Searching for autoimmune encephalitis: Beware of normal CSF

doi:10.1016/j.jneuroim.2020.577285

Journal of Neuroimmunology

Volume 345, 15 August 2020, 577285

https://doi.org/10.1016/j.jneuroim.2020.577285 Get rights and content

Highlights

•
CSF WBC count and protein were within normal for 27% (CI_95%: 19-37) of patients with early active autoimmune encephalitis.
•
When results of oligoclonal banding were added, the proportion of patients with “normal” CSF fell to 14% (CI_95%: 6-16).
•
Older age was inversely associated with the presence of CSF pleocytosis or abnormal oligoclonal bands.
•
Combined abnormal CSF WBC count, protein, and oligoclonal bands was more likely with shorter symptomatic-onset-to-LP delays.

Abstract

Objective

To determine the prevalence of cerebrospinal fluid (CSF) markers associated with inflammation (i.e., elevated white blood cell count, protein concentration, and CSF-specific oligoclonal bands) in patients with early active autoimmune encephalitis (AE).

Methods

CSF characteristics, including WBC count, protein concentration, and oligoclonal banding, were analyzed in patients diagnosed with AE at two tertiary care centers.

Results

Ninety-five patients were included in the study. CSF white blood cell counts and protein levels were within normal limits for 27% (CI_95%: 19–37) of patients with AE. When results of oligoclonal banding were added, 14% (CI_95%: 6–16) of patients with AE had “normal” CSF. The median CSF white blood cell count was 8 cells/mm³ (range: 0–544) and the median CSF protein concentration was 0.42 g/L (range: 0.15–3.92).

Conclusions

White blood cell counts and protein levels were within normal limits in the CSF of a substantial proportion of patients with early active AE. Inclusion of CSF oligoclonal banding identified a higher proportion of patients with an inflammatory CSF profile, especially when CSF was sampled early in the disease process.

Introduction

The number of antibodies associated with autoimmune encephalitis (AE) has markedly increased over the last decade.(Bradshaw and Linnoila, 2018) Despite this expansion, treatment decisions must often be made before results of antibody testing are available, as early treatment is associated with better outcomes.(Balu et al., 2018; Dalmau et al., 2008; Finke et al., 2012, Finke et al., 2017; Hébert et al., 2018; Irani et al., 2010, Irani et al., 2013) To address this issue, diagnostic criteria for AE emphasize early detection of clinical, neuroimaging, and cerebrospinal fluid (CSF) features suggestive of central nervous system inflammation.(Graus et al., 2016) However, cases of definite AE without CSF pleocytosis are increasingly recognized in studies of “paraneoplastic AE”,(Gultekin et al., 2000) epidemiological studies of encephalitis,(Dubey et al., 2018) patients above 60 yearsofage with neuronal cell-surface antibodies,(Escudero et al., 2017) and patients with specific autoantibodies.(Blinder and Lewerenz, 2019; Irani et al., 2013; Warren et al., 2018) The high degree of variability in CSF findings in patients with AE (Blinder and Lewerenz, 2019; Dalmau et al., 2008; Honorat et al., 2017; Petit-Pedrol, 2014; Wang et al., 2016) exemplifies the need to comprehensively evaluate CSF findings in larger cohorts of patients with AE.

To address this clinical gap, we evaluated the period prevalence of commonly-available markers of CSF inflammation in patients presenting with AE at two tertiary care centers. Specifically, we determined the frequency of detection of CSF pleocytosis, elevated protein, and increased CSF-specific oligoclonal bands (OCB) in patients with early active AE. Although protein concentration and CSF-specific OCBs are not part of the current diagnostic criteria for “definite AE”,(Graus et al., 2016) elevated protein may serve as a non-specific marker of central nervous system damage,(Reiber and Peter, 2001) while the detection of OCB may support a diagnosis of “antibody-negative but probable AE”,(Graus et al., 2016) with the potential to identify patients with AE.

Section snippets

Patients and clinical characteristics

The University Health Network (UHN) in Toronto (Ontario, Canada) and Washington University School of Medicine (WUSM)-affiliated Barnes Jewish Hospital in Saint Louis (Missouri, USA) are tertiary centers that care for patients with AE. Information on patients meeting clinical criteria for AE (Graus et al., 2016) was collected from consecutively-encountered patients between January 1st, 2012 and December 31st, 2019. Patients were included if they met diagnostic criteria for “definite AE” or

Results

One-hundred-and-two patients with AE were enrolled between January 1st, 2012 and December 31st, 2019. Seven patients were excluded due to incomplete information concerning the first LP obtained during the early active phase of AE: their median age was 15 years (range 10–29); five were female; CSF NMDAR IgG autoantibodies were detected in 6 patients; and no AE-associated antibodies were detected in 1 patient. Of the 95 patients meeting inclusion criteria, 41 were recruited at WUSM and 54 at UHN.

Discussion

Forty-four percent of patients with AE in this series did not have CSF pleocytosis, thus lacking a key element of the proposed diagnostic criteria for possible AE.(Graus et al., 2016) When taking into account the presence of CSF pleocytosis and high protein only, a substantial proportion (26/95; 27%) of patients with AE had a “normal” CSF in the early active phase of their disease. This proportion is similar to that reported in an epidemiological study of AE in Olmsted County, USA (10/24; 42%; p

Ethical standards

All human and animal studies have been approved by the appropriate ethics committee and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.

Study funding

Funding for work completed at WUSM was provided by the National Institutes of Health (K23AG064029 to GSD), American Academy of Neurology/American Brain Foundation (Clinical Research Training Fellowship to GSD), and via philanthropic contributions from patients and family members to promote research and education into Autoimmune Encephalitis (GSD). JH received funding from the University of Toronto Postgraduate Medical Education bursary program for this work.

Declaration of Competing Interest

Dr. Hébert reports no disclosures.

Dr. Gros reports no disclosures.

Dr. Lapointe reports no disclosures.

Mrs. Amtashar reports no disclosures.

Dr. Steriade receives research funding from Finding A Cure for Seizure and Epilepsy (FACES), UCB and the American Epilepsy Society. She serves as a consultant to the non-profit organization The Epilepsy Study Consortium. She has received compensation for serving on an advisory board for UCB.

Dr. Maurice reports no disclosures.

Dr. Wennberg reports no

Acknowledgement

The Authors thank Dr. Melanie Yarbrough (Department of Pathology and Immunology, Washington University School of Medicine) for clarification concerning laboratory procedures and measures at Washington University School of Medicine.

References (28)

J. Dalmau et al.
Anti-NMDA-receptor encephalitis: case series and analysis of the effect of antibodies
Lancet Neurol.
(2008)
M.J. Garton et al.
Age-related changes in cerebrospinal fluid protein concentrations
J. Neurol. Sci.
(1991)
F. Graus et al.
A clinical approach to diagnosis of autoimmune encephalitis
Lancet Neurol.
(2016)
M. Petit-Pedrol
Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies
Lancet Neurol.
(2014)
H. Reiber et al.
Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs
J. Neurol. Sci.
(2001)
Y. Shin et al.
VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy
J. Neuroimmunol.
(2013)
M. Titulaer et al.
Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study
Lancet Neurol.
(2013)
R. Balu et al.
A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis
Neurology
(2018)
T. Blinder et al.
Cerebrospinal fluid findings in patients with autoimmune encephalitis-a systematic analysis
Front. Neurol.
(2019)
M.J. Bradshaw et al.
An overview of autoimmune and paraneoplastic encephalitides
Semin. Neurol.
(2018)

A. Breiner et al.

Updated cerebrospinal fluid total protein reference values improve chronic inflammatory demyelinating polyneuropathy diagnosis

Muscle Nerve

(2019)

J. Brooks et al.

Testing for N-methyl-D-aspartate receptor autoantibodies in clinical practice

Can. J. Neurol. Sci. J. Can. Sci. Neurol.

(2019)

D. Dubey et al.

Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis

Ann. Neurol.

(2018)

D. Escudero et al.

Antibody-associated CNS syndromes without signs of inflammation in the elderly

Neurology

(2017)

Cited by (36)

Infrequent patterns in cerebrospinal fluid isofocusing test: Clinical significance and contribution of IgG index and Reiber diagram to their interpretation
2024, Multiple Sclerosis and Related Disorders
Cerebrospinal fluid (CSF) isoelectrofocusing (IEF) is considered as the gold standard for detecting an intrathecal synthesis of IgG, which is a hallmark of multiple sclerosis (MS). This corresponds to the presence of CSF-restricted IgG oligoclonal bands (OCB) (typically type 2 pattern). Moreover, this technique can also detect a systemic immune reaction with passive transfer of IgG (type 3 and 4 patterns) for which the clinical relevance is less understood. The aim of our study was to determine the frequency and disease associations of IEF type 3 and 4 patterns and to investigate the potential usefulness of including quantitative data (IgG index and Reiber Diagram) in interpreting such IEF profiles.
Among 544 patients who underwent CSF IEF (Hydragel CSF isofocusing kit, Sebia®, France) in our Laboratory during a six-year-period, those who presented type 3 or 4 patterns were selected. Clinical data and results of other immunological tests were analyzed for 27 patients followed in the Neurological Department.
Frequencies of type 3 and type 4 patterns were relatively low (2.3 % and 3.4 % respectively). Among patients with type 3 pattern included in our study (n = 10), 5 were diagnosed with MS. For the 5 other patients, the diagnosis was a clinically isolated syndrome (CIS) (2 cases), a probable auto-immune encephalitis (2 cases) and a possible genetic neurodegenerative disease (1 case). MS patients had an IgG index >0.7 and fell into area 4 of Reiber diagram while non-MS patients had an IgG index <0.7 and fell into area 1, except the last case. Regarding type 4 pattern (n = 17), the diagnoses were as follows: MS (3), CIS (4), Neuromyelitis optica spectrum disorders with positive anti-AQP4 antibodies (3) and anti-NMDAR autoimmune encephalitis (1). The remaining cases had central nervous system impairment related to vascular, metabolic or tumoral etiologies (3) or peripheral nervous system impairment (3). In this group (type 4 pattern), IgG index was <0.7 in 15/17 cases. Interpretation using Reiber diagram showed an abnormal blood-brain barrier for 8/17 patients.
Type 3 and 4 IEF patterns are infrequently observed in routine neurology practice. It is important for the diagnostic laboratory professional as well as for the neurologist to understand their clinical relevance. Our findings highlight the contribution of quantitative evaluation of CSF (IgG index, Reiber diagram) for the interpretation of such situations. Despite the small size of our study population, our results emphasize the importance of reporting the exact type of IEF pattern and not only the positivity or not of OCB.
Cerebrospinal fluid indices as predictors of treatment response in autoimmune encephalitis
2023, Multiple Sclerosis and Related Disorders
Cerebrospinal fluid (CSF) indices reflecting intrathecal antibody production and blood-brain barrier impairment are not routinely assessed in patients with autoimmune encephalitis (AE). We aimed to study CSF indices and their association with the prognosis of AE.
This retrospective cohort study conducted at Amrita Institute of Medical Sciences (AIMS), Kochi, India, included 60 patients aged more than 18 years with definite/probable/possible AE admitted to the Department of Neurology from August 2016 to November 2021. We introduced a classification of treatment response based on modified Rankin Scale change over time and treatment modalities.
In our cohort of 60 patients (six [10%] seropositive cases), a good rapid treatment response was associated with CSF white blood cell count of more than 4 cells/mm3 (OR, 4.57; 95% CI 1.31–15.96; P = .02) and positive immunoglobulin G (IgG) Local Synthesis (OR, 7.27; 95% CI 1.56–33.86; P = .01). Albumin Index had association with a poor Glasgow Coma Scale score at the nadir of the disease (OR, 1.17; 95% CI 1.01–1.34; P = .04). Similar results were yielded in the seronegative cohort. IgG Local Synthesis appeared to be a strong predictor for good rapid treatment response in both univariate and multivariate (adjusted OR, 28.71; 95% CI 2.12–389.22; P= .01) analysis. Time to immunotherapy was reversely correlated with good response overall (in the cohort with outliers removed [N = 49]: unadjusted OR 0.97, 95% CI 0.95–0.99; P= .01; adjusted OR 0.97; 95% CI 0.95–0.99; P= .008).
CSF indices reflecting intrathecal antibody production and blood-brain barrier impairment appear to be promising predictors of disease severity and therapeutic response in patients with autoimmune encephalitis.
Antineuronal antibodies in cerebrospinal fluid and serum of 104 patients with psychotic disorders compared to 104 individually matched healthy controls
2023, Schizophrenia Research
Antineuronal antibodies can cause psychotic symptoms, particularly NMDAR antibodies; however, studies on the prevalence of antineuronal antibodies in cerebrospinal fluid (CSF) and serum of patients with psychotic disorders compared to matched healthy controls are sparse.
We included 104 patients with a first-time diagnosis of a psychotic disorder within one year prior to inclusion (50 % outpatients) and 104 individually matched healthy controls, all without any known immunological conditions. CSF and serum were tested for IgG antibodies (Abs) against NMDAR NR1-subunit, GAD65, LGI1, CASPR2, AMPAR1, AMPAR2 and GABAb-receptor B1/B2 using commercial fixed cell-based assays (CBAs) (Euroimmun). Positive samples were retested with CBA twice, and tested with tissue-based assays (TBA). Primary outcomes were the presence of any of the seven anti-neuronal antibodies in CSF or serum. Secondarily, we analyzed the prevalence of each autoantibody.
No antineuronal IgG antibodies were consistently found in any CSF sample and NMDAR-antibodies were not consistently present in any of the 208 participants, neither in CSF nor serum. CASPR2-Abs were consistently found in the serum of one patient and one control, and one healthy control, without diabetes, was seropositive for GAD65-Abs. CASPR2 borderline seropositivity was additionally found in one patient and two controls. All samples positive on CBA were negative on TBA.
We found no significant differences between patients and controls. Antineuronal IgG antibodies are very rare when screening a broad group of individuals with recent-onset psychotic disorders without other indications of autoimmune encephalitis. Thus, much larger studies are needed to conclude on potential contrasts in prevalence compared to healthy controls.
Anti-contactin associated protein like 2 autoimmune encephalitis: A case report and review of the literature
2023, Neuroimmunology Reports
Autoimmune encephalitis is an insidious neurological disease that can present with an array of neuropsychiatric symptoms. Further classification of autoimmune encephalitis is determined by the presence of unique antibodies such as anti-contactin-associated protein-like-2 (anti-CASPR2). CASPR2 is a voltage gated potassium channel that is found in both the central and peripheral nervous systems and is involved in regulating areas around the nodes of Ranvier. Anti-CASPR2 can also be associated with limbic encephalitis or Morvan syndrome with symptoms ranging from seizures, cerebellar dysfunction, hyper-excitability, dysautonomia, insomnia, neuropathic pain, and weight loss.
A 50-year-old Caucasian female presented to the neurology clinic with a four-month history of acute onset insomnia causing anxiety, poor concentration, memory loss, paranoia, as well as a 13-pound weight loss. She reported a positive antinuclear antibody test two years prior with no established diagnosis. Additionally, a recent thyroid stimulating hormone (TSH) antibody and thyroglobulin antibody screen was found to be negative. Supplementary previous labs determined adrenocorticotropic hormone (ACTH) was within normal limits. She had previously tried a myriad of medications including zolpidem, doxepin, mirtazapine, trazodone, temazepam, eszopiclone, and conjugated estrogen. Constant anxiety forced her to quit both her daily activities and job. Neurologic exam and physical exam revealed no abnormalities. Cerebrospinal fluid analysis (CSF) exhibited an elevated protein of 50.6 mg/dL (normal 15 – 45) and an elevated albumin of 28.1 mg/dL (normal <27.0). A comprehensive autoimmune and paraneoplastic encephalitis panel was performed on serum and CSF, which was positive for CASPR2 (1:10 dilution) antibodies in the serum. The patient was started on a moderate dose of prednisone 20 mg daily for three months and scheduled for monthly infusions of intravenous immunoglobulin (IVIG) 1g/kg body weight for one year. Evaluation of paraneoplastic syndrome by a CT of the chest, abdomen, and pelvis with and without contrast revealed no abnormalities. The patient's insomnia began to improve after initiation of the corticosteroids and was scheduled to continue with the IVIG infusions and prednisone. She reports an improvement with mood and has resumed her job as an exercise instructor as well as daily activities.
This case report examines the presentation and workup of a 50-year-old female with a four-month history of acute onset insomnia and mood disturbances. She was seen by primary care, sleep medicine, psychiatry, and endocrinology before arriving at the neurology clinic where we discovered anti-CASPR2 antibodies in her serum, suggestive of autoimmune encephalitis. This case review examines the current literature regarding autoimmune encephalitis with CASPR2 antibodies and attempts to elucidate the delay in treatment for patients presenting with acute or subacute onset mood disturbances with insomnia.
Psychosis After Infection With SARS-CoV-2 in an Adolescent: A Case Report
2022, Journal of the American Academy of Child and Adolescent Psychiatry
Autoimmune Meningitis and Encephalitis
2022, Neurologic Clinics
Citation Excerpt :
In addition, normal MRI scans in patients who nevertheless have a clinical syndrome consistent with a particular functional tropism are also suspicious for an antibody-mediated process.5,59 CSF for patients with neuroantibodies typically shows either absent or modest CSF lymphocytic pleocytosis (median 4–8 cells/mm3), normal glucose, and often independent OCBs or elevation in IgG index with some variability.60–62 Anti-NMDA-R and antiglutamic acid decarboxylase (GAD) encephalitis in particular are associated with oligoclonal bands, which are seen less often in VGKC-complex antibody syndromes.62,63

View all citing articles on Scopus

¹: Co-senior authors.

View full text

Searching for autoimmune encephalitis: Beware of normal CSF

Highlights

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Patients and clinical characteristics

Results

Discussion

Ethical standards

Study funding

Declaration of Competing Interest

Acknowledgement

Lancet Neurol.

J. Neurol. Sci.

Lancet Neurol.

Lancet Neurol.

J. Neurol. Sci.

J. Neuroimmunol.

Lancet Neurol.

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

Neurology

Cerebrospinal fluid findings in patients with autoimmune encephalitis-a systematic analysis

Front. Neurol.

An overview of autoimmune and paraneoplastic encephalitides

Semin. Neurol.

Updated cerebrospinal fluid total protein reference values improve chronic inflammatory demyelinating polyneuropathy diagnosis

Muscle Nerve

Testing for N-methyl-D-aspartate receptor autoantibodies in clinical practice

Can. J. Neurol. Sci. J. Can. Sci. Neurol.

Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis

Ann. Neurol.

Antibody-associated CNS syndromes without signs of inflammation in the elderly

Neurology