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Second-line immunotherapy and functional outcomes in autoimmune encephalitis: a systematic review and individual patient data meta-analysis

Significance: We did not observe an association between treatment with second-line immunotherapy and lower final mRS scores in patients with AE. This result should be interpreted with caution given the risk of bias, limited adjustment for disease severity, and insensitivity of the mRS in estimating psychiatric and cognitive disability.

Immune characteristics of children with autoimmune encephalitis and the correlation with a short-term prognosis

CONCLUSION: There is a close correlation between modified Rankin Scale (mRS) scores and the immune function index CD4/CD8 in children with autoimmune encephalitis (AE) when they are admitted to the hospital. A young age, disturbance of consciousness, limb dyskinesia, abnormal immune function in remission and anti-NMDAR encephalitis are risk factors for poor prognoses in children with autoimmune encephalitis (AE). Clinical treatment requires more attention.

Clinical Characteristics and Prognosis of Antibody-Negative Autoimmune Encephalitis in Children: A Single-Center Retrospective Study

Antibody-negative but possible AE is frequent in children who may have a more severe neurological impairment and higher NLR than antibody-positive AE. Aggressive immunotherapy in antibody-negative AE is essential to achieve a good prognosis.

Analysis of risk factors for a poor functional prognosis and relapse in patients with autoimmune encephalitis

This retrospective study analyzed the clinical characteristics of autoimmune encephalitis (AE) patients to explore the predictors of poor prognosis. According to the modified Rankin scale score at the last follow-up, the functional prognosis of the patients was reflected. And the prognosis of the patients was comprehensively evaluated by the functional prognosis and the relapse of the patients. The results showed that disturbance of consciousness and delayed first-line immunotherapy were independent risk factors for the poor functional prognosis of AE. In addition, patients with psychiatric symptoms, should be alert for relapse.

Life after autoantibody-mediated encephalitis: optimizing follow-up and management in recovering patients

 Cognitive impairment, fatigue, and sleep disturbances affect most recovering AME patients. This realization highlights the need for outcome measures that encompass more than motor function. 

Summary: Good outcomes continue to be reported in recovering patients, emphasizing the high potential for recovery following antibody-mediated encephalitis(AME). However, cognitive, behavioral, and physical sequelae may limit the potential for great outcomes following AME. Multidisciplinary follow-up is needed to recognize and treat sequelae that compromise long-term recovery and limit quality of life in recovering patients.

Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes

In this institutional cohort study, patients diagnosed with seronegative AE with available 2-year outcomes were analysed for the disease course, 2-year outcome prediction system, effect of immunotherapy, necessity of further immunotherapy at 6 or 12 months, and pattern of brain atrophy. Seronegative AE was subcategorized into antibody-negative probable AE (ANPRA), autoimmune limbic encephalitis (LE), and acute disseminated encephalomyelitis (ADEM). Poor 2-year outcome was defined by modified Rankin scale [mRS] scores 3‒6, and the 2-year serial data of Clinical Assessment Scales in Autoimmune Encephalitis (CASE) score was used for longitudinal data analyses. A total of 147 patients were included. The frequency of achieving a good 2-year outcome (mRS 0‒2) was 56.5%. The ANPRA subtype exhibited the poorest outcomes, although the baseline severity was similar among the subtypes.

In patients with persistent disease at 6 months, continuing immunotherapy was associated with more improvement, while the effect of continuing immunotherapy for more than 12 months was unclear. In the longitudinal analysis of MRI, the development of cerebellar atrophy indicated poor outcomes, while the absence of diffuse cerebral atrophy or medial temporal atrophy indicated the possibility of a good outcome.

A Prognostic Analysis of the Outcomes in Patients With Anti-γ-Aminobutyric Acid B Receptor Encephalitis

Conclusions: (1) Elderly patients with anti-GABABR antibodies, especially those with severe symptoms, serum tumor markers, and additional onconeuronal antibodies, should be screened for lung cancer. (2) Anti-GABABR encephalitis with tumors has a poor prognosis. (3) Most patients without tumors achieve self-care, but some still experience remaining neurological deficits.

Psychometric Deficits in Autoimmune Encephalitis: A retrospective study from the Australian Autoimmune Encephalitis Consortium

This newly published retrospective study if from Dr. Monif’s Group. 
The group took data from 59 patients across Australia for patient outcomes from AE. Executive dysfunction were the most commonly observed in this cohort, followed by deficits on tasks sensitive to memory. 54.2% were classified as having psychometric impairments across at least two cognitive domains. 29 patterns were observed, showing how complex outcomes in AE can be.
Further detailed and standardized cognitive testing in combination with MRI volumetrics and serum/CSF biomarkers is required to provide rigorous assessments of disease outcomes.

Neurological and cognitive outcomes after antibody-negative autoimmune encephalitis in children

Ab-negative AE was associated with poorer cognitive outcomes than NMDARE at 1-year follow-up. Further studies are required to evaluate if immunotherapy can be optimized to improve outcome.

A Validated Nomogram That Predicts Prognosis of Autoimmune Encephalitis: A Multicenter Study in China

The primary goals of the study were: (1) to develop early predictive model which distinguished poor from good prognosis of patients with AE using a nomogram; and (2) to evaluate nomogram performance using patient-level independent data.  173 subjects were included in the final analysis. 

In this study, we identified age, viral prodrome, consciousness impairment, memory dysfunction and autonomic dysfunction for predicting poor prognosis of AE at discharge using a multivariable regression model. We found that elderly patients were more likely to have poor prognosis than younger individuals. The nomogram, deriving from the model, could accurately predict prognosis in patients with AE graphically and provided a personalized outlook. Our study creates a novel model to pick up patients who probably receive poor prognosis and allows physicians to provide a tailored clinical therapeutic regimen for each patient. Precision medicine for AE patients would lead to favorable prognosis and save their medical cost.

Neurofunctional outcomes in patients with anti-leucine-rich glioma inactivated 1 encephalitis

Objective: To evaluate the cognitive and neurofunctional outcomes in patients with (LGI1) encephalitis.
 
Results: The results showed that 81 of 86 (94.2%) patients with anti-LGI1 encephalitis were successfully followed up, while eight (9.9%) died after discharge. Among the 73 survivors, clinical relapses occurred in 18 (24.7%) patients, and those with relapses were at a higher risk of developing remote symptomatic seizure (p = .019). Although 85.2% of the patients became functionally independent (mRS ≤2), the sequelae of symptomatic seizure, neuropsychiatric symptoms, and cognitive deficits were found in 11.0%, 21.9%, and 39.7% of the patients, respectively. Residual cognitive deficits primarily occurred in the elderly subjects as well as those with symptoms of memory deficit, psychiatric disorders, sleep disturbance, disturbance of consciousness at diagnosis, and higher CSF protein levels.
 
Conclusions: Although most patients survived and became functionally independent, a subset of patients could not return to all premorbid activities. They may have clinical relapses or suffer from remote symptomatic seizure, neuropsychiatric symptoms, and cognitive impairment.

Residual Fatigue and Cognitive Deficits in Patients After Leucine-Rich Glioma-Inactivated 1 Antibody Encephalitis

Fatigue is a major residual feature in LGI1 antibody patients. Inspired by seeing >100 of these patients, and hearing their stories.
 
Leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1-Ab-E) typically affects older men who present with prominent amnesia and frequent seizures1-3 and often shows a marked short-term improvement with immunotherapies.
In particular, seizure cessation occurs within just a few weeks.
However, only traditional cognitive domains have been investigated as longer-term outcomes, with improvements in cognition described as “not good enough.” Here, motivated by
patient feedback and our clinical observations, we aimed to
quantify the residual deficits observed after LGI1-Ab-E across
several functional domains.
The data here indicate that despite a “good” mRS, several long-term residual deficits remain: across domains of cognition,
mood, and fatigue, with a significant effect on employment status. Our cohort’s mean mRS was comparable with other
LGI1-Ab-E studies, suggesting this traditional outcome measure captures only limited long-term morbidity in multiple
studies. Fatigue was the most commonly impaired domain in
our cohort, a novel finding in LGI1-Ab-E. This observation is closely reflected by the many patients in our clinic who volunteer fatigue as a major residual symptom. Also, it parallels findings in pediatric N-methyl-D-aspartate receptor antibody encephalitis, where fatigue is associated with quality of life.

Cognitive impact of neuronal antibodies: encephalitis and beyond

This article explains different antibodies and the course of recovery that is currently understood.

Each neuronal antibody exerts a distinct mechanistic effect and while the downstream effects all include cognitive dysfunction, the affected domains vary between subtypes. However, there is much work to be done in fully
characterizing both the acute and chronic impairments of the  encephalitic syndromes; current descriptions tend to
be mostly qualitative and for the less common subtypes, data is sparse.

Clinical Features, Treatment Strategies and Outcomes in Hospitalized Children with Immune-Mediated Encephalopathies

Results

Seventy-five patients (23 ADEM and 52 AE) were identified. ADEM patients had a higher percentage of abnormal magnetic resonance imaging (MRI) findings (100% vs. 60.8%; p < 0.001) and a shorter time from symptom onset to diagnosis (6 vs. 14 days; p = 0.024). Oligoclonal bands, serum and cerebrospinal fluid (CSF) inflammatory indices were notably higher in AE patients. Nearly all patients received corticosteroids followed by plasmapheresis (PLEX) or intravenous immunoglobulin (IVIG) as first-line therapies, and treatment strategies did not differ significantly between groups. Second-line immune therapies were commonly employed in AE patients. Finally, AE patients had non-significant trends toward longer hospital lengths of stay (21 vs. 13 days) and a higher percentage of neurological disability (mRS greater than 2) at hospital discharge (59.6% vs. 34.8%).

Conclusions

Although ADEM and AE patients may have similar presenting symptoms, we found significant differences in frequency of imaging findings, symptom duration, laboratory and CSF profiles which can assist in distinguishing between the diagnoses. Patients in both groups were treated with a combination of immunomodulating therapies and neurological disability was common at hospital discharge.

The Clinical Features and Prognosis of Anti-NMDAR Encephalitis Depends on Blood Brain Barrier Integrity

Highlights

Decreased consciousness, ICU admission, a higher Neutrophil-to-lymphocyte ratio (NLR), and CSF protein are related to the integrity of the BBB in anti-NMDAR encephalitis patients.

In anti-NMDAR encephalitis patients, albumin/serum albumin (QAlb) increased was positively correlated with the quantitative intrathecal IgG synthesis.
The dysfunction of BBB can be helpful in evaluating anti-NMDAR encephalitis patients’ prognosis.

Clinical outcomes of pediatric Anti-NMDA receptor encephalitis

Highlights 

Despite the favorable outcome, mild cognitive and language deficit can persist in pediatric anti-NMDAR encephalitis patients.
Younger onset patients (<12 years) tended to recover more slowly than older onset patients (12–18 years).
Clinical outcome measure should be specific to delineate the differential effect on outcome according to age of onset.

Current Progress on Assessing the Prognosis for Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis

Here, we review the current advances of prognosis-related research from the clinical manifestations of the disease and auxiliary examinations such as EEG, magnetic resonance imaging (MRI), 18F fluorodeoxyglucose positron emission tomography (FDG-PET), and antibody measurement. In addition, we also discuss the impact of different treatment options on prognosis. In-depth research on the prognosis of patients with anti-NMDAR encephalitis will contribute to a better understanding of this disease, leading to better treatments options and, ultimately, a better prognosis.

Clinical and MRI Outcome Predictors in Pediatric Anti‐NMDA Receptor Encephalitis

We found that NMDARE had a severe impact on the developing brain of children, resulting in brain volume loss and failure of age‐expected brain growth over time.  Further analyses of our pediatric patients revealed reduced cortical and deep gray matter volume with reduced volumes of hippocampus, thalamus, and basal ganglia. This is in line with findings from adult NMDARE patients that identified atrophy and impaired functional connectivity of the hippocampus that correlated with memory impairment. Interestingly, recent studies showed that many children similarly suffer from significant cognitive impairment following NMDARE, suggesting that the hippocampal volume loss found in our study might associate with impaired cognitive recovery.  Future studies are therefore warranted to assess the relationship of MRI changes and persistent cognitive deficits in pediatric NMDARE.

Management and prognostic markers in patients with autoimmune encephalitis

Conclusion In patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.

Prognosticating autoimmune encephalitis: A systematic review

Syndrome and outcome of antibody‐negative limbic encephalitis

Gly receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes

Second-line immunotherapy and functional outcomes in autoimmune encephalitis: a systematic review and individual patient data meta-analysis

Multi-level individual patient data (IPD) meta-analyses was obtained for 356 patients from 25 studies. 

We did not find a statistically significant association between treatment with second-line immunotherapy and final mRS score for the cohort overall (odds ratio (OR) 1.74, 95% CI 0.98-3.08, p = 0.057), or sub-groups with NMDA-receptor encephalitis (OR 1.03, 95% CI 0.45-2.38, p = 0.944) or severe AE (maximum mRS score >2 ; OR 1.673, 95% CI 0.93-3.00, p = 0.085). Treatment with second-line immunotherapy was associated with higher final mRS scores in sub-groups with LGI-1 AE (OR 6.70, 95% CI 1.28-35.1, p = 0.024) and long-term (at least 12 months) follow-up (OR 3.94, 95% CI 1.67-9.27, p = 0.002).

SIGNIFICANCE: We did not observe an association between treatment with second-line immunotherapy and lower final mRS scores in patients with AE. This result should be interpreted with caution given the risk of bias, limited adjustment for disease severity, and insensitivity of the mRS in estimating psychiatric and cognitive disability.

Long-Term Prognosis of Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis Who Underwent Teratoma Removal: An Observational Study

We found that most patients with teratoma recovered slowly. However, favorable clinical outcomes were achieved over long-term follow-up, although mild sequelae may last several years. Immunotherapy was comparably ineffective in patients with teratoma before surgery, but effectiveness improved following removal surgery. Patients with teratoma presented with a more acute onset, more severe neurological symptoms, and higher IgG titer, than those without teratoma. Therefore, earlier and more immunotherapy turns were recommended for these patients. Surgery during the acute phase is strongly recommended for a good long-term prognosis.
 
In conclusion, removal surgery to treat anti-NMDAR encephalitis patients with teratoma is effective. Although anti-NMDAR encephalitis patients with teratoma had more serious medical conditions than patients without teratoma, timely removal surgery enabled favorable long-term outcomes.

Risk Factors for Mortality in Anti-NMDAR, Anti-LGI1, and Anti-GABABR Encephalitis

Conclusion

The general mortality rate of anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis was 15%. Age at onset and type of autoimmune encephalitis antibody were independent predictors of death in these patients.

Encephalitis With Antibodies Against the GABA B Receptor: High Mortality and Risk Factors

Objective: To measure mortality, identify predictors of death and investigate causes of death in patients with anti-gamma-aminobutyric-acid B receptor (anti-GABAB R) encephalitis. Conclusion: Patients with GABAB R encephalitis have a high mortality rate within 5 years. Older age at onset, presence a tumor, the number of complications, and deep venous thrombosis are associated with death.

Long-term cognitive outcome in anti-NMDA receptor encephalitis

This study presents comprehensive longitudinal data for the cognitive outcome in NMDAR encephalitis. All patients had cognitive deficits about 2 years after disease onset, mainly affecting memory and executive function. After 4 years, moderate or severe cognitive deficits persisted in 2/3 of patients despite good functional neurological outcome, indicating that cognitive function is an important outcome measure in addition to the functional neurological scales. Impaired cognitive outcome was predicted by delayed treatment and higher disease severity. However, continued improvement of cognitive function was observed for several years after disease onset in some patients.

Our results demonstrate that cognitive deficits are frequent and severe long-term sequelae following NMDAR encephalitis. These deficits show a slow and incomplete recovery and persist beyond recovery of other neuropsychiatric symptoms of the disease. Consequently, our findings call for rapid diagnosis and treatment at disease onset as well as for continued and customized cognitive rehabilitation to improve the long-term outcome.

Autoimmune Encephalitis in the ICU: Serological Spectrum, Clinical Courses, Complications and Outcomes

Characteristics and Prognosis of Autoimmune Encephalitis in the East of China: A Multi-Center Study

 From January 2015 to December 2019, 226 potential AE patients were recruited from five clinical centers, and a total of 185 patients who met the diagnostic criteria were included in the study. We retrospectively reviewed clinical features, auxiliary examinations, details of treatments, and outcomes of AE, and identified risk factors of poor prognosis. Modified Rankin Scale scores were used to evaluate neurological function, and scores of 3–6 indicated a poor-prognosis.

Analysis of Risk Factors for a Poor Prognosis in Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Construction of a Prognostic Composite Score

Conclusions

Age, disturbance of consciousness at admission, and ≥50% slow waves on the EEG were independent risk factors for a poor prognosis. An age, consciousness, and slow waves (ACS) prognostic composite score could play a role in facilitating early predictions of the prognosis of anti-NMDAR encephalitis.

Assessment of long-term psychosocial outcomes in anti-NMDA receptor encephalitis

Highlights

Anti-NMDARE may have long-term negative psychosocial impact on patients.

Over 30% of participants did not resume work/school after illness.

Misdiagnosis was associated with decreased odds of return to work/school.

Psychiatry follow-up was associated with increased odds of return to work/school.

Ongoing seizures and neuropsychiatric issues were associated with worse outcomes.

Influencing electroclinical features and prognostic factors in patients with anti-NMDAR encephalitis: a cohort follow-up study in Chinese patients

The clinical manifestations of patients with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis in East China and factors associated with prognosis were analyzed. A retrospective study of 106 patients (58 females; 48 males) with anti-NMDAR encephalitis in East China was carried out from June 2015 to February 2019. Clinical features and factors influencing outcomes were reviewed.

Understanding parental perspectives on outcomes following paediatric encephalitis: A qualitative study

A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis

Patient characteristics and outcome associations in AMPA receptor encephalitis

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis

Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis

Clinical Characteristics and Prognosis of Severe Anti-N-methyl-D-aspartate Receptor Encephalitis Patients

Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long‐term outcome in patients with autoimmune encephalitis

Limbic encephalitis: Clinical spectrum and long-term outcome from a developing country perspective

Treatment and prognostic factors for long-term outcome in patients with anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis: a cohort study

Changing Brain Metabolism Patterns in Patients With ANMDARE Serial 18F-FDG PET/CT Findings

Results 

Variable brain metabolic patterns and its association with the clinical course and the levels of NMDA antibody were demonstrated by FDG PET images. First, severe hypometabolism in bilateral occipital lobes and relatively mild hypermetabolism in the partial frontal and basal ganglia in acute and subacute phase, the level of antibody was high. Second, in early recovery phase when the symptoms was partially improved, extensive cortical hypometabolism was observed, and the level of antibody was low. Third, the patients in the recovery phase have no obvious neurological and psychiatric symptoms; PET images were nearly normal, and the antibodies tests were all negative, correspondingly. Fourth, 3 scans of relapsing phase presented heterogeneous brain metabolic abnormalities.

Conclusions 

There existed a specific serial brain metabolic changing pattern that correlated with the clinical course and antibody level in ANMDARE.

In the Clinic-Autoimmune Encephalitis: Persistent Cognitive, Neuropsychological Deficits After Anti-NMDAR Encephalitis Require Therapy, Study Suggests

Of 28 children selected for the study, with a median age of 14 years, only 18 (64 percent) returned to their previous school level. Among 22 patients who participated in the follow-up study, completing questionnaires about work or school performance, the most common problems were word finding difficulties (25 percent); attention and concentration deficits, anxiety, and impulsiveness (all 18 percent); and dyslexia and indecisiveness (both 12 percent).

This underscores the importance of understanding the long-term consequences of the disease. Parents want to know, and need to be informed, about what things to look out for as their children are recovering. We probably aren’t doing a very good job of that right now. Because the presentation of this disease is so dramatic, you can imagine that we’re so relieved that they’ve made such a good recovery that we tend not to place an emphasis on these subtler problems.

Anti-LGI1–associated cognitive impairment Presentation and long-term outcome

Prediction of neutrophil-to-lymphocyte ratio in the diagnosis and progression of autoimmune encephalitis

Elevated LGI1‐IgG CSF index predicts worse neurological outcome

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International Autoimmune Encephalitis Society is a charitable non-profit 501(c)(3) organization founded in 2016 by Tabitha Andrews Orth, Gene Desotell and Anji Hogan-Fesler. Tax ID# 81-3752344. Donations raised directly supports research, patients, families and caregivers impacted by autoimmune encephalitis and to educating healthcare communities around the world. Financial statement will be made available upon request.

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