Patrick Kwan, Monash University, Australia

#### Reviewed by:

Sonja Hochmeister, Medical University of Graz, Austria Adam Strzelczyk, Universitätsklinikum Frankfurt, Germany

> \*Correspondence: Meng-Han Tsai<EMAIL_ADDRESS>
#### Specialty section:

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

Received: 11 July 2018 Accepted: 09 January 2019 Published: 13 February 2019

#### Citation:

Lin C-H, Lu Y-T, Ho C-J, Shih F-Y and Tsai M-H (2019) The Different Clinical Features Between Autoimmune and Infectious Status Epilepticus. Front. Neurol. 10:25. doi: 10.3389/fneur.2019.00025 Methods: This was a retrospective study that included 501 patients with SE within a period of 10.5-years. Patients with inflammatory etiology were collected and separated into infectious and autoimmune SE. The symptoms at onset, SE semiology, status epilepticus severity score, and END-IT score at admission, treatment for SE, and outcome (modified Rankin Scale) on discharge and last follow-up were recorded. Data on the first cerebrospinal fluid, electroencephalography, and magnetic resonance imaging were also collected.

Results: Forty-six (9.2%) of the 501 patients had SE with inflammatory etiology. Twenty-five (5%) patients were autoimmune SE and 21 (4.2%) were infectious SE. Patients with autoimmune SE have younger age and female predominance. As for clinical presentations, psychosis, non-convulsive SE, and super refractory SE were more common in patients with autoimmune SE. Nevertheless, the prognosis showed no difference between the two groups.

Conclusion: The different initial clinical presentations and patient characteristics may provide some clues about the underlying etiology of SE. When inflammatory etiology is suspected in patients with SE, younger age, female sex, psychosis, non-convulsive SE, and super refractory SE are clinical features that suggest an autoimmune etiology.

Keywords: status epilepticus, inflammatory, autoimmune, infection, autoantibody

## INTRODUCTION

Status epilepticus (SE) is a neurological emergency associated with significant morbidity and mortality that usually requires admission to an intensive care unit (1–3). The goal when treating SE is to terminate the clinical and electrographic seizure activities as soon as possible (4). Even though antiepileptic drugs (AEDs) can be used to control seizures (5), the prognosis of SE is highly related to age and the underlying etiology (6–8). To further improve outcomes, targeted management of the underlying causes may be required (4, 9).

Brain inflammation can also cause SE (10, 11), including central nervous system (CNS) infections and autoimmune encephalitis (12). These conditions can be treated and may result in significantly different outcomes (13–15). Altered mental status is the most common initial presentation of inflammatory SE (12). However, it is an ambiguous sign that provides little information on the underlying etiology. Currently available investigations could help in initial differential diagnosis but have some limitations. Laboratory tests such as bacterial or viral culture, polymerase chain reaction (PCR) for specific pathogens, or autoantibody testing may not be immediately available (13, 16) and the results may take a few days or weeks to return. Cerebrospinal fluid (CSF) studies are useful to confirm the diagnose of bacterial infections, but are less effective in distinguishing between viral infections and autoimmune processes (13, 17). Magnetic resonance imaging (MRI) can provide evidence of CNS inflammation, but not the underlying cause of the inflammation (18). Electroencephalography (EEG) may sometimes show patterns that suggest a specific diagnosis, such as extreme delta brush in patients with anti-N-methyl-Daspartate (NMDA) receptor encephalitis, but the findings are mostly non-specific (19).

Only two studies have specifically addressed the differences between infectious and autoimmune etiology. Spatola et al. were the first to report that patients with an infectious etiology were older in age and had a more severe clinical presentation at first encounter (20). Subsequently, Shin et al. found that patients with an autoimmune etiology were younger (11). Herein, we retrospectively reviewed our patients with SE and an inflammatory etiology over a 10.5-year period. We aimed to identify the presenting factors that may assist clinicians in differentiating the two entities earlier, which may lead to faster targeted treatment and better patient outcomes.

### MATERIALS AND METHODS

#### Study Design

We retrospectively reviewed the medical records of all patients with SE admitted to the Neurological Intensive Care Unit at Kaohsiung Chang Gung Memorial Hospital between January 2006 and July 2016. This study was approved by the Chang Gung Medical Foundation Institutional Review Board.

### Definitions and Criteria

SE was defined as 5 min or more of continuous clinical and/or electrographic seizure activity or recurrent seizure activity without recovery (returning to baseline) between seizures (21). Refractory SE was defined as SE not responded to first-line therapy (benzodiazepine) or second-line therapy and requiring general anesthesia (22). Super refractory SE was defined as SE continues 24 h or more after the onset of anesthesia, including those cases in which the SE recurs on the reduction or withdrawal of anesthesia (22). The semiology and etiology of SE were classified according to the International League Against Epilepsy Task Force report (23).

Inflammatory SE was defined as SE due to acute inflammation of the brain parenchyma, with or without the involvement of the meninges (12), and further divided into SE due to CNS infection and autoimmune SE. Autoimmune SE included autoimmune encephalitis and systemic autoimmune disorders causing SE (23). Patients with an identified etiology for SE such as cerebrovascular disease, intracranial tumor, head trauma, metabolic disturbance, alcohol-related, AED withdrawal, neurodegenerative disease, mitochondrial disease, and medically refractory epilepsy were excluded. Patients with an unknown etiology and those without CSF data were also excluded from this study.

Autoimmune SE was defined as suggested by previous experts' consensus (16):

	- New focal CNS findings
	- Seizures not explained by a previously known seizure disorder
	- CSF pleocytosis (white blood cell count of more than five cells per mm3)
	- MRI features suggestive of encephalitis

SE patients who had positive neuronal surface auto-antibodies testing (EUROIMMUN, Autoimmune Encephalitis Mosaic 6 assay, Germany) in serum or CSF were also considered as autoimmune SE.

Infectious SE was diagnosed if microbiologic studies demonstrated an infectious agent. Those without evidence of microbiologic studies would have to fulfill one of the underlying criteria (20): (1) fever>38.5◦C, (2) increased white blood cell count or C-reactive protein, (3) findings highly suggestive of a bacterial infection, such as turbid CSF, neutrophilic pleocytosis, or low CSF to serum glucose ratio (<0.5), or (4) clinical picture suggestive of a viral origin plus lymphocytic pleocytosis on CSF study with positive PCR result or serology test shows a 4-fold increase of viral antibodies 3 weeks after the onset of illness (24).

Clinical information was recorded using a standardized evaluation form, including the symptoms at onset, SE semiology and classification, status epilepticus severity score (STESS) (25) and the END-IT score (26) at admission, treatment for SE, and outcome at discharge and last follow-up. A STESS score ≥3 (25) or an END-IT score ≥3 (26) suggested a poor outcome. Data on the first acquired CSF, EEG, and MRI studies were collected. The EEG was described according to

the 2012 American Clinical Neurophysiology Society's (ACNS) Standardized Critical Care EEG Terminology (27), which we categorized into background slowing activity, sporadic epileptiform discharge, periodic discharge, and electrographic seizures (11). MRI findings including the location and symmetry of signal changes on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) were recorded (10). Clinical outcomes at discharge and the last follow-up were graded using the modified Rankin Scale (mRS). A good outcome was defined as an mRS score <3 and a poor outcome was defined as an mRS score ≧3.

### Statistical Analysis

Statistical analyses were performed using the IBM SPSS Statistics for Windows (version 22; IBM Corp., Armonk, NY, United States). To compare demographic data between infectious and autoimmune groups, categorical variables were assessed using Chi-square or Fisher exact tests, and continuous variables were compared using the Mann-Whitney U-test. p < 0.05 was considered as statistically significant.

## RESULTS

During the 10.5-year study period (January 2006–June 2016), 501 patients with SE were reviewed, of whom 46 (9.2%) had an inflammatory etiology, including 25 females (54.3%) and 21 males (45.7%). Of the excluded patients, 237 had cerebrovascular disease, 77 had metabolic disturbances, 43 had head trauma, 39 had intracranial tumors, 11 had AED withdrawal, 11 had alcohol-related SE, three had neurodegenerative diseases, two had mitochondrial diseases, and three had medically refractory epilepsy. Of the three patients with medically refractory epilepsy, two had Dravet syndrome and one had focal cortical dysplasia. Patients without CSF data (n = 21) and those with an unknown etiology (n = 8) were also excluded (**Figure 1**).

The clinical characteristics of the 46 patients with inflammatory SE are presented in **Table 1**. Among the 46 patients, 25 (54.3%) had autoimmune SE, and 21 (45.7%) had infectious SE. In the patients with autoimmune SE, five were related to anti-NMDA receptor encephalitis, four were related to Hashimoto encephalopathy, one was related to CNS lupus, one was related to anti-collapsin response mediator protein 5 encephalitis, and 14 were diagnosed according to the criteria of autoimmune encephalitis (16). Of these 14 patients, five had received cell-based anti-neuronal antibody assays with negative results. The remaining nine patients did not receive anti-neuronal auto-antibody tests as the test was not available at the time of diagnosis. With regards to the patients with infectious SE, six had bacterial infections, 12 had viral infections, two had cryptococcal meningitis, and one had Creutzfeldt-Jakob disease.

The clinical features of infectious and autoimmune SE are compared in **Table 2**. The median age at onset of the patients with autoimmune SE was younger than that of the patients with infectious SE (32 vs. 56, p = 0.015), and more of the patients with autoimmune SE were female compared to those with infectious SE (68.0 vs. 38.1%, p = 0.043). The initial presentation of both groups was similar, including the STESS and END-IT score at admission, onset symptoms, and latency of seizures after the initial symptoms. Psychosis was the presenting symptom only in the autoimmune SE group (24.0 vs. 0.0%, p = 0.025) and non-convulsive SE was more prevalent among the patients with autoimmune SE compared to those with infectious SE (32.0 vs. 4.8%, p = 0.027). Refractory SE occurred more commonly in the autoimmune SE than in the infectious SE group, but the difference was not statistically significant (88.0 vs. 66.7%, p = 0.081). Super refractory SE was more common in the autoimmune SE group than in the infectious SE group (41.3 vs. 19.0%, p = 0.007). The number of AEDs used was similar between both groups, but the use of general anesthesia was more common in the autoimmune SE group than in the infectious SE group (64.0 vs. 23.8%, p = 0.006). However, the duration of admission or ICU stay, mRS score at discharge, and mortality rate during admission were similar between the two groups. The sensitivity and specificity for STESS to predict the outcome at discharge were 70.6 and 44.8%, respectively, compared to 68.8 and 45.5% at last follow-up. The sensitivity and specificity for the END-IT score to predict the outcome at discharge were 9.4 and 100.0%, respectively, compared to 21.4 and 100.0% at last follow-up.

The results of CSF and EEG are presented in **Table 3** and the MRI findings are summarized in **Table 4**. Patients with infectious SE had a higher median CSF protein level (93.0 mg/dL vs. 34.8 mg/dL, p = 0.014), higher median white blood cell count (20 vs. 3 cell/mm3 , p = 0.011), higher percentage of neutrophilic predominance (52.9 vs. 15.4%, p = 0.034), and higher percentage of low CSF/blood glucose ratio (56.3 vs. 24.0%, p = 0.036) compared to the patients with autoimmune SE, who had a higher percentage of lymphocytic predominance (84.6 vs. 47.1%, p = 0.034). There was no significant difference in IgG index between the two groups. The autoimmune SE group tended to have a higher rate of background slowing activity in the first EEG, but the difference between autoimmune and infection was not statistically different (56.0 vs. 28.6%, p = 0.081). The presence of sporadic epileptiform discharge, periodic discharge, or electrographic seizure was similar among the two groups in the first EEG study. With regards to the first MRI findings, an abnormal FLAIR signal was observed in 11 patients with autoimmune SE and eight patients with infectious SE. A restricted diffusion signal on DWI was found in 14 patients with autoimmune SE and 10 patients with infectious SE. However, there were no significant differences in abnormalities in the FLAIR and DWI signals between the two groups. Detailed descriptions of the locations of the abnormal signals on FLAIR and DWI are presented in **Table 4**.

#### DISCUSSION

Inflammatory SE is a previously under-recognized subgroup of SE. In the current study, 9.2% of all cases of SE were related to an inflammatory etiology, which is in accordance with previous studies (range from 6 to 12.8%) (11, 20). Inflammatory SE has two main etiologies, infectious, and autoimmune SE, which is at times difficult to differentiate at the initial presentation. We found that younger age, female sex, the presence of psychosis, nonconvulsive SE, lymphocytic predominance in CSF were more commonly observed in the patients with autoimmune SE, while a high CSF total protein level, pleocytosis, and reduced glucose ratio were more common in those with infectious SE. EEG and MRI are important tools to confirm the diagnosis of SE and exclude structural lesions (19, 28), but were not particularly helpful in the current study.

TABLE 1 | Demographic data of inflammatory SE patients.

Continuous variables were presented as median (interquartile range)

Categorical variables were presented as n (%).

AED, antiepileptic drug; ICU, intensive care unit; mRS, modified Rankin Scale; SE, status epilepticus; STESS, status epilepticus severity score.

Among all patients with SE, infection accounted for 4.2% and autoimmune accounted for 5%. This suggests that autoimmune SE is as common as infectious SE (20, 29), and therefore clinical features that can distinguish the two entities are important for intensive care physicians who care for patients with SE. We observed some differences in the presenting features of those with autoimmune and infectious SE. The age at onset was younger in the patients with autoimmune SE, which has also been reported in two previous studies (11, 20). Female predominance was also observed in the autoimmune SE group in this study, which is in accordance with previous reports that reported females predominance in autoimmune encephalitis and systemic autoimmune disorders (14, 30, 31).

TABLE 2 | Comparison of the clinical features of autoimmune and infectious SE.

Continuous variables were presented as median (interquartile range).

Categorical variables were presented as n (%).

AED, antiepileptic drug; CI, confidence interval; ICU, intensive care unit; mRS, modified Rankin Scale; OR, odds ratio; SE, status epilepticus; STESS, status epilepticus severity score.

The onset symptoms of autoimmune SE can be various. Alteration in mental status is the cardinal symptom (12), but provides little information about the underlying etiology. In our patients, the presenting symptoms of inflammatory SE included fever, decreased consciousness, seizure, upper respiratory tract infection, headache, psychosis, fatigue, and cognitive decline. Of note, psychosis was present only in those with autoimmune SE and not in those with infectious SE. Other studies have also reported that psychosis is the dominant presenting symptom among patients with autoimmune encephalitis (14, 29, 32, 33). In addition, we found that more of the patients with autoimmune SE had non-convulsive SE compared to those with infectious SE, which was not reported in the two previous studies (11, 20). This may be due to the difficulty in recognizing non-convulsive SE clinically without EEG monitoring or because it was not specifically looked for. Super refractory SE was also more prevalent in the autoimmune SE group, which may be due to the difficulty in making a diagnosis and the ineffectiveness of traditional SE treatment to control seizure activity without immunotherapy (34). When non-convulsive SE or psychosis followed by SE occurs in patients with a young age and female sex, autoimmune SE should be considered.

CSF studies are an important tool to identify the cause of SE, however, such studies can be challenging clinically. Neutrophilic predominant pleocytosis usually points toward a bacterial infection or the early stage of viral encephalitis, especially in the first 24 to 48 hours (24). Lymphocytic predominant pleocytosis was associated with autoimmune SE in our study,

TABLE 3 | The findings of the first cerebrospinal fluid (CSF) and electroencephalography (EEG) studies.

Continuous variables were presented as median (interquartile range).

Categorical variables were presented as n (%).

CI, confidence interval; OR, odds ratio; SE, status epilepticus; WBC, white blood cell.

a The CSF/blood glucose ratio was available in 16 patients with infectious and all patients with autoimmune etiology.

b The IgG index was available in six patients with infectious and 20 patients with autoimmune etiology.

but it was also often seen in cases of viral encephalitis-related SE (17, 24). Intensive care physicians often face a dilemma over whether to use antiviral therapy or immunotherapy when the diagnosis is unclear. Other parameters of the CSF can aid in the differential diagnosis, as our data suggested that the patients with an infectious etiology usually had a higher CSF protein level, although prolonged SE itself may result in a milder elevation of lactate and/or total protein levels. This was also reported by Oyanguren et al. who found similar white blood cell count between patients with viral infections and autoimmune processes, but that the protein level was higher in those with a CNS viral infection (35). Therefore, a high protein level in patients with lymphocytic predominance pleocytosis may suggest a viral etiology.

MRI can aid in the search for the etiology of SE, but with limitations. Limbic encephalitis may present as an increased FLAIR/T2 signal or abnormal DWI in the medial temporal lobes (36–38), and it can be used in helping to make the diagnosis of autoimmune encephalitis (16). Prolonged SE itself can also cause similar changes to some viral infectious in MRI signal with DWI abnormalities in the hippocampus and pulvinar (39), particularly herpes simplex encephalitis (18). Furthermore, these MRI patterns may not be present in all types of autoimmune SE and one study reported that 60% of the MRI findings in patients with anti-NMDA encephalitis may have been normal (14). Our data showed that no specific MRI findings could differentiate autoimmune and infectious SE.

EEG is routinely used to evaluate patients with seizures or disturbed consciousness. Slow background activity was more dominant in autoimmune patients compared with other etiologies of seizure (40), although we found no statistical difference in EEG findings between the two groups. Our study showed that at an early stage of inflammatory SE, it remains difficult to differentiate the two entities using currently available para-clinical investigations. The early use of auto-antibody assays may be needed when autoimmune SE is suspected clinically.

We found that general anesthesia was more commonly used in the patients with autoimmune SE. This is in accordance with previous studies in which patients with autoimmune SE were less responsive to AEDs (11, 20, 30, 41). The reason why AEDs are less effective for autoimmune SE remains to be clarified, although it is well-known that the treatment of autoimmune SE requires prompt immunotherapy (14, 15), which may then reduce the use of general anesthesia.

The functional outcomes were similar in both infectious and autoimmune groups with a similar mRS score at discharge and similar mortality rate during admission. However, most of our patients had a poor outcome at discharge or last follow-up (63.0 and 65.2%, respectively). Our study showed that the predictive values of STESS and END-IT scores were not in the same direction. That is, STESS was more sensitive but END-IT was more specific in terms of predicting the outcomes at discharge. More studies may be needed to compare the use of these two scores. In addition to functional impairments, a recent study reported that patients also had substantial impairments in their quality of life after SE (42). Our patients with autoimmune SE had a mortality rate of 20%, which is similar to other studies ranging from 10 to 23% (20, 30, 43). A recent population-based study conducted in Germany reported a hospital mortality rate for all types of SE of 14.8% with a higher rate in those with refractory SE and super refractory SE (15.0 and 39.9%, respectively) (44). The higher mortality rate in patients with autoimmune etiology compared to those with all-cause SE may be related to the high percentage of super refractory SE among patients with an autoimmune etiology. This higher mortality rate compared to all-cause SE emphasize the need for rapid recognition of the condition and prompt treatment toward the underlying causes in addition to standard SE care.

#### TABLE 4 | The findings of magnetic resonance imaging study.

Categorical variables were presented as n (%).

CI, confidence interval; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; OR, odds ratio; SE, status epilepticus.

The limitations of this study are that it was conducted at a single hospital and that the design was retrospective. In addition, the study was started before the availability of recent autoimmune encephalitis screening tests and immunotherapies, which may have affected the outcomes.

In conclusion, we observed that patients with autoimmune SE had a younger age at onset, female predominance, and often presented with psychosis, super-refractory SE and nonconvulsive SE. The initial clinical investigations including EEG and MRI only provided limited information about the underlying etiology. CSF tests were helpful in diagnosing bacterial infectious-related SE but had difficulty in differentiating viral encephalitis and autoimmune SE. Since these two etiologies have different treatment strategies and the presenting symptoms are quite similar (12, 29), it is important to differentiate the two conditions as soon as possible. The patient characteristics and presenting features identified in our study may provide clinicians with some clues about the underlying etiology. Empiric treatment can be given based on these clinical clues while waiting for the results of more definitive diagnostic tests such as viral serology tests and neuronal surface auto-antibody screening.

### ETHICS STATEMENT

This study is approved by the Chang Gung Medical Foundation Institutional Review Board (IRB No.: 103-3665B and 201800677B0).

#### AUTHOR CONTRIBUTIONS

All authors have read and approved the final manuscript. C-HL contributed to clinical data analysis and draft of the manuscript. Y-TL, C-JH, and F-YS had contributions to clinical data acquisition and analysis. M-HT had substantial contributions to the conception and design of the study, data analysis, critical revision, and final approval of the manuscript.

#### FUNDING

This work was supported in part by research grant CMRPG8G0131 to C-HL from Kaohsiung Chang Gung Memorial Hospital, Taiwan.

#### REFERENCES

multicenter, longitudinal, matched case-control analysis from Germany. Front Neurol. (2017) 8:507. doi: 10.3389/fneur.2017.00507

**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 Lin, Lu, Ho, Shih and Tsai. 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.

# Application of Plasma Exchange in Steroid-Responsive Encephalopathy

Yuting Jiang1†, Xin Tian1†, Yixue Gu1 , Feng Li 1 and Xuefeng Wang1,2 \*

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

Plasma exchange has been widely used in autoimmune neurological diseases and is the standard treatment for myasthenia gravis crisis and Guillain-Barre syndrome. A growing body of research suggests that, in the clinical application of steroid-responsive encephalopathy, such as for Hashimoto's encephalopathy, limbic encephalitis, systemic lupus erythematosus encephalopathy, ANCA-associated vasculitis encephalopathy, and acute disseminated encephalomyelitis, 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. Additionally, plasma exchange can also be used alone or in combination with steroids, immunoglobulins, or other immunosuppressive agents to treat steroid-responsive encephalopathy. This paper reviews the clinical application of plasma exchange in steroid-responsive encephalopathy, including its indications, onset time, course, curative effects, and side effects.

#### Keywords: plasma exchange, steroid, clinical practice, course, onset time, side effects

## INTRODUCTION

Plasma exchange is also known as therapeutic plasma exchange (1). The seventh special issue of the Therapeutic Apheresis in Clinical Practice treatment guidelines, published in 2016 by the American Society for Apheresis, defines plasma exchange as a therapeutic procedure in which the patient's blood is separated into plasma and other blood components by medical devices, and then the plasma is removed and replaced by a replacement solution such as a colloidal solution (albumin and/or plasma) or a combination of crystal/colloidal solutions, thus eliminating or reducing unwanted substances (2). Castillo et al. (3) considered encephalopathy to be accompanied by cognitive impairment and one or more of the following: (i) neuropsychiatric symptoms (hallucinations or delusions and paranoia); (ii) myoclonus; (iii) seizure; and/or (iv) focal neurologic deficits. Steroid responsiveness refers to the complete or nearly complete return to normal neurological baseline status after steroid treatment, while steroid unresponsiveness refers to lack of improvement after at least 4–6 weeks of a sufficient dose of steroids (4). In this paper, steroidresponsive encephalopathy is a general term used to describe diseases characterized by diffuse brain injury and their responsiveness to steroids. These diseases include Hashimoto's encephalopathy, limbic encephalitis, systemic lupus erythematosus encephalopathy, ANCA-associated vasculitis encephalopathy, and acute disseminated encephalomyelitis. Plasma exchange is a rapid-onset, safe, and effective option for patients with steroid-responsive encephalopathy who fail to

#### Edited by:

*Fabienne Brilot, University of Sydney, Australia*

#### Reviewed by:

*Ludger Tebartz Van Elst, Freiburg University Medical Center, Germany Demet Demirkol, Istanbul University, Turkey*

> \*Correspondence: *Xuefeng Wang*

> ><EMAIL_ADDRESS>
*†These author 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: *10 October 2018* Accepted: *07 February 2019* Published: *27 February 2019*

#### Citation:

*Jiang Y, Tian X, Gu Y, Li F and Wang X (2019) Application of Plasma Exchange in Steroid-Responsive Encephalopathy. Front. Immunol. 10:324. doi: 10.3389/fimmu.2019.00324*

**47**

respond to steroids in the short term or for patients who are unable to tolerate the side effects of steroid therapies. It can also be used as an initial treatment (see **Table 1**).

## HISTORY OF PLASMA EXCHANGE

Plasma exchange dates back to 1914. Able et al. (18) described the separation of cell components and plasma from the blood of dogs with uremia. The separated components were mixed with replacement solution and then returned to the subject. Regular plasma exchange began to be used in humans in 1952. Researchers found that repeated plasma exchange reduced the amount of pathological proteins in patients with multiple myeloma (19). In 1960, Schwab and Fahey (20) reported that plasma exchange in Waldenstrom's macroglobulin and hyperviscosity syndrome achieved good therapeutic effects. Therefore, plasma exchange became the standard treatment for Waldenstrom's macroglobulin. In the 1980s, studies reported that plasma exchange was an effective treatment for systemic lupus erythematosus encephalopathy and acute disseminated encephalomyelitis; thereafter, plasma exchange began to be used as a treatment for steroid-responsive encephalopathy (4, 21).

## UNKNOWN MECHANISMS OF PLASMA EXCHANGE OR POTENTIALLY INVOLVED MECHANISMS UNDER EXPLORATION

## Clearing Pathogenic Antibodies From Plasma

The mechanism of plasma exchange for treating systemic lupus erythematosus encephalopathy is the rapid removal of pathogenic autoantibodies such as anti-nuclear antibodies from the blood (22). Anti-neutrophil cytoplasmic antibodies (ANCAs) play an important role in the pathogenesis of ANCA-related vasculitis encephalopathy, and the clearance of pathogenic antibodies from blood by plasma exchange can improve the therapeutic effects (2). Plasma exchange can also effectively remove pathogenic antibodies and can be combined with immunotherapy to suppress the production of autoantibodies and effectively treat limbic encephalitis (23). The mechanism of plasma exchange for treating acute disseminated encephalomyelitis is the removal of autoantibodies (antibodies against myelin oligodendrocyte glycoprotein) as well as complement components and cytokines (4).

### Increasing the Susceptibility of Antibody-Producing Cells to Immunosuppressant and Chemotherapeutic Drugs

Plasma exchange can also induce proliferation of antibodyproducing cells and increase the synthetic ability of antibodies as well as the susceptibility of antibody-producing cells to immunosuppressive or chemotherapy drugs (23). Studies have reported that plasma exchange can increase the synthetic activity of B cells and increase the susceptibility of antibody-producing cells to immunosuppressive agents (24).

## Removing Immune Complexes From Plasma and Enhancing the Function of Macrophages and Monocytes

Plasma exchange can not only directly promote the removal of immune complexes from patients with systemic lupus erythematosus (22) but also upregulate red blood cell (RBC) complement receptors and increase the binding of RBC and immune complexes to remove immune complexes from the circulation. Steven et al. (25) studied the effect of plasma exchange on monocyte function and found that monocytes significantly increased their bactericidal effect by increasing the level of proteolytic enzymes in immune-complexmediated diseases.

## Removing Pathogenic Cytokines and Adhesion Molecules From Plasma

The concentration of soluble adhesion molecules ICAM-1 and VCAM-1 may be decreased after plasma exchange in patients with ANCA-associated vasculitis (26). Yeh et al. (27) found that double-filtration plasmapheresis can effectively remove IL-2, IL-4, IL-5, tumor necrosis factor alpha, and interferon gamma from the serum of patients.

## CLINICAL APPLICATION OF PLASMA EXCHANGE IN STEROID-RESPONSIVE ENCEPHALOPATHY

## Indications of Plasma Exchange for the Treatment of Steroid-Responsive Encephalopathy

Therapeutic plasma exchange is an established treatment method for known or suspected immune-mediated diseases (28). In 2016, the American Society for Apheresis published treatment guidelines for plasma exchange based on evidence-based medical research and proposed that Hashimoto's encephalopathy is a category II indication for plasma exchange and that the recommended level is 2C. Anti-N-methyl-D-aspartate receptor encephalitis is a category I indication, and the recommended level is 1C. Plasma exchange for the treatment of severe systemic lupus erythematosus, including systemic lupus erythematosus encephalopathy, is a category II indication, and the recommended level is 2C (2). Plasma exchange for the treatment of acute disseminated encephalomyelitis is a class II indication, and the recommended level is 2C (2) (See **Tables 2**, **3**).

## Volume, Interval Time, and Frequency of Plasma Exchange for the Treatment of Steroid-Responsive Encephalopathy

The efficacy of plasma exchange is often related to the volume of plasma exchanged, which is dependent on the estimated plasma volume of the patient. The formula for estimating the plasma volume of the patient uses the patient's weight and hematocrit: EPV=[0.065 × wt (kg)] × [1-Hct]. This formula provides a reliable prediction of the therapeutic effect in clinical

TABLE 1 | Case reports of plasma exchange for steroid-responsive

encephalopathy.

*(Continued)*

TABLE 1 |

Continued

TABLE 2 | Category of recommendation for plasma exchange ( 2).

applications. In general, macromolecular substances (immune globulin, lipoprotein cholesterol, cold globulin, etc.) inside and outside of blood vessels become slowly redistributed, achieving a gradual balance. Thus, clearance during a single treatment is limited. One is the concentration of substances in the blood vessels, while the other is the volume of plasma exchanged. Based on these two factors, the percentage of the decrease in pathogenic substances after treatment compared with the pretreatment level can be determined as follows: X 1 = X0 e - V e /EPV, where X 1 is the final plasma concentration, X0 e is the initial plasma concentration, V e is the volume of plasma exchange, and EPV is the estimated plasma volume of patients. If the volume of plasma exchange is equal to the patient's EPV, pretreatment values will drop by 63%, and if the volume of plasma exchange is equal to 1.4 times the EPV, pretreatment values will drop by 75%. However, in the process of a single exchange, the volume of plasma exchanged is further increased. As a result, the pretreatment level decreases less, and thus, the exchange volume would increase, subsequently increasing the duration of treatment and associated costs. For most indications of plasma exchange (including Hashimoto's encephalopathy, limbic encephalitis, systemic lupus erythematosus encephalopathy, ANCA-associated vasculitis encephalopathy, acute disseminated encephalomyelitis, etc.), the volume of plasma exchanged per treatment is 1–1.5 times the plasma volume (30). For a single plasma exchange treatment, this volume will not cause reductions in the overall load of the serum levels caused by partial rebound. Several consecutive plasma exchange sessions, separated by 24–48 h, can remove a substantial percentage of the total body burden. In general, if the rate of production is moderate, then at least five sessions within 7–10 days are required to remove 90% of the patient's initial overall load, and additional sessions will be needed if the production is rapid (30).

#### Curative Effects

Cook et al. (31) retrospectively analyzed plasma exchange for the treatment of 10 Hashimoto's encephalopathy cases and showed that 90% of the symptoms of Hashimoto's encephalopathy significantly improved after plasma exchange. Neuwelt (32 ) reported the use of plasma exchange in eight systemic lupus erythematosus encephalopathy patients who failed to respond to

cyclophosphamide, among whom six were completely relieved of their clinical symptoms. In 2010, a non-blinded prospective study by Wong et al. (33) included nine cases of limbic encephalitis with positive anti-VGKC antibody, and each patient underwent five plasma exchange sessions combined with steroid and immunoglobulin treatment. After treatment, the VGKC antibody titer of all patients returned to normal within 1–4 months. After 1–3 months, clinical and cognitive tests showed that memory function had improved. After 6–9 months, the swelling subsided, and the signal was recovered on brain MRI.

#### Adverse Reactions

Plasma exchange is a relatively safe treatment, mostly with reports of only mild side effects, of which the most common are hypotension, hypocalcemia, urticaria, bleeding (due to loss of platelets or clotting factors), and arrhythmia. These adverse reactions are mainly related to anticoagulants, the replacement fluid used, and central venous catheterization. The incidence of hypocalcemia is 1.5–9% and is related to citrate. The main symptoms include paresthesia, muscle spasm, and arrhythmia. In addition, acid-base imbalance can be induced by citrate. The use of albumin as a replacement fluid may lead to the consumption of clotting factors and immunoglobulin and thus increase the risk of bleeding and infection. Fresh frozen plasma used as a replacement solution may cause HIV and hepatitis virus infection (34). Adverse reactions associated with central venous catheterization include infection, sepsis, thrombosis, and pneumothorax. Hemolysis and hypotension may occur, but the incidence of serious side effects such as severe hypotension, acute pulmonary edema, myocardial infarction, and death is 1.6–22% (35). In 2007, the world plasma exchange registry reported that the incidence of side effects from plasma exchange was 5.7% and that no death occurred in 838 patients who underwent plasma exchange; a plasma exchange team in Canada analyzed 91,000 sessions of plasma exchange and found that the incidence of serious side effects caused by plasma exchange was 0.4%. In addition, blood transfusion-related side effects are more common when plasma is used as the replacement fluid (36). Basic-Jukic et al. (34) studied the side effects of plasma exchange in the treatment of neurological diseases, including 152 patients from January 1982 to December 2003, with a total of 4,857 plasma exchanges performed. The incidence of side effects was 4.74% (231/4857), and the side effects were mostly mild to moderate. In summary, a few studies have reported on the side effects of plasma exchange for steroid-responsive encephalopathy, the results indicate that plasma exchange may be a safe treatment for steroid-responsive encephalopathy.

## APPLICATION OF PLASMA EXCHANGE IN DIFFERENT TYPES OF STEROID-RESPONSIVE ENCEPHALOPATHY

#### Application of Plasma Exchange in Hashimoto's Encephalopathy

Hashimoto's encephalopathy (also known as autoimmune thyroiditis-related steroid-responsive encephalopathy) was first reported by the British scholar Brain in 1966. Hashimoto's encephalopathy is related to Hashimoto's thyroiditis, as antithyroid antibodies were found in serum. The patients' thyroid function can be classified as normal, hypothyroidism or hyperthyroidism (37, 38). The clinical manifestations mainly include two types: vasculitis type, mainly including recurrent stroke-like episodes, seizures, and mental abnormality, and diffuse progressive type, which manifests as cognitive dysfunction (including memory and language dysfunction) dementia, behavior change, confusion, mental derangement, and coma (5). The most common clinical manifestations are seizures, followed by psychiatric symptoms (39). Elevated levels of anti-thyroid peroxidase antibodies (anti-TPOAb) and/or anti-thyroglobulin antibodies (anti-TgAb) are important laboratory characteristics for the diagnosis of Hashimoto's encephalopathy; elevated antithyroid peroxidase antibody levels are most common and are observed in 86% of patients with Hashimoto's encephalopathy, while 48% of the patients with Hashimoto's encephalopathy have elevated anti-thyroglobulin antibody levels (6). Although the pathophysiological mechanism of Hashimoto's encephalopathy is still not clear, high concentrations of anti-thyroid antibodies and effective treatment with immunosuppressive agents both support the important role of autoimmune mechanisms in Hashimoto's encephalopathy (40), which is the theoretical basis of plasma exchange in the treatment of Hashimoto's encephalopathy. Although steroids are the first-line treatment for Hashimoto's encephalopathy (41), no randomized controlled trials have been performed, so the optimal dose and duration of steroids remain unclear. Steroid responsiveness is determined by the dose and administration method. Usually, intravenous methylprednisone (500–1,000 mg/d) is administered for 3–7 days, followed by oral prednisone 1–2 mg/kg/d for 6–8 weeks, and in most cases, clinical improvement is observed within the first 4–6 weeks of treatment (4). When patients are unable to tolerate the side effects of steroid or have no response to steroids in the short term, plasma exchange can be performed to improve treatment efficacy. Moreover, a few reports have demonstrated that plasma exchange can be used for the initial treatment (39).

#### History of Plasma Exchange as a Treatment for Hashimoto's Encephalopathy

In 2001, Boers and Colebatch (42) was the first to report that plasma exchange could effectively treat Hashimoto's encephalopathy that failed to respond to corticosteroids. The author reported a 47-year-old Uruguayan man who was treated for upper limb postural tremor and gait disorder. During hospitalization, the patient developed seizures, short-term memory impairment, visual hallucination, auditory hallucinations, and paranoid delusions. Electroencephalogram (EEG) showed diffuse slow wave activity but no epileptic discharge. Cerebrospinal fluid showed increased pressure and protein (1.06 g/l), but other cerebrospinal fluid examinations (including polymerase chain reaction of herpes simplex virus), brain magnetic resonance plain scan, and enhancement showed no abnormalities. Examinations for thyroid stimulating hormone (TSH) were normal, but the levels of microsomal antibodies and anti-thyroglobulin antibodies significantly increased, so the diagnosis of Hashimoto's encephalopathy was established after ruling out other causes. Intravenous methylprednisolone was initiated, but 4 weeks later, the patient still experienced tremor and difficulty eating and dressing himself, so four plasma exchange sessions were performed with the exchange of 1.5–2 times the estimated plasma volume per session. After the first plasma exchange, the patient's condition improved, and after the fourth plasma exchange, the patient was able to dress, eat, talk, and work independently; in addition, his antibody levels decreased. Afterward, the patient experienced two relapses, and the symptoms were relieved after plasma exchange. Multiple studies have subsequently supported this treatment (5, 6, 40, 43–45). Nieuwenhuis et al. (45) reported a 48-year-old patient with subacute Hashimoto's encephalopathy, and the main manifestations were rapid progressive dementia, visual hallucinations, and myoclonus. Plasma exchange was used as the initial treatment of Hashimoto's encephalopathy, and clinical symptoms relieved after the first plasma exchange.

#### Onset Time of Plasma Exchange for Hashimoto's Encephalopathy

Most of the cases in which plasma exchange used to treat Hashimoto's encephalopathy showed positive effects after the first plasma exchange. Clinical symptoms of Hashimoto's encephalopathy were found to be improved after the first plasma exchange in a report by Boers and Colebatch (42). In addition, Bektas et al. (43) reported one Hashimoto's encephalopathy in which the patient's status epilepticus was controlled after the first plasma exchange.

#### The Course of Plasma Exchange for Hashimoto's Encephalopathy

Most studies on plasma exchange for Hashimoto's encephalopathy lack a specific description of the number of plasma exchange sessions used. Nieuwenhuis et al. (45) used three sessions plasma exchange to treat Hashimoto's encephalopathy successfully. Bektas et al. (43) used nine sessions plasma exchange, while Nagpal and Pande (5) and Gul Mert et al. (6) reports that the number of plasma exchange sessions for the treatment of Hashimoto's encephalopathy should be five. These results are consistent with the American Society for Apheresis, which recommends a total of 3–9 sessions plasma exchange for Hashimoto's encephalopathy, with the most common number of plasma exchange being five and exchanges being performed once every other day. The volume of plasma exchanged per treatment should be 1–1.5 times the estimated plasma volume, and albumin should be used as the replacement solution (2, 5, 31, 45).

#### Clinical Practice of Plasma Exchange for Hashimoto's Encephalopathy

Hussain et al. (44) reported a case of 54-year-old woman with hypothyroidism who presented with progressive cognitive impairment, gait disturbance, and seizures; based on an antithyroid microsomal antibody titer of 1:1,600 and the presence of head abnormalities on MRI without other reasons for cognitive impairment, a definite diagnosis of Hashimoto's encephalopathy was made. The patient began oral prednisone at a dose of 60 mg/d, and her cognitive function, apraxia, and gait disorder improved, but memory impairment remained. Because the patient could not tolerate the side effects of prednisone, the dose was gradually reduced to 15 mg/d. As the patient's cognitive function and gait disorder worsened with the reduction in the dose of prednisone, plasma exchange was performed, with five sessions per course and two courses of plasma exchange at intervals of 5 months. Four weeks after the first course of treatment, the patient's cognitive function markedly improved, and anti-thyroid microsomal antibody levels were reduced to 1:400. Cognitive function began to decline a few months later, but after the patient underwent the second course of plasma exchange, cognitive function continuously improved. Pari et al. (40) reported a 19-year-old girl who had been in good health but experienced a seizure. One month later, she had difficulty finding words and understanding language, along with symptoms of confusion, and disorientation. Electroencephalogram showed a non-convulsive status epilepticus, with a slightly elevated number of cells in CSF, with normal glucose and protein levels. PCR analysis of herpes simplex virus, adenovirus and enterovirus in cerebrospinal fluid were all negative. Brain MRI was normal. An 18F-FDG PET on the left temporal lobe, insula, temporoparietal junction, the right side of the parietal lobe metabolism reduced, diagnosis of Hashimoto's encephalopathy, intravenous methylprednisolone 1 g/d for 8 days, but no obvious improvement was observed. Electroencephalogram improved after five plasma exchange sessions, antithyroglobulin antibody, and thyroid peroxidase antibody, respectively pretreatment of >1,000 IU/ml (normal <4.1 IU/ml), 519 IU/ml (normal for <5.6 IU/ml) dropped to 462 IU/ml, 30 IU/ml. Symptoms of difficulty finding words and understanding speech also improved. In most studies, steroids work within the first 4–6 weeks, while other studies have shown that the time to complete recovery may range from 4 months to 10 years (4). However, in this case, the course of steroids was shorter. If used for a longer duration, the effect may be more pronounced. The patient may be responsive to steroid treatment, but if the clinical symptoms are severe or worsen, plasma exchange can be used to quickly relieve these symptoms. Cook et al. (31) retrospectively analyzed a study on the treatment of Hashimoto's encephalopathy with plasma exchange in 10 cases and showed that 90% of patients had significantly improved symptoms after plasma exchange. Because plasma exchange alone or with other treatments have been used as the second-line treatment for Hashimoto's encephalopathy, in 2016, the American Society for Apheresis published treatment guidelines for plasma exchange and proposed that Hashimoto's encephalopathy is a category II indication of plasma exchange. Moreover, because only observational studies or case series have reported the efficacy of plasma exchange on Hashimoto's encephalopathy and randomized controlled studies are lacking, the recommended level is 2C (2). This study was supported by Simmons and Staley (the volume of plasma exchanged per treatment was 1.0 times the plasma volume) (7) and Endres et al. (8). In addition, Tran et al. (9) found that longterm plasma exchange can be used for maintenance treatment in patients with Hashimoto's encephalopathy accompanied by cerebellar ataxia.

#### Plasma Exchange in Combination With Other Drugs for Hashimoto's Encephalopathy

Plasma exchange is usually combined with steroid, immunoglobulin, and antiepileptic drugs as well as immunosuppressants to treat Hashimoto's encephalopathy (5, 39, 44). Bektas et al. (43) reported a 12-year-old patient with Hashimoto's encephalopathy that mainly manifested status epilepticus, but after the first plasma exchange, his status epilepticus was controlled; subsequently, prednisone combined with a total of nine sessions plasma exchange resulted in normal mental and neurological status in 2 months. Gul et al. (6) also reported two successful cases in which plasma exchange combined with steroid, intravenous immunoglobulin, and antiepileptic drugs to treat Hashimoto's encephalopathy.

However, at present, only case reports and case analyses have shown that plasma exchange is effective at treating Hashimoto's encephalopathy, and because plasma exchange was initiated after failure to respond to steroids or immunoglobulin therapy in most of the studies, we cannot completely rule out the delayed effects of steroids. Nevertheless, because of the narrow time window between clinical symptom improvement and plasma exchange, plasma exchange can be considered for the treatment of Hashimoto's encephalopathy when steroids are ineffective in the short term or when patients cannot tolerate the side effects of steroids, and a few studies have shown that plasma exchange is effective as an initial treatment for Hashimoto's encephalopathy.

#### Side Effects of Plasma Exchange for Hashimoto's Encephalopathy

Plasma exchange is a relatively safe and effective treatment. The application of plasma exchange for the treatment of Hashimoto's encephalopathy is rare, and few studies have evaluated the occurrence of side effects from plasma exchange in Hashimoto's encephalopathy patients. Hussain et al. (44) reported a 54-yearold patient with Hashimoto's encephalopathy treated with plasma exchange who developed a urinary tract infection.

## Application of Plasma Exchange for Limbic Encephalitis

Limbic encephalitis is a neuropsychiatric disease characterized by inflammation of the limbic system, including the hippocampus, amygdala, and less frequently the frontobasal and insular regions. The clinical manifestations are subacute onset of cognitive impairment (mainly short-term memory loss), epilepsy, and mental disorder (46, 47). Radja et al. (48) reported that 97% of VGKC-associated limbic encephalitis presented with memory impairment, 85% with seizures, and 33% with emotional change. Brain MRI may present edema or inflammation that occur selectively on unilateral or bilateral limbic systems, especially in the medial temporal region (49). Electroencephalogram usually shows focal or diffuse slow waves or epileptiform discharge (50), and cerebrospinal fluid usually shows lymphocytosis, slight protein elevation, oligoclonal band positivity, and an increase in the IgG index (51, 52). Limbic encephalitis can be divided into infectious and autoimmune limbic encephalitis according to the etiology. Infectious limbic encephalitis is usually caused by the direct invasion of the brain by pathogens such as herpes simplex virus, while autoimmune limbic encephalitis is caused by an autoimmune disorder and can be divided into paraneoplastic and non-paraneoplastic limbic encephalitis (50).

In 1968, Corsellis et al. (53) used the term "limbic encephalitis" for the first time to describe six patients characterized by progressive memory loss, confusion, and seizures. Of those patients, four had tumors, and three had bronchial carcinomas. An autopsy found that the limbic gray matter in all patients' temporal lobes exhibited inflammation and degeneration, indicating that there was a link between limbic encephalitis and tumors.  Since 1988, several studies have confirmed that patients with tumors outside the central nervous system but have neuropsychiatric symptoms have antitumor and brain tissue antibodies in their serum, including anti-Hu, anti-Yo, anti-CRMP5, anti-Ri, anti-Ma2, and anti-amphiphysin antibodies. Since 2000, studies have shown that some limbic encephalitis are detected antibodies against neuronal cell-surface antigens or antibodies against neuronal ion channels, including voltagegated potassium channels and ligand-gated ion channels and antibodies against VGKC, NMDA, and AMPA receptors, thus providing a therapeutic basis for plasma exchange (47, 50).

#### History of Plasma Exchange for the Treatment of Limbic Encephalitis

Buckley et al. (54) first reported that plasma exchange successfully treated a case of limbic encephalitis. The report described a 47 year-old female stylist with myasthenia gravis. Thymoma was removed 4 years after she was diagnosed with myasthenia gravis, and after her diagnosis of myasthenia gravis for 10 years, her symptoms of myasthenia gravis recurred, the following year, the patient exhibited significant short-term memory loss, irritability, disorientation, inattention, and slowed thinking. The doses of cyclophosphamide and prednisone were reduced, and the patient started using loxapine (fourth generation antipsychotic medication), but her mental status did not improve significantly. After 7 weeks, the patient was transferred to the intensive care unit due to myasthenia crisis, and the myasthenia gravis symptoms were relieved with increased immunosuppression, but her mental status still did not improve. Brain CT and MRI were normal, while cerebrospinal fluid cytology and PCR of herpes simplex virus were negative. The electroencephalogram showed nonspecific slow waves. In the first 10 years after the diagnosis of myasthenia gravis, the VGKC antibody was normal, and significantly increased (750 pM) after the onset of psychiatric symptoms, so the patient was diagnosed with anti-VGKC receptor limbic encephalitis. The myasthenia gravis symptoms and limbic system symptoms improved after six sessions of plasma exchange. Jaben and Winters (55) studied the treatment of five anti-VGKC antibody-related diseases with plasma exchange, of those, four were anti-VGKC antibodyrelated limbic encephalitis with the main clinical manifestations of memory impairment, seizures, and personality changes. All patients were given 1.0 times the plasma volume during each session every other day for a total of 5–6 sessions. Among these patients, three limbic encephalitis were treated with other immunosuppressive agents at the same time, and one significantly experienced symptom relief with plasma exchange alone. Although there have been a number of cases in which plasma exchange was used to treat limbic encephalitis, plasma exchange in combination with steroid and immunoglobulins have also been used to treat all types of limbic encephalitis. Steroid and immunoglobulin treatments are first-line therapy for limbic encephalitis whereas plasma exchange is not (56). Rather, it is implemented when steroid and immunoglobulin therapy has no obvious effect in the short term, alternatively, plasma exchange may be used in combination with steroid and immunoglobulin to treat limbic encephalitis.

#### Onset Time of Plasma Exchange for Limbic Encephalitis

At present, most studies that describe plasma exchange for limbic encephalitis lack a description of the onset time of plasma exchange. Schimme et al. (57) reported a 12-year-old girl with NMDA receptor encephalitis performed with eight sessions of plasma exchange over 13 days. The patient's clinical symptoms markedly improved after the second plasma exchange, and her ability to walk was partially recovered. This treatment schedule was consistent with the onset time of plasma exchange for anti-NMDA receptor encephalitis that was unresponsive to immunoglobulin (0.4 g/kg/d for 5 days) combined with methylprednisolone (1 g/d for 5 days) in the short term, as reported by Wang et al. (58) in 2015, consciousness was regained after the second plasma exchange. Mazzi et al. (11) reported a case of non-paraneoplastic limbic encephalitis with anti-GAD antibody, in which seizures were significantly reduced by the third plasma exchange. Rypulak et al. (59) reported a 23-year-old patient with NMDA receptor encephalitis who received plasma exchange, and after the third session, the patient's neurological symptoms significantly improved. The GCS score increased to 11 points from 6 points.

#### The Course of Plasma Exchange for Limbic Encephalitis

In the study of Batra et al. (10) and Jaben and Winters (55), the number of plasma exchange sessions used to treat limbic encephalitis ranged from 5 to 6. In 2016, the American Society for Apheresis recommended the use of plasma exchange once every other day to treat anti-NMDA receptor encephalitis, and the volume of plasma exchanged per session was 1–1.5 times the plasma volume. Albumin was used as the replacement fluid, and a total of 5–6 sessions were performed. For the treatment of paraneoplastic neuropathy (PNS), including paraneoplastic limbic encephalitis, plasma exchange is recommended once daily or every other day for a total of 5–6 sessions, and the volume of plasma exchanged per procedure should be 1–1.5 times the plasma volume (2).

#### Clinical Practice of Plasma Exchange for the Treatment of Limbic Encephalitis

Plasma exchange is initiated when steroid and immunoglobulin treatments fail to treat limbic encephalitis, alternatively, it can be combined with steroid and immunoglobulin treatments. Therefore, plasma exchange is usually not the first choice. However, at present, no randomized controlled trials have analyzed the therapeutic effect of plasma exchange on limbic encephalitis. In 2011, Markakis et al. (60) reported a case of a 48-year-old female who presented with mental disorders and disorientation 2 years before admission; the patient rapidly developed anterograde amnesia, irritability, hallucinations, refractory temporal lobe seizure, and obvious short-term memory loss in a few weeks. The enhanced T2 weighted sequence of brain MRI suggested bilateral temporal lobe swelling and revealed a high signal intensity in the medial temporal lobe. High concentrations of anti-GAD antibodies were found in serum and cerebrospinal fluid. A diagnosis of anti-GAD antibody-associated limbic encephalitis was established. After methylprednisolone (1 g/d for 5 days) failed, plasma exchange was initiated, each session involved the replacement of 1.2 times the plasma volume. After a total of seven sessions, the epilepsy was under control, but the patient's cognitive function did not improve. Subsequently, the patient underwent one plasma exchange session every 3 weeks along with oral prednisone (1 mg/kg, gradually reduced to 0.25 mg/kg, for at least 1 year). The seizures did not recur, and a simple intelligence test showed that language and visual memory improved, in addition, anti-GAD antibody levels were reduced at the 1-year follow-up. Mccarthy et al. (61) reported one case of a 32-year-old pregnant woman with anti-NMDA receptor encephalitis, in the first 2 weeks of pregnancy, a new symptom developed, continuous daily headache, and in the maternity clinic, the patient experienced a rapid onset of visual and auditory hallucinations, illusions, irritability, paranoid, delusional within 24 h. One week later, the patient lost consciousness, and seizures began to occur. Brain MRI was normal, EEG showed diffuse slow waves, and cerebrospinal fluid protein was elevated to 726 mg/l (normal is 150–450 mg/l). Steroids were initiated (methyl prednisolone 1 g/d for 5 days, then slowly reduced), but the patient became aggravated, and hence stayed in the intensive care unit. After plasma exchange (1.5 times the plasma volume per session), the patient's symptoms improved significantly, and after 8 weeks, the symptoms of encephalopathy were completely resolved. Van Ael et al. (62) used steroids to treat a 26-year-old woman with GAD antibody limbic encephalitis, but the treatment was unsuccessful. Plasma exchange was subsequently initiated, and marked improvements in clinical symptoms, including memory, seizures, and imaging findings were observed. At the 14-month follow-up, the level of GAD antibody, which was initially >7,000 IU, was decreased by plasma exchange to <1,000 IU. Moreover, several other studies have shown that plasma exchange is more effective than intravenous immunoglobulin and steroids for the treatment of limbic encephalitis, including in pregnant women (10, 12, 61, 63). Korff et al. (64) found that plasma exchange was the most effective at reducing antibody levels in limbic encephalitis.

#### Plasma Exchange in Combination With Other Drugs for the Treatment of Limbic Encephalitis

Plasma exchange is rarely used alone in the treatment of limbic encephalitis, but it is often used in combination with other immunomodulatory therapies such as steroids and/or immunoglobulin. Vincent et al. (65) analyzed the clinical features and treatment of 10 cases of anti-VGKC-antibody-associated limbic encephalitis. Among those cases, seven were treated with plasma exchange combined with steroids or immunoglobulin, and the results showed that four patients experienced a significant curative effect, two patients experienced a slight curative effect, and only one patient did not experience an effect. Desena et al. (66) analyzed the use of plasma exchange to treat 14 cases of anti-NMDA receptor encephalitis, including three adults, 10 patients began plasma exchange after failure to respond to steroids, and the results showed that 7/10 NMDA receptor encephalitis patients who underwent plasma exchange exhibited an average increase in the modified Rankin scale of 0.4, and 3/10 patients exhibited an average increase in the modified Rankin scale of 0.1 after treatment with steroids. The results indicated that plasma exchange combined with steroids was more effective than steroids alone for the treatment of anti-NMDA receptor encephalitis.

However, no randomized controlled trials have been performed to support the therapeutic effect of plasma exchange on limbic encephalitis, and plasma exchange is primarily initiated when the patient exhibits no response to steroid treatment in the short term (perhaps because steroid treatment requires a longer time period to elicit effects). Thus, the therapeutic effect of steroid treatment cannot be completely excluded, especially when it is combined with plasma exchange or immunoglobulin, so improvements in the patient's condition should not be attributed solely to plasma exchange. However, the patients receiving plasma exchange had better outcomes, and plasma exchange exhibited a time-dependent effect. The coincidence was small, and a few cases reported plasma exchange as the initial treatment of Hashimoto's encephalopathy. Therefore, plasma exchange may be considered when patients have contraindications to steroid treatment or slow onset time in the short term, but randomized controlled trials are needed for confirmation.

#### Side Effects of Plasma Exchange for Limbic Encephalitis

Suppiej et al. (67) analyzed the efficacy and side effects of plasma exchange for pediatric NMDA receptor encephalitis and showed two cases of transient hypotension that improved after rehydration therapy and blood vessel vasopressors, one case of allergic reaction and shock because of autonomic dysfunction, and one case of pulmonary embolism. Wong et al. (33) prospectively studied nine VGKC antibody-positive limbic encephalitis patients who underwent five sessions of plasma exchange with 50 ml/kg of plasma volume exchanged per session. Side effects associated with plasma exchange were observed in two patients: one had methicillin-resistant staphylococcus aureus septicemia and vertebral body inflammation, while the other had femoral artery puncture hematoma, deep vein thrombosis, and pulmonary embolism, which improved after treatment. Miyauchi et al. (68) reported an 11-year-old patient with anti-NMDA receptor encephalitis who developed hypotension shock ∼1 h after plasma exchange, but the patient's condition improved after rescue. Rypulak et al. (59) reported that hemodynamic instability and coagulation dysfunction occur after treatment of anti-NMDA receptor encephalitis with plasma exchange, and a prolonged interval between plasma exchange sessions can help prevent unwanted side effects. Therefore, the vital signs of patients, especially patients with anti-NMDA receptor encephalitis, should be closely monitored.

## Application of Plasma Exchange in Systemic Lupus Encephalopathy

Systemic lupus erythematosus encephalopathy, also known as neuropsychiatric systemic lupus erythematosus (NPSLE), is a common neurological complication of systemic lupus erythematosus (SLE) (69), patients with NPSLE present a variety of neuropsychological symptoms, including aseptic meningitis, cerebrovascular disease, demyelination, headaches, movement disorders, seizures, confusion, anxiety, cognitive decline, and mood disorders (70), and NPSLE is the main cause of disability and death in patients with systemic lupus erythematosus. The pathogenesis of neuropsychiatric lupus involves a variety of inflammatory factors, autoantibodies, vascular lesions caused by immune complexes, and neuronal dysfunction mediated by autoantibodies (71). For many years, steroids as the first-line drug for systemic lupus erythematosus encephalopathy, often intravenous methylprednisolone (1,000 mg for 3 d), and then oral prednisone (1 mg/kg/d) gradually tapered and stopped within 3–12 months, but long-term use of the steroid has obvious side effects. When SLE encephalopathy has contraindications to steroid, or steroid is not sufficient or ineffective in the short term, plasma exchange may be a rapid-onset, safe, and effective option (72). In 2016, the American Society for Apheresis (ASFA) recommended plasma exchange as a class II indication for severe SLE, including lupus encephalopathy, and the recommended level is 2C (2).

#### History of Plasma Exchange for Systemic Lupus Erythematosus Encephalopathy

In 1976, Jones et al. (71) treated eight SLE patients with plasma exchange and found that plasma exchange can reduce the level of immune complexes in SLE. In 1981, Evans et al. (21) reported a 44-year-old nurse who developed systemic lupus erythematosus encephalopathy 12 years after the diagnosis of SLE, the disease mainly manifests as schizophrenia-like psychosis, personality changes, mood changes, cognitive disorders, delusions, hallucinations, and irrational thoughts and behaviors. High doses of antipsychotic medications such as thiazine, chlorpromazine, and haloperidol combined with prednisone at 200 mg/day failed to treat the patient's mental symptoms. Immune complex levels were significantly increased in the blood and cerebrospinal fluid, and electroencephalograms showed irregular delta waves of 7–8 Hz per s, hence, four sessions of plasma exchange were performed after 35–38 days. An obvious improvement in the patient's mental status was observed 3 days after the fourth plasma exchange. Four weeks later, the dose of prednisone was reduced to 15 mg/d, and all the antipsychotic drugs were stopped at the same time, the patient's mental function and EEG performance gradually returned to normal, and the levels of immune complex and anti-neuronal antibody decreased correspondingly, indicating that plasma exchange can effectively treat lupus encephalopathy in patients with high levels of circulating immune complexes. In 1988, Unterweger et al. (73) reported a case of a 15-year-old girl with lupus encephalopathy. Three years after diagnosis of SLE, the patient manifested a severe depressive episode accompanied by suicidal ideation, disorientation, and delusional behavior, hence, steroids were initiated. After 7 days, the patient still had clinical manifestations of encephalopathy, mainly dementia, and delusions. The symptoms still did not significantly improve within 3 weeks of continued steroids. Therefore, plasma exchange was performed once every 2 days, with a total of five sessions performed over 10 days. The levels of circulating immune complexes decreased, antibody levels decreased, and the symptoms were relieved. Two weeks after the last plasma exchange session, the patient had recovered completely, and based on the results of psychological testing, the patient's attention and memory had returned to normal. Since then, studies have reported that plasma exchange can effectively treat systemic lupus encephalopathy (15, 69, 71, 74, 75). Plasma exchange has recently been reported to successfully treat one lupus encephalopathy case with catatonia as the main manifestation, avoiding the use of electroshock treatment (76). But no randomized controlled trials have confirmed the effect of plasma exchange on systemic lupus erythematosus encephalopathy.

#### The Course of Plasma Exchange for Systemic Lupus Erythematosus Encephalopathy

Kato et al. (77) reported three sessions of plasma exchange for the treatment of systemic lupus erythematosus encephalopathy, and Hussein et al (44) and Perisse et al (76) successfully treated systemic lupus encephalopathy using six sessions. Most studies reporting the use of plasma exchange for lupus encephalopathy lack a specific description of their methods. According to the reports on plasma exchange, for other immune mechanisms mediated neurological diseases, and according to studies reporting the plasma exchange clearance kinetics of immunoglobulin, it should be performed once daily or every other day, with the volume of plasma exchanged per procedure at 1–1.5 times the estimated plasma volume, and a total of 3–6 sessions of plasma exchange.

#### Clinical Practice of Plasma Exchange for the Treatment of Systemic Lupus Erythematosus Encephalopathy

Mild SLE encephalopathy needs only symptomatic treatment, but for severe SLE encephalopathy (disturbance of consciousness, seizures, severe depression, psychotic symptoms, etc.) and lupus encephalopathy in which steroids and cyclophosphamide have contraindications, high concentrations of immune complexes, and steroids have no obvious curative effect in the short term. Plasma exchange can treat lupus encephalopathy effectively, safely, and quickly (78–80). By removing pathogenic autoantibodies, immunoglobulin, immune complexes, and toxins, plasma exchange can also increase the function of regulatory T cells (23, 78). Kato et al. (77) reported a 48 year-old male with lupus encephalopathy that manifested as organic encephalopathy syndrome, specifically exhibiting mental behavior abnormalities, disorientation, memory, and intelligence impairments. Plasma exchange was performed after steroid treatment was deemed ineffective. After the first plasma exchange, the patient's consciousness improved, and their clinical symptoms were relieved. Subsequently, the steroid treatment was continued. Three days after the first plasma exchange session, a second plasma exchange session was conducted, the patient's disorientation was immediately alleviated. Quinter-Del-Rio AI et al. (79) studied a 14-year-old girl with SLE encephalopathy presenting with seizure, after steroid treatment failed, the clinical symptoms were significantly relieved with plasma exchange (1 session/d for 4 days). Gokhale et al. (69) reported three cases of lupus encephalopathy, two of which presented with status epilepticus. Plasma exchange combined with cyclophosphamide was initiated when steroid and cyclophosphamide treatment failed, and the clinical symptoms of all three patients were significantly relieved. Some scholars believe that the combination of synchronous plasma exchange and cyclophosphamide is effective for the treatment of SLE encephalopathy. Neuwelt (32) studied 26 patients who met the 1999 American Society of Rheumatology diagnostic criteria for lupus encephalopathy and treated them with plasma exchange with or without cyclophosphamide. Symptoms were relieved in 74% of patients. Euler et al (80) used plasma exchange and cyclophosphamide to treat 14 cases of severe SLE, of which 12 had complete remission of clinical symptoms within 6 years of follow-up after cessation of treatment.

SLE encephalopathy has various clinical manifestations, and its pathogenesis and pathophysiological mechanisms are still being explored. Although plasma exchange has been shown to be effective at treating SLE encephalopathy, there is a lack of randomized controlled trials to support the efficacy of plasma exchange. Thus, clinicians must weigh the pros and cons of the risk and costs, as well as other factors, to determine whether plasma exchange should be performed. In addition, large-sample, multicenter, randomized controlled trials are still needed to confirm the therapeutic effect of plasma exchange.

#### Side Effects of Plasma Exchange for the Treatment of Systemic Lupus Erythematosus Encephalopathy

Although plasma exchange does have a few side effects, potential life-threatening side effects are very rare, and their incidence is <0.15% (75). Bartolucci et al. (15) analyzed the side effects of plasma exchange as adjuvant treatment for lupus encephalopathy and found five cases: one case of transient hypocalcemia, one case of venous fistula of the indwelling venous catheter, one case of allergic skin reaction to albumin, and two cases of central venous catheter infection.

## Plasma Exchange for the Treatment of ANCA-associated Vasculitis Encephalopathy

ANCA-associated vasculitis includes granulomatosis with polyangiitis (GPA: formerly Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA: formerly Churg-Strauss syndrome), which is a group of systemic vasculitis characterized by oligovascular oligoimmune necrosis inflammation. ANCAs can be detected in the serum of most patients (81). ANCAassociated vasculitis can lead to systemic organ damage, mainly renal and lung, of which renal damage is more prevalent (70%) (81). However, the manifestations that cause central nervous system damage are not common, with an incidence of ∼5–15%. In addition, there is no significant difference in the incidence of each type of ANCA-related vasculitis-induced central nervous system damage. Usually, central nervous system damage is caused by cerebral or spinal vasculitis and granulomas, and the clinical manifestations are complex, ranging from headache to cognitive impairment, memory loss, epilepsy, disturbance of consciousness, paresthesia, etc. (81). Encephalopathy is not a disease, rather, it is a clinical syndrome that describes global brain dysfunction. Mental status alteration is the most typical manifestation, and changes in personality and/or behavior can indicate deterioration in cognitive functioning, a reduction in the level of consciousness, and specific localizing features of injury, such as seizures, ataxia, tremor, and other focal motor signs. There may also be systemic symptoms, such as headache, fever, vomiting, and loss of appetite. In summary, ANCA-associated vasculitis encephalopathy is a global brain dysfunction caused by ANCA-associated vasculitis (82).

Untreated ANCA-associated vasculitis usually leads to death, with a mortality rate as high as 90% in the natural course of 2 years, since the 1950s, when steroids became the basic treatment for ANCA-associated vasculitis, the five-year survival rate has increased to 48%, and after the 1980s, when steroids began to be combined with cyclophosphamide to treat ANCAassociated vasculitis, symptoms could be relieved in 80–90% of patients (83). Because ANCAs play an important role in the pathogenesis of disease, the use of plasma exchange to clear pathogenic antibodies from circulation, and increase the ability of the reticuloendothelial system to clear immune complexes can be combined with immunosuppressive agents for the treatment of severe ANCA-associated vasculitis (84), such as ANCA-associated vasculitis encephalopathy. However, due to the low incidence of ANCA-associated vasculitis encephalopathy, systematic studies on the treatment of ANCAassociated vasculitis encephalopathy by plasma exchange are lacking. There is currently no description of the specific dose and course of plasma exchange for ANCA-associated vasculitis encephalopathy. According to the reports on plasma exchange for other immune mechanisms mediating neurological diseases, it may be recommended once daily or every other day, with the volume of plasma exchanged per session at 1–1.5 times the estimated plasma volume, and a total of five sessions of plasma exchange should be performed.

#### Clinical Practice of Plasma Exchange for the Treatment of ANCA-associated Vasculitis Encephalopathy

The treatment of ANCA-associated vasculitic encephalopathy with plasma exchange is uncommon. In 2000, Deshpande et al. (85) reported a 15-year-old girl with renal failure who developed lethargy for 3 months and suffered from decreased appetite and vomiting in the week prior to admission. At 24 h after admission, renal biopsy showed that 29 of 43 glomeruli contained a mixture of fibrous crescents and cells. The patient was diagnosed with microscopic polyangiitis, and the patient was discharged after her condition improved. Three weeks after discharge, the patient had a severe headache and blurred vision, and blood pressure was 139/92 mmHg. Subsequently, the patient experienced three epileptic seizures, followed by a loss of consciousness, and irritability. Phenytoin and carbamazepine were used to control the seizures, and T2-weighted and T2 FLAIR sequences of brain MRI showed multiple increased signal intensities in the peripheral gray matter of the cerebral hemisphere, especially in the occipital cortex. Vasculitis caused widespread cerebral ischemia. EEG indicated changes consistent with encephalopathy. Headache, disturbance of consciousness, and blurred vision were relieved after the first plasma exchange session, the patient then underwent three sessions of plasma exchange, performed every other day, and after five consecutive plasma exchange sessions, cyclophosphamide was administered intravenously. After 2 months, the abnormal signals on brain MRI showed improvement. Nishio et al (86) reported reversible posterior leukoencephalopathy syndrome caused by vascular damage from Wegener's granulomatosis. A female with Wegener's granulomatosis presented severe headache, nausea, and seizures after severe intestinal complications. Blood pressure was 126/60 mmHg, brain CT showed low-density shadows in the bilateral posterior parietal and occipital lobes, and brain MRI showed high-intensity signals on the T2-weighted sequence in the bilateral occipital white matter, parietal lobe, and frontal lobe. Cerebrospinal fluid was normal. Thus, the diagnosis was reversible posterior white matter encephalopathy syndrome. Two courses of methylprednisolone combined with plasma exchange were administered, followed by intravenous cyclophosphamide at 400 mg/week. After 13 days, brain MRI showed that the abnormal signal had almost completely disappeared. The patient's consciousness and mental status also began to recover, and the concentration of PR3-ANCA antibodies decreased from 164 to 15.7 U/ml, and the intestinal symptoms were relieved. However, studies that treat ANCA-associated vasculitis encephalopathy with plasma exchange are very rare, so more studies are needed in the future to provide supporting evidence of the therapeutic effect of plasma exchange.

## Plasma Exchange for the Treatment of Acute Demyelinating Encephalomyelitis

Acute disseminated encephalomyelitis is an immune-mediated single-phase acute inflammatory demyelinating disease of the central nervous system, which mainly affects the white matter of the brain, brainstem and spinal cord (87). It is common in children and young adults, and most cases occur after viral or bacterial infections or within 2–4 weeks of vaccination (<5%) This disease can exhibit acute or subacute onset, with clinical manifestations of encephalopathy (disturbance of consciousness and behavior change) and multifocal neurological defects. In 2007, an international pediatric multiple sclerosis research group noted that encephalopathy not explained by fever is a necessary clinical manifestation of acute disseminated encephalomyelitis (87, 88), and in the prodromal stage, upper respiratory tract infection, and gastrointestinal symptoms are usually observed. The diagnosis is mainly based on clinical manifestations and imaging examination. Typical cerebrospinal fluid changes include increased pressure, increased lymphocytes, increased protein (usually <1.0 mg/l), and normal glucose. The gamma globulin and IgG levels in cerebrospinal fluid can increase, as can myelin basic protein, with a rare oligoclonal band. Electroencephalography examination presents a slow wave on imaging and is of great value in the diagnosis of acute disseminated encephalomyelitis, especially brain MRI, which can detect multiple or extensive white matter or deep gray matter lesions (thalamus and basal ganglia) within 5–14 days after the onset of symptoms (88, 89).

The pathogenesis of acute disseminated encephalomyelitis is not very clear. Cell-mediated immune dysfunction may play a main role. Humoral factors, including antibodies, complement, immune complex, and cytokines, also play an important role (78), so priority is given to immune modulators (90). No randomized controlled trials have been performed on children or adults to determine the best treatment for ADEM. Systemic intravenous large doses of corticoids are currently considered to be firstline therapy (89). Early intravenous methylprednisolone can shorten the course of the disease. Plasma exchange has been reported to be effective in the treatment of acute disseminated encephalomyelitis when the diagnosis of acute disseminated encephalomyelitis is delayed and cannot be early except for infectious diseases where steroid cannot be used, where there are contraindications to steroid, or where the effects of steroid are not obvious in the short term (90).

#### History of Plasma Exchange for the Treatment of Acute Disseminated Encephalomyelitis

In 1981, Newton et al. successfully treated the first case of acute disseminated encephalomyelitis caused by acute infection through plasma exchange alone (4). Subsequently, Cotter et al. (91) reported the case of a 22-year-old male with acute disseminated encephalomyelitis caused by mycoplasma pneumoniae infection. Eight days after onset, the patient improved after plasma exchange alone. Several studies have shown that plasma exchange can effectively treat acute disseminated encephalomyelitis. However, the current therapeutic effect of plasma exchange lacks the support of randomized controlled trials.

#### Onset Time of Plasma Exchange for the Treatment of Acute Disseminated Encephalomyelitis

Plasma exchange for the treatment of acute disseminated encephalomyelitis usually takes effect after the first plasma exchange (88). Kanter et al. (92) reported that plasma exchange for the treatment of two cases of acute disseminated encephalomyelitis, in which one improved neurological function within a few hours during the first plasma exchange. Shah et al. (93) noted, in their study of plasma exchange for the treatment of one acute disseminated encephalomyelitis, that the neurological deficit was improved after the first plasma exchange, which was supported by findings reported in the study by Yi et al. (94).

#### Course of Plasma Exchange for the Treatment of Acute Disseminated Encephalomyelitis

The course of plasma exchange for the treatment of acute disseminated encephalomyelitis has not been determined. Borras-Novell et al. (90) and Stricker et al. (95), in the study of plasma exchange for treating acute fulminant disseminated encephalomyelitis, included four cases of acute disseminated encephalomyelitis. The number of plasma exchange sessions was 3–10, predominantly 5, and plasma exchange was performed once daily with the volume of plasma exchanged per procedure set at one times the plasma volume, with 5% albumin used as replacement fluid, and all patients improved. Therefore, for the treatment of acute disseminated encephalomyelitis, 3–10 sessions are recommended, typically five, performed once a day or every other day, with the volume of plasma exchanged per sessions set at one times the plasma volume and albumin used as the replacement fluid.

#### Clinical Practice of Plasma Exchange in Acute Disseminated Encephalomyelitis

Miyazawa et al. (96) reported an eleven-year-old patient with acute disseminated encephalomyelitis. Brain MRI revealed extensive multiple high-intensity lesions in the white matter on T2-weighted imaging. Intravenous immunoglobulin (0.125 g/kg/d for 3 days) was administered after 10 days of illness, and 11 days after onset, oral prednisone was initiated at a dose of 60 mg/d, but the patient did not improve. Twelve days after onset, intravenous methylprednisolone was administered (1,000 mg/d) for 3 days. Fourteen days after onset, the patient became comatose, and spinal magnetic resonance T2 weighted images showed cervical segmental spinal cord swelling and abnormally high signal because of the patients' neurologic deterioration. At 17–20 days after onset, three plasma exchange sessions were started using 5% albumin as the replacement fluid. She regained full consciousness, and MRI improved. Lin et al. (97) described plasma exchange for the successful treatment of two cases of acute disseminated encephalomyelitis, including a 26-year-old woman who had a history of rubella vaccination, characterized by disturbance of consciousness, speech, ataxia, and myoclonus.  Initially, she received intravenous methylprednisolone (1,000 mg/d for 5 days and then 500 mg/d for 2 days) and then oral prednisone. However, her neurological function began to deteriorate, and one seizure occurred after 3 days of intravenous methylprednisolone. Five sessions of plasma exchange were initiated, with one session performed every 2 days, and 5% of albumin was used as the replacement fluid. Her symptoms were alleviated after the third plasma exchange. Another a 65-year-old patient presented with acute disseminated encephalomyelitis, unconsciousness, speech disorder, emotional dissonance, and slow movement. T2 weighted images of the brain magnetic resonance showed highintensity signals in the bilateral cerebral hemisphere, an elevated number of cells in the cerebrospinal fluid, normal glucose, and moderately elevated protein levels. She received five plasma exchange sessions (once every 2 days, with 5% albumin as the replacement fluid). After the fourth plasma exchange, her symptoms began to resolve.

Since most studies have shown that the standard dose of immunoglobulin for the treatment of acute disseminated encephalomyelitis is 0.4 g/kg/d for 5 days, steroids are usually administered intravenously at a dose of 20–30 mg/kg/d for (3–5 days), followed by oral prednisone at a dose of 1–2 mg/kg/d (87). Miyazawa and Lin et al reported that a poor response to intravenous immunoglobulin and steroids may be related to inadequate immunoglobulin and steroid dosing. Even so, the delayed effects of steroid and immunoglobulin treatments cannot be excluded as a component of symptom resolution because of the narrow time window between symptom improvement and plasma exchange, indicating that plasma exchange can effectively treat fulminant acute disseminated encephalomyelitis. In addition, Stricker et al. (95) reported four cases of acute disseminated encephalomyelitis due to delayed diagnosis and cannot exclude infection, which were significantly improved by plasma exchange alone. Keegan et al. (98) reviewed 59 cases of acute and severe central nervous system demyelination treated with plasma exchange at the Mayo clinic, including 10 patients with acute disseminated encephalomyelitis (ADEM), of whom 40% experienced symptom relief. Therefore, plasma exchange treatment for acute disseminated encephalomyelitis is effective, and few side effects have been reported. However, there is still a lack of support from randomized controlled studies.

#### REFERENCES

Other types of steroid-responsive encephalopathy are very rarely reported, including hypoglycemic encephalopathy (99) and steroid-responsive encephalopathy caused by cholesterol thrombosis (100), and currently, there are no reports on the effects of plasma exchange therapy on these types.

#### CONCLUSION

In conclusion, plasma exchange is a widely accepted treatment method for autoimmune neurological diseases because it is safe, rapid-onset, and effective. Plasma exchange may be effective for patients with steroid-responsive encephalopathy who do not respond to treatment with steroids in the short term or those who have contraindications for steroid treatment, including patients with Hashimoto's encephalopathy, limbic encephalitis, SLE encephalopathy, ANCA-associated vasculitis encephalopathy, or acute disseminated encephalomyelitis. The main limitation of this study is the lack of systematic treatments reported in the literature. The current data are almost entirely derived from case reports and case analyses. Moreover, plasma exchange is often applied in combination with steroids and other immunosuppressive agents, hence, no high-quality evidence is available to prove the efficacy of plasma exchange on steroidresponsive encephalopathy.

## AUTHOR CONTRIBUTIONS

YJ, XT, and XW provided the initial idea and outline of content for the manuscript. All authors contributed content and critically reviewed and edited the manuscript.

### FUNDING

This study was supported by the National Clinical Key Specialty Construction Foundation of China and the National Natural Science Foundation of China (Nos. 81471319, 81671301).

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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 Jiang, Tian, Gu, Li and Wang. 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.

# Neurological Involvement in Primary Systemic Vasculitis

#### Shanshan Zhang1 , Dongli Yuan2 and Ge Tan1 \*

1 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China, 2 The Institute of Medical Information, Chongqing Medical University, Chongqing, China

Primary systemic vasculitis can affect every structure in both the central and peripheral nervous system, causing varied neurological manifestations of neurological dysfunction. Early recognition of the underlying causes of the neurological symptoms can facilitate timely treatment and improve the prognosis. This review highlights the clinical manifestations of primary systemic vasculitis in the nervous system.

Keywords: primary systemic vasculitis, central nervous system, peripheral nervous system, neurological involvement, clinical manifestation

#### Edited by:

Patrick Kwan, Monash University, Australia

#### Reviewed by:

Ché Serguera, Institut National de la Santé et de la Recherche Médicale (INSERM), France Ulises Gomez-Pinedo, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Spain

> \*Correspondence: Ge Tan<EMAIL_ADDRESS>
#### Specialty section:

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

Received: 09 August 2018 Accepted: 09 April 2019 Published: 26 April 2019

#### Citation:

Zhang S, Yuan D and Tan G (2019) Neurological Involvement in Primary Systemic Vasculitis. Front. Neurol. 10:430. doi: 10.3389/fneur.2019.00430 INTRODUCTION

Primary systemic vasculitis (PSV) can be defined as a heterogeneous group of uncommon diseases characterized by blood vessel inflammation and necrosis. Unlike secondary systemic vasculitis, which usually results from infections, connective tissue diseases, neoplasms, and drugs, PSV is considered to occur with no identified etiology (1). Nevertheless, recent researches have demonstrated that PSV might be associated with farming (2), silica exposure (2, 3), solvent exposure and hydrocarbons (2, 4, 5), allergy and family history of atopy (2, 6). Despite of unknown causes, two mechanisms, deposition of immune complexes and cell-mediated immunity, were found to possibly participate in the pathophysiology of PSV by causing immunological inflammation and necrosis of the vessel wall (7). And according to the classification criteria revised in 1990 by The American College of Rheumatology (8) and in 1994 and 2012 by the Chapel Hill Consensus Conferences (9, 10), the classification of PSV is based primarily on the major size of the affected vessels, although these disease-affected arteries may have overlaps in diameter.

Many neurologists have limited knowledge of PSV because most of these patients are treated by rheumatologists. However, both the central nervous system (CNS) and peripheral nervous system (PNS) are major targets in PSV and may become involved in the earliest stages; thus, patients may be referred to a neurologist first. Since the clinical manifestations of PSV are often non-specific, the differential diagnosis may be challenging.

CNS damage was reported to occur in 24% of cases with PSV, commonly due to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and polyarteritis nodosa. The range of clinical expressions of PSV's CNS damage is relatively wide, including cerebrovascular manifestations such as hemorrhagic and ischemic stroke caused by intra/extra-cerebral vascular stenosis, aneurysm, and sinus venous thrombosis, meningeal and brain parenchymal involvement resulted from granulomatosis and perivasculitis, and encephalopathy due to cytokine damage.

Compared with the frequency of central vasculitic involvement, vasculitic peripheral neuropathies are more common and have been reported to occur in 37% of patients with PSV (11), and 25% of patients experience symptoms of peripheral neuropathy at initial presentation (12). Generally, vasculitic peripheral neuropathies result from the inflammation of precapillary arteries in the nerves, such as eosinophilic granulomatosis with polyangiitis (60–80% of patients),

**64**

polyarteritis nodosa (50–100% of patients), granulomatosis with polyangiitis (Wegener's granulomatosis, 13–26.6% of cases), cryoglobulinemia (70% of cases), and microscopic polyangiitis (6–18% of cases), usually presenting in a uniform pattern such as multiplex mononeuropathy (accounting for 59–85% of cases) and symmetric polyneuropathy (41% of cases) (11–13). Nerve conduction studies have revealed a much higher frequency of peripheral neurological involvement than that in clinical case series and studies. Asymptomatic vasculitic neuropathy was detected in 21 of 270 cases (7.8%) of biopsy-proven vasculitis (14).

In addition, the introduction of nerve sonography, singlephoton emission computed tomography (SPECT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), magnetic resonance spectroscopy (MRS), and apparent diffusion coefficient (ADC) have greatly improved the diagnostic rate and accuracy of vasculitic neuropathy.

#### SEARCH STRATEGY

We performed an advanced literature search in PubMed and EMBASE for the period January 1, 1990, through September 1, 2017, using as a search query "systemic vasculitis" "nervous system." Eligible studies were included according to the following criteria. Only human studies that were written in English were considered. All patients included in the studies were diagnosed according to the classification criteria defined by the American College of Rheumatology or the Chapel Hill Consensus Conference. Retrospective and prospective studies were included to determine the frequency of neurological manifestations. Case reports and case series were added in the reference list only when unusual features were described. Pediatric studies were excluded because the clinical features of children and newborns are different.

### LARGE-VESSEL VASCULITIS

Large vessels were defined as the aorta, vena cava, and their major branches. Large-vessel vasculitis is composed of Takayasu arteritis and giant cell arteritis.

#### Takayasu Arteritis

Takayasu arteritis (TA) is a rare type of primary chronic inflammatory disease, causing stenosis, occlusion and aneurysm of arteries. TA mainly affects large-caliber arteries such as the aorta and its major branches in patients younger than 40 years old (more than 90% of patients are younger than 40), with a female predominance (female to male ratio is 10:1), and is more common in Asians (1). Studies have shown that more than half of patients with TA show neurological manifestations (15, 16) that range from dizziness/headaches to ischemic or hemorrhagic stroke.

Dizziness and headache are the most common complaints in patients with TA with neurological complications, accounting for ∼78.1% (214/274) and 25.5% (70/274), respectively (16). However, headache and dizziness do not necessarily indicate CNS involvement. Visual disturbances affect 4.6–59.3% of patients, and 4–21.9% of TA patients with neurological manifestations were found to have syncope as the main manifestation.

Cerebrovascular complications have always been the focus of researchers. Transient ischemic attack accounts for 3–22.2% of the nervous system manifestations caused by TA. Stroke, as the most severe complication of TA, was found to occur in 10–20% of cases (16–18). Due to lack of knowledgement, the median and average delay between symptom onset and the diagnosis of TA are 2 years (19) and 52.4 months (16), respectively, which delays the treatment of vasculitis. The majority of the strokes caused by TA are ischemic strokes, mostly due to multiple and severe stenosis or occlusive lesions in the aortic arch and its major branches. Couture and colleagues (19) evaluated the impact of stroke on the prognosis of TA patients, and after a median of seven years of follow-up, 59% of the patients had neurological deficits, 35% suffered from stroke recurrence and 24% had epilepsy. However, cerebral aneurysms and subarachnoid hemorrhage are rarely observed in TA patients. The incidence of aneurysm in TA patients is no higher than that in the general population. However, when such incidents occur, aneurysms in TA patients have a high rate of multiplicity and commonly occur in the vertebrobasilar arterial system (20). Posterior reversible encephalopathy syndrome (PRES) is an uncommon neurological complication in TA patients, mainly affecting women under the age of 30, presenting as headache, epilepsy, and neurological deficits in most patients. The pathophysiological mechanism has been suggested to be both endothelial injury and hypertension caused by TA, and the use of immunosuppressants such as cyclosporine and tacrolimus may also be a factor in the development of PRES since they can also induce endothelial dysfunction (21).

In addition, rare complications such as Horner's syndrome and intracranial granulomatosis have been reported as initial manifestations of TA. Other unusual neurological manifestations of TA that have been reported include brachial plexus palsy due to axillary artery aneurysm, unilateral sensorineural hearing loss, subclavian stealing syndrome, Moya-Moya syndrome, multiple cranial nerve palsies, cavernous sinus syndrome, and hypertrophic pachymeningitis.

## Giant Cell Arteritis

Giant cell arteritis (GCA) is the most common large vasculitis in Western countries and mainly affects extracranial branches of the carotid artery and/or the aorta and its large arterial branches, usually affecting people over the age of 50 (22).

Neuro-ophthalmological manifestation is the most frequent and serious event among neurological complications of GCA, accounting for 20–28.8% of affected patients (23, 24), with 15% of them suffering from permanent visual loss (25). Visual symptoms may be caused by ischemic optic neuropathy and retinal ischemia, among which anterior ischemic optic neuropathy accounts for the largest proportion.

Cerebrovascular disease is another severe neurological manifestation, occurring in ∼5% of all GCA-related neurological complications. According to recent studies, the risk ratio of cerebrovascular accident in patients with GCA vs. non-GCA comparators was 1.40 (26), and the risk of cerebrovascular complications was higher during the first year (or month) after GCA diagnosis (27, 28), which means that cerebrovascular events often occur during the active period of the disease. Epidemiological study shows that stroke is observed in 1– 3% of patients (25), among which cerebral infarction is the most common (58%), followed by subarachnoid hemorrhage (24%), and cerebral hemorrhage (18%) (29). The main reasons are considered to be, on the one hand, ischemia or occlusion caused by direct involvement of carotid and vertebrobasilar arteries and, on the other hand, atherosclerotic changes of the vessels caused by chronic inflammation. The incidence of vertebrobasilar artery vascular accident in patients with GCA (35%) has been shown to be higher than that of the general population (which is usually <15%) (27, 28), and one study showed that audiovestibular dysfunction is not uncommon in GCA patients (30). It is interesting to note that in a retrospective study (25), researchers found that most GCA patients who experienced a vertebrobasilar stroke had neurological symptom onset after the start of corticosteroid treatment. However, it is still being debated whether this situation is due to a direct effect of vasculitis or vascular occlusion promoted by the effects of corticosteroids.

Peripheral nervous system involvement was found in 1– 14% of GCA patients, presenting as cranial neuropathies, multiple mononeuropathy, or polyneuropathies (24); existing case reports include multiple cranial nerve palsy, trigeminal autonomic cephalalgia, occipital neuralgia, Horner syndrome, peroneal nerve palsy, cervical radiculopathy, brachial plexopathy, hypertrophic pachymeningitis, and cavernous sinus syndrome.

#### MEDIUM-VESSEL VASCULITIS

Medium vessels refer to the main visceral arteries and veins and their initial branches. Medium-vessel vasculitis consists of polyarteritis nodosa and Kawasaki disease.

### Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a rare systemic necrotizing vasculitis mainly involving medium and small vessels, causing microaneurysm, stenosis, and thrombosis, therefore leading to ischemia or hemorrhage of the supplied tissues. PAN affects women more often than men, usually with an onset between 40 and 50 years of age (31). The condition may affect any organ; however, the most frequently affected organs are the peripheral nerves, followed by muscles, joints, kidneys, skin, gastrointestinal tract, and heart (32).

Involvement of the CNS has been reported to exist in 20– 40% of PAN cases (33) and mainly occurs at late stages (2–3 years) (34). CNS involvement has been recognized as a sign of a poor prognosis, and the expected mortality rate at 5 years is 26% (35, 36). The most common manifestation of CNS involvement includes diffuse encephalopathy and a deficit of focal neurological function. Diffuse encephalopathy may present as new onset seizure and headache, reduced level of consciousness or altered vision, among which some of the cases also suffer from reversible encephalopathy syndrome (37–39). The main manifestations of focal CNS involvement include cerebral infarction (which occurs in 13–17% of PAN patients), hemorrhage, multifocal encephalopathy and episodes of neurological dysfunction that mimic multiple sclerosis (33, 40). Intracranial hemorrhage is a rare complication of PAN, and subarachnoid hemorrhage and intracerebral hemorrhage caused by aneurysms have been reported in PAN cases. The features of these aneurysms were found to be multiple, small in size, and equally located in the infratentorial and supratentorial arteries (41).

Reichart et al. (33) investigated early lacunar strokes complicating PAN and revealed that 33.3% (5/15) of strokes occurred within 1 month after the onset of PAN and 15% (2/13) shortly after the initiation of corticosteroids; ischemic strokes occurred during corticosteroid treatment in 77% (10/13) of the patients, 80% (8/10) of which occurred within 6 months after corticosteroid initiation and 50% (5/10) within 3 weeks. Combined with the results of prior studies showing that all strokes occurred while the patients were under adequate corticosteroid treatment, it was suggested that the promoting effect of corticosteroids in stroke might work by two mechanisms (33). For one thing, corticosteroids promote platelet aggregation in cerebral medium-sized arteries by increasing thromboxane A2, quickly causing a lacunar stroke. Lacunar strokes appearing 1 or more months after initiation of corticosteroids can be explained by the promoting effect of corticosteroids on thrombotic microangiopathies.

PNS involvement is the most common complication of PAN and occurs in 60–70% of cases; it has an onset early in the course of the disease, mostly within a few months of diagnosis (42). The common patterns of PNS involvement include mononeuropathy, polyneuropathy and mononeuritis multiplex, the pathophysiology of which has been recognized as vasculitis of the vasa nervorum. Sudden onset asymmetrical sensorimotor mononeuritis multiplex, which mainly affects the lower extremities, and insidious symmetrical peripheral neuropathy are typical and common in PAN (31). In addition, patients with PAN may also develop pachymeningitis (43) and present with headache or cranial nerve palsy. Sudden bilateral hearing loss (44) and visual alterations caused by optic neuropathy (45) have also been reported.

#### Kawasaki Disease

Kawasaki disease (KD) is a systemic vasculitis that mainly affects medium-sized vessels, occurring predominately in children under 5 years of age. Neurological complications of KD have been described in children, such as encephalopathy, seizures, cerebral infarction, intracranial hemorrhage, ataxia, and cranial nerve palsy (46). However, although rare cases of first onset have also been reported in adult patients, most reported cases are in young adults and the manifestations are due to late-onset sequelae instead of new-onset active disease. We found one case (47) describing a 20-year-old young adult with a history of KD suffering from subarachnoid hemorrhage due to an intracranial aneurysm with a stalk-like narrow neck, located at the trunk of the middle cerebral artery. As the researchers mentioned, coronary aneurysms in KD also arise in places where no branch exists. Therefore, non-bifurcation intracranial aneurysm might be related to KD and might cause intracranial hemorrhage in young adults as a late sequela.

#### Small-Vessel Vasculitis

Small-vessel vasculitis refers to necrotizing inflammation in the wall of small intraparenchymal arteries, arterioles, capillaries, and venules, and to a secondary degree in medium-size arteries. Vascular and perivascular inflammation leads to fibrinoid necrosis and consequently vascular necrosis, occlusion and thrombosis (10). The disease consists of two major groups, ANCA-associated vasculitis and immune complex smallvessel vasculitis.

## ANCA-Associated Vasculitis

ANCA-associated vasculitis is defined as necrotizing small-vessel vasculitis with few or no immune deposits, mostly associated with myeloperoxidase (MPO) ANCA or proteinase 3 (PR3) ANCA (10). Among the cases of ANCA-associated vasculitis, CNS involvement is more common in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) than it is in eosinophilic granulomatosis with polyangiitis (EGPA) (48). Nevertheless, peripheral nerve involvement is more prevalent in EGPA than are MPA and GPA (49).

#### Granulomatosis With Polyangiitis (Wegener's)

Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous inflammation usually associated with antibodies against PR3 and most commonly involves the upper and lower respiratory tract, and sinonasal inflammation and necrotizing glomerulonephritis are frequently present (10). Neurological complications have been shown to be present in 29–50% of all cases (50–52).

CNS involvement occurs in 7–11% of GPA patients (50, 53, 54), and when isolated cranial nerve palsies are included, the rate is 8–28% (51, 54). Since GPA can commonly involve sinonasal structures and cause granulomatous inflammation, which is capable of invading neighboring structures, the orbit, mastoid, optic nerve, chiasma, cranial nerves, meninges, and pituitary gland might be compromised, presenting as oculomotor dysfunction, mastoiditis, visual disturbances, cranial nerve palsy, headache, and endocrine dysfunction. In addition, small and medium arteries in the cranium can be involved, causing ischemia, or hemorrhage in different vascular territories (55). Cranial nerve palsy was reported to occur in 4.7–6% of GPA patients, among which the most commonly affected cranial nerves are II, VI, and VII (50, 51). The pituitary has been reported to be affected in 1.1–1.3% of GPA patients (56, 57). Meningeal pachymeningitis usually occurs i4n the early stages of GPA, with lower incidences of accompanying systemic symptoms (58), which is perhaps due to granulomatous erosion of the skull base in the early phase and may lead to a delay of diagnosis (52). The most common symptom is headache, followed by cranial nerve palsy and symptoms due to venous sinus occlusion. Vasculitis involvement can cause ischemic and hemorrhagic complications of the brain and spinal cord (58). Dysfunction of intracranial arteries may cause PRES, presenting as various symptoms (59–62). Hypophysitis has been widely reported as one of the CNS complications of GPA, and its clinical manifestations vary according to the specific sites involved. Panhypopituitarism might occur as a consequence of granulomatous inflammation of both the anterior and posterior pituitary (56). Anterior pituitary involvement may influence the release of antidiuretic hormone and present as diabetes insipidus, which was shown to occur in 47 of 58 GPA patients (81%) with sellar involvement, according to an analysis of cases performed by Peters et al. (63). Posterior pituitary inflammation may cause diminished secretion of many hormones, leading to secondary hypogonadism (occurred in 32 out of 58 sellar involved GPA patients, 55%), secondary hypothyroidism (20 out of 58 sellar involved GPA patients, 34.5%), secondary adrenal insufficiency, secondary growth hormone deficiency (19 of 58 sellar involved GPA patients, 32.8%). Compression of the pituitary stalk can result in hyperprolactinemia (5 of 58 sellar involved GPA patients, 8.6%) and galactorrhea, and visual alteration may occur if the optic chiasm is compressed (56, 57).

PNS complications have been reported to occur in 11–44% of GPA patients (54), which occurs milder and later in the course of the disease than in other ANCA-associated vasculitis (64), presenting mainly as recurrent mononeuropathies, mononeuritis multiplex, or symmetric polyneuropathy due to ischemia caused by vasculitic inflammation of the vasa nervorum. As the most frequent manifestation, distal symmetrical sensory neuropathy was reported in 7–10% of cases, followed by motor mononeuritis multiplex in 2–12% (51, 53). Commonly, peroneal (90–95%), tibial (38–55%), ulnar (35–45%), and median (26–36%) nerves are involved (29, 51).

#### Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss)

The characteristics of eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophil-rich and granulomatous inflammation that often involves the respiratory tract and is associated with asthma and eosinophilia (10).

Neurological involvement is common in EGPA, accounting for up to 60% of cases and usually manifesting as peripheral neuropathy that tends to present before visceral involvement (29). Therefore, early detection of peripheral nerve involvement is fundamental for early diagnosis and treatment of EGPA. The most common peripheral neurological manifestation is multiple mononeuropathy (accounting for 68% of cases with peripheral neuropathy), followed by distal symmetric polyneuropathy (28%) and asymmetric polyneuropathy (4%) (65). Since mononeuritis multiplex is typical in acute systemic vasculitis, the initial symptoms commonly present as dysesthesia, paresthesia, and edema in distal limbs, especially the lower limbs. The condition will gradually progress into asymmetrical polyneuropathy and may affect motor nerves, leading to muscle atrophy. Electrophysiological studies have shown decreases in the amplitude of sensory nerve action potentials and compound muscle action potentials, indicating the presence of axonal injury (66).

CNS involvement in EGPA is rather rare, accounting for only 6–10% of all cases (67). Cerebral infarctions and intracerebral hemorrhage resulting from intracranial vasculitis are the most common CNS presentations of EGPA. In addition, rarer manifestations have been noted, such as subarachnoid hemorrhage, cranial nerve palsy, encephalopathy, epilepsy, hydrocephalus, headache, sinus venous thrombosis, spinal hemorrhage, meningeal involvement, and optic neuropathy.

#### Microscopic Polyangiitis

Microscopic polyangiitis (MPA) presents with nongranulomatous inflammation with few or no immune deposits in the walls of the affected vessels, mainly associated with antibodies against MPO. Necrotizing glomerulonephritis and alveolar hemorrhage are common complications (10). Peripheral neurological involvement occurs in 55 to 79% of cases with MPA, with no special manifestations compared with those of other ANCA-associated types of vasculitis (mainly presenting as polyneuropathy and mononeuropathy); (64). CNS involvement in MPA is rare and was reported to be able to manifest as intracerebral infarction or hemorrhage, subarachnoid hemorrhage, hypertrophic pachymeningitis, PRES or spinal cord involvement (68).

#### Immune Complex Small-Vessel Vasculitis

Immune complex small-vessel vasculitis is characterized by moderate to marked deposits of immunoglobulin and/or complement components in the small vessel walls.

#### Antiglomerular Basement Membrane Disease

Antiglomerular basement membrane (anti-GBM) disease, also called Goodpasture syndrome, is a vasculitis affecting glomerular capillaries and/or pulmonary capillaries with deposition of anti-GBM autoantibodies on GBM, accounting for 5% of adult patients with glomerulonephritis and leading to acute renal failure in approximately half of the patients. Lung involvement results in pulmonary hemorrhage, and renal involvement leads to glomerulonephritis with necrosis and crescents, which are the classic presentations of anti-GBM disease (10, 69). Neurological involvement is uncommon. According to the rare cases reported (69–73), PRES is the most frequent neurological complication. All patients reported are younger than 40 and they all manifested as hypertension, renal failure, and seizures. Destruction of the blood-brain barrier resulting from inflammatory endothelial injury and increased capillary filtration due to hypertension are important factors in the pathophysiology of PRES in GBM patients.

#### Cryoglobulinemic Vasculitis

Cryoglobulinemic vasculitis (CV) is defined as vasculitis with cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles) caused by chronic inflammation, autoimmune disorders, and lymphoproliferative disorders, frequently involving skin, glomeruli, and peripheral nerves (10). Most cases of cryoglobulinemic vasculitis result from infection, B-cell lymphoproliferative disorders and autoimmune diseases, among which hepatitis C virus infection is the cause in ∼80% of cases (74). In a study of 242 cases with non-infectious mixed cryoglobulinemia vasculitis (75), 117 patients (48%) were found to have no identified causal factor, also defined as idiopathic. However, no study has evaluated the neurological involvement of idiopathic cryoglobulinemia vasculitis alone. For patients with mixed CV, PNS involvement is not uncommon and typically starts with polyneuropathy that affects the sensory nerves initially and later the motor nerves, predominantly involving the lower limbs. CNS involvement is rare, and studies have shown that mixed CV may cause cerebrovascular events, PRES, hydrocephalus and intracranial hypertension (29, 76).

#### IgA Vasculitis (Henoch-Schönlein Purpura)

IgA vasculitis (IgAV) is characterized by IgA1-dominant immune deposits affecting small vessels, often involving the skin and gastrointestinal tract and frequently causing arthritis (10). The majority (75%) of cases occur in young people no more than 20 years of age (77), and CNS involvement has been reported to manifest as headache, decreased consciousness, seizures, focal neurological deficits, and visual and verbal abnormalities. However, PNS involvement has been documented as neuropathies of the brachial plexus and facial, peroneal, femoral and ulnar nerve, and in addition, Guillain–Barre syndrome and mononeuritis multiplex (78). Rare cases of IgAVinduced neurological manifestations have been reported in adult patients as ischemic stroke, axonal sensorimotor polyneuropathy (79, 80), mononeuritis multiplex (81, 82), acoustic neuritis, facial nerve palsy (83), intracerebral hemorrhage (84), anterior ischemic optic neuropathy (85), focal seizures (86), and encephalopathy (87).

#### Hypocomplementemic Urticarial Vasculitis (anti-C1q Vasculitis)

Hypocomplementemic urticarial vasculitis (HUV) is a kind of vasculitis accompanied by urticaria and hypocomplementemia affecting cutaneous small vessels and is associated with anti-C1q antibodies, commonly causing urticaria and multiorgan involvement such as glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation (10). HUV may be induced by connective tissue diseases, infections (such as hepatitis B, hepatitis C and infectious mononucleosis), neoplasms and drugs; however, most cases of HUV are idiopathic (88). Neurological involvement has been occasionally reported as pseudotumor cerebri (89), lower cranial nerve (VIII, IX, and X) palsies (90) and peripheral nerve involvement such as asymmetrical multifocal axonal sensory neuropathy.

## VARIABLE-VESSEL VASCULITIS

Variable-vessel vasculitis refers to vasculitis with no predominant type of vessel involved that can affect vessels of any size (small, medium, and large) and type (arteries, veins, and capillaries) (10).

#### Behçet's Syndrome

Behçet's syndrome is a vasculitis occurring in patients with Behçet's disease (BD) and can affect arteries or veins and lead to a relapsing inflammatory disorder in almost any tissue, with oral and genital ulcerations and uveitis as its most typical symptoms (41). Neurological manifestations of BD, which are called neuro-BD (NBD), occur in 1.3–59% of all cases and usually affect patients aged between 20 and 40 years, with a male predominance (the male to female ratio is 2.8:1) (91–95). NBD commonly appears 3–6 years after other systemic involvement (92, 96, 97) and is considered to be caused by perivasculitis.

The manifestations of neurological involvement can be caused by either CNS parenchymal inflammation or vascular complications in the nervous system, with a reported prevalence of 67–76 vs. 12–20% in all NBD cases (93, 98). The former is considered to be caused by small vasculitis, leading to axonal damage and gliosis, frequently affecting the brain stem (occurs in 25–50% of all parenchymal NBD cases) (92, 93, 99, 100), thalamus and basal ganglia, and, only rarely, the white matter and spinal cord. The main clinical manifestations are subacute cranial neuropathy, ophthalmoparesis, meningoencephalitis, and alteration of cerebellar, pyramidal and extrapyramidal function. Uncommon symptoms such as subcortical dementia, stroke and transverse myelitis have also been reported (91, 101). Vascular complications mainly result from cerebral venous thrombosis (CVT) due to large vessels endothelial cell activation, and rarely, aneurysms due to perivasculitis to the vasa nervorum (91). CVT in BD mainly causes focal neurological deficits and seizures in young men (102). However, not all epileptic seizures in NBD patients result from CVT, and brainstem lesions may also lead to complex partial seizures (103).

In addition, perivasculitis to the vasa nervorum may also cause PNS involvement. However, this condition is extremely rare and was found in merely 8 out of 1,031 cases (0.8%); thus, its relationship with BD is still doubtful (91).

## Cogan Syndrome

Cogan syndrome (CS) is a sequence of clinical manifestations due to a chronic immunological inflammatory multisystem disease of unknown origin, characterized by recurrent episodes of keratitis, vestibuloauditory dysfunction, and systemic vasculitis, frequently leading to visual loss, vertigo, sensorineural hearing loss, tinnitus and systemic manifestations (10). The syndrome mainly affects children and young adults with an average age at onset of 38 years (SD, 15.1 years; range, 9–70 years) (104).

It is worth noting that complications of the eyes and ears do not always occur at the same time (sometimes up to 9 years apart) (105) and in 20% of cases, vestibuloauditory symptoms can be the only presentation (104). Therefore, although the vestibuloauditory involvement in Cogan syndrome is mainly due to inflammation of inner ear structures rather than neurological involvement (105), its manifestations can be easily misdiagnosed as central acute vestibular syndrome of vascular origin, Ménière's disease or vestibular migraine, which are common in neurological out-patients. According to a study that enrolled 60 cases of CS at Mayo Clinic (104), all cases suffered from hearing loss, 90% of the cases experienced vertigo, and tinnitus (80%), ataxia (53%), and oscillopsia (25%) were also common during the course of the disease. Hearing loss is typically sudden, mainly involves bilateral high frequencies, and the decline in hearing fluctuates and progresses gradually. Vestibular function is commonly damaged bilaterally (accounting for 74% of cases that underwent a caloric test) and vestibular symptoms may last for days to weeks (sometimes indefinitely) with no resolution (104, 106). The vestibuloauditory symptoms listed above may recur in 1–13 years after onset (occurs in 22% of patients) (107).

Neurological involvement was reported in 29–56% of cases and usually occurs after eye and ear manifestations (106, 108). CNS involvement may manifest as ischemic stroke (accounting for 2.5–3% of cases reported), encephalitis (5–6%), meningitis (5–22%), encephalopathy, myelopathy, optic nerve disorders, aneurysm, and cerebral venous thrombosis. PNS conditions in Cogan syndrome patients have been reported as peripheral neuropathy (1–12.5%, frequently mononeuritis multiplex), cranial neuropathy (1–10%, mainly cranial nerve II, V, VI, and VII) and myopathy (106).

#### CONCLUSION

Neurological involvement is a common complication of PSV (**Table 1**), and neurologists play an important role in the identification and diagnosis of PSV patients with otherwise

#### REFERENCES

unexplained neurological symptoms as their chief complaint. This article summarizes the neurological manifestations of PSV and hopes to improve neuroscientists' understanding of this broad range of diseases.

#### AUTHOR CONTRIBUTIONS

SZ conceived the article and wrote the manuscript. DY and GT reviewed and edited the manuscript. All authors read and approved the manuscript.

#### ACKNOWLEDGMENTS

The authors are grateful to the Chongqing Science and Technology Commission, Chongqing Education Commission and the Chongqing Health and Family Planning Commission for funding this project.

polyarteritis nodosa, case report, and diagnostic challenges. Front Neurol. (2017) 8:490. doi: 10.3389/fneur.2017.00490

**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.