Journal of Neuroimmunology 265 (2013) 75–81

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VGKC-complex/LGI1-antibody encephalitis: Clinical manifestations and response to immunotherapy Yong-Won Shin a,b,1, Soon-Tae Lee a,b,1, Jung-Won Shin a,b, Jangsup Moon a,b, Jung-Ah Lim a,b, Jung-Ick Byun a,b, Tae-Joon Kim a,b, Keon-Joo Lee a,b, Young-Su Kim c, Kyung-Il Park d, Keun-Hwa Jung a,b, Sang Kun Lee a,b, Kon Chu a,b,⁎ a

Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea Program in Neuroscience, Seoul National University College of Medicine, Seoul, South Korea c Department of Neurology, Seoul National University Bundang Hospital, Seoul, South Korea d Department of Neurology, Seoul Paik Hospital, Inje University College of Medicine, Seoul, South Korea b

a r t i c l e

i n f o

Article history: Received 7 July 2013 Received in revised form 7 October 2013 Accepted 11 October 2013 Keywords: Encephalitis LGI1 Immunotherapy

a b s t r a c t Leucine-rich glioma inactivated 1 (LGI1) was recently identified as a target protein in autoimmune synaptic encephalitis, a rare condition associated with autoantibodies against structures in the neuronal synapse. Studies dealing with LGI1 are small in number and the various outcomes of different therapeutic regimens are not well studied. Here, we analyzed clinical characteristics of 14 patients with LGI1 antibodies, and outcomes according to therapeutic strategies. Most patients exhibited abnormal brain positron emission tomography and that patients treated with steroids alone were more likely to relapse and had less favorable outcomes than those treated with steroids and intravenous immunoglobulins. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Autoimmune synaptic encephalitis (ASE) is a disorder that is associated with antibodies targeting the cell surface or synaptic proteins. Reported symptoms of ASE include seizure, memory dysfunction, abnormal behavior, and decreased consciousness. The known neuronal autoantigens associated with ASE include N-methyl- D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid receptor-B (GABAB-R), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated proteinlike 2 (CASPR2), contactin-2, glycine receptor (GlyR), and metabotropic glutamate receptor 5 (mGluR5) (Bien and Scheffer, 2011; Vincent et al., 2011; Lancaster and Dalmau, 2012; Rubio-Agusti et al., 2013). Interestingly, it has recently come to light that LGI1, CASPR2 and, less frequently, contactin-2 are specific targets of voltage-gated potassium channel (VGKC)-complex antibodies (Irani et al., 2010; Lai et al., 2010; Vincent and Irani, 2010; Lancaster et al., 2011a, 2011b; Paterson et al., in press). Ever since anti-NMDAR encephalitis was first recognized, many patients with idiopathic encephalitis have been diagnosed with ASE

⁎ Corresponding author at: Department of Neurology, Seoul National University Hospital, 101 Daehang-no, Chongro-gu, Seoul 110-744, South Korea. Tel.: + 82 2 2072 1878; fax: + 82 2 2072 7424. E-mail address: [email protected] (K. Chu). 1 The first two authors contributed equally to this work. 0165-5728/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jneuroim.2013.10.005

(Dalmau et al., 2007). However, aside from the discovery of several antibodies associated with the disorder, a general lack of knowledge about ASE limits our understanding of the disease's characteristics and therapeutic outcome. The benefit of early therapy and of immunotherapy responsiveness has addressed in previous studies of VGKC-complex associated encephalitis (Thieben et al., 2004; Vincent et al., 2004; Irani et al., 2008; Tan et al., 2008; Quek et al., 2012). However, no study has compared outcomes in patients with LGI1 antibodies after immunotherapy between initial monotherapy and combination therapy. Additionally, to our knowledge, there has only been 1 study evaluating fluorodeoxyglucose positron emission tomography (FDG-PET) findings of VGKC-complex associated encephalitis with only LGI1 antibodies (Irani et al., 2011). Here, we present 14 cases of VGKC-complex/LGI1antibody encephalitis, including an evaluation of the FDG-PET findings, and a description of the overall treatment outcome.

2. Methods This study comprised of 631 consecutive patients who were suspected of having autoimmune encephalitis between June 2012 and May 2013. Clinical features, electroencephalogram (EEG), brain magnetic resonance image (MRI), laboratory findings, cerebrospinal fluid (CSF) profile, wholebody and brain FDG-PET, and other radiologic screenings for a systemic neoplasm were reviewed. Clinical information was obtained by the authors or provided by referring physicians.

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In the majority of patients, autoantibodies to NMDAR, LGI1, CASPR2, AMPA1, AMPA2, GABAB-R, and classic paraneoplastic antibodies (antiHu, -Yo, -Ri, -Ma2, -CV2/CRMP5, and -Amphiphysin) were checked by indirect immunofluorescence test on serum or CSF (Euroimmune Ag, Germany). Two patients (see Table 2) visited our institution before autoantibody studies for limbic encephalitis were available; therefore, these patients were screened for antibodies to either NMDAR, LGI1, CASPR2, GlyR or NMDAR, LGI1, AMPA 1, AMPA2, or GlyR outside of our institution (John Radcliffe Hospital, Oxford, UK). In all patients, testing for contactin-2 was not conducted. Studies were approved by the institutional review boards of the Seoul National University Hospital. Kendall's tau-b or c was used as appropriate correlation analyses for binary and ordinal data. SPSS 18.0 (SPSS Inc., Chicago, IL) was used for the all analyses and p b 0.05 was considered as statistically significant. 3. Results 3.1. Clinical features of anti-LGI encephalitis Among the 125 patients (19.8%) who showed positive results, NMDAR antibodies were identified in 80 patients (64% of positive cases), GABAB-R antibodies were present in 4 patients (3.2%), and AMPA1, AMPA2, and CASPR2 antibodies were found in 1 patient (0.8%) each. Additionally, classic paraneoplastic antibodies were found in 19 patients (15.2%). LGI1 antibodies were identified in 14 patients (11.2%) ranging in age from 41 to 78 years (median, 60.5 years), with a male to female ratio of 4:3. All patients presented with seizures, 4 of which had (36%) status epilepticus (3 with non-convulsive status epilepticus). Additionally, among the 14 patients, 10 (71.4%) experienced faciobrachial dystonic seizures (FBDS), while 12 patients (85.7%) showed cognitive dysfunction, mainly deficits in memory and abnormal behavior, and 3 patients (21.4%) exhibited autoimmune dysautonomias, such as orthostatic hypotension, constipation, and urinary incontinence. Clinical characteristics are summarized in Tables 1 and 3. 3.2. Diagnostic testing for VGKC-complex/LGI1-antibody encephalitis Tables 2 and 3 and Fig. 1 shows EEG, brain MRI, brain FDG-PET, and CSF findings. Ten of the 14 patients (76.9%) exhibited abnormalities in their EEGs, with epileptiform discharges being detected in 8 patients (61.5%) and focal rhythmic slowing in 2 patients. MRI scans were

Table 1 Demographic and clinical featuresa. Patient Age Sex Symptom/signs 1 2 3

43 43 61

F M M

4 5

70 73

F M

6 7 8 9

41 60 61 78

M F F F

10 11 12 13

66 53 62 55

M M F M

14

58

M

FBDS, seizure, memory impairment, confusion, abnormal behavior Seizure, decreased mentality FBDS, memory impairment, abnormal behavior, decreased mentality FBDS, memory impairment, confusion FBDS, memory impairment, confusion, tremor, orthostatic hypotension, constipation, urinary incontinence, insomnia, depression Seizure Seizure, confusion, abnormal behavior FBDS, other seizure, memory impairment FBDS, abnormal behavior, confusion, agitation, tremor, insomnia, orthostatic hypotension FBDS, seizure FBDS, seizure, memory impairment, confusion Seizure, memory impairment FBDS, seizure, memory impairment, confusion, constipation, urinary incontinence, insomnia FBDS, seizure, memory impairment

FBDS, faciobrachial dystonic seizure. a Patient 2 had convulsive status epilepticus and patients 1, 4 and 9 showed nonconvulsive status epilepticus.

performed in all patients, with 10 patients (71.4%) showing increased signals on MRI fluid-attenuated inversion recovery or T2 sequences. Nine patients (64.3%) had medial temporal lesions, and 5 (55.6%) of them exhibited bilateral lesions, while 1 patient showed multiple lesions in the bilateral basal ganglia, thalamus, white matter, and central pons. Brain sections of FDG-PET images were available for review in 10 patients; 7 (70%) of which showed hypermetabolism in the medial temporal areas (3 of them exhibited hypermetabolism bilaterally), and 7 patients (70%) demonstrated bilateral hypermetabolism in the basal ganglia. Of the 13 patients who underwent CSF examination, 10 (76.9%) were found to have normal CSF while 3 had mildly increased protein concentrations (58 mg/dL, 55 mg/dL, and 58.9 mg/dL) and 1 had mild white blood cell pleocytosis (6/mm3). Screening for malignant tumors via computed tomography (CT) of the chest and abdomen, or whole-body FDG-PET imaging, revealed normal findings, except for 1 subject who was found to have renal cell carcinoma. Paraneoplastic antibodies (anti-Hu, -Yo, -Ri, -Ma2, -CV2/CRMP5, and -Amphiphysin) were not detected in any of the 12 patients who were screened (patients 3 to 14). Of the various tests used for detecting intracranial pathology, brain FDG-PET is the most sensitive test in detecting abnormalities (90%) followed by EEG (76.9%) and MRI (71.4%). There were 2 patients who showed only brain FDG-PET abnormalities among these 3 tests, and bilateral basal ganglia hypermetabolism was the sole abnormality in 1 patient. Among the 10 patients who were evaluated using both MRI and FDG-PET, 7 showed medial temporal lesions and exactly the same number of patients had basal ganglia lesions. Additionally, of the 8 patients who had FBDS and underwent both MRI and FDG-PET, 5 showed temporal abnormalities and 7 exhibited a disruption in the basal ganglia. Therefore, the number of patients who presented basal ganglia abnormalities was not significantly different from that of the patients who had medial temporal lesions. Additionally, within the patients presenting FBDS, detection rates of altered glucose metabolism was found to be higher in the basal ganglia than in the temporal area. Among the 4 patients who presented with status epilepticus (SE), 3 underwent FDG-PET scans and all showed medial temporal hypermetabolism. The presence of SE positively correlated with medial temporal lesions, nearly reaching statistical significance (τb = 0.429, p = 0.053). Additionally, abnormalities in the basal ganglia were found in 2 patients, which we found were not correlated with SE (τb = −0.048, p = 0.882). Lastly, initial modified Rankin Scores (mRS) were not associated with either medial temporal (τc = 0.346, p = 0.231) or basal ganglia abnormalities (τc = 0.099, p = 0.814), and the detection of medial temporal lesions via MRI was not associated with either SE (τb = 0.239, p = 0.379) or initial mRS (τc = 0.343, p = 0.809). 3.3. Different outcomes according to treatment regimen and time point of therapy initiation Records of the clinical course taken were available for review in 12 of the 13 patients that received immunotherapy (Table 2). We divided these 12 patients into 2 groups according to initial treatment; group 1 consisted of 7 patients who were treated with corticosteroids only while group 2 comprised of 5 patients who concurrently received both corticosteroids and intravenous immunoglobulins (IVIg). In group 1 (corticosteroid only; n = 7), all patients demonstrated positive responses to immunotherapy and exhibited symptomatic improvement. Two of the 7 patients (28.6%) showed a dramatic response, in that there was a near complete recovery of cognitive function and an mRS of 0 with a complete loss of FBDS and other symptoms, while 2 different patients (patients 9 and 13) initially showed only a partial response to corticosteroid treatment, but addition of IVIg therapy yielded a greater improvement in cognitive function and suppressed seizure activity. In group 2 (combined immunotherapy; n = 5), 4 patients (80%) showed a dramatic response with a near complete recovery and no relapse. Patient 2 showed minimal response to combined

Table 2 Ancillary tests, time from onset to diagnosisa, treatment and outcome. EEG

MRI

Brain FDG-PET

CSF

Tumor (modality)

Time from symptom onset to diagnosis (onset)

Treatment, ordered chronologically

mRS initial ➔ final (duration of follow-up)

Relapse

1

Rhythmic theta to delta activity, bilateral temporal areas PLEDs, Lt. hemisphere

T2 high signal in the bilateral mT

Hypermetabolism in the bilateral mT and BG

Normal

Not found (PET-CT)

9 months (2011.8)

MPd, IVIg, Plasmapheresis, Rituximab, Tacrolimus

3 ➔ 2 (1 year and 5 months)

Yes

Multiple lesionsb

Diffuse hypometabolism with bilateral medial temporal hypermetabolism

WBC 6/μL, Protein 58 mg/dL

Not found (PET-CT)

2 years (2010.4)

5 ➔ 5 (2 years)

No

T2 high signal in the left mT T2 high signal in the bilateral mT Normal

Hypermetabolism in the left mT and bilateral BG Hypermetabolism in the left mT and bilateral BG No abnormal hypermetabolic lesion Hypermetabolism in the left mT N/A

Normal

Not found (PET-CT)

1 month (2012.9)

Oral prednisolone + IVIg, azathioprine, Cyclophosphamide, Rituximab MPd + IVIg

3 ➔ 0 (5 months)

No

Normal

Not found (PET-CT)

3 days (2012.10.8)

MPd + IVIg

3 ➔ 0 (5 months)

No

N/A

Not found (PET-CT)

3 years (2009)

MPd + IVIg, Tacrolimus

2 ➔ 0 (1 year)

No

Normal

Not found (PET-CT)

≤1 month (2012.12)

MPd

2 ➔ 0 (3 months)

No

Protein 55 mg/dL

Not found (CT)

≤1 month (2013.1)

MPd, azathioprine

3 ➔ 1 (6 months)

Yes

N/A

Normal

Not found (CT)

2 months (2012.12)

No immunotherapy

N/A

No

N/A

Normal

Not found (CT)

2 months (2012.1)

MPd, IVIg

3 ➔ 2 (4 months)

No

Hypermetabolism in the bilateral BG Hypermetabolism in the bilateral mT and BG N/A

Normal

Not found (PET-CT)

≤1 month (2013.2)

MPd

2 ➔ 0 (3 months)

No

Normal

≤1 month (2013.2)

MPdc

2 ➔ 1 (2 months)

No

Normal

Renal cell carcinoma (PET-CT) Not found (PET-CT)

4 years (2009.4)

Oral prednisolone

3 ➔ N/A

N/A

Normal

Not found (PET-CT)

5 weeks (2013.4)

MPd, IVIg, Rituximab

3 ➔ 1 (1 month)

No

Protein 58.9

Not found (PET-CT)

6 weeks (2013.3)

MPd + IVIg

3 ➔ 0 (1 month)

No

2

3

7

Focal slowing, right temporal area Spikes-and-waves, left frontotemporal areas Spikes-and-waves, left temporal area Spikes-and-waves, left frontotemporal area Normal

8

N/A

9

10

Epileptiform discharge, rt. posterior temporo-occipital areas Normal

11

Normal

Normal

12

Frequent sharp wave, right temporal area Spikes-and-waves, right frontal area Semirhythmic delta slow activity, both frontotemporal area

T2 high signal in the bilateral mT T2 high signal in the left mT Normal

4 5 6

13 14

T2 high signal in the bilateral mT T2 high signal in the bilateral mT T2 high signal in the right mT T2 high signal in the bilateral mT Normal

Hypermetabolism in the left mT and bilateral BG Hypermetabolism in the bilateral BG

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Patient

EEG, electroencephalogram; MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; PET, positron emission tomography; CSF, cerebrospinal fluid; mRS, modified Rankin Scale; mT, medial temporal lobe; BG, basal ganglia; CT, computed tomography; MPd, intravenous methylprednisolone pulse therapy 500 mg or 1 g for 5 days; IVIg, intravenous immunoglobulin, 400 mg/kg for 5 days; PLEDs, periodic lateral epileptiform discharges; WBC, white blood cells; Oral prednisolone + IVIg, concurrent administration of oral prednisolone and IVIg; MPd + IVIg concurrent administration of MPd and IVIg; N/A, not applicable; NMDAR, N-methyl-D-aspartate receptor; LGI1, leucin-rich glioma-inactivated 1; CASPR2, contactin-associated protein-like 2; GlyR, glycine receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. a Patient 1 was screened for antibodies to NMDAR, LGI1, CASPR2, and GlyR, and patient 2 was screened for antibodies to NMDAR, LGI1, AMPAR 1, AMPAR 2, and GlyR (John Radcliffe Hospital, Oxford, UK). b T2 high signal in the central pons, bilateral basal ganglia, thalamus, and white matter, with diffusion restriction. Diffuse cerebral cortical gyral swelling with enhancement. c Intravenous methylprednisolone 250 mg for 2 days.

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Y.-W. Shin et al. / Journal of Neuroimmunology 265 (2013) 75–81 Table 3 Summary of clinical assessment. Subject characteristics

No. (%)

Age, yr, median (range) Male Clinical features Seizure FBDS Cognitive dysfunction Autonomic dysfunction EEG (of 13 patients) Total abnormality Epileptiform discharge Slowing MRI Total abnormality Medial temporal Unilateral Bilateral Other regiona Brain FDG-PET (of 10 patients) Total abnormality Medial temporal Unilateral Bilateral Bilateral basal ganglia CSF (of 13 patients) Total abnormalityb Pleocytosis Increased protein concentration Tumor

60.5 (41–78) 8 (57.1) 14 (100) 10 (71.4) 12 (85.7) 3 (21.4) 10 (76.9) 8 (61.5) 2 (15.4) 10 (71.4) 9 (64.3) 4 (28.6) 5 (35.7) 1 (7.1) 9 (90) 7 (70) 4 (40) 3 (30) 7 (70) 3 (23.1) 1 (7.7) 3 (23.1) 1 (7.1)

FBDS, faciobrachial dystonic seizure; EEG, electroencephalogram; MRI, magnetic resonance imaging; FDG-PET, fluorodeoxyglucose positron emission tomography; CSF, cerebrospinal fluid. a Central pons, bilateral basal ganglia, thalamus, and white matter. b CSF white blood cell count of N5/μL and protein levels of N45 mg/dL were considered abnormal.

immunotherapy, but was suffering refractory convulsive status epilepticus and was taking anticonvulsants without immunotherapy for 1 month before being admitted to our institution. The JFK coma recovery scale-revised score (Giacino et al., 2004) of this patient was a 3, and the score only improved to 5 after combination therapy. Additional treatment with azathioprine, cyclophosphamide, and rituximab was not effective. A correlation analysis showed no significant association with initial treatment regimen (corticosteroid only or addition of IVIg) and outcome measured by mRS (τc = − 0.321, p = 0.271; Fig. 2A). However, when another analysis was run which excluding patient 2, we found a significant association between treatment regimen and outcome (τc = − 0.661, p = 0.001). Achievement of mRS = 0 also correlated with initial treatment regimen (τb = 0.507, p = 0.042; Fig. 2B). During the follow-up period (median, 4.5 months; range, 1– 24 months), 2 patients in group 1 (patients 1 and 7) showed clinical relapses. Patient 1 had 2 relapses at 1 and 3 months after initial treatment. A few days after steroid discontinuation, the patient showed motionless staring and aggravation of memory impairment. Following treatment with IVIg, this patient improved, but the symptoms recurred once again manifesting as generalized tonic–clonic seizures 3 months after the initial treatment period. Five cycles of plasmapheresis achieved another improvement, and the patient finally demonstrated a lack of relapse during the 1-year follow-up period after receiving rituximab and tacrolimus. Patient 7 also had 1 relapse with a pilomotor seizure occurring 4 months after treatment. This patient started taking azathioprine; however, the evaluation of the efficacy of azathioprine was limited to a short period of time during the follow-up (1 month). Lastly, no patient in group 2 experienced a clinical relapse. Association between initial treatment regimen and relapse, however, didn't reach statistical significance (τc = −0.278, p = 0.099). Time from initial symptom onset to immunologic diagnosis was variable, and ranged from 3days to 4years (median, 2months). However, 10 patients were correctly diagnosed within 2 months and 9 of these

patients received immunotherapy. Four of the 6 patients who received immunotherapy within 1 month from symptom onset showed dramatic improvements and all 5 patients who received immunotherapy within 1month demonstrated a good outcome with mRS≤1. Treatment initiated within 1 month of symptom onset seemed to be associated with clinical outcome (τc = −0.500, p = 0.058; Fig. 2A). However, outcome measured by achievement of mRS = 0 failed to show statistical significance (τb = 0.333, p = 0.221; Fig. 2B). Taken together, all patients showed at least partial response to immunotherapy with 6 patients (50%) exhibiting a near complete recovery. Excluding patient 2, all patients in group 2 demonstrated a complete loss of symptoms, and 2 patients who initially received corticosteroid alone showed additive effects with IVIg. Two patients had 3 relapses, both of whom were initially treated with corticosteroids only. The addition of rituximab and tacrolimus lead to a cessation of any further relapse in 1 of these 2 patients. Statistical analyses suggest initial treatment regimen and early therapy may be associated with better outcome. 3.4. Brain image findings and treatment outcome We also analyzed the association of FDG-PET and MRI results with outcome. Patients without medial temporal hypermetabolism on FDG-PET scans were associated with better outcome and lower mRS (τc = − 0.480, p = 0.02; Fig. 2C). Recovery with mRS = 0 was also related to medial temporal hypermetabolism (τb = − 0.535, p = 0.02; Fig. 2D). Among patients with medial temporal lesions, a unilateral lesion was associated with a favorable outcome (τc = 0.898, p b 0.001; Fig. 2C) and achievement of mRS = 0 (τb = 0.750, p = 0.001; Fig. 2D). In contrast, basal ganglia hypermetabolism had no association with mRS (τc = −0.040, p = 0.907) or achievement of mRS = 0 (τb = −0.089, p = 0.774), and medial temporal lesions on MRI also failed to show association with mRS (τc = 0.111, p = 0.726) or recovery to mRS = 0 (τb = −0.169, p = 0.552). None of these image parameters were related to recurrence. 4. Discussion LGI1 is a glycoprotein secreted from presynaptic terminals that interacts with presynaptic ADAM22 and postsynaptic ADAM23, and influences synaptic transmission by regulating presynaptic kv.1 channels and postsynaptic AMPA receptors (Lai et al., 2010). It is accepted that mutations in the LGI1 gene are responsible for autosomal dominant partial epilepsy with auditory features (Kalachikov et al., 2002), and knock-out mice void of LGI1 expression develop lethal epilepsy (Fukata et al., 2010). The association between LGI1 and ASE was identified recently (Lai et al., 2010) showing that VGKC-complex/LGI1-antibody encephalitis usually invades the medial temporal area and causes memory dysfunction and seizures. Additionally, bilateral lesions in the basal ganglia are frequently found in brain FDG-PET scans. FBDS is a characteristic finding in VGKC-complex/LGI1-antibody encephalitis, and it usually precedes other manifestations (Irani et al., 2011). Abnormal, involuntary movement is brief, usually lasting less than 3 s, but slower than myoclonus. Additionally, dozens of stereotyped movements can be viewed in a 1 day observation period. The seizure-like episodes were initially described in patients with limbic encephalitis and VGKC-complex antibodies (Irani et al., 2008; Barajas et al., 2010), which were later termed as FBDS (Irani et al., 2011) after identification of the LGI1 antibody. The relationship between LGI1, limbic encephalitis and FBDS has also been discussed in other reviews (Bien and Scheffer, 2011; Vincent et al., 2011; Rubio-Agusti et al., 2013). Whole body FDG-PET scans are often conducted to find hidden malignancy because early detection and removal of neoplasms are associated with better outcomes in some cases of ASE and paraneoplastic limbic encephalitis (Basu and Alavi, 2008; Titulaer et al., 2013). Additional information may also be obtained from brain sections of

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Fig. 1. Brain magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) findings. T2-weighted or fluid attenuated inversion recovery MRI scans show high signals in the medial temporal lobes (A, B, E, F, I, J, M, N). F-18 FDG-PET images shows hypermetabolism in the medial temporal lobes (C, D, G, H, K, O, P) and basal ganglia (D, H, P). Images from patient 1 (A–D), patient 2 (E–H), patient 3 (I–L), patient 9 (M), and patient 4 (N–P) are presented.

the VGKC-complex/LGI1-antibody encephalitis. Irani et al. proposed that the basal ganglia involvement observed by FDG-PET is a relatively specific feature of patients with FBDS and that the involvement of this brain area may also be related to the movement (Irani et al., 2011). However, it is still controversial whether FBDS is a seizure or just an extrapyramidal manifestation (Irani et al., 2011; Andrade et al., 2011; Striano, 2011; Plantone et al., 2013). In our study, 10 patients (71.4%) had FBDS and 7 of 8 who underwent FDG-PET showed hypermetabolism in the bilateral basal ganglia. Interestingly, there was 1 patient who had basal ganglia hypermetabolism as a sole finding out of all the ancillary tests we performed. This supports the previous report that FBDS, along with basal ganglia hypermetabolism, precedes limbic encephalitis (Irani et al., 2011). According to the report 9 of 9 patients who had FBDS without cognitive impairment showed normal MRI scans. After presenting limbic encephalitis, 12 of 26 patients had normal MRI scans, but abnormal glucose metabolism in the basal ganglia was observed in 5 of 8 patients using FDG-PET (Irani et al., 2011). Another study also showed that 15 of 32 patients with autoimmune epilepsy demonstrated negative findings on MRIs, but development of inflammatory changes were observed in 5 of 12 patients who had subsequent MRIs (Quek et al., 2012). Our results revealed a high rate of total abnormality (90%) in the FDG-PET study with more abnormalities found in the basal ganglia (7 of 10) than the

medial temporal area (5 of 10). These findings are in contrast to the MRI abnormalities observed in 10 of the 14 patients (71.4%). Therefore, FBDS and FDG-PET scans can aid in the diagnosis of VGKC-complex/ LGI1-antibody encephalitis even though MRIs and EEGs may show negative results. The diagnostic value of FDG-PET in patients suspected of having ASE, but that have found to be negative for LGI1 antibodies and for differential diagnosis of ASE or encephalitis cases with other etiology needs further investigation which we are now working to address. In addition to our findings in support of the value of FDG-PET as a diagnostic tool, we found that the presence of medial temporal hypermetabolism and bilaterality was associated with a less favorable outcome. Therefore, the prognostic value of FDG-PET is also worth further studies and over larger populations. VGKC-complex/LGI1-antibody encephalitis has been known to be weakly associated with cancer (Irani et al., 2011; Lancaster and Dalmau, 2012), and in the current study, there was only 1 patient who had been diagnosed with cancer, specifically renal cell carcinoma; however, this may be an incidental finding unrelated to VGKC-complex/LGI1-antibody encephalitis. While cancer is weakly associated with VGKC-complex/ LGI1-antibody encephalitis, hyponatremia is a characteristic feature of the encephalitis (Lai et al., 2010) and we found 6 patients with hyponatremia.

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Fig. 2. Association of therapeutic outcome with initial treatment regimen, timing of treatment, and brain imaging findings. Graphs show the distribution of final mRS of VGKC-complex/ LGI1-antibody encephalitis patients according to initial therapeutic regimen, timing of treatment (A, B), and medial temporal hypermetabolism on fluorodeoxyglucose positron emission tomography (FDG-PET; C, D). Outcome was analyzed by final modified Rankin Score (mRS; A, C) or achievement of mRS = 0 (B, D). Patients in group 2 showed better outcome and significantly more patients in group 2 achieved mRS = 0 (p = 0.042). Patients who started immunotherapy within 1 month also seemed to be associated with better outcome, however, it didn't reach statistical significance (p = 0.058). Existence and bilaterality of medial temporal hypermetabolism on FDG-PET scans were associated with less favorable outcome (p = 0.02 and p b 0.001, respectively). Achievement of mRS = 0 also correlated with the presence and bilaterality of medial temporal lesion (p = 0.02 and p = 0.001, respectively). Group 1, corticosteroid only group; Group 2, combination therapy with corticosteroid and intravenous immunoglobulin; IVIg, intravenous immunoglobulin; mT lesion, existence of medial temporal hypermetabolism; Unilateral mT, presence of unilateral hypermetabolism on either side of the medial temporal lobe (*p b 0.05).

Previous reports have demonstrated that VGKC-complex/LGI1antibody encephalitis is fairly responsive to immunotherapy (Thieben et al., 2004; Vincent et al., 2004; Irani et al., 2008; Tan et al., 2008; Irani et al., 2011; Quek et al., 2012). One of the suggested guideline is using high doses of corticosteroid, IVIg and plasmapheresis as firstline therapy and adding rituximab and cyclophosphamide as secondline therapies in refractory cases (Lancaster et al., 2011a). Recently, an observational study on 577 patients with anti-NMDAR encephalitis showed that second-line therapy can be effective in refractory cases and can even reduce relapse events (Titulaer et al., 2013). In our study, all patients responded to first-line immunotherapy. Impressively, and with the exception of 1 patient who was comatose and did not receive immunotherapy, all patients with combination therapy showed a near full recovery in comparison to the corticosteroidonly group that demonstrated 3 relapses (along with 2 cases where additional immunotherapy was used to control symptoms). Second-line therapy was effective in 1 patient who had recurrent relapses. A recent report by Quek et al. presented 32 cases of autoimmune epilepsy (Quek et al., 2012), and in that cohort we extracted data from the 14 patients that exhibited LGI1 antibodies. Of these 14 patients who received immunotherapy 9 of the patients initially received corticosteroids only and 3 of them underwent relapses including 2 patients who did not achieve a seizure-free state following immunotherapy. In contrast, seizure freedom and absence of relapse were seen in 4 patients who received 2 or 3 of the first-line agents. It should be noted that there was a lack of a detailed regimen in 1 patient. There are 2 approaches that can be taken when treating patients with firstline immunotherapy: the first approach deals with using 1 first-line agent and adding another agent in when a patient relapses or shows insufficient response. The second approach deals with treating the patient with an initial combination therapy. Corticosteroid monotherapy usually shows good response with or without mild sequelae. However, none of the patients who showed recurrence or partial response to corticosteroid monotherapy in our study achieved complete recovery. Likewise, among the 14 patients with LGI1 antibodies in the previous report,

2 of 3 patients who relapsed failed to reach seizure freedom (Quek et al., 2012). Considering the generally fair response to immunotherapy in VGKC-complex/LGI1-antibody encephalitis, therapeutic targets should aim to achieve outcomes that are not comprised of bothersome sequelae of FBDS or intermittent seizures. Although the association between therapeutic regimen and rate of relapse failed to reach statistical significance in our study, our results, taken together with those of the 14 cases in the previous report (Quek et al., 2012), provide a compelling argument that combination therapy might be superior to monotherapy in reducing the rate of relapse and improving the degree of recovery. VGKC-complex/LGI1-antibody encephalitis is distinguishable from other ASE types because of FBDS, basal ganglia hypermetabolism in FDG-PET, hyponatremia, a weak association with cancer, and its good response to immunotherapy. Thus, in the absence of MRI and EEG abnormalities, both FBDS and hypermetabolism in the basal ganglia in FDG-PET would be helpful in the early diagnosis of VGKC-complex/ LGI1-antibody encephalitis. While symptoms may be limited to FBDS, delayed immunotherapy can culminate in status epilepticus and can even lead to coma. Although antiepileptic drugs have some role in controlling seizure activity, their effects are limited. Near full recovery can be expected if immunotherapy is conducted within a short period after symptom onset and second-line therapy could be helpful in refractory cases. Lastly, combination therapy might be superior to corticosteroids, but this needs further evaluation because of the limited number of patients and short follow-up period in the current study.

Acknowledgment This study was supported by a grant from the Ministry of Health and Welfare (A120480-1201-0000100). S.K.L. was supported by Seoul National University Hospital (0420130580). K.H.J. was supported by Seoul National University Hospital (0420131120, 0420120990). The authors thank Hong-Il Seo, Yoo-Jin Lee, Duk-Soo Park, Sang-Won Yoo, and Hyunjin Kim for providing clinical information of the patients.

Y.-W. Shin et al. / Journal of Neuroimmunology 265 (2013) 75–81

References Andrade, D.M., Tai, P., Dalmau, J., Wennberg, R., 2011. Tonic seizures: a diagnostic clue of anti-LGI1 encephalitis? Neurology 76, 1355–1357. Barajas, R.F., Collins, D.E., Cha, S., Geschwind, M.D., 2010. Adult-onset drug-refractory seizure disorder associated with anti-voltage-gated potassium-channel antibody. Epilepsia 51, 473–477. Basu, S., Alavi, A., 2008. Role of FDG-PET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying malignancy and the brain PETMRI correlates. Mol. Imaging Biol. 10, 131–137. Bien, C.G., Scheffer, I.E., 2011. Autoantibodies and epilepsy. Epilepsia 52, 18–22. Dalmau, J., Tüzün, E., Wu, H., Masjuan, J., Rossi, J.E., Voloschin, A., Baehring, J.M., Shimazaki, H., Koide, R., King, D., Mason, W., Sansing, L.H., Dichter, M.A., Rosenfeld, M.R., Lynch, D.R., 2007. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann. Neurol. 61, 25–36. Fukata, Y., Lovero, K.L., Iwanaga, T., Watanabe, A., Yokoi, N., Tabuchi, K., Shigemoto, R., Nicoll, R.A., Fukata, M., 2010. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc. Natl. Acad. Sci. U.S.A. 107, 3799–3804. Giacino, J.T., Kalmar, K., Whyte, J., 2004. The JFK coma recovery scale-revised: measurement characteristics and diagnostic utility. Arch. Phys. Med. Rehabil. 85, 2020–2029. Irani, S.R., Buckley, C., Vincent, A., Cockerell, O.C., Rudge, P., Johnson, M.R., Smith, S., 2008. Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology 71, 1647–1648. Irani, S.R., Alexander, S., Waters, P., Kleopa, K.A., Pettingill, P., Zuliani, L., Peles, E., Buckley, C., Lang, B., Vincent, A., 2010. 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, 2734–2748. Irani, S.R., Michell, A.W., Lang, B., Pettingill, P., Waters, P., Johnson, M.R., Schott, J.M., Armstrong, R.J.E., S Zagami, A., Bleasel, A., Somerville, E.R., Smith, S.M.J., Vincent, A., 2011. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69, 892–900. Kalachikov, S., Evgrafov, O., Ross, B., Winawer, M., Barker-Cummings, C., Martinelli Boneschi, F., Choi, C., Morozov, P., Das, K., Teplitskaya, E., Yu, A., Cayanis, E., Penchaszadeh, G., Kottmann, A.H., Pedley, T.A., Hauser, W.A., Ottman, R., Gilliam, T.C., 2002. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat. Genet. 30, 335–341. Lai, M., Huijbers, M.G.M., Lancaster, E., Graus, F., Bataller, L., Balice-Gordon, R., Cowell, J.K., Dalmau, J., 2010. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 9, 776–785. Lancaster, E., Dalmau, J., 2012. Neuronal autoantigens–pathogenesis, associated disorders and antibody testing. Nat. Rev. Neurol. 8, 380–390.

81

Lancaster, E., Martinez-Hernandez, E., Dalmau, J., 2011a. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77, 179–189. Lancaster, E., Huijbers, M.G.M., Bar, V., Boronat, A., Wong, A., Martinez-Hernandez, E., Wilson, C., Jacobs, D., Lai, M., Walker, R.W., Graus, F., Bataller, L., Illa, I., Markx, S., Strauss, K.A., Peles, E., Scherer, S.S., Dalmau, J., 2011b. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann. Neurol. 69, 303–311. Paterson, R.W., Zandi, M.S., Armstrong, R., Vincent, A., Schott, J.M., 2013. Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre. J. Neurol. Neurosurg. Psychiatry. http:// dx.doi.org/10.1136/jnnp-2013-305811 (Epub ahead of print, in press). Plantone, D., Renna, R., Grossi, D., Plantone, F., Iorio, R., 2013. Teaching NeuroImages: basal ganglia involvement in facio-brachial dystonic seizures associated with LGI1 antibodies. Neurology 80, e183–e184. Quek, A.M.L., Britton, J.W., McKeon, A., So, E., Lennon, V.A., Shin, C., Klein, C., Watson, R.E., Kotsenas, A.L., Lagerlund, T.D., Cascino, G.D., Worrell, G.A., Wirrell, E.C., Nickels, K.C., Aksamit, A.J., Noe, K.H., Pittock, S.J., 2012. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch. Neurol. 69, 582–593. Rubio-Agusti, I., Salavert, M., Bataller, L., 2013. Limbic encephalitis and related cortical syndromes. Curr. Treat. Options Neurol. 15, 169–184. Striano, P., 2011. Faciobrachial dystonic attacks: seizures or movement disorder? Ann. Neurol. 70, 179–180. Tan, K.M., Lennon, V.A., Klein, C.J., Boeve, B.F., Pittock, S.J., 2008. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 70, 1883–1890. Thieben, M.J., Lennon, V.A., Boeve, B.F., Aksamit, A.J., Keegan, M., Vernino, S., 2004. Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 62, 1177–1182. Titulaer, M.J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L.S., Benseler, S.M., Kawachi, I., Martinez-Hernandez, E., Aguilar, E., Gresa-Arribas, Núria, Ryan-Florance, N., Torrents, A., Saiz, A., Rosenfeld, M.R., Balice-Gordon, R., Graus, F., Dalmau, J., 2013. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157–165. Vincent, A., Irani, S.R., 2010. Caspr2 antibodies in patients with thymomas. J. Thorac. Oncol. 5, S277–S280. Vincent, A., Buckley, C., Schott, J.M., Baker, I., Dewar, B.K., Detert, N., Clover, L., Parkinson, A., Bien, C.G., Omer, S., Lang, B., Rossor, M.N., Palace, J., 2004. Potassium channel antibodyassociated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 127, 701–712. Vincent, A., Bien, C.G., Irani, S.R., Waters, P., 2011. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol. 10, 759–772.

LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy.

Leucine-rich glioma inactivated 1 (LGI1) was recently identified as a target protein in autoimmune synaptic encephalitis, a rare condition associated ...
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