Curr Neurol Neurosci Rep (2015) 15:3 DOI 10.1007/s11910-015-0529-1

INFECTION (ML SOLBRIG, SECTION EDITOR)

Autoimmune Encephalitis and Its Relation to Infection Arun Venkatesan & David R. Benavides

# Springer Science+Business Media New York 2015

Abstract Encephalitis, an inflammatory condition of the brain that results in substantial morbidity and mortality, has numerous causes. Over the past decade, it has become increasingly recognized that autoimmune conditions contribute significantly to the spectrum of encephalitis causes. Clinical suspicion and early diagnosis of autoimmune etiologies are of particular importance due to the need for early institution of immune suppressive therapies to improve outcome. Emerging clinical observations suggest that the most commonly recognized cause of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, may in some cases be triggered by herpes virus infection. Other conditions such as Rasmussen’s encephalitis (RE) and febrile infection-related epilepsy syndrome (FIRES) have also been posited to be autoimmune conditions triggered by infectious agents. This review focuses on emerging concepts in central nervous system autoimmunity and addresses clinical and mechanistic findings linking autoimmune encephalitis and infections. Particular consideration will be given to antiNMDA receptor encephalitis and its relation to herpes simplex encephalitis.

Keywords Autoimmune encephalopathy . CNS autoimmunity . Anti-NMDA receptor antibodies . FIRES . Rasmussen’s syndrome . Molecular mimicry

This article is part of the Topical Collection on Infection A. Venkatesan (*) : D. R. Benavides Johns Hopkins Encephalitis Center, Department of Neurology, Johns Hopkins University School of Medicine, Meyer 6-113, 600 N. Wolfe Street, Baltimore, MD 21287, USA e-mail: [email protected]

Introduction Encephalitis refers to inflammation of the brain parenchyma with associated neurologic dysfunction and is usually defined on the basis of selected clinical, laboratory, and neuroimaging features [1–7]. Clinical signs and symptoms typically include a combination of fever, confusion, amnesia, personality changes, paralysis, seizures, language dysfunction, and autonomic dysfunction. Although the true incidence of encephalitis is challenging to determine, recent estimates have suggested an incidence of 5–10 cases per 100,000 people per year [8, 9]. The causes of encephalitis are myriad and include infectious and autoimmune etiologies. While infectious encephalitis can be caused by numerous microorganisms including bacteria, fungi, and parasites, viruses are by far the most commonly identified pathogens [4, 10, 11]. Regarding autoimmune causes, it has long been recognized that certain cancers can rarely be associated with neurologic dysfunction and evidence of brain inflammation; these paraneoplastic conditions, in which tumor antigens drive central nervous system (CNS) autoimmunity, include syndromes such as anti-Hu-associated limbic encephalitis [12]. More recently, however, there has been an increased appreciation of the contribution of additional autoimmune etiologies to encephalitis. This has been spurred by the discovery of a growing list of neuronal cell surface proteins, including NMDA receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, gamma-aminobutyric acid (GABA) A receptors, leucine-rich, glioma-inactivated protein 1 (LGI1), and contactinassociated protein-like 2 (CASPR2), which can serve as targets for CNS autoimmunity with resultant encephalitis [13]. Early identification of such syndromes is important, since autoimmune encephalitis is associated with significant morbidity and mortality [14, 15•] although potentially treatable [2, 16]. Here, we review the link between infection and autoimmune encephalitis, with emphasis on three conditions with

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varying levels of evidence for infection and autoimmunity: (1) anti-NMDA receptor encephalitis, a known autoimmune condition, which, in some cases, follows a documented CNS infection by the herpes simplex virus; (2) Rasmussen’s encephalitis (RE), where there is compelling evidence for autoimmunity but a tenuous infectious link; and (3) febrile infection-related epilepsy syndrome (FIRES), a condition associated with infection but for which there is weaker evidence for autoimmunity.

CNS Autoimmunity and Infection In general, autoimmune disease is characterized by persistent inflammation and immune responses directed against host antigens (or self-antigens). It is well-recognized that hereditary and environmental factors trigger autoimmunity [17] although the precise mechanisms underlying autoimmune disease have not yet been fully elucidated. Processes contributing to the development of systemic autoimmunity include inappropriate modulation of autoreactive CD4+ T helper lymphocytes, defective modulation of CD4+ T regulatory and CD8+ T suppressor cells, and dysregulated signaling via inflammatory cytokines [18, 19]. The CNS has long been considered an immuneprivileged tissue and, as such, may be more tolerant of the introduction of novel antigens than peripheral tissues. However, the link between systemic inflammation and neural dysfunction has been well-established for a number of diseases of inflammation, autoimmunity, and immunodeficiency [20]. Infectious causes of autoimmune disease were first proposed over 100 years ago, and delineating the mechanisms by which infection may relate to CNS autoimmunity has been the source of much interest for decades. Indeed, it has been hypothesized that many autoimmune and demyelinating diseases, including multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica, may be triggered by infection [21]. Potential mechanisms by which infection can lead to breaking of CNS immune tolerance are manifold and include molecular mimicry, change in antigen expression, alternative splicing, posttranslational modification, covalent modification, enzymatic processing, protein misfolding, unmasking of cryptic neural epitopes, dysregulation of immune regulators, bystander activation, and “epitope spreading” in the infectious microenvironment [18, 22]. Molecular mimicry is the process whereby an immune response directed at a microbial surface protein causes immune cross-reactivity with self-antigens [18]. Most co-evolving microbes are not likely to trigger such an immune response, but in instances where such autoantibody cross-reactivity does occur, the antibody is not likely to be pathogenic (as evidenced by the prevalence of natural autoantibodies [23]). However, crossreactive autoantibodies may contribute to the exposure of sequestered epitopes on the same protein target, leading to

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pathogenic autoantibodies, through a process of epitope spreading [18]. The first step in autoimmune disease involves autoantigen presentation by antigen-presenting cells, which in the CNS include myeloid lineage macrophages and parenchymal microglia [19]. Antigen presentation is dictated by human leukocyte antigen (HLA) genes and their antigen repertoire. Recent studies have identified HLA association with acute disseminated encephalomyelitis, an immunopathologic condition [24]. Moreover, atypical HLA molecules could be induced in vitro by Japanese encephalitis virus [25], supporting the notion that neurotropic viral infection may alter the molecular machinery leading to breaking of immune tolerance. Alteration in antigenic proteins through expression level changes, alternative splicing, posttranslational modification, or mutation may contribute to breaking immune tolerance [18]. The persistence of a transformed antigenic protein may not be necessary for the maintenance of the immune response, as it may simply suffice for the altered protein to initiate the immunopathology against native proteins. CNS pathogens have been known to cause dramatic effects on host gene mRNA expression and protein function. For example, a recent study showed alterations in expression of a number of genes involved in the interferon response, innate immunity, cell survival and death signaling, and glutamate signaling in neural tissue following infection with various flaviviruses [26]. Such changes following infection may both underlie CNS immune dysregulation and modulate the expression of potential selfantigens that can contribute to CNS autoimmunity. Dysregulation of immune regulatory cascades may also contribute to breaking CNS immune tolerance. In addition to HLA genes, a number of non-HLA genes have been associated with susceptibility to autoimmune disease, including AIRE, CTL4A, PTPN22, TNFa, and FOXP3 [18, 27]. In addition, a role for specific cytokines or T cell subsets has been posited in infection-related CNS autoimmunity. Recent studies of acute encephalomyelitis by the JHM strain of mouse hepatitis virus, for example, demonstrated that IL-27 may impair control of CNS viral replication while promoting the demyelination that is associated with the viral and accompanying T cell response [28]. In addition, regulatory T cells may mediate the immune privilege of the CNS by suppression of CNS-specific T helper cells in the setting of infection [29]. Taken together, these findings add to an already complex molecular cascade resulting in a balance between CNS immune tolerance and context-specific immunity which may be perturbed in the setting of infection, thus resulting in autoimmunity.

Anti-NMDA Receptor Encephalitis Anti-NMDA receptor (anti-NMDAR) encephalitis is now firmly established as an important cause of encephalitis in children and adults. The syndrome is typically characterized

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by a combination of psychiatric manifestations, seizures, a hyperkinetic movement disorder, dysautonomia, and coma and is more common in young women [30]. In up to half of cases, anti-NMDAR encephalitis is associated with ovarian teratoma [31], where reactivity of patient antibodies with both rodent brain tissue and neuronal cells within the ovarian teratoma provides compelling evidence for a paraneoplastic syndrome. However, the pathogenesis of the remaining cases of anti-NMDAR encephalitis—those not associated with ovarian teratoma or related tumors—is an active area of investigation, as are the triggers of acute encephalitis in those with tumors. Here, we will describe the links between infection and antiNMDAR encephalitis, with a focus on the role of herpes simplex virus (HSV) as a trigger for autoimmunity. Infectious Links Up to three quarters of patients with anti-NMDAR encephalitis present with prodromal symptoms that include headache, fever, nausea, diarrhea, or upper respiratory tract symptoms [30]. Such symptoms typically predate the onset of psychiatric and other manifestations of anti-NMDAR encephalitis by days to weeks, suggesting the possibility that an infectious disorder may trigger or enhance the autoimmune process [32]. Notably, the temporal progression of cerebrospinal fluid (CSF) abnormalities also provides support for the notion of an infectious trigger for anti-NMDAR encephalitis. CSF obtained early in the disease course—within several weeks of prodromal symptoms—typically demonstrates a lymphocytic pleocytosis that can number in hundreds of lymphocytes per milliliter. On the other hand, CSF obtained later in the disease course—4 weeks or longer following the prodromal symptoms—is less commonly associated with a pleocytosis [33]. In addition, there is a temporal evolution in the presence of oligoclonal bands (OCBs), which are representative of local intrathecal antibody synthesis; early in the disease course, OCBs tend to be absent while CSF sampled at later timepoints more commonly demonstrates their presence [33]. An attractive, though simplistic, explanation for these CSF findings is that an initial infectious event results in breach of the bloodbrain barrier (BBB), associated with or resulting in a lymphocytic pleocytosis. Breach of the BBB allows peripheral antibodies to gain access to the central nervous system; when followed by epitope spreading within the CNS, OCBs emerge in the CSF. Among the reports describing patients with anti-NMDAR encephalitis, there has been co-incident identification of several infectious etiologies including mycoplasma pneumonia [34], H. influenza, HHV6, mumps, and enterovirus. These reports help support the notion that pathogen-induced immunological activation can create a microenvironment that predisposes to CNS autoimmunity. Notably, these reports do not establish causation between these pathogens and CNS

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autoimmunity, since mechanistic studies linking these infections with anti-NMDAR encephalitis are lacking. Herpes Simplex Encephalitis as a Trigger for Anti-NMDAR Encephalitis In 2012, the presence of antibodies to NMDAR was reported in 13 of 44 patients during the course of herpes simplex encephalitis (HSE) [35••]. In many such cases, the antibodies were present at hospital admission, though in some they developed later in the course of HSE. Moreover, such antibodies were not found in the small number of cases of enteroviral and varicella zoster virus (VZV) encephalitis investigated, suggesting specificity of the finding. In this initial study, however, the clinical course did not differ between those with and those without antibodies to NMDAR, and thus the clinical significance of the presence of antibodies to NMDAR remained unclear [35••]. Regardless, these findings raised the possibility that post-HSE choreoathetosis and/or other neurologic relapses following appropriately treated HSE may represent an autoimmune phenomenon related to the development of antiNMDAR antibodies. Several subsequent reports now support the concept that HSE can trigger the clinical syndrome of antiNMDAR encephalitis. In one particularly well-documented report, for example, a 24-year-old man developed confusion, delusion, and disorientation; was noted to have symptoms and signs compatible with HSE; and was found to have a substantial CSF pleocytosis and positive HSV polymerase chain reaction (PCR) in his CSF [36]. After treatment with intravenous acyclovir, he was gradually recovering when he developed mania, pressured speech, and evolving brain MRI changes. Upon re-evaluation, his CSF HSV PCR was negative and the CSF pleocytosis was less marked, but anti-NMDAR IgG antibodies were detected in the CSF. He was diagnosed with anti-NMDAR encephalitis and treated with steroids in addition to another course of acyclovir, with substantial improvement. Crucially, CSF and serum from his initial evaluation tested negative for the anti-NMDAR antibodies, suggesting that that the antibody developed subsequent to HSV infection. Thus, this patient developed typical anti-NMDAR encephalitis following classic HSE. Over the past several years, there have been a number of reports that suggest a link between HSE and the presence of NMDAR antibodies and/or anti-NMDAR encephalitis; these are summarized in Table 1 [35••, 36–42, 43••]. Despite this accumulating evidence, criticisms have been raised regarding the methodology for identification and quantification of antibody presence and titers by the various laboratories and testing facilities. The reports linking HSE to antiNMDAR encephalitis included patients evaluated in both commercial and research laboratories undergoing detection of IgM, IgA, and IgG subclasses of antibodies. To date, there is no clear consensus for the identification of anti-NMDAR

Age and sex

66-year-old female

64-year-old female

59-year-old female

31-year-old male

52-year-old male

50-year-old male

79-year-old female

46-year-old female

24-year-old male

44-year-old female

53-year-old male

59-year-old female

62-year-old male

28-month-old female

24-year-old male

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Fever, vomiting, malaise, memory impairment, headache Headache, fever, vomiting, confusion somnolence Headache, confusion, seizures, fever Personality change, vomiting, headache, fever, confusion Headache, fever, memory impairment, confusion, somnolence, status epilepticus Headache, fever, vomiting, memory impairment, cognitive slowing Personality change, inappetance, headache, fever, memory impairment, confusion Memory impairment, personality change, fever, confusion, complex partial seizure Fever, irritability, focal seizures, dysphagia, dysarthria

Memory impairment, fever, aphasia, confusion, somnolence Headache, fever, vomiting, personality change, memory impairment Fever, headache, aphasia, confusion

Fever, malaise, vomiting, headache, confusion, memory loss Confusion, aphasia, dizziness, fever, somnolence

Symptoms at HSE onset

N/A

CSF HSV PCR positive

14

23

N/A

Fever, diarrhea, agitation, insomnia, choreoathetosis

CSF HSV PCR positive

CSF HSV1 PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF HSV1 PCR positive; CSF HSV1 PCR

45

12

N/A

CSF HSV PCR positive

9

5

30

N/A

N/A

CSF HSV PCR positive

b

3102

4

7

5

7

7

5

10

Interval from HSE onset to detection of anti-NMDAR antibody (days)

IgA

IgG, IgMc

IgA, IgG, IgMc

IgG, IgMc

IgG, IgMc

IgA, IgM

IgA, IgG, IgM

Negative

IgG, IgM

IgG

IgA, IgM

IgM

IgA

IgA, IgM

IgA, IgM

IgG

Negative or not tested

CSF anti-NMDAR antibody classa

IgA, IgM

Negative

IgA, IgG, IgM

IgG

IgG

IgG

Not tested

Not tested

Not tested

IgA

IgA, IgM

IgA, IgG

IgA, IgM

Serum antiNMDAR antibody classa

No anti-NMDAR antibodies detected at onset of HSE, [42, 43••]

[35••]

[35••]

[35••]

[35••]

Additional antibody to neuropil detected, [35••]

[35••]

[35••]

[35••]

Only recognized GluN1/ GluN2B, not GluN1 alone, [35••]

Pruss [35••]

[35••]

Only recognized GluN1/ GluN2B, not GluN1 alone, [35••]

[35••]

Notes, reference

Page 4 of 11

CSF HSV PCR positive

N/A

N/A

N/A

CSF HSV PCR positive

CSF HSV PCR positive

CSF HSV PCR positive

N/A

N/A

CSF HSV PCR positive

CSF HSV PCR positive

N/A

CSF HSV PCR positive

N/A

N/A

CSF HSV PCR positive

CSF HSV PCR positive

Subsequent symptoms

HSV result

Cases of herpes simplex encephalitis and anti-NMDA receptor autoimmunity

Patient

Table 1

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Age and sex

2-month-old male

6-month-old female

8-month-old male

45-year-old female

41-year-old male

82-year-old male

Infant male

20s-year-old male

11-month-old female

7-year-old male

8-month-old female

Patient

16

17

18

19

20

21

22

23

24

25

26

Table 1 (continued)

Fever, drowsiness, vomiting, focal seizure

Fatigue, vomiting, fever, seizure

Fever, vomiting, diarrhea, status epilepticus

Headaches, malaise, confusion, fever

Mental status changes, hyperkinetic movements, seizure

Fever, headache, seizures, aphasia, confusion, coma, Bell’s palsy, hemiparesis

Fever, headache, confusion, psychosis, seizures Confusion, fever, mental status change, lethargy

Fever, irritability, focal seizures

Fever, diarrhea, focal seizures

Fever, focal seizures

Confusion, delusions, memory impairment, personality change

Symptoms at HSE onset

CSF HSV2 PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF HSV PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF HSV1 PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF HSV1 PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection Intrathecal HSV1 IgG positive

CSF HSV1 PCR positive

Intrathecal HSV1 IgG positive

CSF PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF HSV1 PCR positive

negative at time of antiNMDAR detection

HSV result

No anti-NMDAR antibodies detected at onset of HSE, [43••] [43••]

IgA, IgG, IgMc

IgG, IgMc

23

Irritability, unresponsiveness, seizures, choreoathetosis

[37]

Negative

IgGd

Not tested

IgG, IgMe

IgGf,g

Not tested

IgGc

Not tested

IgGd

IgG, IgMe

IgGf,g

IgGf,g

42

>28

>28

21

15

Nonverbal, unresponsiveness, poor head control, gaze preference, choreoathetosis Aphasia, behavioral change

Fever, behavioral change, irritability, sleep disturbance, choreoathetosis/dystonia Encephalopathy, chorea, dystonia, dysautonomia

Encephalopathy, chorea

15

No anti-NMDAR antibodies detected at onset of HSE, additional IgG to neuropil/cell surface target detected in serum and CSF, [43••]

IgG, IgMc

IgG, IgMc

61

Additional anti-D2R antibody detected, [39]

[39]

No anti-NMDAR antibodies detected at onset of HSE, [38]

[37]

[43••]

IgG, IgMc

Not tested

Memory dysfunction, personality changes Confusion, social inappropriate behavior, perseveration, choreic-like movements/ seizures, autonomic and respiratory dysfunction Cognitive decline

74

No anti-NMDAR antibodies detected at onset of HSE, [43••]

IgG, IgMc

IgG, IgMc

52

Fever, diarrhea, irritability, insomnia, choreoathetosis, unresponsiveness

No anti-NMDAR antibodies detected at onset of HSE, [43••]

No anti-NMDAR antibodies detected at onset of HSE, [36], [43••]

Notes, reference

IgG, IgMc

CSF anti-NMDAR antibody classa

IgGc

Serum antiNMDAR antibody classa

24

Interval from HSE onset to detection of anti-NMDAR antibody (days)

Choreoathetosis, irritability, sleep disorder

Progressive mania, irritability, disorientation, memory impairment

Subsequent symptoms

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10-month-old female

15-year-old female

3-year-old female

19-month-old female

27

28

29

30

Drooling, aphasia, focal seizures

Fever, vomiting, headaches, progressive encephalopathy

Headaches, fever, behavioral change, altered consciousness

Prolonged seizure and encephalopathy

Symptoms at HSE onset

CSF HSV PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF HSV PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF HSV PCR positive; CSF HSV PCR negative at time of anti-NMDAR detection CSF HSV PCR positive, HSV IgG positive; CSF HSV PCR negative at time of anti-NMDAR detection

HSV result

Not tested

Not tested

Not tested

IgGg

IgGi

IgGc

IgGi

IgGg

>10 yearsh

>36

>31

28

Encephalopathy, orofacial dyskinesia, choreoathetosis, cognitive regression Encephalopathy, cognitive regression

Encephalopathy, orofacial dyskinesia, choreoathetosis, stereotypies, seizures Hallucinations, choreoathetosis, orofacial dyskinesia

i

Clinical information indicate recurrent episodes over 10 years prompting recent evaluation of anti-NMDAR antibodies

Antibody class deduced from available information on manufacturer’s website: http://www.euroimmun.com/fileadmin/template/flash/produktkatalog_2014_en/files/assets/basic-html/page118.html

Detection method utilized flow cytometry cell-based assay and commercial cell-based assay (Euroimmun)

Detection method utilized cell-based assay, rodent brain immunohistochemistry, and rodent neuronal culture

h

g

Detection method not described

Antibody class deduced from available information on testing laboratory websites: http://ltd.aruplab.com/Tests/Pub/2004221 and http://ltd.aruplab.com/Tests/Pub/2005164

Detection method utilized cell-based assay and rodent brain immunohistochemistry

No clinical information available regarding interval delay in the evaluation of anti-NMDAR antibodies

Detection method utilized cell-based assay; using HEK293, cells were transfected with the GluN1 or GluN1/GluN2B subunits of the NMDAR, unless otherwise noted

No anti-NMDAR antibodies detected at onset of HSE, [40]

No anti-NMDAR antibodies detected in serum at onset of HSE, [41]

[41]

[41]

Notes, reference

Page 6 of 11

f

e

d

c

b

a

CSF anti-NMDAR antibody classa

Serum antiNMDAR antibody classa

Interval from HSE onset to detection of anti-NMDAR antibody (days)

Subsequent symptoms

HSE herpes simplex encephalitis, HSV herpes simplex virus, PCR polymerase chain reaction, NMDAR N-methyl-D-aspartate receptor, N/A not available

Age and sex

Patient

Table 1 (continued)

3 Curr Neurol Neurosci Rep (2015) 15:3

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antibodies, but the most extensive techniques employ a multipronged approach that includes the following: (1) immunohistochemistry using rodent brain tissue, (2) immunocytochemistry in dissociated rodent neuronal culture, and (3) a cellbased assay using overexpression of GluN1 or GluN1/ GluN2 subunits in HEK cells [44]. Recently, Brilot and colleagues reported the use of a flow cytometry-transfected cell assay to identify NMDAR antibodies in two children with post-HSE chorea [39]. Although these results were confirmed using a commercially available transfected cell-based kit, it should be noted that reliance on cell-based assays alone may result in spurious findings. As the clinical spectrum of antiNMDAR autoimmunity continues to grow, future studies will be necessary to investigate the clinicopathological correlates between antigenic regions and clinical features. How might infection with herpes simplex virus result in the clinical syndrome of anti-NMDAR encephalitis? Accumulating evidence suggests a direct pathogenic role for anti-NMDAR antibodies in the CNS, as evidenced by in vitro analyses of antibody effects on neurons and in animal models [44, 45•, 46, 47]. The main epitope of the GluN1 subunit of the NMDAR has been mapped to the extracellular region near the agonist binding region of the protein [45•]. Binding of pathogenic antibodies to GluN1 acutely increases the channel open time of NMDARs [45•], but over time, receptor cross-linking and internalization leads to a reduction in NMDAR clusters at synaptic sites with a concomitant decrease in NMDAR-mediated currents [47, 48•]. These observations were extended to show that synaptic NMDAR-EphB2R interactions were disrupted by autoantibodies, facilitating the initial NMDAR excitation and subsequent internalization and degradation [49•]. Pathogenic antibodies have also been shown to alter the abundance of inhibitory synapses in vitro, suggesting possible mechanisms for homeostatic or network plasticity in anti-NMDAR pathogenesis [48•]. These findings have been correlated in vivo, where passive transfer of pathogenic antibodies into rodents results in impaired performance in object recognition task [46]. Both the NMDAR internalization and behavioral effects have been shown to be reversible with elimination of pathogenic antibodies [46, 47, 50]. As discussed in previous sections, a viral infection such as HSE may result in the generation of pathogenic anti-NMDAR antibodies by several potential mechanisms. In the context of HSE and anti-NMDAR encephalitis, the possibilities of molecular mimicry and release of antigens after herpesviral infection have been raised [51, 52]. Indeed, the unmasking of cryptic epitopes is a particularly attractive molecular mechanism in this setting. In addition, posttranslational modification by N-linked glycosylation or deamidation of N368 of GluN1 may be important to the development of antibodies following infection [45•]. Future studies investigating this or similar modifications on GluN1 in patients with HSE or other infectious processes linked with anti-NMDAR encephalitis would be of significant interest.

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Notably, NMDAR antibodies generated following HSE may differ from antibodies in classic anti-NMDAR encephalitis. Non-HSE anti-NMDAR patient CSF did not induce changes in spine morphology or levels of synaptic proteins including AMPA receptors, postsynaptic density protein 95 (PSD-95), and the presynaptic protein bassoon [47]. Further, the number of excitatory synapses was unchanged in cultured neurons exposed to patient CSF or serum, as assessed by colabeling of vesicular glutamate transporter (VGLUT) and PSD-95 [47]. In contrast, in similar experiments from patient serum following HSE, a dramatic reduction occurred in presynaptic puncta, as assessed by synapsin-positive clusters [35••]. Interestingly, in a large study of HSE patients, two patients were noted to have unique reactivity in the cellbased assay, suggesting that post-HSE anti-NMDAR encephalitis may display a broader antigenic repertoire than the classic syndrome [35••]. Together, these findings may further distinguish the clinicopathological phenotypes of the classic antiNMDAR autoimmune encephalitis syndrome and the postinfectious anti-NMDAR clinical syndrome. Alternatively, there may be additional immune-related agents in the postinfectious condition that are contributing to these observed differences. Indeed, among the case reports of HSE reporting the presence of antibodies to surface neuronal markers, there were two cases that had antibodies to dopamine 2 receptors (D2R); one of which occurred with anti-NMDAR antibodies [39], 10 cases with unknown neuronal surface cellular antibodies, one of which occurred with anti-NMDAR antibodies [51], and one with unknown neuronal surface staining pattern in neuropil [35••]. These findings suggest that HSE may be a general trigger for CNS autoimmunity, of which antiNMDAR encephalitis is a component. Finally, it deserves mention that many of the putative mechanisms by which HSE can trigger anti-NMDAR may also occur in the setting of other CNS infections, and thus the spectrum of infections associated with anti-NMDAR encephalitis may continue to expand.

Rasmussen’s Encephalitis First described over 50 years ago, RE is characterized by progressive neurologic dysfunction, refractory epilepsy, and unilateral inflammation in the cerebral cortex [53–55]. Pathological hallmarks include microglial and lymphocytic nodules, perivascular cuffing, and neuronal cell loss. Two decades ago, autoantibodies reactive to the neuronal cell surface protein GluR3 were identified in RE, sparking a flurry of research surrounding antibody-mediated mechanisms of disease [56]. However, GluR3 antibodies were subsequently found in only a minority of patients with RE and were noted to be of questionable specificity [57–59]. Several other autoantibodies, including those directed against the nicotinic

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alpha7-acetylcholine receptor and Munc-18, an intracellular protein critical for the release of synaptic vesicles, were also reported in small numbers of patients with RE [60, 61]. In recent years, enthusiasm for an antibody-mediated process has diminished as earlier studies have not been consistently replicated. Attention has now turned to the role of cytotoxic T cells in the pathogenesis of the disease. CD8+ T cells have been found in close apposition to neurons and glial cells, and granzyme B, a cytotoxic protein released by T cells, has been found within neurons [62, 63]. Moreover, spectral analysis of individual T cells from brain lesions indicates clonal expansion of CD8+ cells, suggesting an antigen-driven CD8+ T cell-mediated autoimmune process [63]. In addition, mRNA from brain tissue of patients with RE has shown increased expression of a number of genes associated with T lymphocyte function [64••]. Taken together, these data provide compelling evidence for the role of T cells in the pathogenesis of RE. Regardless of whether the immune response in RE is driven by humoral or cell-mediated mechanisms, the possibility that foreign, rather than endogenous, antigens may be the pathogenic target in RE has been repeatedly raised. Indeed, the predilection of the disease for a single hemisphere has suggested the possibility of a focal infection with progressive spreading as a cause of the syndrome. Almost four decades ago, brain pathology from a child with focal motor seizures and hemiparesis demonstrated perivascular cuffing and virus crystals on electron microscopy, although the identity of the putative virus was not established [65]. Subsequently, several authors have reported the presence of various human herpesviruses, including herpes simplex virus 1, cytomegalovirus, and Epstein-Barr virus, in brains of those with RE via in situ hybridization or polymerase chain reaction, though viral antigen has not been reliably detected [66–68]. Notably, low levels of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) have also been detected by PCR in the brains of individuals with intractable epilepsy but without encephalitis, raising questions about the specificity of this finding [69]. Thus, although the inciting factors for autoimmunity remain unknown, there has yet to be convincing evidence for viral causality.

FIRES FIRES, as its name would suggest, is a syndrome characterized by refractory status epilepticus in previously healthy children that occurs in the setting of, or following, a febrile illness [70]. In up to half of patients, the fever disappears prior to the onset of seizure. In initial reports, the prodromal febrile illness consisted of a broad variety of infections, including upper respiratory illnesses, bronchitis, pneumonia, pharyngitis, mastoiditis, and otitis media [71]. In a few cases, specific

pathogens, including rhinovirus, respiratory syncytial virus, and Epstein-Barr virus, were identified in the serum or in nasopharyngeal aspirates. However, despite extensive testing, pathogens were not identified in the CNS, raising the possibility that a systemic infection induced CNS dysfunction, potentially by triggering an autoimmune syndrome with resultant encephalitis [71]. Overall, however, there is limited evidence for encephalitis in cases of FIRES. Indeed, many cases classified within the syndrome of FIRES are not associated with the paraclinical evidence of CNS inflammation to support consideration of encephalitis. Initial brain MRI is normal in half of cases, while 65 % of cases are associated with fewer than 10 WBC/mm3 in the initial CSF examination [72••]. Brain biopsies, too, do not suggest a prominent inflammatory component. Of 13 patients who underwent brain biopsy, eight had abnormal histopathology and seven had gliosis while only one had leptomeningeal inflammatory infiltrates [72••]. Although CSF oligoclonal bands suggestive of intrathecal antibody synthesis were reported in 4 of 12 cases, and specific autoantibodies may be found (anti-GAD found in 2/5 patients, anti-GluR3 in 1/4, and a single case of FIRES associated with antibodies to VGKC has been reported) [72••, 73], the pathogenic significance of these autoantibody findings is unclear and a subsequent, more comprehensive, autoantibody evaluation has not borne out a major role for known autoantibodies [74]. Thus, although a systemic infection is likely to contribute to the pathogenesis of FIRES, a role for autoimmunity has not been established.

Conclusions Mechanisms by which infections may lead to CNS autoimmunity are manifold, and there is now substantial evidence that HSE can trigger anti-NMDAR encephalitis. For other conditions, including RE and FIRES, either the autoimmune or infectious component is fairly well-established while evidence for the other remains lacking. In order to better define the link between infection and autoimmune encephalitis, careful clinical phenotyping is necessary, as it may suggest subgroups of individuals in which there is likely to be a link. Such phenotyping, in combination with newer pathogen discovery techniques as well as broad screening for autoantibody- and cell-mediated autoimmunity, will likely result in the identification of novel infection-associated autoimmune encephalitides. However, it should be noted that the presence of coincident infection with an autoimmune process is not sufficient to establish causality and that mechanistic studies are needed to firmly establish such a link. We anticipate that a mechanistic understanding will, in turn, result in the identification of biomarkers of disease risk or outcome and may provide the basis for new therapeutic or preventative treatment strategies for autoimmune encephalitis following infection.

Curr Neurol Neurosci Rep (2015) 15:3 Acknowledgments David R. Benavides is supported by NINDS T32 training grant in neuroimmunology and neurological infectious disease (T32NS069351). Arun Venkatesan receives support from the National Institutes of Health, Maryland Stem Cell Research Fund, and Accelerated Cure Project for Multiple Sclerosis.

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Compliance with Ethics Guidelines 14. Conflict of Interest Arun Venkatesan and David R. Benavides declare that they have no conflict of interest. 15.• Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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