Disease course and psychosocial outcome for children and adolescents with anti-N-methyl-D-aspartate receptor encephalitis

Introduction

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is an auto-immune mediated encephalitis that was first described in 2007. The disease can be triggered by a tumor or a viral infection (Dalmau et al., 2019). It has been described in both sexes and all age groups, but tumor association is more often found in young women and prepubertal children (Gong et al., 2021; Titulaer et al., 2013). The full-blown syndrome starts typically with predominantly psychiatric symptoms. These are followed or accompanied by neurological symptoms, sometimes evolving to a life-threatening state with dysautonomia, hypoventilation and coma (Dalmau et al., 2019). The psychiatric symptoms during disease onset often mimic a first psychotic episode with agitation and psychotic symptoms like perceptual disturbances, disorganized behavior and delusions. Consequently, up to half of the patients are first admitted to a psychiatric ward and misdiagnosed with a primary psychiatric disorder (Blum et al., 2020; Guasp et al., 2022). In prepubertal children the most common psychiatric phenotype is agitation. However, in this group the psychiatric symptoms are often less prominent than the neurological symptoms like seizures, fever and disturbances of consciousness (Sarkis et al., 2019). Early diagnosis and treatment are important since a delay in treatment is associated with poorer outcome (Gong et al., 2021). First-line pharmacological treatments include high-dose steroids, intravenous immune globulin (IVIG), and plasmapheresis alone or combined. As second- and third-line therapies respectively rituximab/cyclophosphamide and bortezomib/tocilizumab are used. In order to manage the psychiatric symptoms benzodiazepines and antipsychotics are often used, with the important notice that neuroleptic sensitivity is common in anti-NMDARE (Dalmau et al., 2019; Huang et al., 2020; Sarkis et al., 2019).

In several studies the outcome after anti-NMDARE is solely assessed with the modified ranking scale (mRS) that measures functional outcome on a scale of 0–6, whereby a score of ≤2 represents a good recovery with no or only mild residual symptoms. With this measurement a good functional recovery after anti-NMDARE is reported in up to 85% of patients (Florance et al., 2009; Gong et al., 2021; Titulaer et al., 2013). However, other domains need to be considered when evaluating outcome after anti-NMDARE. Particularly in the last 5 years studies have been paying more attention to this field of research, progressively bringing to surface the extent of persistent deficits in long-term follow-up after anti-NMDARE in both adults and children. First of all cognitive outcome has been most extensively researched and studies have shown persisting memory deficits, concentration problems and deficits in executive functioning in 40–66% of the patients over the years after disease onset (Flet-Berliac et al., 2022; Guasp et al., 2022; Heine et al., 2021). Furthermore a small amount of studies has been exploring some aspects of the psychosocial outcome in the long-term. Persistence of fatigue with an impact on the quality of life has been reported, as well as disturbances of academic and work trajectories (Blum et al., 2020; de Bruijn et al., 2018; Flet-Berliac et al., 2022; Guasp et al., 2022). However, the psychosocial outcome is not the main focus in these studies, whereby information is limited. Finally some studies have tried to identify the psychiatric symptoms persisting after the post-acute and reported presence of irritability in 25%, aggression in 21%, depressive symptoms in 5–15% and emotional or impulse control issues in 56–66% of patients (Blum et al., 2020; Guasp et al., 2022; Liu et al., 2019; Tomlinson et al., 2020; Wang et al., 2019). However in these studies, the psychiatric symptoms were inventoried with questionnaires and only one study conducted a qualitative psychiatric evaluation with semi-structured interviews that allows proper assessment of psychiatric functioning (Guasp et al., 2022). More research on especially psychosocial and psychiatric outcome is necessary to further investigate these findings. Therefore we chose to focus on these domains in our exploratory case series. We describe the disease course of anti-NMDARE in our patients with a special focus on psychiatric symptoms and provide an extensive assessment of the psychosocial outcome after anti-NMDARE in children, with inclusion of a psychiatric evaluation, a measurement of the global functioning in daily life and the quality of life of both the patients and their caregivers.

Methods

We selected all patients under the age of 18 years old that were treated for anti-NMDAR encephalitis in the participating hospital. In total 6 patients were treated in the hospital of which four patients could be recruited for the study. One patient was excluded because of language barrier and one patient was lost in follow-up. One of the included patients was already extensively described in a previous case report (Depreitere et al., 2022). The study was approved by the Ethics committee (EC) and all patients and their caregivers provided written consent.

Clinical variables and information about the disease course were retrieved from the medical records. Patients had been treated and followed-up in the hospital until stable functioning after pharmacotherapy was stopped. Follow-up in the hospital ranged from 1 year to 6.5 years. One patient was currently still in follow-up. Psychosocial outcome after the disease was assessed retrospectively and in addition an assessment of current psychosocial functioning was made. Information was assembled from several sources and qualitatively analyzed by the researcher. In the medical records information was retrieved about recovery, residual symptoms and functioning during follow-up. A qualitative survey was set up by the researchers and filled in by the caregivers to retrieve supplementary information about subjective residual symptoms, current support/therapies, schooling trajectory, hobbies, social functioning and impact of the disease on family functioning.

Via the Structured Clinical Interview for DSM-5 Disorders junior version (SCID-5 junior) psychiatric symptoms were investigated retrospectively since disease onset and at present. The SCID-5 junior is a semi-structured interview guide for making diagnoses according to the diagnostic criteria published in the American Psychiatric Association’s Diagnostic and Statistical Manual for Mental Disorders (DSM), adapted for children and adolescents from 8-18 years old. Both the patients and their caregivers were invited for a visit to the clinic and were interviewed for 1.5 hour. Since one patient was only 7 years old at time of assessment, we only interviewed the caregivers in this case. Interviews were conducted and analyzed qualitatively by the researcher, MD and fifth year resident in child and adolescent psychiatry. The semi-structured nature of the interview made a comprehensive evaluation of psychiatric and psychosocial functioning possible.

Both the patients and caregivers filled in the age-appropriate versions (age 5–7 years and age 13–18 years) of the child self-report and parent proxy-report of the Pediatric Quality of Life Inventory (PedsQL) TM 4.0 Generic Core Scales. The 23-item 0-4 scales are developed to measure health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. The questions cover the domains of emotional, physical, social and school functioning. Normative data in a healthy Dutch population are available for the parent proxy-report age 5–7 years (Schepers et al., 2017) and the child self-report age 12–18 years (van Muilekom et al., 2021). The caregivers additionally filled in the 36-item PedsQL TM 2.0 Family impact Module. The module was designed to measure the impact of pediatric chronic health conditions on parents and the family. Items on the PedsQL Generic Core Scales are reverse scored and transformed to a 0-100 scale. Higher scores indicate better health related quality of life.

The modified ranking scale (mRS) as well as the children’s global assessment scale (CGAS) were scored at time of assessment based on the retrieved information. The mRS measures the degree of disability or dependence in the daily activities on a scale of 0–5, with a score of zero corresponding to no symptoms and a score of 5 indicating severe disability. In the CGAS the patients receive a score from 0-100, putting them in one of ten categories that range from ‘extremely impaired’ (1–10) to ‘doing very well’ (91–100).

Results

We studied the cases of four female patients with a history of anti-NMDARE retrospectively and at present. Patient demographics and clinical information on disease course are summarized in Table 1. Clinical information on follow-up and results of the current assessment are summarized in Table 2. The most relevant results are more extensively described below.

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Table 1.

Demographics and Disease Course.

	Patient 1	Patient 2	Patient 3	Patient 4
Gender	Female	Female	Female	Female
Age at disease onset	2,7 y	6 y	10,6 y	14,2 y
History			IQ 135	Traumatic event 1 m before disease onset
			1 y psychotherapy
Viral prodrome	yes	yes	yes	no
First symptoms	Anorexia, altered behavior, episodes of staring	Fever, vomiting, abdominal pain, absence seizures, headache	Fatigue, headache, anorexia, weakness in the limbs, severe weight loss	Staring episodes, concentration and memory problems, apraxia
Setting of first assessment	Pediatric department: Suspicion of auto-immune encephalitis	Pediatric department, suspicion of herpes simplex encephalitis	Pediatric department followed by psychiatric department: Suspicion of conversion disorder, eating disorder and depression	General practitioner: Suspicion of psychological decompensation
Psychiatric symptoms	Disorganized behavior, agitation, aggression, anxiety	Concentration problems, confusion, altered behavior: infantile and disorganized	Fatigue, anorexia, regurgitation, depressive mood, thoughts about death, inability to walk, weight loss	Episodes of agitation/anxiety, nightmares, confusion, altered behavior
Neurological symptoms	Disturbed speech, uncoordinated movements, episodes of areactivity	Absence seizures, headache	Headache, hypersomnia, weakness in limbs	Seizures, slowing on EEG, episodes of areactivity, decreasing level of consiousness
MRI imaging	Normal	Normal	Normal	Normal
Screening neoplasms	Negative	Negative	Negative	Negative
Diagnosis delay	5 d	26 d	3.5 m	21 d
Ab in serum/CSF	Anti-NMDARE Ab+ in serum, not measured in CSF	HSV-1 DNA+ in CSF	Anti-NMDARE Ab+ in serum, not measured in CSF	EBV IgM+ and IgG+
		Anti-NMDARE Ab+ in serum, Ab not measured in CSF		Anti-NMDARE Ab+ in serum, insufficient fluid to test in CSF
Treatment	- Antiepileptic drugs	- Antiepileptic drugs	- Physical therapy	- Antiepileptic drugs
	- IVMP followed by oral CS	- IVMP followed by oral CS	- Enteral feeding	- 1st course of IVMP
	- Plasmapheresis		- Psychotherapy	- 2nd course of IVMP followed by oral CS
	- Risperdal/Temesta		- Fluoxetine/Aripiprazole	- Trazodone (paradoxal effect)
	- Physical therapy		- IVMP followed by oral CS	- Psychological support
	- Psychological support		- Course of IVIG	- Physical therapy

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Table 2.

Long-term Follow-up and Current Assessment.

	Patient 1	Patient 2	Patient 3	Patient 4
Age at current assessment	7 y	13 y	16 y	16 y
Follow-up time from diagnosis to current assessment	4,5 y	6,5 y	6 y	2 y
(Suspected) clinical relapses in months after disease onset	- 6 m: Ab+	- No relapse	- 15 m: Ab+	- 12 m: Ab-
	- 9 m: Ab-		- 18 m: Ab-
	- 11 m: Ab+		- 23 m: Ab+
			- Several more over the following years with or without Ab+
Treatment of relapse(s)	- IVMP + oral CS	-/	- IVMP + oral CS	No treatment since no confirmation with Ab+
	- MMF for 16 m		- Plasmapheresis
	- Antiepileptic drugs		- IVIG
			- MMF, RTX, CIC, BZM
Duration of post-acute phase a	6 m after first episode	6 m	13,5 m after first episode	9 m
Persisting symptoms in post-acute phase	Sleep problems, fatigue, behavioral problems, learning difficulties	Fatigue, hypersomnia, concentration problems	Gastro-intestinal problems, fatigue, physical weakness, aggressive outbursts, anxiety	Physical weakness, fatigue, difficulties with concentration and memory
Persisting symptoms in long-term follow-up	Difficulties with learning, language development, concentration and hyperactivity (clinical scores for ADHD)	Difficulties with concentration, tires more quickly than peers	Fluctuating severe mood and behavioral problems, gastro-intestinal problems, physical weakness, fatigue	One transient depressive episode during follow-up, fatigue, short-term memory difficulties
Child and parent reports of the PedsQL TM 4.0 Generic Core scales	Child report: 69	Child report: 57	Child report: 70	Child report: 80
	Adult report: 86	Adult report: 80	Adult report: 30	Adult report: 76
PedsQL TM 2.0 Family Impact module	100	84	42	63
mRS	1	1	2	1
CGAS	65	85	50	80

^atime to recovery to a stable level of functioning.

Legend: y = years, m = months, Ab+ = antibodies positive in serum, Ab- = antibodies negative in serum, IVMP = intravenous methylprednisolone, CS = corticosteroids, MMF = mycophenolate mofetil, IVIG = intravenous immune globulin, RTX = rituximab, CIC = ciclosporin, BZM = bortezomib, ADHD = attention deficit-/hyperactivity disorder, PedsQL = Pediatric Quality of Life Inventory, mRS = modified ranking scale, CGAS = Children’s Global Assessment Scale.

Discussion

The psychiatric symptoms during the disease course of anti-NMDARE can pose diagnostic challenges. Still up to 50% of patients with anti-NMDARE are primarily misdiagnosed with a primary psychiatric disorder and are first admitted to a psychiatric ward (Guasp et al., 2022), with delayed treatment as a consequence. This is a common problem since on the one hand neurological symptoms can arise only secondarily and on the other hand neurological symptoms like fatigue, headache and confusion can be subtle and/or also fit within a psychiatric disorder. It is important for both neurologists and psychiatrists to have knowledge of the possible clinical features of anti-NMDARE so it can be taken into the differential diagnosis when first symptoms arise. A combination of psychiatric symptoms and subtle neurological symptoms atypical for a psychiatric disorder should bring to mind the diagnosis of anti-NMDARE. Also in follow-up after the disease psychiatric symptoms can cause diagnostic challenges in distinguishing psychiatric problems from relapses of the disease. A multidisciplinary approach is therefore helpful during treatment and follow-up.

When we assess recovery and outcome in our case series we can distinguish a post-acute phase ranging from 5-10 months, followed by a state of relatively stable functioning. In the post-acute phase there were still several persisting symptoms that took months to gradually ameliorate and eventually resolve. In this period these symptoms still had an important impact on both the physical, cognitive and psychosocial functioning of our patients. These results add on to the findings of Guasp et al. (2022) on the course of recovery after anti-NMDARE. They also described patients going through a post-acute phase with cognitive deficits and psychiatric alterations that gradually improved over time until they reached a stable level of functioning. During this phase these residual symptoms affected the basic activities of daily living of almost 75% of the patients (Guasp et al., 2022). It is therefore important that persisting symptoms are identified at discharge from the hospital so adequate support can be provided to minimize the impact on daily functioning.

Although an important part of these persisting symptoms seems to clear up in the first year after disease onset, both in our case series and in other research up till three-quarters of patients still experience mild to severe residual symptoms with a possible impact on their daily functioning after the post-acute phase (Blum et al., 2020; de Bruijn et al., 2018; Flet-Berliac et al., 2022; Guasp et al., 2022). When we look at psychosocial outcome we can identify several domains that can be disturbed even years after the disease.

First of all fatigue was mentioned during assessment in three out of four patients. In two patients the fatigue is mild, but in one patient it is severe and enables her to pursue her hobbies. Fatigue has been recurrently described as a residual symptom in 27–80% of patients after anti-NMDARE (Blum et al., 2020; de Bruijn et al., 2018; Tomlinson et al., 2020; Yeshokumar et al., 2022) and in one of these studies fatigue was linked to a poorer QoL (de Bruijn et al., 2018). Disease related fatigue is often multifactorial and difficult to manage, but can have an important impact on quality of life and daily functioning (Hersche et al., 2022). In clinical practice it seems therefore important to actively question the patient for fatigue and explore management strategies.

In all our patients the disease influenced their academic trajectory. For one patient this was limited to a period of homeschooling during the post-acute phase. There was a longer lasting impact on the trajectory of the other patients. One had to change study program to a less demanding program, one needed an individually adapted program for several years and one patient still has special education needs up till now. Also in other research disturbances of the academic trajectory was common. In a Dutch and a French study that studied long-term outcome in children and adolescents with anti-NMDARE 19%–25% of children had special needs in their academic trajectory and 11%–23% had to switch to a lower educational level (de Bruijn et al., 2018; Flet-Berliac et al., 2022). In studies with both adults and children we find similar results concerning 19% of patients needing special accommodations at work or school and 31%–58% of patients that did not return to school/work after anti-NMDARE (Blum et al., 2020; Tomlinson et al., 2020). These results indicate the importance of involving the school after discharge so adequate follow-up and support in the academic trajectory can be provided. Thereby it would be interesting to investigate in further research which causal factors can be identified for the disturbance of the academic trajectory. In our case series fatigue, as well as cognitive deficits and persisting psychiatric symptoms seemed to play a role.

When we look at psychiatric symptoms in our sample, they seem most severe and disturbing in the acute and post-acute phase of the disease. Most of these symptoms resolved or ameliorated during the post-acute phase. Nevertheless, three of our patients still experienced mild and one patient severe psychiatric symptoms after the post-acute phase. This learns us that adequate identification and management of the psychiatric symptoms is important not only in the post-acute phase but also in long-term follow-up. This could possibly prevent psychiatric symptoms from becoming chronic. Besides that, correct treatment of these symptoms could diminish their impact on functioning. However we need to be critical on these findings, since it is difficult to evaluate whether or not the observed psychiatric symptoms are linked to the disease. Our youngest patient fulfilled at current assessment the criteria for ADHD according to the SCID and has learning disabilities that require rehabilitation therapy. However, since she was only 2.5 years old at diagnosis of anti-NMDAR encephalitis, it is difficult to define if the difficulties that she experiences today can be linked to the disease or fit within a developmental disorder. Another patient went through a depressive episode several months after the post-acute phase, which was resolved without medication. A hypothesis could be that the disease made her more susceptible to depression, but another possibility could be that the impact of the persisting deficits on her functioning lead to a depressed mood. Our patient with the most severe psychiatric symptoms knew a complex disease course with several relapses. Her psychiatric symptoms follow a waxing and waning course and vary in severity. Over time it became increasingly difficult to distinguish symptoms of clinical relapse of anti-NMDARE from a psychiatric comorbidity. Our case series shows that the course of persisting psychiatric symptoms can be fluctuating and complex. To further investigate the link between psychiatric symptoms and anti-NMDARE, studies with psychiatric evaluations during and after anti-NMDARE in larger cohorts are needed.

There is barely any research on how these long-term persisting deficits impact global functioning and quality of life of patients. In our case series we used the PedQL questionnaires and CGAS score to assess quality of life and global functioning. We noticed that the patients gave lower scores on the items that were influenced by their persisting difficulties. This suggests an impact of these difficulties on their quality of life. The two patients with ongoing psychiatric disorders and continued need of rehabilitation or therapy score lowest on CGAS, indicating an impact on their global functioning. Important to note is that regarding the mRS scale all our patients have a score 1 or 2, corresponding to a good recovery with mild or no residual symptoms. As delineated in other studies this confirms that solely using the mRS scale to measure outcome after anti-NMDARE is insufficient to obtain a complete assessment (de Bruijn et al., 2018).

In our study we decided to also measure the impact of the disease on the family, since caregivers are constantly involved especially in children and adolescents. The low scores on the PedQL family impact module in two out of four of our patients shows that the disease can have an important impact on family functioning and QoL of caregivers. Additionally, the caregivers of the other patients added that there is no more impact at present on family functioning, but that their scores would have been significantly lower when measured during the acute or post-acute phase of the disease. As far as we know only one other study has looked into this issue and also found that caregivers of anti-NMDARE patients expressed moderate to severe levels of caregiver burden (Tomlinson et al., 2020). These results indicate that it is important to consider both the needs of patients and their caregivers during follow-up.

Conclusion

After the acute phase of anti-NMDARE patients go through a post-acute phase in which an important part of the persisting symptoms gradually resolve over months to a year. Some patients are free of persistent deficits after this post-acute phase, but a significant number of patients still experience mild to severe residual difficulties which can have a mild to moderate impact on the global functioning and quality of life of both the patients and their caregivers. It is therefore important to provide sufficient support in short- and long-term follow-up after anti-NMDARE, with special attention to physical and cognitive rehabilitation, psychological/psychiatric needs and aid in resuming the academic trajectory.