NeuroRehabilitation 35 (2014) 863–875 DOI:10.3233/NRE-141176 IOS Press

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Case Report

Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis: Case reports Laura J. Bach Specialist Acquired Brain Injury Unit Outreach Team, Homerton University Hospital, Homerton Row, London E9 6SR, UK Tel.: +44 208 510 7967; Fax: +44 208 510 7640 E-mail: [email protected]

Abstract. BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an auto immune-disorder. It is a life threatening condition that typically presents with viral illness, headaches, severe psychiatric symptoms, seizures, behavioural changes, decreasing levels of unconsciousness and progressive unresponsiveness, cognitive impairment, abnormal movements (e.g., dyskinesia), ataxia and hypoventilation. OBJECTIVE: This paper describes the long term outcome and rehabilitation management of patients with NMDAR encephalitis and highlights the diverse outcome of this condition and the unique and individual long term management needs associated with this disorder. METHODS: This is a case report study of three different patients with NMDAR encephalitis. All three cases are young women, two of whom presented with ovarian teratoma. Patient KH is the most impaired and was resident in a slow stream rehabilitation care home and presented with challenging behaviour. Patients RM and OA both lived in the community and presented with similar anxieties but diverse levels of cognition and motivation. A review of the literature is provided summarizing the disorder, interventions, management and challenges of this varied and complex condition. Standard neuropsychological tests and questionnaires to assess community integration (BICRO-39), quality of life (QOLIBRI-OS) and mood (HADS) were administered. RESULTS: Positive outcomes were achieved for all three patients using a variety of interventions which included behavioural management, family psycho-education and an integrated holistic multi-disciplinary team community approach. Memory and executive deficits were persistent in the long term and severity of impairments showed wide variability between patients. Emotional distress and behavioural difficulties were prominent and persistent and had a pronounced impact on rehabilitation. Continence issues were also a major factor impacting on the rehabilitation. CONCLUSIONS: Long term integrated and multi-disciplinary input by a variety of therapies and health disciplines is required in order to improve the long term outcome and quality of life for NMDAR patients and their families, and ultimately leads to improved positive outcomes. Each of these cases had markedly differing cognitive profiles suggesting that in the context of long term rehabilitation outcome, cognition may have less valence than emotional and behavioural factors. Guidelines and standardised procedures for ethical issues and counselling for iatrogenic infertility should be developed and integrated into long term programmes of rehabilitation care. Keywords: NMDAR, rehabilitation outcome, community integration, BICRO, QOLIBRI, quality of life, fertility, cognition

1053-8135/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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L.J. Bach / Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis

1. Introduction In recent years there has been a burgeoning interest by clinicians in anti-NMDA receptor (NMDAR) encephalitis, as reflected in a steadily growing medical literature and increasing number of publications in medical journals. This is primarily the result of the characterisation and categorisation of this disease by Dalmau and colleagues in 2005 who provided a comprehensive description in their report of 2007. NMDAR encephalitis is an acute form of encephalitis. It is an auto-immune reaction primarily against the NR1 subunit of the NMDA receptor. It has a complex presentation and frequently is associated with a teratoma tumour and is thus considered a paraneoplastic syndrome. The overall incidence of the condition is unknown (Pruss et al., 2010). The California Encephalitis Project (CEP) was established in 2007 to study the epidemiology of encephalitis. The CEP reported a higher incidence of NMDAR encephalitis compared to other types of viral-induced encephalitis; specifically, NMDAR encephalitis was identified as significantly occurring more than 4 times as frequently as HSV-1, WNV, or VZV. 65% of NMDAR encephalitis occurred in patients aged ≤18 years and females were affected significantly more often than males, at nearly 3 times the rate compared to other causes of encephalitis (Gable et al., 2012). In the UK, Granerod, Ambrose, Clewley et al. (2010) conducted a prospective study over two years of 203 patients with encephalitis in England and found 42% had infectious causes and 4% of these were the result of NMDAR encephalitis. NMDAR encephalitis typically presents with predominantly psychiatric symptoms; acute behavioural change, psychosis, and catatonia, and generally develops with seizures, cognitive deficits of memory loss and speech problems, dyskinesia and breathing dysregulation (Titulaer et al., 2013; Consoli et al., 2011). Psychiatric and behavioural changes commonly include agitated aggression, anxiety, avoidance, phobic preoccupations and obsessive-compulsive behaviours, withdrawal, depression, auditory and visual hallucinations, paranoid ideations and delusions, hyper- or hypo-somnia, mood lability, inhibition and hypersexuality (Titulaer et al., 2013). NMDAR encephalitis presents across the whole age spectrum; in children, adolescents, adults and in elderly individuals (Lim et al., 2014; Titulaer et al., 2013; Gable et al., 2012; Florance et al., 2009; Dalmau et al., 2008). There has been one report of a three year old boy diagnosed with NMDAR

subsequent to a respiratory infection one month previously which has suggested a putative genetic factor may predispose individuals to this particular autoimmune disorder (Verhelst et al., 2011). It may occur with or without tumour, mostly teratoma of the ovaries. Reports have documented approximately 50% of cases present with ovarian teratoma (Florance et al., 2005; Dalmau et al., 2007; Irani et al., 2010) and in males NMDAR encephalitis may be associated with testicular tumours (Florance et al., 2009; Irani et al., 2010). However, there are a substantial number of cases with no detectable tumour (Irani et al., 2010, Lim et al., 2014). For patients with tumour, the long term prognosis is generally better and the chance of relapse is much lower. Frequency of tumours is less in children and increases with age; 9% of girls under 14 years of age rising to 40% of girls under 18 years (Florance et al, 2009). Early diagnosis and treatment has been shown to significantly improve patient outcome (Fink et al., 2012). Presentation differs across ages; adults typically present with psychiatric signs whereas children tend to present with neurological and movement disorders (ataxia and hemiparesis) (Titulaer et al., 2013; Dalmau et al., 2011). A number of reports describe catatonia associated with NMDAR encephalitis in adolescents successfully treated with immuno-suppressive therapy and plasma exchange (Consoli et al., 2001; Lee, Glick, Dinwiddie, 2006; Schimmel et al., 2009). Consoli et al. (2006) have thus emphasized the importance to search for a medical condition or etiology when young people present with catatonia in order to expediate provision of treatment and avoid severe neurological sequelae or death. With regard to differential diagnosis, magnetic resonance imaging (MRI) scans, electroencephalogram (EEG) and cerebrospinal fluid (CSF) examinations are often normal; with a third to just under half of patients’ MRI scans showing only minor, non-specific signs (Titulaer et al., 2013, Gable et al., 2012). Abnormal EEGs are relatively high with reports of 79% to 88% of EEGs exhibiting diffuse slow activity, highly expressed in frontal and limbic areas. 90% demonstrate pleocytosis and elevated protein concentration in CSF (Titulaer et al., 2013). Gable et al. (2012) echo the sentiments of Consili et al. (2006) in focusing attention on ‘the preponderance of psychiatric symptoms, primarily psychosis with hallucinations and personality change, usually in combination with EEG or MRI abnormalities that do not converge on the temporal lobe, and lower levels of pleocytosis and protein content in the CSF serve to highlight this diagnosis’.

L.J. Bach / Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis

Psychiatric symptoms and movement disorders are more prevalent in NMDAR encephalitis compared to encephalitis of other viral origins. Gable et al. (2012) report hallucinations, psychosis and movement disorders, in about two-thirds or more of NMDAR cases compared with 20% or less cases associated with other etiologies. Due to the preponderance of psychiatric symptoms most NMDAR encephalitis patients are seen by psychiatrists, rather than neurologists, and it is therefore crucial that all physicians (especially psychiatrists) consider NMDAR encephalitis as a cause for acute psychosis in individuals with no past neuropsychiatric history. The disorder typically evolves through a number of stages and outcome can range from medically full recovery, to very limited recovery or death in 25% of cases (Consoli et al., 2011). The Prodromal phase is characterised by a nonspecific cold or viral like symptoms (fever, fatigue or headache) lasting a mean period of 5 days, after which the development of psychobehavioral symptoms emerge. This Psychotic phase occurs within 2 weeks (mean 6.8 days) of developing symptoms and is characterised by emotional disturbance (apathy, lack of emotion, depression, loneliness, fear), cognitive decline (e.g. difficulty using everyday devices e.g. mobile phone), prominent schizophrenia like symptoms (disorganized thinking, compulsive ideation, delusions, hallucinations, and loss of self-awareness), amnesia (not prominent at onset), strange behaviours (e.g. staring oddly at self-reflection in a mirror). The third stage comprises an Unresponsive phase including catalepsy-like symptoms (mute, akinetic, unresponsive to verbal commands while keeping their eye open), bizarre and inappropriate smiling, dystonic postures, echo phenomenon (mimicking the examiner’s movement), normal brainstem reflexes, but no eye movement with visual threat. This is followed by a Hyperkinetic phase where the patient gradually develops orolingual dyskinesias (lip licking or chewing, and athetoid dystonic postures of the fingers), intractable bizarre orofacial-limb dyskinesias, sustained jaw movements, forceful clenching of the teeth, jaw-opening dystonia, grimacing, intermittent ocular deviation or disconjugation, athetoid dystonic movements, and dancing-like movements of the arms) and symptoms of autonomic instability. The final stage is the gradual Recovery phase. It is typically slow, symptoms may relapse, especially in patients with undetected or recurrent tumours and patients with no associated tumours. Duration of the hospital admission is approximately 2 to 14 months (mean 7 months). It is important for all professionals

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involved in the long term care of these patients following medical recovery, to be aware of the stages that these patients journey through as this has significant implications for both patients and their families for long term management and rehabilitation which will be further elaborated in the discussion section. NMDA receptors are critically involved in synaptic transmission and learning related plasticity and these receptors are highly expressed in forebrain, limbic system and hypothalamus (Chapman and Vause, 2011; Li and Tzien, 2009; Onur et al., 2012). One outcome of the disorder is persisting amnesia for the acute stage. This is not surprising due to the disruption of synaptic processes in limbic structures and especially the hippocampus which is critically involved in aspects of memory and learning. Recovery from this disorder is typically slow, and relapse may occur. Identification of the disorder is fairly new thus the extant literature on treatments and outcomes remains fairly limited. Titulaer et al. (2013) found that 81% of a cohort of 577 patients had a good outcome (i.e. improvement from severe to slight disability and no need for admission to an intensive care unit) in the first 24 months following diagnosis, and 45 patients (12%) had a relapse requiring continued immunotherapy and supportive care in intensive care. Predictors of good outcome were early treatment and no admission to an intensive care unit. Chapman and Vause (2011) note however that even in cases of full recovery or those with only mild persistent deficits more than 85% of patients show significant psychiatric symptoms at time of discharge with persistent cognitive deficits of memory loss, impairments in executive function, including inattention, poor organisation and planning difficulties, disinhibition and lack of impulse control. More optimistically, Iizuka, Yoshii, Kan, Hamada, Dalmau, Sakai, and Mochizuki (2010) followed up two patients, with severe NMDAR encephalitis, over 4 to 5 years and found not only improved cognitive function but a dramatic improvement of the atrophy and frontotemporal hypofusion indicating that the severe and prolonged deficits in NMDAR encephalitis are potentially reversible, and further suggesting that long-term rehabilitation input is potentially warranted for these patients. Due to the rarity, and the largely unfamiliarity within the medical profession of this disorder, there are very few reports in the literature describing the long term rehabilitation of patients with NMDAR encephalitis. Indeed, this author found only two reports outlining rehabilitation outcome in adults; Tham and

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Kong, (2012), and Mart´ın-Monz´on, Trujillo-Pozo and Romer´o (2012). Tham and Kong describe a single case within a subacute rehabilitation unit and report on the importance of the role of multi-disciplinary input. Mart´ın-Monz´on, Trujillo-Pozo and Romer´o (2102) also report a single case study and focus on the neuropsychological outcome. They describe a 35 year old woman who suffered 4 relapses over a period of three and a half years. Cognitive assessment was conducted at 6, 12 and 72 months post disease onset to monitor her progress. Additionally MRI brain scans were performed over this 6 year period. Memory recall and recognition, learning, executive function and visuo-perceptual skills were impaired at 6 and 12 month post diagnosis however at 72 months significant improvements were noted in attention, memory, and problem-solving. MRI at 6 months and 12 months was abnormal in limbic structures including hippocampus. At 72 months atrophy was observed in hippocampus bilaterally. Despite temporal lobe atrophy this patient demonstrated improved general intellectual function (IQ), memory and learning at 72 months indicating the positive benefits of neurorehabilitation in the long-term. The complex nature and presentation of NMDAR encephalitis, means that treatment needs to be individualised. Physiotherapy and Occupational therapy input is required to address and manage general physical deconditioning and difficulties with functional activities of daily living skills. Swallowing, feeding and speech problems require input from Speech and Language therapy and psychiatric, cognitive, behavioural and emotional problems need support from psychiatry and neuropsychology input. Thus an integrated multi-disciplinary team approach should be taken. Fink, Kopp, Pr¨uss, Dalmau et al. (2012) have described the long term post-acute cognitive impairments present in a small sample (N = 9) of patients with NMDAR encephalitis. 89% at three and a half years post diagnosis demonstrated memory and executive deficits and severity of deficits was variable between cases. Fink et al. (2012) further noted that severity of deficits was associated with time of immunosuppressive treatment, with those patients who had received early treatment showing less severe cognitive deficits. This case series describes the management and long term outcome of NMDAR encephalitis in three different patients referred to a community rehabilitation team. The behavioural and psychological management of this relatively rare syndrome is presented with a view to highlighting the long term challenges and support required for this condition.

1.1. Case study 1 (KH) This case presents the use of targeting emotional memory as a mechanism to facilitate the reduction of aggressive, non-compliant behaviour during rehabilitation, in a 28 year old, young woman, with NMDAR encephalitis. Specific interventions included personalised and meaningful goals based on emotional memories which were employed to reduce challenging behaviour during rehabilitation. Mobility goals in physiotherapy were associated with meaningful emotional memories as a method of positive reinforcement to facilitate engagement. A positive outcome was rapidly attained using this strategy. This case study manipulated both antecedent environmental factors and consequences within an operant behavioural paradigm. The behavioural program was embedded within a neuropsychological framework that took into consideration the cognitive, neuroanatomical and personal context of the patient and their brain injury. 1.1.1. Background KH is a 28 year old, right handed, young woman who suffered antibody NMDAR encephalitis and bilateral frontal infarcts. She initially presented with headaches, behavioural disturbance, hallucinations and agitation. She had an oophorectomy and EEG established the presence of tonic clonic seizures. KH was admitted to the Regional Neuro Rehabilitation Unit (RNRU), Homerton University Hospital. During her admission she had a severely disrupted sleep-wake cycle. For example, she would sleep for two days and then be awake for two days. She had no verbal words but did recognise her family. Itching episodes were observed which were considered to be behavioural. She was pegfed. Her seizures were on-going. She was discharged after 6 months to a Care Home, for slow stream rehabilitation. 10 months later KH was referred to the RNRU Outreach team for assessment and management of challenging behaviour which was adversely impacting on her rehabilitation at the Care Home. She was initially assessed by the neuropsychologist from the RNRU Outreach team a year later i.e. two and a half years post initial diagnosis of NMDAR encephalitis. KH’s current medication included anti-seizure medication, steroids, warfarin and antipsychotics. KH had shown some improvements but also some deterioration since admission to the care home. She no longer had a disrupted sleep-wake cycle. She was continent during the day and able to engage in some personal activities of daily living e.g. she was able to comb her hair

L.J. Bach / Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis

independently, blow dry her own hair, brush her teeth independently and help with putting on the top half of her clothes. Her communication and verbal comprehension had improved; KH was consistent with her responses. However her seizures persisted. 1.1.2. Cognition KH showed reduced attention and was easily distracted. Her short term episodic memory was impaired, but repetition did facilitate learning. Her emotional memories were strong and intact. For example, she was able to remember her wedding and holidays. Her comprehension, reasoning and executive function were limited. She appeared rigid in her thinking and was unable to link concepts such as the need for rehabilitation and the positive implications of rehabilitation. Her own focus was mainly on her immediate needs. Her insight into her cognitive deficits was impaired. 1.1.3. Communication Her verbal communication was limited due to severe dysarthria and cognitive communication difficulties and she used an alphabet chart and a word app to communicate basic needs. She was able to follow single stage commands and give some limited verbal responses. For example, she was able to say the name of her husband, Mum, Dad, and her dogs’ names. 1.1.4. Current behaviour KH showed challenging behaviour; she did not like wearing her leg splints nor enjoy physiotherapy exercises. She found the leg splints painful and had been refusing to wear them. She avoided engaging in her physiotherapy session and exhibited physical aggression by kicking out. Frequency of this behaviour was daily as she was requested to wear her splints every day. 1.1.5. Behavioural program At baseline (see Fig. 1) KH was refusing to wear her splints and refusing to walk in the parallel bars. The therapist’s goal was to get KH to wear her splints and engage in walking in the parallel bars during her physiotherapy session. The motivational goal identified was for KH to be able to walk her dogs independently. KH had impaired episodic short term memory and learning however it was observed that repetition facilitated learning, we thus developed a graded behavioural program employing KH’s dogs as positive reinforcements and to enhance positive emotional memories. KH’s two dogs were brought into the session and KH was given the lead to hold along with the physiotherapist for safety.

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Additionally, verbal encouragement was provided and the long term goal of taking her dogs outside for a walk was emphasised. 1.1.6. Outcome KH engaged quickly and made steady progress (see Fig. for details), overreaching the target of 10 lengths of the parallel bars within a few weeks and this was consistently maintained in the long term and KH progressed to walking with a rear walker. At 12 months follow-up KH showed further improvements; KH is now living back at home and supported by her husband. She is able to walk with crutches up to 35 metres inside her home and her fatigue levels are mild. Her concentration and memory continue to improve although executive difficulties remain for planning and organisational tasks. Her mood is much improved and KH describes herself as positive and happy. Outbursts of frustration are minimal. 1.2. Case study 2 (RM) RM is a 24 year old, right handed, young woman who was admitted to the RNRU inpatient unit with a two week history of worsening confusions, dysphasia, dyspraxia and emotional lability with personality change. MRI brain scan was normal and EEG revealed focal temporal and occipital changes. No virus was detected and a presumptive diagnosis of possible NMDAR encephalitis was made. Plasma exchange was commenced and she was treated with a course of intravenous immunoglobulin. Investigations for an underlying neoplasm were unrevealing. RM was partially oriented but demonstrated severe cognitive deficits for memory recall and facial recognition, poor verbal fluency, and word finding difficulties. She was dyspraxic and had a tendency to perseverate. She displayed some athetoid movement in both hands and a postural tremor more marked in the left. Her insight was poor regarding her condition. RM was discharged home after 6 months having made good gains regarding her activities of daily living; she was independent with personal care and some domestic activities but cognitive impairments persisted. Physically she was deconditioned and had gained weight. Following hospital discharge a deterioration in function was noted with ongoing cognitive difficulties including reduced concentration, poor memory and reduced speed of information processing. The most significant deterioration was that she has become doubly incontinent. Medical test results including MRI and EEG, were negative suggesting, that the functional

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Fig. 1. KH progress in mobility chart.

deterioration observed within the community was likely to have an underlying psychological and/or behavioural basis. She was thus referred to the RNRU Outreach Team for further management and rehabilitation. At assessment we noted that RM had gained at least three stone in weight and felt miserable, irritable and frustrated. She was anxious in crowds and did not go out on her own because she was frightened that she may have another episode of confusion. In her own past medical history there was nothing of significance. However, her father has a diagnosis of schizophrenia. At the time of diagnosis RM had been working full time in a clerical role. She had not returned to work due to her cognitive and physical difficulties. 1.2.1. Everyday functional activities The Brain Injury Community Rehabilitation Outcome Scale (BICRO-39), (Powell et al., 2002, 1998) was used to assess RM’s everyday functional abilities (see Table 1 for details). RM was independent in personal care but required constant help/assistance to organise herself. She did not arrange any appointments, did not use memory aids, was unable to manage and keep track of her money, pay bills or write letters. She required help to enable her to go outside the home. 1.2.2. Cognition RM was fully oriented for time, place and person. Psychometry (see Table 2 for neuropsychology

data) indicated impairments in verbal reasoning ability, sustained attention, memory, speed of information processing and executive difficulties on planning tasks. 1.2.3. Social cognition A 10 item questionnaire to assess, ability to understand other’s mental states and general social cognition was completed independently by RM and an informant version by her mother. This indicated that RM had some difficulties with empathising, tactfulness, ability to sympathise and some reduced insight into these problems. 1.2.4. Mood RM had significant anxiety issues and low mood. She was highly anxious about going outside on her own as she was worried that she may suffer an episode of confusion. She reported low self-esteem and reduced confidence in her abilities to do things. Her low mood further reflected cognitive difficulties plus the many losses in her life including her job, financial income, independence and reduced social network. On a screening self-report measure of mood (HADS) she showed borderline symptoms of anxiety and depression. 1.2.5. Quality of life RM completed the Quality of Life After Brain Injury Overall Scale (QOLIBRI-OS, von Steinbuechel, Wilson, Gibbons et al., 2012), a brief 6 item self-report scale

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Table 1 Brain Injury Community Rehabilitation Outcome (BICRO-39∗ ) scores BICRO-39 Scale∗

RM Baseline average score

RM Discharge average score

RM 6 month follow-up average score

RM Baseline Informant average score

RM Discharge Informant average score

RM 6 month Informant follow-up average score

Personal Care Mobility Self-Organisation Socialising Productive Employment Psychological Wellbeing

0 4 3 4 5 5

0 3.0∗∗ 2.0∗∗ 5 3.0∗∗

0.7 2.3∗∗ 2.5∗∗ 2.7∗∗ 4.5∗∗ 2.3∗∗

0 4 4 4 5 5

0 2.8∗∗ 3.0∗∗ 5 5

1.5 2.8∗∗ 2.5∗∗ 3.0∗∗ 5 3.7∗∗

Personal Care Mobility Self-Organisation Socialising Productive Employment Psychological Wellbeing

OA 0.2 3.8 3.8 3.2 5 2.8

OA 0 0.4∗∗ 2.0∗∗ 2.7∗∗ 3.5∗∗ 2.2∗∗

OA 0 0.0∗∗ 1.3∗∗ 3.0∗∗ 4.0∗∗ 2.2∗∗

OA 0 3.6 3.5 2.7 4.7 3.2

OA 0 0.6∗∗ 1.7∗∗ 2.3∗∗ 3.2∗∗ 3.2

OA 0 0.0∗∗ 2.0∗∗ 2.5∗∗ 4.2∗∗ 3.7

∗ BICRO-39

scoring system: coring ranges from 0 (doesn’t do at all) to 5 (no help). Lower scores indicate greater independence. See Appendix for further details of scoring system. ∗∗ indicates improvement in BICRO-39 average scores from baseline score. Table 2 Neuropsychological Profile for cases RM and OA Test WAIS-IV Similarities Matrix reasoning Digit Span Digits Forwards Digits Backwards WMS-IV Logical Stories Immed Logical Stories Delayed Verbal Fluency Letter (FAS) Fluency Semantic Fluency Trail Making Test (TMT) TMT Part A TMT Part B BADS Rule Shift Action program Key search Temporal Judgement Zoo map Modified six elements Hospital Anxiety and Depression Scale (HADS)

of quality of life satisfaction (see Table 3 for details). She reported reduced level of quality of life in a number of domains including her current situation and future prospects, mood, ability to carry out daily activities, social life and level of cognitive function. 1.2.6. Behaviour RM complained of fatigue, showed lack of motivation and avoidance to engage in specific tasks. She

RM

OA

Age Scaled Score 5 11 5 5 (unreliably) 3 (reliably) 4 (unreliably) 2 (reliably) Age Scaled Score 15 5 Age Scaled Score 5 9 Time (secs) Centile 39 < 10 74 < 10 Profile score 4 4 4 1 2 4 Anxiety score = 9 Depression score = 8

Age Scaled Score 15 7 11 6 (unreliably) 5 (reliably) 4 (reliably) Age Scaled Score 11 10 Age Scaled Score 10 11 Time (secs) Centile 53 < 10 84 < 10 Profile score 3 2 0 3 2 2 Anxiety score = 9 Depression score = 7

found tasks and activities effortful and overwhelming. Her low mood and anxiety acted as a barrier to her engaging in tasks. 1.2.7. Family issues RM was supported by her family and in particular her mother. Although her family were supportive her mother struggled to provide her with the structure and guidance she required at home. Thus for efficiency

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L.J. Bach / Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis Table 3 Mood (HADS) and Quality of Life (QOLIBRI-OS∗ ) scores for RM and OA

SCALE Patient RM HADS Anxiety score HADS Depression score QOLIBRI-OS Physical condition QOLIBRI-OS Cognitive QOLIBRI-OS Mood and emotions QOLIBRI-OS ability to carry out day to activities QOLIBRI-OS personal and social life QOLIBRI-OS current situation and future prospects QOLIBRI-OS Average score Patient OA HADS Anxiety score HADS Depression score QOLIBRI-OS Physical condition QOLIBRI-OS Cognitive QOLIBRI-OS Mood and emotions QOLIBRI-OS ability to carry out day to activities QOLIBRI-OS personal and social life QOLIBRI-OS current situation and future prospects QOLIBRI-OS Average score

Baseline

Discharge

6 month follow-up

9 8 Quite Moderately Slightly Slightly Slightly Not all 2.3

12 10 Moderately Slightly Slightly Slightly Slightly Moderately∗∗ 2.3

15 9 Moderately Slightly Moderately∗∗ Slightly Moderately∗∗ Slightly∗∗ 2.5∗∗

9 7 Not at all Moderately Moderately Slightly Moderately Slightly 2.3

9 5 Slightly∗∗ Moderately Quite∗∗ Moderately∗∗ Moderately Moderately∗∗ 3

9 4 Moderately∗∗ Moderately Moderately Quite∗∗ Moderately Moderately∗∗ 3.2∗∗

∗ QOLIBRI-OS scoring system: Not at all satisfied = 1, Slightly satisfied = 2, Moderately satisfied = 3, Quite satisfied = 4, Very satisfied = 5. See Appendix for further details of scoring system. ∗∗ indicates improvement in QOLIBRI score from baseline.

RM’s mother often completed tasks which RM could have done given time. 1.2.8. Intervention We instigated a graded behavioural exposure program to help reduce RM’s anxiety. She required much encouragement to engage fully due to her anxiety. We provided general brain injury education and specific education around graded exposure strategies, executive function and the need for structure and use of compensatory strategies to both RM and her mother. 1.2.9. Outcome RM adopted compensatory strategies e.g. diary use, to help support aspects of her poor memory functioning. With structured support, encouragement and guidance RM was able to engage in a number of activities e.g. preparing family meals once a week and going out alone to the local shop. Her satisfaction with her quality of life regarding her current situation and future prospects had markedly improved and she was moderately satisfied in this domain. However, she continued to demonstrate both a significant need for further rehabilitation (see Tables 2 & 3). Although, she engaged more and was increasingly confident completing activities within her home environment, her ability to access the community or to be on her own remained limited. Her levels of anxiety and depression remained borderline.

At 6 month follow-up RM showed some deterioration in everyday community integration for personal care, self-organisation, socialising and psychological wellbeing, suggesting that without continued rehabilitation input and structure her motivation and support structures had weakened resulting in lack of maintenance of her gains and decline in function and mood. Despite this she reported positive changes in quality of life for mood, and personal and social life. 1.3. Case study 3 (OA) OA is a 23 year old, right handed, young woman who suffered NMDAR encephalitis and ovarian mass. She presented with seizures and lowered GCS to the local general hospital. She was admitted to ITU and after 3 weeks transferred to a major teaching hospital for surgery and plasma exchange. Following this she returned to her local hospital and was discharged back to home after 6 months. When assessed by the RNRU Outreach team she reported lack of motivation due to fatigue after initiating tasks. She was sensitive to noise and hyper sensitive to taste. She complained of daily headaches and pain throughout her body. In her personal and educational history, OA had just completed an undergraduate degree and had been about to enrol in a Masters degree. Her ambition was to return to university to achieve her Masters degree and then commence teacher training.

L.J. Bach / Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis

1.3.1. Cognition OA had relatively good insight into her difficulties. Her general cognitive function was broadly intact (see Table 1 for psychometry scores), however there was a significant deterioration in her working memory, executive skills and speed of information processing. OA showed marked difficulties with problem-solving, planning and organisational abilities for both concrete and more abstract tasks and showed mild difficulties with temporal judgement. The severity of her executive impairments suggested that these deficits may have a significant impact on her future plans and re-integration into education and future employment prospects. In everyday function OA reported poor short term memory and concentration and her family report that OA was less organised in her thinking. This was supported by her scores on the BICRO-39 scale. 1.3.2. Social cognition OA completed a questionnaire to assess her ability to understand other’s mental states and general social cognition. She reported some difficulties in recognising that she said things that upset others, understanding jokes, showing sympathy and being tactful. Her mother completed an informant version which was broadly consistent with OA’s report. 1.3.3. Mood OA reported loss of confidence in herself and her abilities along with fears that her illness may reoccur. She had episodes of low mood and occasional social withdrawal. She did not go out on her own because she was fearful she may ‘pass out’. She completed the HADS questionnaire which indicated borderline symptoms of anxiety. 1.3.4. Quality of life OA showed a marked reduction in her satisfaction with her level of quality of life, particularly for her physical condition, ability to carry out day-to-day activities, and her current situation and future prospects, as measured by the QOLIBRI-OS. 1.3.5. Behaviour OA showed lack of motivation for physical exercise and completion of tasks. The major long term aims of OA were to return to university, lose weight and pass the theory component of her driving test. Our aim was to help support OA to have

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a realistic plan for returning to University, including having study strategies and support. 1.3.6. Intervention We provided OA and her family with psychoeducation around NMDAR encephalitis and behavioural intervention. For cognitive problems our intervention focussed on cognitive strategies to support attention, memory and executive function e.g. supporting and encouraging increased self-monitoring. Fatigue management and a regular fitness programme were instigated. In terms of her affective state, cognitive behavioural therapy (CBT) was introduced to help OA to manage her reduced level of confidence and the anxiety associated with her recent illness, fear of illness recurrence and low mood. OA was very determined to return to university as soon as possible. We supported OA to pursue this, through practising the journey to university; meeting with her and her future course tutor, and supporting appropriate strategies to manage study plans. OA also agreed to complete her course part-time. 1.3.7. Outcome By discharge, OA had returned to university and was studying part time for a Masters degree in English literature. She was able to complete her journey to and from university independently and was using appropriate strategies to manage her studies at university. Not surprisingly, her mood was positive and she was hopeful about her future prospects. Unfortunately OA did not maintain this gain over the next two months as she found the commute to university fatiguing. Further funding was requested to enable ongoing input for fatigue management. In summary, OA demonstrated modest, positive outcomes on measures of community integration, mood and quality of life. In particular, she reported improved quality of life with increased satisfaction with her physical condition, emotions, everyday functional abilities, and her current situation and was more positive about her future prospects. OA’s mood remained relatively stable. These gains were maintained at 6 month followup despite her setback in educational plans due to physical fatigue.

2. Conclusion The three cases of NMDAR encephalitis reported in this paper outline the diverse outcome for these patients and the challenges faced by rehabilitation

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teams. A striking feature of the two cases who were living at home was the severe anxiety associated with recurrence of the disease and resultant fear of being alone especially outside the home. It is important for rehabilitation teams to be aware of the stages through which these patients have progressed and the potential consequent effect on patients and families. NMDAR encephalitis has a strong behavioural phase where psychotic features and unpredictable, bizarre and strange behaviours predominate. Patients appear highly sensitive to this phase and it is hugely distressing for families to witness. Additionally, uncertainty and delay surrounding diagnosis can contribute to persisting psychopathology for patients and their families. Each of these cases required significant input from carers and/or family members. All required supervision to varying degrees and all had ongoing rehabilitation needs. NMDAR encephalitis leaves patients with persistent and significant cognitive, behavioural and emotional problems, well after discharge from hospital and these patients require long term management and input of varying levels of intensity from multidisciplinary agencies. Communication lines between all professional working with these patients is vital as information about NMDAR needs to be consistent across all those involved in the patient’s care. The two patients (RM and OA) who were living at home both demonstrated positive NMDAR antibodies and their titres at times were higher than at initial presentation. Families require education and information on what these levels mean to alleviate worry and fear of potential relapse. Both these cases developed poor sleep and ongoing issues of fatigue which greatly impacted on their rehabilitation. Although depression was not overtly marked on formal questionnaires, in everyday function low mood was observed. The deficits observed in these patients support the observation by Finke et al. (2012) that memory and executive deficits are persistent in the long term and that severity of impairments do show wide variability between patients. Additionally, emotional distress and behavioural difficulties are prominent and persistent in all three patients, and have a pronounced impact on rehabilitation. Each of these patients had markedly differing cognitive profiles suggesting that in the context of long term rehabilitation outcome, cognition may have less valence than emotional and behavioural factors. Continence issues were a major factor impacting on the rehabilitation of these patients. For patient RM incontinence was a persistent symptom whereas for OA this was a re-emerging symptom not present at the

start of therapy. For these patients continence issues are highly distressing, and both RM and OA found it difficult to divulge this issue to us, which had a major impact on their rehabilitation. Rehabilitation teams need to be aware of this issue and explore with sensitivity patients feelings and anxieties associated with their continence and how to support them. For patient KH behavioural difficulties were the most challenging issue affecting rehabilitation. Towards the end of intervention KH began to resist her peg feed and risperidone was introduced and citalopram medication increased. During her time in the care home KH had exhibited a range of behaviours (itching, salivating picking her nose, resisting wearing ankle splint, refusing to engage in physiotherapy, refusing peg-feed) which could not be easily linked to any identifiable triggers or modulators. One possibility was that KH was trying to exert autonomy or control over her situation for some of these behaviour (e.g. physiotherapy, peg-feed) but not all (salivation, itching, nose picking). Clinician’s should be alert to the diversity of unexplained behaviours, the susceptibility of these patients to such a wide range of behaviours and where possible attempt to identify modulators to manage this. Cases OA and RM demonstrate the very positive value of long term rehabilitation MDT input for NMDAR patients discharged back into the community. OA and her family were supported across a range of difficulties and this facilitated OA in returning to university. It is clear that without our MDT rehabilitation input OA would not have achieved this goal and without our input, OA was at risk of deterioration in mood, social isolation, inability to return to voluntary or even gainful employment, and an increase in associated care and benefit costs. For patient RM, progress was evidenced across the majority of domains (mobility, self-organisation, socialising, productive employment and psychological wellbeing) which was maintained over 6 months. Improvements in satisfaction with perceived quality of life were present but across fewer domains and over 6 months improvements continued across a variety of domains. The main issues addressed across the three cases were, behavioural, cognitive deficits, fatigue, low mood and anxiety. These cases indicate that a variety of models of treatment including, behavioural learning paradigms, emotional stimulus valence enhancement of motivation and learning, use of compensatory strategies (e.g. diaries, checklists, smartphone alerts, verbal prompts and auditory and visual cuing), CBT (reframing challenging negative automatic thoughts), systemic

L.J. Bach / Long term rehabilitation management and outcome of anti-NMDA receptor encephalitis

family therapy, psycho-education around brain injury, and relaxation therapies can be modified and used successfully to address these difficulties for patients with NMDAR encephalitis. The patients and their families were able to engage with our service and the patients were able to markedly benefit from simple functional aids and modified, simple, education and counselling approaches. Integrated joined-up working was enabled and was effective in facilitating treatments. Consistent with our treatment findings is a report of Mart´ınMonz´on, Trujillo-Pozo and Romero. (2012) who also describe positive outcomes using compensatory strategies, multimodal consolidation techniques, and stimulus valence for encoding and retrieval memory processing. These three cases, highlight the variability in terms of when and how long for intervention is required. More severe cases may potentially show continued spontaneous improvements and the focus of intervention should be early on but with regular assessment reviews in the longer term as the rehabilitation needs are likely to change. For those with more mild and moderate deficits, protracted, long term rehabilitation may be warranted in order to mitigate deterioration in function and thus maintain gains made. Integrated and joined-up working across services is of critical importance to provide a consistent approach for successful implementation and maintenance of interventions. For example, we found liaising with neurology and psychiatry services critically important especially as our patients failed to fully divulge their problems when reviewed at outpatient clinics. It is recognised that these conclusions are based on our own experience and thus lacking in terms of evidence based medical support. It is our intention to expand our data collection to include collection of cognitive, behavioural and social cognition data not only at admission but also at discharge and 6 month follow-up, in order to explore more fully the progression of this disease and the long term outcome of community rehabilitation for patients with NMDAR encephalitis. Many other questions arise regarding whether subgroups of NMDAR patients can be defined and how this potentially relates to type of treatment intervention and frequency and duration of intervention. Similarly, it would be interesting to explore whether type of intervention/treatment outcome varies between subgroups and indeed between the different varieties of virus-related encephalitis. Our experience has been that aetiology tends to be less important in ABI including viral encephalitides, than other factors such as psychological (e.g. motivation to change, premorbid personality characteristics and

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premorbid coping strategies), economic factors, family support and available community resources (Powell et al, 2002). Further research in this area is clearly warranted to more fully unpick and identify the salient factors in achieving positive outcomes for this disorder. It is most interesting to note that for the more able of the patients (RM and OA), specialised MDT community rehabilitation resulted in enhanced quality of life in a number of domains and this was maintained in the long term once rehabilitation input had terminated and despite deterioration in other aspects of community function suggesting that quality of life may be independent of function and overall mood and possibly an aspect of patients’ perception of self-awareness into their condition and recognition of some improvements in their daily life. This is an area we hope to explore further. Finally, a further concern, but of seminal importance is the issue of fertility. Oophorectomy is conducted when ovarian tumour is detected, rendering these young women infertile. The issue of when, how to, and who should address this sensitive outcome with these patients appears to be marginalised. Certainly this is understandable during the acute and post acute stages of recovery. However, there needs to be communication and consensus between the treating medical professionals for each individual patient as to how this subject should be broached. Each patient is individual with their own unique personality, ways of coping, support resources available and also cognitive profile, the latter which may significantly impact on their ability to comprehend or remember what they are being told. For the more severely cognitively impaired patients ethical issues arise as to whether indeed there is any benefit to informing the patient of such devastating news. For more cognitively able patients counselling around infertility should be integrated into standard guidelines of best practise and routinely offered to these patients. It is acknowledged that only three patients were explored in this study and further long term outcome studies are required in order to help clarify the significant factors acting as barriers to good outcome. It is hoped that this report has stimulated increased thought and perhaps change in practise to facilitate positive outcomes for these patients.

Declaration of interest This author reports no conflicts of interest. The author alone is responsible for the content and writing of this paper.

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Appendix BICRO-39 Scales scoring system – for further details please see Powell et al. (2002).

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• Personal care: independence in basic self-care activities (for example, using the toilet) and mobility/access to facilities within the home (0 = with no help to 5 = can’t do at all). • Mobility: independence in more physically demanding tasks (for example, laundry, shopping; 0 = with no help to 5 = can’t do at all). • Self-organisation: independence with structuring personal and domestic activities (for example, bill payments, managing appointments; 0 = with no help to 5 = can’t do at all). • Socialising: frequency of contact with people other than immediate family (for example, friends, colleagues; 0 = never to 5 = daily). • Productive employment: frequency of engagement in education, work, or childcare (0 = not at all to 5 = several hours a day). • Psychological wellbeing: frequency of feeling impatient with self, bored, lonely, worn out, hopeless about the future, and angry with others (0 = never to 5 = almost always) QOLIBRI-OS Scoring system – The quality of life after brain injury overall scale (QOLIBRI-OS) scale is a recently developed instrument that provides a profile of health-related quality of life (HRQoL) in domains typically affected by brain injury. For further details please see (von Steinbuechel et al, 2012). Overall how satisfied are you with your physical condition? Overall how satisfied are you with your cognition, memory and thinking skills? Overall how satisfied are you with your emotional condition? Overall how satisfied are you with your ability to carry out day-to-day activities? Overall how satisfied are you with your personal and social life? Overall how satisfied are you with your current situation and future prospects? Scored on a 4 point scale Not at all satisfied = 0 Slightly satisfied = 1 Moderately satisfied = 2 Quite satisfied = 3 Very satisfied = 4

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