None  Finke et al. (2013)  Stroop test Computerized go = no-go test Semantic fluency  Bach (2014)  None  Bach (2014)  BADS: Rule Shift Action program Key search Temporal Judgment Zoo map Modified six elements  Vahter et al. (2014)  Visual Spatial Memory: Immediate &Delayed recall  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  ROCFT: Immediate, Delayed & Recall  McKeon et al. (2016)  D-KEFS: TMT Tower Test Verbal Fluency Proverbs Test Inhibition Test (Stroop Test) Inhibition/Switching Test Hayling Test  Urakami (2016)  WMS-R: Visual memory (assume all subtests)  Urakami (2016)  None  McIvor and Moore (2017)  WMS-IV: Visual reproduction I & II  McIvor and Moore (2017)  D-KEFS: TMT Verbal Fluency Test  Cognitive function  Tests used  Cognitive function  Tests used  Working memory    Visuospatial ability    Loughan et al. (2016)  WAIS-IV: Digit Span Arithmetic  Loughan et al. (2012)  WAIS-IV: Block design RBANS: Figure Copy   Finke et al. (2012)  WAIS-IV: Digit Span Block Span  Finke et al. (2012)  ROCFT: Copy  Martín-Monzón et al. (2012)  WAIS-III: Digit Symbol Coding Digit Span backwards Letter Number Sequencing Arithmetic  Martín-Monzón et al. (2012)  Benton Visual Form Discrimination Test WAIS-III: Picture Completion  Marcos-Arribas et al. (2013)  WMS-III: Letter-Number Sequencing WAIS-III: Digit span  Marcos-Arribas et al. (2013)  ROCFT: Copy  Finke et al. (2013)  (WAIS?): Digit span backwards  Finke et al. (2013)  ROCFT: Copy  Bach (2014)  WAIS-IV: Digit Span  Bach (2014)  None  Vahter et al. (2014)  None  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  WAIS-IV: Digit Span  McKeon et al. (2016)  ROCFT: Copy  Urakami (2016)  WAIS-III & WMS-R (assume digit span, arithmetic, symbol & spatial span)  Urakami (2016)  WAIS-III (assume block design)  McIvor and Moore (2017)  WMS-IV: VWMI-Spatial Addition & Spatial Span  McIvor and Moore (2017)  None  Social Cognition  Bach (2014)  No tests; A 10 item questionnaire to assess ability to understand other’s mental states and general social cognition    McKeon et al. (2016)  Mind in the Eyes Test Advanced ToM Test Social Situations Test Emotion Attribution Task    Cognitive function  Tests used  Cognitive function  Tests used  Verbal memory    Attention & Processing Speed    Loughan et al. (2016)  RBANS: List learning & Recall Story Memory & Recall  Loughan et al. (2012)  TMT: Part A & B  Finke et al. (2012)  RAVLT  Finke et al. (2012)  TAP  Martín-Monzón et al. (2012)  WMS III: Logical Memory Selective Reminding test  Martín-Monzón et al. (2012)  TMT: Part A WAIS-III: Digit Symbol-Coding   Finke et al. (2013)  RAVLT  Finke et al. (2013)  None named  Marcos-Arribas et al. (2013)  WMS-III: Logical Memory I & II Verbal Paired Associates I & II Word Pairs I & II Letter-Number Sequencing  Marcos-Arribas et al. (2013)  WAIS-III: Digit Symbol-Coding  Bach (2014)  WMS-IV: Logical Memory I  Bach (2014)  TMT: Part A & B  Vahter et al. (2014)  WMS?: Verbal memory (assume all subtests) Buschke selective verbal memory, controlled long-term retrieval, long-term storage & later recall  Vahter et al. (2014)  TMT: Part A & B  McKeon et al. (2016)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McKeon et al. (2016)  Digit Span Forwards Visual Scanning Time Letter Sequencing Time Number Sequencing Time Motor Speed Time Color Naming Time Word Reading Time PRP Paradigm SART  Urakami (2016)  WMS-R (assume all verbal memory subtests)  Urakami (2016)  WAIS-III: Coding Symbol search  McIvor and Moore (2017)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McIvor and Moore (2017)  None  Cognitive function  Tests used  Cognitive function  Tests used  Visual memory    Executive function    Finke et al. (2012)  ROCFT: Copy, Delayed & Recall  Finke et al. (2012)  BADS Stroop Test Tower of London  Loughan et al. (2016)  RBANS: Figure Copy & Recall  Loughan et al. (2012)  D-KEFS  Martín-Monzón et al. (2012)  ROCFT: Immediate & Delayed recall WAIS-III: Design Immediate recall & Delayed recall   Martín-Monzón et al. (2012)  WAIS-III Matrix Reasoning TMT: Part B Stroop Colors and words Verbal fluency Wisconsin Categories  Marcos-Arribas et al. (2013)  ROCFT: Immediate & Delayed recall  Marcos-Arribas et al. (2013)  None  Finke et al. (2013)  None  Finke et al. (2013)  Stroop test Computerized go = no-go test Semantic fluency  Bach (2014)  None  Bach (2014)  BADS: Rule Shift Action program Key search Temporal Judgment Zoo map Modified six elements  Vahter et al. (2014)  Visual Spatial Memory: Immediate &Delayed recall  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  ROCFT: Immediate, Delayed & Recall  McKeon et al. (2016)  D-KEFS: TMT Tower Test Verbal Fluency Proverbs Test Inhibition Test (Stroop Test) Inhibition/Switching Test Hayling Test  Urakami (2016)  WMS-R: Visual memory (assume all subtests)  Urakami (2016)  None  McIvor and Moore (2017)  WMS-IV: Visual reproduction I & II  McIvor and Moore (2017)  D-KEFS: TMT Verbal Fluency Test  Cognitive function  Tests used  Cognitive function  Tests used  Working memory    Visuospatial ability    Loughan et al. (2016)  WAIS-IV: Digit Span Arithmetic  Loughan et al. (2012)  WAIS-IV: Block design RBANS: Figure Copy   Finke et al. (2012)  WAIS-IV: Digit Span Block Span  Finke et al. (2012)  ROCFT: Copy  Martín-Monzón et al. (2012)  WAIS-III: Digit Symbol Coding Digit Span backwards Letter Number Sequencing Arithmetic  Martín-Monzón et al. (2012)  Benton Visual Form Discrimination Test WAIS-III: Picture Completion  Marcos-Arribas et al. (2013)  WMS-III: Letter-Number Sequencing WAIS-III: Digit span  Marcos-Arribas et al. (2013)  ROCFT: Copy  Finke et al. (2013)  (WAIS?): Digit span backwards  Finke et al. (2013)  ROCFT: Copy  Bach (2014)  WAIS-IV: Digit Span  Bach (2014)  None  Vahter et al. (2014)  None  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  WAIS-IV: Digit Span  McKeon et al. (2016)  ROCFT: Copy  Urakami (2016)  WAIS-III & WMS-R (assume digit span, arithmetic, symbol & spatial span)  Urakami (2016)  WAIS-III (assume block design)  McIvor and Moore (2017)  WMS-IV: VWMI-Spatial Addition & Spatial Span  McIvor and Moore (2017)  None  Social Cognition  Bach (2014)  No tests; A 10 item questionnaire to assess ability to understand other’s mental states and general social cognition    McKeon et al. (2016)  Mind in the Eyes Test Advanced ToM Test Social Situations Test Emotion Attribution Task    WMS-R/III/IV = Weschler Memory Scale Revised/Third/Fourth Edition; WAIS III/IV = Weschler Adult Intelligence Scale Third/Fourth Edition; TMT = Trail Making Test; ROCFT = Rey-Osterrieth Complex Figure Test; RAVLT = Rey Auditory Verbal Learning Test; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; DT-VMI = Beery-Buktenica Developmental Test of Visual-Motor Integration; DTVP = Beery-Buktenica Developmental Test of Visual Perception; DKEFS = Delis-Kaplan Executive Function System; TOL = Tower of London test; BADS = Behavioral Assessment of the Dysexecutive Syndrome; TAP = Test battery for the assessment of attention. View Large Synthesis Results The results of the synthesis are presented below; however, it should be stressed that the results are based on relatively small numbers of cases, particularly in the acute phase. The number of participants who were found to have cognitive difficulties for the cognitive domain are indicated alongside the relevant references (for example, N = 13). Reflected in the quality assessment tool, a common methodological limitation of the case studies and series was inadequate reporting of the procedure of neuropsychological assessment and of participant demographics (Table 3). For example, pre-morbid functioning was not assessed in half of the papers studied and as such any cognitive deficit found cannot be solely attributed to the effects of the illness. Therefore, the results below should be interpreted with caution, with close examination of both the number of participants included within each result summary and the quality assessment scores of the papers included. Furthermore, there was a great deal of disparity with regards to how cognitive functions were classified and described by the articles. This is particularly evident for memory, which was subdivided differently by each of the articles. To present the results for memory, the most referred to memory subdivisions within the articles are summarized in each of the results sections. Table 3. Study quality ratings Study  A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  TOTAL  Finke et al. (2012)  1  2  2  1  1  0  0  0  0  1  0  0  0  1  2  1  1  1  2  0  1  0  1  1  0  0  18 Med  Martín-Monzón et al. (2012)  1  2  0  1  1  1  0  1  0  1  0  1  1  0  0  0  0  2  2  1  0  0  0  1  0  0  16 Med  Finke et al. (2013)  1  2  2  1  0  0  0  0  0  0  1  0  0  0  0  1  1  1  2  0  0  0  1  1  0  0  14 Med  Marcos-Arribas et al. (2013)  1  2  0  1  1  1  1  1  0  1  0  0  1  0  0  0  0  1  1  1  0  0  0  1  0  0  14 Med  Vahter et al. (2014)  1  2  0  1  1  0  0  0  0  1  0  0  0  0  0  0  0  1  2  0  0  0  0  2  0  0  11 Low  Bach (2014)  1  1  1  1  0  0  0  0  0  0  0  0  0  0  2  0  0  0  2  0  1  0  1  1  1  1  13 Med  Loughan et al. (2016)  1  2  0  1  1  1  1  1  0  1  1  1  1  1  3  0  1  1  2  0  1  0  1  1  0  1  24 High  McKeon et al. (2016)  1  2  2  1  1  1  0  0  0  1  0  0  0  1  3  1  1  1  2  0  1  0  0  1  1  0  21 Med  Urakami (2016)  1  2  2  1  1  0  0  0  0  0  0  0  0  0  0  1  0  0  2  1  1  0  0  1  0  1  14 Med  McIvor and Moore (2017)  1  2  0  1  1  1  1  0  0  1  0  0  0  1  0  0  1  0  2  2  1  0  1  1  0  0  19 Med  Study  A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  TOTAL  Finke et al. (2012)  1  2  2  1  1  0  0  0  0  1  0  0  0  1  2  1  1  1  2  0  1  0  1  1  0  0  18 Med  Martín-Monzón et al. (2012)  1  2  0  1  1  1  0  1  0  1  0  1  1  0  0  0  0  2  2  1  0  0  0  1  0  0  16 Med  Finke et al. (2013)  1  2  2  1  0  0  0  0  0  0  1  0  0  0  0  1  1  1  2  0  0  0  1  1  0  0  14 Med  Marcos-Arribas et al. (2013)  1  2  0  1  1  1  1  1  0  1  0  0  1  0  0  0  0  1  1  1  0  0  0  1  0  0  14 Med  Vahter et al. (2014)  1  2  0  1  1  0  0  0  0  1  0  0  0  0  0  0  0  1  2  0  0  0  0  2  0  0  11 Low  Bach (2014)  1  1  1  1  0  0  0  0  0  0  0  0  0  0  2  0  0  0  2  0  1  0  1  1  1  1  13 Med  Loughan et al. (2016)  1  2  0  1  1  1  1  1  0  1  1  1  1  1  3  0  1  1  2  0  1  0  1  1  0  1  24 High  McKeon et al. (2016)  1  2  2  1  1  1  0  0  0  1  0  0  0  1  3  1  1  1  2  0  1  0  0  1  1  0  21 Med  Urakami (2016)  1  2  2  1  1  0  0  0  0  0  0  0  0  0  0  1  0  0  2  1  1  0  0  1  0  1  14 Med  McIvor and Moore (2017)  1  2  0  1  1  1  1  0  0  1  0  0  0  1  0  0  1  0  2  2  1  0  1  1  0  0  19 Med  View Large Table 3. Study quality ratings Study  A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  TOTAL  Finke et al. (2012)  1  2  2  1  1  0  0  0  0  1  0  0  0  1  2  1  1  1  2  0  1  0  1  1  0  0  18 Med  Martín-Monzón et al. (2012)  1  2  0  1  1  1  0  1  0  1  0  1  1  0  0  0  0  2  2  1  0  0  0  1  0  0  16 Med  Finke et al. (2013)  1  2  2  1  0  0  0  0  0  0  1  0  0  0  0  1  1  1  2  0  0  0  1  1  0  0  14 Med  Marcos-Arribas et al. (2013)  1  2  0  1  1  1  1  1  0  1  0  0  1  0  0  0  0  1  1  1  0  0  0  1  0  0  14 Med  Vahter et al. (2014)  1  2  0  1  1  0  0  0  0  1  0  0  0  0  0  0  0  1  2  0  0  0  0  2  0  0  11 Low  Bach (2014)  1  1  1  1  0  0  0  0  0  0  0  0  0  0  2  0  0  0  2  0  1  0  1  1  1  1  13 Med  Loughan et al. (2016)  1  2  0  1  1  1  1  1  0  1  1  1  1  1  3  0  1  1  2  0  1  0  1  1  0  1  24 High  McKeon et al. (2016)  1  2  2  1  1  1  0  0  0  1  0  0  0  1  3  1  1  1  2  0  1  0  0  1  1  0  21 Med  Urakami (2016)  1  2  2  1  1  0  0  0  0  0  0  0  0  0  0  1  0  0  2  1  1  0  0  1  0  1  14 Med  McIvor and Moore (2017)  1  2  0  1  1  1  1  0  0  1  0  0  0  1  0  0  1  0  2  2  1  0  1  1  0  0  19 Med  Study  A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  TOTAL  Finke et al. (2012)  1  2  2  1  1  0  0  0  0  1  0  0  0  1  2  1  1  1  2  0  1  0  1  1  0  0  18 Med  Martín-Monzón et al. (2012)  1  2  0  1  1  1  0  1  0  1  0  1  1  0  0  0  0  2  2  1  0  0  0  1  0  0  16 Med  Finke et al. (2013)  1  2  2  1  0  0  0  0  0  0  1  0  0  0  0  1  1  1  2  0  0  0  1  1  0  0  14 Med  Marcos-Arribas et al. (2013)  1  2  0  1  1  1  1  1  0  1  0  0  1  0  0  0  0  1  1  1  0  0  0  1  0  0  14 Med  Vahter et al. (2014)  1  2  0  1  1  0  0  0  0  1  0  0  0  0  0  0  0  1  2  0  0  0  0  2  0  0  11 Low  Bach (2014)  1  1  1  1  0  0  0  0  0  0  0  0  0  0  2  0  0  0  2  0  1  0  1  1  1  1  13 Med  Loughan et al. (2016)  1  2  0  1  1  1  1  1  0  1  1  1  1  1  3  0  1  1  2  0  1  0  1  1  0  1  24 High  McKeon et al. (2016)  1  2  2  1  1  1  0  0  0  1  0  0  0  1  3  1  1  1  2  0  1  0  0  1  1  0  21 Med  Urakami (2016)  1  2  2  1  1  0  0  0  0  0  0  0  0  0  0  1  0  0  2  1  1  0  0  1  0  1  14 Med  McIvor and Moore (2017)  1  2  0  1  1  1  1  0  0  1  0  0  0  1  0  0  1  0  2  2  1  0  1  1  0  0  19 Med  View Large Acute Cognitive Effects (≤12 months) Description of Articles Seven of the 10 articles included in this review assessed participants within the first 12 months from either diagnosis, symptom onset or at the start of rehabilitation, and are discussed below (Bach, 2014; Loughan et al., 2016; Martín-Monzón, Trujillo-Pozo, & Romeron, 2012; Marcos-Arribas, Almonacid, & Dolado, 2013; McIvor & Moore, 2017; Urakami, 2016; Vahter et al., 2014). A total of 13 participants were assessed across the seven articles. The mean age of the participants was 28.7 (range: 19–47 years), with a higher ratio of female participants (10F: 3M). All but one article (Loughan et al., 2016) conducted case series where participants were assessed at two or more time points within the first 12 months. The case series or studies were judged as “Medium” quality, except Vahter and colleagues (2014), which was of “Low” quality and Loughan and colleagues (2016) which was “High” quality, both largely due to the level of detail provided in the participant background section of the quality measure. Memory Memory was tested in all seven of the articles (Number of participants [N] = 13) with each study reporting some form of memory difficulty. Working/Short-term Memory Working/short-term memory difficulties were specifically noted in three articles (Bach, 2014; McIvor & Moore, 2017; Urakami, 2016; N = 9), with McIvor and Moore (2017) and Urakami (2016) reporting working memory deficits persisting at 12 months following treatment and treatment with rehabilitation respectively. Episodic Recall Immediate recall difficulties were reported in four of the studies (Marcos-Arribas et al., 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; Vahter et al., 2014; N = 4) and delayed recall difficulties were reported in six articles (Bach, 2014; Loughan et al., 2016; Marcos-Arribas et al., 2013; Martín-Monzón et al., 2012; McIvor &, Moore, 2017; Vahter et al., 2014; N = 7). Visual memory difficulties were cited in four of the articles (Marcos-Arribas et al., 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; Urakami, 2016; N = 9) and verbal memory difficulties reported in all seven articles (Bach, 2014; Loughan et al., 2016; Marcos-Arribas et al., 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; Urakami, 2016; Vahter et al., 2014; N = 13). McIvor and Moore (2017) reported deterioration in immediate recall, with their untreated participant’s immediate memory score at 6 months dropping from the average to the low average range at 12 months. Within this, immediate verbal memory was within the low average range and significantly lower than predicted, however, immediate visual memory remained within the average range. The participant’s overall delayed recall index score was not significantly improved at 12 months. Delayed visual memory in particular had not significantly improved from 6 to 12 months. Marcos-Arribas et al. (2013) reported significant immediate and delayed verbal and visual recall difficulties in the first few days of the participant presenting in hospital. However, investigation of the raw scores suggests that at four weeks all recall difficulties were resolved, although statistical significance was not reported. Vahter and colleagues (2014) found severe impairments in immediate verbal recall at Day 8 of the onset of the illness, but at 8 months and 12 months these had returned to “normal”. Delayed verbal memory showed improvement in one subtest (Logical Memory II), however, other delayed verbal memory tests (Buschke) indicated moderate to severe difficulties, with Vahter and colleagues (2014) concluding that (delayed) verbal memory was the most impaired function at 8 and 12 months. The participant’s immediate and delayed visuospatial memory remained “normal” throughout testing. Martín-Monzón and colleagues (2012) participant had immediate recall difficulties at 6 months that were largely consistent at 12 months. Immediate visual recall showed no improvement by 12 months, with the participant scoring zero both times. Verbal recall deteriorated at 12 months, however it was unclear whether this was for immediate recall only or an average of both immediate and delayed recall, as only one score is reported. Loughan and colleagues (2016) reported “lowered delayed” verbal and visual recall scores in their participant when tested at 6 months. One of Bach’s (2014) participants displayed difficulties in delayed verbal memory 6 months after symptom onset, however, no serial assessments were carried out. Urakami (2016) found that group level verbal and visual memory difficulties found at 6 months had shown significant improvement after 12 months of treatment and rehabilitation, and had improved in relation to participants with herpes simplex encephalitis. Executive Functioning Deficits in executive functioning were reported in four of the seven articles (Bach, 2014; Loughan et al., 2016; Martín-Monzón et al., 2012; Vahter et al., 2014; N = 5). Bach (2014), Loughan and colleagues (2016) and Martín-Monzón and colleagues (2012) reported deficits in executive functions, such as planning, organization, reasoning, problem solving, set shifting and maintenance and category fluency at 6 months, with some difficulties remaining in Martín-Monzón and colleagues (2012) participant at 12 months. However, no statistical analyses were performed on the latter. Bach (2014) reported that one participant’s executive difficulties were sufficiently pronounced to have an impact on her reintegration into education and on her future career. However, whilst Vahter and colleagues (2014) reported deficits in some tests of executive functioning at day eight, ranging from severe to mild, these appeared to return to the “normal” range by 8 months after onset. McIvor and Moore (2017) reported that their untreated participant had some difficulty when switching was introduced to the Trail Making Test, however overall they found his performance remained largely static and was not strongly suggestive of underlying executive dysfunction. Marcos-Arribas et al. (2012) also tested for executive function but reported normal scores in these tasks. Attention and Processing Speed Six of the seven articles reported difficulties with attention and processing speed (Martín-Monzón et al., 2012; Marcos-Arribas et al., 2013; Bach, 2014; Loughan et al., 2016; Urakami, 2016; Vahter et al., 2014; N = 12), however, the majority reported mild to moderate levels of dysfunction that resolved at or before 12 months, across a range of attentional processes: selective and prolonged (Martín-Monzón et al., 2012); sustained (Loughan et al., 2016); and information processing tasks (Loughan et al., 2016; Vahter et al., 2014; Marcos-Arribas et al., 2013; Urakami, 2016). McIvor and Moore (2017) did not report any specific attentional difficulties in their patient and Urakami (2016) concluded participants with anti-NMDAR also showed significant improvement in attentional function within 12 months, in comparison to patients with herpes simplex encephalitis. Language Three articles found evidence of expressive and receptive language impairment (Bach, 2014; Loughan et al., 2016; Vahter et al., 2014; N = 4). However, language impairment was often not formally tested and had improved in all three cases after 3–6 months of treatment. Vahter and colleagues (2014) reported that 1 month after the disease onset, their participant developed progressive sensorimotor aphasia. However, 3 months after the first symptoms the aphasia had reportedly subsided. Bach (2014) qualitatively reported their participant had limited comprehension and no verbal words in the acute stage of illness. However, this improved throughout rehabilitation with only subtle deficits in language remaining. Loughan and colleagues (2016) reported language impairment in the acute phase, for which their participant received speech therapy. By the time of neuropsychological assessment 6 months post-diagnosis, his language appeared to have improved, with intact receptive language, and only mild word finding difficulties persisting. Visuospatial Abilities Only one article reported impairment in visuospatial ability specifically (Martín-Monzón et al., 2012; N = 1). Martín-Monzón and colleagues (2012) reported that their patient had difficulty, at both 6 and 12 months testing, with specific visuospatial skills such as cube analysis, position discrimination and number location. However, elementary visual perception (e.g. shape detection) and more elaborate functions (recognition of degraded stimuli, object identification) were undisturbed. Social Cognition Social cognition was only investigated in one of the eight articles (Bach, 2014; N = 2). The author used a 10-item questionnaire to assess patients’ ability to understand other people’s mental states and general cognition. Both individual participant and informant versions were given to two of the three cases studied in this article. Bach (2014) reported that one participant’s score indicated she had newly acquired difficulties in empathizing, tactfulness and ability to sympathize, together with reduced insight into these difficulties. Another patient reported new difficulties recognizing that she said things that upset others, understanding jokes, showing sympathy and being tactful. Informant scores corroborated this, however, no formal social cognitive tasks were administered. Chronic Cognitive Effects (>12 Months) Description of Cases Six out of the 10 articles presented in this review assessed patients a minimum of 1 year since disease onset/diagnosis (range 1–6.5 years; Finke et al., 2012; Finke et al., 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; McKeon et al., 2016; Vahter et al., 2014). A total of 43 participants were studied across the six articles, mean age 27.6 (the approximate range was 16–44, however, two papers only reported the mean). Again, there were more female participants than male (37F:6M). All the papers were “Medium” quality, except Vahter and colleagues (2014), which was scored as a “Low” quality paper. Memory Memory difficulties persisting after the acute 12-month period were reported in all six articles (N = 43). Working/Short-term Memory Working and short-term memory difficulties were cited in five of the studies (Finke et al., 2012, 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; McKeon et al., 2016; N = 42). Finke and colleagues (2012), in their study of nine participants tested at a median of 43 months (range 23–69 months) after disease onset, found significant impairments in working memory in four of the participants, in the routine neuropsychological assessment of working memory. The authors also administered an additional battery of short-term memory (STM) tasks (delayed match-to-sample tasks), which they claim have been previously validated in patients with hippocampal damage (Braun et al., 2008; Finke et al., 2008). Participants were required to remember the color, location or the association of color and location of visual stimuli across delays of 900 or 5,000 ms. They found that five participants had delay-dependent deficits in some aspect of this battery. However, they reported that three of these participants performed normally in the routine neuropsychological assessment of STM memory. Finke and colleagues (2013) also reported that their participants (N = 24) showed substantial deficits in working memory at a median of 35 months after disease onset. Furthermore, McKeon and colleagues (2016) found the scores of their anti-NMDAR participant group fell significantly below (medium to large effect sizes) the control group in working memory. Martín-Monzón and colleagues (2012) report improvements in memory tasks at the 72-month follow-up. However, examination of the participant’s raw scores suggests some residual impairment in working memory (on subtests of the WAIS-III). McIvor and Moore (2017) found their untreated participant’s visual working memory remained largely unchanged from 6 to 30 months, staying in the low average range. However, his visual working memory score was largely impacted by his spatial addition score, which was significantly lower than predicted. Episodic Recall Immediate recall difficulties were found in four of the six articles (Finke et al., 2012, 2013; Martín-Monzón et al., 2012; McKeon et al., 2016,N = 41) and delayed recall difficulties in five articles (Finke et al., 2012, 2013; Martín-Monzón et al., 2012; McKeon et al., 2016; Vahter et al., 2014; N = 42). Verbal memory difficulties were also reported in five of the articles (Finke et al., 2012, 2013; McIvor & Moore, 2017; McKeon et al., 2016; Vahter et al., 2014; N = 42) and visual memory difficulties reported in two articles (Finke et al., 2012; Martín-Monzón et al., 2012; N = 10). McKeon and colleagues (2016) found that the scores of the anti-NMDAR participant group fell significantly below the control group in tests of verbal immediate and delayed recall, but not immediate or delayed visual recall. Similarly, Finke and colleagues (2013) also observed significant impairments in immediate and delayed verbal recall, but not visual, across 24 participants. Finke and colleagues (2012) reported significantly impaired immediate and delayed verbal recall in two of their nine participants and significantly impaired immediate and delayed visual recall in one participant. Vahter and colleagues (2014) found that 20 months after disease onset there remained a mild deficit in verbal delayed memory. They concluded that the most impaired function at long-term follow-up was delayed verbal memory, however, significance levels were not reported. McIvor and Moore (2017) reported that their untreated participant’s verbal memory index at 30 months was comparable to his score at 12 months and so was not deemed to be a statistically significant change. However, his immediate and delayed verbal memory scores were in the average range. Martín-Monzón and colleagues (2012) single case study showed persistent immediate and delayed visual recall difficulties 6 years after disease onset, whilst verbal memory showed improvement. However, it is unclear whether the scores reflected clinically significant change. Furthermore, again, verbal memory was not divided into immediate and delayed recall so it is unknown if one was preferentially improved. Finke and colleagues (2012) found that in their specific STM battery, five participants had deficits in either STM of locations and/or color–location associations, suggesting difficulties with immediate visual memory. Executive Functioning Executive functioning difficulties were reported in five of the six articles (Finke et al., 2012; 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; McKeon et al., 2016; N = 42), with difficulties such as reasoning, rule finding, set shifting and set maintenance, category fluency visuospatial planning/organization, and problem solving. Finke and colleagues (2012) found persistent impairments in executive functioning in five of nine patients. Finke and colleagues (2013) reported substantial group deficits in executive functions (N = 24), although this appeared to be based only on performance in the STROOP test. Nonetheless, of the 24 participants, five did subjectively report executive functioning difficulties. McKeon and colleagues (2016) found the anti-NMDAR patients’ group performance was significantly below matched controls for some aspects of executive functioning (visuospatial planning/organization and problem solving) but not others (abstraction, response inhibition, flexibility, and verbal fluency). They reported that aspects of executive functioning were amongst the most severely affected abilities at the individual level, but profiles ranged from “normal” to “extensive dysfunction”. Martín-Monzón and colleagues (2012) participant showed some improvement in certain tests of executive functioning at 72 months post-initial onset, however, it is unclear whether these scores fell within “normal” ranges. Vahter and colleagues (2014) found their participant’s test scores in executive functioning remained in the normal range at 20 months. McIvor and Moore (2017) found some increased variability in individual task performance for executive functioning at 30 months, compared to 6 months. However, as before, they concluded his results were not strongly suggestive of underlying executive dysfunction. Attention and Processing Speed Attention and processing speed difficulties were reported in two of the articles (Finke et al., 2012; McKeon et al., 2016; N = 16). Finke and colleagues (2012) observed impairments in attention in four of their nine participants, with one of these four patients also subjectively reporting attention difficulties. McKeon and colleagues (2016) found medium to large effect size differences between the anti-NMDAR participants and the control group for both sustained and divided attention and information processing speed. Seven out of 24 patients in the study by Finke and colleagues (2013) subjectively reported difficulties with attention. However, the authors reported neuropsychological tests showed intact attention. Language Language was investigated in three of the six articles for long-term follow up (Finke et al., 2013; Martín-Monzón et al., 2012; McKeon et al., 2016; N = 32) but no deficits were found. McKeon and colleagues (2016) reported that expressive language (Vocabulary, Graded Naming Test, spontaneous speech) was comparable between the anti-NMDAR group and matched controls. Finke and colleagues (2013) and Martin et al. (2012) both reported that testing revealed language was intact in their patients. Visuospatial Abilities Visuospatial difficulties were reported in one of the six articles (McKeon et al., 2016; N = 7) and tested in an additional three articles but no impairments were found (Finke et al., 2013; Martín-Monzón et al., 2012; Vahter et al., 2014; N = 32). McKeon and colleagues (2016) tested for visuospatial organization via the Rey figure copy and found a significant difference between the anti-NMDAR participants and matched controls. Social Cognition Only one article tested for social cognition (McKeon et al., 2016; N = 7), with this being the main aim of the study. McKeon and colleagues (2016) administered the Mind in the Eyes Test, Advanced Test of Malingering (ToM), the Social Situations Test and the Emotion Attribution Task to seven patients with anti-NMDAR and compared their scores to matched controls. They found significant differences between the groups on using mental-state information to make sense of social situations and judge the severity of interpersonal violations. Subjectively four out of the seven participants reported social withdrawal and one participant specifically reported occasional misinterpretation of social situations. McKeon and colleagues (2016) report that subjective social dysfunction experienced by participants can correspond to deficits in social cognition tasks and that anti-NMDAR may adversely affect the ability to decode and adaptively use mental-state information. However, the authors recognized their small sample size and that they ran many statistical comparisons. Therefore, they suggest the results should be interpreted cautiously. Discussion Acute Cognitive Effects (≤12 Months) Memory was the cognitive domain most tested, with all seven articles citing significant difficulties with some aspect of memory in their participants. Delayed verbal memory was the most commonly reported memory difficulty in all seven articles. Immediate and visual memory were the next most cited difficulties in four articles. Working/short-term memory difficulties were only reported in three of the articles. Attentional and processing speed difficulties were highly reported, in six of the seven articles, however these difficulties appeared to largely resolve across the first 12 months since disease onset/diagnosis. Four of the seven articles cited some form of executive dysfunction, such as difficulties problem solving, rule finding and set shifting. Language impairments were found in three articles, with word finding and verbal fluency being the most frequently evidenced deficits. Visuospatial difficulties were found in only two of the studies. Social cognition was the least explored cognitive domain with only one of the articles examining social cognition. However, formal neuropsychological testing was not used. Chronic Cognitive Effects (>12 Months) Memory was, again, one of the cognitive domains most affected in the chronic phase. Persistent memory difficulties of some form were reported in all six articles. Delayed verbal memory was also the most commonly discussed deficit in the chronic phase, reported in five articles. Working/short-term memory difficulties were the second most commonly reported difficulty, present in five of the articles. Immediate recall difficulties were reported in four of the articles and visual memory difficulties in only two articles. Executive dysfunction was a frequently reported deficit in the chronic phase, reported in five of the six articles. However, again, these differed greatly between participants, both within studies and between studies, with difficulties from problem solving to response inhibition and varying from mild to severe. Attention/processing speed difficulties were reported in only two of the articles. Visuospatial difficulties were only reported in one article and language difficulties were not found in any of the current articles. Social cognition was again the least explored cognitive domain, with only one article assessing social cognition and finding impairment. However, they did use formal neuropsychological testing, albeit on a small case sample. Summary of Findings Memory was the cognitive domain most affected by anti-NMDAR in these studies, with all articles citing some form of memory difficulty. Deficit in memory is consistent with knowledge that NMDA receptors are highly concentrated in the limbic system, particularly the hippocampus, and are essential to aspects of learning and memory (Kruse et al., 2014; Lo et al., 2010). Although NMDARs are thought to reactivate after immunological recovery has taken place, it is thought not possible for the grey and white matter to be increased (Martín-Monzón et al., 2012). This was reported by Finke and colleagues (2016), who found evidence for long-standing reduced microstructural integrity of both hippocampi, relative to controls. They reported that disease severity and duration predicted the extent of hippocampal damage, which then correlated with memory performance. They also found volumes of the left hippocampal formation correlated with verbal memory performance, which is in line with the theorized specificity of the left hippocampus for verbal stimuli and consistent with the findings of delayed verbal memory difficulties in all the current 10 articles. Executive functioning difficulties were reported in eight of the 10 articles overall. However, results for the executive functioning tasks were variable, with deficits found across a variety of different tests, and participants’ scores ranging from normal to severe. This is perhaps not surprising given that “executive function” is an umbrella term that overarches a wide range of quite divergent skills and functions (Elliott, 2003). Nonetheless, these findings may be accounted for by Finke and colleagues (2013) who found reduced functional connectivity between the hippocampus bilaterally and the aDMN. The DMN includes the medial prefrontal cortex, which is associated with executive functions and working memory (Finke et al., 2013). The findings of this adult population appear to be slightly varied from pediatric and adolescent cases, which seem diverse within themselves. Iadisernia and colleagues (2012) found deficits in attention, executive functioning, verbal fluency, and rapid naming in two pediatric patients. Poloni et al. (2010) also reported attention difficulties, together with deficits in working memory in one pediatric patient. Gitiaux and colleagues (2013) reported that three of the six children tested at follow up (median duration of 12 months; range 10 months to 5 years) received special education due to persistent semantic memory deficit (word retrieval difficulties) and visual episodic and working memory impairment. Matricardi and colleagues (2016) found over half of their pediatric patients (total of 11) had residual deficits indicating frontal lobe dysfunction after, at least, a 1 year follow-up. Overall, investigation of neuropsychological sequelae in pediatric cases is extremely limited, indicating a need for more larger scale studies. Limitations This systematic review provides a summary of cognitive difficulties commonly reported in 10 neuropsychological case studies/series. However, the results should be interpreted with caution given the large number of extraneous variables present. The articles differed greatly, with disparities in for example, whether participants received neurorehabilitation and which tests were used (Table 2). This necessitated a narrative review because data synthesis was precluded, meaning more tentative conclusions were drawn regarding a cognitive profile for this population. It is recognized that the “chronic” phase is a large timeframe (up to 6.5 years), however, the given the infancy of the current literature base, there was an insufficient number of case studies to further subdivide this time period. Future systematic reviews could attend to this, particularly given the potential for improved cognitive functioning over time. Furthermore, the severity of the illness, for example whether there was intensive care treatment, is not indexed or reported consistently, nor are details of the treatments and when they were commenced and completed. Impact of the treatments, such as corticosteroids and Rituximab should also be taken into consideration as these can cause side effects such as fatigue, flu-like symptoms and pain (Cancer Research UK, 2015; Ikeguchi et al., 2012), all of which could negatively impact participant’s test scores (Lezak, 2012, p. 125). Of particular note is the protracted use of corticosteroids, which have been implicated in cognitive difficulties referred to as a “steroid dementia” (Brown, 2009; Keenan et al., 1996; Sacks & Shulman, 2005; Wolkowitz, Lupien, & Bigler, 2007; Wolkowitz, Lupien, Bigler, Levin, & Canick, 2004). There remains a scarcity of research in this area, particularly high quality research. Most studies in this review were of “Medium” quality. Reporting of the cases was not strong, with a significant lack of reporting of important neuropsychological variables such as, pre-morbid intellectual functioning, psychiatric history and any existing acquired brain injury (ABI; Hebben & Milberg, 2009). For example, pre-morbid functioning was not estimated in half of the papers studied and even when it was assessed it was often not appropriately compared to the IQ score at the time of testing. This is despite analysis of the raw scores indicating there was not a statistical difference between the two (Finke et al., 2012, 2013; McKeon et al., 2016). Without sufficient background information, it cannot be confirmed whether any cognitive difficulties found represent the direct impact of anti-NMDAR on cognitive functioning. Furthermore, often participants acted as their own control, with repeated testing, but sufficient discussion was not given to a host of other possible extraneous variables. For example, whether there were practice effects, how the participant presented on that day, whether the same test conditions were in place, and whether the same person administered the battery each time. If test scores did differ across administrations, it would be difficult to attribute this entirely to a change in cognitive functioning. The reporting of the scores was typically weak, often with a mixture of raw scores and index scores within the same articles’ results section, and little discussion of whether a change in scores across administrations reflected clinically significant change (for example, Martín-Monzón et al., 2012). Half of the studies were single case studies or series and so only offer limited insight into how cognitive difficulties may present in people with anti-NMDAR. The chronic cognitive deficits discussed in this study have increased generalizability due to the larger case studies included (Finke et al., 2012, 2013; McKeon et al., 2016; N = 40) and so provide greater evidence of the chronic cognitive effects of anti-NMDAR. This is promising given that chronic effects of anti-NMDAR are arguably more pertinent to investigate due to their potential impact on important aspects of day-to-day functioning, such as return to work. However, the data are insufficient to allow interpretation for predicting cognitive function at specific time points within the “chronic phase”. Despite the potential for cognitive functioning to impact day-to-day functioning, this remained largely unexamined in the current papers. Furthermore, the meaning the individuals then ascribed to their level of participation, and overall quality of life (QoL), remained equally unexamined. The latter is important to assess given the mixed findings in other neurological conditions of the impact of cognitive functioning on QoL (Baumstarck-Barrau et al., 2011; Benedict et al., 2005; Dijkers, 2004; Glanz et al., 2010; Goretti et al., 2010; Ponsford, Draper, & Schönberger, 2008; Siponkoski, Wilson, Steinbüchel, Sarajuuri & Koskinen, 2013; Tate, Broe, Cameron, Hodgkinson, & Soo, 2005). In a study of 109 encephalitis survivors Ramanuj and colleagues (2014) found that a poor Glasgow Outcome Score was the most strongly associated with a poor Health Related QoL (HRQoL). Further, that less than half of participants who made a “good” recovery reported a HRQoL equivalent to the general population (Ramanuj et al., 2014). This suggests that the impact of encephalitis had adverse effects on many survivors’ QoL. However, these participants did not undergo neuropsychological testing, so the direct impact of cognitive functioning on QoL cannot be discussed. In the current reviewed articles, subjective complaints were only stated in five of the 10 papers, and were usually reported in table form or only briefly in the main body. Furthermore, only Bach (2014) administered a formal measure, finding significant increases in satisfaction at follow-up on the QOLIBRI-OS (von Steinbuechel et al., 2012). Psychological wellbeing was also only explored in four of the 10 articles. This is significant given that if individuals perceive themselves to have cognitive difficulties, and feel they impact on their participation in their usual day-to-day life, this would likely cause anxiety and interact with the person’s ability to engage meaningfully in neuropsychological assessment. Researchers who did assess psychological wellbeing largely administered either the Hospital Anxiety and Depression Scale (Snaith, 2003) or the Beck Anxiety and Depression Inventories (Beck and Steer, 1990; Beck, Steer & Brown, 1996). Only two articles (Bach, 2014; McKeon et al., 2016) discussed the impact of mood on functioning and QoL, either in the results section or discussion. Specific psychosocial difficulties such as the individual’s reconstruction of their identity (Charmaz, 1983) were also not explored in these articles or any other articles on anti-NMDAR encephalitis to date. A specific battery of cognitive assessments has not yet been devised to screen for cognitive deficits in anti-NMDAR. As discussed, whilst there were overlaps between tests used across the studies, there was disparity between the cognitive domains tested and which tests were used to examine performance in these domains (Table 2). Instead a “scattergun” approach appears to have been used, often with an extensive neuropsychological battery administered to see if any impairments can be detected. However, this approach can lead to Type I errors (Schatz, Jay, McComb, & McLaughlin, 2005). An exception to this was Finke and colleagues (2012) who reported that they conducted a neuropsychological assessment using memory tasks they claimed had previously been shown sensitive to hippocampal dysfunction. Ecological validity of the neuropsychological assessments used was also not discussed, which is important given most tests used were not specifically designed to predict real-life functioning, such as the ability to live independently or return to work (Chaytor and Schmitter-Edgecombe, 2003; Sbordone, 2001). In these tests, the real-world context is removed and can be completed with few distractions, giving an artificial performance. As such the verisimilitude and veridicality approaches should be considered in future research (Spooner & Pachana, 2006). Selection bias was evident across articles as participants typically recruited to the studies were opportunistically sampled from referrals to neurology or neuropsychology departments. Participants may have been chosen if their presentation was particularly unique (Barić, Andrijašević, & Beydoun, 2013; Rison, 2013; Rison, Shepphird & Beydoun, 2016; Wong, 2008), which may skew the cognitive profile detected for this population. Finally, given that there were few pediatric case studies available and given the potential differences between child/adolescent and adult neurobiology, case studies with individuals under the age of 18 were not included, which could be seen to limit this review. Suggestions for Theory and Further Research There is an overall lack of research into the neuropsychological sequelae of anti-NMDAR encephalitis and larger case studies are warranted to develop a more robust cognitive profile for this population. Chronic cognitive deficits have been found in seven articles, with two studies reporting difficulties up to six years after onset (Finke et al., 2013; Martín-Monzón et al., 2012). Therefore, longitudinal neuropsychological testing would be recommended. Further studies are needed to examine the cognitive effects of anti-NMDAR in children/adolescents and to allow future systematic reviews to establish a cognitive profile for this population or across the lifespan. Professional consensus on a neuropsychological battery, grounded in neuropsychological theory, is needed to reduce the number of extraneous variables and provide replicability and generalizability. In their case series of three adolescents, Hinkle and colleagues (2017) concluded with the recommendation that batteries that formally assess memory, executive functioning, as well as language and attention, may be the most sensitive in identifying the common cognitive sequelae in anti-NMDAR. However, further professional opinion is needed regarding an appropriate battery. Larger scale research projects would also help reduce selection bias and extraneous variables and would enable a more scientific approach to developing a cognitive profile for this population, rather than opportunistic sampling. Furthermore, careful consideration should be given to the utility and ethics of performing neuropsychological tests in clinical settings and how these results are fed back to patients (BPS, 2009; Monden, Gentry, & Cox, 2016). A small number of studies (N = 5) have begun investigating the benefits of neurorehabilitation, however, further larger scale studies are needed for the anti-NMDAR group. Gracey, Evans, and Malley (2009) propose a Y-shaped model for rehabilitation in ABI, which identifies key discrepancies, such as between pre-injury and current self, and suggests how these could be targeted in rehabilitation. A model such as the Y-Shaped could be a useful tool for application with people with an ABI as a result of anti-NMDAR. Anti-NMDAR is a relatively newly categorized illness (Dalmau et al., 2007) and as such so far there has been a focus on the medical understanding of the illness, with increasing drive towards neuropsychological understanding. However, taking into consideration the biopsychosocial approach, there is a need for understanding the psychological and social factors associated with the illness, as well as the biomedical, and the interactions between all three (Gracey et al., 2009). Understanding the impact of this illness on QoL is crucial if health care professionals aim to provide person-centered care and improve the wellbeing of people diagnosed with anti-NMDAR. Future research needs to be focussed on the personal meaning of the illness to the individual (Gracey et al., 2009). Conclusions A systematic review of the current literature suggests that the neuropsychological sequelae for anti-NMDAR encephalitis can include memory impairments, particularly delayed verbal memory; executive dysfunction and attentional/processing speed difficulties in the acute phase. However, further high quality studies are needed in this area to form a more substantial cognitive profile for this population. Psychological studies into this client group are so far absent and as such studies investigating individual experience of the illness and its impact on quality of life should be undertaken in the first instance. Supplementary Material Supplementary material is available at Archives of Clinical Neuropsychology online. Conflict of Interest None declared. Acknowledgements With special thanks to Dr Jessica Quirke, Consultant Clinical Neuropsychologist, for providing valuable feedback and advice. References Bach, L. J. ( 2014). Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis: case reports. NeuroRehabilitation , 35, 863– 875. Barić, H., Andrijašević, L., & Beydoun, S. R. ( 2013). Why should medical editors CARE about case reports? Croatian Medical Journal , 54, 507– 509. http://doi.org/10.3325/cmj.2013.54.507. Google Scholar CrossRef Search ADS   Barry, H., Byrne, S., Barrett, E., Murphy, K. C., & Cotter, D. R. ( 2015). 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A Systematic Review of the Neuropsychological Sequelae of People Diagnosed with Anti N-Methyl-D-Aspartate Receptor Encephalitis in the Acute and Chronic Phases

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© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Abstract

Abstract Objective A systematic review was conducted to investigate the emerging cognitive profile for people diagnosed with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. Method Ten papers met the review criteria including five neuropsychological case studies and five case series; three of the 10 studies used matched controls. The cognitive functioning of 54 participants (46 female: eight male) was studied. Paper quality assessment was undertaken and outcomes summarized. Neuropsychological results during the acute phase (≤12 months) and chronic phase (>12 months) were extracted and a narrative review of the papers’ findings undertaken. Results A range of neuropsychological test batteries were used across the studies, administered between one and four times. The review revealed difficulties with memory, particularly delayed verbal memory, and executive functioning. This may be consistent with the role of NMDA receptors in the limbic system, specifically the hippocampus, which are thought to be essential to aspects of learning and memory. Conclusions To date, there is a paucity of high quality neuropsychological and psychological research concerning the impact of anti-NMDAR encephalitis on cognitive function and psychosocial wellbeing, both of adults and particularly of those under 18 years. Significant limitations of the literature reviewed include lack of attention to pre-morbid functioning, insufficient rationale for neuropsychological battery choice, use of samples of convenience, and limited translation of neuropsychological findings into rehabilitation. Limitations of this review include exclusive focus on an adult population and the necessity of a narrative review given the methodological diversity in studies making up the evidence base. Anti-NMDAR, Encephalitis, Autoimmune, Neuropsychology, Cognitive functioning Introduction Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDAR) is a rare form of autoimmune encephalitis, officially categorized and named only in 2007 (Dalmau et al., 2007). It is an acute and often severe illness caused by the body’s antibodies attacking, predominantly, the NR1 subunit of the NMDA receptors in the brain (Dalmau et al., 2008). It is often associated with a teratoma tumor, frequently ovarian in women and possibly testicular in men (Irani et al., 2010). However, there are an increasing number of cases reported with no identifiable tumor (Lim et al., 2014). Women have been found to be significantly more affected than men (Finke et al., 2012). The illness typically initiates with prodomal influenza or viral type symptoms, such as headache, fever, and nausea (Dalmau, Lancaster, Martinez-Hernandez, Rosenfeld, & Balice-Gordon, 2011). Symptoms such as delusional thinking, mood disturbances and aggression then frequently develop (Kayser, Titulaer, Gresa-Arribas, & Dalmau, 2013). These symptoms mean that 77% of patients first present for assessment by a psychiatrist (Kuppuswamy, Takala & Sola, 2014) and that there is a risk of anti-NMDAR going undiagnosed (Lennox, Coles, & Vincent, 2012) or resulting in a protracted time to diagnosis. This is significant given that quicker diagnosis and treatment is thought to improve prognosis (Byrne, McCoy, Lynch, Webb, & King, 2014; Kuppuswamy et al., 2014). Following the initial phase, most patients proceed into a period of alternating between catatonia and agitation with symptoms such as decreased levels of consciousness, hypoventilation, autonomic instability, and oro-lingual-facial dyskinesias (involuntary repetitive movements of the mouth and face) (Dalmau et al., 2011; Iizuka, & Sakai, 2008; Titulaer et al., 2013). Loughan, Allen, Perna, and Malkin (2016) report that in around 50% of anti-NMDAR cases, MRI scans of the brain have been normal (Dalmau et al., 2011; Maneta & Garcia, 2014) and any abnormalities found are usually small/transient despite the severity and duration of symptoms (Dalmau et al., 2011). Dalmau and colleagues (2011) reported that single photon emission topography (SPECT) results have been variable, with some studies finding variable multifocal cortical and subcortical abnormalities, which change during the course of the disease (Llorens et al., 2010), and other studies finding no abnormalities (Iizuka & Sakai, 2008). Therefore, confirmation of the clinical diagnosis is typically determined via positive identification of NMDA antibodies in the cerebrospinal fluid and/or serum (Barry, Byrne, Barrett, Murphy, & Cotter, 2015; Gresa-Arribas et al., 2014). For all patients, management of anti-NMDAR consists of first-line immunotherapy, including corticosteroids, intravenous immunoglobulins, or plasma exchange (Chen et al., 2016; Dalmau et al., 2011). Teratomas are resected if identified (Irani et al., 2010). Some patients, such as those with a delayed diagnosis, will go on to have second-line immunotherapy, such as Rituximab (Dalmau et al., 2011). Incidence and prevalence rates of anti-NMDAR encephalitis have yet to be established. However, research so far suggests that most patients recover fully medically or have mild sequelae, although a minority die or remain severely disabled (Dalmau et al., 2008). In a longitudinal study of 501 patients, Titulaer and colleagues (2013) found that 81% had a favorable outcome and 9.5% of patients had died after a median follow-up of 24 months. Three independent factors were predictive of good outcome: the rapid commencement of immunotherapy; tumor resection if needed; and less severe symptoms (i.e. not needing intensive care unit support). Titulaer and colleagues (2013) found 12% of their patients relapsed within 24 months, particularly when there was no associated tumor or undetected/recurrent tumors. However, the authors also found relapses were less frequent when patients received second-line immunotherapy (Titulaer et al., 2013). With regards cognitive function, amnesia during the initial stages is often reported (Leypoldt et al., 2012; Titulaer et al., 2013). Dalmau and colleagues (2008) stated that, in their study of 100 patients with anti-NMDAR (91 women; mean age 23 years), 23 presented with short-term memory loss. Language is also affected, with a reduction of verbal output, some echolalia (often together with echopraxia), and in some cases mutism (Dalmau et al., 2011). However, clinicians suggest memory difficulties and other neurocognitive abnormalities can be overlooked due to the dominance of psychiatric symptoms (Parfene, Lipira, Gunning, & Gordon-Elliott, 2016) and speech difficulties, which interfere with the assessment of memory (Dalmau et al., 2008, 2011). Memory deficits are said to be consistent with the distribution and function of NMDARs in the brain, which are required for long-term potentiation in the hippocampus, thought to be the center for learning and memory (McKeon et al., 2016; Rezvani, 2006). Research into the long-term neurophysiological and structural consequences of anti-NMDAR is still lacking given the relative infancy of the disease categorization. Most research has been undertaken by Finke and colleagues (2012, 2013,,2016). Using resting state fMRI, Finke and colleagues (2013) found significantly reduced bilateral functional connectivity between the hippocampus and the anterior default mode network (aDMN). This was shown to be correlated with individual memory performance, despite normal routine clinical MRI and grey matter morphology. The DMN is found to be more active in resting, internally focused tasks and researchers suggest it is involved in episodic memory processing and imagination (Finke et al., 2013). These findings are consistent with the knowledge that the CA1 region of the hippocampus has the highest density of NMDARs in the brain (Finke et al., 2013). Whilst neuroimaging results are important in understanding the neurophysiological and structural impacts of anti-NMDAR, neuropsychological studies are needed to establish a cognitive profile and understand the impact of any cognitive difficulties on functioning and wellbeing. Although this research is starting to emerge, a systematic review of neuropsychological studies of anti-NMDAR has not yet been completed. The aim of this study is to systematically investigate current literature on neuropsychological sequelae, to evaluate its quality and to attempt to establish a cognitive profile for this clinical population, both in the acute (≤12 months) and chronic (>12 months) phases. Given previous research it is hypothesized that short-term memory difficulties, along with language difficulties, will be common in the acute phase of the illness (Dalmau et al., 2008, 2011; Parfene et al., 2016), and long-term memory difficulties in the chronic phase (Finke et al., 2013). Some difficulties related to the DMN, such as relating to others and imagination might also be present in the chronic phase given the research by Finke and colleagues (2013). Method In this review of the literature, a systematic approach was adopted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance (Moher, Liberati, Tetzlaff, Altman, & PRISMA Group, 2009). The following search string was used: anti-NMDAR OR Anti-N-Methyl-d-Aspartate AND encephalitis AND Neuropsycholog* OR cogniti*. Appropriate studies were identified using PsycINFO, MEDLINE, Scopus and Web of Science. The search was limited to the English language. Given that anti-NMDAR was only officially categorized in 2007, the period of 2007 to March 2017 was searched, accepting articles and reviews. Studies of children (under age 18, based on a typical UK research cut-off) were excluded, due to the specificities of neurodevelopmental level on cognitive functioning (Johnson, Blum, & Giedd, 2009). The search was devised to identify papers where the search terms appeared in the title, abstract or keywords. The abstracts identified in each of the four databases were downloaded into a reference manager and duplicates automatically removed. Titles and abstracts were screened and relevant papers’ full texts were downloaded. Reference sections were then hand searched for any further relevant papers. Fig. 1 shows the search process. Single case studies were included given the limited literature in this area. Fig. 1. View largeDownload slide Overview of searching and screening process PRISMA (Moher et al., 2009). Fig. 1. View largeDownload slide Overview of searching and screening process PRISMA (Moher et al., 2009). An Assessment of Methodological Quality An examination of existing standardized quality appraisal checklists was carried out including consideration of the Critical Appraisal Skills Programme (CASP, 2017) and the Scottish Intercollegiate Guidelines Network (SIGN, 2017). The case control study tools provided by both could be applied to the five studies that used a control group, but not to the remaining five. Moreover, both tools lacked questions to examine potentially confounding factors such as pain, mental health difficulties, pre-morbid functioning or effort; crucial information for attribution of the neuropsychological assessment outcomes to anti-NMDAR. Therefore, a checklist was developed for the purpose of this review. This was informed by the foregoing existing checklists and by guidance from: Evans (2010) on potential contra-indicators to neuropsychological testing validity; guidelines on psychometric testing (Psychologists Board New Zealand, 2015); information on single-case methodology in neuropsychology (Crawford, 2017) and guidance on reporting of medical case studies (Cohen, 2006; Green, Johnson, Long, Harkins, & Meeker, 2006; McCarthy, & Reilly, 2000). Each article was reviewed and given an overall score (possible maximum of 33; see Supplementary data 1) based upon which criteria were met. For ease of reference, articles are referred to as “Low” (0–11), “Medium” (12–22) or “High” (23–33) quality, depending on their score. Given the small number of papers meeting the inclusion criteria, no articles were excluded on the basis of their score on the quality checklist, rather, this was used to critically appraise the quality of current literature and provide recommendations for future research. Two independent raters piloted the quality of the assessment tool, any differences in scoring were discussed and the tool’s wording changed accordingly. An independent rater then formally reviewed a total of five articles, which demonstrated moderate inter-rater reliability (k = 0.72). All the scores were within the same category (Low, Medium, High), aside from Vahter and colleagues (2014), which the first author rated as “Low” quality and the second rater as “Medium” quality (one point difference). Data Extraction Data were extracted from the articles by the first author and divided into acute (≤12 months), and chronic cognitive deficits (>12 months). This was in an attempt to establish a cognitive profile, firstly for the “acute” neuropsychological phase of the illness, i.e., from the onset of the symptoms (the period when most treatment is commenced and completed), and secondly for the “chronic” phase, i.e., for any cognitive difficulties remaining once the systemic effects of the illness have receded. It should be noted there is currently little agreement as to the definition of “acute” and “chronic” periods and papers largely base this on medical and treatment criteria. McIvor and Moore (2017) refer to the acute stage as 4–6 weeks after symptom onset; post-acute stage as 2–6 months and the chronic stage as 6–13 months. However, time to treatment is under-reported across the 10 articles: patients may not start treatment until several months after symptom onset (Urakami, 2016); or it may be unknown (McKeon et al., 2016). Therefore, the “acute” phase for the purpose of this neuropsychological review was defined as 0–12 months on the premise that if patients were still recovering from the systemic effects of the illness, and if treatment was still being received, this would affect cognitive functioning. The terms “chronic” and “acute” were used as opposed to short and long- term to reduce confusion with short and long-term memory references. Results Search Results and Characteristics of Studies The search and screening process identified 10 eligible articles, including five case studies (one single case study, four with multiple) and five case series (four with a single case and one with multiple; Table 1). Three studies had matched controls and all participants neuropsychological test results were compared to normative samples. The data were derived from 54 participants diagnosed with anti-NMDAR from eight different countries. The time of “neuropsychological testing since diagnosis” varied considerably from eight days to 6 years (Table 1). Of note is the large timeframe in the “chronic” section, with “time tested since diagnosis” ranging from 12 to 72 months, both within and between articles. The results of the case series are presented in the results section and differences between participants’ scores across different time periods are discussed. How articles described “time tested since diagnosis” varied; seven articles described time since disease/symptom onset, one article described time since diagnosis and one reported time since treatment completion. Five of the studies carried out neuropsychological testing with participants who had medical treatment only, four with those who had treatment and rehabilitation and one with a participant who had no treatment or rehabilitation. Eight articles were rated as “Medium” quality, one “High” quality and one “Low” quality (Table 3). Consistent with the current evidence on epidemiology of anti-NMDAR (Titulaer et al., 2013), there were more female participants than males (46F:8M). Table 1. Table of study characteristics Study  Setting  Participant information  Treatment/Rehabilitation  Study or series & time assessed  Domains assessed  Cognitive deficits reported  Quality rating  Finke et al. (2012)  Participants recruited from the Department of Neurology, University Hospital, Germany.  8F,1M Mean age 28.4 years Range 21–44 Matched controls: 12 healthy participants without a history of neurological or psychiatric disorders who were matched for sex, age and educational level.  Five participants received first-line (immunotherapies including corticosteroids, intravenous immunoglobulin or both) during first 3 months of the disease, three participants received immunotherapy later in course of disease and one did not receive immunotherapy. One participant received second-line immunotherapy with methotrexate for 5 years. Two patients, ovarian teratomas were found and removed surgically. No rehabilitation.  Case study. Median 43 months after disease onset. Range 23–69 months.  Perceptual organization; attention; processing speed; verbal and non-verbal short-term memory; working memory, verbal and non-verbal episodic memory; executive functioning; general intellectual abilities.  Working memory, episodic memory, delay-dependent deficits in STM tasks; executive functioning; attention.  18 Med  Martin et al. (2012)  Participant sent for neuropsychological testing following admission to the Department of Neurology, at the Virgen del Rocío Hospital (Seville)  1F 35 years  Treatment with steroids, intravenous immunoglobulins, azathioprine, plasma exchange and cyclophosphamide. Four relapses despite of adequate treatment. Neurorehabilitation over a period of 6 years.  Case series. Tested at 6, 12, 72 months after disease onset.  Orientation; general cognitive functions; verbal and figural short- and long-term memory; frontal executive functions; language; visuospatial cognition; motor skills.  STM, anterograde, declarative memory; executive functioning; attention; visuoperceptive.  16 Med  Finke et al. (2013)  Participants were recruited in Germany and Austria between July 2011 and July 2012 and were referred to the outpatient clinic of the Department of Neurology of Charite Universit, Berlin for further counseling and treatment.  21F, 3M Mean age 27.9 years. Matched controls: 21F, 3M Mean age 28.0 years.  Immunotherapy reported, not specified. No rehabilitation. Neuropsychological battery completed after the acute phase.  Case study. Mean 33 months. Median 35 months. Range 9–72 months. Calculated by the first author from the reported time between first symptoms and imaging. Working on the assumption neuropsychological testing would have been performed around the same time.  Verbal memory; non-verbal short-term memory; working memory; verbal and non-verbal episodic memory; executive functioning; pre-morbid intelligence quotient; general intellectual abilities.  Working memory, verbal LTM; executive functioning.  14 Med  Marcos-Arribas et al. (2013)  Participant sent for neuropsychological testing following admission to the Neurology Department, Hospital Clínico San Carlos, Madrid, Spain  1F 24 years  Neuropsychological battery completed on admission. The participant underwent surgery within 7 days since admission and the diagnosis of mature ovarian teratoma was confirmed by pathology studies. Then nine alternate days sessions of plasmapheresis were then started. After 1 month the neuropsychological battery was repeated. No rehabilitation.  Tested at symptom onset & 1 month from symptom onset  Short-term memory; working memory; attention; semantic and episodic memories, visuospatial, praxical, thinking and language functions.  Short-term verbal & visual memory; retrograde amnesia of 2 months; attention.  14 Med  Vahter et al. (2014)  Participant sent for neuropsychological testing following admission to the Department of Neurology, West-Tallinn Central Hospital, Estonia.  1F 29 years  Immunotherapy with plasma exchange, intravenous IgG, followed later by cyclophosphamide. Neuropsychological testing throughout acute period. No rehabilitation.  Tested four times at symptom onset, 8 months, 12 months, 20 months after symptom onset.  Verbal memory; visuospatial memory; logical memory; executive functioning; information processing speed; verbal fluency; visuoconstructive abilities.  Long-term verbal memory; executive functioning; attention; language; visuoconstructive.  11 Low  Bach (2014)  Participants referred to the Specialist Acquired Brain Injury Unit Outreach Team (community rehabilitation team), London.  2F 24 & 23 years  Surgery (one participant) plasma exchange and course of intravenous immunoglobulin. Outreach Team for further management and rehabilitation.  Case study. Tested approximately 6 months after symptom onset. Determined from the narrative description of the cases.  Verbal memory; working memory; immediate memory; delayed memory; perceptual organization; verbal fluency; attention; executive functioning; processing speed.  Memory (long-term verbal memory), working memory, STM; executive functioning; attention; language; social cognition.  13 Med  Loughan et al. (2016)  Participant referred for neuropsychological evaluation, Department of Neurology, USA  1M 42 years  Plasmapheresis, IV steroids, Rituximab, Cyclophosphamide. Inpatient rehabilitation for 2 months. Neuropsychological testing completed once discharged.  Case study. Tested 6 months post-diagnosis.  Working memory; verbal fluency; global ability; attention; effort; executive functioning; verbal comprehension; perceptual reasoning; verbal memory; visual memory; immediate memory; delayed memory.  Verbal memory; executive functioning; attention; processing speed; language.  24 High  McKeon et al. (2016)  Participants recruited via Queensland-based physicians to Neuropsychology Research Unit, Australia.  6F, 1 M Mean age, 26.4 years Range 16–37 years Matched controls: 10F, 4M Mean age, 25.8 years Range, 16–38 years without significant psychiatric or neurological histories  Four participants (P2, P3, P6, P7) received immunotherapy within a month of symptom onset, and had not relapsed. The remaining three participants (P1, P4, P5) had lengthy psychiatric histories and comparatively poorer response to immunotherapy. No rehabilitation.  Case study. Tested: Mean 19 months (median 22.5 months; range 7–41 months). Calculated by the first author from estimated time between treatment completion & neuropsychological assessment and mean 23 months (median 20 months, range 4–35 months). As calculated from estimated time between treatment initiation & current assessment. Three participants had treatment ongoing at time of testing due to residual symptoms.  Episodic memory; semantic memory; language; auditory short-term memory; working memory; attention; processing speed; executive functioning  Verbal & visual episodic memory, verbal STM, working memory; executive functioning; attention; processing speed; visuospatial organization; social cognition  20 Med  Urakami (2016)  Participants undergoing rehabilitation at the National Rehabilitation Center for Persons with Disabilities, Japan.  5F, 1 M Mean age 33.3 years Range 20–47 years  Corticosteroids, intravenous immunotherapy (IVIg) and appropriate ovarian teratoma removal. Rehabilitation of 6 months approximately. Neuropsychological testing both before and after neurorehabilitation.  Case series. Tested twice. Mean 6 months after onset of symptoms (calculated by the first author from Table 1) and after rehabilitation (interval between start & end of rehab = mean 184.8 days).  Attention, verbal and non-verbal short-term and working memory, executive functioning; general intellectual abilities.  Working memory, verbal memory, visual memory; attention; processing speed.  14 Med  McIvor & Moore (2017)  Participant referred to Department of Clinical Neuropsychology, The Walton Center NHS Foundation Trust, Liverpool, UK.  1M 19 years  No treatment or rehabilitation. Spontaneous recovery assessed.  Case series. An untreated case tested three times over 30 months.  Delayed memory; immediate memory, visual memory; visual working memory; auditory memory; executive functioning; pre-morbid functioning.  STM, auditory memory, delayed memory.  19 Med  Study  Setting  Participant information  Treatment/Rehabilitation  Study or series & time assessed  Domains assessed  Cognitive deficits reported  Quality rating  Finke et al. (2012)  Participants recruited from the Department of Neurology, University Hospital, Germany.  8F,1M Mean age 28.4 years Range 21–44 Matched controls: 12 healthy participants without a history of neurological or psychiatric disorders who were matched for sex, age and educational level.  Five participants received first-line (immunotherapies including corticosteroids, intravenous immunoglobulin or both) during first 3 months of the disease, three participants received immunotherapy later in course of disease and one did not receive immunotherapy. One participant received second-line immunotherapy with methotrexate for 5 years. Two patients, ovarian teratomas were found and removed surgically. No rehabilitation.  Case study. Median 43 months after disease onset. Range 23–69 months.  Perceptual organization; attention; processing speed; verbal and non-verbal short-term memory; working memory, verbal and non-verbal episodic memory; executive functioning; general intellectual abilities.  Working memory, episodic memory, delay-dependent deficits in STM tasks; executive functioning; attention.  18 Med  Martin et al. (2012)  Participant sent for neuropsychological testing following admission to the Department of Neurology, at the Virgen del Rocío Hospital (Seville)  1F 35 years  Treatment with steroids, intravenous immunoglobulins, azathioprine, plasma exchange and cyclophosphamide. Four relapses despite of adequate treatment. Neurorehabilitation over a period of 6 years.  Case series. Tested at 6, 12, 72 months after disease onset.  Orientation; general cognitive functions; verbal and figural short- and long-term memory; frontal executive functions; language; visuospatial cognition; motor skills.  STM, anterograde, declarative memory; executive functioning; attention; visuoperceptive.  16 Med  Finke et al. (2013)  Participants were recruited in Germany and Austria between July 2011 and July 2012 and were referred to the outpatient clinic of the Department of Neurology of Charite Universit, Berlin for further counseling and treatment.  21F, 3M Mean age 27.9 years. Matched controls: 21F, 3M Mean age 28.0 years.  Immunotherapy reported, not specified. No rehabilitation. Neuropsychological battery completed after the acute phase.  Case study. Mean 33 months. Median 35 months. Range 9–72 months. Calculated by the first author from the reported time between first symptoms and imaging. Working on the assumption neuropsychological testing would have been performed around the same time.  Verbal memory; non-verbal short-term memory; working memory; verbal and non-verbal episodic memory; executive functioning; pre-morbid intelligence quotient; general intellectual abilities.  Working memory, verbal LTM; executive functioning.  14 Med  Marcos-Arribas et al. (2013)  Participant sent for neuropsychological testing following admission to the Neurology Department, Hospital Clínico San Carlos, Madrid, Spain  1F 24 years  Neuropsychological battery completed on admission. The participant underwent surgery within 7 days since admission and the diagnosis of mature ovarian teratoma was confirmed by pathology studies. Then nine alternate days sessions of plasmapheresis were then started. After 1 month the neuropsychological battery was repeated. No rehabilitation.  Tested at symptom onset & 1 month from symptom onset  Short-term memory; working memory; attention; semantic and episodic memories, visuospatial, praxical, thinking and language functions.  Short-term verbal & visual memory; retrograde amnesia of 2 months; attention.  14 Med  Vahter et al. (2014)  Participant sent for neuropsychological testing following admission to the Department of Neurology, West-Tallinn Central Hospital, Estonia.  1F 29 years  Immunotherapy with plasma exchange, intravenous IgG, followed later by cyclophosphamide. Neuropsychological testing throughout acute period. No rehabilitation.  Tested four times at symptom onset, 8 months, 12 months, 20 months after symptom onset.  Verbal memory; visuospatial memory; logical memory; executive functioning; information processing speed; verbal fluency; visuoconstructive abilities.  Long-term verbal memory; executive functioning; attention; language; visuoconstructive.  11 Low  Bach (2014)  Participants referred to the Specialist Acquired Brain Injury Unit Outreach Team (community rehabilitation team), London.  2F 24 & 23 years  Surgery (one participant) plasma exchange and course of intravenous immunoglobulin. Outreach Team for further management and rehabilitation.  Case study. Tested approximately 6 months after symptom onset. Determined from the narrative description of the cases.  Verbal memory; working memory; immediate memory; delayed memory; perceptual organization; verbal fluency; attention; executive functioning; processing speed.  Memory (long-term verbal memory), working memory, STM; executive functioning; attention; language; social cognition.  13 Med  Loughan et al. (2016)  Participant referred for neuropsychological evaluation, Department of Neurology, USA  1M 42 years  Plasmapheresis, IV steroids, Rituximab, Cyclophosphamide. Inpatient rehabilitation for 2 months. Neuropsychological testing completed once discharged.  Case study. Tested 6 months post-diagnosis.  Working memory; verbal fluency; global ability; attention; effort; executive functioning; verbal comprehension; perceptual reasoning; verbal memory; visual memory; immediate memory; delayed memory.  Verbal memory; executive functioning; attention; processing speed; language.  24 High  McKeon et al. (2016)  Participants recruited via Queensland-based physicians to Neuropsychology Research Unit, Australia.  6F, 1 M Mean age, 26.4 years Range 16–37 years Matched controls: 10F, 4M Mean age, 25.8 years Range, 16–38 years without significant psychiatric or neurological histories  Four participants (P2, P3, P6, P7) received immunotherapy within a month of symptom onset, and had not relapsed. The remaining three participants (P1, P4, P5) had lengthy psychiatric histories and comparatively poorer response to immunotherapy. No rehabilitation.  Case study. Tested: Mean 19 months (median 22.5 months; range 7–41 months). Calculated by the first author from estimated time between treatment completion & neuropsychological assessment and mean 23 months (median 20 months, range 4–35 months). As calculated from estimated time between treatment initiation & current assessment. Three participants had treatment ongoing at time of testing due to residual symptoms.  Episodic memory; semantic memory; language; auditory short-term memory; working memory; attention; processing speed; executive functioning  Verbal & visual episodic memory, verbal STM, working memory; executive functioning; attention; processing speed; visuospatial organization; social cognition  20 Med  Urakami (2016)  Participants undergoing rehabilitation at the National Rehabilitation Center for Persons with Disabilities, Japan.  5F, 1 M Mean age 33.3 years Range 20–47 years  Corticosteroids, intravenous immunotherapy (IVIg) and appropriate ovarian teratoma removal. Rehabilitation of 6 months approximately. Neuropsychological testing both before and after neurorehabilitation.  Case series. Tested twice. Mean 6 months after onset of symptoms (calculated by the first author from Table 1) and after rehabilitation (interval between start & end of rehab = mean 184.8 days).  Attention, verbal and non-verbal short-term and working memory, executive functioning; general intellectual abilities.  Working memory, verbal memory, visual memory; attention; processing speed.  14 Med  McIvor & Moore (2017)  Participant referred to Department of Clinical Neuropsychology, The Walton Center NHS Foundation Trust, Liverpool, UK.  1M 19 years  No treatment or rehabilitation. Spontaneous recovery assessed.  Case series. An untreated case tested three times over 30 months.  Delayed memory; immediate memory, visual memory; visual working memory; auditory memory; executive functioning; pre-morbid functioning.  STM, auditory memory, delayed memory.  19 Med  View Large Table 1. Table of study characteristics Study  Setting  Participant information  Treatment/Rehabilitation  Study or series & time assessed  Domains assessed  Cognitive deficits reported  Quality rating  Finke et al. (2012)  Participants recruited from the Department of Neurology, University Hospital, Germany.  8F,1M Mean age 28.4 years Range 21–44 Matched controls: 12 healthy participants without a history of neurological or psychiatric disorders who were matched for sex, age and educational level.  Five participants received first-line (immunotherapies including corticosteroids, intravenous immunoglobulin or both) during first 3 months of the disease, three participants received immunotherapy later in course of disease and one did not receive immunotherapy. One participant received second-line immunotherapy with methotrexate for 5 years. Two patients, ovarian teratomas were found and removed surgically. No rehabilitation.  Case study. Median 43 months after disease onset. Range 23–69 months.  Perceptual organization; attention; processing speed; verbal and non-verbal short-term memory; working memory, verbal and non-verbal episodic memory; executive functioning; general intellectual abilities.  Working memory, episodic memory, delay-dependent deficits in STM tasks; executive functioning; attention.  18 Med  Martin et al. (2012)  Participant sent for neuropsychological testing following admission to the Department of Neurology, at the Virgen del Rocío Hospital (Seville)  1F 35 years  Treatment with steroids, intravenous immunoglobulins, azathioprine, plasma exchange and cyclophosphamide. Four relapses despite of adequate treatment. Neurorehabilitation over a period of 6 years.  Case series. Tested at 6, 12, 72 months after disease onset.  Orientation; general cognitive functions; verbal and figural short- and long-term memory; frontal executive functions; language; visuospatial cognition; motor skills.  STM, anterograde, declarative memory; executive functioning; attention; visuoperceptive.  16 Med  Finke et al. (2013)  Participants were recruited in Germany and Austria between July 2011 and July 2012 and were referred to the outpatient clinic of the Department of Neurology of Charite Universit, Berlin for further counseling and treatment.  21F, 3M Mean age 27.9 years. Matched controls: 21F, 3M Mean age 28.0 years.  Immunotherapy reported, not specified. No rehabilitation. Neuropsychological battery completed after the acute phase.  Case study. Mean 33 months. Median 35 months. Range 9–72 months. Calculated by the first author from the reported time between first symptoms and imaging. Working on the assumption neuropsychological testing would have been performed around the same time.  Verbal memory; non-verbal short-term memory; working memory; verbal and non-verbal episodic memory; executive functioning; pre-morbid intelligence quotient; general intellectual abilities.  Working memory, verbal LTM; executive functioning.  14 Med  Marcos-Arribas et al. (2013)  Participant sent for neuropsychological testing following admission to the Neurology Department, Hospital Clínico San Carlos, Madrid, Spain  1F 24 years  Neuropsychological battery completed on admission. The participant underwent surgery within 7 days since admission and the diagnosis of mature ovarian teratoma was confirmed by pathology studies. Then nine alternate days sessions of plasmapheresis were then started. After 1 month the neuropsychological battery was repeated. No rehabilitation.  Tested at symptom onset & 1 month from symptom onset  Short-term memory; working memory; attention; semantic and episodic memories, visuospatial, praxical, thinking and language functions.  Short-term verbal & visual memory; retrograde amnesia of 2 months; attention.  14 Med  Vahter et al. (2014)  Participant sent for neuropsychological testing following admission to the Department of Neurology, West-Tallinn Central Hospital, Estonia.  1F 29 years  Immunotherapy with plasma exchange, intravenous IgG, followed later by cyclophosphamide. Neuropsychological testing throughout acute period. No rehabilitation.  Tested four times at symptom onset, 8 months, 12 months, 20 months after symptom onset.  Verbal memory; visuospatial memory; logical memory; executive functioning; information processing speed; verbal fluency; visuoconstructive abilities.  Long-term verbal memory; executive functioning; attention; language; visuoconstructive.  11 Low  Bach (2014)  Participants referred to the Specialist Acquired Brain Injury Unit Outreach Team (community rehabilitation team), London.  2F 24 & 23 years  Surgery (one participant) plasma exchange and course of intravenous immunoglobulin. Outreach Team for further management and rehabilitation.  Case study. Tested approximately 6 months after symptom onset. Determined from the narrative description of the cases.  Verbal memory; working memory; immediate memory; delayed memory; perceptual organization; verbal fluency; attention; executive functioning; processing speed.  Memory (long-term verbal memory), working memory, STM; executive functioning; attention; language; social cognition.  13 Med  Loughan et al. (2016)  Participant referred for neuropsychological evaluation, Department of Neurology, USA  1M 42 years  Plasmapheresis, IV steroids, Rituximab, Cyclophosphamide. Inpatient rehabilitation for 2 months. Neuropsychological testing completed once discharged.  Case study. Tested 6 months post-diagnosis.  Working memory; verbal fluency; global ability; attention; effort; executive functioning; verbal comprehension; perceptual reasoning; verbal memory; visual memory; immediate memory; delayed memory.  Verbal memory; executive functioning; attention; processing speed; language.  24 High  McKeon et al. (2016)  Participants recruited via Queensland-based physicians to Neuropsychology Research Unit, Australia.  6F, 1 M Mean age, 26.4 years Range 16–37 years Matched controls: 10F, 4M Mean age, 25.8 years Range, 16–38 years without significant psychiatric or neurological histories  Four participants (P2, P3, P6, P7) received immunotherapy within a month of symptom onset, and had not relapsed. The remaining three participants (P1, P4, P5) had lengthy psychiatric histories and comparatively poorer response to immunotherapy. No rehabilitation.  Case study. Tested: Mean 19 months (median 22.5 months; range 7–41 months). Calculated by the first author from estimated time between treatment completion & neuropsychological assessment and mean 23 months (median 20 months, range 4–35 months). As calculated from estimated time between treatment initiation & current assessment. Three participants had treatment ongoing at time of testing due to residual symptoms.  Episodic memory; semantic memory; language; auditory short-term memory; working memory; attention; processing speed; executive functioning  Verbal & visual episodic memory, verbal STM, working memory; executive functioning; attention; processing speed; visuospatial organization; social cognition  20 Med  Urakami (2016)  Participants undergoing rehabilitation at the National Rehabilitation Center for Persons with Disabilities, Japan.  5F, 1 M Mean age 33.3 years Range 20–47 years  Corticosteroids, intravenous immunotherapy (IVIg) and appropriate ovarian teratoma removal. Rehabilitation of 6 months approximately. Neuropsychological testing both before and after neurorehabilitation.  Case series. Tested twice. Mean 6 months after onset of symptoms (calculated by the first author from Table 1) and after rehabilitation (interval between start & end of rehab = mean 184.8 days).  Attention, verbal and non-verbal short-term and working memory, executive functioning; general intellectual abilities.  Working memory, verbal memory, visual memory; attention; processing speed.  14 Med  McIvor & Moore (2017)  Participant referred to Department of Clinical Neuropsychology, The Walton Center NHS Foundation Trust, Liverpool, UK.  1M 19 years  No treatment or rehabilitation. Spontaneous recovery assessed.  Case series. An untreated case tested three times over 30 months.  Delayed memory; immediate memory, visual memory; visual working memory; auditory memory; executive functioning; pre-morbid functioning.  STM, auditory memory, delayed memory.  19 Med  Study  Setting  Participant information  Treatment/Rehabilitation  Study or series & time assessed  Domains assessed  Cognitive deficits reported  Quality rating  Finke et al. (2012)  Participants recruited from the Department of Neurology, University Hospital, Germany.  8F,1M Mean age 28.4 years Range 21–44 Matched controls: 12 healthy participants without a history of neurological or psychiatric disorders who were matched for sex, age and educational level.  Five participants received first-line (immunotherapies including corticosteroids, intravenous immunoglobulin or both) during first 3 months of the disease, three participants received immunotherapy later in course of disease and one did not receive immunotherapy. One participant received second-line immunotherapy with methotrexate for 5 years. Two patients, ovarian teratomas were found and removed surgically. No rehabilitation.  Case study. Median 43 months after disease onset. Range 23–69 months.  Perceptual organization; attention; processing speed; verbal and non-verbal short-term memory; working memory, verbal and non-verbal episodic memory; executive functioning; general intellectual abilities.  Working memory, episodic memory, delay-dependent deficits in STM tasks; executive functioning; attention.  18 Med  Martin et al. (2012)  Participant sent for neuropsychological testing following admission to the Department of Neurology, at the Virgen del Rocío Hospital (Seville)  1F 35 years  Treatment with steroids, intravenous immunoglobulins, azathioprine, plasma exchange and cyclophosphamide. Four relapses despite of adequate treatment. Neurorehabilitation over a period of 6 years.  Case series. Tested at 6, 12, 72 months after disease onset.  Orientation; general cognitive functions; verbal and figural short- and long-term memory; frontal executive functions; language; visuospatial cognition; motor skills.  STM, anterograde, declarative memory; executive functioning; attention; visuoperceptive.  16 Med  Finke et al. (2013)  Participants were recruited in Germany and Austria between July 2011 and July 2012 and were referred to the outpatient clinic of the Department of Neurology of Charite Universit, Berlin for further counseling and treatment.  21F, 3M Mean age 27.9 years. Matched controls: 21F, 3M Mean age 28.0 years.  Immunotherapy reported, not specified. No rehabilitation. Neuropsychological battery completed after the acute phase.  Case study. Mean 33 months. Median 35 months. Range 9–72 months. Calculated by the first author from the reported time between first symptoms and imaging. Working on the assumption neuropsychological testing would have been performed around the same time.  Verbal memory; non-verbal short-term memory; working memory; verbal and non-verbal episodic memory; executive functioning; pre-morbid intelligence quotient; general intellectual abilities.  Working memory, verbal LTM; executive functioning.  14 Med  Marcos-Arribas et al. (2013)  Participant sent for neuropsychological testing following admission to the Neurology Department, Hospital Clínico San Carlos, Madrid, Spain  1F 24 years  Neuropsychological battery completed on admission. The participant underwent surgery within 7 days since admission and the diagnosis of mature ovarian teratoma was confirmed by pathology studies. Then nine alternate days sessions of plasmapheresis were then started. After 1 month the neuropsychological battery was repeated. No rehabilitation.  Tested at symptom onset & 1 month from symptom onset  Short-term memory; working memory; attention; semantic and episodic memories, visuospatial, praxical, thinking and language functions.  Short-term verbal & visual memory; retrograde amnesia of 2 months; attention.  14 Med  Vahter et al. (2014)  Participant sent for neuropsychological testing following admission to the Department of Neurology, West-Tallinn Central Hospital, Estonia.  1F 29 years  Immunotherapy with plasma exchange, intravenous IgG, followed later by cyclophosphamide. Neuropsychological testing throughout acute period. No rehabilitation.  Tested four times at symptom onset, 8 months, 12 months, 20 months after symptom onset.  Verbal memory; visuospatial memory; logical memory; executive functioning; information processing speed; verbal fluency; visuoconstructive abilities.  Long-term verbal memory; executive functioning; attention; language; visuoconstructive.  11 Low  Bach (2014)  Participants referred to the Specialist Acquired Brain Injury Unit Outreach Team (community rehabilitation team), London.  2F 24 & 23 years  Surgery (one participant) plasma exchange and course of intravenous immunoglobulin. Outreach Team for further management and rehabilitation.  Case study. Tested approximately 6 months after symptom onset. Determined from the narrative description of the cases.  Verbal memory; working memory; immediate memory; delayed memory; perceptual organization; verbal fluency; attention; executive functioning; processing speed.  Memory (long-term verbal memory), working memory, STM; executive functioning; attention; language; social cognition.  13 Med  Loughan et al. (2016)  Participant referred for neuropsychological evaluation, Department of Neurology, USA  1M 42 years  Plasmapheresis, IV steroids, Rituximab, Cyclophosphamide. Inpatient rehabilitation for 2 months. Neuropsychological testing completed once discharged.  Case study. Tested 6 months post-diagnosis.  Working memory; verbal fluency; global ability; attention; effort; executive functioning; verbal comprehension; perceptual reasoning; verbal memory; visual memory; immediate memory; delayed memory.  Verbal memory; executive functioning; attention; processing speed; language.  24 High  McKeon et al. (2016)  Participants recruited via Queensland-based physicians to Neuropsychology Research Unit, Australia.  6F, 1 M Mean age, 26.4 years Range 16–37 years Matched controls: 10F, 4M Mean age, 25.8 years Range, 16–38 years without significant psychiatric or neurological histories  Four participants (P2, P3, P6, P7) received immunotherapy within a month of symptom onset, and had not relapsed. The remaining three participants (P1, P4, P5) had lengthy psychiatric histories and comparatively poorer response to immunotherapy. No rehabilitation.  Case study. Tested: Mean 19 months (median 22.5 months; range 7–41 months). Calculated by the first author from estimated time between treatment completion & neuropsychological assessment and mean 23 months (median 20 months, range 4–35 months). As calculated from estimated time between treatment initiation & current assessment. Three participants had treatment ongoing at time of testing due to residual symptoms.  Episodic memory; semantic memory; language; auditory short-term memory; working memory; attention; processing speed; executive functioning  Verbal & visual episodic memory, verbal STM, working memory; executive functioning; attention; processing speed; visuospatial organization; social cognition  20 Med  Urakami (2016)  Participants undergoing rehabilitation at the National Rehabilitation Center for Persons with Disabilities, Japan.  5F, 1 M Mean age 33.3 years Range 20–47 years  Corticosteroids, intravenous immunotherapy (IVIg) and appropriate ovarian teratoma removal. Rehabilitation of 6 months approximately. Neuropsychological testing both before and after neurorehabilitation.  Case series. Tested twice. Mean 6 months after onset of symptoms (calculated by the first author from Table 1) and after rehabilitation (interval between start & end of rehab = mean 184.8 days).  Attention, verbal and non-verbal short-term and working memory, executive functioning; general intellectual abilities.  Working memory, verbal memory, visual memory; attention; processing speed.  14 Med  McIvor & Moore (2017)  Participant referred to Department of Clinical Neuropsychology, The Walton Center NHS Foundation Trust, Liverpool, UK.  1M 19 years  No treatment or rehabilitation. Spontaneous recovery assessed.  Case series. An untreated case tested three times over 30 months.  Delayed memory; immediate memory, visual memory; visual working memory; auditory memory; executive functioning; pre-morbid functioning.  STM, auditory memory, delayed memory.  19 Med  View Large The articles also varied in the numbers of participants tested and presence or absence of a control group (Table 1). Additionally, many different neuropsychological tests were used to measure cognitive functioning across studies (Table 2). Therefore, comparison of the articles was difficult and data synthesis was not appropriate. As such, a narrative synthesis of the results was undertaken. Five of the studies were case series, four of which assessed patients both during the acute and chronic phases, and as such the relevant results are discussed in the “acute” and “chronic” sections (Martín-Monzón, Trujillo-Pozo, & Romero, 2012; McIvor, & Moore, 2017; Urakami, 2016; Vahter et al., 2014). Bach (2014) reported three case studies, but only the two participants assessed with formal neuropsychological testing, within the first 12 months, were included in the ≤12-month analysis. The patient assessed at 30 months did not undergo formal neuropsychological testing; data reported derives from behavioral observations and clinical judgment. The main results are presented under different cognitive domains, based on Lezak (2012) and the DSM-5 approach to classifying neurocognitive disorders (Sachdev et al., 2014). This is also in keeping with general reporting of neuropsychological assessment by clinical neuropsychologists and should make for ease of reference in a clinical setting. Table 2. Tests used by each study Cognitive function  Tests used  Cognitive function  Tests used  Verbal memory    Attention & Processing Speed    Loughan et al. (2016)  RBANS: List learning & Recall Story Memory & Recall  Loughan et al. (2012)  TMT: Part A & B  Finke et al. (2012)  RAVLT  Finke et al. (2012)  TAP  Martín-Monzón et al. (2012)  WMS III: Logical Memory Selective Reminding test  Martín-Monzón et al. (2012)  TMT: Part A WAIS-III: Digit Symbol-Coding   Finke et al. (2013)  RAVLT  Finke et al. (2013)  None named  Marcos-Arribas et al. (2013)  WMS-III: Logical Memory I & II Verbal Paired Associates I & II Word Pairs I & II Letter-Number Sequencing  Marcos-Arribas et al. (2013)  WAIS-III: Digit Symbol-Coding  Bach (2014)  WMS-IV: Logical Memory I  Bach (2014)  TMT: Part A & B  Vahter et al. (2014)  WMS?: Verbal memory (assume all subtests) Buschke selective verbal memory, controlled long-term retrieval, long-term storage & later recall  Vahter et al. (2014)  TMT: Part A & B  McKeon et al. (2016)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McKeon et al. (2016)  Digit Span Forwards Visual Scanning Time Letter Sequencing Time Number Sequencing Time Motor Speed Time Color Naming Time Word Reading Time PRP Paradigm SART  Urakami (2016)  WMS-R (assume all verbal memory subtests)  Urakami (2016)  WAIS-III: Coding Symbol search  McIvor and Moore (2017)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McIvor and Moore (2017)  None  Cognitive function  Tests used  Cognitive function  Tests used  Visual memory    Executive function    Finke et al. (2012)  ROCFT: Copy, Delayed & Recall  Finke et al. (2012)  BADS Stroop Test Tower of London  Loughan et al. (2016)  RBANS: Figure Copy & Recall  Loughan et al. (2012)  D-KEFS  Martín-Monzón et al. (2012)  ROCFT: Immediate & Delayed recall WAIS-III: Design Immediate recall & Delayed recall   Martín-Monzón et al. (2012)  WAIS-III Matrix Reasoning TMT: Part B Stroop Colors and words Verbal fluency Wisconsin Categories  Marcos-Arribas et al. (2013)  ROCFT: Immediate & Delayed recall  Marcos-Arribas et al. (2013)  None  Finke et al. (2013)  None  Finke et al. (2013)  Stroop test Computerized go = no-go test Semantic fluency  Bach (2014)  None  Bach (2014)  BADS: Rule Shift Action program Key search Temporal Judgment Zoo map Modified six elements  Vahter et al. (2014)  Visual Spatial Memory: Immediate &Delayed recall  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  ROCFT: Immediate, Delayed & Recall  McKeon et al. (2016)  D-KEFS: TMT Tower Test Verbal Fluency Proverbs Test Inhibition Test (Stroop Test) Inhibition/Switching Test Hayling Test  Urakami (2016)  WMS-R: Visual memory (assume all subtests)  Urakami (2016)  None  McIvor and Moore (2017)  WMS-IV: Visual reproduction I & II  McIvor and Moore (2017)  D-KEFS: TMT Verbal Fluency Test  Cognitive function  Tests used  Cognitive function  Tests used  Working memory    Visuospatial ability    Loughan et al. (2016)  WAIS-IV: Digit Span Arithmetic  Loughan et al. (2012)  WAIS-IV: Block design RBANS: Figure Copy   Finke et al. (2012)  WAIS-IV: Digit Span Block Span  Finke et al. (2012)  ROCFT: Copy  Martín-Monzón et al. (2012)  WAIS-III: Digit Symbol Coding Digit Span backwards Letter Number Sequencing Arithmetic  Martín-Monzón et al. (2012)  Benton Visual Form Discrimination Test WAIS-III: Picture Completion  Marcos-Arribas et al. (2013)  WMS-III: Letter-Number Sequencing WAIS-III: Digit span  Marcos-Arribas et al. (2013)  ROCFT: Copy  Finke et al. (2013)  (WAIS?): Digit span backwards  Finke et al. (2013)  ROCFT: Copy  Bach (2014)  WAIS-IV: Digit Span  Bach (2014)  None  Vahter et al. (2014)  None  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  WAIS-IV: Digit Span  McKeon et al. (2016)  ROCFT: Copy  Urakami (2016)  WAIS-III & WMS-R (assume digit span, arithmetic, symbol & spatial span)  Urakami (2016)  WAIS-III (assume block design)  McIvor and Moore (2017)  WMS-IV: VWMI-Spatial Addition & Spatial Span  McIvor and Moore (2017)  None  Social Cognition  Bach (2014)  No tests; A 10 item questionnaire to assess ability to understand other’s mental states and general social cognition    McKeon et al. (2016)  Mind in the Eyes Test Advanced ToM Test Social Situations Test Emotion Attribution Task    Cognitive function  Tests used  Cognitive function  Tests used  Verbal memory    Attention & Processing Speed    Loughan et al. (2016)  RBANS: List learning & Recall Story Memory & Recall  Loughan et al. (2012)  TMT: Part A & B  Finke et al. (2012)  RAVLT  Finke et al. (2012)  TAP  Martín-Monzón et al. (2012)  WMS III: Logical Memory Selective Reminding test  Martín-Monzón et al. (2012)  TMT: Part A WAIS-III: Digit Symbol-Coding   Finke et al. (2013)  RAVLT  Finke et al. (2013)  None named  Marcos-Arribas et al. (2013)  WMS-III: Logical Memory I & II Verbal Paired Associates I & II Word Pairs I & II Letter-Number Sequencing  Marcos-Arribas et al. (2013)  WAIS-III: Digit Symbol-Coding  Bach (2014)  WMS-IV: Logical Memory I  Bach (2014)  TMT: Part A & B  Vahter et al. (2014)  WMS?: Verbal memory (assume all subtests) Buschke selective verbal memory, controlled long-term retrieval, long-term storage & later recall  Vahter et al. (2014)  TMT: Part A & B  McKeon et al. (2016)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McKeon et al. (2016)  Digit Span Forwards Visual Scanning Time Letter Sequencing Time Number Sequencing Time Motor Speed Time Color Naming Time Word Reading Time PRP Paradigm SART  Urakami (2016)  WMS-R (assume all verbal memory subtests)  Urakami (2016)  WAIS-III: Coding Symbol search  McIvor and Moore (2017)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McIvor and Moore (2017)  None  Cognitive function  Tests used  Cognitive function  Tests used  Visual memory    Executive function    Finke et al. (2012)  ROCFT: Copy, Delayed & Recall  Finke et al. (2012)  BADS Stroop Test Tower of London  Loughan et al. (2016)  RBANS: Figure Copy & Recall  Loughan et al. (2012)  D-KEFS  Martín-Monzón et al. (2012)  ROCFT: Immediate & Delayed recall WAIS-III: Design Immediate recall & Delayed recall   Martín-Monzón et al. (2012)  WAIS-III Matrix Reasoning TMT: Part B Stroop Colors and words Verbal fluency Wisconsin Categories  Marcos-Arribas et al. (2013)  ROCFT: Immediate & Delayed recall  Marcos-Arribas et al. (2013)  None  Finke et al. (2013)  None  Finke et al. (2013)  Stroop test Computerized go = no-go test Semantic fluency  Bach (2014)  None  Bach (2014)  BADS: Rule Shift Action program Key search Temporal Judgment Zoo map Modified six elements  Vahter et al. (2014)  Visual Spatial Memory: Immediate &Delayed recall  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  ROCFT: Immediate, Delayed & Recall  McKeon et al. (2016)  D-KEFS: TMT Tower Test Verbal Fluency Proverbs Test Inhibition Test (Stroop Test) Inhibition/Switching Test Hayling Test  Urakami (2016)  WMS-R: Visual memory (assume all subtests)  Urakami (2016)  None  McIvor and Moore (2017)  WMS-IV: Visual reproduction I & II  McIvor and Moore (2017)  D-KEFS: TMT Verbal Fluency Test  Cognitive function  Tests used  Cognitive function  Tests used  Working memory    Visuospatial ability    Loughan et al. (2016)  WAIS-IV: Digit Span Arithmetic  Loughan et al. (2012)  WAIS-IV: Block design RBANS: Figure Copy   Finke et al. (2012)  WAIS-IV: Digit Span Block Span  Finke et al. (2012)  ROCFT: Copy  Martín-Monzón et al. (2012)  WAIS-III: Digit Symbol Coding Digit Span backwards Letter Number Sequencing Arithmetic  Martín-Monzón et al. (2012)  Benton Visual Form Discrimination Test WAIS-III: Picture Completion  Marcos-Arribas et al. (2013)  WMS-III: Letter-Number Sequencing WAIS-III: Digit span  Marcos-Arribas et al. (2013)  ROCFT: Copy  Finke et al. (2013)  (WAIS?): Digit span backwards  Finke et al. (2013)  ROCFT: Copy  Bach (2014)  WAIS-IV: Digit Span  Bach (2014)  None  Vahter et al. (2014)  None  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  WAIS-IV: Digit Span  McKeon et al. (2016)  ROCFT: Copy  Urakami (2016)  WAIS-III & WMS-R (assume digit span, arithmetic, symbol & spatial span)  Urakami (2016)  WAIS-III (assume block design)  McIvor and Moore (2017)  WMS-IV: VWMI-Spatial Addition & Spatial Span  McIvor and Moore (2017)  None  Social Cognition  Bach (2014)  No tests; A 10 item questionnaire to assess ability to understand other’s mental states and general social cognition    McKeon et al. (2016)  Mind in the Eyes Test Advanced ToM Test Social Situations Test Emotion Attribution Task    WMS-R/III/IV = Weschler Memory Scale Revised/Third/Fourth Edition; WAIS III/IV = Weschler Adult Intelligence Scale Third/Fourth Edition; TMT = Trail Making Test; ROCFT = Rey-Osterrieth Complex Figure Test; RAVLT = Rey Auditory Verbal Learning Test; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; DT-VMI = Beery-Buktenica Developmental Test of Visual-Motor Integration; DTVP = Beery-Buktenica Developmental Test of Visual Perception; DKEFS = Delis-Kaplan Executive Function System; TOL = Tower of London test; BADS = Behavioral Assessment of the Dysexecutive Syndrome; TAP = Test battery for the assessment of attention. View Large Table 2. Tests used by each study Cognitive function  Tests used  Cognitive function  Tests used  Verbal memory    Attention & Processing Speed    Loughan et al. (2016)  RBANS: List learning & Recall Story Memory & Recall  Loughan et al. (2012)  TMT: Part A & B  Finke et al. (2012)  RAVLT  Finke et al. (2012)  TAP  Martín-Monzón et al. (2012)  WMS III: Logical Memory Selective Reminding test  Martín-Monzón et al. (2012)  TMT: Part A WAIS-III: Digit Symbol-Coding   Finke et al. (2013)  RAVLT  Finke et al. (2013)  None named  Marcos-Arribas et al. (2013)  WMS-III: Logical Memory I & II Verbal Paired Associates I & II Word Pairs I & II Letter-Number Sequencing  Marcos-Arribas et al. (2013)  WAIS-III: Digit Symbol-Coding  Bach (2014)  WMS-IV: Logical Memory I  Bach (2014)  TMT: Part A & B  Vahter et al. (2014)  WMS?: Verbal memory (assume all subtests) Buschke selective verbal memory, controlled long-term retrieval, long-term storage & later recall  Vahter et al. (2014)  TMT: Part A & B  McKeon et al. (2016)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McKeon et al. (2016)  Digit Span Forwards Visual Scanning Time Letter Sequencing Time Number Sequencing Time Motor Speed Time Color Naming Time Word Reading Time PRP Paradigm SART  Urakami (2016)  WMS-R (assume all verbal memory subtests)  Urakami (2016)  WAIS-III: Coding Symbol search  McIvor and Moore (2017)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McIvor and Moore (2017)  None  Cognitive function  Tests used  Cognitive function  Tests used  Visual memory    Executive function    Finke et al. (2012)  ROCFT: Copy, Delayed & Recall  Finke et al. (2012)  BADS Stroop Test Tower of London  Loughan et al. (2016)  RBANS: Figure Copy & Recall  Loughan et al. (2012)  D-KEFS  Martín-Monzón et al. (2012)  ROCFT: Immediate & Delayed recall WAIS-III: Design Immediate recall & Delayed recall   Martín-Monzón et al. (2012)  WAIS-III Matrix Reasoning TMT: Part B Stroop Colors and words Verbal fluency Wisconsin Categories  Marcos-Arribas et al. (2013)  ROCFT: Immediate & Delayed recall  Marcos-Arribas et al. (2013)  None  Finke et al. (2013)  None  Finke et al. (2013)  Stroop test Computerized go = no-go test Semantic fluency  Bach (2014)  None  Bach (2014)  BADS: Rule Shift Action program Key search Temporal Judgment Zoo map Modified six elements  Vahter et al. (2014)  Visual Spatial Memory: Immediate &Delayed recall  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  ROCFT: Immediate, Delayed & Recall  McKeon et al. (2016)  D-KEFS: TMT Tower Test Verbal Fluency Proverbs Test Inhibition Test (Stroop Test) Inhibition/Switching Test Hayling Test  Urakami (2016)  WMS-R: Visual memory (assume all subtests)  Urakami (2016)  None  McIvor and Moore (2017)  WMS-IV: Visual reproduction I & II  McIvor and Moore (2017)  D-KEFS: TMT Verbal Fluency Test  Cognitive function  Tests used  Cognitive function  Tests used  Working memory    Visuospatial ability    Loughan et al. (2016)  WAIS-IV: Digit Span Arithmetic  Loughan et al. (2012)  WAIS-IV: Block design RBANS: Figure Copy   Finke et al. (2012)  WAIS-IV: Digit Span Block Span  Finke et al. (2012)  ROCFT: Copy  Martín-Monzón et al. (2012)  WAIS-III: Digit Symbol Coding Digit Span backwards Letter Number Sequencing Arithmetic  Martín-Monzón et al. (2012)  Benton Visual Form Discrimination Test WAIS-III: Picture Completion  Marcos-Arribas et al. (2013)  WMS-III: Letter-Number Sequencing WAIS-III: Digit span  Marcos-Arribas et al. (2013)  ROCFT: Copy  Finke et al. (2013)  (WAIS?): Digit span backwards  Finke et al. (2013)  ROCFT: Copy  Bach (2014)  WAIS-IV: Digit Span  Bach (2014)  None  Vahter et al. (2014)  None  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  WAIS-IV: Digit Span  McKeon et al. (2016)  ROCFT: Copy  Urakami (2016)  WAIS-III & WMS-R (assume digit span, arithmetic, symbol & spatial span)  Urakami (2016)  WAIS-III (assume block design)  McIvor and Moore (2017)  WMS-IV: VWMI-Spatial Addition & Spatial Span  McIvor and Moore (2017)  None  Social Cognition  Bach (2014)  No tests; A 10 item questionnaire to assess ability to understand other’s mental states and general social cognition    McKeon et al. (2016)  Mind in the Eyes Test Advanced ToM Test Social Situations Test Emotion Attribution Task    Cognitive function  Tests used  Cognitive function  Tests used  Verbal memory    Attention & Processing Speed    Loughan et al. (2016)  RBANS: List learning & Recall Story Memory & Recall  Loughan et al. (2012)  TMT: Part A & B  Finke et al. (2012)  RAVLT  Finke et al. (2012)  TAP  Martín-Monzón et al. (2012)  WMS III: Logical Memory Selective Reminding test  Martín-Monzón et al. (2012)  TMT: Part A WAIS-III: Digit Symbol-Coding   Finke et al. (2013)  RAVLT  Finke et al. (2013)  None named  Marcos-Arribas et al. (2013)  WMS-III: Logical Memory I & II Verbal Paired Associates I & II Word Pairs I & II Letter-Number Sequencing  Marcos-Arribas et al. (2013)  WAIS-III: Digit Symbol-Coding  Bach (2014)  WMS-IV: Logical Memory I  Bach (2014)  TMT: Part A & B  Vahter et al. (2014)  WMS?: Verbal memory (assume all subtests) Buschke selective verbal memory, controlled long-term retrieval, long-term storage & later recall  Vahter et al. (2014)  TMT: Part A & B  McKeon et al. (2016)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McKeon et al. (2016)  Digit Span Forwards Visual Scanning Time Letter Sequencing Time Number Sequencing Time Motor Speed Time Color Naming Time Word Reading Time PRP Paradigm SART  Urakami (2016)  WMS-R (assume all verbal memory subtests)  Urakami (2016)  WAIS-III: Coding Symbol search  McIvor and Moore (2017)  WMS IV: Logical Memory I & II Verbal Paired Associates I & II  McIvor and Moore (2017)  None  Cognitive function  Tests used  Cognitive function  Tests used  Visual memory    Executive function    Finke et al. (2012)  ROCFT: Copy, Delayed & Recall  Finke et al. (2012)  BADS Stroop Test Tower of London  Loughan et al. (2016)  RBANS: Figure Copy & Recall  Loughan et al. (2012)  D-KEFS  Martín-Monzón et al. (2012)  ROCFT: Immediate & Delayed recall WAIS-III: Design Immediate recall & Delayed recall   Martín-Monzón et al. (2012)  WAIS-III Matrix Reasoning TMT: Part B Stroop Colors and words Verbal fluency Wisconsin Categories  Marcos-Arribas et al. (2013)  ROCFT: Immediate & Delayed recall  Marcos-Arribas et al. (2013)  None  Finke et al. (2013)  None  Finke et al. (2013)  Stroop test Computerized go = no-go test Semantic fluency  Bach (2014)  None  Bach (2014)  BADS: Rule Shift Action program Key search Temporal Judgment Zoo map Modified six elements  Vahter et al. (2014)  Visual Spatial Memory: Immediate &Delayed recall  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  ROCFT: Immediate, Delayed & Recall  McKeon et al. (2016)  D-KEFS: TMT Tower Test Verbal Fluency Proverbs Test Inhibition Test (Stroop Test) Inhibition/Switching Test Hayling Test  Urakami (2016)  WMS-R: Visual memory (assume all subtests)  Urakami (2016)  None  McIvor and Moore (2017)  WMS-IV: Visual reproduction I & II  McIvor and Moore (2017)  D-KEFS: TMT Verbal Fluency Test  Cognitive function  Tests used  Cognitive function  Tests used  Working memory    Visuospatial ability    Loughan et al. (2016)  WAIS-IV: Digit Span Arithmetic  Loughan et al. (2012)  WAIS-IV: Block design RBANS: Figure Copy   Finke et al. (2012)  WAIS-IV: Digit Span Block Span  Finke et al. (2012)  ROCFT: Copy  Martín-Monzón et al. (2012)  WAIS-III: Digit Symbol Coding Digit Span backwards Letter Number Sequencing Arithmetic  Martín-Monzón et al. (2012)  Benton Visual Form Discrimination Test WAIS-III: Picture Completion  Marcos-Arribas et al. (2013)  WMS-III: Letter-Number Sequencing WAIS-III: Digit span  Marcos-Arribas et al. (2013)  ROCFT: Copy  Finke et al. (2013)  (WAIS?): Digit span backwards  Finke et al. (2013)  ROCFT: Copy  Bach (2014)  WAIS-IV: Digit Span  Bach (2014)  None  Vahter et al. (2014)  None  Vahter et al. (2014)  Clock drawing  McKeon et al. (2016)  WAIS-IV: Digit Span  McKeon et al. (2016)  ROCFT: Copy  Urakami (2016)  WAIS-III & WMS-R (assume digit span, arithmetic, symbol & spatial span)  Urakami (2016)  WAIS-III (assume block design)  McIvor and Moore (2017)  WMS-IV: VWMI-Spatial Addition & Spatial Span  McIvor and Moore (2017)  None  Social Cognition  Bach (2014)  No tests; A 10 item questionnaire to assess ability to understand other’s mental states and general social cognition    McKeon et al. (2016)  Mind in the Eyes Test Advanced ToM Test Social Situations Test Emotion Attribution Task    WMS-R/III/IV = Weschler Memory Scale Revised/Third/Fourth Edition; WAIS III/IV = Weschler Adult Intelligence Scale Third/Fourth Edition; TMT = Trail Making Test; ROCFT = Rey-Osterrieth Complex Figure Test; RAVLT = Rey Auditory Verbal Learning Test; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; DT-VMI = Beery-Buktenica Developmental Test of Visual-Motor Integration; DTVP = Beery-Buktenica Developmental Test of Visual Perception; DKEFS = Delis-Kaplan Executive Function System; TOL = Tower of London test; BADS = Behavioral Assessment of the Dysexecutive Syndrome; TAP = Test battery for the assessment of attention. View Large Synthesis Results The results of the synthesis are presented below; however, it should be stressed that the results are based on relatively small numbers of cases, particularly in the acute phase. The number of participants who were found to have cognitive difficulties for the cognitive domain are indicated alongside the relevant references (for example, N = 13). Reflected in the quality assessment tool, a common methodological limitation of the case studies and series was inadequate reporting of the procedure of neuropsychological assessment and of participant demographics (Table 3). For example, pre-morbid functioning was not assessed in half of the papers studied and as such any cognitive deficit found cannot be solely attributed to the effects of the illness. Therefore, the results below should be interpreted with caution, with close examination of both the number of participants included within each result summary and the quality assessment scores of the papers included. Furthermore, there was a great deal of disparity with regards to how cognitive functions were classified and described by the articles. This is particularly evident for memory, which was subdivided differently by each of the articles. To present the results for memory, the most referred to memory subdivisions within the articles are summarized in each of the results sections. Table 3. Study quality ratings Study  A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  TOTAL  Finke et al. (2012)  1  2  2  1  1  0  0  0  0  1  0  0  0  1  2  1  1  1  2  0  1  0  1  1  0  0  18 Med  Martín-Monzón et al. (2012)  1  2  0  1  1  1  0  1  0  1  0  1  1  0  0  0  0  2  2  1  0  0  0  1  0  0  16 Med  Finke et al. (2013)  1  2  2  1  0  0  0  0  0  0  1  0  0  0  0  1  1  1  2  0  0  0  1  1  0  0  14 Med  Marcos-Arribas et al. (2013)  1  2  0  1  1  1  1  1  0  1  0  0  1  0  0  0  0  1  1  1  0  0  0  1  0  0  14 Med  Vahter et al. (2014)  1  2  0  1  1  0  0  0  0  1  0  0  0  0  0  0  0  1  2  0  0  0  0  2  0  0  11 Low  Bach (2014)  1  1  1  1  0  0  0  0  0  0  0  0  0  0  2  0  0  0  2  0  1  0  1  1  1  1  13 Med  Loughan et al. (2016)  1  2  0  1  1  1  1  1  0  1  1  1  1  1  3  0  1  1  2  0  1  0  1  1  0  1  24 High  McKeon et al. (2016)  1  2  2  1  1  1  0  0  0  1  0  0  0  1  3  1  1  1  2  0  1  0  0  1  1  0  21 Med  Urakami (2016)  1  2  2  1  1  0  0  0  0  0  0  0  0  0  0  1  0  0  2  1  1  0  0  1  0  1  14 Med  McIvor and Moore (2017)  1  2  0  1  1  1  1  0  0  1  0  0  0  1  0  0  1  0  2  2  1  0  1  1  0  0  19 Med  Study  A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  TOTAL  Finke et al. (2012)  1  2  2  1  1  0  0  0  0  1  0  0  0  1  2  1  1  1  2  0  1  0  1  1  0  0  18 Med  Martín-Monzón et al. (2012)  1  2  0  1  1  1  0  1  0  1  0  1  1  0  0  0  0  2  2  1  0  0  0  1  0  0  16 Med  Finke et al. (2013)  1  2  2  1  0  0  0  0  0  0  1  0  0  0  0  1  1  1  2  0  0  0  1  1  0  0  14 Med  Marcos-Arribas et al. (2013)  1  2  0  1  1  1  1  1  0  1  0  0  1  0  0  0  0  1  1  1  0  0  0  1  0  0  14 Med  Vahter et al. (2014)  1  2  0  1  1  0  0  0  0  1  0  0  0  0  0  0  0  1  2  0  0  0  0  2  0  0  11 Low  Bach (2014)  1  1  1  1  0  0  0  0  0  0  0  0  0  0  2  0  0  0  2  0  1  0  1  1  1  1  13 Med  Loughan et al. (2016)  1  2  0  1  1  1  1  1  0  1  1  1  1  1  3  0  1  1  2  0  1  0  1  1  0  1  24 High  McKeon et al. (2016)  1  2  2  1  1  1  0  0  0  1  0  0  0  1  3  1  1  1  2  0  1  0  0  1  1  0  21 Med  Urakami (2016)  1  2  2  1  1  0  0  0  0  0  0  0  0  0  0  1  0  0  2  1  1  0  0  1  0  1  14 Med  McIvor and Moore (2017)  1  2  0  1  1  1  1  0  0  1  0  0  0  1  0  0  1  0  2  2  1  0  1  1  0  0  19 Med  View Large Table 3. Study quality ratings Study  A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  TOTAL  Finke et al. (2012)  1  2  2  1  1  0  0  0  0  1  0  0  0  1  2  1  1  1  2  0  1  0  1  1  0  0  18 Med  Martín-Monzón et al. (2012)  1  2  0  1  1  1  0  1  0  1  0  1  1  0  0  0  0  2  2  1  0  0  0  1  0  0  16 Med  Finke et al. (2013)  1  2  2  1  0  0  0  0  0  0  1  0  0  0  0  1  1  1  2  0  0  0  1  1  0  0  14 Med  Marcos-Arribas et al. (2013)  1  2  0  1  1  1  1  1  0  1  0  0  1  0  0  0  0  1  1  1  0  0  0  1  0  0  14 Med  Vahter et al. (2014)  1  2  0  1  1  0  0  0  0  1  0  0  0  0  0  0  0  1  2  0  0  0  0  2  0  0  11 Low  Bach (2014)  1  1  1  1  0  0  0  0  0  0  0  0  0  0  2  0  0  0  2  0  1  0  1  1  1  1  13 Med  Loughan et al. (2016)  1  2  0  1  1  1  1  1  0  1  1  1  1  1  3  0  1  1  2  0  1  0  1  1  0  1  24 High  McKeon et al. (2016)  1  2  2  1  1  1  0  0  0  1  0  0  0  1  3  1  1  1  2  0  1  0  0  1  1  0  21 Med  Urakami (2016)  1  2  2  1  1  0  0  0  0  0  0  0  0  0  0  1  0  0  2  1  1  0  0  1  0  1  14 Med  McIvor and Moore (2017)  1  2  0  1  1  1  1  0  0  1  0  0  0  1  0  0  1  0  2  2  1  0  1  1  0  0  19 Med  Study  A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  TOTAL  Finke et al. (2012)  1  2  2  1  1  0  0  0  0  1  0  0  0  1  2  1  1  1  2  0  1  0  1  1  0  0  18 Med  Martín-Monzón et al. (2012)  1  2  0  1  1  1  0  1  0  1  0  1  1  0  0  0  0  2  2  1  0  0  0  1  0  0  16 Med  Finke et al. (2013)  1  2  2  1  0  0  0  0  0  0  1  0  0  0  0  1  1  1  2  0  0  0  1  1  0  0  14 Med  Marcos-Arribas et al. (2013)  1  2  0  1  1  1  1  1  0  1  0  0  1  0  0  0  0  1  1  1  0  0  0  1  0  0  14 Med  Vahter et al. (2014)  1  2  0  1  1  0  0  0  0  1  0  0  0  0  0  0  0  1  2  0  0  0  0  2  0  0  11 Low  Bach (2014)  1  1  1  1  0  0  0  0  0  0  0  0  0  0  2  0  0  0  2  0  1  0  1  1  1  1  13 Med  Loughan et al. (2016)  1  2  0  1  1  1  1  1  0  1  1  1  1  1  3  0  1  1  2  0  1  0  1  1  0  1  24 High  McKeon et al. (2016)  1  2  2  1  1  1  0  0  0  1  0  0  0  1  3  1  1  1  2  0  1  0  0  1  1  0  21 Med  Urakami (2016)  1  2  2  1  1  0  0  0  0  0  0  0  0  0  0  1  0  0  2  1  1  0  0  1  0  1  14 Med  McIvor and Moore (2017)  1  2  0  1  1  1  1  0  0  1  0  0  0  1  0  0  1  0  2  2  1  0  1  1  0  0  19 Med  View Large Acute Cognitive Effects (≤12 months) Description of Articles Seven of the 10 articles included in this review assessed participants within the first 12 months from either diagnosis, symptom onset or at the start of rehabilitation, and are discussed below (Bach, 2014; Loughan et al., 2016; Martín-Monzón, Trujillo-Pozo, & Romeron, 2012; Marcos-Arribas, Almonacid, & Dolado, 2013; McIvor & Moore, 2017; Urakami, 2016; Vahter et al., 2014). A total of 13 participants were assessed across the seven articles. The mean age of the participants was 28.7 (range: 19–47 years), with a higher ratio of female participants (10F: 3M). All but one article (Loughan et al., 2016) conducted case series where participants were assessed at two or more time points within the first 12 months. The case series or studies were judged as “Medium” quality, except Vahter and colleagues (2014), which was of “Low” quality and Loughan and colleagues (2016) which was “High” quality, both largely due to the level of detail provided in the participant background section of the quality measure. Memory Memory was tested in all seven of the articles (Number of participants [N] = 13) with each study reporting some form of memory difficulty. Working/Short-term Memory Working/short-term memory difficulties were specifically noted in three articles (Bach, 2014; McIvor & Moore, 2017; Urakami, 2016; N = 9), with McIvor and Moore (2017) and Urakami (2016) reporting working memory deficits persisting at 12 months following treatment and treatment with rehabilitation respectively. Episodic Recall Immediate recall difficulties were reported in four of the studies (Marcos-Arribas et al., 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; Vahter et al., 2014; N = 4) and delayed recall difficulties were reported in six articles (Bach, 2014; Loughan et al., 2016; Marcos-Arribas et al., 2013; Martín-Monzón et al., 2012; McIvor &, Moore, 2017; Vahter et al., 2014; N = 7). Visual memory difficulties were cited in four of the articles (Marcos-Arribas et al., 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; Urakami, 2016; N = 9) and verbal memory difficulties reported in all seven articles (Bach, 2014; Loughan et al., 2016; Marcos-Arribas et al., 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; Urakami, 2016; Vahter et al., 2014; N = 13). McIvor and Moore (2017) reported deterioration in immediate recall, with their untreated participant’s immediate memory score at 6 months dropping from the average to the low average range at 12 months. Within this, immediate verbal memory was within the low average range and significantly lower than predicted, however, immediate visual memory remained within the average range. The participant’s overall delayed recall index score was not significantly improved at 12 months. Delayed visual memory in particular had not significantly improved from 6 to 12 months. Marcos-Arribas et al. (2013) reported significant immediate and delayed verbal and visual recall difficulties in the first few days of the participant presenting in hospital. However, investigation of the raw scores suggests that at four weeks all recall difficulties were resolved, although statistical significance was not reported. Vahter and colleagues (2014) found severe impairments in immediate verbal recall at Day 8 of the onset of the illness, but at 8 months and 12 months these had returned to “normal”. Delayed verbal memory showed improvement in one subtest (Logical Memory II), however, other delayed verbal memory tests (Buschke) indicated moderate to severe difficulties, with Vahter and colleagues (2014) concluding that (delayed) verbal memory was the most impaired function at 8 and 12 months. The participant’s immediate and delayed visuospatial memory remained “normal” throughout testing. Martín-Monzón and colleagues (2012) participant had immediate recall difficulties at 6 months that were largely consistent at 12 months. Immediate visual recall showed no improvement by 12 months, with the participant scoring zero both times. Verbal recall deteriorated at 12 months, however it was unclear whether this was for immediate recall only or an average of both immediate and delayed recall, as only one score is reported. Loughan and colleagues (2016) reported “lowered delayed” verbal and visual recall scores in their participant when tested at 6 months. One of Bach’s (2014) participants displayed difficulties in delayed verbal memory 6 months after symptom onset, however, no serial assessments were carried out. Urakami (2016) found that group level verbal and visual memory difficulties found at 6 months had shown significant improvement after 12 months of treatment and rehabilitation, and had improved in relation to participants with herpes simplex encephalitis. Executive Functioning Deficits in executive functioning were reported in four of the seven articles (Bach, 2014; Loughan et al., 2016; Martín-Monzón et al., 2012; Vahter et al., 2014; N = 5). Bach (2014), Loughan and colleagues (2016) and Martín-Monzón and colleagues (2012) reported deficits in executive functions, such as planning, organization, reasoning, problem solving, set shifting and maintenance and category fluency at 6 months, with some difficulties remaining in Martín-Monzón and colleagues (2012) participant at 12 months. However, no statistical analyses were performed on the latter. Bach (2014) reported that one participant’s executive difficulties were sufficiently pronounced to have an impact on her reintegration into education and on her future career. However, whilst Vahter and colleagues (2014) reported deficits in some tests of executive functioning at day eight, ranging from severe to mild, these appeared to return to the “normal” range by 8 months after onset. McIvor and Moore (2017) reported that their untreated participant had some difficulty when switching was introduced to the Trail Making Test, however overall they found his performance remained largely static and was not strongly suggestive of underlying executive dysfunction. Marcos-Arribas et al. (2012) also tested for executive function but reported normal scores in these tasks. Attention and Processing Speed Six of the seven articles reported difficulties with attention and processing speed (Martín-Monzón et al., 2012; Marcos-Arribas et al., 2013; Bach, 2014; Loughan et al., 2016; Urakami, 2016; Vahter et al., 2014; N = 12), however, the majority reported mild to moderate levels of dysfunction that resolved at or before 12 months, across a range of attentional processes: selective and prolonged (Martín-Monzón et al., 2012); sustained (Loughan et al., 2016); and information processing tasks (Loughan et al., 2016; Vahter et al., 2014; Marcos-Arribas et al., 2013; Urakami, 2016). McIvor and Moore (2017) did not report any specific attentional difficulties in their patient and Urakami (2016) concluded participants with anti-NMDAR also showed significant improvement in attentional function within 12 months, in comparison to patients with herpes simplex encephalitis. Language Three articles found evidence of expressive and receptive language impairment (Bach, 2014; Loughan et al., 2016; Vahter et al., 2014; N = 4). However, language impairment was often not formally tested and had improved in all three cases after 3–6 months of treatment. Vahter and colleagues (2014) reported that 1 month after the disease onset, their participant developed progressive sensorimotor aphasia. However, 3 months after the first symptoms the aphasia had reportedly subsided. Bach (2014) qualitatively reported their participant had limited comprehension and no verbal words in the acute stage of illness. However, this improved throughout rehabilitation with only subtle deficits in language remaining. Loughan and colleagues (2016) reported language impairment in the acute phase, for which their participant received speech therapy. By the time of neuropsychological assessment 6 months post-diagnosis, his language appeared to have improved, with intact receptive language, and only mild word finding difficulties persisting. Visuospatial Abilities Only one article reported impairment in visuospatial ability specifically (Martín-Monzón et al., 2012; N = 1). Martín-Monzón and colleagues (2012) reported that their patient had difficulty, at both 6 and 12 months testing, with specific visuospatial skills such as cube analysis, position discrimination and number location. However, elementary visual perception (e.g. shape detection) and more elaborate functions (recognition of degraded stimuli, object identification) were undisturbed. Social Cognition Social cognition was only investigated in one of the eight articles (Bach, 2014; N = 2). The author used a 10-item questionnaire to assess patients’ ability to understand other people’s mental states and general cognition. Both individual participant and informant versions were given to two of the three cases studied in this article. Bach (2014) reported that one participant’s score indicated she had newly acquired difficulties in empathizing, tactfulness and ability to sympathize, together with reduced insight into these difficulties. Another patient reported new difficulties recognizing that she said things that upset others, understanding jokes, showing sympathy and being tactful. Informant scores corroborated this, however, no formal social cognitive tasks were administered. Chronic Cognitive Effects (>12 Months) Description of Cases Six out of the 10 articles presented in this review assessed patients a minimum of 1 year since disease onset/diagnosis (range 1–6.5 years; Finke et al., 2012; Finke et al., 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; McKeon et al., 2016; Vahter et al., 2014). A total of 43 participants were studied across the six articles, mean age 27.6 (the approximate range was 16–44, however, two papers only reported the mean). Again, there were more female participants than male (37F:6M). All the papers were “Medium” quality, except Vahter and colleagues (2014), which was scored as a “Low” quality paper. Memory Memory difficulties persisting after the acute 12-month period were reported in all six articles (N = 43). Working/Short-term Memory Working and short-term memory difficulties were cited in five of the studies (Finke et al., 2012, 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; McKeon et al., 2016; N = 42). Finke and colleagues (2012), in their study of nine participants tested at a median of 43 months (range 23–69 months) after disease onset, found significant impairments in working memory in four of the participants, in the routine neuropsychological assessment of working memory. The authors also administered an additional battery of short-term memory (STM) tasks (delayed match-to-sample tasks), which they claim have been previously validated in patients with hippocampal damage (Braun et al., 2008; Finke et al., 2008). Participants were required to remember the color, location or the association of color and location of visual stimuli across delays of 900 or 5,000 ms. They found that five participants had delay-dependent deficits in some aspect of this battery. However, they reported that three of these participants performed normally in the routine neuropsychological assessment of STM memory. Finke and colleagues (2013) also reported that their participants (N = 24) showed substantial deficits in working memory at a median of 35 months after disease onset. Furthermore, McKeon and colleagues (2016) found the scores of their anti-NMDAR participant group fell significantly below (medium to large effect sizes) the control group in working memory. Martín-Monzón and colleagues (2012) report improvements in memory tasks at the 72-month follow-up. However, examination of the participant’s raw scores suggests some residual impairment in working memory (on subtests of the WAIS-III). McIvor and Moore (2017) found their untreated participant’s visual working memory remained largely unchanged from 6 to 30 months, staying in the low average range. However, his visual working memory score was largely impacted by his spatial addition score, which was significantly lower than predicted. Episodic Recall Immediate recall difficulties were found in four of the six articles (Finke et al., 2012, 2013; Martín-Monzón et al., 2012; McKeon et al., 2016,N = 41) and delayed recall difficulties in five articles (Finke et al., 2012, 2013; Martín-Monzón et al., 2012; McKeon et al., 2016; Vahter et al., 2014; N = 42). Verbal memory difficulties were also reported in five of the articles (Finke et al., 2012, 2013; McIvor & Moore, 2017; McKeon et al., 2016; Vahter et al., 2014; N = 42) and visual memory difficulties reported in two articles (Finke et al., 2012; Martín-Monzón et al., 2012; N = 10). McKeon and colleagues (2016) found that the scores of the anti-NMDAR participant group fell significantly below the control group in tests of verbal immediate and delayed recall, but not immediate or delayed visual recall. Similarly, Finke and colleagues (2013) also observed significant impairments in immediate and delayed verbal recall, but not visual, across 24 participants. Finke and colleagues (2012) reported significantly impaired immediate and delayed verbal recall in two of their nine participants and significantly impaired immediate and delayed visual recall in one participant. Vahter and colleagues (2014) found that 20 months after disease onset there remained a mild deficit in verbal delayed memory. They concluded that the most impaired function at long-term follow-up was delayed verbal memory, however, significance levels were not reported. McIvor and Moore (2017) reported that their untreated participant’s verbal memory index at 30 months was comparable to his score at 12 months and so was not deemed to be a statistically significant change. However, his immediate and delayed verbal memory scores were in the average range. Martín-Monzón and colleagues (2012) single case study showed persistent immediate and delayed visual recall difficulties 6 years after disease onset, whilst verbal memory showed improvement. However, it is unclear whether the scores reflected clinically significant change. Furthermore, again, verbal memory was not divided into immediate and delayed recall so it is unknown if one was preferentially improved. Finke and colleagues (2012) found that in their specific STM battery, five participants had deficits in either STM of locations and/or color–location associations, suggesting difficulties with immediate visual memory. Executive Functioning Executive functioning difficulties were reported in five of the six articles (Finke et al., 2012; 2013; Martín-Monzón et al., 2012; McIvor & Moore, 2017; McKeon et al., 2016; N = 42), with difficulties such as reasoning, rule finding, set shifting and set maintenance, category fluency visuospatial planning/organization, and problem solving. Finke and colleagues (2012) found persistent impairments in executive functioning in five of nine patients. Finke and colleagues (2013) reported substantial group deficits in executive functions (N = 24), although this appeared to be based only on performance in the STROOP test. Nonetheless, of the 24 participants, five did subjectively report executive functioning difficulties. McKeon and colleagues (2016) found the anti-NMDAR patients’ group performance was significantly below matched controls for some aspects of executive functioning (visuospatial planning/organization and problem solving) but not others (abstraction, response inhibition, flexibility, and verbal fluency). They reported that aspects of executive functioning were amongst the most severely affected abilities at the individual level, but profiles ranged from “normal” to “extensive dysfunction”. Martín-Monzón and colleagues (2012) participant showed some improvement in certain tests of executive functioning at 72 months post-initial onset, however, it is unclear whether these scores fell within “normal” ranges. Vahter and colleagues (2014) found their participant’s test scores in executive functioning remained in the normal range at 20 months. McIvor and Moore (2017) found some increased variability in individual task performance for executive functioning at 30 months, compared to 6 months. However, as before, they concluded his results were not strongly suggestive of underlying executive dysfunction. Attention and Processing Speed Attention and processing speed difficulties were reported in two of the articles (Finke et al., 2012; McKeon et al., 2016; N = 16). Finke and colleagues (2012) observed impairments in attention in four of their nine participants, with one of these four patients also subjectively reporting attention difficulties. McKeon and colleagues (2016) found medium to large effect size differences between the anti-NMDAR participants and the control group for both sustained and divided attention and information processing speed. Seven out of 24 patients in the study by Finke and colleagues (2013) subjectively reported difficulties with attention. However, the authors reported neuropsychological tests showed intact attention. Language Language was investigated in three of the six articles for long-term follow up (Finke et al., 2013; Martín-Monzón et al., 2012; McKeon et al., 2016; N = 32) but no deficits were found. McKeon and colleagues (2016) reported that expressive language (Vocabulary, Graded Naming Test, spontaneous speech) was comparable between the anti-NMDAR group and matched controls. Finke and colleagues (2013) and Martin et al. (2012) both reported that testing revealed language was intact in their patients. Visuospatial Abilities Visuospatial difficulties were reported in one of the six articles (McKeon et al., 2016; N = 7) and tested in an additional three articles but no impairments were found (Finke et al., 2013; Martín-Monzón et al., 2012; Vahter et al., 2014; N = 32). McKeon and colleagues (2016) tested for visuospatial organization via the Rey figure copy and found a significant difference between the anti-NMDAR participants and matched controls. Social Cognition Only one article tested for social cognition (McKeon et al., 2016; N = 7), with this being the main aim of the study. McKeon and colleagues (2016) administered the Mind in the Eyes Test, Advanced Test of Malingering (ToM), the Social Situations Test and the Emotion Attribution Task to seven patients with anti-NMDAR and compared their scores to matched controls. They found significant differences between the groups on using mental-state information to make sense of social situations and judge the severity of interpersonal violations. Subjectively four out of the seven participants reported social withdrawal and one participant specifically reported occasional misinterpretation of social situations. McKeon and colleagues (2016) report that subjective social dysfunction experienced by participants can correspond to deficits in social cognition tasks and that anti-NMDAR may adversely affect the ability to decode and adaptively use mental-state information. However, the authors recognized their small sample size and that they ran many statistical comparisons. Therefore, they suggest the results should be interpreted cautiously. Discussion Acute Cognitive Effects (≤12 Months) Memory was the cognitive domain most tested, with all seven articles citing significant difficulties with some aspect of memory in their participants. Delayed verbal memory was the most commonly reported memory difficulty in all seven articles. Immediate and visual memory were the next most cited difficulties in four articles. Working/short-term memory difficulties were only reported in three of the articles. Attentional and processing speed difficulties were highly reported, in six of the seven articles, however these difficulties appeared to largely resolve across the first 12 months since disease onset/diagnosis. Four of the seven articles cited some form of executive dysfunction, such as difficulties problem solving, rule finding and set shifting. Language impairments were found in three articles, with word finding and verbal fluency being the most frequently evidenced deficits. Visuospatial difficulties were found in only two of the studies. Social cognition was the least explored cognitive domain with only one of the articles examining social cognition. However, formal neuropsychological testing was not used. Chronic Cognitive Effects (>12 Months) Memory was, again, one of the cognitive domains most affected in the chronic phase. Persistent memory difficulties of some form were reported in all six articles. Delayed verbal memory was also the most commonly discussed deficit in the chronic phase, reported in five articles. Working/short-term memory difficulties were the second most commonly reported difficulty, present in five of the articles. Immediate recall difficulties were reported in four of the articles and visual memory difficulties in only two articles. Executive dysfunction was a frequently reported deficit in the chronic phase, reported in five of the six articles. However, again, these differed greatly between participants, both within studies and between studies, with difficulties from problem solving to response inhibition and varying from mild to severe. Attention/processing speed difficulties were reported in only two of the articles. Visuospatial difficulties were only reported in one article and language difficulties were not found in any of the current articles. Social cognition was again the least explored cognitive domain, with only one article assessing social cognition and finding impairment. However, they did use formal neuropsychological testing, albeit on a small case sample. Summary of Findings Memory was the cognitive domain most affected by anti-NMDAR in these studies, with all articles citing some form of memory difficulty. Deficit in memory is consistent with knowledge that NMDA receptors are highly concentrated in the limbic system, particularly the hippocampus, and are essential to aspects of learning and memory (Kruse et al., 2014; Lo et al., 2010). Although NMDARs are thought to reactivate after immunological recovery has taken place, it is thought not possible for the grey and white matter to be increased (Martín-Monzón et al., 2012). This was reported by Finke and colleagues (2016), who found evidence for long-standing reduced microstructural integrity of both hippocampi, relative to controls. They reported that disease severity and duration predicted the extent of hippocampal damage, which then correlated with memory performance. They also found volumes of the left hippocampal formation correlated with verbal memory performance, which is in line with the theorized specificity of the left hippocampus for verbal stimuli and consistent with the findings of delayed verbal memory difficulties in all the current 10 articles. Executive functioning difficulties were reported in eight of the 10 articles overall. However, results for the executive functioning tasks were variable, with deficits found across a variety of different tests, and participants’ scores ranging from normal to severe. This is perhaps not surprising given that “executive function” is an umbrella term that overarches a wide range of quite divergent skills and functions (Elliott, 2003). Nonetheless, these findings may be accounted for by Finke and colleagues (2013) who found reduced functional connectivity between the hippocampus bilaterally and the aDMN. The DMN includes the medial prefrontal cortex, which is associated with executive functions and working memory (Finke et al., 2013). The findings of this adult population appear to be slightly varied from pediatric and adolescent cases, which seem diverse within themselves. Iadisernia and colleagues (2012) found deficits in attention, executive functioning, verbal fluency, and rapid naming in two pediatric patients. Poloni et al. (2010) also reported attention difficulties, together with deficits in working memory in one pediatric patient. Gitiaux and colleagues (2013) reported that three of the six children tested at follow up (median duration of 12 months; range 10 months to 5 years) received special education due to persistent semantic memory deficit (word retrieval difficulties) and visual episodic and working memory impairment. Matricardi and colleagues (2016) found over half of their pediatric patients (total of 11) had residual deficits indicating frontal lobe dysfunction after, at least, a 1 year follow-up. Overall, investigation of neuropsychological sequelae in pediatric cases is extremely limited, indicating a need for more larger scale studies. Limitations This systematic review provides a summary of cognitive difficulties commonly reported in 10 neuropsychological case studies/series. However, the results should be interpreted with caution given the large number of extraneous variables present. The articles differed greatly, with disparities in for example, whether participants received neurorehabilitation and which tests were used (Table 2). This necessitated a narrative review because data synthesis was precluded, meaning more tentative conclusions were drawn regarding a cognitive profile for this population. It is recognized that the “chronic” phase is a large timeframe (up to 6.5 years), however, the given the infancy of the current literature base, there was an insufficient number of case studies to further subdivide this time period. Future systematic reviews could attend to this, particularly given the potential for improved cognitive functioning over time. Furthermore, the severity of the illness, for example whether there was intensive care treatment, is not indexed or reported consistently, nor are details of the treatments and when they were commenced and completed. Impact of the treatments, such as corticosteroids and Rituximab should also be taken into consideration as these can cause side effects such as fatigue, flu-like symptoms and pain (Cancer Research UK, 2015; Ikeguchi et al., 2012), all of which could negatively impact participant’s test scores (Lezak, 2012, p. 125). Of particular note is the protracted use of corticosteroids, which have been implicated in cognitive difficulties referred to as a “steroid dementia” (Brown, 2009; Keenan et al., 1996; Sacks & Shulman, 2005; Wolkowitz, Lupien, & Bigler, 2007; Wolkowitz, Lupien, Bigler, Levin, & Canick, 2004). There remains a scarcity of research in this area, particularly high quality research. Most studies in this review were of “Medium” quality. Reporting of the cases was not strong, with a significant lack of reporting of important neuropsychological variables such as, pre-morbid intellectual functioning, psychiatric history and any existing acquired brain injury (ABI; Hebben & Milberg, 2009). For example, pre-morbid functioning was not estimated in half of the papers studied and even when it was assessed it was often not appropriately compared to the IQ score at the time of testing. This is despite analysis of the raw scores indicating there was not a statistical difference between the two (Finke et al., 2012, 2013; McKeon et al., 2016). Without sufficient background information, it cannot be confirmed whether any cognitive difficulties found represent the direct impact of anti-NMDAR on cognitive functioning. Furthermore, often participants acted as their own control, with repeated testing, but sufficient discussion was not given to a host of other possible extraneous variables. For example, whether there were practice effects, how the participant presented on that day, whether the same test conditions were in place, and whether the same person administered the battery each time. If test scores did differ across administrations, it would be difficult to attribute this entirely to a change in cognitive functioning. The reporting of the scores was typically weak, often with a mixture of raw scores and index scores within the same articles’ results section, and little discussion of whether a change in scores across administrations reflected clinically significant change (for example, Martín-Monzón et al., 2012). Half of the studies were single case studies or series and so only offer limited insight into how cognitive difficulties may present in people with anti-NMDAR. The chronic cognitive deficits discussed in this study have increased generalizability due to the larger case studies included (Finke et al., 2012, 2013; McKeon et al., 2016; N = 40) and so provide greater evidence of the chronic cognitive effects of anti-NMDAR. This is promising given that chronic effects of anti-NMDAR are arguably more pertinent to investigate due to their potential impact on important aspects of day-to-day functioning, such as return to work. However, the data are insufficient to allow interpretation for predicting cognitive function at specific time points within the “chronic phase”. Despite the potential for cognitive functioning to impact day-to-day functioning, this remained largely unexamined in the current papers. Furthermore, the meaning the individuals then ascribed to their level of participation, and overall quality of life (QoL), remained equally unexamined. The latter is important to assess given the mixed findings in other neurological conditions of the impact of cognitive functioning on QoL (Baumstarck-Barrau et al., 2011; Benedict et al., 2005; Dijkers, 2004; Glanz et al., 2010; Goretti et al., 2010; Ponsford, Draper, & Schönberger, 2008; Siponkoski, Wilson, Steinbüchel, Sarajuuri & Koskinen, 2013; Tate, Broe, Cameron, Hodgkinson, & Soo, 2005). In a study of 109 encephalitis survivors Ramanuj and colleagues (2014) found that a poor Glasgow Outcome Score was the most strongly associated with a poor Health Related QoL (HRQoL). Further, that less than half of participants who made a “good” recovery reported a HRQoL equivalent to the general population (Ramanuj et al., 2014). This suggests that the impact of encephalitis had adverse effects on many survivors’ QoL. However, these participants did not undergo neuropsychological testing, so the direct impact of cognitive functioning on QoL cannot be discussed. In the current reviewed articles, subjective complaints were only stated in five of the 10 papers, and were usually reported in table form or only briefly in the main body. Furthermore, only Bach (2014) administered a formal measure, finding significant increases in satisfaction at follow-up on the QOLIBRI-OS (von Steinbuechel et al., 2012). Psychological wellbeing was also only explored in four of the 10 articles. This is significant given that if individuals perceive themselves to have cognitive difficulties, and feel they impact on their participation in their usual day-to-day life, this would likely cause anxiety and interact with the person’s ability to engage meaningfully in neuropsychological assessment. Researchers who did assess psychological wellbeing largely administered either the Hospital Anxiety and Depression Scale (Snaith, 2003) or the Beck Anxiety and Depression Inventories (Beck and Steer, 1990; Beck, Steer & Brown, 1996). Only two articles (Bach, 2014; McKeon et al., 2016) discussed the impact of mood on functioning and QoL, either in the results section or discussion. Specific psychosocial difficulties such as the individual’s reconstruction of their identity (Charmaz, 1983) were also not explored in these articles or any other articles on anti-NMDAR encephalitis to date. A specific battery of cognitive assessments has not yet been devised to screen for cognitive deficits in anti-NMDAR. As discussed, whilst there were overlaps between tests used across the studies, there was disparity between the cognitive domains tested and which tests were used to examine performance in these domains (Table 2). Instead a “scattergun” approach appears to have been used, often with an extensive neuropsychological battery administered to see if any impairments can be detected. However, this approach can lead to Type I errors (Schatz, Jay, McComb, & McLaughlin, 2005). An exception to this was Finke and colleagues (2012) who reported that they conducted a neuropsychological assessment using memory tasks they claimed had previously been shown sensitive to hippocampal dysfunction. Ecological validity of the neuropsychological assessments used was also not discussed, which is important given most tests used were not specifically designed to predict real-life functioning, such as the ability to live independently or return to work (Chaytor and Schmitter-Edgecombe, 2003; Sbordone, 2001). In these tests, the real-world context is removed and can be completed with few distractions, giving an artificial performance. As such the verisimilitude and veridicality approaches should be considered in future research (Spooner & Pachana, 2006). Selection bias was evident across articles as participants typically recruited to the studies were opportunistically sampled from referrals to neurology or neuropsychology departments. Participants may have been chosen if their presentation was particularly unique (Barić, Andrijašević, & Beydoun, 2013; Rison, 2013; Rison, Shepphird & Beydoun, 2016; Wong, 2008), which may skew the cognitive profile detected for this population. Finally, given that there were few pediatric case studies available and given the potential differences between child/adolescent and adult neurobiology, case studies with individuals under the age of 18 were not included, which could be seen to limit this review. Suggestions for Theory and Further Research There is an overall lack of research into the neuropsychological sequelae of anti-NMDAR encephalitis and larger case studies are warranted to develop a more robust cognitive profile for this population. Chronic cognitive deficits have been found in seven articles, with two studies reporting difficulties up to six years after onset (Finke et al., 2013; Martín-Monzón et al., 2012). Therefore, longitudinal neuropsychological testing would be recommended. Further studies are needed to examine the cognitive effects of anti-NMDAR in children/adolescents and to allow future systematic reviews to establish a cognitive profile for this population or across the lifespan. Professional consensus on a neuropsychological battery, grounded in neuropsychological theory, is needed to reduce the number of extraneous variables and provide replicability and generalizability. In their case series of three adolescents, Hinkle and colleagues (2017) concluded with the recommendation that batteries that formally assess memory, executive functioning, as well as language and attention, may be the most sensitive in identifying the common cognitive sequelae in anti-NMDAR. However, further professional opinion is needed regarding an appropriate battery. Larger scale research projects would also help reduce selection bias and extraneous variables and would enable a more scientific approach to developing a cognitive profile for this population, rather than opportunistic sampling. Furthermore, careful consideration should be given to the utility and ethics of performing neuropsychological tests in clinical settings and how these results are fed back to patients (BPS, 2009; Monden, Gentry, & Cox, 2016). A small number of studies (N = 5) have begun investigating the benefits of neurorehabilitation, however, further larger scale studies are needed for the anti-NMDAR group. Gracey, Evans, and Malley (2009) propose a Y-shaped model for rehabilitation in ABI, which identifies key discrepancies, such as between pre-injury and current self, and suggests how these could be targeted in rehabilitation. A model such as the Y-Shaped could be a useful tool for application with people with an ABI as a result of anti-NMDAR. Anti-NMDAR is a relatively newly categorized illness (Dalmau et al., 2007) and as such so far there has been a focus on the medical understanding of the illness, with increasing drive towards neuropsychological understanding. However, taking into consideration the biopsychosocial approach, there is a need for understanding the psychological and social factors associated with the illness, as well as the biomedical, and the interactions between all three (Gracey et al., 2009). Understanding the impact of this illness on QoL is crucial if health care professionals aim to provide person-centered care and improve the wellbeing of people diagnosed with anti-NMDAR. Future research needs to be focussed on the personal meaning of the illness to the individual (Gracey et al., 2009). Conclusions A systematic review of the current literature suggests that the neuropsychological sequelae for anti-NMDAR encephalitis can include memory impairments, particularly delayed verbal memory; executive dysfunction and attentional/processing speed difficulties in the acute phase. However, further high quality studies are needed in this area to form a more substantial cognitive profile for this population. Psychological studies into this client group are so far absent and as such studies investigating individual experience of the illness and its impact on quality of life should be undertaken in the first instance. Supplementary Material Supplementary material is available at Archives of Clinical Neuropsychology online. Conflict of Interest None declared. Acknowledgements With special thanks to Dr Jessica Quirke, Consultant Clinical Neuropsychologist, for providing valuable feedback and advice. References Bach, L. J. ( 2014). Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis: case reports. NeuroRehabilitation , 35, 863– 875. Barić, H., Andrijašević, L., & Beydoun, S. R. ( 2013). Why should medical editors CARE about case reports? Croatian Medical Journal , 54, 507– 509. http://doi.org/10.3325/cmj.2013.54.507. Google Scholar CrossRef Search ADS   Barry, H., Byrne, S., Barrett, E., Murphy, K. C., & Cotter, D. R. ( 2015). 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Published: Mar 31, 2018

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