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Keywords:

  • Antibodies;
  • Diagnosis;
  • Pathogenesis;
  • Limbic encephalitis;
  • Encephalopathy

Summary

  1. Top of page
  2. Summary
  3. Epilepsy as a Presentation of Autoimmune Diseases (A. Vincent, Oxford, United Kingdom)
  4. Encephalitis with NMDAR Antibodies (J. Honnorat, Lyon, France)
  5. Epilepsy and Antibodies to Glutamic Acid Decarboxylase (GAD) (M. Carreño, Barcelona, Spain)
  6. Autoantibodies in Unselected Series of Epilepsy Patients (B. Lang, Oxford, United Kingdom)
  7. Additional Contributors
  8. Disclosures
  9. References

In a substantial number of patients with epilepsy, the etiology of the seizure disorder remains unknown. In recent years, the detection of autoantibodies has contributed to the etiologic understanding of a substantial number of so far unexplained epilepsies. The associated syndromes are mainly related to the temporal lobes (with presentation as limbic encephalitis or chronic mediotemporal lobe epilepsy) or to extended brain areas (presenting as diffuse encephalopathies with seizures). However, the full spectrum of autoantibody-associated epilepsies is about to be determined. A promising example for this incipient expansion of the clinical spectrum is the description of a novel seizure type found in patients with antibodies to the voltage-gated potassium channel (VGKC) complex. At present, the antibodies most relevant in epileptology are those directed to molecules on the surface of neurons, namely to components of the VGKC complex and to the N-methyl-d-aspartate-receptor; other antigenic targets located on the surface of neurons are the γ-aminobutyric acid (GABA)B-receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor. There are several reasons to believe that these antibodies are directly pathogenic to the brain. Other autoantibodies target intracellular antigens like those directed to the enzyme glutamic acid decarboxylase (GAD) and the onconeural antibodies. Most researchers think that these antibodies are markers of the immunopathological process rather than being pathogenically active by themselves. Especially the epilepsies associated with antibodies to surface antigens seem to respond to immunotherapies. This offers novel promising therapeutic avenues for the epileptologist. The precise pathogenic effects of autoantibodies still need to be elucidated.

Although epilepsy is one of the most common neurologic disorders affecting millions of people worldwide, in a substantial number of individuals the etiology remains unknown. Over the last few years there has been increasing support for the hypothesis that some forms of epilepsy may have an autoimmune component. Circumstantial evidence in support of this idea includes the apparent association of seizures with certain autoimmune diseases (e.g., systemic lupus erythematosus and Hashimoto’s encephalopathy) and, in some patients, an acute or subacute onset of the seizures, a rapidly progressive course, and a favorable response to immunotherapy. Recently, clinically relevant autoantibodies have been detected in a number of central nervous system (CNS) disorders that often present with recurrent seizures, as discussed below.

Epilepsy as a Presentation of Autoimmune Diseases (A. Vincent, Oxford, United Kingdom)

  1. Top of page
  2. Summary
  3. Epilepsy as a Presentation of Autoimmune Diseases (A. Vincent, Oxford, United Kingdom)
  4. Encephalitis with NMDAR Antibodies (J. Honnorat, Lyon, France)
  5. Epilepsy and Antibodies to Glutamic Acid Decarboxylase (GAD) (M. Carreño, Barcelona, Spain)
  6. Autoantibodies in Unselected Series of Epilepsy Patients (B. Lang, Oxford, United Kingdom)
  7. Additional Contributors
  8. Disclosures
  9. References

There are a number of autoimmune disorders in which epilepsy may occur, often associated with antibodies directed to antigens on neuronal cell surfaces (Irani et al., 2010). Epilepsies resulting from conditions related to autoantibodies can be grouped into (1) disorders mainly localized to the temporal lobe, sometimes with more widespread involvement of the cortex (“limbic encephalitis” in the classical sense with subacute onset of severe memory impairment and mood disturbances in addition to the recurrent temporal lobe seizures, but also temporal lobe epilepsies with less prominent memory and behavioral problems) and (2) encephalopathies with diffuse involvement of the brain. Classical limbic encephalitis with temporal lobe seizures can be associated with onconeural antibodies directed to the intracellular proteins Hu, Ma1/2, amphiphysin, or CV2. In recent years, however, an increasing number of temporal lobe disorders, often with prominent temporal lobe seizures, have been associated with antibodies to molecules located on neuronal membranes. These molecules have extracellular domains to which the antibodies can bind. The most sensitive and specific method for measuring these antibodies is to demonstrate human immunoglobulin G (IgG) binding to the surface of cells that have been transfected with the complementary deoxyribonucleic acid (cDNAs) for the target molecule. In the following, these antibodies and their related phenotypes are discussed.

Disorders affecting the temporal lobe (and sometimes more widespread cortical involvement)

Antibodies may be directed to the following targets: the voltage-gated potassium channel (VGKC) complex, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, or the γ-aminobutyric acid (GABA)B receptor, and rarely to the N-methyl-d-aspartate (NMDA) receptor (Irani et al., 2010). The VGKC complex antibodies have been measured by immunoprecipitation of VGKC Kv1 subunits solubilized in detergent from rabbit brain tissue and radioactively labeled by 125I-dendrotoxin, a snake toxin that binds very strongly to Kv1.1, 1.2, and 1.6. A series of experiments has recently shown that the antibodies in patients with acquired neuromyotonia, limbic encephalitis, or the much rarer Morvan’s syndrome mostly do not, contrary to what had been believed, bind directly to Kv1 subunits but rather to other molecules that are closely complexed with the Kv1 in brain extracts. The most frequently associated molecules identified so far are LGI1 and CASPR2, with the great majority of the patients with limbic encephalitis and temporal lobe epilepsy having antibodies to LGI1 (Lai et al., 2010). Their typical disease onset is at older than 50 years of age, with male patients more frequently affected than female patients (3:2 ratio).

Very recently, a proportion of patients with high-titer VGKC complex antibodies were found to have characteristic faciobrachial dystonic seizures (FBDS) prior to the development of temporal lobe seizures and other features of limbic encephalitis. This usually occurred in older adults. In 90% of these cases the specific target was LGI1 (Irani et al., 2011); one also had contactin-2 antibodies and two had additional CASPR2 antibodies. FBDS typically occurred many times per day (median of 50 attacks per day, range 6–320). They comprised brief (<3 s) episodes of simultaneous facial grimacing and ipsilateral arm dystonia. When ictal electroencephalography (EEG) abnormalities were detectable during FBDS, they revealed contralateral rhythmic frontotemporal spikes. These seizures responded very well to immunotherapies. However, a high incidence of adverse reactions to antiepileptic drugs (AEDs) (namely skin reactions) was observed. The identification of FBDS as the seizure hallmark of VGKC complex antibody-mediated disease is of significant clinical importance. This is an excellent example of the fruitful impact of antibody-driven research on the field of epileptology.

Other antibody targets in patients with limbic encephalitis and temporal lobe seizures are the GABAB receptor (Lancaster et al., 2010) and the AMPA receptor (Lai et al., 2009). Antibodies to the extracellular region of the GABAB receptor (B1 subunit) have been reported in 15 patients presenting with refractory temporal lobe seizures as well as other symptoms of limbic dysfunction. Seven patients had tumors (five were small-cell lung cancer). Nine of the 10 patients who received immunotherapy, with tumor treatment as appropriate, showed neurologic improvement compared with none in the untreated group.

In contrast, patients who have limbic encephalitis with antibodies to the AMPA receptor (GluR1/2) are less likely to present with seizures. Only 3 of 10 patients had seizures as an early symptom, and one patient had seizures after a relapse (Lai et al., 2009).

Encephalopathy with NMDAR antibodies

Clinically quite distinct from these supratentorial cortical disorders is the stage-wise encephalopathy associated with NMDA receptor (NMDAR) antibodies (Dalmau et al., 2008). This condition is so distinctive that it has been coined anti-NMDAR encephalitis. About 80% of patients experience seizures during the first few weeks of the disease; in parallel, other neuropsychiatric symptoms are typically observed. The seizures are of extratemporal origin. After the first stage of the disease, patients usually progress to a more severe phase with a characteristic choreoathetoid movement disorder, dysautonomia, and impaired consciousness but undetectable seizures. Correspondingly, the EEG shows diffuse slowing.

Occasionally, different phenotypes may occur in association with NMDAR antibodies. Patients may have a pure seizure disorder without prominent neuropsychiatric involvement. They present with nonconvulsive status epilepticus or refractory temporal lobe epilepsy. More details on anti-NMDAR encephalitis are provided in the next section.

Future directions

This is a very exciting area of research with significant clinical impact. Patients are now being recognized worldwide and treated with immunotherapies that often lead to definite clinical improvement (Vincent et al., 2010). However, recognition of the syndromes is not as complete as it might be, and antibody-mediated disease is usually low on the list of potential differential diagnoses (Niehusmann et al., 2009). Clinicians should seriously consider an immune-mediated etiology in patients with unexplained subacute onset of seizures particularly in the presence of magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) evidence of inflammation.

There are, however, questions regarding the relative roles of serum and CSF antibodies, and whether immunotherapies should target the intrathecal compartment. There is a need to develop assays that can be used in national or even local laboratories for rapid diagnosis; some progress is being made by a number of companies. Finally, effort should be applied to identifying new antibodies, by proteomic or candidate approaches, which could help with the diagnosis of potentially treatable forms of epilepsy still considered to be of unknown origin.

Encephalitis with NMDAR Antibodies (J. Honnorat, Lyon, France)

  1. Top of page
  2. Summary
  3. Epilepsy as a Presentation of Autoimmune Diseases (A. Vincent, Oxford, United Kingdom)
  4. Encephalitis with NMDAR Antibodies (J. Honnorat, Lyon, France)
  5. Epilepsy and Antibodies to Glutamic Acid Decarboxylase (GAD) (M. Carreño, Barcelona, Spain)
  6. Autoantibodies in Unselected Series of Epilepsy Patients (B. Lang, Oxford, United Kingdom)
  7. Additional Contributors
  8. Disclosures
  9. References

A recently delineated neurologic syndrome has been associated/defined by NMDAR antibodies (Dalmau et al., 2008). NMDAR are ligand-gated cation channels with crucial roles in synaptic transmission and plasticity. The receptors are heteromers of NR1 subunits, which bind glycine, and NR2 subunits, which bind glutamate. NMDARs are expressed on neurons throughout the brain; their highest densities are found in the amygdala, hypothalamus, prefrontal cortex, and hippocampus. Overactivity of NMDARs is a proposed underlying mechanism for epilepsy or dementia, whereas low activity may produce symptoms of schizophrenia. The first 15 patients with autoantibodies against NMDARs presented with encephalitis, ovarian teratoma, and NMDAR-Abs (Dalmau et al., 2008). All were young women who also had psychiatric disturbances consisting of delusions or behavioral problems. Following the original description, many further cases have been reported and the frequency of encephalitis associated with NMDAR-Ab appears to be high. Indeed, the first 100 patients were reported less than one year after NMDAR-Abs were discovered, and more than 275 additional patients with NMDAR-Abs were diagnosed between January 2006 and June 2009 (Dalmau et al., 2011). In Honnorat’s reference center in France, 50 patients have been identified over the last 18 months. Even though NMDAR antibodies are mainly observed in young women, these autoantibodies have been also described in children and men. The more substantial body of recent data shows that <45% of cases are associated with tumors.

The patients with this characteristic encephalopathy present with stereotyped clinical features, including acute psychiatric disorders (e.g., delirium with visual or auditory delusions, aggression, and irritability), epileptic seizures, and loss of consciousness. Dysautonomia with or without acute central respiratory failure requiring resuscitation occurs in one-third of patients. Brain MRI is normal in 45% of cases but CSF examination reveals inflammation in >90% of cases (i.e., an elevated white cell count, mainly lymphocytes, and mildly elevated protein content with or without oligoclonal bands). Electroencephalography studies are abnormal in >90% of cases. A good response to immunotherapy is observed in nearly half of patients. However, no study demonstrates the superiority of one treatment over another. Intravenous immunoglobulin, plasma exchange, and corticosteroids are the most commonly used treatments, but rituximab and cyclophosphamide have recently been advocated (Dalmau et al., 2011)

Pathophysiology of encephalitis with NMDAR antibodies

NMDAR antibody targets the N-terminal extracellular domain of the NR1 subunit of the NMDAR. Antibodies are present in patients’ sera and CSF with intrathecal synthesis. In vitro, NMDAR antibodies lower NMDAR cluster density in a manner that is reversible, with the removal of the antibodies from neuronal cell cultures. In vitro and in vivo studies show that NMDAR antibodies decrease the surface density and receptor localization of NMDAR clusters via antibody-mediated capping and internalization. This effect is independent of the presence of complement and spares other synaptic proteins, AMPA currents, and synapse density (Hughes et al., 2010). These changes in NMDAR surface density and localization correlate with antibody titer. Not surprisingly, therefore, NMDAR-mediated synaptic currents decrease with NMDAR antibody exposure. Using microdialysis in a rat model, Dr Honnorat’s group demonstrated that patients’ CSF and purified IgGs from patients with NMDAR antibodies increased both extracellular glutamate levels and susceptibility to AMPA receptor stimulation (unpublished data). Moreover, blockade of GABAA receptors magnified the increase in glutamate concentration observed in the presence of NMDA antibodies. Therefore, NMDAR antibodies seem to block the extracellular epitopes of the NR1 subunit of the NMDA receptor, resulting in a hyperglutamatergic state in the brain, with an imbalance between NMDA and AMPA pathways, which create a cortical hyperexcitability (Hughes et al., 2010; Manto et al., 2011). Encephalitis with NMDAR antibodies can be severe and even fatal, but is potentially reversible; patients may recover if the disorder is recognized and treated in time. In one patient’s brain, prominent B-cell cuffing was found around brain vessels accompanied by some plasma cells, whereas macrophages and T cells were scattered throughout the brain parenchyma.

Future directions

The available evidence suggests that NMDAR antibodies play a direct role in the symptoms of encephalitis; nevertheless, other immune cells, chemokines, and cytokines may also play a major role that further studies should elucidate.

Epilepsy and Antibodies to Glutamic Acid Decarboxylase (GAD) (M. Carreño, Barcelona, Spain)

  1. Top of page
  2. Summary
  3. Epilepsy as a Presentation of Autoimmune Diseases (A. Vincent, Oxford, United Kingdom)
  4. Encephalitis with NMDAR Antibodies (J. Honnorat, Lyon, France)
  5. Epilepsy and Antibodies to Glutamic Acid Decarboxylase (GAD) (M. Carreño, Barcelona, Spain)
  6. Autoantibodies in Unselected Series of Epilepsy Patients (B. Lang, Oxford, United Kingdom)
  7. Additional Contributors
  8. Disclosures
  9. References

GAD is the rate-limiting enzyme for the synthesis of GABA. GAD antibodies are found in up to 80% of patients with newly diagnosed type I diabetes mellitus (DM1), and also in patients with polyendocrine autoimmune syndrome. High levels of GAD antibodies (>100-fold higher than those typically found in DM1; e.g., >1,000 units/ml) are found in other neurologic diseases: up to 80% of patients with stiff person syndrome, some patients with late isolated cerebellar ataxia (usually associated with DM1 or polyendocrine autoimmune syndrome), and other disorders such as downbeat nystagmus, palatal tremor, brainstem dysfunction, and epilepsy.

In addition, GAD antibodies may be found in patients with epilepsy in two different settings: acute/subacute onset of seizures accompanied by variable degrees of cognitive and psychiatric disturbance, typically in association with MRI evidence of inflammation of the mesial temporal structures (limbic encephalitis), and also in patients with chronic epilepsy without clinical or MRI evidence of active CNS inflammation. However, the possible pathogenic role of GAD antibodies remains to be elucidated, despite data regarding direct interaction with neuronal cultures and from studies in experimental animals (Manto et al., 2007). For example, serum from GAD-ab positive patients applied on hippocampal neurons in culture has been reported to interfere with GABA function and consequently with neuronal inhibition. GAD-Ig from CSF of ataxic patients has also been shown to reduce GABA release in slices of rat cerebellum, depressing GABAA receptor–mediated inhibitory transmission. These neurophysiologic changes derived from altered GABAergic transmission could lead to increased excitability and lower seizure threshold.

Chronic epilepsy

GAD antibodies have been found in some patients with epilepsy with focal seizures (Liimatainen et al., 2010). These patients have had a long evolution of refractory epilepsy, often in the setting of a normal MRI. In general, no association has been found between GAD antibody levels and severity of epilepsy. However, the method of determination and the levels of antibodies considered relevant have been variable among different studies, and intrathecal synthesis has not been consistently reported. In those patients with drug-resistant seizures who have been given immunomodulatory treatments, the response has been unclear, although some positive responses have been reported.

In a recent study of patients with different types of chronic epilepsy, both controlled and drug resistant, high serum GAD antibody levels were found in 2.8% of cases using a radioimmunoassay (>1,000 RU/ml) (Liimatainen et al., 2010). The GAD antibody–positive patients had predominantly temporal lobe epilepsy. Intrathecal GAD antibody synthesis was found in two of five patients with high serum levels and available CSF. They often had serologic (antithyroid antibodies, anti-GM1 antibodies, antinuclear antibodies) or clinical evidence of other autoimmune diseases.

The experience of the Barcelona group (Carreño et al.) is similar. They have found five patients with epilepsy and high (>2,000 UI/ml) levels of GAD antibodies, with variable epilepsy duration (2–16 years) and variable seizure control. These patients had temporal lobe epilepsy according to clinical semiology and EEG studies and had normal MRI. When available, neuropsychological studies showed a memory deficit that was congruent with the epileptogenic zone. There was no correlation between GAD antibody levels and the severity of seizures. Intrathecal synthesis of GAD antibodies was found in three of four patients tested. Association with other autoimmune diseases was common: DM1 (three patients), psoriatic arthritis and hypothyroidism (one patient), ocular myasthenia gravis (one patient).

Limbic encephalitis

High levels of GAD antibodies can also be found in patients with nonparaneoplastic limbic encephalitis, that is, patients with recent onset epilepsy and MRI evidence of mediotemporal encephalitis (Malter et al., 2010). These patients, compared to the patients with limbic encephalitis with VGKC complex antibodies, are usually younger and have mainly temporal lobe seizures and less prominent cognitive or psychiatric disturbances. Some of these patients develop other autoimmune diseases and all have positive intrathecal synthesis of GAD. Seizures are generally resistant to anticonvulsants and immunomodulatory treatment, resulting in a chronic disorder dominated by temporal lobe epilepsy.

Future directions

Prospective controlled clinical trials should clarify the efficacy and safety of immunomodulatory treatments in these patients. At present, it is unclear if only patients with proven intrathecal synthesis should be treated, and the best way to monitor response to treatment has not yet been delineated.

In the case of drug-resistant seizures associated with GAD antibody–positive limbic encephalitis, new immunotherapeutic strategies should be prospectively evaluated to avoid the chronic and unremitting course that seems characteristic.

Autoantibodies in Unselected Series of Epilepsy Patients (B. Lang, Oxford, United Kingdom)

  1. Top of page
  2. Summary
  3. Epilepsy as a Presentation of Autoimmune Diseases (A. Vincent, Oxford, United Kingdom)
  4. Encephalitis with NMDAR Antibodies (J. Honnorat, Lyon, France)
  5. Epilepsy and Antibodies to Glutamic Acid Decarboxylase (GAD) (M. Carreño, Barcelona, Spain)
  6. Autoantibodies in Unselected Series of Epilepsy Patients (B. Lang, Oxford, United Kingdom)
  7. Additional Contributors
  8. Disclosures
  9. References

The presence of autoantibodies has been investigated in an unselected series of patients in whom seizures were the presenting (and, in many cases, the only) symptom. This analysis was carried out with the view that antibody testing might be valuable in the substantial proportion of patients in which the etiology of their epilepsy is unknown. In collaboration with Drs. Hart and Howell, Lang collected sera from consecutive adult patients with epilepsy attending clinics in Oxford and Sheffield (n = 236); Drs. Sills and Brodie provided newly diagnosed, previously untreated epilepsy patients at the Epilepsy Unit, Western Infirmary, Glasgow (n = 185). Autoantibodies to the VGKC complex were found in 10% of all patients with epilepsy (controls 0.5%, n = 163), the highest titers being found in patients who had an acute or subacute onset of disease. Antibodies to NMDAR were more commonly found in the newly diagnosed patients (7% compared to 2.5% in the consecutive cohort). Antibodies to the intracellular antigen GAD were found at a lower frequency (1.6–1.7%) in both cohorts. The majority of patients with GAD antibodies had focal epilepsy. In a small cohort of children (n = 34) with otherwise unexplained status epilepticus (from Dr. Dale), over 20% had raised VGKC complex antibodies.

Future directions

Lang’s group is currently expanding its study to look for the incidence of these and other autoantibodies in additional cohorts and to define any clinical phenotypes that may be associated with these autoantibodies. Until now, the Oxford group has taken a “candidate antigen” approach to this study, looking only for autoantibodies that can be detected by standard diagnostic means, but the search for novel antigens through proteomic studies should be undertaken. Finally, and most importantly, the pathogenicity of the antibodies detected needs to be clarified in order to determine if the antibodies are causative or simply a marker of underlying inflammatory processes.

References

  1. Top of page
  2. Summary
  3. Epilepsy as a Presentation of Autoimmune Diseases (A. Vincent, Oxford, United Kingdom)
  4. Encephalitis with NMDAR Antibodies (J. Honnorat, Lyon, France)
  5. Epilepsy and Antibodies to Glutamic Acid Decarboxylase (GAD) (M. Carreño, Barcelona, Spain)
  6. Autoantibodies in Unselected Series of Epilepsy Patients (B. Lang, Oxford, United Kingdom)
  7. Additional Contributors
  8. Disclosures
  9. References
  • Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR. (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7:10911098.
  • Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10:6374.
  • Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons TD, Lynch DR, Dalmau J, Balice-Gordon RJ. (2010) Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 30:58665875.
  • Irani SR, Alexander S, Waters P, Kleopa KA, 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 133:27342748.
  • Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, Schott JM, Armstrong RJE, Zagami A, Bleasel A, Somerville ER, Smith SMJ, Vincent A. (2010) Faciobrachial dystonic seizures precede Lgi1-antibody limbic encephalitis. Ann Neurol Oct 28. doi:10.1002/ana.22307 [Epub ahead of print].
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  • Liimatainen S, Peltola M, Sabater L, Fallah M, Kharazmi E, Haapala AM, Dastidar P, Knip M, Saiz A, Peltola J. (2010) Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia 51:760767.
  • Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG. (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67:470478.
  • Manto MU, Laute MA, Aguera M, Rogemond V, Pandolfo M, Honnorat J. (2007) Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Ann Neurol 61:544551.
  • Manto M, Dalmau J, Didelot A, Rogemond V, Honnorat J. (2011) Afferent facilitation of corticomotor responses is increased by IgGs of patients with NMDA-receptor antibodies. J Neurol 258:2733.
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