Depression readmission risk is elevated in multiple sclerosis compared to other chronic illnesses.

OBJECTIVE: Assess readmissions for depression or suicide attempt (SA) after MS admission versus other chronic inflammatory illnesses. METHODS: This retrospective cohort study identified MS, asthma, rheumatoid arthritis (RA), depression, and SA in the 2013 National Readmissions Database by International Classification of Diseases codes. Index admissions (MS, n = 7698; asthma, n = 93,590; RA, n = 3685) and depression or SA readmission rates were analyzed. Hazard ratios (HRs) estimated 1-year depression/SA readmission hazard, comparing MS to asthma or RA, adjusting for age, sex, psychiatric comorbidity, substance abuse, tobacco use, income, and index hospitalization characteristics. RESULTS: MS had more baseline depression (24.7%) versus asthma (15.6%) and RA (14.6%). Ninety-day depression readmission rate was higher in MS (0.5%) than asthma (0.3%) and RA (0.03%). Depression readmission HR was higher after MS admission versus asthma (HR = 1.37, 95% confidence interval (CI) = 1.00-1.86, p = 0.0485) and RA (HR = 4.68, 95% CI = 1.60-13.62, p = 0.0047). HR was not different for SA readmission across groups. Depression readmission HR was more than double in MS patients with psychiatric disease or substance abuse versus RA or asthma patients with either comorbidity. CONCLUSION: Depression readmission risk after MS hospitalization was elevated versus asthma/RA. Substance use and baseline psychiatric comorbidity were more strongly associated with depression readmission in MS patients.

Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis.

Importance: Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear. Objective: To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. Data Sources: Systematic search in PubMed from inception to January 1, 2019. Study Selection: Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data. Data Extraction and Synthesis: Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models. Main Outcomes and Measures: The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset). Results: Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P < .001), concurrent with a falling relapse rate over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P = .006). Modified NEOS score (including 4 of 5 original NEOS items) was associated with probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P = .05). Conclusions and Relevance: Factors influencing functional outcomes and relapse are different and need to be considered independently in development of evidence-based optimal management guidelines of patients with NMDARE.

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis.

OBJECTIVE: To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE). METHODS: After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement). RESULTS: Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided. CONCLUSION: These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.

Seizures in autoimmune encephalitis-A systematic review and quantitative synthesis.

OBJECTIVE: This study aimed to evaluate the proportion of patients with seizures and electroencephalography (EEG) abnormalities in autoimmune encephalitis (AE) and its most common subtypes. METHODS: This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standards and was registered with the International Prospective Register of Systematic Reviews (PROSPERO). We searched Medline All, Embase, and PsychINFO in Ovid from inception to June 2019 for articles pertaining to AE and seizure. Included studies reported seizure and/or EEG data in cohorts of ≥10 AE patients. Patient demographics, antibody type, seizure incidence, and EEG findings were extracted. Review of studies and data extraction were performed in duplicate. In addition to descriptive analysis, quantitative synthesis stratified by autoantibody subtype was performed with logistic regression and chi-square analyses. RESULTS: Our search yielded 3856 abstracts: 1616 were selected for full-text review and 118 studies met eligibility criteria. Of 3722 antibody-positive AE patients, 2601 (69.9%) had clinical seizures during the course of their illness. Of the 2025 patients with antibody-positive AE and available EEG data, 1718 (84.8%) had some EEG abnormality (eg, epileptiform discharges, slowing, and so on). Anti- N-methyl-d-aspartate (NMDA) receptor encephalitis (anti-NMDARE) was the most commonly reported type of AE (1985/3722, 53.3%). Of the anti-NMDARE patients with available seizure or EEG data, 71.8% (n = 1425/1985) had clinical seizures during their illness, and 89.7% (n = 1172/1306) had EEG abnormalities. For all AE patients and in the anti-NMDARE subpopulation, seizures were more common in younger patients (p < .05). SIGNIFICANCE: This systematic review provides an estimate of the proportion of AE patients with seizures, confirming the magnitude of seizure burden in this population. Prospective studies are needed to understand population-based prevalence of seizures, identify factors associated with seizures, and evaluate particular EEG findings as biomarkers of seizures and outcomes in AE.

Clinical and electrographic features of persistent seizures and status epilepticus associated with anti-NMDA receptor encephalitis (anti-NMDARE).

Based on a multicenter cohort of people with anti-NMDA receptor encephalitis (anti-NMDARE), we describe seizure phenotypes, electroencephalographic (EEG) findings, and anti-seizure treatment strategies. We also investigated whether specific electrographic features are associated with persistent seizures or status epilepticus after acute presentation. In this retrospective cohort study, we reviewed records of children and adults with anti-NMDARE between 2010 and 2014 who were included in the Rare Epilepsy of New York City database, which included the text of physician notes from five academic medical centers. Clinical history (e.g., seizure semiology) and EEG features (e.g., background organization, slowing, epileptiform activity, seizures, sleep architecture, extreme delta brush) were abstracted. We compared clinical features associated with persistent seizures (ongoing seizures after one month from presentation) and status epilepticus, using bivariate and multivariable analyses. Among the 38 individuals with definite anti-NMDARE, 32 (84%) had seizures and 29 (76%) had seizures captured on EEG. Electrographic-only seizures were identified in five (13%) individuals. Seizures started at a median of four days after initial symptoms (IQR: 3-6 days). Frontal lobe-onset focal seizures were most common (n=12; 32%). Most individuals (31/38; 82%) were refractory to anti-seizure medications. Status epilepticus was associated with younger age (15 years [9-20] vs. 23 years [18-27]; p=0.04) and Hispanic ethnicity (30 [80%] vs. 8 [36%]; p=0.04). Persistent seizures (ongoing seizures after one month from presentation) were associated with younger age (nine years [3-14] vs. 22 years [15-28]; p<0.01). Measured electrographic features were not associated with persistent seizures. Seizures associated with anti-NMDARE are primarily focal seizures originating in the frontal lobes. Younger patients may be at increased risk of epileptogenesis and status epilepticus. Continuous EEG monitoring helps identify subclinical seizures, but specific EEG findings may not predict the severity or persistence of seizures during hospitalization.

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

PURPOSE: The purpose of this study was to assess long-term psychosocial outcomes of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (anti-NMDARE). METHODS: Adolescents and adults with self-reported anti-NMDARE were invited to complete an online survey distributed by relevant patient organizations. Demographic and clinical information was collected, including the diagnoses initially given for anti-NMDARE symptoms and posthospital care received. Patient-Reported Outcomes Measurement Information System (PROMIS) Psychosocial Impact Illness - Negative short form (Negative PSII) was administered to assess psychosocial outcome of anti-NMDARE. Associations between clinical factors and psychosocial outcomes were evaluated. RESULTS: Sixty-one individuals with anti-NMDARE age 15 years and above participated. Mean age was 33.7 years (standard deviation [SD]: 12.8), and participants were predominantly female (90.2%, n = 55). Mean T-score on PROMIS Negative PSII was 60.7, >1 SD higher (worse psychosocial function) than that of the provided normalized sample enriched for chronic illness (50, SD: 10). Initial misdiagnosis of anti-NMDARE symptoms was associated with decreased odds (odds ratio [OR]: 0.11, p < 0.05), and follow-up with a psychiatrist after hospitalization with increased odds (OR: 8.46, p < 0.05), of return to work/school after illness. Younger age of symptom onset and presence of ongoing neuropsychiatric issues were predictive of worse Negative PSII scores (p < 0.05). CONCLUSION: Individuals with anti-NMDARE demonstrate poor psychosocial outcomes, yet there are no current standards for long-term assessment or management of such symptoms in this population. These findings highlight the need for use of more comprehensive outcome measures that include assessment of psychosocial function and the importance of developing interventions that address this domain for individuals with anti-NMDARE.

Assessment of care transitions and caregiver burden in anti-NMDA receptor encephalitis.

PURPOSE: The purpose of the study was to assess care transitions and caregiver burden among caregivers of individuals with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (anti-NMDARE). METHODS: Caregivers of individuals with anti-NMDARE were recruited via patient organization websites. Demographic and clinical information as well as responses to the Care Transition Measure 15 (CTM-15) and Zarit Burden Interview (ZBI) were collected. Exploratory factor analysis (EFA) was conducted on the ZBI, and underlying constructs were analyzed for associations with the CTM-15 and clinical characteristics. RESULTS: Seventy-six caregivers participated. On the CTM-15, the top items where caregivers disagreed or strongly disagreed were the following: "when the patient left the hospital, I had a readable and easily understood written plan that described how all of their healthcare needs were going to be met" (73%), "when the patient left the hospital, I was confident that I know how to manage their health" (62%), and "when the patient left the hospital, I had all the information I needed to be able to take care of them" (58%). Worse care transitions significantly predicted higher caregiver burden scores. Mean ZBI score was 44, falling in the moderate to severe burden range. Exploratory factor analysis was conducted and found four common underlying factors associated with total score. Factor 1, the impact of caring on caregivers' personal lives (accounting for 51% of total score variance), was selected for further analysis because of its modifiable nature. Higher ZBI scores were associated with lower CTM-15 scores (p < 0.003) and the individual with anti-NMDARE not returning to driving (p < 0.002). CONCLUSION: This study identified specific elements of care transitions and caregiver burden that are not currently being addressed for individuals with anti-NMDARE. Attention to these aspects of care in the development of targeted interventions may improve outcomes in individuals with anti-NMDARE and their caregivers.

Autoimmune encephalitis: A costly condition.

OBJECTIVE: To assess the inpatient hospitalization burden and costs of patients with autoimmune encephalitis (AE) at a tertiary care institution. METHODS: Adult inpatients with AE were identified retrospectively from July 1, 2005, to June 30, 2015. Demographic and clinical data were collected and analyzed. Billing data were compared to those of patients with herpes simplex encephalitis (HSE). Charges were adjusted for inflation. RESULTS: Of 244 admissions for encephalitis reviewed, 63 patients met criteria for probable or definite AE. Thirty-one (49%) patients were antibody positive, and 27 (43%) were admitted to the intensive care unit (ICU). Median hospital charges per patient with AE were more than $70,000; median length of stay (LOS) was 15 days; and in-hospital mortality was 6%. Patients admitted to the ICU had substantially higher median hospital charges (ICU $173,000 per admission vs non-ICU $50,000 per admission, p < 0.001). LOS was strongly associated with charges and was driven by delay in diagnosis of AE, prolonged treatment courses, and lack of response to therapy. Compared with HSE, median hospital charges per patient with AE were nearly 4 times higher, median AE LOS was 3 times higher, and total charges over the study period were nearly twice as high. CONCLUSIONS: Patients with AE used more inpatient health care resources per patient during a 10-year period than patients with HSE at our institution. ICU-admitted patients with AE were responsible for a substantially higher financial burden than non-ICU-admitted patients with AE. Our data underscore the need for the development of novel diagnostic and therapeutic modalities to improve patient outcomes and to decrease hospital burden in AE.

Comparative Outcomes in Children and Adults With Anti- N-Methyl-D-Aspartate (anti-NMDA) Receptor Encephalitis.

This study compared neurologic disability and adaptive function in children and adults >1 year following anti- N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis diagnosis. Retrospective record review identified 12 patients with anti-NMDAR encephalitis. At last follow-up, all surviving patients had "good" modified Rankin Score (0-2). Four children, 6 adults, and their families participated in a telephone interview. Median duration since diagnosis was similar for children (2.42 years, interquartile range 2.12-3.32) and adults (3.55 years, interquartile range 2.08-5.50 years). 3/4 (75%) pediatric and 3/5 (60%) adult patients reported neuropsychiatric symptoms (fatigue, emotional lability, short-term memory deficits or concentration deficits). On the Adaptive Behavior Assessment System (ABAS-3), although overall adaptive function was intact for adults (general adaptive composite standard score: median 104.5, interquartile range 98.8-112.5), the median for children was below average (General Adaptive Composite Standard Score: median 82.0, interquartile range 79.0-89.0). Children with anti-NDMAR encephalitis may have long-term effects impacting daily life while adults regain normal function.

Gait Disturbance as the Presenting Symptom in Young Children With Anti-NMDA Receptor Encephalitis.

This case series demonstrates a novel clinical phenotype of gait disturbance as an initial symptom in children <3 years old with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Anti-NMDAR encephalitis is one of the most common causes of encephalitis in children, more common than any of the viral encephalitides and the second most common autoimmune cause after acute disseminated encephalomyelitis. Anti-NMDAR encephalitis in children often presents with disrupted speech and sleep patterns followed by progression to motor dysfunction, dyskinesias, and seizures. Because this condition can present initially with vague symptoms, diagnosis and treatment of anti-NMDAR encephalitis are often delayed. Although nearly 40% of all reported patients are <18 years old, few infants and toddlers have been reported with this disease. Four children <3 years old were diagnosed with anti-NMDAR encephalitis at our institution. Interestingly, each child presented initially with the chief concern of gait disturbance. One child presented with unsteady walking and slurred speech, suggestive of cerebellar ataxia, and 3 had inability to bear weight on a unilateral lower extremity, resulting in unsteady gait. Two of these children had seizures at the time of hospital presentation. All developed classic behavioral changes, insomnia, dyskinesias, or decreased speech immediately before or during hospitalization. When seen in the setting of other neurologic abnormalities, gait disturbance should raise the concern for anti-NMDAR encephalitis in young children. The differential diagnosis for gait disturbance in toddlers and key features suggestive of anti-NMDAR encephalitis are reviewed.

Ongoing Cerebral Vasculitis During Treatment of Rocky Mountain Spotted Fever.

BACKGROUND: Rocky Mountain spotted fever is a tickborne infection that produces a systemic small-vessel vasculitis; its prognosis is excellent if appropriate treatment is initiated early. Because the advent of effective antirickettsial therapies predates the widespread use of brain magnetic resonance imaging, there are limited data on the effect of untreated Rocky Mountain spotted fever infection on neuroimaging studies. PATIENT DESCRIPTION: We describe a 7-year-old girl with delayed treatment of Rocky Mountain spotted fever who suffered severe neurological impairment. Serial brain magnetic resonance images revealed a progressive "starry sky appearance," which is proposed to result from the same small vessel vasculitis that causes the characteristic skin rash of this infection. CONCLUSION: Neurological injury can continue to occur despite specific antirickettsial therapy in Rocky Mountain spotted fever. This child's clinical features raise questions about the optimal management of this infection, particularly the utility of immune modulating therapies in cases of delayed treatment and neurological involvement.