# ADVANCES IN STEROID-RESPONSIVE ENCEPHALOPATHY

EDITED BY : Xin Tian, Xuefeng Wang and Patrick Kwan PUBLISHED IN : Frontiers in Neurology and Frontiers in Immunology

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ISSN 1664-8714 ISBN 978-2-88966-042-1 DOI 10.3389/978-2-88966-042-1

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# ADVANCES IN STEROID-RESPONSIVE ENCEPHALOPATHY

Topic Editors:

Xin Tian, First Affiliated Hospital of Chongqing Medical University, China Xuefeng Wang, First Affiliated Hospital of Chongqing Medical University, China Patrick Kwan, Monash University, Australia

Citation: Tian, X., Wang, X., Kwan, P., eds. (2020). Advances in Steroid-Responsive Encephalopathy. Lausanne: Frontiers Media SA. doi: 10.3389/978-2-88966-042-1

# Table of Contents

Jianzhao Zhang, Taoyun Ji, Qian Chen, Yanan Jiang, Huan Cheng, Ping Zheng, Wenqiang Ma, Ting Lei, Yao Zhang, Yiwen Jin, Cuijie Wei, Ye Wu, Xingzhi Chang, Xinhua Bao, Yuehua Zhang, Hui Xiong, Xinna Ji, Shuo Feng, Haitao Ren, Jian Yang and Yuwu Jiang

*107 Epidemiology of Antibody-Positive Autoimmune Encephalitis in Southwest China: A Multicenter Study*

Yixue Gu, Min Zhong, Liang He, Wei Li, Yuanyuan Huang, Jing Liu, Yangmei Chen and Zheng Xiao

# Editorial: Advances in Steroid-Responsive Encephalopathy

Xin Tian1 \*, Xuefeng Wang1 \* and Patrick Kwan2,3 \*

*1 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China, 2 Department of Neuroscience, The Central Clinical School, Monash University, Melbourne, VIC, Australia, 3 Departments of Medicine and Neurology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia*

Keywords: steroid-responsive encephalopathy, mechanism, diagnosis, treatment, prognosis

**Editorial on the Research Topic**

#### **Advances in Steroid-Responsive Encephalopathy**

In neurology, "steroid-responsive encephalopathy" is a general term for diseases characterized by diffuse brain injury and responsiveness to steroids. These diseases include autoimmune encephalitis (AE), Hashimoto's encephalopathy (HE), limbic encephalitis, and anti-neutrophil cytoplasmic antibody (ANCA)-associated vacuities encephalopathy, among others. These diseases are common and complicated in clinical management. Further understanding of their epidemiology, pathophysiological mechanism, diagnosis, treatment and prognosis from various perspectives can help improve the insights of clinicians and researchers. To provide a platform for sharing the latest research findings in steroid-responsive encephalopathy, we organized this special issue, in which 11 manuscripts have been accepted for publication, including 6 original research articles, four reviews, and one mini review. To a certain extent, these manuscripts have expanded the current understanding of such diseases.

To date, there have been few large-scale epidemiological investigations of AE in adults or children, and its epidemiological characteristics remain unclear. Gu et al. provided a detailed description of the epidemiological characteristics of 189 patients with antibody-positive AE at six large general hospitals, and they also analyzed the differences in composition ratios, ICU occupancy, ventilator use, tumor and surgery, and prognosis among different age groups, gender groups, antibody groups, and disease characteristics. Separately, Qiu et al. retrospectively analyzed clinical features, laboratory and imaging results, and predictors of poor prognosis in 50 patients with an initial diagnosis of AE at their hospital. The authors found that the neutrophil-to-lymphocyte ratio might have predictive value for poor outcomes in AE and that early initiation of immunotherapy was associated with a good prognosis.

In a study focusing on pediatric AE, Zhang et al. retrospectively analyzed the clinical characteristics of 103 children with AE in two Chinese tertiary pediatric neurology centers, including 89 patients with anti-NMDA receptor (NMDAR) encephalitis, two with anti-LGI1 encephalitis, one with anti-CASPR2 encephalitis, and 11 autoantibody-negative patients with probable AE. Anti-NMDAR encephalitis is the most common form of AE in pediatric patients. Another study by Zhang et al. analyzed the demographic characteristics, clinical features, treatment, and outcomes of 34 children with anti-NMDAR encephalitis treated at Children's Hospital of Fudan University. The authors found that most of the included children were sensitive to first-line immunotherapy

#### Edited and reviewed by:

*Robert Weissert, University of Regensburg, Germany*

#### \*Correspondence:

*Xin Tian<EMAIL_ADDRESS>Xuefeng Wang<EMAIL_ADDRESS>Patrick Kwan<EMAIL_ADDRESS>
#### Specialty section:

*This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology*

Received: *05 June 2020* Accepted: *25 June 2020* Published: *06 August 2020*

#### Citation:

*Tian X, Wang X and Kwan P (2020) Editorial: Advances in Steroid-Responsive Encephalopathy. Front. Neurol. 11:793. doi: 10.3389/fneur.2020.00793*

**4**

and achieved good outcomes, and higher Modified Rankin Scale scores before immunotherapy predicted poor outcomes. In addition, the authors also concluded that long-term use of antiepileptic drugs (AEDs) may not be necessary for pediatric patients with anti-NMDAR encephalitis.

Many patients with encephalitis have seizures during the development of the disease. Huang et al. followed up 75 outpatients with AE and reported in detail on the characteristics of those patients' seizures and their long-term use of AEDs. That study compared outcomes between patients with early and late AED withdrawal and determined the probable risk factors for seizure relapse and refractory epilepsy. As in Zhang et al. findings on pediatric anti-NMDAR encephalitis, these AE patients had a high rate of seizure remission after proper immunotherapy, and long-term use of AEDs may not be necessary to control their seizures. Compared with adults, young patients are more likely to become seizure free without AEDs. In addition, Huang et al. also reported that patients with anti-GABAB receptor (GABABR) antibodies, status epilepticus (SE), and cortical abnormalities had an increased risk of developing refractory epilepsy or seizure relapse.

A study by Lin et al. focused on the different clinical signs of infectious and autoimmune SE. These two entities may present with similar symptoms initially but require different treatment strategies. Since the prognosis of SE largely depended on etiology, faster-targeted treatment is required at the initial encounter. On this basis, Lin et al. conducted a retrospective study that included 501 patients with SE within a period of 10.5-years. Their study suggested that autoimmune SE had a relatively early age of onset; that it occurred predominantly in females; and that it often presented as psychosis, non-convulsive SE, and super-refractory SE. A lymphocytic predominance in cerebrospinal fluid was more commonly observed in patients with autoimmune SE than in those with infectious SE. These patient characteristics and signs may help clinicians select initial investigations and ensuing therapies that may improve overall outcomes.

HE has become increasingly recognized as an important and treatable cause of AE. Seizure disorders were observed in ∼60– 70% of patients with HE, and often as the first manifestation of the disease. HE is easily misdiagnosed because of the low incidence and the atypical symptoms. The manuscript by Li et al. discusses HE, the characteristic of its accompanying seizure disorders and the appropriate diagnostic approach.

Many neurologists may have limited experience in treating primary systemic vasculitis (PSV), mainly because most of these patients are diagnosed and managed by rheumatologists. However, PSV can affect every structure in both the central and the peripheral nervous systems, causing various neurological manifestations of dysfunction. Therefore, PSV patients may sometimes be referred to a neurologist first. The clinical manifestations of PSV are often non-specific, and differential diagnosis may be difficult. With these considerations in mind, Zhang et al. provide a comprehensive review of the clinical manifestations of PSV in the nervous system.

ANCA-associated vasculitis (AAV) is a multisystem inflammatory disease that can involve the central nervous system (CNS). Treatment with steroids, sometimes combined with immunosuppressants, can dramatically improve the outcome. However, for neurologists, the wide clinical spectrum of CNS involvement often complicates the diagnosis and thus delays treatment. Thus, Zheng et al. reviewed the manifestations of CNS involvement in AAV and emphasized ANCA testing, a crucial AAV diagnostic that requires appropriate result interpretation; the authors hoped to increase awareness and expand understanding of AAV-related CNS diseases among neurologists.

Immunoglobulin formulations have been used in an increasing number of diseases. In most cases, such formulations are safe and well-tolerated, but an increasing number of studies have reported potentially adverse effects of immunoglobulin treatment, some of which are severe and even fatal. In Guo et al. 's manuscript, the authors reviewed the incidence, risk factors and clinical characteristics of these adverse immunoglobulin-induced effects and addressed methods to minimize and prevent them.

Plasma exchange is widely used in the treatment of neurological diseases in which autoimmune mechanisms play a leading role. A growing body of research suggests that in the clinical treatment of steroid-responsive encephalopathies such as HE, limbic encephalitis, systemic lupus erythematosus encephalopathy, and ANCA-associated vacuities encephalopathy, plasma exchange is a safe and effective option when steroids or other immunosuppressive therapies are ineffective in the short term or when contraindications are present. A study by Jiang et al. provides a detailed review of the indications, onset time, course, curative effects, and side effects of plasmapheresis as applied clinically to steroid-responsive encephalopathy.

## AUTHOR CONTRIBUTIONS

XT, XW, and PK organized this special issue and wrote the editorial. All authors have approved the final version of the editorial.

## ACKNOWLEDGMENTS

We thank the authors for contributing their valuable work to this special issue and we thank the reviewers for their constructive comments. We are also grateful to the editorial board for approving this topic and we hope this issue will advance the state of research on steroid-responsive encephalopathy. PK was supported by a Medical Research Future Fund Fellowship (MRF113642).

**Conflict of Interest:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2020 Tian, Wang and Kwan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Adverse effects of immunoglobulin Therapy

#### *Yi Guo1†, Xin Tian1† , Xuefeng Wang1,2 and Zheng Xiao1 \**

*1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China, 2Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China*

Immunoglobulin has been widely used in a variety of diseases, including primary and secondary immunodeficiency diseases, neuromuscular diseases, and Kawasaki disease. Although a large number of clinical trials have demonstrated that immunoglobulin is effective and well tolerated, various adverse effects have been reported. The majority of these events, such as flushing, headache, malaise, fever, chills, fatigue and lethargy, are transient and mild. However, some rare side effects, including renal impairment, thrombosis, arrhythmia, aseptic meningitis, hemolytic anemia, and transfusion-related acute lung injury (TRALI), are serious. These adverse effects are associated with specific immunoglobulin preparations and individual differences. Performing an early assessment of risk factors, infusing at a slow rate, premedicating, and switching from intravenous immunoglobulin (IVIG) to subcutaneous immunoglobulin (SCIG) can minimize these adverse effects. Adverse effects are rarely disabling or fatal, treatment mainly involves supportive measures, and the majority of affected patients have a good prognosis.

#### *Edited by:*

*Thomas G. Forsthuber, University of Texas at San Antonio, United States*

#### *Reviewed by:*

*Mark Gorelik, Baylor College of Medicine, United States Rebecca S. Romero, University of Texas Health Science Center San Antonio, United States*

#### *\*Correspondence:*

*Zheng Xiao<EMAIL_ADDRESS>
*† These authors have contributed equally to this work and share first authorship.*

#### *Specialty section:*

*This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology*

*Received: 11 February 2018 Accepted: 24 May 2018 Published: 08 June 2018*

#### *Citation:*

*Guo Y, Tian X, Wang X and Xiao Z (2018) Adverse Effects of Immunoglobulin Therapy. Front. Immunol. 9:1299. doi: 10.3389/fimmu.2018.01299*

Keywords: immunoglobulin, adverse effects, risk factors, preventive measures, premedication

### INTRODUCTION

Immunoglobulin, also known as gamma globulin, is a therapeutic preparation comprising pooled blood donated from large numbers of healthy people. IgG is the main component of immunoglobulin, but it also contains small amounts of IgA and varying trace amounts of auxiliary materials (maltose, sucrose, etc.) (1). Applications involving immunoglobulin have expanded to include treatment for immunodeficiency diseases, idiopathic thrombocytopenic purpura (ITP), Kawasaki disease, and neurologic disorders (including Guillain–Barre syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, multiple myositis, multiple sclerosis, and autoimmune encephalitis) (2–8). Although immunoglobulin is well tolerated, adverse effects do occur. The majority of these adverse effects are mild and alleviated after infusion withdrawal, but some rare side effects are serious, including aseptic meningitis, renal impairment, thrombosis, and hemolytic anemia (9). In this paper, we reviewed the incidence, risk factors, clinical manifestations of and preventive measures for adverse effects related to immunoglobulin. The processes employed to minimize adverse reactions are briefly addressed in **Figure 1**.

### HISTORICAL PERSPECTIVE

In 1890, the German scholar Behring won the 1901 Nobel Prize in medicine for developing a serum therapy for diphtheria, representing a new chapter in the search for immunotherapies (10). In 1941, Cohn et al. (11) successfully developed a process for the large-scale production of human immunoglobulin. Next, immunoglobulin was widely used during World War II. In 1952, Bruton

**6**

(12) was the first to use immunoglobulin to treat a patient identified as immunodeficient, and it later became a standard therapy for immunodeficiency diseases. Intramuscular immunoglobulin preparations were not widely applied because of their poor tolerance. Hence, many scholars began to explore intravenous immunoglobulin (IVIG) preparations. Until 1979, IVIG was approved to treat immunodeficiency disease by the American Food and Drug Administration (13). Imbach et al. (14) then introduced IVIG as a treatment for ITP, with desirable effects. Since then, IVIG has been widely used for an increasing number of diseases.

### INCIDENCE OF ADVERSE EFFECTS

Patients who receive immunoglobulin therapy are often treated with immunoglobulin in repeated infusions over a long period of time, and the incidence of adverse effects related to immunoglobulin varies across a wide range. For example, in the study by Matsumoto et al. (15), 14 of 567 (2.5%) patients experienced adverse effects during infusion with IVIG. However, another study reported that 87.5% (14/16) of patients had adverse effects during treatment with repeated infusions of IVIG (16). The majority of studies have focused on the rate of adverse effects in patients receiving multiple infusions over time; however, information regarding the rate of a single infusion is scarce. For subcutaneous immunoglobulin (SCIG) preparations, many studies suggested that the adverse effects of SCIG were much lower than those of IVIG, and the incidence varied across a wide range. However, these studies cannot reveal the occurrence of adverse effects due to multiple interfering factors, such as differences in immunoglobulin preparations, individual differences, or study design variations.

Variations in immunoglobulin brands used may be the main cause for this lack of information regarding the occurrence of adverse effects, considering that different immunoglobulin formulations can have different adverse event profiles. Many clinical trials aimed to evaluate the safety of investigational immunoglobulin products that were not standardized with respect to data collection and provide a definition for adverse effect. Different studies focused on various segments of the population, and these patients had many diseases and fluctuating risk factors. Furthermore, patients who tolerated the infusions may have been shifted from the hospital to home-based infusion therapy, thereby explaining the broad range of adverse effects.

Study design variations also affected the rate of adverse effects. Most trials have involved a limited sample size, and few trials that were performed to support licensed marketed products included a control group. The lack of a control group increases the difficulty involved in unambiguously ascribing causality, and some studies did not report the frequency. In the study design, we advised investigators to predefine the time frame over which adverse effects are considered temporally associated with the infusion of the product (i.e., within 24, 48, or 72 h of the end of the infusion) in the protocol. Based on prior experience with the same products and to include all the adverse effects, *a priori* algorithm for assigning causality was developed to observe adverse effects and preidentify a list of these adverse events, which are presumed to be related to the administration of the test products.

Analyzing the epidemiology of adverse effects in clinical research is important. For patients receiving long-term IVIG replacement, the rate of adverse effects should be calculated according to the infusion times (per infusion, not per patient). Furthermore, a nationwide database for immunoglobulin-related adverse effects should be created, but the following factors that affected the passive reporting of post-marketing surveillance data in this database should be taken into consideration: (1) Some adverse effects occurring during the IVIG infusion may not be associated with IVIG; (2) some adverse events can be duplicated and result in double counting, especially adverse events that last over an extended period of time; and (3) substantial underreporting is likely to occur as it is a voluntary system.

### GENERAL RISK FACTORS

#### Immunoglobulin Preparation-Related Risk Factors

A high concentration of IgA and anti-Rh blood group, D antigen (RhD) increases the occurrence of immunoglobulin-related adverse effects. Manlhiot et al. (17) found that adverse effects were reported more often in patients treated with immunoglobulin products that contained a concentration of IgA higher than 15 µg/ml (15 VS 8%). Similarly, a high titer of anti-RhD also increased the occurrence of adverse effects; therefore, the level of anti-RhD should be maintained as low as possible (18, 19). However, preparations produced by different manufacturers have different excipients that may increase the rates of specific adverse reactions (20) (**Table 1**).

#### Patient-Related Risk Factors

Patients who developed adverse effects during a previous course and those receiving a first infusion are at an increased risk of adverse effects. Sherer et al. (21) found that 9 of 10 (90%) patients who experienced an adverse effect during the first treatment course also had adverse effects during subsequent courses. A survey conducted in Iran verified that the risk was higher in patients receiving a first course than in those receiving subsequent treatment courses (16.2 VS 6.9%, respectively) (22).

Some studies have suggested that IgA-deficient patients may be at a higher risk of adverse effects. Iranian researchers found

Table 1 | Components of immunoglobulin products associated with adverse effects.

that the incidence of immunoglobulin-induced adverse effects was higher in patients with primary antibody defects, especially those with low levels of IgA (22, 23). In contrast, Rachid and colleagues found that the role of IgA-deficiency in anaphylaxis in patients during immunoglobulin therapy remains controversial (24, 25). Therefore, immunoglobulin infusion should never be withheld from IgA-deficient patients.

#### CLASSIFICATION OF ADVERSE EFFECTS

Adverse effects are classified as immediate or delayed depending on the time of occurrence. Immediate adverse effects mainly include flu-like syndrome, dermatologic side effects, arrhythmia, hypotension, and transfusion-related acute lung injury (TRALI). Immediate side effects are categorized as mild, moderate, and severe. Mild adverse effects include light headache, fever, chills, and fatigue; they are alleviated when the infusion is slowed down or when antihistamines and nonsteroidal anti-inflammatory drugs (NSAIDs) are administered. Moderate adverse effects include chest pain, anhelation, vomiting, arthralgia, and severe headache; these effects require the infusion to be discontinued or antihistamines and NSAIDs to be administered. Severe adverse effects include hypertension, anaphylaxis, bronchospasm, and altered consciousness; these adverse effects require the infusion to be stopped immediately and for corresponding medical attention to be provided (22).

#### Immediate Adverse Effects

#### Flu-Like Symptoms

Flu-like symptoms are the most frequent adverse effects. These include flushing, nausea, fatigue, fever, chills, malaise, and lethargy. One retrospective study showed that 14 of 16 (87.5%) patients developed flu-like symptoms during immunoglobulin administration (16). Bichuetti-Silva et al. (26) found that flu-like symptoms account for more than 80% of immunoglobulininduced adverse effects. These symptoms always occur within the first hour of infusion, and some adverse effects (such as fever or fatigue) may also arise within 24 h. The mechanism underlying these symptoms remains unclear, but it may be associated with the presence of cytokines, such as IL-6, TNF-α, prekallikrein activator, and kallikrein, in immunoglobulin products. The solution media and complement activation of an immunoglobulin preparation may also represent causes of these effects (27, 28). The majority of these symptoms are associated with rapid infusion and develop during the initial period of infusion. Hence, it is recommended that infusion should start at a slow rate for the first 30 min (29).

#### Dermatological Adverse Effects

The incidence of immunoglobulin-related dermatological adverse effects is nearly 6% (30, 31). The manifestations of dermatological adverse effects vary among individuals and can include urticaria, spot papules, eczema, pompholyx, lichenoid dermatitis, and desquamation. Epidermolysis is observed in some severe cases, and all of these skin lesions can occur in all parts of the body, although the hands and feet are the most common sites. Gerstenblith et al. (32) found that 62.5% of patients had pompholyx alone or Guo et al. Immunoglobulin Therapy

a combination including pompholyx on the hands or feet. The mechanism underlying these dermatological adverse effects is unclear. Most of these reactions develop within 2 weeks of immunoglobulin administration. Interestingly, a significant number of patients with skin lesions had neurological disorders, and the repeated administration of a high-dose immunoglobulin infusion within a short period of time may be the cause of this high preponderance (32, 33). Dermatological adverse effects can be successfully treated with corticosteroids. Some severe cases require hospitalization for further management, but there are no reports of deaths resulting from severe adverse reactions of the skin in immunoglobulin-treated patients. Switching to another batch of immunoglobulin product may also reduce adverse effects to some extent (33).

#### Arrhythmia and Hypotension

Arrhythmia occurring during or after immunoglobulin infusion has been reported in several studies and can include supraventricular tachycardia and bradycardia, while most of the cases had a history of heart disease. In 1997, Savasan et al. (34) showed that arrhythmia developed during IVIG in two children with thrombocytopenia who both had a history of arrhythmia, and the condition was resolved in both cases with antiarrhythmic therapy. In 2015, Tufekci et al. (35) reported that supraventricular tachycardia occurred during IVIG administration in two newborn infants with immune hemolysis. Raheja et al. (36) described a case of asymptomatic bradycardia that occurred after IVIG administration in a female with ITP who reached a lowest heart rate of 30 bpm before returning to baseline levels without any therapy. Although it is not fully understood whether arrhythmia is directly related to immunoglobulin infusion, cardiac monitoring during IVIG infusion is recommended in patients with a history of cardiac disorders.

Hypotension is a rare symptom related to immunoglobulin. Some patients with hypotension also experience anaphylactic shock. Dashti-Khavidaki et al. (22) reported 216 patients who developed adverse effects, and only one of these patients developed hypotension combined with allergy and bronchospasm. Charhon et al. (37) later described a case with hypotension (a decrease in systolic blood pressure from 130–60 mmHg) and an altered mental state during immunoglobulin therapy.

#### Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury, a serious blood transfusionrelated adverse effect with high mortality, manifests with acute respiratory distress and noncardiac pulmonary edema within 6 h of transfusion and is the main cause of blood transfusion-related death. Immunoglobulins are blood products and may also be associated with TRALI. In 2001, Risk (38) first reported a 23-year-old male with multifocal motor neuropathy who developed TRALI following IVIG therapy; the patient's condition resolved in 5 days with only nasal oxygen and bed rest. In 2008, Ahituv et al. (39) presented an adolescent patient with ITP who developed TRALI during immunoglobulin infusion. In several cases, patients with Sjögren's syndrome, Guillain–Barre syndrome, lung transplantation, immunodeficiency, or myasthenia gravis have reportedly developed TRALI after immunoglobulin infusion (40–44). Akin to blood-infusion TRALI, immune-mediated processes and the neutrophil-priming hypothesis have been proposed as possible mechanisms (45). TRALI following IVIG is a serious complication that requires urgent treatment. Diagnosing TRALI depends mainly on clinical symptoms that present after blood products are infused in the absence of other evident causes of respiratory insufficiency; a chest radiogram showing diffuse bilateral pulmonary edema is also needed (46). Patients with TRALI often require adjuvant ventilatory therapy and will recover with proper ventilation.

#### Delayed Adverse Effects

Delayed adverse effects can be severe or even lethal and affect less than 1% of patients. These events include thrombotic events, neurological disorders, renal impairment, hematologic disorders, electrolyte disturbance, and transfusion-related infection.

#### Thrombotic Events

Thrombotic events are serious adverse effects of immunoglobulin treatment with an estimated incidence of 1–16.9% (47). Daniel et al. (48) reviewed thrombotic adverse events recorded in a large administrative database from 2008 to 2010 and found that 1% (122/11785) of the patients developed immunoglobulin-induced thrombotic events. Ramírez et al. (49) found that thrombotic events affected up to 16.9% of 303 patients who received immunoglobulin infusion. The manifestations of thrombosis, which can occur in arteries, veins, and intracranial vein sinuses, are varied, and arterial thrombotic events (such as stroke, myocardial infarction, and pulmonary embolism) are the most common. A recent review identified 100 cases of thrombotic events related to the administration of immunoglobulin that occurred from 2006 to 2011; among this cohort, 80% of the thrombotic events were stroke and myocardial infarction that occurred within 24 h of completing immunoglobulin administration (50). Risk factors for thrombosis include a first infusion consisting of a large dose, oral contraceptive use, advanced age, prior/current thrombosis, preexisting atherosclerotic disease, elevated serum viscosity, a hereditary hypercoagulable state or ITP. Rajabally et al. (51) found that patients with coronary disease and prior thrombosis who were administered a daily dose ≥35 g of IVIG had a higher risk of thrombotic events. Daniel et al. (48) also found that advanced age (>45years old), prior thrombotic events, and a hypercoagulable state were risk factors for the development of thrombotic events. Moreover, an increasing number of studies have confirmed that patients with ITP are more likely to develop thrombosis when receiving IVIG (52–55). The presence of four or more risk factors seems to be significantly associated with the onset of immunoglobulin-related thrombotic events (51, 56).

Mechanisms that could potentially trigger thrombotic events include an increase in plasma viscosity, the activation of procoagulant factors, vasospasm, autoimmune vasculitis, and an increased platelet count. Increased plasma viscosity contributes most to the occurrence of thrombotic events. Bentley et al. (57) showed that IVIG can cause plasma viscosity to acutely and cumulatively rise across the complete treatment course. Similarly, Baba et al. (58) also found that increased plasma viscosity was associated with IgG concentrations during or after immunoglobulin infusion. In addition, the average IgG half-life among individuals varied from 23 to 30 days and could be even longer in some cases (59, 60). Thrombotic complications can be prevented or minimized by early assessment in patients suspected of being at high risk, and anti-thrombus treatment is needed in patients with thrombotic complications.

#### Neurological Disorders

Neurological disorders associated with immunoglobulin treatment include headache, aseptic meningitis, posterior reversible encephalopathy syndrome (PRES), seizure, and abducens nerve palsy.

Headache post IVIG is a common adverse effect. More than half of patients develop headaches after immunoglobulin administration. Many studies have reported headache as an immunoglobulin-related adverse effect, while no studies have described the characteristics of immunoglobulin-related headache in detail. Headache also has a delayed onset of 6–12 h after an infusion and can last between 24 and 72 h. High-dose immunoglobulin infusion is the main risk factor for headache. Some studies have found that patients with a history of migraine are prone to developing headaches after IVIG infusion (61, 62). Among these studies, the overall incidence of IVIG-related headache in patients with a history of migraine was small, which may be due to the small sample size and patient selection bias. Prophylactic treatment used in several studies included acetaminophen, aspirin, opioids, NSAIDs, propranolol, sumatriptan, and corticosteroids alone or in combination, and all the protocols seemed to be fairly effective in the recruited individuals; however, the best drug for the treatment of immunoglobulin-related headache remains unknown (63). Alternatively, non-pharmacotherapy-related approaches, including a reduction in the infusion rate and switching to an alternative brand of IVIG or SCIG, can also reduce headache to some extent. When a headache lasts for a long time or is resistant to drug therapy, the possibility of aseptic meningitis should not be ignored.

Aseptic meningitis has been identified as an adverse effect of IVIG and affects 0.6–1% of patients. Kemmotsu et al. (64) retrospectively examined 384 patients with Kawasaki disease who received immunoglobulin infusion during 2000–2009 and identified four patients who developed aseptic meningitis, suggesting an overall incidence of 1%. In another retrospectively study, Bharath et al. (65) found that 0.6% (8/1324) of patients developed immunoglobulin-related aseptic meningitis. Several studies have reported that aseptic meningitis appears within 48 h of the initiation of IVIG therapy (64, 66, 67). The most common presenting symptoms of this condition are persistent headache, nausea, vomiting, photophobia, fever, chills, and positive Kernig's and Brudzinski's signs. In addition, in affected patients, lumbar puncture typically produces clear cerebral spinal fluid with an increased level of nucleated cells, high protein content and negative culture results (64, 66). Contributing factors include a large cumulative IVIG dose and a history of migraines. Previous studies have suggested that most patients who develop aseptic meningitis receive 1–2 g/kg immunoglobulin therapy (64, 65). Sekul et al. (66) found that patients with a history of migraines are particularly susceptible to developing aseptic meningitis.

Posterior reversible encephalopathy syndrome is another neurological disorder that can develop following immunoglobulin therapy. In 2005, Nakajia (68) reported a patient with Miller–Fisher syndrome who developed PRES following IVIG therapy. Stetefeld et al. (69) and Ribeiro et al. (70) later reported additional patients with Miller–Fisher syndrome who developed PRES during immunoglobulin infusion. The clinical manifestations in these patients include an acute onset characterized by headache, generalized seizure, visual impairment, and an altered mental state (69–71). In all of these cases, complete resolution was achieved after immunoglobulin administration ceased. While PRES is a rare complication of IVIG treatment, it should be considered in all cases with disease-typical MRI findings and clinical manifestations.

Few case reports have described patients with IVIG-associated seizures. In 2003, Kao et al. (72) reported a 37-year-old male with myelopathy who developed repetitive generalized tonic-clonic seizures following IVIG therapy. Later, aseptic meningitis was considered the cause of the seizures, and the patient's condition was controlled with valproate. In 2014, Bichuetti-Silva et al. (26) identified a separate case of seizure in a patient with common variable immunodeficiency disease following IVIG infusion, and a history of herpetic encephalitis was later recorded.

Immunoglobulin infusion may rarely be the underlying etiology of abducens nerve palsy. Wright et al. (73) reported a patient with renal transplantation who developed abducens nerve palsy during high-dose IVIG infusion. The patient recovered completely after 2 weeks, and aseptic meningitis was considered the underlying cause. Furthermore, two case reports described patients with Kawasaki disease who developed abducens nerve palsy after IVIG therapy (74, 75). However, whether abducens nerve palsy was directly related to immunoglobulin therapy in these cases is unclear.

#### Renal Impairment

Renal impairment following immunoglobulin treatment is a rare but dangerous adverse effect. The incidence of immunoglobulinassociated renal impairment has not been accurately determined. The FDA received information related to 114 cases of immunoglobulin-associated renal impairment or acute renal failure that occurred between 1981 and 1998 (76). Moreover, from 1999 to 2005, the French National Security Agency of Medicines and Health Products recorded 91 cases of renal impairment associated with immunoglobulin infusion (77). The precise mechanism underlying IVIG-related renal impairment remains unclear. Potential mechanisms include the precipitation of immune complexes in the glomeruli, osmotic nephritis, immunological hemolysis-associated acute tubular obstruction, and transient vascular ischemia due to a reduction in renal perfusion (78–80).

Patients with advanced age, diabetes, preexisting renal dysfunction, and dehydration have an increased risk of developing renal impairment following immunoglobulin administration. Renal impairment typically develops within 10 days after the start of immunoglobulin infusion. Oliguria, hematuria, a decreased glomerular filtration rate, and elevated serum creatinine levels are typical manifestations of renal impairment. Serum creatinine levels usually peak around day 5, and oliguric renal failure is more common than other types of renal dysfunction (9, 81, 82). Renal function usually returns to normal after IVIG infusion is discontinued or short-term hemodialysis is performed, but a few patients with immunoglobulin-related renal impairment have developed chronic renal insufficiency or died (83, 84). Previous studies have shown that death occurs in 8–15% of these patients, but the majority of patients who die have severe underlying conditions, such as advanced age, uncontrolled diabetes, or prior renal dysfunction; therefore, the cause of this effect needs further study (83, 85, 86). In patients with renal insufficiency, renal function should be closely monitored both before and after treatment (including serum creatinine, blood urea nitrogen levels, and glomerular filtration rate). If renal function progressively declines, the rate of infusion should be reduced or treatment should be discontinued. Epstein et al. (76) verified that sucrose-containing preparations should be avoided because they are associated with a risk of osmotic nephritis. However, Kim et al. (87) found that sucrose-free IVIG could also result in renal impairment.

#### Hematologic Disorders: Hemolysis and Neutropenia

Hemolysis is an adverse effect related to IVIG administration that occurs in approximately 1.6% of patients but is usually neither recognized nor treated because it lacks clinical symptoms. Hemolysis can result in acute renal failure and thrombosis. In 2008, a case series conducted at Ottawa Hospital identified 16 cases of hemolysis among approximately 1,000 patients who received IVIG infusion (resulting in an incidence of 1.6%) (88). Most cases with hemolysis present no obvious clinical symptoms and are diagnosed with low hemoglobin levels on a blood examination. IVIG infusion-associated hemolysis was observed from 12 h to 10 days after the first infusion of IVIG, with the lowest hemoglobin level occurring between 1 day and 2 weeks after the last IVIG infusion. Hemolysis is a common complication of high-dose IVIG derived from non-group O blood. In a systematic review conducted by Desborough and colleagues, 62 cases of hemolysis were identified, and 97% of those patients had received a high dose of IVIG (at least 2 g/kg). Of those 62 cases, IVIG-induced hemolysis was most common in patients with type A (65%) or AB (26%) blood (89). Several more recent studies have also verified that administration of a high dose of IVIG is a contributing factor in hemolysis (90–92). This effect may be associated with the presence of A and B isoagglutinin (anti-A and anti-B antibodies) in the IVIG product. A recent cohort study found that the risk of hemolysis was lower when donors with high plasma titers of anti-A antibodies were excluded, especially in patients requiring ≥1.75 g IVIG/kg (93). Abnormal laboratory tests that may indicate hemolysis include decreased hemoglobin and haptoglobin levels, increased lactate dehydrogenase levels, and increased hemobilirubin and reticulocyte counts (94). The management plans generally proposed in affected patients aim to slow down the rate of infusion, switch to another IVIG product, or check the blood type for potential indications for hemolysis. Hemolysis is self-limiting in the majority of mild and moderate cases. However, proper blood transfusion is needed in severe cases when a Coombs test or a direct or indirect antiglobulin test is negative (89, 95, 96).

Immunoglobulin therapy can cause hemolysis, but it can also cause neutropenia (97). In 1998, Majer et al. (98) first described neutropenia as a complication of IVIG therapy in children with ITP. Veys et al. (99) also reported two cases of neutropenia following IVIG infusion for ITP. In addition, Matsuda et al. (100) and Bajaj et al. (101) reported that patients with neurological disorders could develop neutropenia with IVIG administration. Currently, immunoglobulin-induced neutrophils have been reported only in case reports. This condition usually occurs within 4 days after infusion and recovers spontaneously without infection in 2 weeks. However, premedication with corticosteroids may be an effective measure to prevent neutropenia (98–103).

#### Electrolyte Disturbance

Electrolyte disturbance is a rare adverse effect of immunoglobulin administration. In 1997, a study that examined variations in serum chemistry among 46 patients receiving IVIG infusion found that sodium and magnesium levels were significantly lower in infused patients (4 and 7% below baseline, respectively) (104). Daphnis et al. (105) retrospectively evaluated a cohort of 66 patients with ITP who received repeated IVIG infusions and found that serum sodium levels fell by 2.7 mmol/l in patients with normal renal dysfunction and 5.7 mmol/l in patients with acute renal failure. These electrolyte disturbances usually have no clinical symptoms, and affected patients generally recover without electrolyte supplementation. With regards to patients with severely compromised renal function, it is recommended that electrolyte levels can be monitored to identify hyponatremia and hyperkalemia.

#### Infection Risk

The long-term safety of immunoglobulin preparations is excellent. Until recently, the majority of physicians believed that IVIG infusion was associated with no risk of infection. Since immunoglobulins are blood products, there will always be a risk of underlying infection, which may be fatal. Until recently, the most commonly reported infection was the hepatitis C virus. In 1994, the FDA and Centers for Disease Control and Prevention received reports of over 100 cases of acute hepatitis virus infection in recipients of IVIG from several countries (Norway, United States, Europe, and Puerto Rico). The brand names Gammagard and Polygam accounted for the majority of the cases of hepatitis C in both the United States and Europe (106, 107). Razvi et al. (108) reported the outcomes of 58 cases with IVIG-transmitted hepatitis C, and the prognosis of these subjects was poor. Since then, no cases of immunoglobulin-induced hepatitis C have been reported.

Apart from immunoglobulin-transmitted hepatitis C, no cases of IVIG-related hepatitis B virus (HBV) have been reported. However, IVIG-related passive transfer of hepatitis B antibodies has also been reported. Several scholars have reported cases in which the patient developed positive HBV core antibodies and surface antibodies after IVIG infusion, and subsequent multiple tests revealed false-positive results due to immunoglobulin (109, 110). Ramsay and colleagues conducted a cross-sectional study that suggested that HBV antibodies (HBsAb and HBcAb) are common in patients receiving IVIG and who have confounding diagnostic results (111). Thus, the measurement of baseline HBV antibodies should be implemented when commencing immunoglobulin infusion. If the test results are negative, and there is an absence of hepatitis or risk factors, any future positive results in the context of ongoing immunoglobulin therapy should be considered false positives, HBV-DNA levels should be measured, and antiviral treatment should be given cautiously.

Since the introduction of adequate management and advanced testing technologies, no cases of IVIG-related prion disease or HIV transmission have been reported. Radomski et al. (112) found that two dedicated and one supplemental step [solvent/ detergent (S/D) treatment and nanofiltration (20 nm) in combination with ion-exchange chromatography] could prevent pathogen transmission. Although the infection risk is much lower in IVIG than in other blood products, the possibility of infection can never be neglected.

#### Other Adverse Effects

Other adverse effects of immunoglobulin therapy include uveitis, passively acquired thyroid autoantibodies and reversible splenial lesion syndrome. Kocak et al. (113) reported a case in which a 44-year-old female developed bilateral uveitis following the administration of IVIG for 2 days. The patient was treated with topical corticosteroids and had achieved complete resolution at 1-month follow-up. In 2017, Uchida et al. (114) reported two cases in which thyroid autoantibodies passively acquired following IVIG administration. Finally, Uygur et al. (115) described a case of reversible splenial lesion syndrome caused by IVIG therapy.

#### PREVENTIVE MEASURES

#### Risk Assessment and Adequate Monitoring

Immunoglobulins cause various adverse effects; some of these effects are severe and fatal. Hence, a detailed medical history should be obtained in every patient being considered for immunoglobulin treatment. This information should include age, the infusion course of immunoglobulin, concomitant diseases (diabetes, hypertension, coronary heart disease, stroke, thrombotic events, hemadostenosis, etc.), and co-medications (e.g., contraceptive drugs and diuretics). Laboratory tests are also needed, such as a blood group test, routine blood tests, and tests of liver and kidney function. A variety of risk factors must be considered when evaluating possible adverse effects, and special precautions should be considered in patients with a history of allergies or thrombotic events. In these patients who have a heightened risk of developing adverse effects, special monitoring should be employed within the first 24 h following immunoglobulin administration in a hospital. The proposed factors that predispose a patient to immunoglobulin-induced adverse effects are shown in **Table 2**.

#### Slowing Down the Infusion Rate

The adverse effects described here are closely related to the rate of immunoglobulin infusion. Hence, slowing down the rate of infusion can greatly reduce the rate of adverse reactions, especially flu-like symptoms, hemolysis, thrombosis, and renal impairment (22, 63, 116). Strictly controlling the infusion rate during the first administration is recommended. During the first infusion, an initial slower rate should be implemented for the first 30 min, and then the rate may be increased if no adverse effects occur (we recommend

using the infusion rate according to the instructions provided by different brands). Slowing the rate should be considered if any adverse effects occur. The infusion should be discontinued if slowing the rate does not alleviate these adverse reactions.

#### Premedication and Prehydration

Premedication with antihistamines, corticosteroids, or NSAIDs can markedly reduce the severity and incidence of IVIG-induced adverse effects. In 1998, Roberton et al. (117) assessed the effect of premedication with methylprednisolone in a large crossover study that included 10 patients who had previously experienced frequent adverse reactions. Methylprednisolone was administered at a dose of 1 mg/kg 20 min prior to IVIG infusion, and the pretreated patients exhibited a marked decrease in the severity of IVIGinduced immediate adverse events (*P*< 0.01), with only one patient discontinuing IVIG infusion, whereas IVIG was interrupted in 8 of the 10 patients who were not pretreated with methylprednisolone. Souayah et al. (118) examined the safety profile of home infusion of IVIG in patients with neuroimmunologic disorders. In all, 276 patients were premedicated with antihistamines, corticosteroids, or NSAIDs, and the incidence of IVIG-induced adverse effects was significantly lower in the premedicated group than in the non-premedicated group (18.4 VS 27.1%, *P* = 0.04). However, the results of a separate study indicated that the rate of immunoglobulin-induced immediate adverse events was not altered by premedication (29). With regards to thrombotic events, Huang et al. (119) implemented a protocol in which treatment with antiplatelets and anticoagulation before IVIG infusion eliminated IVIG-related thrombotic events. However, because their sample size was small, further studies are needed to determine the safety and efficacy of this protocol.

Prehydration with normal saline is also used to prevent immunoglobulin-induced adverse effects. Many studies have proposed that prehydration can be helpful for headache, thrombolysis, renal impairment, and hemolysis (63, 120, 121); however, the implementation protocol, the dose of saline (250 or 500 ml, etc.), and the duration of saline infusion remain unclear. All of these studies utilized a protocol that combined hydration and other measures; therefore, the efficacy of prehydration should be further evaluated in a well-designed study.

## Switching From IVIG to SCIG or Other Immunoglobulin Preparations

Switching from IVIG to SCIG seems to be an effective strategy that attenuates immunoglobulin-induced adverse effects, especially for patients who have previously experienced severe adverse effects or are at high risk of developing adverse effects. An increasing number of well-designed studies show that SCIG can be used as a treatment for immunodeficiency diseases, multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, and myasthenia gravis (6, 122–136) (**Table 3**). The results of two randomized, crossover studies indicate that the rate of systematic adverse effects was lower following SCIG than following IVIG, and no severe adverse effects were reported in patients treated with SCIG (123, 135). However, the sample sizes of these two studies were small (30 and 20). Racosta et al. (137) performed a meta-analysis of reports that explored the efficacy and safety of SCIG VS IVIG and identified a total of 8 studies comprising 138 patients with inflammatory demyelinating polyneuropathies. Their results showed that the relative risk of moderate and/or systemic adverse effects was 28% lower in the SCIG group [95% confidence interval, 0.11–0.76]. Due to the small sample size of these studies, the efficiency of SCIG

Table 3 | Subcutaneous immunoglobulin (SCIG) treatment in a variety of diseases.

should be further explored, and more randomized controlled trials with larger samples of patients with various diseases are needed.

It remains unclear how the dose should be adjusted when switching from IVIG to SCIG. Berger and colleagues found that using 137 and 153% of the IVIG dose when switching to SCIG produced the same effect in patients being treated for primary immunodeficiencies (138). Another study concluded that sustained serum IgG levels can be achieved after switching to SCIG despite the use of a reduced immunoglobulin dose in patients with primary hypogammaglobulinemia (129). Individualizing the dosage based on the disease state and the clinical response is preferable to using mean pharmacokinetic parameters when switching from IVIG to SCIG. In addition, more studies focused on pharmacokinetics in immune-mediated diseases are needed.

Detailed information regarding the immunoglobulin preparation should always be recorded, including the manufacturer, batch, and drug instructions. It is clear that the content, composition, and characteristics of each immunoglobulin preparation can adversely affect patients in different manners. Hence, if patients frequently develop adverse effects following administration with an IVIG preparation, switching to another immunoglobulin preparation may lead to fewer adverse effects (62).

#### Other Measures

Many patients develop immunoglobulin-associated adverse effects, and the majority of these effects are mild to moderate and resolve with appropriate treatment. The observed effects include immediate adverse effects, aseptic meningitis, hemolysis, neutropenia, and electrolyte disturbances. Some of these severe adverse effects should be treated according to the principle underlying the corresponding diseases, such as an effective antithrombotic therapy in patients with thrombosis or short-term renal replacement therapy in patients with severely damaged renal function.

### FUTURE PROSPECTS

Immunoglobulin preparations have been widely used in a variety of diseases, but controlled studies have not been performed for many diseases, such as myasthenia gravis, some forms of lupus erythematosus, septic syndrome, and polymyositis. The improper usage of immunoglobulin increases the risk of adverse effects to some extent; therefore, further studies are needed to demonstrate the proper indications for the use of immunoglobulin.

The majority of adverse effects are associated with high doses of immunoglobulin; thus, determining individualized dosages to guarantee the efficacy of therapy and minimize adverse effects is an urgent focus. Ameratunga (139) suggested that the initial IVIG dose should be based on adjusted body weight in obese patients with primary immunodeficiency disorders. As this study was a single

#### REFERENCES

observation and focused on only obese patients, additional special populations, such as the elderly, should be studied to determine the parameters of individualized dosing for immunoglobulin therapy.

Many measures have been used to prevent or minimize immunoglobulin-related adverse effects, as summarized above. Given that these studies were case controlled or small sample size studies, the efficacy of these measures should be verified by randomized controlled studies or head-to-head studies with larger sample sizes. Simultaneously, the use of only one preventive measure may not prevent adverse effects, and a series of measures serving as a standard protocol may be effective for preventing serious adverse effects, such as combining prehydration with anti-thrombosis to minimize thrombotic events.

Currently, immunoglobulin may be given intravenously or subcutaneously to treat a variety of disorders. However, IVIG and SCIG preparations also result in adverse effects. It is possible that other routes of immunoglobulin administration may reduce the rate of adverse effects. In 1982, Barnes et al. (140) found that oral administration of immunoglobulin could be used for the prevention and treatment of rotavirus diarrhea in low-birth weight babies. Later, several meta-analysis studies concluded that oral administration of immunoglobulin could not prevent rotavirus diarrhea and necrotizing enterocolitis (141, 142). Although these studies have several limitations (small sample size and few well-designed studies), oral administration may be a promising preparation to attenuate the occurrence of adverse effects.

Many factors affect the rate of immunoglobulin-related adverse effects. Several characteristics of newer generation immunoglobulin products should be improved, including specific functions, purity, and biological safety. Thus, advanced separation and purification technologies should be developed.

#### AUTHOR CONTRIBUTIONS

YG and XT conceived the article and wrote the manuscript. XW and ZX reviewed and edited the manuscript. All authors read and approved the manuscript.

### FUNDING

This study was supported by the medical research project of Chongqing Health and Family Planning Commission (2013-1-012) and the National Clinical Key Specialty Construction Foundation of China and the National Natural Science Foundation of China (Nos. 81471320,<PHONE_NUMBER>, 81471319, 81671301). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

the correct clinical approach. *Int Immunopharmacol* (2017) 52:136–42. doi:10.1016/j.intimp.2017.09.005

3. Qin YH, Zhou TB, Su LN, Lei FY, Zhao YJ, Huang WF. The efficacy of different dose intravenous immunoglobulin in treating acute idiopathic thrombocytopenic purpura: a meta-analysis of 13 randomized controlled trials. *Blood Coagul Fibrinolysis* (2010) 21(8):713–21. doi:10.1097/MBC. 0b013e3283401490

with Kawasaki disease. *Pediatr Rheumatol Online J* (2011) 9:28. doi:10.1186/ 1546-0096-9-28

following intravenous immunoglobulin therapy. *Nephron Clin Pract* (2007) 106(4):c143–8. doi:10.1159/000104424

in patients with primary immunodeficiency diseases. *J Clin Immunol* (2006) 26(3):265–73. doi:10.1007/s10875-006-9021-7

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2018 Guo, Tian, Wang and Xiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Characteristics of Seizure and Antiepileptic Drug Utilization in Outpatients With Autoimmune Encephalitis

Qi Huang, Meigang Ma, Xing Wei, Yuhan Liao, Hengchang Qi, Yuejuan Wu and Yuan Wu\*

Department of Neurology, First Affiliated Hospital, Guangxi Medical University, Nanning, China

Autoimmune encephalitis (AE) is one kind of encephalitis that associates with specific neuronal antigens. Most patients with AE likely suffer from seizures, but data on the characteristics of seizure and antiepileptic drugs (AEDs) utilization in this patient group remains limited. This study aimed to report the clinical status of seizure and AEDs treatment of patients with AE, and to evaluate the relationship between AEDs discontinuation and seizure outcomes. Patients with acute neurological disorders and anti-N-methyl-D-aspartate receptor (NMDAR), γ-aminobutyric acid B receptor (GABABR), leucine-rich glioma inactivated 1, or contactin-associated protein-like 2 (CASPR2) antibodies were included. As patients withdrew from AEDs, they were divided into the early withdrawal (EW, AEDs used ≤3 months) and late withdrawal (LW, AEDs used >3 months) groups. Seizure remission was defined as having no seizures for at least 1 year after the last time when AEDs were administered. Seizure outcomes were assessed on the basis of remission rate. The factors affecting the outcomes were assessed through Spearman analysis. In total, we enrolled 75 patients (39 patients aged <16 years, male/female = 39/36) for follow-up, which included 67 patients with anti-NMDAR encephalitis, 4 patients with anti-GABABR encephalitis, 2 patients with anti-voltage-gated potassium channel encephalitis, and 2 patients with coexisting antibodies. Among the 34 enrolled patients with anti-NMDAR encephalitis who were withdrawn from AEDs, only 5.8% relapse was reported during the 1-year follow-up, with no significant difference in the percentage of relapse between the EW and LW groups (P = 0.313). Fifteen patients (an average age of 6.8, 14 patients with anti-NMDAR encephalitis and 1 patient with anti-CASPR2 encephalitis) presented seizure remission without any AEDs. Seventy five percent of patients with anti-GABABR antibodies developed refractory seizure. Other risk factors which contributed to refractory seizure and seizure relapse included status epilepticus (P = 0.004) and cortical abnormalities (P = 0.028). Given this retrospective data, patients with AE have a high rate of seizure remission, and the long-term use of AEDs may not be necessary to control the seizure. Moreover, seizures in young patients with anti-NMDAR encephalitis presents self-limited. Patients with anti-GABABR antibody, status epilepticus, and cortical abnormalities are more likely to develop refractory seizure or seizure relapse.

Keywords: autoimmune encephalitis, outpatients, seizure remission, antiepileptic drug withdrawal, refractory seizure

#### Edited by:

Xin Tian, First Affiliated Hospital of Chongqing Medical University, China

#### Reviewed by:

Ché Serguera, Institut National de la Santé et de la Recherche Médicale (INSERM), France Anil Chauhan, Saint Louis University, United States

> \*Correspondence: Yuan Wu<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology

Received: 24 June 2018 Accepted: 10 December 2018 Published: 08 January 2019

#### Citation:

Huang Q, Ma M, Wei X, Liao Y, Qi H, Wu Y and Wu Y (2019) Characteristics of Seizure and Antiepileptic Drug Utilization in Outpatients With Autoimmune Encephalitis. Front. Neurol. 9:1136. doi: 10.3389/fneur.2018.01136

## INTRODUCTION

Autoimmune encephalitis (AE) is kind of encephalitis which associates with humoral or cellular responses against specific neuronal antigens (1, 2). The clinical characteristics of these patients include seizure, abnormal behavior, speech dysfunction, movement disorders, and autonomic dysfunction (3). With the development of biochemical assays, several antibodies, such as the anti-N-methyl-D-aspartate receptor (NMDAR), anti-γ-aminobutyric acid B receptor (GABABR), anti-leucinerich glioma inactivated 1 (LGI1), and anti-contactin-associated protein-like 2 (CASPR2) antibodies, have emerged as the leading causes of AE. Therapeutic regimens included firstline immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), and second-line immunotherapy (rituximab, cyclophosphamide). Despite the severity of the disease in acute phase, most patients recover after proper immunotherapy and intensive support (4).

In acute phase, seizure is a highly prevalent symptom, and parts of patients develop status epilepticus (SE) (5–7). Hence, multiple anti-epileptic drugs (AEDs) are often necessary to control the attacks. However, based on the previous studies and data from our center, most patients likely recover completely after adequate immunotherapy, and seizure is rarely reported in the chronic phase (5, 8, 9). Considering the adverse events of AEDs, some patients stop taking AEDs at the early stage. However, an instructional database describing the long-term use of AEDs with AE is lacking.

This retrospective study aimed to report the seizure characteristics and long-term use of AEDs in outpatients with AE. Our secondary goals included assessing the outcomes between patients with early and late AEDs withdrawal, and determining the probable risk factors for seizure relapse and refractory seizures.

## MATERIALS AND METHODS

## Study Population

This study was conducted in compliance with the ethical standards of Guangxi Medical University. Written consents were obtained from the patients.

The antibodies, including NMDAR, GABABR, LGI1, and CASPR2, were detected in patients' cerebrospinal fluid and serum samples. The anti-NMDAR antibody was detected by specific staining against NMDAR isolated from rat' hippocampus and cerebellum, and positive cell-based assay with HEK293 cells transfected with NR1. Other antibodies were detected using transfected HEK293 cells with the respective target proteins.

Patients with acute neurological disorders of either sex or any age were considered eligible for this study if they presented any positive antibodies from January 2012 to May 2017. The exclusion criteria included (1) patients diagnosed with epilepsy, cerebral infarction, cerebral trauma, cerebral tumor, and other nervous system disease prior to the onset of encephalitis, (2) patients with evidence of infectious encephalitis, for example, viral, bacteria, mycobacterium tuberculosis, or fungal, (3) patients in the acute phase of autoimmune encephalitis and still required hospitalization. Immunotherapies were used in the acute phase (**Figure 3A**). The decisions about the type and duration of immunotherapy were based on the clinical symptoms, curative, and side effects. The available onset medical data (seizure characteristics, AEDs utilization, and electroencephalogram/neuroimaging findings) were recorded. The electroencephalogram and neuroimaging findings were recorded in the acute phase of the disease.

#### Definitions

The chronic stage of AE was defined by 3 months after the onset of AE symptoms. SE was defined as continuous seizure activity lasting >5 min or recurrent seizures without regaining consciousness between seizures for >5 min (10). Refractory seizure was defined as an uncontrolled seizure after treatment by more than three standard therapeutic schedules (11). Seizure remission was defined as having no seizure for at least 1 year after the last time when AEDs were used (12). Seizure with focal characteristics was defined as a partial seizure or a patient with seizure and hemiplegia or hemianesthesia.

## Outcome Assessment and Grouping

AEDs utilization and seizure outcomes were assessed through outpatient services and/or telephone interview. AEDs utilization in the chronic stage (time of continuation/withdrawal) and outcomes (refractory, relapse, or remission) data were collected on patients. Before evaluating the outcomes, the patients who discontinued AEDs were observed for at least 1 year after the last AEDs use.

Patients who withdraw AEDs were divided into two groups based on the duration of AEDs use. The early withdrawal (EW) group had AEDs withdrawn within 3 months, and the late withdrawal (LW) group had AEDs withdrawn after 3 months. Outcomes were assessed based on seizure remission rate and the modified Rankin Scale (mRS) (13).

### Statistical Analysis

Data analysis was performed using IBM SPSS Statistics 22. The skewness and kurtosis coefficients were used to evaluate whether the quantitative data fit a normal distribution. Data were regarded as a normal distribution if the skewness and kurtosis coefficients <1. For the data that did not fit this criterion, we used the Mann–Whitney test to evaluate significance. Other data was compared using a t-test or a Fisher's exact test. The factors affecting the outcomes were assessed through Spearman analysis.

## RESULTS

We identified 83 patients with AE. **Figures 1**, **2** show a summary of these patients. In the charts reviewed, 5 patients were lost and 3 patients died of severe pneumonia. As a result, 75 patients were enrolled to follow-up. Among the 75 patients, 12 continued taking AEDs, 15 were not given any AEDs, and 37 patients who withdrew from AEDs were followed up for at least 1 year (**Figure 1**). The group with AEDs withdrawal

included 34 patients with anti-NMDAR encephalitis, 1 with anti-LGI1 encephalitis, 1 with anti-GABABR encephalitis, and 1 patient presented coexisting antibodies of anti-LGI1 and CASPR2 (**Figure 1**).

#### Anti-NMDAR Encephalitis

Among the patients with anti-NMDAR encephalitis, 14 were not given any AEDs, in which 7 suffered from one-time seizure attack at the onset of the encephalitis. Compared to the patients with AEDs, the majority of this group was considerably young (6.8 ± 3.26, P = 0.004, **Table 1**) and less likely to have repetitive seizures (P = 0.038, **Table 1**). The median duration of follow up was 20 months (range: 14–36 months), and no relapse was reported. Furthermore, 12 patients (85.7%) had good outcomes with a 0 mRS score; the remaining 2 patients presented with cognitive dysfunction.

Among the 34 patients (20 men and 14 women, 23 in EW and 11 in LW) who were discontinued from AEDs, 7 patients (20.6%) did not report seizure, and 5 patients (14.7%) reported a onetime seizure at the onset. Two patients in the EW group reported hemianesthesia before presenting seizures. The occurrence of SE was 32.4% in total. Eighteen patients had an magnetic resonance imaging (MRI) scan and abnormalities were found in 33.3% of the patients, including 4 patients with white matter changes and 2 patients with cortical mass (**Table 1**). The patterns of AEDs selection and discontinuation were variable (**Figure 3B**). Monotherapy was the most common selection, with 69.5% in the EW group and 63.9% in the LW group. At the early stage, carbamazepine (n = 11) and oxcarbazepine (n = 16) were the most chosen AEDs. Valproic acid was among the most commonly continued therapies over the course of follow-up (**Figure 3B**). Seven patients without seizure were treated with AEDs upon onset. Five of these discontinued AEDs within 1 month, and the remaining 2 patients underwent LW because of frequent subclinical discharge.

The patients' data were compared between the EW and LW groups (**Table 1**). No statistically significant difference was observed between the two groups in terms of age (P = 0.935), sex (P = 0.458), seizure characteristics (P = 0.359), antibody TABLE 1 | Clinical characteristics and outcomes of patients with anti-NMDA encephalitis.

AED, Antiepileptic drug. P1, P-value among No AED, Early withdraw, and late withdraw group. P2, P-value between Early withdraw, and late withdraw group.

titers (P = 0.727), SE (P = 0.259), MRI findings (P = 0.329), or AEDs selection (P = 0.934). The medium durations of follow up were 36 months (range: 15–50 months) and 32 months (range: 17–62 months) for the EW and LW groups, respectively. 2 patients in the EW group relapsed in the first month after drug discontinuation. No remarkable difference in the percentage of relapse was observed between the two groups.

Detail of patients with anti-NMDAR encephalitis was presented in **Supplementary File 1**.

#### Other AEs

A 44-year-old woman who was diagnosed with anti-CASPR2 encephalitis presented lethargy and headache without seizure at the onset. She did not take any AEDs. No relapse was reported during her 16-month follow up. A 72-year-old man with anti-LGI1 encephalitis and a 35-year-old woman with anti-GABABR encephalitis presented frequent seizures at onset and underwent an AED withdrawal 3 and 6 months later, respectively. No relapse was reported during their 1-year follow up. The other two elder patients (50 and 64 years-old, respectively) with anti-GABAB encephalitis presented refractory seizures (**Figure 2**).

We also reviewed 2 coexisting AE. One is a 30-yearold female who presented with anti-NMDAR and GABABR encephalitis. She had a seizure 10 years ago before she was diagnosed with AE through CSF detection. Her EEG presented δ brushes with generalized paroxysmal θ activities. The brain MRI was unremarkable. She developed refractory seizures after being treated by oxcarbazepine, carbamazepine, and clonazepam. The other patient was a 43-year-old woman with LGI1 and CASPR2 antibodies. She presented repeated generalized tonicclonic seizure and paroxysmal speech dysfunction. Bilateral paracentral lesion was found in the MRI scan. She was given levetiracetam and valproic acid. The AEDs were withdrawn 2 years later, and no relapse was reported during her 1-year follow up (**Figure 2**).

#### Risk Factors

Among the 12 patients who remained on AEDs, 9 patients presented refractory seizure, including 6 patients with anti-NMDAR encephalitis, 2 patients with anti-GABABR encephalitis, and 1 patient with anti-NMDAR and GABABR encephalitis (**Figure 2**). Among patients with anti-NMDAR encephalitis, refractory seizures occurred more often in the patients younger than 30 years of age (**Figure 2**), and who presented repetitive seizures and SE, moreover, 4 patients (66%) showed cortical abnormalities on the MRI scan.

By combining the data of the 2 relapse cases, we evaluated the risk factors that contributed to the worse outcomes of anti-NMDAR encephalitis. The patients with relapse or refractory seizure were more likely to be accompanied with cortical lesions on MRI (P = 0.028) and SE (P = 0.004) than those who reached seizure remission (**Table 2**). Moreover, the seizures with

TABLE 2 | Spearman analysis of factors associated with outcomes.

focal characteristics (P < 0.001), SE (P < 0.001), and MRI abnormalities (P = 0.010) were significantly associated with refractory seizure (**Table 2**). For other kinds of AEs, we found 3 patients with anti-GABABR encephalitis (75% in all, including 1 patient with concomitant disease) developed refractory seizure; this number is much higher than those of others.

## DISCUSSIONS

Parts of AE have been linked to cell surface antigens, which included voltage-gated potassium channel (VGPC, e.g., LGI1 and CASPR2), NMDAR, and GABABR (14). To evaluate the AEDs utilization associated with AE, we focused on seizure in a cohort of patients with anti-NMDAR, anti-GABABR, anti-LGI1, and CASPR2 encephalitis. This study demonstrated low recurrence rates in young patients with AE who experienced first unprovoked seizures and highlighted an overall remission rate of 94% after the patients discontinued AEDs therapy. No difference was noted between the EW (≤3 months) and LW (>3 months) of AEDs. Moreover, a higher number of patients with anti-GABABR antibody, SE, cortical abnormalities, and focal neurological dysfunction experienced refractory seizure or seizure relapses compared to those who did not.

## Seizure Remission in Anti-NMDAR Encephalitis

Since 2005, the characteristics and long-term outcomes of anti-NMDAR encephalitis have aroused public attention due to the high incidence in young patients with serious neurological dysfunctions (15). According to a previous study, we found that the probable predicted factors for poor outcomes in the acute phase included older age, altered consciousness, and SE, and the process of terminating SE was particularly important for anti-NMDAR encephalitis (5). By evaluating patients through the mRS score, the other multi-institutional study which included clinical data from 577 patients with anti-NMDAR antibodies observed that 81% of the patients responded to immunotherapy (8). Seizure occurs as a prominent feature in AE (16), whether long-term AEDs are necessary after patients achieving good outcomes has not been established (14, 16).

AEDs withdrawal after a successful seizure control may prevent adverse side effects and excessive cost. However, the studies which have evaluated the safety of AEDs weaning in patients with anti-NMDAR encephalitis are rare. One study demonstrated that no difference in seizure recurrence between 1 and 2 years of AEDs therapy in children with viral encephalitis (17), and the relative risk factors might have included EEG abnormalities or HIV infection (18). However, the duration of AEDs in anti-NMDAR encephalitis tended to be shorter (19). Among the 34 enrolled patients with AEDs withdrawal, only 5.8% suffered from relapse during the follow up. Moreover, no difference was found between the EW (≤3 months) and LW (>3 months) groups, which is consistent with that of a previous study (16).

Information regarding AEDs use in adolescents and adults with anti-NMDAR encephalitis has been reported previously, but data from younger children remain limited (16). In the present study, we enrolled 14 young patients with average age of 6.8 (range: 3–12 years). Compared with the older age group, the young group was more likely be seizure free during the long-term follow-up without AEDs, even if they suffered onetime seizure attacks at the onset. The key treatment decisions after the first unprovoked seizure are a controversial issue in children (20, 21). In some epilepsy syndromes, such as in benign childhood epilepsy with centrotemporal spikes or childhood absence epilepsy, remission is a regular feature of the natural history, whereas juvenile myoclonic epilepsy or other symptomatic epilepsies have long been considered to present in AEDs continuation (22). By using the statistical methods for survival analysis, one study indicated that the cumulative risk of repetitive seizure in children was 29% in the first year and elevated to 45% within the 10-year follow up (23). However, the factors associated with recurrences after the first seizure are complex. The probable risk factors may include age (24) and etiology (25). For anti-NMDA encephalitis, our data indicated that seizure in young patients tended to be self-limited. Moreover, some scholars indicate that a cognitive comorbidity likely accompany with the initial seizure if AEDs are not used (26). However, evaluation of mRS score revealed that the majority of children in this group presented normal daily activities.

Although our data supports that seizure remission is common and that long-term use of AEDs may not be necessary, the significance of immunotherapy cannot be ignored to control the seizure. Numerous studies demonstrated that it is the immunotherapies that control the symptoms in anti-NMDAR encephalitis (5, 8, 9). Moreover, one retrospective study which focused on the outcome of AEDs alone in controlling the seizure of patients with anti-VGPC-complex antibodies indicated that only 23.5% of patients became seizure free compared with 61.5% of patients with immunotherapy (14).

## Seizure Remission in Anti-GABABR, LGI1, and CASPR2 Encephalitis

Anti-GABABR, LGI1, and CASPR2 antibodies have been recently detected in patients with limbic encephalitis (27). Seizures are frequently reported in limbic encephalitis, but autonomic and psychiatric symptoms are more highlighted. In these antibodymediated seizures, remission rate is variable, and may be related to complications, immunotherapy, and ICU management (7).

Although rare, seizure with additional auto-antibodies may be a other probable risk factor. LGI1 and CASPR2 are the extracellular domains of VGPC. The coexistence of anti-LGI1 and anti-CASPR2 encephalitis may contribute to seizure, cognitive disturbance, movement disorders, and pain (7). Besides AEDs use, the empirical approach to seizure control is corticosteroid treatment (28, 29). A GABABR antibody is rarely accompanied with other antibodies in a same patient, and a probable reason may involve different genetic predispositions (30, 31). In our study, the presented patients developed refractory seizure and severe cognitive dysfunction. One possible mechanism of AEDs resistance may be associated with different interaction sites, as anti-NMDAR antibodies have been suggested to decrease the synaptic levels of receptors, whereas the anti-GABABR antibody would further alter the synaptic function (32).

## Risk Factors for Refractory Seizure and Seizure Relapse

As AEDs are supposedly unnecessary to seizure outcomes in AE after appropriate immunotherapy, we evaluate the other probable independent risk factors that contribute to refractory seizure and seizure relapse. In addition to involving the anti-GABABR antibody, our result shows that patients with SE, cortical abnormalities in MRI, and focal neurological dysfunction are more likely to develop worse outcomes than those who did not accompany these findings. SE has been proven to be an independent risk factor in major types of epilepsy (33, 34). The complications of SE, such as severe pneumonia and ICU admission, have also contributed to poor outcomes (5). Cortical abnormalities seem positively correlate with refractory seizure. By using structural MRI scans, one study demonstrated a strong association between incomplete recovery and superficial white matter lesions (35). This observation indicates that the injured connection between adjacent cortices may play a crucial role in seizure control after AE.

#### LIMITATIONS

This study has some limitations. First, we tried to discuss the risk factors of seizure outcomes for AE after appropriate immunotherapy. However, as antibodies were not measured at later time points, the direct relationship between persistent antibody levels and seizure outcomes remained unclear. A previous study presented that the neurological recovery accompanied with reduced antibody titer (15), while the correlation between antibody titer and refractory seizure showed unremarkable in our study. One probability which caused the difference might involve the time when antibody was measured. Though the seizure outcomes were assessed based on the data of outpatients, the patients who developed refractory seizure might have persistent higher titer level than those who did not. Second, as the relapse rate was altered with the follow-up period (23), long follow-up times are necessary. However, 54–100% of seizures after AE occurred within the first year, and new-onset seizure after 1 year of follow up was rare (36–38). Third, the results were limited because of the relatively small cohort. Combined with the previous data (16), a probable correlation between seizure remission and AED utilization was noted, and further trials and meta-analysis are needed to confirm these results.

#### REFERENCES

## CONCLUSION

Patients with AE have a high rate of seizure remission after proper immunotherapies. The long-term use of AEDs appears not be necessary to control their seizures. Compared with adults, young patients are more likely to become seizure free without AEDs. The risk factors that contribute to refractory seizure or seizure relapse may include anti-GABABR encephalitis, SE, and cortical abnormalities.

#### AUTHOR CONTRIBUTIONS

QH is the first author of this manuscript. YuaW is the corresponding author of this manuscript, they contributed to the study design, data collection and analysis, and draft writing of this work. MM, XW, and YL have revised and improved the manuscript. HQ and YueW contributed in the data collection and figures. All authors have seen and agreed on the finally submitted version of the manuscript.

#### ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China Grants (No. 81760242), Natural Science Foundation of Guangxi Grants (No. 2017GXNSFAA198047), and China Association Against Epilepsy-UCB Science Foundation (No. 2017003).

#### SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur. 2018.01136/full#supplementary-material

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Huang, Ma, Wei, Liao, Qi, Wu and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Central Nervous System Involvement in ANCA-Associated Vasculitis: What Neurologists Need to Know

Yang Zheng1 , Yinxi Zhang1 , Mengting Cai 1 , Nanxi Lai 2 , Zhong Chen1,2 \* and Meiping Ding1 \*

1 Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China, 2 Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, China

Objective: To provide a comprehensive review of the central nervous system (CNS) involvement in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including the pathogenesis, clinical manifestations, ancillary investigations, differential diagnosis, and treatment. Particular emphasis is placed on the clinical spectrum and diagnostic testing of AAV.

#### Edited by:

Xin Tian, First Affiliated Hospital of Chongqing Medical University, China

#### Reviewed by:

Tatsuro Misu, Tohoku University, Japan Moussa Antoine Chalah, Hôpitaux Universitaires Henri Mondor, France

#### \*Correspondence:

Zhong Chen<EMAIL_ADDRESS>Meiping Ding<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology

Received: 06 October 2018 Accepted: 17 December 2018 Published: 10 January 2019

#### Citation:

Zheng Y, Zhang Y, Cai M, Lai N, Chen Z and Ding M (2019) Central Nervous System Involvement in ANCA-Associated Vasculitis: What Neurologists Need to Know. Front. Neurol. 9:1166. doi: 10.3389/fneur.2018.01166 Recent Findings: AAV is a pauci-immune small-vessel vasculitis characterized by neutrophil-mediated vasculitis and granulomatousis. Hypertrophic pachymeninges is the most frequent CNS presentation. Cerebrovascular events, hypophysitis, posterior reversible encephalopathy syndrome (PRES) or isolated mass lesions may occur as well. Spinal cord is rarely involved. In addition, ear, nose and throat (ENT), kidney and lung involvement often accompany or precede the CNS manifestations. Positive ANCA testing is highly suggestive of the diagnosis, with each ANCA serotype representing different groups of AAV patients. Pathological evidence is the gold standard but not necessary. Once diagnosed, prompt initiation of induction therapy, including steroid and other immunosuppressants, can greatly mitigate the disease progression.

Conclusions and Relevance: Early recognition of AAV as the underlying cause for various CNS disorders is important for neurologists. Ancillary investigations especially the ANCA testing can provide useful information for diagnosis. Future studies are needed to better delineate the clinical spectrum of CNS involvement in AAV and the utility of ANCA serotype to classify those patients.

Evidence Review: We searched Pubmed for relevant case reports, case series, original research and reviews in English published between Sep 1st, 2001 and Sep 1st, 2018. The following search terms were used alone or in various combinations: "ANCA," "proteinase 3/PR3-ANCA," "myeloperoxidase/MPO-ANCA," "ANCA-associated vasculitis," "Wegener's granulomatosis," "microscopic polyangiitis," "Central nervous system," "brain" and "spinal cord". All articles identified were full-text papers.

Keywords: anti-neutrophil cytoplasmic antibodies, vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, central nervous system

## INTRODUCTION

Central nervous system (CNS) vasculitis, with its myriad and evolving presentations, always poses a great diagnostic challenge for neurologists. It occurs either as part of a systemic vasculitis, or a primary disorder restricted to the CNS (1). Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), a systemic small-vessel vasculitis, is characterized by pathogenic ANCA production (1). In the clinical practice, AAV mainly includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) (1). Timely recognition and diagnosis of AAV is important, since the progressive disease can be dramatically mitigated by prompt use with steroid and other immunosuppressive agents.

Neurologic involvement is not uncommon in AAV throughout the disease course, ranging from 22 to 54% in patients with GPA (2–5) and 34 to 72% in those with MPA (2–4). CNS is affected in <15% of patients with AAV (5) but accounts for much of the morbidity in those patients (1–3, 7–10). However, the heterogeneous CNS symptoms in AAV may hinder early diagnosis among neurologists, causing treatment delays and disease progression, leading to relapses, or even death.

Therefore, this review aims to increase the awareness of AAV among neurologists. We mainly focus on GPA and MPA, which have distinctive features compared with EGPA (6– 10). This review comprehensively illustrates the pathogenesis, CNS manifestations, ancillary investigations, and treatment algorithms warranted for AAV patients with CNS involvement. In particular, we put a special emphasis on its clinical spectrum and the utility of ACNA testing in diagnosing and subtyping those patients.

## PATHOPHYSIOLOGY

A basic understanding of how pathogenic ANCAs are induced, take effect and invade the CNS helps to understand its manifestations and illuminate potential targets for treatment in AAV. Pathogenic ANCAs, targeting mainly at proteinase 3 (PR3) and myeloperoxidase (MPO) expressed by innate immune cells, are the major contributor to the pathogenesis of AAV, according to in vitro and in vivo experimental data (11). An overview of the pathophysiology is shown in **Figure 1**. Pathogenic ANCAs are induced by the interplay of multiple environmental, genetic, and immunological factors (8, 11, 15). An encounter with the antisense peptides of PR3 or MPO triggers the immunological self-amplication network (11). The antigen-recognition capability of each individual, however, is more likely genetically determined (8). In addition, the generation of pathogenic ANCAs is further facilitated by an impaired immunological regulation, as in the pathogenesis of the few treatable neurological disorders (16–19). The function of regulatory T (TREG) cells and regulatory B cells with CD5 expression are suppressed, whereas the circulating effector memory T cells (TEM) (20) and ANCA-producing B cells (15) are proliferated and activated.

Following the generation of pathogenic ANCAs, different pathways lead to the two major pathological changes in AAV, namely vasculitis, and granulomatosis. Neutrophils, activated by pathogenic ANCAs and fueled by the alternative complement pathway (13), play the central role. Activated neutrophils can transmigrate the vessel wall and undergo respiratory burst, degranulation, neutrophil extracellular traps (NETs), apoptosis and necrosis (14), causing disruptions of the endothelium and thus activation of the coagulation cascade, leading to fibroid necrosis at sites of vasculitic inflammation. This neutrophilactivation process is further augmented by the complement system, especially the alternative pathway, with C5a playing a key role in-between (13). By contrast, the pathogenesis of extravascular granulomatosis is less well-understood. Current thinking holds that the chronic inflammation is initiated by the acute neutrophil-mediated necrosis (21). Subsequently, defects in the cell death machinery and aberrant reaction of monocytes and macrophages contribute to the chronic inflammation and granulomatosis formation in AAV.

CNS can be affected in AAV through one of the following pathways (22, 23): (1) inflammation, obstruction or increased permeability of the small to medium-sized cerebral vessels due to systemic vasculitis; (2) infiltration or compression of granulomatous pathology from adjacent structures; (3) granulomatous lesions developing de novo within the CNS. Mechanisms vary according to the specific CNS structures involved. In general, extra-axial lesions involving the dura, or pituitary gland are mainly attributed to granulomatous inflammation, while parenchyma pathologies are mediated by vasculitis and breakdown of blood brain barrier (24). However, it remains unclear whether pathogenic ANCAs are produced intrathecally or from the systemic circulation and how the two ANCA serotypes contribute to different CNS manifestations.

#### THE MANY FACES OF AAV WITH CNS INVOLVEMENT

#### Epidemiology

AAV, especially GPA and MPA, is a multisystem disease. Up to 40–50% of patients have a remitting-relapsing course (7, 12). The onset of CNS flare is mostly acute or subacute, depending on the specific neurological syndrome. CNS symptoms usually present late in the disease course (5, 25). No gender predilection is observed and most patients tend to have their first CNS flare in the middle age (5, 25, 26).

## Overview of Systemic AAV

It is of great help to know the accompanying systemic symptoms at the time of or prior to CNS flare. A longterm history of constitutional symptoms like fever, weight loss, fatigue and arthralgia are often suggestive of an autoimmune etiology. In addition, organs susceptible to AAV damage include ear, nose and throat (ENT), lung and kidney (6). ENT involvement for over 3 months, presenting as chronic sinusitis, otitis media, or mastoiditis, is diagnostic of AAV, (3, 7, 24). History of renal dysfunction (proteinuria, hematuria

surface or inside the cytoplasm of resting neutrophils (11, 12). The interplay among genetic, environmental, and immunological factors contributes to the high membrane expression and release of PR3 and MPO, leading to the production and proliferation of pathogenic ANCAs. Primed neutrophils are activated by ANCAs and transmigrate the vessel wall, undergoing respiratory bursts, degranulation, and neutrophil extracellular traps (NETs) generation (11), which are further augmented by the alternative complement pathway (13). The neutrophil-mediated processes are the major contributor to the injury and inflammation of the endothelial cells lining the vascular wall in the early phase (14). Monocytes are subsequently recruited at sites of acute inflammation and necrosis, inducing the development of granulomatous inflammation mainly mediated by an exaggerated monocyte/macrophage reaction (11). Potential treatment targets are illustrated by red arrows in the figure, including the T-cell and B-cell dysregulation, environmental triggers (microbes, drugs), aberrant activation of alternative complement pathway and NETs. ANCA, anti-neutrophil cytoplasmic antibody; MPO, myeloperoxidase; PR3, proteinase 3; NET, neutrophil extracellular trap.

and acute kidney failure) and pulmonary problems (pulmonary nodules, infiltration, alveolar hemorrhage, chronic cough, asthma, or rarely respiratory failure) were also frequently reported. Therefore, for patients suspected with AAV, an investigation of systemic symptoms is warranted. Manifestations highly suggestive of AAV are listed in **Table 1**.

## Clinical and Imaging Spectrum of CNS Involvement in AAV

CNS presentations in AAV patients vary, including headache, ischemic infarction, intracranial hemorrhage, encephalopathy (seizures, neuropsychiatric disorders, confusion, or altered consciousness), and rarely spinal cord symptoms. Those symptoms are caused by the involvement of corresponding CNS structures including the dura mater, brain parenchyma, pituitary gland, spinal cord, and leptomeninges with decreasing frequency.

## Brain Parenchyma Involvement

### **(a) Cerebrovascular events**

Ischemic infarctions and intracranial hemorrhages, though rare, can be the initial presentation of AAV and are always associated with significant morbidity (29–31). Timely recognition of AAV as the underlying cause is difficult at the first visit in the emergency room due to its rarity. Therefore, the distinguishing features of AAVrelated strokes can aid in early diagnosis and improve

TABLE 1 | Systemic manifestations of AAV other than CNS# .

#The table is adapted from previous reviews on related topics (6, 12, 27).

\*Clinical features highly suggestive of AAV (6, 28).

AAV, anti-neutrophil cytoplasmic antibody-associated vasculitis; CNS, central nervous system.

prognosis. Ischemic infarctions typically present as an isolated or multiple lesions affecting the white matter, since distal penetrating vessels are predominantly affected. Medullary and pontine infarctions were also reported in some cases (29, 30). Ischemic infarctions caused by AAV are typically resistant to antiplatelet therapy and tend to recur without proper immunosuppressive therapy. Patients with AAV are also at an increased risk of hemorrhagic transformation after reperfusion therapy of ischemic stroke (32). Hemorrhagic events occur less often. They more often affect the brain parenchyma (31), and sometimes the subarachnoid space (33). Brain Imaging findings usually correspond to the specific disease in each patient, involving ischemic, hemorrhagic lesions, or variable degrees of smallvessel diseases affecting both white and gray matter (34). Nonspecific white matter lesions with T2 hyperintensities can appear in the periventricular, subcortical regions, the basal ganglia, the mesencephalon and pons.

#### **(b) Posterior reversible encephalopathy syndrome**

Posterior reversible encephalopathy syndrome (PRES) is a rare yet unique complication in the late phase of AAV (35, 36). Clinically, this entity typically presents with an acute onset. Symptoms are generalized and include encephalopathy, seizures, headache and visual disturbance. Brain imaging typically reveals findings consistent with vasogenic edema, predominantly involving the bilateral parieto-occipital regions. Most patients with PRES have a dramatic improvement within days to weeks, with only the supportive therapy. Symptoms may recur when the underlying AAV is not well-controlled.

#### **(c) Isolated parenchymal mass lesions**

Isolated parenchymal mass lesions were very rarely reported in AAV (37–39), which often present with a discrete granuloma. Symptoms vary depending on the location of lesions, with seizures as the most frequent presentation (38). Brain magnetic resonance imaging (MRI) of isolated parenchymal granulomas reveals a well-delineated mass with a high signal intensity on T2-weighted images and enhancement on gadolinium-enhanced sequences (39).

#### **(d) Cognitive impairment**

Cognitive decline, though mostly subclinical and mild, can occur in AAV patients as well, with an estimated prevalence of 30% (40). According to one study of 13 AAV patients (40), the pattern of cognitive impairment, mainly affecting abstract reasoning, attention and non-verbal memory, is different from that of age-related dementia. On brain MRI, multiple white matter lesions, mainly located in the periventricular or juxtacortical areas, are often associated with the cognitive impairment (40).

#### Brain Meninges Involvement

Pachymeninges is affected more frequently than leptomeninges (41). The frequency of hypertrophic pachymeningitis (HP) in adult AAV ranges from 18 to 35%, depending on the methodology of studies and the sample populations selected (41, 42). Manifestations of AAV-related pachymeningitis vary depending on the location and extent of inflammation. Headache, the dominant symptom of HP, is often severe and resistant to analgesics (22). Besides, neck stiffness is not commonly seen along with headache. Cranial nerves may be compressed by the thickened dura mater and cause symptoms such as visual loss, double vision, and facial palsies. Other times the pachymeningeal inflammation may infiltrate the brain parenchyma and cause impaired consciousness and seizures (24, 42). Notably, an entity named "CNS-limited AAV" was recently proposed by Yoloseki et al. for patients with MPO-ANCApositive hypertrophic pachymeningitis, characterized by an elderly female predominance, less severe neurological damages, and lower rates of developing into the generalized disease (24). Yet it remains unclear whether the "CNS-limited AAV" represents a novel AAV phenotype or merely a transient disease stage (24).

Imaging studies are valuable in identifying hypertrophic thickening of the dura mater, monitoring disease activity and assessing the damage of adjacent structures. On brain MRI and computed tomography (CT) scans, HP typically shows linear thickening of dura mater or a bulging mass with enhancement. Gadolinium-enhanced T1-weighted MR imaging offers certain advantages over other sequences in identifying active inflammation of the thickened dura mater with superior spatial resolution. The brain pachymeningitis can involve the tentorium cerebelli, cranial fossa, cavernous sinus, falx cerebri, or convexity with no site preference. Additionally, brain-imaging studies can help assess the potential sinonasal and orbital involvement, a common occurrence in AAV. Additionally, the damage of adjacent bone structures is prominent on brain CT scans (41, 43).

#### Pituitary Gland and Stalk Involvement

Inflammation of the pituitary, termed hypophysitis, is rarely seen in AAV, yet requiring special consideration (44–46). Constitutional symptoms including fatigue, lethargy, headache, weight loss, and appetite loss frequently occur. Endocrine disturbances most commonly include diabetes insipidus, and hypogonadism (45). Other less common ones include hypothyroidism, adrenocorticotropic hormone (ACTH) deficiency and growth hormone (GH) deficiency (45, 47). Pituitary stalk compression resulting from pituitary enlargement may cause hyperprolectinemia as well (22). Visual deficits result with optic chiasm compression (45). Outcome of hypopituitarism is less favorable, despite the treatment with immunosuppressive agents. Pituitary dysfunction tends to persist, even though other systemic symptoms can come to remission after standard treatment (45, 46).

Brain MRI typically shows an enlarged pituitary gland or thickened stalk with peripheral enhancement on post-contrast sequences. Other findings include the lack of posterior pituitary hyperintensity on T1 images. Normal MRI, as reported in some cases, does not exclude pituitary involvement (47).

#### Spinal Cord Involvement

In general, spinal cord is rarely involved in AAV (48). The three possible mechanisms underlying spinal cord involvement include necrotizing inflammation of the spinal vasculature, compression of the spinal cord by inflamed thickened meninges as well as the formation of primary spinal granulomas (48). Clinical syndromes of the spinal cord include hypertrophic pachymeningitis (41, 48) and compressive myelopathy (49). Contrast-enhanced MRI of the spinal cord is of great diagnostic value and biopsy is often warranted to confirm the diagnosis.

#### Non-CNS Entities Highly Associated With CNS Involvement

#### **(a) Cranial neuropathy**

Cranial neuropathies are rarely the only manifestation in AAV, but rather coexist with other CNS symptoms such as headache and systemic symptoms. Previous investigations found a prevalence between 2 and 10% of cranial neuropathies in patients diagnosed with GPA (50) and MPA (51, 52). Commonly affected cranial nerves in AAV include cranial nerve II–VIII (50). Bulbar palsy, by contrast, is less commonly involved (53).

#### **(b) Orbital disease**

Eye involvement was reported in around 30–50% of patients diagnosed with GPA (54), with the orbit and sclera most frequently involved. MPA, by contrast, rarely impair eye movement (52). Symptoms vary and typically include proptosis, diplopia, decreased vision and orbital pain (55), resulting from compressions of ocular granuloma, granulomatous inflammation of the optic nerve and ischemic optic neuropathy due to vascular occlusion (56). MR imaging and CT can help reveal mucosal and bony lesions in the orbit and rule out continuous extension.

#### **(c) Parasinal disease**

For patients with CNS manifestations suspected of AAV, an evaluation of paranasal sinuses is a must. Findings indicative of granulomatosis in the paranasal sinuses include a softtissue mass, thickening of the sinus wall, or "ground-glass" material in the lumen (34). As in orbital involvement, noncontrast CT scan has its diagnostic value in evaluating the nasal cavity, paranasal sinuses, mastoids and temporal bone, due to a better resolution of mucosal and bony pathologies compared with MRI (43). Brain MRI may also aid in the evaluation of soft tissue masses within those cavities.

#### Differences Between ANCA Serotypes

There is an increasing consensus that the ANCA serotype, either MPO-ANCA or PR3-ANCA, has a crucial role in AAV (12). Distinctively, previous studies revealed that the ANCA serotype represents two separate groups of patients in epidemiology, genetic background, clinical features, laboratory features as well as prognosis. We summarized the differences between MPOand PR3-ANCA positive AAV in **Table 2**. Specifically, for AAV patients with CNS involvement, the ANCA serotype matters as well (24). Though the two serotypes tended to affect the nervous system with a similar frequency (57), they differ in the pattern and severity of CNS involvement. According to one study of patients with HP in Japan, MPO-ANCA-positive HP had an elderly female predominance, more frequently had lesions limited to the dura mater and upper airways, and was less likely to have a generalized systemic progression. On the contrary, PR3-ANCA-positive HP tended to have more severe neurological damages and a generalized disease progression (24). However, evidence remains limited to patients with HP. Extrapolation of the utility of ANCA serotype in other CNS manifestations remains to be further studied.

### DIAGNOSIS

The diagnosis of CNS involvement in AAV, similar to the disease overall, requires consideration of clinical, serological, radiographic, and, when available, pathological evidence (61). In patients with established AAV, new-onset neurologic deficits with abnormal radiological and cerebrospinal fluid (CSF) findings are suggestive of CNS involvement. For patients without established underlying disease, neurologic symptoms closely compatible with CNS syndromes known to arise in AAV warrant further investigations for the systemic disease. In either case, ancillary tests are of important value in making the

#### TABLE 2 | Comparison of PR3- and MPO-ANCA-positive AAV.

PR3, proteinase 3; MPO, myeloperoxidase; ANCA, anti-neutrophil cytoplasmic antibodies; AAV, anti-neutrophil cytoplasmic antibody-associated vasculitis; HLA, human leukocyte antigen; ENT, ear, nose and throat.

#### Box 1 | Investigations in AAV-related CNS involvement.

ANCA immunoassays (MPO- and PR3- ANCA testing)

Endocrine panel (to evaluate the pituitary function)

Screening for HIV, hepatitis, and tuberculosis

Analysis of cerebrospinal fluid (measure inflammatory mediators and degradation proteins, assess the blood-brain barrier and exclude infection) Chest CT

Brain imaging (CT; MRI, suggested sequences include T1/T2 weightedimaging, FLAIR, DWI, SWI and contrast enhanced T1 sequences) Biopsy

AAV, anti-neutrophil cytoplasmic antibody-associated vasculitis; ANCA, antineutrophil cytoplasmic antibodies; MPO, myeloperoxidase; PR3, proteinase 3; CBC, complete blood count; CMP, comprehensive metabolic panel; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; HIV, human immunodeficiency virus; CT, computed tomography; MRI, magnetic resonance imaging; FLAIR, fluid-attenuating inversion recovery; DWI, diffusion-weighted imaging; SWI, susceptibility-weighted imaging.

diagnosis and excluding other causes of the CNS abnormalities (**Box 1**). This section describes workup that can aid in the diagnosis of AAV with CNS involvement, and with special interest, pays extra attention to the value of ANCA testing in-between.

#### ANCA Serology

ANCA testing is strongly recommended for patients with clinical features suggestive of AAV (**Table 1**) (6, 62). Its value lies mainly in AAV screening, and when positive, warrants further investigations for confirmative diagnosis. Positivity of the test is highly suggestive of AAV but not diagnostic by itself (6). However, the combination of ANCA positivity and certain clinical features are sufficient for AAV diagnosis, according to the widely-used classification algorithm proposed by Watts (28). A negative ANCA immunoassay, which occurs in up to half of pathologically diagnosed GPA and MPA, does not exclude AAV (6, 63). The negativity may be related to the limited sensitivity of ANCA testing, especially at the early stage of disease without systemic involvement (7). The diagnosis of AAV cannot be excluded merely based on a negative ANCA test. Therefore, biopsy of the affected organ is required for seronegative patients (6).

Regarding the testing techniques of ANCA, the most recent consensus recommended high-quality antigen-specific immunoassays for MPO- and PR3- ANCAs detection (6). ELISAs are the preferred screening methodology with a high sensitivity and specificity. Indirect immunofluorescence (IIF) for cytoplasmic ANCA (C-ANCA) and perinuclear ANCA (P-ANCA) detection is no longer prioritized as the screening test, given its large variability and poor diagnostic accuracy (6). When necessary, performing another assay or testing with another different methodology can yield higher sensitivity and specificity (6). In cases of emergency such as pulmonary-renal syndrome, rapid screening assays for ANCAs, including dot blots and biochip technology, are also available (64).

Controversy remains in the role of ANCA levels in monitoring disease activity and prediction of prognosis (63). Published studies reveal inconsistent results regarding the role of ANCA levels in predicting clinical relapse and reflecting disease activity (65–67). A meta-analysis in 2012 concluded that both a rise in ANCA and persistently positive ANCA were strongly associated with disease relapse and had a modest predictive value (66). Furthermore, results from a recent single-center study indicated that the predictive value of ANCA was only significant in renalinvolved AAV, compared with those without renal involvement (68). Overall, current thinking holds that ANCA levels alone are helpful but not sufficient to determine relapse or reflect disease activity (6), and ANCA testing is not recommended to guide clinical decisions on treatment (61). Nevertheless, severe relapses are unlikely without elevated ANCA levels (69). The significance of serial monitoring remains to be proven.

### Other Laboratory Investigations

A diligent workup should be ordered for patients suspected of AAV, including complete blood count (CBC), complete metabolic profile (CMP), acute phase reactants, the autoimmune panel, the endocrine panel, the complement level and investigations for potential infections. For patients with endocrine dysfunction or abnormal pituitary on MRI, levels of pituitary hormones also need to be investigated. Laboratory tests typically show elevated markers of inflammation. Leukocytosis, thrombocytosis, normochromic normocytic anemia, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values are indicative of the diagnosis (3, 7). Kidney functions, including serum creatinine and urinalysis, are warranted for the evaluation of renal injury. Regarding the autoimmune panel, autoantibodies other than ANCAs can be present (63), including antinuclear antibodies, rheumatoid factors, IgG4, anti-glomerular basement membrane antibodies and antiphospholipid antibodies, with unknown significance (63). Lastly, for differential diagnosis, investigations for potential infections (tuberculosis, human immunodeficiency virus, hepatitis) and complement levels are also required.

### Cerebrospinal Fluid

Lumbar puncture is warranted for suspected patients as well. CSF analysis has a high sensitivity but low specificity in the diagnosis of AAV-related CNS disease. Most had mild lymphocytepredominant pleocytosis, elevated protein levels and normal glucose level (7, 25, 37). Therefore, a normal CSF analysis makes the diagnosis of AAV less likely. Infectious etiology and flow cytometry for atypical cancer cells should be tailored to clinical manifestations and risk factors.

### Pathology

Histopathology is the gold standard for diagnosis of small vessel vasculitis. Samples can be taken from affected organs, most commonly the kidney and the skin. Lung and nasal biopsies are rarely performed, limited by the high rate of false negatives. Brain biopsies can also be taken from corresponding structures including the dura, brain parenchyma and the overlying leptomeninges. Typically two types of pathological findings have been described: (1) necrotizing vasculitis affecting small to medium vessels; (2) granulomatosis with inflammatory cell infiltration (monocytes, plasma cells, eosinophils, and polymorphonuclear leukocytes) (41). Fibrinoid necrosis and edema were also detected in some cases. In patients of HP, fibrosis of the dura mater was always present as well (24, 41). A negative yield of biopsy, however, does not exclude the diagnosis of AAV due to its segmental nature of lesions.

### Differential Diagnosis

AAV must be distinguished from ANCA-positive conditions where ANCA does not exert a direct role in pathophysiology (**Box 2**). Multiple conditions other than AAV show an elevated titer of serum ANCAs. Nonetheless, ANCAs do not mediate a direct pathogenic role, but rather indicate a chronic immune response of neutrophil cell death most times (63). Compared with the mimics, a high level and affinity of ANCAs and clinical

features suggestive of AAV are important clues for the correct diagnosis (6).

Differential diagnosis can be further narrowed down to entities with both similar CNS manifestations and ANCA positivity. These mainly include systemic inflammatory diseases (IgG4 related-disease, rheumatoid arthritis, systemic lupus erythematosus, Bechet syndrome), infective diseases (tuberculosis, human immunodeficiency virus) and malignancies (lymphoma).

In particular, diagnosis of AAV can be especially difficult at an early stage with only CNS presentations and a seronegative ANCA test, which may be an under-recognized common occurrence (24). Characteristics and diagnostic criteria of this entity remain to be elucidated. Differential diagnosis is therefore protean, varying according to the specific CNS manifestation of the patient. We suggest a thorough investigation of systemic involvement to exclude alternative causes including infection and malignancy. In particular, A continued monitoring of ANCA testing may be useful for those with idiopathic hypertrophic pachymeningitis (24). Most importantly, biopsy of the lesion is highly recommended in such cases to confirm the diagnosis.

## TREATMENT

Treatment should be started in a timely manner for patients highly suspected of AAV, even in the absence of pathological evidence. Steroid is an essential part of therapy, with the addition of a well-chosen immunosuppressant critical to prevent relapses and achieve remission of CNS symptoms in the long run. The treatment algorithm is shown in **Figure 2**. There are two phases of treatment, namely remissioninduction and remission-maintenance. The choice of regimen in each phase depends mainly on the disease stage of the

patient, as per the European Renal Association—European Dialysis and Transplant Association (ERA-EDTA) management recommendations for AAV (61). Generally, CNS involvement is regarded as an organ-threatening manifestation in AAV, especially for those with meningeal inflammation or retro-orbital disease. Remission-induction treatment for organ-threatening AAV typically consists of high-dose glucocorticoids and oral or intravenous (IV) cyclophosphamide (CYC) (1), termed CYCbased therapy. Glucocorticoids usually start with the dose of 1g intravenous methylprednisolone on 3 consecutive days, followed with 1 mg/kg daily oral corticosteroids (up to 80 mg per day), and a gradual reduction to daily dose of 7.5 to 10 mg within 3– 5 months (7, 10). CYC can be given either intravenously in pulses or orally. The intravenous CYC, at a dose of 15 mg/kg (up to 1200 mg), are prescribed every 2 weeks initially and every 3 weeks from the 4th pulse. Daily oral CYC is given at a dose of 2 mg/kg/d. The CYC-based therapy is effective in 70-90% of patients (70), and the oral regimen can better prevent relapses (71). However, the daily oral regimen, compared with intravenous CYC, also poses more safety issues due to the cumulative toxicity (71, 72) including infertility, bladder hemorrhage, severe cytopenias, serious infection, and an increased risk of malignancy. Apart from the most recognized CYC-based therapy, the identification of the important role of B cells in the pathogenesis of AAV facilitated the use of rituximab (RTX) as an alternative to CYC (73). Two large randomized trials revealed RTX (375 mg/m2 , once a week for four infusions) to be equivalent to CYC in terms of efficacy and safety in remission induction for AAV among treatment-naïve patients, and likely superior for relapsing disease (74).

Once complete remission (absence of any disease activity, usually attained after 8–12 weeks of treatment) is achieved, patients should be started with maintenance therapy to prevent further relapses, which should be continued for at least 24 months (61). In the remission maintenance phase, the induction regimen is switched to a combination of low-dose glucocorticoids and an oral immunosuppressive agent such as azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or RTX (61). AZA (2 mg/kg/day) is the most commonly used immunosuppressive agent for remission maintenance, with MTX (20–25 mg/kg/week) as a similar alternative (72). AZA, with a lower relapse rate, is generally preferred over MMF. However, the relapse rate remains as high as 40% by 2 years despite the maintenance therapy with AZA or MTX (75). RTX is a potentially safer maintenance drug with a higher efficacy (76). However, the utility and toxicity profile of RTX require further confirmation (76–80). In addition, the adjunctive use of plasma exchange (PLEX) (7 sessions over 2 weeks) in AAV patients with severe renal dysfunction and/or alveolar hemorrhage seems reasonable in the short-term, but remains elusive in the long run (81).

Another issue to tackle in AAV is the treatment response. Refractory to remission-induction treatment is defined as follows: (1) unchanged or increased disease activity after 4 weeks of treatment (2) <50% reduction in the disease score [e.g., Birmingham Vasculitis Activity Score (BVAS)] after 6 weeks of treatment (3) Presence of at least one major or three minor items on the disease activity score after over 12 weeks of treatment (61, 82). For AAV patients refractory to therapy, reevaluation and optimization of treatment, in close collaboration with experts, are recommended (61). Adjunctive intravenous immunoglobulin may help for those with persistent low disease activity (61, 83). Furthermore, relapses are not uncommon in AAV. Major relapses with organ- or life-threatening conditions are treated as per new disease, while non-severe relapses should be managed with an escalation or modification of the previous immunosuppressive regimen (61).

## CONCLUSION AND FUTURE PERSPECTIVES

For neurologists, prompt diagnosis of AAV in patients with CNS presentations allows timely treatment and thus a dramatic improvement in prognosis. A myriad of CNS presentations including hypertrophic pachymeningitis, ischemic stroke, intracranial hemorrhage and pituitary dysfunction, combined

#### REFERENCES

with certain systemic symptoms, raise the suspicion of AAV. Further ancillary tests are required, among which ANCA testing yields a great diagnostic value. ANCA positivity strongly suggests the diagnosis of AAV but ANCA negativity does not rule out the diagnosis. Once diagnosed, early treatment with steroid and immunosuppressant is essential to prevent neurological relapses and sequelae.

Recent evidence suggests the presence of "CNS-limited AAV" as a distinct subset in AAV. Efforts to better elucidate its phenotypic features, optimal treatment and long-term outcome are an important focus of future research. Furthermore, accumulating studies suggest that PR3-ANCAs and MPO-ANCAs define distinctive conditions among patients with AAV. Whether the same rule applies to the neurological conditions in CNS-involved AAV, however, remains unknown. Continued attempts are needed to validate the utility of ANCA specificity in classifying CNS manifestations, guiding treatment decisions, and predicting prognosis.

## AUTHOR CONTRIBUTIONS

YZ: contributed to data collection, conception of the work and drafting the manuscript. YxZ: conception of the work and revising the manuscript. MC: revising the manuscript and figures. NL: revising the manuscript and tables. ZC and MD: revising the manuscript and final approval of the version to be published.

### FUNDING

This work was supported by the National Natural Science Foundation of China (grant numbers 81671283; 81872844).

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**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Zheng, Zhang, Cai, Lai, Chen and Ding. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# The Different Clinical Features Between Autoimmune and Infectious Status Epilepticus

Chih-Hsiang Lin1 , Yan-Ting Lu1 , Chen-Jui Ho1 , Fu-Yuan Shih2 and Meng-Han Tsai 1 \*

1 Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung, Taiwan, 2 Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung, Taiwan

Objective: The prognosis of status epilepticus (SE) is highly related to the underlying etiology. Inflammation of the central nervous system (CNS), including infection and autoimmune encephalitis, is one of the treatable conditions causing SE. The initial presentation of infectious and autoimmune CNS disorders can be quite similar, which may be difficult to differentiate at the beginning. However, treatment for these entities can be quite different. In this study, we aim to identify the differences in clinical features among patients with infectious and autoimmune SE, which could help the clinicians to select initial investigation and ensuing therapies that may improve overall outcomes.

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