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Sarosh R Irani

Autoimmune Encephalitis — New Awareness, Challenging Questions

Abstract: The field of autoimmune encephalopathies has expanded rapidly in the last few years. It is now well-established that a substantial proportion of encephalitides are associated with autoantibodies directed against the extracellular domains of cell-surface proteins which are critical in the regulation of neuronal excitability. These include LGI1, CASPR2, contactin-2 (VGKC-complex antibodies), and the NMDA, AMPA, and GABAB receptors. The clinical importance of these conditions lies in their frequent immunotherapy-response and, less commonly, their association with distinctive tumors. Studies which have examined cohorts of patients defined by these serum antibodies have identified a number of clinical features that have helped understand the core phenotypes of these conditions. In addition, sensitive antibody assays have allowed the expansion of the phenotypes to include a minority of patients with isolated epilepsies or psychoses. There is also evidence that autoimmune encephalitis may progress to adult-onset hippocampal sclerosis. Clinical, and accumulating scientific, data strongly suggest direct pathogenicity of these autoantibodies. The generation of the autoantibody, in some patients, can be explained by the presence of tumors which express their antigenic target. Serum antibody levels are higher than their levels in CSF in the vast majority of cases. However, the majority of patients do not harbor a tumor and the etiology of the disease in these patients is less clear. Below, we suggest models for the etiology and pathogenic mechanisms of these autoantibodies by incorporating concepts such as serum generation of the autoantibodies, the blood-brain barrier, intrathecal antibody production, and prodromal infections.


Pathogenic autoantibodies have been described in diseases of the peripheral nervous system since the 1970’s. The classical autoantibody-mediated diseases include myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). Antibodies in these diseases have been shown to target the muscle acetylcholine receptor (AChR) and the presynaptic calcium channel (P/Q-type), respectively, which are essential for effective neuromuscular transmission. There are conclusive clinical and scientific data to support the pathogenicity of the antibodies including the correlation between antibody levels and severity of clinical features in an individual and, more formally, the development of similar diseases in experimental animals after antibody (immunoglobulin G, IgG) transfer (reviewed by Vincent, 2002). One consistent feature of these conditions is their clear and often excellent response to immunotherapies, in particular plasma exchange. Another is their relationship with very characteristic tumors: MG can be associated with thymomas and LEMS is associated with small cell lung cancers. As the neurological presentation often precedes the tumor detection, this knowledge facilitates early tumor recognition and treatment.

All these paradigms also apply to a disease of peripheral nerve hyperexcitability known as neuromyotonia (NMT). NMT is characterized by continuous muscle activity and often presents with cramps, stiffness, and some autonomic dysfunction. Voltage-gated potassium channel antibodies are present in around half of these patients (Newsom-Davis and Mills, 1993; Hart et al., 2002). NMT has been shown to respond well to immunotherapies (including plasma exchange) and is associated with thymomas in around 25% of cases; passive transfer of patient IgG to mice can reproduce some of the electrophysiological features of NMT (Sinha et al., 1991).

This review will focus on the extent to which these paradigms apply in antibody-mediated diseases of the central nervous system, in particular autoimmune encephalitis.

What Are the Autoimmune Encephalitides?

The subacute onset of amnesia, disorientation, and seizures has traditionally generated a differential diagnosis including viral encephalitis, Hashimoto’s encephalopathy, and Wernicke’s encephalopathy. Historically, a number of these “viral” encephalitides were never ascribed a clear cause (reviewed by Granerod et al., 2010a). More recent surveys have suggested that a proportion of these previously idiopathic cases are associated with autoantibodies directed against neuronal proteins (Granerod et al., 2010b). The importance of this identification lies in the potential for a response to immunotherapies.

The origins of autoimmune encephalitis came from the 1960’s. At that time, post mortem examinations suggested lymphocytic infiltration of the medial temporal lobe (”limbic encephalitis”) in patients with a remote cancer (Brierley et al., 1960). The importance of this cancer was emphasized over the next 40 years with the discovery of antibodies which were almost always associated with underlying systemic tumors. These antibodies (including Hu, CV2/CRMP5, and Ma2) were directed against intracellular proteins and were, therefore, very unlikely to be directly pathogenic (Vincent et al., 1999; Vincent et al., 2006). Indeed, these patients often had a very poor prognosis and little or no response to immunotherapies (Dalmau and Rosenfeld, 2008).

Subsequently, it was recognized that antibodies which target the extracellular domain of neuronal proteins may also be associated with autoimmune encephalitis. The most common targets defined so far are LGI1 (leucine-rich glioma inactivated 1), a component of the voltage-gated potassium channel complex, and the N-methyl D-aspartate (NMDA) receptor.

The Clinical Spectrum of Diseases Associated with “Voltage-gated Potassium Channel” (VGKC) Antibodies

Limbic encephalitis (LE)

VGKC-antibodies, originally identified in patients with NMT, were defined by their ability to precipitate voltage-gated potassium channel complexes from brain tissue (VGKC-complex antibodies). Almost all the LE cases were found to be over 50 years of age, more commonly male than female, and had an immunotherapy-responsive syndrome which was not associated with an underlying tumor (Vincent et al., 2004; Thieben et al., 2004). A serum hyponatremia was a characteristic feature of the condition [usually an SIADH (syndrome of inappropriate antidiuretic hormone secretion) pattern] as was MRI T2/FLAIR high signal in the medial temporal lobe. Both of these features were seen in around 60% of cases (Vincent et al., 2004; Irani et al., 2010a; Thieben et al., 2004). The serum concentrations of the VGKC-complex antibodies were far higher than those in the cerebrospinal fluid (CSF), which were highly variable and sometimes undetectable. While a few cases have spontaneously entered remission (e.g., Buckley et al., 2001), immunotherapies were often used with success. They reduced serum VGKC-complex antibody levels and produced significant functional benefits: improvements were greatest in the patients administered early steroid therapies (Vincent et al., 2004). This condition is now being frequently recognized by neurologists as an immunotherapy-responsive encephalopathy.

Faciobrachial dystonic seizures

Most recently, it has become clear that a number of patients with LE associated with VGKC-complex antibodies have a specific seizure semiology which commonly precedes the onset of the amnesia and confusion. This semiology was first described in three patients with adult-onset, frequent, and brief (3-5 seconds) events comprising facial grimacing and ipsilateral arm posturing (Irani et al., 2008). These “faciobrachial dystonic seizures” (FBDS) showed an excellent response to corticosteroids, often administered after multiple antiepileptic agents were ineffective (Irani et al., 2008). This response was paralleled by a decrease in the VGKC-complex antibody levels. Other authors appear to have reported very similar events in VGKC-complex antibody positive patients (Park et al., 2007; Barajas et al., 2010). Since the 2008 report (Irani et al., 2008), an additional 26 cases with FBDS have been reported (Irani et al., 2011a). The differential responses to immunotherapies and antiepileptic drugs (AEDs) are illustrated in Figure 1. While it is clear that FBDS control was far better with immunotherapies than with AEDs, AEDs were also responsible for a remarkably high rate (41%) of, often severe, adverse reactions. Some patients developed a systemic hypersensitivity syndrome requiring intensive care admission and many had cutaneous reactions including erythroderma.

Figure 1. Response of faciobrachial dystonic seizures (FBDS) frequency to antiepileptic drugs (AEDs, left pie chart) and immunotherapies (right pie chart) in 29 cases from Irani et al., 2011a. Reduction in frequency <20% (blue), 20-50% (red) or >50% (green) within first month of therapy. FBDS is often a prequel to limbic encephalitis.

Figure 1. Response of faciobrachial dystonic seizures (FBDS) frequency to antiepileptic drugs (AEDs, left pie chart) and immunotherapies (right pie chart) in 29 cases from Irani et al., 2011a. Reduction in frequency <20% (blue), 20-50% (red) or >50% (green) within first month of therapy. FBDS is often a prequel to limbic encephalitis.

Interestingly, 77% of these patients developed FBDS prior to the onset of amnestic and other cognitive changes (Irani et al., 2011a). Therefore, it may be that FBDS provides a window of therapeutic opportunity to prevent the onset of amnesia and florid limbic encephalitis which often necessitates a long hospital stay and may have serious cognitive sequelae. In support of this concept, all 3 patients with FBDS and no cognitive impairment who were given immunotherapies, with a subsequent fall in antibody levels, did not go on to develop amnesia or confusion.

Morvan’s syndrome

Morvan’s syndrome is a rare entity characterized by peripheral and central nervous system involvement, specifically, neuromyotonia plus hallucinations, delirium, insomnia, and autonomic disturbance. It may be associated with tumors, particularly thymomas. Therefore, it has been suggested to be a syndrome with features of both neuromyotonia and LE. Patients with Morvan’s syndrome are known to often have VGKC-complex antibodies (Liguori et al., 2001), although seronegative cases have been reported (Rinaldi et al., 2009), and many cases have an immunotherapy-responsive illness (Madrid et al., 1996; Liguori et al., 2001; Spinazzi et al., 2008; Sadnicka et al., 2011).

How can we explain this clinical heterogeneity? The VGKC-complex — LGI1, CASPR2, and contactin-2 antibodies

Since these clinical observations, it has been difficult to explain how such a range of phenotypes — neuromyotonia, Morvan’s syndrome, limbic encephalitis, and faciobrachial dystonic seizures — can be associated with the same, probably pathogenic, antibody. An explanation has arrived in the last year. It has become clear that the antibodies in NMT, Morvan’s, and LE are only very rarely directed against the VGKCs themselves, but are usually directed against other proteins within the VGKC-complex, which are tightly associated with VGKCs and coprecipitate with the VGKCs in the diagnostic radioimmunoassay (Vincent et al., 2009). These complexed proteins include LGI1 (leucine-rich glioma inactivated 1), CASPR2 (contactin-associated protein 2), and contactin-2 (Irani et al., 2010a). These can be determined by incubating patient sera with cells expressing the protein of interest (cell-based assay). Almost all patients with LE (Irani et al., 2010a; Lai et al., 2010) and FBDS (Irani et al., 2011a) have LGI1-antibodies, whereas those with Morvan’s syndrome and NMT more commonly have antibodies against CASPR2 (Irani et al., 2010a; Irani et al, in preparation). Contactin-2 antibodies appear to be uncommon and often coexist with CASPR2 antibodies (Irani et al., 2010a). These clinical associations correlate well with the known distributions of the target antigens. LGI1 is a secreted protein which is expressed mainly in the central nervous system, particularly within the hippocampus (Schulte et al., 2006; Fukata et al., 2006; Irani et al., 2010a), with very low-level expression in peripheral nerves (Ogawa et al., 2010; Irani et al., 2010a). By contrast, CASPR2 and contactin-2 are expressed strongly in both central and peripheral nervous system neurons (Poliak et al., 1999; Irani et al., 2010a).

These clinical observations also match the genetic diseases associated with LGI1 and CASPR2 mutations. LGI1 mutations produce a lateral temporal lobe epilepsy syndrome without peripheral nervous system involvement (Kalachikov et al., 2002; Morante-Redolat et al., 2002) and CASPR2 mutations have been found in a family with cognitive impairment, epilepsy, and areflexia, emphasizing its functional importance in peripheral and central neurons (Strauss et al., 2006).

Of clinical utility, almost all the patients with tumors (thymomas, usually) had CASPR2 antibodies (Irani et al., 2010a; Vincent and Irani, 2010). However, the majority of the CASPR2 antibody positive patients do not have tumors, so this appears to be a test with a high negative predictive value only. In addition, some patients with negative VGKC-complex antibodies, as defined by the radioimmunoprecipitation assay, have detectable antibodies against CASPR2 when using cell-based assays (Irani, Pettingill, and Vincent, unpublished).

Other Antibodies Associated with Limbic Encephalitis

While LGI1 appears to be the commonest antibody associated with LE, antibodies to glutamic acid decarboxylase (GAD; Malter et al., 2010), the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor (Lai et al., 2009), and the GABAB receptor have also recently been associated with this syndrome (Lancaster et al., 2010). In addition, some patients with typical LE who have CASPR2 antibodies (Irani et al., 2010a) or NMDA receptor antibodies (see below; Graus et al., 2008; Zandi et al., 2009) have been identified.

By comparison with the LGI1-antibody positive cases, many of those with AMPAR and GABABR antibodies have an underlying neoplasm but have an immunotherapy-responsive condition associated with antibodies which react with the extracellular domain of neuronal cell-surface receptors, continuing the paradigm generated by the discovery of the VGKC-complex antibody (Vincent et al., 2004; Thieben et al., 2004). The tumor incidence and clinical features associated with AMPAR and GABABR antibodies may vary when more patients are identified.

Panencephalitis Associated with NMDA (N-methyl D-aspartate) Receptor Antibodies


The encephalitis associated with NMDA-receptor (NMDAR) antibodies was originally observed in 12 young women with ovarian teratomas and some consistent clinical features as part of a more complex encephalopathy (Dalmau et al., 2007). Since this description, it has become clear that NMDAR-antibody encephalitis can also present in males or children (Dalmau et al., 2008; Irani et al., 2010b) in whom tumors are uncommon. Overall, the tumor rate is highly dependent on the age and sex of the patient: young women (18-40 years) are at highest risk of ovarian teratomas (Florence et al., 2009; Irani et al., 2010b). By striking contrast to the patients with VGKC-complex antibodies, most patients with NMDAR-antibodies are under 50 years of age (see Table 1 for comparisons), and cases under 2 years old, and as young as 8 months old, have been identified (Wong-Kisiel et al., 2010; Vincent, unpublished).

Classical phenotype and therapies

NMDAR-antibody encephalitis does not usually cause a typical limbic encephalitis although some of the, particularly early, features are likely to localize to the temporal lobe. The disease may be divided into two main stages, based on data regarding time of symptom onset (Irani et al., 2010b). The early stage was characterized by psychiatric features, confusion, amnesia, and seizures. The second stage, 10 to 20 days later, consisted variably of movement disorders, dysautonomia, and reduction in levels of consciousness. The movement disorder was a very characteristic feature (Dalmau et al., 2008; Kleinig et al., 2008) and most commonly hyperkinetic and associated with orofacial (and limb) dyskinesias. Less frequently, it may be hypokinetic, often presenting as an akinetic-mute syndrome. Some of the patients developed an infectious prodrome to their illness but in most cases the appearance of fever was coincident with the onset of a more florid dysautonomia (Irani et al., 2010b).

The likely anatomical basis for these two stages was supported by EEG and MRI evidence which in some patients showed epileptiform activity early in the disease, and slow waves appeared with a lag of around 10-20 days. In addition, although few patients showed MRI abnormalities, those with cortical changes were noted early and those with subcortical lesions seen later (Irani et al., 2010b). These data, taken together, led to the proposal of a cortical to subcortical transition in the localization of the major pathology in NMDAR-encephalitis. The early pleocytosis and later appearance of oligoclonal bands may offer insights into the intrathecal immunology during these two, possibly anatomically-distinct, stages (Irani et al., 2010b).

This disease is clearly not a new entity, although the discovery of the NMDAR-antibody as a biomarker has exponentially increased its recognition as an immune-mediated disease and enabled patients to receive appropriate treatment. Patients who are very likely to have suffered from the same illness include those with encephalitis lethargica, in whom NMDAR-antibodies have been identified (Dale et al., 2009), immune-mediated chorea encephalopathy syndrome in childhood (Hartley et al., 2002), acute encephalitis with refractory, repetitive partial seizures (Sakuma et al., 2010), and acute non-herpetic encephalitis (Kamei et al., 2009). The condition can be diagnosed with a cell-based assay. This requires incubation of patient serum/CSF with NMDAR-transfected HEK cells. Differences in the methodology of the assays (for example, compare Dalmau et al., 2008 with Irani et al., 2010b) are likely to account for the varied spectrum of clinical phenotypes reported and the varied rates of CSF and serum “positivity” in the literature (reviewed by Irani and Vincent, 2011).

Once confirmed, or with a sufficiently high index of clinical suspicion, patients should undergo an intensive course of immunotherapy. An intensive course appears to be important as the natural history of the condition entails hospital stays of many months, long periods of invasive ventilation, and a slow recovery. In addition, at least 25% of untreated patients without tumors have been noted to have a relapsing disease (Irani et al., 2010b). In the minority of cases who appear to have an ovarian tumor, removal of the tumor has been shown to expedite recovery (Dalmau et al., 2008). In the non-paraneoplastic cases, which are increasingly recognized, steroids and intravenous Ig (IVIg)/plasma exchange are usually used as first-line therapies. Often these patients will require additional immunotherapy and rituximab and cyclophosphamide are used most frequently (Dalmau et al., 2008; Irani et al., 2010b). Early and aggressive immunotherapy administration has been shown to be of benefit (Irani et al., 2010b; Dalmau et al., 2011).

Serum-CSF NMDAR antibody concentrations

It is important to note that serum levels of NMDAR-antibodies are almost always higher than CSF levels (mean=13.5 times; Irani et al., 2010b; Dale et al., 2009; Pruss et al., 2010). This is likely to imply that the disease begins in the periphery, and not the brain, in both the paraneoplastic and non-paraneoplastic patients. However, upon relating to total IgG concentrations, this ratio is reversed showing “intrathecal synthesis” (Dalmau et al., 2008; Irani et al., 2010b; Pruss et al., 2010). The serum-predominant antibody concentration is also seen in VGKC-complex antibody encephalitis, although in this case intrathecal synthesis is highly variable and can be absent.

Can Autoimmune Encephalitides Teach Us About Other Related Conditions?

A recent population based survey has shown that autoimmune encephalitides are more common than previously believed, accounting for 21% of unselected encephalitis cases in the U.K. (Granerod et al., 2010b). Many of these cases had VGKC-complex and NMDAR antibodies. However, recent observations have suggested that these diseases may inform the more common related conditions of epilepsy and psychosis, which are often prominent features of autoimmune encephalitis.


As reviewed previously (Vincent et al., 2010; Irani et al., 2011b), seizures are a common feature in patients with autoimmune encephalitis as described above. In addition, in cohort studies, around 10% of patients with varied forms of epilepsy, without the more florid cognitive impairment typical of LE, were found to have, often low positive, levels of VGKC-complex antibodies or GAD-antibodies (McKnight et al., 2005). This included patients with temporal lobe epilepsy and drug-refractory epilepsies. The presence of NMDAR-antibodies has also been demonstrated in a similar number of otherwise idiopathic epilepsies (Niehusmann et al., 2009), although in some cases these patients developed a few subtle features of NMDAR-antibody associated encephalitis. And from surveys of patients with VGKC-complex antibody or NMDAR-antibody positive serum, a small proportion of patients (most commonly adults with temporal lobe epilepsy) were found to have isolated epilepsy (Irani et al., 2010a; Irani et al., 2010b). Furthermore, it is clear that patients with faciobrachial dystonic seizures (FBDS) without memory impairment, or other more widespread cognitive features, responded to immunotherapies and not anti-epileptic drugs. It may be that therapeutic trials of corticosteroids in patients with other forms of isolated epilepsy become useful clinical maneuvers.

Finally, careful analyses of adult patients with hippocampal sclerosis have suggested that around 20% of these cases had an episode of limbic encephalitis, and not childhood febrile convulsions, as the probable cause for their current symptomatic epilepsy (Bien et al., 2007; Soeder et al., 2009). This observation ties in with the recognition of hippocampal atrophy as a long-term complication of an acute limbic encephalitis (for example, Schott et al., 2003).


While it has been clear for many years that psychiatric features may dominate the clinical presentation of patients with encephalitis, many of these cases have progressed to develop more clear-cut “neurological” features such as seizures, delirium, or amnesia. Only recently have patients been found with pure psychiatric diseases in association with antibodies which target cell surface receptors. For example, VGKC-complex (n=1) or NMDAR antibodies (n=2) were found in 3 of 46 cases with a first episode of psychosis. All antibody-positive cases were below 30 years of age (Zandi et al., 2010). This study identified one additional case with NMDAR-antibodies whose psychosis responded well to plasma exchange, although a natural remission of the disease could not be excluded. NMDAR-antibody positive patients with prominent psychiatric features have also been described from other centers (e.g., DeNayer et al., 2009). In addition, two AMPAR-antibody positive patients have been reported with a predominantly psychotic disease (Graus et al., 2010). Although these antibody-positive patients account for the very small minority of cases with psychosis so far, this may form a paradigm for autoimmunity as a cause of some schizophreniform illnesses.

Are these antibodies pathogenic and what are their mechanisms of action?

Clinical studies have shown that in most cases of VGKC-complex antibody LE, clinical improvements are induced with immunotherapies and that the sequential serum antibody levels appear to correlate well with the clinical features (Vincent et al., 2004; Irani et al., 2010a). This is also true in Morvan’s and pure epilepsy syndromes. In fact, this concept is particularly well demonstrated in patients with frequent seizures whose seizure frequency is often dramatically reduced with corticosteroids (Irani et al., 2008; Barjaras et al., 2009; Irani et al., 2011a). This observation is in stark contrast to antibodies directed against intracellular antigens, such as Hu or GAD, whose levels often remain high in the few patients that improve. The antibodies which target extracellular domains are often associated with syndromes which are immunotherapy-responsive which would be expected if the antibodies are causative (Vincent et al., 1999; Graus et al., 2008). Indeed, there is accumulating evidence to suggest that these antibodies do indeed produce pathogenic effects in animals or in vitro.

For example, in the central nervous system, NMDAR-antibodies and LGI1-antibodies have been shown to mediate potentially pathogenic effects. Internalization capabilities of NMDAR-IgG have previously been shown (Dalmau et al., 2008; Hughes et al., 2010). In the study of Hughes et al. (2010), infusion of NMDAR-IgG into mouse hippocampi for 14 days produced downregulation in surface NMDARs. This effect was mimicked in vitro, using hippocampal neurons, and was reversible with removal of the IgG. This study did not examine the effect of complement on hippocampal neurons, and as NMDAR-IgG is almost exclusively of the IgG1 complement fixing subclass, it is possible this will play a role in vivo. In a separate study, application of LGI1-antibodies to rat hippocampal slices produced synaptic hyperexcitability which was mimicked by alpha-dendrotoxin, a selective blocker of Kv1-VGKCs (Lalic et al., 2010). This was the first evidence that LE IgG may reduce VGKC function at CNS synapses. It is possible that this effect is mediated through IgG-induced co-internalization of LGI1 and the VGKCs. Direct effects on channel kinetics, such as antagonism or agonist function, are yet to be proven in any of these diseases.

The generation of the antibody is likely to require a combination of factors. The presence of a systemic tumor, particularly in the patients with NMDA, AMPA, and GABA receptor antibodies, is clearly one triggering factor. The expression of ectopic antigen, within the tumor, may be the major factor in breaking tolerance. However, in most NMDAR-antibody positive cases no tumor is found. In these cases, the initiating factor may be a prodromal infection which, via the mechanism of molecular mimicry, could generate a pathogenic antibody as has been proven in Guillian-Barre syndrome. Indeed around 30% of patients with NMDAR-antibody encephalitis (Irani et al., 2010b) and around 10% of those with VGKC-complex antibody encephalopathy (Irani and Vincent, unpublished) have a prodromal infection with sufficient latency to generate a cross-reactive IgG. However, the organism, when identified, is highly variable (Vincent et al., 2004; Irani et al., 2010b; Pruss et al., 2010) and this would argue against a direct role for molecular mimicry. Alternatively, the systemic innate immune response associated with any microbial agent may be sufficient to disrupt blood-brain barrier integrity and allow the efflux of the serum-predominant antibody into the CSF and brain parenchyma. Although this may be a method to promote antibody entry to the CNS, it seems likely that antibody can constitutively cross the blood-brain barrier (BBB; Dalakas, 2002) and so maybe the “hit” to the BBB is not required. Alternatively, it may be that B or antibody-producing plasma cells entering the CSF are crucial for production of sufficient specific antibody to cause CNS disease. However, the lack of intrathecal synthesis in many cases of LGI1/CASPR2-antibody encephalitis would argue against intrathecal synthesis being essential, at least for typical LE. With these possibilities in mind, a number of questions remain unanswered. First, is it purely the tissue distribution of the antigen which determines the phenotype generated? This is plausible if IgG can access the brain constitutively and if only a minority of patients have a possible BBB insult either clinically or radiologically. For example, LGI1 is highly expressed within the hippocampus and the vast majority of the features of the associated LE can be explained on the basis of medial temporal lobe pathology. The SIADH pattern of hyponatremia may however also require hypothalamic involvement, and indeed LGI1 is expressed within this region. However, antigen tissue distribution does not explain the minority of CASPR2-antibody positive patients with LE but without NMT. Second, as all these antibodies are serum-predominant in the majority of cases, but have their effect within the CNS, is it serum or CSF antibody reductions which best correlate with clinical outcome? The latter may be answered with serial studies of antibodies in both serum and CSF, in conjunction with quantitative methods to assess clinical recovery.


Some cases of encephalitis may be associated with autoantibodies to cell surface proteins. These syndromes have characteristic clinical features and often a good response to immunotherapies. As more antibody assays are developed, the spectrum of immunotherapy-responsive phenotypes will continue to expand.


S.R.I. was supported by the National Institute for Health Research (NIHR), Department of Health, U.K. This work has been supported by the NIHR-funded Oxford Biomedical Research Centre.


A.V. and the Department of Clinical Neurology in Oxford receive royalties and payments for antibody assays. A.V. is the inventor on patent application WO/2010/046716 entitled ”Neurological Autoimmune Disorders.” The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. A.V. acts as a paid consultant for Athena Diagnostics, and is employed by University of Oxford and University College London. A.V and S.R.I. may receive royalties for testing of VGKC-complex antibodies.


Barajas RF, Collins DE, Cha S, Geschwind MD. Adult-onset drug-refractory seizure disorder associated with anti-voltage-gated potassium-channel antibody. Epilepsia 51(3):473-477, 2010.

Bien CG, Urbach H, Schramm J, Soeder BM, Becker AJ, Voltz R, Vincent A, Elger CE. Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology 69(12):1236-1244, 2007.

Brierley JB, Corsellis JAN, HIerons R, Nevin S. Subacute encephalitis of later adult life, mainly affecting the limbic areas. Brain 83:357-368, 1960.

Buckley C, Oger J, Clover L, Tüzün E, Carpenter K, Jackson M, Vincent A. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol 50(1):73-78, 2001.

Dalakas MC. Mechanisms of action of IVIg and therapeutic considerations in the treatment of acute and chronic demyelinating neuropathies. Neurology 59(12 Suppl 6):S13-S21, 2002.

Dale RC, Irani SR, Brilot F, Pillai S, Webster R, Gill D, Lang B, Vincent A. N-methyl-D-aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica. Ann Neurol 66(5):704-709, 2009.

Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7(12):1091-1098, 2008.

Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10(1):63-74, 2011.

Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 7(4):327-340, 2008.

Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, Baehring JM,Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61(1):25-36, 2007.

De Nayer AR, Myant N, Sindic CJ. A subacute behavioral disorder in a female adolescent. Autoimmune anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Biol Psychiatry 66(6):e13-e14, 2009.

Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, Campen CJ, Moss H, Peter N, Gleichman AJ, Glaser CA, Lynch DR, Rosenfeld MR, Dalmau J. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 66(1):11-18, 2009.

Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA, Fukata M. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science 313(5794):1792-1795, 2006.

Granerod J, Tam CC, Crowcroft NS, Davies NW, Borchert M, Thomas SL. Challenge of the unknown. A systematic review of acute encephalitis in non-outbreak situations. Neurology 75(10):924-932, 2010a.

Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D, Cunningham R, Zuckerman M, Mutton KJ, Solomon T, Ward KN, Lunn MP, Irani SR, Vincent A, Brown DW, Crowcroft NS; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 10(12):835-844, 2010b.

Graus F, Boronat A, Xifró X, Boix M, Svigelj V, García A, Palomino A, Sabater L, Alberch J, Saiz A. The expanding clinical profile of anti-AMPA receptor encephalitis. Neurology 74(10):857-859, 2010.

Graus F, Saiz A, Lai M, Bruna J, López F, Sabater L, Blanco Y, Rey MJ, Ribalta T, Dalmau J. Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology 71(12):930-936, 2008.

Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 125(Pt8):1887-1895, 2002.

Hartley LM, Ng SY, Dale RC, Church AJ, Martinez A, de Sousa C. Immune mediated chorea encephalopathy syndrome in childhood. Dev Med Child Neurol 44(4):273-277, 2002.

Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons TD, Lynch DR, Dalmau J, Balice-Gordon RJ. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 30(17):5866-5875, 2010.

Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang B, Vincent A. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 133(9):2734-2748, 2010a.

Irani SR, Bera K, Waters P, Zuliani L, Maxwell S, Zandi MS, Friese MA, Galea I, Kullmann DM, Beeson D, Lang B, Bien CG, Vincent A. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133(Pt 6):1655-1667, 2010b.

Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, Schott JM, Armstrong RJ, S Zagami A, Bleasel A, Somerville ER, Smith SM, Vincent A. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 69(5):892-900, 2011a.

Irani SR, Bien CG, Lang B. Autoimmune epilepsies. Curr Opin Neurol 24(2):146-153, 2011b.

Irani SR, Buckley C, Vincent A, Cockerell OC, Rudge P, Johnson MR, Smith S. Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology 71(20):1647-1648, 2008.

Irani SR, Vincent A. NMDA Receptor Antibody Encephalitis. Curr Neurol Neurosci Rep, epub ahead of print, Feb. 18, 2011.

Kamei S, Kuzuhara S, Ishihara M, Morita A, Taira N, Togo M, Matsui M, Ogawa M, Hisanaga K, Mizutani T, Kuno S. Nationwide survey of acute juvenile female non-herpetic encephalitis in Japan: relationship to anti-N-methyl-D-aspartate receptor encephalitis. Intern Med 48(9):673-679, 2009.

Kleinig TJ, Thompson PD, Matar W, Duggins A, Kimber TE, Morris JG, Kneebone CS, Blumbergs PC. The distinctive movement disorder of ovarian teratoma-associated encephalitis. Mov Disord 23(9):1256-1261, 2008.

Lai M, Hughes EG, Peng X, Zhou L, Gleichman AJ, Shu H, Matà S, Kremens D, Vitaliani R, Geschwind MD, Bataller L, Kalb RG, Davis R, Graus F, Lynch DR, Balice-Gordon R, Dalmau J. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 65(4):424-434, 2009.

Lai M, Huijbers MG, Lancaster E, Graus F, Bataller L, Balice-Gordon R, Cowell JK, Dalmau J. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 9(8):776-785, 2010.

Lalic T, Pettingill P, Vincent A, Capogna M. Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission. Epilepsia 52(1):121-131, 2010.

Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J, Friedman D, Skeen MB, Grisold W, Kimura A, Ohta K, Iizuka T, Guzman M, Graus F, Moss SJ, Balice-Gordon R, Dalmau J. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 9(1):67-76, 2010.

Liguori R, Vincent A, Clover L, Avoni P, Plazzi G, Cortelli P, Baruzzi A, Carey T, Gambetti P, Lugaresi E, Montagna P. Morvan’s syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 124(Pt 12):2417-2426, 2001.

Madrid A, Gil-Peralta A, Gil-Néciga E, González JR, Jarrín S. Morvan’s fibrillary chorea: remission after plasmapheresis. J Neurol 243(4):350-353, 1996.

Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67(4):470-478, 2010.

McKnight K, Jiang Y, Hart Y, Cavey A, Wroe S, Blank M, Shoenfeld Y, Vincent A, Palace J, Lang B. Serum antibodies in epilepsy and seizure-associated disorders. Neurology 65(11):1730-1736, 2005.

Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, Sáenz A, Poza JJ, Galán J, Gesk S, Sarafidou T, Mautner VF, Binelli S, Staub E, Hinzmann B, French L, Prud’homme JF, Passarelli D, Scannapieco P, Tassinari CA, Avanzini G, Martí-Massó JF, Kluwe L, et al. Mutations in the LGI1/epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet 11(9):1119-1128, 2002.

Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs’ syndrome). Report of five cases and literature review. Brain 116(Pt 2):453-469, 1993.

Niehusmann P, Dalmau J, Rudlowski C, Vincent A, Elger CE, Rossi JE, Bien CG. Diagnostic value of N-methyl-D-aspartate receptor antibodies in women with new-onset epilepsy. Arch Neurol 66(4):458-464, 2009.

Park DC, Murman DL, Perry KD, Bruch LA. An autopsy case of limbic encephalitis with voltage-gated potassium channel antibodies. Eur J Neurol 14(10):e5-e6, 2007.

Prüss H, Dalmau J, Harms L, Höltje M, Ahnert-Hilger G, Borowski K, Stoecker W, Wandinger KP. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology 75(19):1735-1739, 2010.

Rinaldi C, Russo CV, Filla A, De Michele G, Marano E. Course and outcome of a voltage-gated potassium channel antibody negative Morvan’s syndrome. Neurol Sci 30(3):237-239, 2009.

Sadnicka A, Reilly MM, Mummery C, Brandner S, Hirsch N, Lunn MP. Rituximab in the treatment of three coexistent neurological autoimmune diseases: chronic inflammatory demyelinating polyradiculoneuropathy, Morvan syndrome and myasthenia gravis. J Neurol Neurosurg Psychiatry 82(2):230-232, 2011.

Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, Sugai K, Sasaki M. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand 121(4):251-256, 2010.

Schott JM, Harkness K, Barnes J, della Rocchetta AI, Vincent A, Rossor MN. Amnesia, cerebral atrophy, and autoimmunity. Lancet 361(9365):1266, 2003.

Schulte U, Thumfart JO, Klöcker N, Sailer CA, Bildl W, Biniossek M, Dehn D, Deller T, Eble S, Abbass K, Wangler T, Knaus HG, Fakler B. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron 49(5):697-706, 2006.

Sinha S, Newsom-Davis J, Mills K, Byrne N, Lang B, Vincent A. Autoimmune aetiology for acquired neuromyotonia (Isaacs’ syndrome). Lancet 338(8759):75-77, 1991.

Soeder BM, Gleissner U, Urbach H, Clusmann H, Elger CE, Vincent A, Bien CG. Causes, presentation and outcome of lesional adult onset mediotemporal lobe epilepsy. J Neurol Neurosurg Psychiatry 80(8):894-899, 2009.

Spinazzi M, Argentiero V, Zuliani L, Palmieri A, Tavolato B, Vincent A. Immunotherapy-reversed compulsive, monoaminergic, circadian rhythm disorder in Morvan syndrome. Neurology 71(24):2008-2010, 2008.

Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, Stephan DA, Morton DH. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354(13):1370-1377, 2006.

Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S. Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 62(7):1177-1182, 2004.

Vincent A, Buckley C, Schott JM, Baker I, Dewar BK, Detert N, Clover L, Parkinson A, Bien CG, Omer S, Lang B, Rossor MN, Palace J. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 127(Pt 3):701-712, 2004.

Vincent A, Irani SR, Lang B. The growing recognition of immunotherapy-responsive seizure disorders with autoantibodies to specific neuronal proteins. Curr Opin Neurol 23(2):144-150, 2010.

Vincent A, Irani SR. Caspr2 antibodies in patients with thymomas. J Thorac Oncol 5(10 Suppl 4):S277-S280, 2010.

Vincent A, Lang B, Kleopa KA. Autoimmune channelopathies and related neurological disorders. Neuron 52(1):123-138, 2006.

Vincent A, Lily O, Palace J. Pathogenic autoantibodies to neuronal proteins in neurological disorders. J Neuroimmunol 100(1-2):169-180, 1999.

Vincent A. Antibodies to contactin-associated protein 2 (Caspr2) in thymoma and Morvan’s syndrome (Abstract). Ann Neurol 66(Suppl 13):S3, 2009.

Vincent A. Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2:797-804, 2002.

Wong-Kisiel LC, Ji T, Renaud DL, Kotagal S, Patterson MC, Dalmau J, Mack KJ. Response to immunotherapy in a 20-month-old boy with anti-NMDA receptor encephalitis. Neurology 74(19):1550-1551, 2010.

Zandi MS, Irani SR, Follows G, Moody AM, Molyneux P, Vincent A. Limbic encephalitis associated with antibodies to the NMDA receptor in Hodgkin lymphoma. Neurology 73(23):2039-2040, 2009.

Zandi MS, Irani SR, Lang B, Waters P, Jones PB, McKenna P, Coles AJ, Vincent A, Lennox BR. Disease-relevant autoantibodies in first episode schizophrenia. J Neurol 258(4):686-688, 2011.

[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(60):449-458, May 2011.]

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