Journal of Neuroimmunology 270 (2014) 45–50
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Clinical manifestations and outcomes of the treatment of patients with GABAB encephalitis Tae-Joon Kim a,b, Soon-Tae Lee a,b,⁎, Jung-Won Shin a,b, Jangsup Moon a,b, Jung-Ah Lim a,b, Jung-Ick Byun a,b, Yong-Won Shin a,b, Keon-Joo Lee a,b, Keun-Hwa Jung a,b, Young-Soo Kim c, Kyung-Il Park d, Kon Chu a,b, Sang Kun Lee a,b a
Department of Neurology, Seoul National University Hospital, Seoul, South Korea Program in Neuroscience, Seoul National University College of Medicine, Seoul, South Korea c Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, 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 11 December 2013 Received in revised form 20 February 2014 Accepted 24 February 2014 Keywords: Encephalitis Autoimmune synaptic encephalitis GABAB
a b s t r a c t Encephalitis associated with anti-γ-aminobutyric acid-B (GABAB) receptor antibodies has been identified recently. However, only a few cases have been reported to date and its clinical manifestations and prognosis have not been investigated systematically. We identified five cases of GABAB encephalitis in Korea. Here we present the clinical features, treatment responses, and brain positron emission tomography findings of the cases. The patients had a clinical triad of memory changes, seizure, and association with small-cell lung cancer. Early diagnosis and comprehensive immune modulation may provide a good outcome. © 2014 Elsevier B.V. All rights reserved.
1. Background Autoimmune synaptic encephalitis (ASE) is a recently recognized emerging disease that is now thought to comprise many of the cases of encephalitis with unknown etiology. ASE results from antibody reactions to the neuronal surface or synaptic proteins (Lancaster et al., 2011) and typically causes memory or behavioral problem and seizures. Recently, several autoantibodies have been identified, including those against N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy5-methyl-4-isoxazoleprionic acid (AMPA) receptor, and voltage-gated potassium channels and their associated proteins, namely leucinrich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and γ-aminobutyric acid-B (GABA B ) receptor. Compared with classic paraneoplastic neurological syndromes, such as anti-Hu, Yo, Ri, Ma2, and CV2 syndromes, ASE can occur even without cancer and respond better to immunotherapy (Lancaster et al., 2011). Recently, several cases of GABAB encephalitis have been reported as a subgroup of ASE (Lancaster et al., 2010; Boronat et al., 2011; Höftberger et al., 2013). GABAB encephalitis is a relatively rare disease
⁎ Corresponding author at: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea. Tel.: + 82 2 2072 4757; fax: +82 2 3672 7553. E-mail address: [email protected] (S.-T. Lee).
http://dx.doi.org/10.1016/j.jneuroim.2014.02.011 0165-5728/© 2014 Elsevier B.V. All rights reserved.
entity that accounts for about 5% of all cases of ASE (Lancaster et al., 2011). This disorder usually involves the typical symptoms of limbic encephalitis (such as cognitive problems, memory impairment, behavior changes, and seizures). In approximately half of the patients with GABAB encephalitis, the immune response occurs as a paraneoplastic event, particularly because of small-cell lung cancer. Patients with GABA B encephalitis often respond to cancer treatments and immunotherapy. However, the number of cases of this condition reported to date is small and there is no case study in the Asian population. We reported previously the case of a 64-year-old Korean woman with GABAB encephalitis presenting with transient abnormal behavior and memory deficit (Park et al., 2012). In the current study, we have prospectively screened autoantibodies in cases of autoimmune encephalitis and investigated the clinical features and responses to treatments in these patients. 2. Methods From June 2012 to May 2013, 631 patients with suspicious autoimmune encephalitis of unknown origin were screened for autoantibodies against neuronal surface proteins. The characteristics of autoimmune encephalitis comprise subacute onset of memory deficits, behavioral problems, seizures, or involvement of the temporal lobes on electroencephalography (EEG) or imaging studies.
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Cell-based indirect immunofluorescence tests were used to detect the autoantibodies (anti-NMDA receptor, anti-LGI1, anti-CASPR2, antiAMPA1 receptor, anti-AMPA2 receptor, and anti-GABAB receptor), and classic paraneoplastic antibodies (anti-Hu, -Yo, -Ri, -Ma2, -CV2/ CRMP5, and -Amphiphysin). Briefly, diluted patient's serum (initially at 1:10, and confirmation at 1:100) or cerebrospinal fluid (CSF) (1:10) was reacted with HEK293 cells transfected with plasmids containing human target gene sequences (Euroimmun AG, Lübeck, Germany). FITC-labeled anti-human IgG was used as the secondary antibody. The determination of positive reactions was achieved by cytoplasmic immunofluorescence. Patients with anti-GABAB receptor antibodies were included in the analysis. We have not tested for anti-glutamic acid decarboxylase and anti-voltage-gated calcium channel antibodies. Clinical information and laboratory test results were obtained by the investigators or provided by the referring physicians. The study was approved by the Institutional Review Board of the Seoul National University Hospital, and written informed consent was obtained from all patients or their representatives. 3. Results 3.1. Overview of the cases Among the 631 patients analyzed, 83 patients (13.2%) showed positive results; anti-NMDA receptor antibodies were identified in 42 patients (50.6% of positive cases), anti-LGI1 antibodies in 14 patients (16.9%), and anti-AMPA1, anti-AMPA2 receptors, and antiCASPR2 antibodies in 1 patient (1.2%) respectively. Additionally, classic paraneoplastic antibodies were found in 19 patients (22.9%). Anti-GABAB receptor antibodies were identified in 5 patients (6.0%): four from a single tertiary institution and one from a referral hospital. Table 1 shows the demographic and clinical features of the five patients. The female patient reported previously (case #5) was also included in the present analysis. The median age of the five patients was 63 years (range, 58–71 years); three were female. All patients presented with behavioral disorder and mental confusion, which are characteristic of limbic encephalitis. In three of the five patients, clinical seizures were the initial symptom. Electroencephalography (EEG) revealed the following abnormalities: temporal epileptic discharges in two patients, temporal slow waves in one patient, and diffuse slowing in the remaining two patients. CSF study was abnormal in four patients: lymphocytic pleocytosis was present in two patients and protein increase was observed in the remaining two patients. Magnetic resonance imaging (MRI) revealed that T2 high-signal abnormalities were restricted to the medial temporal lobes in two patients, whereas the remaining patients had unremarkable findings (Table 1). All patients underwent brain-covered 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) imaging for the objective assessment of functional brain abnormalities and correlation of the imaging findings with clinical characteristics and disease activity. None of the patients showed overt seizure activity during the FDG-PET scans. Brain FDG-PET showed medial temporal hypermetabolism in two patients and diffuse cortical hypometabolism in one patient. The incidence of abnormal FDG-PET findings (3/5; 60%) was higher compared with the incidence of the MRI finding of T2 hyperintensity (2/5; 40%). In two patients, mesiotemporal T2 hyperintensity in MRI and hypermetabolism in FDG-PET findings were correlated. The patient with hypometabolism in the cerebral cortex showed normal MRI (Fig. 1). Four patients had small-cell lung cancer. In three of them, the diagnosis of GABAB encephalitis preceded the detection of cancer; thus, the correct diagnosis facilitated the early detection of cancer (Table 2). In two patients, another paraneoplastic antibody, an anti-Hu antibody, was detected concomitantly. All patients had neurological response to immunotherapy or cancer treatments. Neurological improvement occurred fully (modified Rankin Score, mRS b 2) in two patients and partially (mRS ≥ 2) in three patients, and was correlated with prompt
immunomodulation and cancer treatment. In addition, one patient (case #5) without cancer showed a complete response to treatment. The median follow-up period of four patients was 6 months (range, 3–12 months). One patient was not followed up after discharge. We compared our five cases with the previous report (Table 3). Our data strengthened the typical triad of the clinical presentation, including memory changes, seizures, and small-cell lung cancer. In addition, the novel PET findings indicated hypermetabolic activities in the limbic brains of the patients. 3.2. Case #1 A 61-year-old man presented with a sudden onset of altered mental status and behavioral changes that lasted for 2 weeks. He was finally admitted to the Department of Neurology of the Seoul National University Hospital in a postictal state after recurrent generalized tonic–clonic seizure (GTCS), which had developed 2 days before admission. On admission, he exhibited a drowsy, disoriented, and confusional mental status without fever. Initial and follow-up brain MRI investigations were performed at the first and fifteenth days, respectively, from symptom onset; they were normal (Fig. 1A). EEG showed intermittent generalized slowing without epileptiform discharge. CSF analysis detected mild lymphocytic pleocytosis of 11 white blood cells/μL, but protein and glucose levels were normal. Herpes simplex virus polymerase chain reaction (PCR), Cryptococcus antigen test, Japanese encephalitis virus antibody, Epstein–Barr virus PCR, tuberculosis culture and PCR, CSF cytology, and classic paraneoplastic antibodies were all negative, and thyroid function tests, anti-thyroglobulin antibody, and thyroid microsomal antibody were within normal values. On the seventh hospital day, a test of the antibody against the GABAB receptor in the serum was positive. FDG-PET imaging was ordered not only to screen for malignancy, but also to resolve diagnostic uncertainty. Whole-body FDG-PET scans revealed a hypermetabolic mass on the lower lobe of the left lung, which was proven by biopsy to be smallcell lung cancer. FDG-PET brain imaging showed brain lesions with diffuse cortical hypometabolism without focal hypermetabolism (Fig. 1B, C). The combination of all test results with the clinical presentation confirmed the diagnosis of GABAB encephalitis. Immunomodulating therapy with immunoglobulins (400 mg/kg/day) was administered intravenously and immediately, with a course of 5 days. Subsequently, chemotherapy with etoposide and carboplatin was given to treat cancer. Although seizure did not recur after the administration of antiepileptic drugs, his aggressive behavior and irritability were aggravated. Clinical improvement of the limbic dysfunction was achieved only after the completion of immunotherapy and chemotherapy. He was discharged 1 month after the onset of symptoms, when his mental status became alert and irritability decreased. On his 3-month outpatient follow-up, behavioral and cognitive functions were partially improved. 3.3. Case #2 A 63-year-old woman was admitted to the hospital with confusion and disorientation that started acutely at dawn on the same day. The patient's brain MRI demonstrated a hyperintense lesion in the right hippocampus on fluid-attenuated inversion recovery (FLAIR) sequences (Fig. 1D) that was compatible with limbic encephalitis. Left-lateralized temporal epileptiform discharges were seen on EEG, but limbic dysfunction was refractory to antiepileptic drugs. CSF analysis was normal, and no infectious cause was identified. On the second hospital day, antiGABAB and anti-Hu antibodies were detected in the serum. Consequently, the search for malignancy resulted in the identification of biopsyproven small-cell lung cancer on the upper lobe of the right lung. Brain FDG-PET revealed consistent hypermetabolism on the right medial temporal lobe. Immunotherapy with a combination of immunoglobulins (intravenous, 400 mg/kg/day) and high-dose steroids (intravenous methylprednisolone, 1000 mg/day) was initiated,
F/63
M/58
F/71
F/64
2
3
4
5
CSF, cerebrospinal fluid; EEG, electroencephalography; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; FDG-PET, 18-fluoro-deoxyglucose positron emission tomography; mT HSI, mesiotemporal high signal intensity; mT Hyper, mesiotemporal hypermetabolism; GTCS, generalized tonic–clonic seizure; WBC, white blood cells; P, polymorphonuclear leukocytes; L, lymphocytes; O, other cells; Ptn, protein level; Glu, glucose level; n-s: non-specific. a Patients #1, #2, #4, #5: Patients at the Seoul National University Hospital, Patient #3: Patient from a referred clinic. b CSF normal values: WBC b4/μL; Ptn 16–46 mg/dL; Glu 55–80 mg/dL. c Findings are unrelated to the category.
n-s n-s – 11 WBC 0 Ptn 62, Glc 65
M/62 1
Confusion, memory deficit, GTCS Confusion, abnormal behavior
17
Left temporal spike-andslow waves
Slow posterior dominant rhythm –
–
n-s
n-s
Bilateral (right b left) – –
Bilateral (right b left) – Left temporal epileptiform discharge – 11
–
Right – Right Both temporal slowing 2
–
– n-s – Intermittent theta slowing –c 24
WBC 11 (P0, L10, O1), Ptn 39, Glu 52 WBC 1 (P0, L0, O1), Ptn 34, Glu 75 WBC 14 (P0, L13, O1), Ptn 23.4, Glu 109 WBC 0, Ptn 67, Glu 72 GTCS, confusion, decreased mentality Confusion, abnormal behavior GTCS, disorientation
–
mT Hyper
Diffuse cortical hypometabolism in whole cerebral cortex –
FDG-PET
Additional findings MRI (FLAIR)
mT HSI Diffuse
Symptom onset to diagnosis (days) CSFb Presenting symptoms Sex/age Patienta
Table 1 Clinical features, CSF, EEG, MRI and FDG-PET findings.
EEG
Temporal
Additional findings
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with a course of 5 days. After the initial treatment, steroid therapy was tapered off slowly from oral prednisolone (50 mg/day). For the small-cell lung cancer, concurrent chemoradiotherapy (60 Gy in 30 fractions) with etoposide and cisplatin was started. The patient had recovered fully at 3 months after symptom onset. 3.4. Case #3 A 58-year-old man was admitted to the referring hospital for relapsing GTCS and disorientation that started 3 days before admission. Brain MRI revealed a left-dominant mesiotemporal hyperintensity on FLAIR sequences. Epileptiform discharges on the left temporal lobe were detected on EEG. A CSF profile showed lymphocytic pleocytosis of 14 white blood cells/μL. Serum and CSF samples were offered to our laboratory for the analysis of autoantibodies, and antibodies to the GABAB receptor were reported on the seventh day. Whole-body FDGPET scans led to the discovery of a mass lesion on the lower lobe of the left lung, which was confirmed to be small-cell lung cancer. FDGPET brain imaging revealed a typical pattern of mesiotemporal hypermetabolism. While immunotherapy was not used, according to the treatment policy of the referring hospital, concurrent chemoradiotherapy (60 Gy in 30 fractions) with etoposide and cisplatin targeting smallcell lung cancer was administered. The patient was transferred to the department of psychiatry for behavior control, and his limbic symptoms improved partially only after chemotherapy. He was discharged 1 month after the onset of the initial symptoms and was not followed up thereafter. 3.5. Case #4 A 71-year-old woman developed memory impairment, confusion, disorientation, abnormal behavior, and subsequent GTCS 2 days before admission to the hospital. She had underlying small-cell lung cancer with metastasis to the mediastinal lymphatics and thoracic vertebrae, which had been diagnosed 1 year before this episode and was treated using three courses of chemotherapy with etoposide and carboplatin. Brain MRI was normal and EEG was negative, with the exception of a slow posterior dominant rhythm. FDG-PET scans showed an improved state of the cancer, and covered brain images were nonspecific. CSF analysis detected an elevated protein level of 67 mg/dL, but no nucleated cells. No infective pathogen was discovered in serum or CSF samples. An antibody test identified anti-GABAB and anti-Hu antibodies in the serum. Initial immunomodulating therapy with immunoglobulins (intravenous, 400 mg/kg/day for five days) and high-dose steroids (intravenous methylprednisolone, 1000 mg/day) was started, followed by the tapering off of the steroids. Second-line treatment with rituximab was considered, but was unavailable because of the patient's financial situation. On the 24th day after symptom onset, the patient was discharged with intact orientation and mild memory deficit, which persisted until the 8-month outpatient follow-up. 3.6. Case #5 (Park et al., 2012) A 64-year-old woman visited the hospital presenting with abnormal behavior, memory impairment and confusion. She had history of breast cancer surgically resected 18 years ago which has no evidence of disease state, and left orbital lymphoma since 3 years ago which was in partial remission on chemotherapy. Brain MRI showed no abnormality except the known left orbital mass, which has been unchanged since the previous study. Although there was no witnessed seizure-like activity, EEG revealed left temporal spike-and-slow waves. Considering limbic dysfunction and EEG abnormality, an anti-epileptic drug (oxcarbazepine 900 mg/day) was started. FDG-PET including brain scans was nonspecific. CSF analysis detected an elevated protein level of 62 mg/dL without pleocytosis. Her workup including blood and routine CSF studies was unremarkable. Indirect immunofluorescence
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Fig. 1. Brain magnetic resonance imaging (MRI) and 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) findings of patients #1 and #2. The fluid-attenuated inversion recovery (FLAIR) MRI of patient #1 is nonspecific (A), but FDG-PET images show hypometabolism in the cerebral cortex (B, C). Patient #2 has hyperintensities on the right medial temporal lobe on FLAIR MRI (D), which is correlated with hypermetabolism in FDG-PET (E, F).
assays with patient's serum revealed the presence of autoantibodies against GABAB receptor. The patient showed significant improvement after initiating immunotherapy (intravenous immunoglobulins 400 mg/kg/day and methylprednisolone 1000 mg/day for five days). EEG was normalized on the eighth day after symptom onset, and on the 20th day, the patient was fully recovered and discharged with premorbid intellectual function.
4. Discussion Our study demonstrated the clinical characteristics of GABAB encephalitis in an Asian population, and found abnormal brain FDG-PET patterns in this unique autoimmune encephalitis. GABAB encephalitis showed typical clinical patterns of afebrile limbic encephalitis and intractable seizures, and was associated with small-cell lung cancer.
Immunomodulation and cancer chemotherapy improved the neurological deficits. Synaptic proteins, including inhibitory GABA receptors, play an important role in neural transmission and in synaptic plasticity associated with learning, memory, and cognitive functions (Collingridge et al., 2004). GABAB receptors are G-protein-coupled receptors that are representative inhibitory synaptic proteins in neurons. They are distributed in the central and peripheral nervous systems; within the central nervous system, they are highly localized in the hippocampus, thalamus, and cerebellum (Ulrich and Bettler, 2007). In animal models, pharmacological or genetic knockout of GABAB receptors results in seizures and disorders of memory, learning, and behavior (Prosser et al., 2001). Therefore, immune responses against these receptors have been thought to yield similar symptoms. Moreover, recently, antibodies to GABAB receptors were identified as a causative agent of limbic encephalitis (Lancaster et al., 2010). The clinical features and association with
Table 2 Tumor association, other antibodies, treatment and outcome. Patient
Tumor
Other antibodies
Immunotherapy
Tumor treatment
Clinical outcome (initial → follow-up mRS)
Follow-up (months)
1
Small cell lung cancer Small cell lung cancer Small cell lung cancer Small cell lung cancera
None
IVIg
Chemotherapy (EC #1)
Partial (3 → 2)
3
Anti-Hu
IVIg, prednisolone
Complete (3 → 1)
3
None
No immunotherapy
Partial (3 → 2)
At discharge
Anti-Hu
IVIg, prednisolone
Chemotherapy (EP #5) and definitive radiation (on chest) Chemotherapy (EP #1) and definitive radiation (on chest) Chemotherapy (EC #3)
Partial (3 → 2)
9
None
IVIg, prednisolone
No tumor
Complete (2 → 1)
12
2 3 4 5
b
mRS, modified Rankin Scale; IVIg, intravenous immunoglobulin; EC, etoposide and carboplatin; EP, etoposide and cisplatin. a In contrary to the other three patients with small cell lung cancer, case #4 patient had underlying small cell lung cancer 1 year prior to the encephalitis occurrence. b History of breast cancer surgically resected 18 years ago and no evidence of disease state; history of left orbital lymphoma 3 years ago and stable disease state.
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Table 3 Comparison of clinical manifestations with previous report. Report from Lancaster et al. (2011)
5 Korean cases
Age Gender Syndrome CSF MRI FDG-PET
Median 62 (24–75) 50% female Classic limbic encephalitis, early and prominent seizures 90% abnormal; frequent intrathecal synthesis of antibodies ~66% medial temporal lobe increase of FLAIR signal Not available
Tumor Other antibodies Tendency to relapse
60% small-cell lung cancer ~50% (N-type VGCC, GAD65, TPO, SOX1) Infrequent
Mean 63 (58–71) 60% female (3/5) Classic limbic encephalitis, prominent seizures (3/5) 80% (4/5) abnormal; 2 pleocytosis, 2 protein increase 40% (2/5) medial temporal lobe T2 high signal intensity 60% (3/5) abnormality, 2 medial temporal hypermetabolism and 1 diffuse cortical hypometabolism 80% (4/5) small-cell lung cancer 40% (2/5, anti-Hu Ab) None
CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; FDG-PET, 18-fluoro-deoxyglucose positron emission tomography; VGCC, voltagegated calcium channel; GAD65, glutamic acid decarboxylase 65; TPO, thyroid peroxidase; SOX1, sex determining region Y-box 1.
cancer observed in these five Korean patients were consistent with the cases reported previously (Table 3). The diagnosis of GABAB encephalitis is based on characteristic clinical symptoms, as well as the detection of specific GABAB autoantibodies. The criteria used for the diagnosis of ASE proposed by Zuliani et al. (2012) can be applied to GABAB encephalitis. These criteria indicated that one can make the diagnosis of definite ASE if known autoantibodies are present in the serum or CSF and there is a clinical response to immunotherapies. Four of our patients with GABAB encephalitis fit these criteria, and one (case #3) falls under the category of probable ASE since he did not receive immunotherapy. In clinical settings, a suspicion of GABAB encephalitis based on symptoms at presentation and study findings is of diagnostic importance, as the presenting symptoms of GABAB encephalitis are less stereotypic compared with the representative psychomotor symptoms of anti-NMDA receptor encephalitis (Lancaster et al., 2011) or the faciobrachial dystonic seizures observed in anti-LGI1 encephalitis (Irani et al., 2008, 2011a). In addition, the clinical phenotypes of GABAB encephalitis are stable, while those of anti-NMDA receptor encephalitis evolve over time (Dalmau et al., 2011). Accordingly, in the cases of probable autoimmune encephalitis with unknown etiology, the suspicion of GABAB receptor encephalitis is important. Although our cases demonstrated clinical seizures in three and electrical seizure (EEG) in one among total five patients, the early and prominent seizure is one of the characteristics of GABAB receptor encephalitis (Lancaster et al., 2010). Among the imaging studies available, brain FDG-PET potentially plays an important role in the diagnostic evaluation of ASE, especially in patients with normal MRI findings. The MRI abnormalities reported in patients with ASE are mostly hyperintensities in the medial temporal lobes on T2-weighted or FLAIR images (Lancaster et al., 2010). However, the majority of patients have normal or nonspecific findings on MRI, and these patients sometime have specific PET patterns (Basu and Alavi, 2008; Fisher et al., 2012; Baumgartner et al., 2013). For the use of FDG-PET in autoimmune or paraneoplastic encephalitis, diverse patterns of FDG-PET findings have been reported in the literature (Lee et al., 2004; Ances et al., 2005; Basu and Alavi, 2008; Fisher et al., 2012; Baumgartner et al., 2013). Majority of the patients with antibodies to voltage-gated potassium channel complex including LGI1 revealed typical patterns of basal ganglia hypermetabolism (Irani et al., 2011a; Rey et al., 2012; Kamaleshwaran et al., 2013; Shin et al., 2013). In six patients with anti-NMDA receptor encephalitis, the brain FDG-PET of the patients showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism (Leypoldt et al., 2012). The changes in FDG-PET images were correlated with disease activity (Leypoldt et al., 2012; Shin et al., 2013). To our knowledge, this is the first report demonstrating brain FDG-PET patterns in GABAB encephalitis. In this study, three patients showed abnormalities in PET images, which were two temporal hypermetabolism and one cortical hypometabolism. Cortical hypometabolism might be a characteristic of synaptic dysfunction, whereas mesiotemporal
hypermetabolism might be related to inflammatory process (Basu and Alavi, 2008; Fisher et al., 2012; Rey et al., 2012). Although the difference between the two patterns may be attributed to the clinical course or disease severity, our data is not sufficient to solve this question. Serial FDGPET scans will be necessary to elucidate the correlation between clinical courses and imaging findings. Therefore, more cases with GABAB encephalitis evaluated with FDG-PET will provide the diagnostic value and clinical implications of FDG-PET images in this disease. Anti-Hu antibodies were detected in two patients (cases #2, #4). Anti-Hu antibodies are present at low titer in a significant fraction (15.9%) of lung cancer patients without paraneoplastic syndrome (Dalmau et al., 1990). In those patients, the anti-Hu antibody is not thought to be directly pathogenic, but rather marks a cytotoxic T-cell response (Dalmau et al., 1990). A previous study revealed that only nine patients (6.5%) of 139 patients with anti-Hu syndrome were improved after treatment: four with only immunotherapy, four with antineoplastic therapy with concomitant immunotherapy and one with only tumor treatment (Graus et al., 2001). Moreover, median survival of 200 with anti-Hu syndrome patients was 11.8 months (Graus et al., 2001). On the contrary, 30 (68%) of 44 patients with GABAB encephalitis showed partial or complete response to treatment from the three reported series (Lancaster et al., 2010; Boronat et al., 2011; Höftberger et al., 2013). Since the prognosis of the true anti-Hu syndrome is worse than GABAB encephalitis and anti-Hu syndrome is frequently associated with sensory polyneuropathy (Graus et al., 2001), the symptoms of our two patients are likely to be related with anti-GABAB receptor antibody than anti-Hu antibody. Thus, in patients with lung cancer, limbic encephalitis, and anti-Hu antibody, it would be necessary to test other co-existing antibodies such as anti-GABAB receptor antibody. This might be even more important if the patients respond to immunotherapy. For the treatment of GABAB encephalitis, both immunomodulating therapy and cancer treatment in the presence of malignancy are necessary. It has recently been shown that ASE patients with epileptic seizures are often refractory to treatment with standard antiepileptic drugs and, in contrast, may respond well to immunomodulating therapy (Irani et al., 2011b). Similar to what was observed in other ASEs, immunotherapy might be the first treatment option for GABAB encephalitis. Although large studies of treatment responses in anti-NMDA receptor encephalitis have been reported (Titulaer et al., 2013), there are few case reports of the treatment of GABAB encephalitis, because of the low prevalence of the disease (Lancaster et al., 2010; Höftberger et al., 2013). GABAB encephalitis appears to have a relatively partial response to treatment, and the majority of our patients only recovered partially. This might be attributed to insufficient immunomodulating therapy, including second-line treatment such as rituximab, as observed in anti-NMDA receptor encephalitis (Titulaer et al., 2013). In addition, the association with small-cell lung cancer indicates poor prognosis, as noted by another recent report (Höftberger et al., 2013). It remains unknown whether
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different mechanisms of autoantibody–antigen reaction participate in the pathogenesis of GABAB encephalitis (Moscato et al., 2010). The accumulation of multicenter cases and systematic analyses are necessary to identify the optimal treatment options for, and prognosis of this rare and unique encephalitis. Author declaration As a corresponding author, I take full responsibility for the data, the analyses and interpretation of the report. The manuscript, including related figures, has not been previously reported or published. The manuscript is not under consideration elsewhere and that it will not be submitted elsewhere while under review by the “Journal of Neuroimmunology”. All authors have read and approved the submission of the manuscript. Acknowledgment This study was supported by a grant (A121911) of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea. References Ances, B.M., Vitaliani, R., Taylor, R.A., Liebeskind, D.S., Voloschin, A., Houghton, D.J., Galetta, S.L., Dichter, M., Alavi, A., Rosenfeld, M.R., Dalmau, J., 2005. Treatmentresponsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128, 1764–1777. 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. Baumgartner, A., Rauer, S., Mader, I., Meyer, P.T., 2013. Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types. J. Neurol. 260, 2744–2753. Boronat, A., Sabater, L., Saiz, A., Dalmau, J., Graus, F., 2011. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD associated neurologic disorders. Neurology 76, 795–800. Collingridge, G.L., Isaac, J.T., Wang, Y.T., 2004. Receptor tracking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962. Dalmau, J., Furneaux, H.M., Gralla, R.J., Kris, M.G., Posner, J.B., 1990. Detection of the antiHu antibody in the serum of patients with small cell lung cancer—a quantitative Western blot analysis. Ann. Neurol. 27, 544–552. Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M.R., Balice-Gordon, R., 2011. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 10, 63–74. Fisher, R.E., Patel, N.R., Lai, E.C., Schulz, P.E., 2012. Two different 18F-FDG brain PET metabolic patterns in autoimmune limbic encephalitis. Clin. Nucl. Med. 37, e213–e218. Graus, F., Keime-Guibert, F., Reñe, R., Benyahia, B., Ribalta, T., Ascaso, C., Escaramis, G., Delattre, J.Y., 2001. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 124, 1138–1148.
Höftberger, R., Titulaer, M.J., Sabater, L., Dome, B., Rózsás, A., Hegedus, B., Hoda, M.A., Laszlo, V., Ankersmit, H.J., Harms, L., Boyero, S., de Felipe, A., Saiz, A., Dalmau, J., Graus, F., 2013. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 81, 1500–1506. 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., 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., 2011a. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69, 892–900. Irani, S.R., Bien, C.G., Lang, B., 2011b. Autoimmune epilepsies. Curr. Opin. Neurol. 24, 146–153. Kamaleshwaran, K.K., Iyer, R.S., Antony, J., Radhakrishnan, E.K., Shinto, A., 2013. 18F-FDG PET/CT findings in voltage-gated potassium channel limbic encephalitis. Clin. Nucl. Med. 38, 392–394. Lancaster, E., Lai, M., Peng, X., Hughes, E., Constantinescu, R., Raizer, J., Friedman, D., Skeen, M.B., Grisold, W., Kimura, A., Ohta, K., Iizuka, T., Guzman, M., Graus, F., Moss, S.J., Balice-Gordon, R., Dalmau, J., 2010. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 9, 67–76. Lancaster, E., Martinez-Hernandez, E., Dalmau, J., 2011. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77, 179–189. Lee, B.Y., Newberg, A.B., Liebeskind, D.S., Kung, J., Alavi, A., 2004. FDG-PET findings in patients with suspected encephalitis. Clin. Nucl. Med. 29, 620–625. Leypoldt, F., Buchert, R., Kleiter, I., Marienhagen, J., Gelderblom, M., Magnus, T., Dalmau, J., Gerloff, C., Lewerenz, J., 2012. Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease. J. Neurol. Neurosurg. Psychiatry 83, 681–686. Moscato, E.H., Jain, A., Peng, X., Hughes, E.G., Dalmau, J., Balice-Gordon, R.J., 2010. Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies. Eur. J. Neurosci. 32, 298–309. Park, B.S., Kim, Y.S., Lee, S.T., Jung, K.H., Lee, S.G., Chu, K., 2012. Anti-GABA-B receptor autoimmune encephalitis. J. Korean Epilepsy Soc. 16, 59–62. Prosser, H.M., Gill, C.H., Hirst, W.D., Grau, E., Robbins, M., Calver, A., Soffin, E.M., Farmer, C.E., Lanneau, C., Gray, J., Schenck, E., Warmerdam, B.S., Clapham, C., Reavill, C., Rogers, D.C., Stean, T., Upton, N., Humphreys, K., Randall, A., Geppert, M., Davies, C.H., Pangalos, M.N., 2001. Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Mol. Cell. Neurosci. 17, 1059–1070. Rey, C., Koric, L., Guedj, E., Felician, O., Kaphan, E., Boucraut, J., Ceccaldi, M., 2012. Striatal hypermetabolism in limbic encephalitis. J. Neurol. 259, 1106–1110. Shin, Y.W., Lee, S.T., Shin, J.W., Moon, J., Lim, J.A., Byun, J.I., Kim, T.J., Lee, K.J., Kim, Y.S., Park, K.I., Jung, K.H., Lee, S.K., Chu, K., 2013. VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J. Neuroimmunol. 265, 75–81. 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, N., 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. Ulrich, D., Bettler, B., 2007. GABA(B) receptors: synaptic functions and mechanisms of diversity. Curr. Opin. Neurobiol. 17, 298–303. Zuliani, L., Graus, F., Giometto, B., Bien, C., Vincent, A., 2012. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J. Neurol. Neurosurg. Psychiatry 83, 638–645.
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Clinical manifestations and outcomes of the treatment of patients with GABAB encephalitis Tae-Joon Kim a,b, Soon-Tae Lee a,b,⁎, Jung-Won Shin a,b, Jangsup Moon a,b, Jung-Ah Lim a,b, Jung-Ick Byun a,b, Yong-Won Shin a,b, Keon-Joo Lee a,b, Keun-Hwa Jung a,b, Young-Soo Kim c, Kyung-Il Park d, Kon Chu a,b, Sang Kun Lee a,b a
Department of Neurology, Seoul National University Hospital, Seoul, South Korea Program in Neuroscience, Seoul National University College of Medicine, Seoul, South Korea c Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, 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 11 December 2013 Received in revised form 20 February 2014 Accepted 24 February 2014 Keywords: Encephalitis Autoimmune synaptic encephalitis GABAB
a b s t r a c t Encephalitis associated with anti-γ-aminobutyric acid-B (GABAB) receptor antibodies has been identified recently. However, only a few cases have been reported to date and its clinical manifestations and prognosis have not been investigated systematically. We identified five cases of GABAB encephalitis in Korea. Here we present the clinical features, treatment responses, and brain positron emission tomography findings of the cases. The patients had a clinical triad of memory changes, seizure, and association with small-cell lung cancer. Early diagnosis and comprehensive immune modulation may provide a good outcome. © 2014 Elsevier B.V. All rights reserved.
1. Background Autoimmune synaptic encephalitis (ASE) is a recently recognized emerging disease that is now thought to comprise many of the cases of encephalitis with unknown etiology. ASE results from antibody reactions to the neuronal surface or synaptic proteins (Lancaster et al., 2011) and typically causes memory or behavioral problem and seizures. Recently, several autoantibodies have been identified, including those against N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy5-methyl-4-isoxazoleprionic acid (AMPA) receptor, and voltage-gated potassium channels and their associated proteins, namely leucinrich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and γ-aminobutyric acid-B (GABA B ) receptor. Compared with classic paraneoplastic neurological syndromes, such as anti-Hu, Yo, Ri, Ma2, and CV2 syndromes, ASE can occur even without cancer and respond better to immunotherapy (Lancaster et al., 2011). Recently, several cases of GABAB encephalitis have been reported as a subgroup of ASE (Lancaster et al., 2010; Boronat et al., 2011; Höftberger et al., 2013). GABAB encephalitis is a relatively rare disease
⁎ Corresponding author at: Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea. Tel.: + 82 2 2072 4757; fax: +82 2 3672 7553. E-mail address: [email protected] (S.-T. Lee).
http://dx.doi.org/10.1016/j.jneuroim.2014.02.011 0165-5728/© 2014 Elsevier B.V. All rights reserved.
entity that accounts for about 5% of all cases of ASE (Lancaster et al., 2011). This disorder usually involves the typical symptoms of limbic encephalitis (such as cognitive problems, memory impairment, behavior changes, and seizures). In approximately half of the patients with GABAB encephalitis, the immune response occurs as a paraneoplastic event, particularly because of small-cell lung cancer. Patients with GABA B encephalitis often respond to cancer treatments and immunotherapy. However, the number of cases of this condition reported to date is small and there is no case study in the Asian population. We reported previously the case of a 64-year-old Korean woman with GABAB encephalitis presenting with transient abnormal behavior and memory deficit (Park et al., 2012). In the current study, we have prospectively screened autoantibodies in cases of autoimmune encephalitis and investigated the clinical features and responses to treatments in these patients. 2. Methods From June 2012 to May 2013, 631 patients with suspicious autoimmune encephalitis of unknown origin were screened for autoantibodies against neuronal surface proteins. The characteristics of autoimmune encephalitis comprise subacute onset of memory deficits, behavioral problems, seizures, or involvement of the temporal lobes on electroencephalography (EEG) or imaging studies.
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T.-J. Kim et al. / Journal of Neuroimmunology 270 (2014) 45–50
Cell-based indirect immunofluorescence tests were used to detect the autoantibodies (anti-NMDA receptor, anti-LGI1, anti-CASPR2, antiAMPA1 receptor, anti-AMPA2 receptor, and anti-GABAB receptor), and classic paraneoplastic antibodies (anti-Hu, -Yo, -Ri, -Ma2, -CV2/ CRMP5, and -Amphiphysin). Briefly, diluted patient's serum (initially at 1:10, and confirmation at 1:100) or cerebrospinal fluid (CSF) (1:10) was reacted with HEK293 cells transfected with plasmids containing human target gene sequences (Euroimmun AG, Lübeck, Germany). FITC-labeled anti-human IgG was used as the secondary antibody. The determination of positive reactions was achieved by cytoplasmic immunofluorescence. Patients with anti-GABAB receptor antibodies were included in the analysis. We have not tested for anti-glutamic acid decarboxylase and anti-voltage-gated calcium channel antibodies. Clinical information and laboratory test results were obtained by the investigators or provided by the referring physicians. The study was approved by the Institutional Review Board of the Seoul National University Hospital, and written informed consent was obtained from all patients or their representatives. 3. Results 3.1. Overview of the cases Among the 631 patients analyzed, 83 patients (13.2%) showed positive results; anti-NMDA receptor antibodies were identified in 42 patients (50.6% of positive cases), anti-LGI1 antibodies in 14 patients (16.9%), and anti-AMPA1, anti-AMPA2 receptors, and antiCASPR2 antibodies in 1 patient (1.2%) respectively. Additionally, classic paraneoplastic antibodies were found in 19 patients (22.9%). Anti-GABAB receptor antibodies were identified in 5 patients (6.0%): four from a single tertiary institution and one from a referral hospital. Table 1 shows the demographic and clinical features of the five patients. The female patient reported previously (case #5) was also included in the present analysis. The median age of the five patients was 63 years (range, 58–71 years); three were female. All patients presented with behavioral disorder and mental confusion, which are characteristic of limbic encephalitis. In three of the five patients, clinical seizures were the initial symptom. Electroencephalography (EEG) revealed the following abnormalities: temporal epileptic discharges in two patients, temporal slow waves in one patient, and diffuse slowing in the remaining two patients. CSF study was abnormal in four patients: lymphocytic pleocytosis was present in two patients and protein increase was observed in the remaining two patients. Magnetic resonance imaging (MRI) revealed that T2 high-signal abnormalities were restricted to the medial temporal lobes in two patients, whereas the remaining patients had unremarkable findings (Table 1). All patients underwent brain-covered 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) imaging for the objective assessment of functional brain abnormalities and correlation of the imaging findings with clinical characteristics and disease activity. None of the patients showed overt seizure activity during the FDG-PET scans. Brain FDG-PET showed medial temporal hypermetabolism in two patients and diffuse cortical hypometabolism in one patient. The incidence of abnormal FDG-PET findings (3/5; 60%) was higher compared with the incidence of the MRI finding of T2 hyperintensity (2/5; 40%). In two patients, mesiotemporal T2 hyperintensity in MRI and hypermetabolism in FDG-PET findings were correlated. The patient with hypometabolism in the cerebral cortex showed normal MRI (Fig. 1). Four patients had small-cell lung cancer. In three of them, the diagnosis of GABAB encephalitis preceded the detection of cancer; thus, the correct diagnosis facilitated the early detection of cancer (Table 2). In two patients, another paraneoplastic antibody, an anti-Hu antibody, was detected concomitantly. All patients had neurological response to immunotherapy or cancer treatments. Neurological improvement occurred fully (modified Rankin Score, mRS b 2) in two patients and partially (mRS ≥ 2) in three patients, and was correlated with prompt
immunomodulation and cancer treatment. In addition, one patient (case #5) without cancer showed a complete response to treatment. The median follow-up period of four patients was 6 months (range, 3–12 months). One patient was not followed up after discharge. We compared our five cases with the previous report (Table 3). Our data strengthened the typical triad of the clinical presentation, including memory changes, seizures, and small-cell lung cancer. In addition, the novel PET findings indicated hypermetabolic activities in the limbic brains of the patients. 3.2. Case #1 A 61-year-old man presented with a sudden onset of altered mental status and behavioral changes that lasted for 2 weeks. He was finally admitted to the Department of Neurology of the Seoul National University Hospital in a postictal state after recurrent generalized tonic–clonic seizure (GTCS), which had developed 2 days before admission. On admission, he exhibited a drowsy, disoriented, and confusional mental status without fever. Initial and follow-up brain MRI investigations were performed at the first and fifteenth days, respectively, from symptom onset; they were normal (Fig. 1A). EEG showed intermittent generalized slowing without epileptiform discharge. CSF analysis detected mild lymphocytic pleocytosis of 11 white blood cells/μL, but protein and glucose levels were normal. Herpes simplex virus polymerase chain reaction (PCR), Cryptococcus antigen test, Japanese encephalitis virus antibody, Epstein–Barr virus PCR, tuberculosis culture and PCR, CSF cytology, and classic paraneoplastic antibodies were all negative, and thyroid function tests, anti-thyroglobulin antibody, and thyroid microsomal antibody were within normal values. On the seventh hospital day, a test of the antibody against the GABAB receptor in the serum was positive. FDG-PET imaging was ordered not only to screen for malignancy, but also to resolve diagnostic uncertainty. Whole-body FDG-PET scans revealed a hypermetabolic mass on the lower lobe of the left lung, which was proven by biopsy to be smallcell lung cancer. FDG-PET brain imaging showed brain lesions with diffuse cortical hypometabolism without focal hypermetabolism (Fig. 1B, C). The combination of all test results with the clinical presentation confirmed the diagnosis of GABAB encephalitis. Immunomodulating therapy with immunoglobulins (400 mg/kg/day) was administered intravenously and immediately, with a course of 5 days. Subsequently, chemotherapy with etoposide and carboplatin was given to treat cancer. Although seizure did not recur after the administration of antiepileptic drugs, his aggressive behavior and irritability were aggravated. Clinical improvement of the limbic dysfunction was achieved only after the completion of immunotherapy and chemotherapy. He was discharged 1 month after the onset of symptoms, when his mental status became alert and irritability decreased. On his 3-month outpatient follow-up, behavioral and cognitive functions were partially improved. 3.3. Case #2 A 63-year-old woman was admitted to the hospital with confusion and disorientation that started acutely at dawn on the same day. The patient's brain MRI demonstrated a hyperintense lesion in the right hippocampus on fluid-attenuated inversion recovery (FLAIR) sequences (Fig. 1D) that was compatible with limbic encephalitis. Left-lateralized temporal epileptiform discharges were seen on EEG, but limbic dysfunction was refractory to antiepileptic drugs. CSF analysis was normal, and no infectious cause was identified. On the second hospital day, antiGABAB and anti-Hu antibodies were detected in the serum. Consequently, the search for malignancy resulted in the identification of biopsyproven small-cell lung cancer on the upper lobe of the right lung. Brain FDG-PET revealed consistent hypermetabolism on the right medial temporal lobe. Immunotherapy with a combination of immunoglobulins (intravenous, 400 mg/kg/day) and high-dose steroids (intravenous methylprednisolone, 1000 mg/day) was initiated,
F/63
M/58
F/71
F/64
2
3
4
5
CSF, cerebrospinal fluid; EEG, electroencephalography; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; FDG-PET, 18-fluoro-deoxyglucose positron emission tomography; mT HSI, mesiotemporal high signal intensity; mT Hyper, mesiotemporal hypermetabolism; GTCS, generalized tonic–clonic seizure; WBC, white blood cells; P, polymorphonuclear leukocytes; L, lymphocytes; O, other cells; Ptn, protein level; Glu, glucose level; n-s: non-specific. a Patients #1, #2, #4, #5: Patients at the Seoul National University Hospital, Patient #3: Patient from a referred clinic. b CSF normal values: WBC b4/μL; Ptn 16–46 mg/dL; Glu 55–80 mg/dL. c Findings are unrelated to the category.
n-s n-s – 11 WBC 0 Ptn 62, Glc 65
M/62 1
Confusion, memory deficit, GTCS Confusion, abnormal behavior
17
Left temporal spike-andslow waves
Slow posterior dominant rhythm –
–
n-s
n-s
Bilateral (right b left) – –
Bilateral (right b left) – Left temporal epileptiform discharge – 11
–
Right – Right Both temporal slowing 2
–
– n-s – Intermittent theta slowing –c 24
WBC 11 (P0, L10, O1), Ptn 39, Glu 52 WBC 1 (P0, L0, O1), Ptn 34, Glu 75 WBC 14 (P0, L13, O1), Ptn 23.4, Glu 109 WBC 0, Ptn 67, Glu 72 GTCS, confusion, decreased mentality Confusion, abnormal behavior GTCS, disorientation
–
mT Hyper
Diffuse cortical hypometabolism in whole cerebral cortex –
FDG-PET
Additional findings MRI (FLAIR)
mT HSI Diffuse
Symptom onset to diagnosis (days) CSFb Presenting symptoms Sex/age Patienta
Table 1 Clinical features, CSF, EEG, MRI and FDG-PET findings.
EEG
Temporal
Additional findings
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47
with a course of 5 days. After the initial treatment, steroid therapy was tapered off slowly from oral prednisolone (50 mg/day). For the small-cell lung cancer, concurrent chemoradiotherapy (60 Gy in 30 fractions) with etoposide and cisplatin was started. The patient had recovered fully at 3 months after symptom onset. 3.4. Case #3 A 58-year-old man was admitted to the referring hospital for relapsing GTCS and disorientation that started 3 days before admission. Brain MRI revealed a left-dominant mesiotemporal hyperintensity on FLAIR sequences. Epileptiform discharges on the left temporal lobe were detected on EEG. A CSF profile showed lymphocytic pleocytosis of 14 white blood cells/μL. Serum and CSF samples were offered to our laboratory for the analysis of autoantibodies, and antibodies to the GABAB receptor were reported on the seventh day. Whole-body FDGPET scans led to the discovery of a mass lesion on the lower lobe of the left lung, which was confirmed to be small-cell lung cancer. FDGPET brain imaging revealed a typical pattern of mesiotemporal hypermetabolism. While immunotherapy was not used, according to the treatment policy of the referring hospital, concurrent chemoradiotherapy (60 Gy in 30 fractions) with etoposide and cisplatin targeting smallcell lung cancer was administered. The patient was transferred to the department of psychiatry for behavior control, and his limbic symptoms improved partially only after chemotherapy. He was discharged 1 month after the onset of the initial symptoms and was not followed up thereafter. 3.5. Case #4 A 71-year-old woman developed memory impairment, confusion, disorientation, abnormal behavior, and subsequent GTCS 2 days before admission to the hospital. She had underlying small-cell lung cancer with metastasis to the mediastinal lymphatics and thoracic vertebrae, which had been diagnosed 1 year before this episode and was treated using three courses of chemotherapy with etoposide and carboplatin. Brain MRI was normal and EEG was negative, with the exception of a slow posterior dominant rhythm. FDG-PET scans showed an improved state of the cancer, and covered brain images were nonspecific. CSF analysis detected an elevated protein level of 67 mg/dL, but no nucleated cells. No infective pathogen was discovered in serum or CSF samples. An antibody test identified anti-GABAB and anti-Hu antibodies in the serum. Initial immunomodulating therapy with immunoglobulins (intravenous, 400 mg/kg/day for five days) and high-dose steroids (intravenous methylprednisolone, 1000 mg/day) was started, followed by the tapering off of the steroids. Second-line treatment with rituximab was considered, but was unavailable because of the patient's financial situation. On the 24th day after symptom onset, the patient was discharged with intact orientation and mild memory deficit, which persisted until the 8-month outpatient follow-up. 3.6. Case #5 (Park et al., 2012) A 64-year-old woman visited the hospital presenting with abnormal behavior, memory impairment and confusion. She had history of breast cancer surgically resected 18 years ago which has no evidence of disease state, and left orbital lymphoma since 3 years ago which was in partial remission on chemotherapy. Brain MRI showed no abnormality except the known left orbital mass, which has been unchanged since the previous study. Although there was no witnessed seizure-like activity, EEG revealed left temporal spike-and-slow waves. Considering limbic dysfunction and EEG abnormality, an anti-epileptic drug (oxcarbazepine 900 mg/day) was started. FDG-PET including brain scans was nonspecific. CSF analysis detected an elevated protein level of 62 mg/dL without pleocytosis. Her workup including blood and routine CSF studies was unremarkable. Indirect immunofluorescence
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Fig. 1. Brain magnetic resonance imaging (MRI) and 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) findings of patients #1 and #2. The fluid-attenuated inversion recovery (FLAIR) MRI of patient #1 is nonspecific (A), but FDG-PET images show hypometabolism in the cerebral cortex (B, C). Patient #2 has hyperintensities on the right medial temporal lobe on FLAIR MRI (D), which is correlated with hypermetabolism in FDG-PET (E, F).
assays with patient's serum revealed the presence of autoantibodies against GABAB receptor. The patient showed significant improvement after initiating immunotherapy (intravenous immunoglobulins 400 mg/kg/day and methylprednisolone 1000 mg/day for five days). EEG was normalized on the eighth day after symptom onset, and on the 20th day, the patient was fully recovered and discharged with premorbid intellectual function.
4. Discussion Our study demonstrated the clinical characteristics of GABAB encephalitis in an Asian population, and found abnormal brain FDG-PET patterns in this unique autoimmune encephalitis. GABAB encephalitis showed typical clinical patterns of afebrile limbic encephalitis and intractable seizures, and was associated with small-cell lung cancer.
Immunomodulation and cancer chemotherapy improved the neurological deficits. Synaptic proteins, including inhibitory GABA receptors, play an important role in neural transmission and in synaptic plasticity associated with learning, memory, and cognitive functions (Collingridge et al., 2004). GABAB receptors are G-protein-coupled receptors that are representative inhibitory synaptic proteins in neurons. They are distributed in the central and peripheral nervous systems; within the central nervous system, they are highly localized in the hippocampus, thalamus, and cerebellum (Ulrich and Bettler, 2007). In animal models, pharmacological or genetic knockout of GABAB receptors results in seizures and disorders of memory, learning, and behavior (Prosser et al., 2001). Therefore, immune responses against these receptors have been thought to yield similar symptoms. Moreover, recently, antibodies to GABAB receptors were identified as a causative agent of limbic encephalitis (Lancaster et al., 2010). The clinical features and association with
Table 2 Tumor association, other antibodies, treatment and outcome. Patient
Tumor
Other antibodies
Immunotherapy
Tumor treatment
Clinical outcome (initial → follow-up mRS)
Follow-up (months)
1
Small cell lung cancer Small cell lung cancer Small cell lung cancer Small cell lung cancera
None
IVIg
Chemotherapy (EC #1)
Partial (3 → 2)
3
Anti-Hu
IVIg, prednisolone
Complete (3 → 1)
3
None
No immunotherapy
Partial (3 → 2)
At discharge
Anti-Hu
IVIg, prednisolone
Chemotherapy (EP #5) and definitive radiation (on chest) Chemotherapy (EP #1) and definitive radiation (on chest) Chemotherapy (EC #3)
Partial (3 → 2)
9
None
IVIg, prednisolone
No tumor
Complete (2 → 1)
12
2 3 4 5
b
mRS, modified Rankin Scale; IVIg, intravenous immunoglobulin; EC, etoposide and carboplatin; EP, etoposide and cisplatin. a In contrary to the other three patients with small cell lung cancer, case #4 patient had underlying small cell lung cancer 1 year prior to the encephalitis occurrence. b History of breast cancer surgically resected 18 years ago and no evidence of disease state; history of left orbital lymphoma 3 years ago and stable disease state.
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Table 3 Comparison of clinical manifestations with previous report. Report from Lancaster et al. (2011)
5 Korean cases
Age Gender Syndrome CSF MRI FDG-PET
Median 62 (24–75) 50% female Classic limbic encephalitis, early and prominent seizures 90% abnormal; frequent intrathecal synthesis of antibodies ~66% medial temporal lobe increase of FLAIR signal Not available
Tumor Other antibodies Tendency to relapse
60% small-cell lung cancer ~50% (N-type VGCC, GAD65, TPO, SOX1) Infrequent
Mean 63 (58–71) 60% female (3/5) Classic limbic encephalitis, prominent seizures (3/5) 80% (4/5) abnormal; 2 pleocytosis, 2 protein increase 40% (2/5) medial temporal lobe T2 high signal intensity 60% (3/5) abnormality, 2 medial temporal hypermetabolism and 1 diffuse cortical hypometabolism 80% (4/5) small-cell lung cancer 40% (2/5, anti-Hu Ab) None
CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; FDG-PET, 18-fluoro-deoxyglucose positron emission tomography; VGCC, voltagegated calcium channel; GAD65, glutamic acid decarboxylase 65; TPO, thyroid peroxidase; SOX1, sex determining region Y-box 1.
cancer observed in these five Korean patients were consistent with the cases reported previously (Table 3). The diagnosis of GABAB encephalitis is based on characteristic clinical symptoms, as well as the detection of specific GABAB autoantibodies. The criteria used for the diagnosis of ASE proposed by Zuliani et al. (2012) can be applied to GABAB encephalitis. These criteria indicated that one can make the diagnosis of definite ASE if known autoantibodies are present in the serum or CSF and there is a clinical response to immunotherapies. Four of our patients with GABAB encephalitis fit these criteria, and one (case #3) falls under the category of probable ASE since he did not receive immunotherapy. In clinical settings, a suspicion of GABAB encephalitis based on symptoms at presentation and study findings is of diagnostic importance, as the presenting symptoms of GABAB encephalitis are less stereotypic compared with the representative psychomotor symptoms of anti-NMDA receptor encephalitis (Lancaster et al., 2011) or the faciobrachial dystonic seizures observed in anti-LGI1 encephalitis (Irani et al., 2008, 2011a). In addition, the clinical phenotypes of GABAB encephalitis are stable, while those of anti-NMDA receptor encephalitis evolve over time (Dalmau et al., 2011). Accordingly, in the cases of probable autoimmune encephalitis with unknown etiology, the suspicion of GABAB receptor encephalitis is important. Although our cases demonstrated clinical seizures in three and electrical seizure (EEG) in one among total five patients, the early and prominent seizure is one of the characteristics of GABAB receptor encephalitis (Lancaster et al., 2010). Among the imaging studies available, brain FDG-PET potentially plays an important role in the diagnostic evaluation of ASE, especially in patients with normal MRI findings. The MRI abnormalities reported in patients with ASE are mostly hyperintensities in the medial temporal lobes on T2-weighted or FLAIR images (Lancaster et al., 2010). However, the majority of patients have normal or nonspecific findings on MRI, and these patients sometime have specific PET patterns (Basu and Alavi, 2008; Fisher et al., 2012; Baumgartner et al., 2013). For the use of FDG-PET in autoimmune or paraneoplastic encephalitis, diverse patterns of FDG-PET findings have been reported in the literature (Lee et al., 2004; Ances et al., 2005; Basu and Alavi, 2008; Fisher et al., 2012; Baumgartner et al., 2013). Majority of the patients with antibodies to voltage-gated potassium channel complex including LGI1 revealed typical patterns of basal ganglia hypermetabolism (Irani et al., 2011a; Rey et al., 2012; Kamaleshwaran et al., 2013; Shin et al., 2013). In six patients with anti-NMDA receptor encephalitis, the brain FDG-PET of the patients showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism (Leypoldt et al., 2012). The changes in FDG-PET images were correlated with disease activity (Leypoldt et al., 2012; Shin et al., 2013). To our knowledge, this is the first report demonstrating brain FDG-PET patterns in GABAB encephalitis. In this study, three patients showed abnormalities in PET images, which were two temporal hypermetabolism and one cortical hypometabolism. Cortical hypometabolism might be a characteristic of synaptic dysfunction, whereas mesiotemporal
hypermetabolism might be related to inflammatory process (Basu and Alavi, 2008; Fisher et al., 2012; Rey et al., 2012). Although the difference between the two patterns may be attributed to the clinical course or disease severity, our data is not sufficient to solve this question. Serial FDGPET scans will be necessary to elucidate the correlation between clinical courses and imaging findings. Therefore, more cases with GABAB encephalitis evaluated with FDG-PET will provide the diagnostic value and clinical implications of FDG-PET images in this disease. Anti-Hu antibodies were detected in two patients (cases #2, #4). Anti-Hu antibodies are present at low titer in a significant fraction (15.9%) of lung cancer patients without paraneoplastic syndrome (Dalmau et al., 1990). In those patients, the anti-Hu antibody is not thought to be directly pathogenic, but rather marks a cytotoxic T-cell response (Dalmau et al., 1990). A previous study revealed that only nine patients (6.5%) of 139 patients with anti-Hu syndrome were improved after treatment: four with only immunotherapy, four with antineoplastic therapy with concomitant immunotherapy and one with only tumor treatment (Graus et al., 2001). Moreover, median survival of 200 with anti-Hu syndrome patients was 11.8 months (Graus et al., 2001). On the contrary, 30 (68%) of 44 patients with GABAB encephalitis showed partial or complete response to treatment from the three reported series (Lancaster et al., 2010; Boronat et al., 2011; Höftberger et al., 2013). Since the prognosis of the true anti-Hu syndrome is worse than GABAB encephalitis and anti-Hu syndrome is frequently associated with sensory polyneuropathy (Graus et al., 2001), the symptoms of our two patients are likely to be related with anti-GABAB receptor antibody than anti-Hu antibody. Thus, in patients with lung cancer, limbic encephalitis, and anti-Hu antibody, it would be necessary to test other co-existing antibodies such as anti-GABAB receptor antibody. This might be even more important if the patients respond to immunotherapy. For the treatment of GABAB encephalitis, both immunomodulating therapy and cancer treatment in the presence of malignancy are necessary. It has recently been shown that ASE patients with epileptic seizures are often refractory to treatment with standard antiepileptic drugs and, in contrast, may respond well to immunomodulating therapy (Irani et al., 2011b). Similar to what was observed in other ASEs, immunotherapy might be the first treatment option for GABAB encephalitis. Although large studies of treatment responses in anti-NMDA receptor encephalitis have been reported (Titulaer et al., 2013), there are few case reports of the treatment of GABAB encephalitis, because of the low prevalence of the disease (Lancaster et al., 2010; Höftberger et al., 2013). GABAB encephalitis appears to have a relatively partial response to treatment, and the majority of our patients only recovered partially. This might be attributed to insufficient immunomodulating therapy, including second-line treatment such as rituximab, as observed in anti-NMDA receptor encephalitis (Titulaer et al., 2013). In addition, the association with small-cell lung cancer indicates poor prognosis, as noted by another recent report (Höftberger et al., 2013). It remains unknown whether
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different mechanisms of autoantibody–antigen reaction participate in the pathogenesis of GABAB encephalitis (Moscato et al., 2010). The accumulation of multicenter cases and systematic analyses are necessary to identify the optimal treatment options for, and prognosis of this rare and unique encephalitis. Author declaration As a corresponding author, I take full responsibility for the data, the analyses and interpretation of the report. The manuscript, including related figures, has not been previously reported or published. The manuscript is not under consideration elsewhere and that it will not be submitted elsewhere while under review by the “Journal of Neuroimmunology”. All authors have read and approved the submission of the manuscript. Acknowledgment This study was supported by a grant (A121911) of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea. References Ances, B.M., Vitaliani, R., Taylor, R.A., Liebeskind, D.S., Voloschin, A., Houghton, D.J., Galetta, S.L., Dichter, M., Alavi, A., Rosenfeld, M.R., Dalmau, J., 2005. Treatmentresponsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128, 1764–1777. 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. Baumgartner, A., Rauer, S., Mader, I., Meyer, P.T., 2013. Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types. J. Neurol. 260, 2744–2753. Boronat, A., Sabater, L., Saiz, A., Dalmau, J., Graus, F., 2011. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD associated neurologic disorders. Neurology 76, 795–800. Collingridge, G.L., Isaac, J.T., Wang, Y.T., 2004. Receptor tracking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962. Dalmau, J., Furneaux, H.M., Gralla, R.J., Kris, M.G., Posner, J.B., 1990. Detection of the antiHu antibody in the serum of patients with small cell lung cancer—a quantitative Western blot analysis. Ann. Neurol. 27, 544–552. Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M.R., Balice-Gordon, R., 2011. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 10, 63–74. Fisher, R.E., Patel, N.R., Lai, E.C., Schulz, P.E., 2012. Two different 18F-FDG brain PET metabolic patterns in autoimmune limbic encephalitis. Clin. Nucl. Med. 37, e213–e218. Graus, F., Keime-Guibert, F., Reñe, R., Benyahia, B., Ribalta, T., Ascaso, C., Escaramis, G., Delattre, J.Y., 2001. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 124, 1138–1148.
Höftberger, R., Titulaer, M.J., Sabater, L., Dome, B., Rózsás, A., Hegedus, B., Hoda, M.A., Laszlo, V., Ankersmit, H.J., Harms, L., Boyero, S., de Felipe, A., Saiz, A., Dalmau, J., Graus, F., 2013. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 81, 1500–1506. 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., 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., 2011a. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69, 892–900. Irani, S.R., Bien, C.G., Lang, B., 2011b. Autoimmune epilepsies. Curr. Opin. Neurol. 24, 146–153. Kamaleshwaran, K.K., Iyer, R.S., Antony, J., Radhakrishnan, E.K., Shinto, A., 2013. 18F-FDG PET/CT findings in voltage-gated potassium channel limbic encephalitis. Clin. Nucl. Med. 38, 392–394. Lancaster, E., Lai, M., Peng, X., Hughes, E., Constantinescu, R., Raizer, J., Friedman, D., Skeen, M.B., Grisold, W., Kimura, A., Ohta, K., Iizuka, T., Guzman, M., Graus, F., Moss, S.J., Balice-Gordon, R., Dalmau, J., 2010. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 9, 67–76. Lancaster, E., Martinez-Hernandez, E., Dalmau, J., 2011. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77, 179–189. Lee, B.Y., Newberg, A.B., Liebeskind, D.S., Kung, J., Alavi, A., 2004. FDG-PET findings in patients with suspected encephalitis. Clin. Nucl. Med. 29, 620–625. Leypoldt, F., Buchert, R., Kleiter, I., Marienhagen, J., Gelderblom, M., Magnus, T., Dalmau, J., Gerloff, C., Lewerenz, J., 2012. Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease. J. Neurol. Neurosurg. Psychiatry 83, 681–686. Moscato, E.H., Jain, A., Peng, X., Hughes, E.G., Dalmau, J., Balice-Gordon, R.J., 2010. Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies. Eur. J. Neurosci. 32, 298–309. Park, B.S., Kim, Y.S., Lee, S.T., Jung, K.H., Lee, S.G., Chu, K., 2012. Anti-GABA-B receptor autoimmune encephalitis. J. Korean Epilepsy Soc. 16, 59–62. Prosser, H.M., Gill, C.H., Hirst, W.D., Grau, E., Robbins, M., Calver, A., Soffin, E.M., Farmer, C.E., Lanneau, C., Gray, J., Schenck, E., Warmerdam, B.S., Clapham, C., Reavill, C., Rogers, D.C., Stean, T., Upton, N., Humphreys, K., Randall, A., Geppert, M., Davies, C.H., Pangalos, M.N., 2001. Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Mol. Cell. Neurosci. 17, 1059–1070. Rey, C., Koric, L., Guedj, E., Felician, O., Kaphan, E., Boucraut, J., Ceccaldi, M., 2012. Striatal hypermetabolism in limbic encephalitis. J. Neurol. 259, 1106–1110. Shin, Y.W., Lee, S.T., Shin, J.W., Moon, J., Lim, J.A., Byun, J.I., Kim, T.J., Lee, K.J., Kim, Y.S., Park, K.I., Jung, K.H., Lee, S.K., Chu, K., 2013. VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J. Neuroimmunol. 265, 75–81. 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, N., 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. Ulrich, D., Bettler, B., 2007. GABA(B) receptors: synaptic functions and mechanisms of diversity. Curr. Opin. Neurobiol. 17, 298–303. Zuliani, L., Graus, F., Giometto, B., Bien, C., Vincent, A., 2012. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J. Neurol. Neurosurg. Psychiatry 83, 638–645.
