Voltage-gated potassium channel–complex autoimmunity and associated clinical syndromes

Handbook of Clinical Neurology, Vol. 133 (3rd series) Autoimmune Neurology S.J. Pittock and A. Vincent, Editors © 2016 Elsevier B.V. All rights reserved

Chapter 11

Voltage-gated potassium channel–complex autoimmunity and associated clinical syndromes SAROSH R. IRANI* AND ANGELA VINCENT Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK

Abstract Voltage-gated potassium channel (VGKC)–complex antibodies are defined by the radioimmunoprecipitation of Kv1 potassium channel subunits from brain tissue extracts and were initially discovered in patients with peripheral nerve hyperexcitability (PNH). Subsequently, they were found in patients with PNH plus psychosis, insomnia, and dysautonomia, collectively termed Morvan’s syndrome (MoS), and in a limbic encephalopathy (LE) with prominent amnesia and frequent seizures. Most recently, they have been described in patients with pure epilepsies, especially in patients with the novel and distinctive semiology termed faciobrachial dystonic seizures (FBDS). In each of these conditions, there is a close correlation between clinical measures and antibody levels. The VGKC–complex is a group of proteins that are strongly associated in situ and after extraction in mild detergent. Two major targets of the autoantibodies are leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2). The patients with PNH or MoS are most likely to have CASPR2 antibodies, whereas LGI1 antibodies are found characteristically in patients with FBDS and LE. Crucially, each of these conditions has a good response to immunotherapies, often corticosteroids and plasma exchange, although optimal regimes require further study. VGKC–complex antibodies have also been described in neuropathic pain syndromes, chronic epilepsies, a polyradiculopathy in porcine abattoir workers, and some children with status epilepticus. Increasingly, however, the antigenic targets in these patients are not defined and in some cases the antibodies may be secondary rather than the primary cause. Future serologic studies should define all the antigenic components of the VGKC–complex, and further inform mechanisms of antibody pathogenicity and related inflammation.

INTRODUCTION Autoantibodies against the voltage-gated potassium channel (VGKC) complex have been associated with an expanding spectrum of phenotypes (Fig. 11.1A), which range from different forms of peripheral nerve hyperexcitability (PNH) to Morvan’s syndrome (MoS), limbic encephalitis (LE) and epilepsies, including faciobrachial dystonic seizures (FBDS) (Vincent et al., 2011a; Irani et al., 2014a). The PNH syndromes were first associated with VGKC–complex antibodies in 1995 (Shillito et al., 1995), 34 years after Isaacs’ clinical description (Isaacs, 1961). In 2001, VGKC–complex antibodies were

found in a patient with the central and peripheral nerve syndrome that is often attributed to Morvan (MoS) (Morvan, 1890; Liguori et al., 2001). Subsequently, they were described in 2 patients with LE (Buckley et al., 2001), which had first been described clinicopathologically in the 1960s by Corsellis, Brierley, and others (Brierley et al., 1960; Corsellis et al., 1968; Vincent, 2014). The initial description of a distinct seizure syndrome, later termed faciobrachial dystonic seizures (FBDS), during and often preceding LE, occurred in 2008 (Irani et al., 2008). Thus the immunoprecipitation of VGKC–complexes has linked a number of clinical

*Correspondence to: Sarosh R. Irani, Nuffield Department of Clinical Neurosciences, West Wing, Level 6, John Radcliffe Hospital, Oxford, OX3 9DU, UK. Tel: +44-1865-234630, Fax: +44-1865-222402, E-mail: [email protected]

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S.R. IRANI AND A. VINCENT VGKC-complex antibodies Central Nervous System (CNS) Peripheral Nervous System (PNS)

Dysautonomia and insomnia Psychiatric Pain Cognitive Movement disorders

B

Seizures CFS-NMT

Morvan

Encephalopathy FBDS

Tumour frequency

Other epilepsies

Abnormal MRI / CSF

LGI1 CASPR2 NSAb NEGATIVE

A

C

Fig. 11.1. (A) The phenotype spread of voltage-gated potassium channel (VGKC)–complex, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2) antibodies. The relative proportions of patients with LGI1 and CASPR2antibodies and those who remain without a known antigenic target (“seronegative”) are depicted in the gradient bars. Movement disorders include ataxia, chorea, and parkinsonism (Tan et al., 2008; Becker et al., 2012; Tofaris et al., 2012). A number of patients, especially those with cramp–fasciculation syndrome–neuromyotonia (CFS-NMT; high-frequency discharges shown) and epilepsy (excluding faciobrachial dystonic seizures: FBDS) currently have no defined antigenic target (NSAb negative), although their sera precipitate VGKC–complexes in the radioimmunoassay. (Modified with permission from Irani et al., 2014b. Copyright © 2014 American Medical Association. All rights reserved.) (B) and (C) Stills of FBDS. MRI/CSF, magnetic resonance imaging/ cerebrospinal fluid. Reproduced from Irani et al. (2011b), with permission.

syndromes which otherwise might have remained distinct (Table 11.1). Today, these four clinical syndromes account for the majority of cases seen in whom the antibodies are likely to be pathogenic, and the occurrence of VGKC–complex antibodies in other conditions and in children may be of less direct relevance. Below, we describe the VGKC–complex and the associated antigenic targets before discussing the clinical features and the treatment responses of the patients. We will begin in the peripheral nervous system and move to the brain (Fig. 11.1A), reflecting the chronology of the discoveries.

Autoantibodies to the VGKC–complex VGKC–complex antibodies were first, and are still, detected by radioimmunoassay (RIA) in which mammalian brain membranes are solubilized in the mild detergent, digitonin, and the extracted VGKCs labeled with radioiodinated dendrotoxin (125I-DTX), which binds very specifically to certain Kv1 subtypes of VGKCs (Shillito et al., 1995). The patient sera are incubated with the labeled extract, and antibody–VGKC–complexes immunoprecipiated using an anti-human IgG secondary antibody. Levels between 100 pM and 400 pM were seen in around 35% of elderly individuals (Vincent et al.,

2004) and are frequently found (around 40%; Hart et al., 2002) in patients with predominantly peripheral hyperexcitability, and also some with MoS. Levels above 400 pM are most consistently seen in patients with central nervous system (CNS) diseases. Early studies suggested that the antibodies did indeed co-localize with Kv1 subunits on tissue sections (Kleopa et al., 2006), but they did not bind detectably to Kv1 subunits expressed in human embryonic kidney cells using live cell-based assays (CBAs: Irani et al., 2010; see Chapter 9). Experimental studies concluded that most patient IgGs bound to proteins which were tightly complexed to VGKCs in brain membranes, but were not the VGKCs themselves (Irani et al., 2010). The VGKC–complex contains, among others, the proteins leucine-rich, glioma-inhibited 1 (LGI1), contactin-associated protein 2 (CASPR2), and contactin-2, and patient antibodies were shown to bind in diagnostic CBAs to extracellular domains of one or occasionally more of these antigenic targets (Irani et al., 2010, 2013; Lai et al., 2010; Loukaides et al., 2012; Klein et al., 2013). While the VGKC–complex RIA is able to detect antibodies directed against LGI1 or CASPR2, it does not define the identity of the target, and may fail to detect samples with low levels of CBA-determined LGI1 or

VOLTAGE-GATED POTASSIUM CHANNEL–COMPLEX AUTOIMMUNITY

187

Table 11.1 Comparison of Morvan’s syndrome with voltage-gated potassium channel (VGKC)–complex antibody-positive limbic encephalitis and neuromyotonia

Tumor Males Myasthenia gravis Peripheral nerve Neuromyotonia EMG-proven neuromyotonic discharges Pain Peripheral neuropathy features Autonomic Dysautonomia (any) Hyperhidrosis Tachycardia Blood pressure abnormalities Sleep Insomnia Neuropsychiatric Any Disorientation/confusion Amnesia Hallucinations Agitation Delusions Seizures Generalized tonic-clonic Systemic features Weight loss Skin lesions or itching Investigations Normal MRI Normal CSF Serum hyponatremia Death

Morvan’s syndrome n ¼ 29 (%)

Limbic encephalitis n ¼ 64 (%)

Neuromyotonia n ¼ 58 (%)

12 (41.4) 27 (93.1) 9 (31.0)

0 (0.0) 44 (68.8) 1 (1.6)

19 (32.8) 37 (63.8) 11 (19.0)

29 (100.0) 28 (96.6)

0 (0.0) 0 (0.0)

58 (100.0) 55 (94.8)

18 (62.1) 15 (51.7)

3 (4.7) 1 (1.6)

12 (20.7) 5 (8.6)

27 (93.1) 25 (86.2) 11 (37.9) 9 (33.3)

7 (10.9) 6 (9.4) 0 (0.0) 0 (0.0)

32 (55.2) 29 (50.0) 1 (1.7) 1 (1.7)

26 (89.7)

6 (9.4)

4 (6.9)

28 (96.6) 19 (65.5) 15 (55.6) 14 (51.9) 10 (34.5) 7 (25.9)

64 (100.0) 64 (100.0) 64 (100.0) 11 (17.2) 4 (6.3) 14 (21.9)

12 (20.7) 0 (0.0) 0 (0.0) 1 (1.7) 1 (1.7) 1 (1.7)

10 (34.5)

59 (92.2)

0 (0.0)

13 (48.2) 6 (22.2)

1 (1.6) 0 (0.0)

2 (3.4) 0 (0.0)

23 of 25 (92.0) 11 of 21 (52.3) 7 of 28 (25.0) 9 (31.0)

24 (37.5) 43 (67.2) 38 (59.4) 0 (0.0)

10 of 10 (100.0) 20 of 31 (64.5) 0 (0.0) 4 (6.9)

EMG, electromyogram; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid. Adapted from Irani et al. (2012) with permission.

CASPR2 antibodies (Becker et al., 2012; Irani et al., 2013), particularly after treatments when antibody levels drop. However, the RIA also detects VGKC–complex antibodies which do not bind to the known components, LGI1, CASPR2, or contactin-2. For example, a small percentage of the VGKC–complex antibodies appear to directly target the VGKCs (Irani et al., 2010; Hacohen et al., 2015). The antigenic target of the remaining VGKC–complex antibodies and their clinical relevance require future studies. They may bind to extracellular or intracellular epitopes, suggesting the presence of both pathogenic and nonpathogenic antibody specificities

(Fig. 11.2A; Irani et al., 2014a). In patients where there is a high clinical suspicion of a VGKC–complex antigen-related disease, both VGKC–complex RIA and antigen-specific CBAs can be helpful, although there is a move towards restricting the search to individual antigens. As in N-methyl-D-aspartate receptor (NMDAR)antibody encephalitis (see Chapter 12), serum usually shows higher concentrations of VGKC–complex/LGI1-/ CASPR2-antibody levels than cerebrospinal fluid (CSF) (Thieben et al., 2004; Vincent et al., 2004). However, by comparison with NMDAR-antibody

188

S.R. IRANI AND A. VINCENT MoS> NMT> LE IvIg

C A S P R 2

DTX VGKC

C O N T A C T I N 2

Extracellular

VGKC Ab (pM)

LGI1

1500

Intracellular

*

AZA PRED 20MG NO AZA PRED 30MG

1000

60 PRED 25MG + AZA

40

20

0

B

PRED 15MG

500

0

A

80 PEX/ PRED 50MG

500

1000

SEIZURES PER DAY

FBDS > LE> MoS

0 1500

Days from onset

Pred and IvIg AEDs 60

*

4000

40

2000

20

0 0

C

50

100

150

200

250

SEIZURES PER DAY

VGKC Ab (pM)

6000

0 2000 4000

Days from onset

D

Fig. 11.2. (A) Depiction of the voltage-gated potassium channel (VGKC)–complex labeled with dendrotoxin (DTX), the snake neurotoxin that binds strongly to VGKC, to show antibodies known to bind the extracellular domains of leucine-rich gliomainactivated 1 (LGI1) (in patients with limbic encephalitis (LE), faciobrachial dystonic seizures (FBDS), and Morvan syndrome (MoS)), and contactin-associated protein 2 (CASPR2) in patients with MoS more frequently than in neuromyotonia (NMT) or LE. Contactin-2 antibodies are rare. Some antibodies may bind the intracellular domains of some molecules within the VGKC–complex (blue antibody). (B) and (C) Graphics to demonstrate effects of antiepileptic drugs (AEDs), prednisolone (Pred), intravenous immunoglobulins (IvIg), plasma exchange (PEX), and azathioprine (AZA) on VGKC–complex antibody levels (VGKC Ab, black) and frequency of FBDS (red). Purple star denotes onset of cognitive impairment. (D) Modified Rankin score (mRS) in patients with nonparaneoplastic LGI1 antibody-associated encephalitis at peak of illness (pink) and latest follow-up (black). Patients treated with corticosteroids (ST), with or without intravenous immunoglobulins (IVIG) and/or plasma exchange (PLEX). One patient died in the ST + IVIG + PLEX group (mRS score 6). Median follow-up was for 48 months (range 19–95) with no differences between treatment groups (p ¼ 0.77, Kruskal–Wallis test). (Modified with permission from Irani et al., 2014b. Copyright © 2014 American Medical Association. All rights reserved.)

encephalitis, intrathecal synthesis of VGKC–complex/ LGI1/CASPR2 antibodies is much more variable.

Epidemiology and genetics In the United Kingdom, between two and five new cases per million per year are reported as positive for VGKC– complex antibodies with titers >400 pM. MoS is the rarest of these four syndromes, and LE is the commonest, followed by FBDS and PNH (Irani et al., 2010; Huda et al., 2015). A UK community-based survey was likely

to have underestimated the rates of VGKC–complex antibodies as criteria were principally intended to capture cases with infective encephalitis (Granerod et al., 2013). The VGKC–complex antibody-associated diseases most often affect patients above 50 years of age, with male-to-female ratios of 3:2, but the gender distribution is principally determined by the syndrome (see below). The VGKC–complex antibody levels also broadly differ between the different syndromes, with highest levels in LE and FBDS, moderate levels in MoS, and lowest levels (often <400 pM) in PNH

VOLTAGE-GATED POTASSIUM CHANNEL–COMPLEX AUTOIMMUNITY (Irani et al., 2010; Huda et al., 2015). In addition, a number of positive results, usually of lower titers, have been reported in a few individual patients with neuroinflammatory or occasionally neurodegenerative diseases in which the role of the antibodies is less clear and their target is not known (discussed above). This has been demonstrated in one systematic study of 39 children with VGKC–complex antibodies (Hacohen et al., 2015), and suggests that they may be non-pathogenic biomarkers for inflammatory disease.

Clinical course and prognosis While there are no formally accepted diagnostic criteria for these diseases, there are a number of highly distinctive features. Recognition of the clinical features can be supported by paraclinical investigations, especially antibody testing. However, as observed in other antibodymediated syndromes, there are a number of patients who do not have the antibody but who do show the core clinical syndrome. These “seronegative” patients are important to diagnose clinically and often treated in the same way as the seropositive patients (Vincent et al., 1998; Hart et al., 2002; Samarasekera et al., 2007; Rinaldi et al., 2009; Irani et al., 2012).

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features, and 25% describe insomnia or anxiety: in one study 2 of 60 (3%) patients required antipsychotics for severe psychiatric symptoms (Hart et al., 2002). This CNS involvement was particularly relevant given the clinical descriptions which followed (see below). Around 20% of patients with PNH have a thymoma, sometimes associated with clinical manifestations of myasthenia gravis. A number of other autoimmune and tumor associations have been described, including individual cases with small-cell lung cancer, Addison’s syndrome, rheumatoid arthritis, celiac disease, vitiligo, vitamin B12 deficiency, Hodgkin’s lymphoma, and a plasmacytoma (Hart et al., 2002; Maddison, 2006). A number of these observations led to an antibodymediated hypothesis (Newsom-Davis and Mills, 1993). This was supported by patient improvements following plasma exchange, and by the demonstration of neurophysiologic effects of patient IgG in mice (Sinha et al., 1991; Newsom-Davis and Mills, 1993; Shillito et al., 1995), and the first description of VGKC–complex antibodies (Shillito et al., 1995). Indeed, the disease usually referred to as MoS was principally PNH (Morvan, 1890), with only 1 patient demonstrating, in addition, central features, including insomnia.

PERIPHERAL NERVE HYPEREXCITABILITY

MORVAN’S SYNDROME

The term PNH is used to group patients whose disease falls under many synonyms, including Isaacs’ syndrome, Merten’s syndrome, Merten–Isaacs’ syndrome, continuous motor nerve discharges, generalized myokymia, myotonia with impaired muscular relaxation, cramp fasciculation syndrome, and neuromyotonia (NMT) (Maddison, 2006). While pseudomyotonia is described in patients with PNH, true myotonia is not present in this condition, and therefore PNH is the preferred term, although NMT is often used as it refers to specific neurophysiologic findings. Symptoms associated with PNH develop over weeks or months, with cramps, stiffness, weakness, and sensory symptoms (Hart et al., 1997, 2002; Heidenreich and Vincent, 1998; Maddison et al., 2006). The distribution of the muscle cramps is often unusual, affecting limbs but also trunk and sometimes face. Weakness occurs in about 30% of patients and can be clinically confirmed. The sensory features, seen in around 30% of patients, include dysesthesias, paresthesias, and numbness. Many patients notice visible muscle contractions, electrophysiologically, often termed myokymia, and impaired muscle relaxation (pseudomyotonia). In addition, some patients can develop focal dystonia (Gantenbein et al., 2010). Around 40% of patients with PNH have hyperhidrosis, with few other autonomic

The first patient with MoS clearly related to VGKC– complex antibodies was described in 2001 (Liguori et al., 2001), and since then around more than 50 cases have been reported in the literature (Irani et al., 2012). There are a number of highly characteristic features (Table 11.1): marked male predominance (9 male: 1 female), onset in later life (median 57 years, range 19–80 years), co-occurrence of CNS and peripheral nervous system features, and the nature and severity of these features (Abou-Zeid et al., 2012; Irani et al., 2012). Patients develop profound insomnia, with day–night pattern reversal. Sleep–wake cycle disruptions (Cornelius et al., 2011) can be associated with stereotyped gestures (“oneiric stupor”) and autonomic hyperactivity, collectively termed agrypnia excitata (Montagna and Lugaresi, 2002; Lugaresi et al., 2011). The dysautonomia in patients with MoS is usually severe, and affects multiple organs, with hyperhidrosis, tachycardia, labile blood pressure, and urinary features as the commonest manifestations (Josephs et al., 2004; Bajaj and Shrestha, 2007; Diaz-Manera et al., 2007). The neuropsychiatric features are confusion (65%), amnesia (55%), hallucinations (52%), agitation (35%), and delusions (26%). Seizures are seen in 35%, but only rarely include the LGI1 antibody-associated FBDS (Abou-Zeid et al., 2012; Irani et al., 2012). Sometimes patients exhibit other

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features such as small-fiber neuropathy (62%), or features of a larger-fiber neuropathy (52%) (Irani et al., 2012). In fact, VGKC–complex antibodies are associated with other pain syndromes, often in coexistence with a small-fiber neuropathy (Klein et al., 2012; see Chapter 20). VGKC–complex antibodies are not, however, found frequently in complex region pain syndrome (Klein et al., 2012), despite the occurrence of both pain and autonomic disturbance in that condition. Patients with MoS also develop systemic features, including weight loss (48%, even in patients without a tumor) and a high incidence of itch and skin lesions (22%), which may result from a cutaneous dysautonomia. This syndrome carries a higher rate of thymomas than PNH (around 50%) and other tumors are unusual (Vincent and Irani, 2010). There are no clear triggers for this disease but various forms of surgery, most consistently scrotal hydrocele drainage (Sharma and Sharma, 2013), have been associated: this is of interest, given the male preponderance, and as CASPR2 (the commonest antigenic target, see below) is expressed in the prostate (Poliak et al., 1999).

anterograde and retrograde components (Vincent et al., 2004; Frisch et al., 2013; Bettcher et al., 2014; Butler et al., 2014). Some patients behave similarly to the famous patient HM, with “groundhog day” encounters (Deweer et al., 2001). Around 40% of patients have frontal and psychiatric features (Parthasarathi et al., 2006; Somers et al., 2011; Bettcher et al., 2014), and a smaller number have mild autonomic dysfunction (including hyperhidrosis and gut dysfunction: Sekiguchi et al., 2008) and/or sleep disruption, including insomnia and rapid-eye-movement sleep behavior disorder (Iranzo et al., 2006; Cornelius et al., 2011). Seizures are found in 90% of patients. Focal seizures are most common and can be very frequent, while generalized seizures are usually infrequent, with only one or two occurring during the course of the illness. The focal seizures often show a typical medial temporal-lobe semiology with manual and orofacial automatisms, epigastric aura, fear, anxiety, and prolonged limb posturing (Malter et al., 2010; Quek et al., 2012). While these are helpful features, they are, of course, not specific to this illness. By contrast, some specific, and almost pathognomonic, seizure semiologies have been described in recent years.

Limbic encephalopathy Around the time MoS was described with VGKC– complex antibodies, antibodies determined using the same radioimmunoprecipitation assay were found in patients with a noninfectious form of encephalitis (Buckley et al., 2001; Schott et al., 2003; Thieben et al., 2004; Vincent et al., 2004). This is currently the commonest indication for requesting the antibody test and is now a well-recognized treatable form of cognitive impairment and seizures. This disorder has traditionally been termed limbic encephalitis, but as more patients are diagnosed without evidence of magnetic resonance imaging or routine CSF-based evidence of inflammation, the disorder may be better classified as an limbic encephalopathy (Vincent et al., 2004; Parthasarathi et al., 2006). This form of LE shares some clinical overlaps with both PNH and MoS, although there are strikingly different relative frequencies of the overlapping features (Table 11.1). Patients with this form of LE develop amnesia, disorientation, psychiatric features, and seizures (Thieben et al., 2004; Vincent et al., 2004; Irani et al., 2010). Usually this presents over days to weeks, occasionally acutely, but sometimes insidiously, taking many months to reach medical attention. Partly for this reason, the term “autoimmune dementia” has gained favor (Flanagan et al., 2010). The encephalopathy associated with VGKC–complex antibodies shows a slight male preponderance and tends to affect those over 50 years of age (median 63 years; Irani et al., 2010). The amnesia is often profound in the acute phase, affecting

Epilepsies The possibility of antibodies in patients with unexplained epilepsies is not new (Giometto et al., 1998; Palace and Lang, 2000; Peltola et al., 2000; Irani et al., 2011a; Vincent et al., 2011b), and identifying seizures in patients with LE and VGKC–complex antibodies led to further studies. Some looked at patients with other features suggestive of autoimmunity (McKnight et al., 2005; Quek et al., 2012) while others determined frequencies in unselected epilepsy populations (Brenner et al., 2013; Lilleker et al., 2013; Iorio et al., 2015). These studies found 3–5% of cryptogenic epilepsies to be associated with VGKC– complex antibodies. The patients appear to have frequent antiepileptic drug (AED)-resistant seizures, with common neuropsychiatric features (Quek et al., 2012; Brenner et al., 2013; Iorio et al., 2015). In addition, a small number of children with various forms of epilepsy, including status epilepticus, have positive VGKC– complex antibodies (Suleiman et al., 2011a, b). Importantly, however, children very seldom have the specific antibodies to LGI1 or CASPR2 and there are no data yet to support the pathogenicity of the antibodies detected in these patients with epilepsy alone. By contrast, three seizure semiologies have been described recently which are strongly associated with VGKC–complex antibody antibodies and encephalitis. These are ictal bradycardia, piloerection, and FBDS. Seeing these as part of a seizure should make one consider requesting the antibody test. This is especially relevant in

VOLTAGE-GATED POTASSIUM CHANNEL–COMPLEX AUTOIMMUNITY patients with the other characteristics of autoimmune/ antibody-mediated epilepsy, described below. Ictal bradycardia is seen in around 0.5% of patients with seizures on video electroencephalogram (EEG) monitoring units (Marynissen et al., 2012). The implantation of a cardiac pacemaker in patients with ictal bradycardia or ictal asystole can prevent falls and injuries. Two case reports describe VGKC–complex antibody LE with early ictal bradycardia, often in combination with other epileptic features (Naasan et al., 2014; Willis et al., 2014), resulting in cardiac pacemaker implantation in one patient. Interestingly, imaging often showed insular inflammation, a region known to be critical in autonomic function, and the ictal bradycardia preceded the onset of encephalopathy by around 2 months. A few case reports have suggested pilomotor seizures as a specific feature of seizures associated with VGKC– complex antibodies (Wieser et al., 2005), and sometimes other causes of antibody-mediated LE. Indeed, in a recent review of 766 patients attending for video telemetry in specialist epilepsy centers, piloerection was only identified in 5 of 766. All 5 had LE, most commonly associated with LGI1 antibodies (Rocamora et al., 2014). Piloerection has, however, also been associated with other etiologies, such as seizures secondary to brain tumors (Fisch et al., 2012). FBDS are a seizure semiology which are even more suggestive for the LGI1 subtype of antibodies within the VGKC–complex (Irani et al., 2008, 2011b, 2013; Barajas et al., 2010). This seizure semiology was first described when studying patients known to have VGKC–complex antibodies. Extending these observations, a highly specific, and almost pathognomonic, set of clinical events have been described. The seizures typically consist of brief (<3 seconds) events involving posturing of the arm (in 100% of patients) and grimacing of the ipsilateral face (80%). Around 30% of patients have involvement of the leg, which is rarely seen in isolation. The seizures tend to occur on one side or the other, and are seldom simultaneously bilateral. The attacks occur between 10 and 360 times per day. To describe these distinctive frequent focal seizures usually involving dystonic movements of arm and face, the term FBDS was proposed (Fig. 11.1; Irani et al., 2011b; Boesebeck et al., 2013; Yoo and Hirsch, 2014). The coincident ictal occurrence of piloerection, sensory auras, speech arrest plus postictal fear and agitation, despite the infrequent loss of awareness during an event, substantially strengthened the case for these being epileptic in origin rather than a movement disorder (Striano, 2011). Around 60% of patients develop FBDS prior to the onset of the cognitive impairment which characterizes VGKC–complex / LGI1 antibody LE. Around another 30% develop them after recognition of cognitive

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impairment, and a small percentage were noticed to develop FBDS in isolation. These latter patients had been treated with AEDs and immunotherapies and will be discussed further below. In summary, FBDS have a frequent and characteristic semiology and are a form of antibody-mediated epilepsy.

DIAGNOSTIC EVALUATION Other than serum autoantibodies (see below), serum hyponatremia is a frequent clue to the presence of a VGKC–complex antibody LE but rare in the other syndromes (Irani et al., 2012). In all VGKC–complex antibody-associated disorders, as routine CSF tests (including cell count, protein, glucose, and oligoclonal bands) are often normal, CSF may be most useful in helping to exclude other disorders (see differential diagnosis below) (Thieben et al., 2004; Vincent et al., 2004).

Clinicoserologic associations As illustrated in Figure 11.2A, LGI1 antibody-associated disorders are typically LE and FBDS, and some cases with other epilepsies (Irani et al., 2010; Lai et al., 2010). Over 95% of cases with clinically defined FBDS have LGI1 antibodies (Irani et al., 2011b, 2013; Shin et al., 2013). IgG from around 80% of patients with VGKC–complex antibody LE have LGI1 specificity and about 10% have CASPR2 antibodies (Irani et al., 2010; Klein et al., 2013). This fits well with the almost exclusive expression of LGI1 in the CNS (Irani et al., 2010; Kegel et al., 2013). Around 70% of patients with MoS have CASPR2 antibodies, coexisting with LGI1 antibodies in 75% (Irani et al., 2012), and CASPR2 is expressed at the juxtaparanodes in peripheral and central axons. The other patients with MoS have LGI1 antibodies alone, no known specificities, and a few have novel antigenic targets. Finally, around 30% of patients with PNH have CASPR2 antibodies, few have LGI1 antibodies in isolation, and many currently have no known antigenic target (Irani et al., 2010; Rubio-Agusti et al., 2011). The relationship between these antibodies and the clinical features is not absolute and it remains unclear as to why patients with LE rarely demonstrate PNH, and why only some patients with CASPR2 antibodies have CNS and autonomic features. The group of patients whose VGKC–complex antibodies do not recognize one of the three specific antigens LGI1, CASPR2 or contactin-2-includes a small number of patients with Creutzfeldt–Jakob disease (CJD), including genetic prion disease (Jammoul et al., 2014; Jones et al., 2014), some neurodegenerative dementias (Paterson et al., 2014), a high proportion of abattoir workers with polyradiculoneuropathy (Meeusen et al., 2012), other pain syndromes (Klein et al., 2012), and some chronic

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epilepsies (McKnight et al., 2005; Quek et al., 2012; Brenner et al., 2013). VGKC–complex antibodies have also been identified, usually at <400 pM, in conjunction with other cell surface-directed antibodies (e.g., GABAA R (Ohkawa et al., 2014; Pettingill et al., 2015). In many of these situations, these VGKC–complex antibodies may be binding to the intracellular domains of the VGKC subunits themselves or other intracellular proteins of the complex and be secondary to neuronal damage rather than a primary cause (Fig. 11.2A), but in children they appear to be found principally in reversible neuroinflammatory conditions (Hacohen et al., 2015).

INVESTIGATIONS Neuroimaging The classic imaging abnormalities in LE consist of high signal in the hippocampi on T2-weighted or fluidattenuated inversion recovery (FLAIR) sequences (Thieben et al., 2004; Vincent et al., 2004). Imaging changes can be unilateral and can involve the amygdala (Wagner et al., 2015). In patients with FBDS, but not exclusively, the basal ganglia may show inflammation on magnetic resonance and positron emission tomography imaging (Irani et al., 2011b, 2013; Boesebeck et al., 2013). These changes are different to the cortical ribboning and basal ganglia high signal seen on diffusionweighted imaging in CJD (an important differential diagnosis, described below) (Geschwind et al., 2008; Vitali et al., 2011). Once the high signal has disappeared, the medial temporal-lobe structures may show volume loss. This could contribute to the 20% of patients with adult-onset hippocampal sclerosis and temporal-lobe epilepsy (Bien et al., 2000, 2007), and likely results from the neuronal loss seen in the few postmortem or biopsy specimens available (Bien et al., 2012). In MoS, however, despite the multifocal and severe CNS involvement, imaging is usually normal.

Cancer investigation Thymomas are found in patients with MoS (around 50%) and NMT (around 20%) (Vincent and Irani, 2010). Few are found in patients with LE (Erkmen et al., 2011), but as they may occasionally be present, appropriate chest imaging is usually performed. A variety of other cancers have been reported and at rates a little higher than that of the general population (Paterson et al., 2014; Huda et al., 2015).

Electrophysiology Electroencephalography often demonstrates diffuse or focal slowing in around 60% of patients with LE and

MoS. Around 15% of patients with FBDS have proven ictal epileptic discharges, but these are only observed in a minority of events (Irani et al., 2011b). Electromyography is a helpful diagnostic tool in PNH where the peripheral nerve discharges can be detected in the spontaneous and continuous muscle fiber activity with a high intraburst frequency and waning (Gutmann and Libell, 2001; Maddison, 2006). However, it is important to sample fibers in affected muscles, and even then extensive sampling may be required, as not all motor nerves are affected.

DIFFERENTIAL DIAGNOSIS Disorders that may mimic LE include Wernicke– Korsakoff syndrome, infective encephalitis (especially herpes simplex virus), CJD (Geschwind et al., 2008), Hashimoto’s encephalopathy (Lee et al., 2011), nonconvulsive status epilepticus, and drug/toxin overdose. MoS is highly distinctive when the full set of associated features is present, but disorders which may resemble a more limited MoS include motor neurone disease, prion diseases (especially fatal familial insomnia; Liguori et al., 2001; Provini et al., 2008) and heavy-metal (gold, mercury, or manganese) poisoning (Haug et al., 1989; Walusinski and Honnorat, 2013).

PATHOPHYSIOLOGYAND IMMUNOPATHOLOGY Localizations The terminal peripheral nerve endings were discovered to be the localization of NMT pathology by a series of elegant experiments (Isaacs, 1961) which showed ongoing clinical and electrophysiologic discharges after administration of the general anesthetic agent thiopental, and after lidocaine-induced proximal nerve block. By contrast, electric silence was noted after administration of the neuromuscular blocking agent curare (Isaacs, 1961). LE is conventionally localized to the medial temporal lobe. However, patients do have frontal and basal ganglia features which suggest involvement of medial temporal networks or more diffuse localization, consistent with the widespread brain expression profiles of LGI1 and CASPR2 (Poliak et al., 1999; Schulte et al., 2006). MoS appears to show cortical, brainstem, and diencephalon features and, consistent with the latter, the orexin and antidiuretic hormone-expressing neurons are bound by patient antibodies (Irani et al., 2012). However, the localization of the antigen alone does not explain the many distinctive and specific disease features. In FBDS, despite the clinically evident focal localization of the seizures, the EEG is often normal. Therefore other factors,

VOLTAGE-GATED POTASSIUM CHANNEL–COMPLEX AUTOIMMUNITY including relative access of antibody to brain regions, the precise nature of the bound epitopes, and endogenous factors governing neuronal susceptibility and plasticity, are likely to determine the disease manifestations.

Antibody pathogenicity Most authors believe that the LGI1 and CASPR2 antibodies are directly pathogenic. While, of course, T cells must be required for formation of a classswitched hypermutated antibody response, these cells are not thought to be directly pathogenic. Antibodies may mediate pathogenic effects by modulating target function, such as direct channel modulation or internalization, or via complement fixation. Firstly, evidence for antibody pathogenicity comes from the frequently tight correlations between patient antibody levels and clinical state. Two examples are shown for patients with FBDS and LE (Fig. 11.2B and C). In terms of experimental studies, there have been relatively few and the results, although suggestive of an effect on VGKC function, have not been conclusive. Effects of PNH IgG on potassium channel currents in cell lines and primary cultures (Shillito et al., 1995; Tomimitsu et al., 2004), and in some mice injected with patient IgG, were consistent with potassium channel modulation, similar to that seen with aminopyridines (Shillito et al., 1995; Tomimitsu et al., 2004). One study showed that LE IgG induced evidence of hyperexcitability in hippocampal slice cultures, which mimicked the effect of DTX which blocks the VGKC channel itself (Lalic et al., 2011). Another study of many IgG preparations found that LGI1 antibodies prevented the interaction of LGI1 with ADAM22 and ADAM23, the pre- and postsynaptic receptors (Ohkawa et al., 2013), and this was associated with a-amino-3-hydroxy5-methyl-4 isoxazole propionic acid (AMPA) receptor downregulation. Detailed and systematic passive transfer of LE and MoS IgG and active immunization models are required to formally establish mechanisms of antibody pathogenicity. Biopsy and autopsy material from the brains of patients with VGKC–complex antibody LE were compared with biopsies from patients with other forms of autoimmune encephalitis (Bien et al., 2012). In VGKC–complex antibody LE, particularly from a patient who died before treatment commenced, there were relatively few T, B, or plasma cells present in the hippocampus, but there was acute neuronal death and deposition of the terminal complement product, C9neo, consistent with an antibody-mediated attack (Bien et al., 2012). Interestingly, similar findings were observed in brain tissue from felines that develop LGI1 antibody-associated encephalitis (Pakozdy et al., 2014).

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The results were different from those in NMDARantibody encephalitis, where there was little neuronal death and no identifiable complement, although only the frontal cortex was examined in NMDAR-Ab patients, which may limit the interpretation.

THERAPEUTIC APPROACH Symptomatic treatments AEDs are usually sufficient for the treatment of PNH. Occasionally, patients require plasma exchange or alternative immunotherapies (Newsom-Davis and Mills, 1993). AEDs can also be useful in patients with LE and FBDS. However, the seizures are usually refractory to AEDs and respond much better to immunotherapy (see below). Antipsychotics are occasionally required for control of the behavioral disturbance seen in some patients with LE. Of course, identification of a tumor should lead to prompt removal where possible.

Immunotherapy LIMBIC ENCEPHALOPATHY Despite no randomized controlled trials, clinicians who have looked after these patients, and most papers reporting outcomes, suggest immunotherapies have beneficial effects. Retrospective observational studies generate the available evidence. Early treatment seems to be important in improving short-term outcomes (Vincent et al., 2004; Flanagan et al., 2010; Irani et al., 2013), but a retrospective 4-year outcome follow-up suggested no difference between corticosteroids alone, corticosteroids with intravenous immunoglobulins (IVIG), or corticosteroids with IVIG and plasma exchange (Fig. 11.2D) (Irani et al., 2014a). This could indicate that corticosteroids are the key to improving long-term outcomes, but alternatively it is possible that the natural course of the disease is not altered by available immunotherapies. Rituximab appears to have only modest benefit, probably as it does not eliminate CD20-negative plasma cells (Irani et al., 2014b), and the effects are delayed compared with the observed rapid corticosteroid responses. It is of interest that three retrospectively diagnosed patients who received no immunotherapies had variable cognitive impairment but were seizure-free after several years of follow-up (Buckley et al., 2001; Szots et al., 2014); one of the three patients had hippocampal sclerosis.

IN FBDS AND OTHER AUTOIMMUNE EPILEPSIES In FBDS, there are a few clinical observations which make treatment with immunotherapy a more compelling recommendation (Irani et al., 2011b, 2013). Firstly, around 80–90% of patients show no response to AEDs

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but the seizures respond, often very rapidly, to corticosteroids and other immunotherapies. Secondly, the onset of FBDS often precedes the onset of cognitive impairment associated with LE. This has been demonstrated in both retrospective and prospective studies, in around 60% of affected patients. The reported patients treated with immunotherapies, and whose FBDS ceased, did not appear to develop cognitive impairment (Irani et al., 2008, 2011b, 2013, 2014a; Sen et al., 2014; Iorio et al., 2015). This may also have been true for the patients who developed ictal bradycardia early in their disease course without cognitive impairment (Naasan et al., 2014). Thirdly, time to administration of immunotherapy is correlated with time to recovery of baseline function. In recent experience, for both LGI1 antibody-associated LE and FBDS, steroid-sparing agents are seldom required as the disease is often self-limiting after several months. Relapses do occur early in the illness but usually during a too rapid weaning of immunotherapy (Irani et al., 2013). In patients with evidence of VGKC–complex antibody-associated epilepsy without a specific semiology, there are also increasing data to suggest that immunotherapies are more effective than AEDs. This was especially true in patients with more recent-onset seizures and many patients showed a remarkably prompt response to corticosteroids (Quek et al., 2012; Lilleker et al., 2013; Iorio et al., 2015).

FUTURE THERAPIES Drugs which aim to target plasma cell production of IgG are likely to be effective in these, and other, antibodymediated diseases. Alternatively, if the pathology is at least partly complement-mediated, which appears to be the case in the few postmortem or biopsy studies (Bien et al., 2012), drugs which inhibit complement formation might be helpful in reducing the effects of the antibodies and the associated neuronal death and subsequent atrophy.

FUTURE DIRECTIONS The field of VGKC–complex antibodies has generated a number of immunotherapy-responsive conditions in which the antibodies are likely to be pathogenic. This applies in particular to the LGI1 and CASPR2 antibodies, the commonest two known targets within the VGKC– complex. Further studies should aim to establish models in which to study the pathogenicity of these two antibodies and clarify the disease relevance of the other antibodies, currently without known targets. Parallel clinical studies should help establish treatment responses to various therapeutic options and determine the long-term outcomes for these patients.

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