Suspected autoimmune encephalitis: A retrospective study of patients referred for therapeutic plasma exchange.

INTRODUCTION: Autoimmune encephalitis (AE) comprises a heterogeneous group of autoantibody-mediated disorders targeting the brain parenchyma. Therapeutic plasma exchange (TPE), one of several first-line therapies for AE, is often initiated when AE is suspected, albeit prior to an established diagnosis. We sought to characterize the role of TPE in the treatment of suspected AE. METHODS: A single-center, retrospective analysis was performed of adults (≥18 years) who underwent at least one TPE procedure for "suspected AE." The following parameters were extracted and evaluated descriptively: clinicopathologic characteristics, treatment course, TPE-related adverse events, outcomes (e.g., modified Rankin scale [mRS]), and diagnosis once investigation was complete. RESULTS: A total of 37 patients (median age 56 years, range 28-77 years, 62.2% male) were evaluated. Autoimmune antibody testing was positive in serum for 43.2% (n = 16) and cerebrospinal fluid for 29.7% (n = 11). Patients underwent a median of five TPE procedures (range 3-16), with 97.3% (n = 36) via a central line and 21.6% (n = 8) requiring at least one unit of plasma as replacement fluid. Fifteen patients (40.5%) experienced at least one TPE-related adverse event. Compared with mRS at admission, the mRS at discharge was improved in 21.6% (n = 8), unchanged in 59.5% (n = 22), or worse in 18.9% (n = 7). Final diagnosis of AE was determined to be definite in 48.6% (n = 18), probable in 8.1% (n = 3) and possible in 27.0% (n = 10). Six (16.2%) patients were ultimately determined to have an alternate etiology. CONCLUSION: Empiric TPE for suspected AE is generally well-tolerated. However, its efficacy remains uncertain in the absence of controlled trials, particularly in the setting of seronegative disease.

Quantitative brain 18F-FDG PET/CT analysis in seronegative autoimmune encephalitis.

OBJECTIVE: Brain 18F-FDG PET/CT is a useful diagnostic in evaluating patients with suspected autoimmune encephalitis (AE). Specific patterns of brain dysmetabolism have been reported in anti-NMDAR and anti-LGI1 AE, and the degree of dysmetabolism may correlate with clinical functional status.18FDG-PET/CT abnormalities have not yet been described in seronegative AE. METHODS: We conducted a cross-sectional analysis of brain18FDG-PET/CT data in people with seronegative AE treated at the Johns Hopkins Hospital. Utilizing NeuroQ™ software, the Z-scores of 47 brain regions were calculated relative to healthy controls, then visually and statistically compared for probable and possible AE per clinical consensus diagnostic criteria to previous data from anti-NMDAR and anti-LGI1 cohorts. RESULTS: Eight probable seronegative AE and nine possible seronegative AE were identified. The group only differed in frequency of abnormal brain MRI, which was seen in all of the probable seronegative AE patients. Both seronegative groups had similar overall patterns of brain dysmetabolism. A common pattern of frontal lobe hypometabolism and medial temporal lobe hypermetabolism was observed in patients with probable and possible seronegative AE, as well as anti-NMDAR and anti-LGI1 AE as part of their respective characteristic patterns of dysmetabolism. Four patients had multiple brain18FDG-PET/CT scans, with changes in number and severity of abnormal brain regions mirroring clinical status. CONCLUSIONS: A18FDG-PET/CT pattern of frontal lobe hypometabolism and medial temporal lobe hypermetabolism could represent a common potential biomarker of AE, which along with additional clinical data may facilitate earlier diagnosis and treatment.

Predictors of elevations in fasting lipid levels in adults with epilepsy on a modified Atkins diet.

BACKGROUND: Ketogenic diet therapies can improve seizure control in patients with drug-resistant epilepsy (DRE). The current study investigated whether dietary fat composition is associated with elevations in serum lipid levels in adults with epilepsy who began a modified Atkins diet (MAD). METHODS: Adults with DRE were instructed to follow the MAD. Food records collected at baseline and follow-up were analyzed to extract median daily macro- and micronutrient composition. Total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, non-HDL and TC/HDL ratio were measured at baseline and follow-up. RESULTS: Study participants initiating MAD showed higher fat intake at 1 month (p<0.001) and 2 months (p<0.001) and lower carbohydrate intake at 1 month (p<0.001) and 2 months (p<0.001) compared to baseline. Study participants also showed higher intake of cholesterol (p<0.001), saturated fatty acid (p<0.001) and monounsaturated fatty acid (p<0.001) over time. Following MAD initiation, study participants showed significant increases in levels of TC (p = 0.007), LDL (p<0.001), and non-HDL (p = 0.009) over time. Dietary intake variables, including cholesterol and fat subtypes, were significantly associated with difference in 1 month TC and LDL levels from baseline but not absolute 1 month lipid values. In a sub-analysis, participants with baseline dyslipidemia showed smaller changes in lipid values during diet use. CONCLUSIONS: Adults with DRE starting MAD increased fat intake, particularly saturated and monounsaturated fat subtypes, and reduced carbohydrate intake. Changes in TC and LDL levels 1 month after MAD initiation are associated with dietary intake of cholesterol and fat.

Comparison of quantitative FDG-PET and MRI in anti-LGI1 autoimmune encephalitis.

OBJECTIVES: Anti-leucine glioma-inactivated protein 1 (anti-LGI1) autoimmune encephalitis (AE) presents as subacute memory loss, behavioral changes, and seizures. Diagnosis and treatment delays can result in long term sequelae, including cognitive impairment. 18F-FDG PET/CT may be more sensitive than MRI in patients with AE. Our objective was to determine if anti-LGI1 is associated with a distinct pattern of FDG uptake and whether this pattern persists following treatment. METHODS: Nineteen18F-FDG PET/CT brain scans (13 pre-treatment, 6 convalescent phase) for 13 patients with anti-LGI1 were studied using NeuroQ™ and CortexID™. The sensitivity of the PET images was compared to MRI. The Z scores of 47 brain regions between the pre-treatment and next available follow-up images during convalescence were compared. RESULTS: All 18F-FDG PET/CT scans demonstrated abnormal FDG uptake, while only 6 (42.9%) pre-treatment brain MRIs were abnormal. The pre-treatment scans demonstrated hypermetabolism in the bilateral medial temporal cortices, basal ganglia, brain stem, and cerebellum and hypometabolism in bilateral medial and mid frontal, cingulate, and parietotemporal cortices. Overall, the brain uptake during convalescence showed improvement of the Z scores towards 0 or normalization of previous hypometabolic activity in medial frontal cortex, inferior frontal cortex, Broca's region, parietotemporal cortex, and posterior cingulate cortex and previous hypermetabolic activity in medial temporal cortices, caudate, midbrain, pons and cerebellum. CONCLUSIONS: Brain FDG uptake was more commonly abnormal than MRI in the pre-treatment phase of anti-LGI1, and patterns of dysmetabolism differed in the pre-treatment and convalescent phases. These findings may expedite the diagnosis, treatment, and monitoring of anti-LGI1 patients.

Perspectives on Diagnosis and Management of All-Cause Encephalitis: A National Survey of Adult Infectious Diseases Physicians.

Background: Encephalitis is widely recognized as a challenging condition to diagnose and manage. The care of patients with encephalitis typically involves multiple disciplines, including neurologists and infectious disease (ID) physicians. Our objective was to describe the perspectives and needs of ID physicians regarding encephalitis, using a cross-sectional questionnaire survey. Methods: We performed a survey among physician members of the Infectious Diseases Society of America's (IDSA) Emerging Infections Network (EIN). Results: Response rate was 33% (480 among 1472 active EIN physician members). More than 75% of respondents reported caring for patients with suspected encephalitis. Although one-third were involved in the care of multiple patients with autoimmune encephalitis (AE) annually, comfort in diagnosing and managing encephalitis, and in particular AE, was low. Experience with advanced diagnostic tools was variable, as were approaches toward deployment of such tools. Respondents noted that training could be improved by incorporating a multidisciplinary approach taking advantage of online and virtual platforms. ID physicians report a heavy reliance on the 2008 IDSA guidelines for the management of encephalitis, and indicated strong support for a formal update. Conclusions: ID physicians play an important role in the diagnosis and management of all-cause encephalitis. Despite exposure to AE, few ID physicians are comfortable in recognizing, diagnosing, and treating AE. Moreover, comfort with and use of advanced diagnostic tools for infectious encephalitis was highly variable. Training in encephalitis should include a focus on use and stewardship of advanced diagnostic tools and on collaborative approaches with neurologists and other practitioners on mechanisms and clinical presentations of AE. There is a need for a formal update of 2008 guidelines on the management of encephalitis.

The effect of anti-seizure medications on lipid values in adults with epilepsy.

PURPOSE: Certain anti-seizure medications (ASMs) adversely impact lipid values. Here, we explored the impact of ASMs on lipid values in adults with epilepsy. METHODS: A total of 228 adults with epilepsy were divided into four groups based on ASMs used: strong EIASMs, weak EIASMs, non-EIASMs, and no ASMs. Demographic information, epilepsy-specific clinical history, and lipid values were obtained through chart review. RESULTS: While there was no significant difference in lipid values between groups, there was a significant difference in the proportion of participants with dyslipidemia. Specifically, more participants exhibited elevated low-density lipoprotein (LDL) level in the strong EIASM group compared to the non-EIASM group (46.7% vs 18%, p < 0.05). In addition, more participants showed elevated LDL level in the weak EIASM group compared to the non-EIASM group (38% vs 18%, p < 0.05). Users of strong EIASMs showed greater odds of high LDL level (OR 5.734, p = 0.005) and high total cholesterol level (OR 4.913, p = 0.008) compared to users of non-EIASMs. When we analyzed the impact of individual ASMs used by more than 15% of the cohort on lipid levels, participants using valproic acid (VPA) showed lower high-density lipoprotein (p = 0.002) and higher triglyceride levels (p = 0.002) compared to participants not using VPA. CONCLUSION: Our study demonstrated a difference in the proportion of participants with dyslipidemia between ASM groups. Thus, adults with epilepsy using EIASMs should have careful monitoring of lipid values to address the risk of cardiovascular disease.

Development and Validation of a Risk Score to Differentiate Viral and Autoimmune Encephalitis in Adults.

BACKGROUND: Encephalitis represents a challenging condition to diagnose and treat. To assist physicians in considering autoimmune encephalitis (AE) sooner, we developed and validated a risk score. METHODS: The study was conducted as a retrospective cohort of patients with a diagnosis of definite viral encephalitis (VE) and AE from​​ February 2005 to December 2019. Clinically relevant and statistically significant features between cases of AE and VE were explored in a bivariate logistic regression model and results were used to identify variables for inclusion in the risk score. A multivariable logistic model was used to generate risk score values and predict risk for AE. Results were externally validated. RESULTS: A total of 1310 patients were screened. Of the 279 enrolled, 36 patients met criteria for definite AE and 88 criteria for definite VE. Patients with AE compared with VE were more likely to have a subacute to chronic presentation (odds ratio [OR] = 22.36; 95% confidence interval [CI], 2.05-243.7), Charlson comorbidity index <2 (OR = 6.62; 95% CI, 1.05-41.4), psychiatric and/or memory complaints (OR = 203.0; 95% CI, 7.57-5445), and absence of robust inflammation in the cerebrospinal fluid defined as <50 white blood cells/µL and protein <50 mg/dL (OR = 0.06; 95% CI, .005-0.50). Using these 4 variables, patients were classified into 3 risk categories for AE: low (0-1), intermediate (2-3), and high (4). Results were externally validated and the performance of the score achieved an area under the curve of 0.918 (95% CI, .871-.966). DISCUSSION: This risk score allows clinicians to estimate the probability of AE in patients presenting with encephalitis and may assist with earlier diagnosis and treatment.

Six-month effects of modified Atkins diet implementation on indices of cardiovascular disease risk in adults with epilepsy.

BACKGROUND/AIMS: Ketogenic diet therapies (KDTs) offer a needed therapeutic option for patients with drug-resistant epilepsy. The current study investigated biochemical and anthropometric indices of cardiovascular disease (CVD) risk in adults with epilepsy treated with KDT over 6 months. METHOD: 65 adults with epilepsy naïve to diet therapy were enrolled in a prospective longitudinal study and instructed on modified Atkins diet (MAD) use. Seizure frequency, anthropometric measures, blood levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoproteins A1 and B, and lipoprotein sub-fractions were assessed at baseline, 3 months, and 6 months. RESULTS: Subsequent to study enrollment, 34 participants were lost to follow-up, elected not to start, or stopped MAD prior to study completion, leaving a total of 31 participants in the study at 6 months. Compared to baseline, participants on MAD showed significant reductions in median seizure frequency/week, weight, body mass index, waist and hip circumference, and percent body fat at 3 and 6 months. Compared to baseline, participants on MAD for 3 months showed significantly increased levels of total, small and medium LDL particles, ApoB and ApoB/A1 ratio. At 6 months, only small LDL particles and ApoB levels remained elevated and levels of ApoA1 had risen, suggesting possible compensatory adaptation over time. CONCLUSIONS: This study provides evidence demonstrating the efficacy and cardiovascular safety of 6 months of MAD use by adults with epilepsy. It also highlights an index of CVD risk - small LDL particles - that should be closely monitored.Trial registration: ClinicalTrials.gov identifier: NCT02694094..

Fatigue in Survivors of Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: To evaluate the impact of fatigue after autoimmune encephalitis, determine associations with patients' characteristics, and identify factors that contribute to its development. METHODS: In a first cohort recruited via several encephalitis support organizations, self-reported questionnaires were used to evaluate fatigue, depression, and sleep quality in adults after autoimmune encephalitis. In a second cohort where more in-depth clinical characterization could be performed, adults with encephalitis from 2 tertiary hospitals were evaluated using the same questionnaires. Patients' characteristics were retrospectively captured. RESULTS: In the first cohort (mean [SD] age; 43 [16] years, 220 [65%] female), 220 of 338 participants (65%) reported fatigue, 175 of 307 (57%) depression, and 211 of 285 (74%) poor sleep quality. In the second cohort (48 [19] years; 43 [50%] women), 42 of 69 participants (61%) reported fatigue, whereas 23 of 68 (34%) reported depression and 44 of 66 (67%) poor sleep quality, despite more than 80% having "good" modified Rankin scale (mRS) scores (0-2). Individuals with anti-NMDA receptor encephalitis reported lower fatigue scores than those with other autoimmune encephalitis types. In a multivariate analysis examining factors at discharge that might predict fatigue scores, only anti-NMDA receptor encephalitis was a (negative) predictor of fatigue and remained so when potential confounders were included. DISCUSSION: The impact of fatigue after autoimmune encephalitis is prominent and not fully accounted for by depression or sleep quality, nor adequately captured by mRS scores for disability. Fatigue is pervasive across autoimmune encephalitis, although lower scores are reported in anti-NMDA receptor encephalitis. Fatigue should be screened routinely, considered as an outcome measure in clinical trials, and further studied from a mechanistic standpoint.

The psychiatric effects of ketogenic diet therapy on adults with chronic epilepsy.

OBJECTIVES: Patients with epilepsy are known to exhibit high rates of comorbid psychiatric disorders such as depression, anxiety, and other mood disorders. Little is known about the psychiatric effects of a ketogenic diet therapy (KDT) on adults with epilepsy. The objective of this study was to better understand the relationship between KDT and psychological state based on depressive and anxiety symptoms in adults with chronic epilepsy. METHODS: Adults at the Johns Hopkins Adult Epilepsy Diet Center on a modified Atkins diet (MAD) for at least one month were surveyed retrospectively. Adults who were diet naïve were given a baseline survey and an additional survey after 3 months or more on MAD. Surveys included validated measures of depressive and anxiety symptoms as well as their severity. Participant demographics, seizure frequency, and use of concomitant antiseizure drugs (ASDs), chronic anxiolytics (excluding as-needed benzodiazepines for seizure rescue only), and/or antidepressant drugs were extracted from electronic medical records. RESULTS: One-hundred participants aged 19-75 enrolled in the study. Sixty participants filled out a single retrospective survey. Of 40 diet naïve participants who filled out a baseline prospective survey, 19 completed a follow-up survey while on MAD and 21 participants were lost to follow-up. Longer diet duration was significantly associated with fewer anxiety and depressive symptoms, based on psychiatric measure scores, in retrospective study participants. Lower seizure frequency was also significantly associated with less anxiety symptoms in the retrospective cohort. Prospective study participants did not experience significant change in anxiety or depressive symptoms on the diet. There was a significant correlation between higher ketone level and responder rate (≥50% seizure reduction) in the prospective cohort, although no correlation between ketone level and change in psychiatric symptoms was seen. SIGNIFICANCE: Psychiatric comorbidity among patients with epilepsy is quite common and can be influenced by multiple factors such as seizure frequency, the use of various ASDs, social factors, and underlying etiology. Although ketogenic diet therapies have been in clinical use for one century, the psychiatric impacts have been insufficiently explored. This study provides preliminary evidence that KDT may have a positive impact on psychological state independent of seizure reduction or ketone body production and may be influenced by longer duration of diet therapy. These results support further investigation into specific effects and potential therapeutic benefits on various psychiatric disorders.

Prevalence and Characteristics of Neuroinfectious Disease Inquiries Within the Emerging Infections Network: A 22-Year Retrospective Study.

BACKGROUND: To monitor emerging infectious diseases, the Centers for Disease Control and Prevention and the Infectious Disease Society of America established the Emerging Infections Network (EIN), allowing infectious disease specialists to post inquiries about clinical cases. We describe the frequency and characteristics of neuroinfectious disease-related inquiries. METHODS: The EIN listserv was retrospectively reviewed from February 1997 to December 2019 using search terms associated with neurologic diseases. We recorded case summaries, disease type (ie, meningitis, encephalitis), inquiry type (diagnostic approach, result interpretation, management decisions), unique patient populations, exposures, pathogens, ultimate diagnosis, and change in clinical care based on responses. RESULTS: Of 2348 total inquiries, 285 (12.1%) related to neuroinfectious diseases. The majority involved meningitis (99, 34.7%) or encephalitis (56, 19.6%). One hundred fifteen inquiries (40%) related to management, 34 (12%) related to diagnostic workup, and 22 (8%) related to result interpretation. Eight (2.8%) specifically involved results of cerebrospinal fluid polymerase chain reaction testing. Sixty-three (22.1%) involved immunosuppressed patients (29 human immunodeficiency virus-positive cases [46%]). The most common pathogens were Treponema pallidum (19, 6.7%) and Cryptococcus neoformans (18, 6.3%). In 74 (25%) inquiries, patients had neurologic symptoms without a clear infection, 38 (51.3%) of which included noninfectious neurologic etiologies in the differential diagnosis. CONCLUSIONS: This study demonstrates the significant challenges of diagnosis and management of neuroinfectious diseases within the field of infectious diseases. It also highlights the importance of curated forums to guide the approach of difficult cases, in particular instances that mimic infectious diseases. Finally, the EIN listserv may assist in identifying areas for research and training to address these complexities.

Ketogenic diet therapy provision in the COVID-19 pandemic: Dual-center experience and recommendations.

The current coronavirus-19 pandemic has changed dramatically how neurologists care for children and adults with epilepsy. Stay-at-home orders and resistance to hospitalizations by patients have led epileptologists to engage in telemedicine and reevaluate how to provide elective services. Ketogenic diet therapy is often started in the hospital, with families educated in hospital-based classes, but this is difficult to do in this current pandemic. At our two academic centers, both our pediatric and adult epilepsy diet centers have had to quickly consider alternative methods to both start and maintain ketogenic diet therapy. This paper provides several examples of how ketogenic diet therapy can be provided to patients in unique ways, along with recommendations from other experts and patients, learned over the past few months.