Immunotherapy-responsive limbic encephalitis with antibodies to glutamic acid decarboxylase Ioannis Markakis, Harry Alexopoulos, Cornelia Poulopoulou, Sofia Akrivou, Athanasios Papathanasiou, Vassiliki Katsiva, Georgios Lyrakos, Georgios Gekas, Marinos C. Dalakas PII: DOI: Reference:

S0022-510X(14)00322-0 doi: 10.1016/j.jns.2014.05.032 JNS 13209

To appear in:

Journal of the Neurological Sciences

Received date: Revised date: Accepted date:

27 November 2013 11 May 2014 15 May 2014

Please cite this article as: Markakis Ioannis, Alexopoulos Harry, Poulopoulou Cornelia, Akrivou Sofia, Papathanasiou Athanasios, Katsiva Vassiliki, Lyrakos Georgios, Gekas Georgios, Dalakas Marinos C., Immunotherapy-responsive limbic encephalitis with antibodies to glutamic acid decarboxylase, Journal of the Neurological Sciences (2014), doi: 10.1016/j.jns.2014.05.032

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Immunotherapy-responsive limbic encephalitis with

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antibodies to glutamic acid decarboxylase.

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Ioannis Markakis1, Harry Alexopoulos2, Cornelia Poulopoulou3, Sofia

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Akrivou 2, Athanasios Papathanasiou4, Vassiliki Katsiva5, Georgios Lyrakos1, Georgios Gekas1, Marinos C. Dalakas2 1

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Department of Neurology, “St. Panteleimon” General State Hospital. 3

Mantouvalou St., 18454, Nikaia, Greece 2

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Neuroimmunology Unit, Department of Pathophysiology, Medical

School, University of Athens. 75 Mikras Asias St., 11527, Athens Greece 3

of

Experimental

Neurophysiology,

Department

of

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Laboratory

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Neurology, Medical School, University of Athens. 72-74 Vas. Sophias

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Ave., 115 28, Athens, Greece

Department of Neurology, Essex Centre for Neurological Sciences,

Queen's Hospital, Romford, Essex, UK. 5

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Department of Radiology, “St. Panteleimon” General State Hospital. 3

Mantouvalou St., 18454, Nikaia, Greece

Author contact details: I. Markakis: [email protected]; H. Alexopoulos: [email protected]; C. Poulopoulou: [email protected], S. Akrivou: [email protected], T. Papathanasiou: [email protected]; V. Katsiva: [email protected]; G. Lyrakos: [email protected] ; G. Gekas: [email protected]; M. Dalakas: [email protected]

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Corresponding author: Ioannis Markakis, MD, Department of Neurology, “St.

Panteleimon”

General

State

Hospital,

Nikaia,

Greece.

Tel:

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00306977071285, e-mail: [email protected] )

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Abstract

Glutamic acid decarboxylase (GAD) has been recently identified as a target of

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humoral autoimmunity in a small subgroup of patients with non-paraneoplastic limbic encephalitis (NPLE). We present a patient with NPLE and positive anti-

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GAD antibodies who showed significant improvement after long-term immunotherapy. A 48-year old female was admitted with a two-year history of

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anterograde amnesia and seizures. Brain MRI revealed bilateral lesions of

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medial temporal lobes. Screening for anti-neuronal antibodies showed high anti-GAD titers in both serum and cerebrospinal fluid (CSF) with strong

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evidence of intrathecal production. The patient received treatment with prednisolone and long-term plasma exchange. During a 12-month follow-up,

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she exhibited complete seizure remission and an improvement in memory and visuo-spatial skills. Anti-GAD antibodies may serve as a useful marker to identify a subset of NPLE patients that respond to immunoregulatory treatment.

Keywords: limbic encephalopathy, glutamic acid decarboxylase, plasma exchange, autoimmune, treatment, steroids

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1. Introduction Limbic encephalopathy (LE) is an uncommon neurological disorder

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characterized by memory loss, seizures and affective disturbances in

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association with inflammatory lesions of limbic structures, mainly in the medial

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temporal lobes. The aetiology of LE may be either infective or autoimmune (paraneoplastic or non-paraneoplastic). Limbic encephalopathy (LE) has been associated with autoantibodies against various neuronal antigens, mainly

receptors,

AMPA

(α-amino-3-hydroxy-5-methyl-4-

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methyl-D-aspartate

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voltage-gated potassium channel-associated proteins (LGI1 and CASPR2), N-

isoxazolepropionic acid) receptors and gamma-amino-butyric acid receptors

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[1]. Recently, glutamic acid decarboxylase (GAD), an enzyme catalyzing the

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conversion of glutamic acid to gamma-aminobutyric acid, has also been identified as a target of humoral autoimmunity in a subgroup of these patients

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[2, 3]. We present a case of non-paraneoplastic LE with anti-GAD antibodies, who in spite of a 2-year delay in therapy initiation, improved slowly one year

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after intense immunotherapy with plasmapheresis.

2. Case report A 48-year old woman was evaluated two years ago because of episodes of confusion and disorientation that evolved, within weeks, to a severe anterograde amnesia associated with agitation, hallucinations and temporal lobe seizures. Her past medical history was unremarkable; she had no family history of seizures or other neurological and immune disorders. MRI scans revealed bilateral swelling with contrast enhancement and T2-hyperintensities in the medial temporal lobes (Figure 1A). A proton MR spectroscopy showed

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myoinositol

(mI)

and

choline

(Cho)

and

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N-

acetylaspartate (NAA) levels, raising the suspicion of a low-grade glioma

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(Figure 1B) but a brain biospy revealed only neuronal loss and reactive

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astrocytosis. Routine serological tests and cerebrospinal fluid analysis

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including search for infectious pathogens by polymerase chain reaction such as HSV1/2, VZV, EBV, CMV, HHV-6, HIV and Treponema pallidum was negative. She received various combinations of anti-epileptics with poor

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seizure control. She was then referred to our hospital.

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On admission, the neuropsychological assessment revealed a profound impairment of recent memory with preserved language functions.

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She was confused and displayed frequent confabulations. A brain MRI

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showed remission of signal abnormalities compared to the previous examinations, but significant atrophy of the medial temporal lobes (Figure

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1C). EEG demonstrated slow-wave and spike discharges over both temporal regions. Routine laboratory testing, serum protein electrophoresis and thyroid

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function studies were normal. Search for autoantibodies was negative. The cerebrospinal fluid had 5 cells/mm3, a protein content of 20 mg/dl, immunoglobulin G (IgG) index: 0.7, and positive oligoclonal bands. Extensive investigation for occult malignancy, including chest and abdominal computed tomography scans, mammography, Pap smear and serum neoplastic markers were negative. We suspected limbic encephalopathy but the search for antineuronal antibodies (anti-Hu, Yo, Ri, LGI1, CASPR2, Ma2/Ta, CRMP5/CV2, amphiphysin, AMPAR and NMDAR), was negative. However, enzyme-linked immuno-absorbent assay (ELISA) revealed high titers of anti-GAD antibodies in serum (37,550 IU/ml) and CSF (15,400 IU/ml). CSF concentrations of

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albumin and immunoglobulin G were 23.3 mg/dl and 5 mg/dl respectively. Serum

albumin

concentration

was

3600

mg/dl,

whereas

serum

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immunoglobulin G concentration was 1400 mg/dl. The GAD antibody index

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([anti-GADCSF/anti-GADserum]/[albuminCSF/albuminserum]) was 63, demonstrating

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an active intrathecal synthesis of anti-GAD IgG. CSF anti-GAD reactivity was also confirmed by double labelling with an anti-GAD commercial antibody in mouse brain cerebellar sections (Figure 2).

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The patient was initially treated with a combined antiepileptic regimen

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(phenytoin 100 mg t.i.d, levetiracetam 1000 mg b.i.d, phenobarbital 50 mg b.i.d), but she continued to present multiple partial sensory seizures and

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intermittent secondary generalized seizures on a daily basis. After the

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detection of anti-GAD antibodies, a 5-day course of intravenous methylprednisolone administered, at 1 gram/day, was ineffective. She was then

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submitted to seven series of plasma exchange (1.2 plasma volumes per session) on an alternate-day basis, followed by a second 5-day trial of

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intravenous methyl-prednisolone. She became seizure-free but her cognitive impairment remained unchanged. Treatment with plasma exchange continued every three weeks on a long-term basis, along with oral prednisolone (started at 1 mg/kg, and gradually tapered to 0.25 mg/kg, over a year period). During the ensuing 12 months, she not only remained seizure-free but also exhibited a significant improvement in verbal and visual memory, as confirmed by MiniMental State Examination and formal pschycometric testing. Serum anti-GAD titers showed a parallel decline, falling to 15,700 IU/ml after 6 months and 9,600 IU/ml after 12 months.

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3. Discussion We report a patient who developed severe memory deficits and

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intractable complex partial seizures in association with bilateral medial

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temporal pathology and typical features of CNS autoimmunity (CSF

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oligoclonal bands; presence of anti-GAD antibodies in serum and CSF), consistent with a non-paraneoplastic GAD-associated limbic encephalopathy. In spite of a 2-year delay in treatment initiation, the patient improved after

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several series of plasma exchanges with complete cessation of seizures.

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Long-term plasma exchange in combination with oral steroids resulted in marked improvement of cognitive functions, albeit with residual deficits,

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probably because of significant mediotemporal lobe atrophy owing to the

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delayed therapy. Atrophy and neuronal loss have also been described in antiGAD associated cerebellar ataxia [4] but not in stiff -person syndrome [5],

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indicating a pathogenetic heterogeneity in GAD-associated disorders. Although plasma exchange has been used to treat other GAD-associated

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syndromes such as Stiff Person Syndrome (SPS) [6] and cerebellar ataxia [4, 7] with various results, this is the first application of a successful treatment with long-term plasmapheresis in GAD-encephalitis, implying a pathogenic role of GAD or another circulating factor in this disorder. The anti–GAD titers declined at the end of therapy but whether the improvement was related to the removal of GAD antibodies remains uncertain considering that GAD is an intracellular antigen [8]. In a recent report of nine patients with anti-GADassociated NPLE, the poor outcome following monthly intravenous steroid infusions was also accompanied by a modest decrease of antibody titres [2]. The

diversity

of

neurological

syndromes

associated

with

anti-GAD

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autoimmunity [9] may either be attributed to selective impairment of distinct GABAergic pathways or to a neurodegenerative process [5].

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Targeting of different epitopes on the GAD protein has been proposed

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as a potential mechanism to account for the variability of clinical phenotypes.

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In a recent study [10], intra-cerebellar injection of anti-GAD positive serum from patients with either SPS or cerebellar ataxia was shown to induce different neurophysiological and neurochemial deficits on rodent cerebellum in

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vivo. More specifically, sera from SPS patients increased extracellular

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glutamate accumulation, whereas the serum from a patient with cerebellar ataxia markedly decreased membrane turnover, as estimated by monitoring of

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extracellular glycerol concentrations.

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A selective impairment of hippocampal GABAergic circuits by anti-GAD antibodies which in our patient were intrathecally produced in a rate higher

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than any other reported case, could account for the clinical features of NPLE: GABAergic interneurons are known to mediate inhibitory neurotransmission,

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thereby restricting epileptic activity [11]. Although it can be argued that the improvement of cognitive function was related to the cessation of seizures, the improvement was clearly observed several months later when GAD antibodies had also declined. Our case illustrates that, like in other antibody-mediated LE, improvement can take several months after treatment initiation but intense immunotherapy can be gratifying. Whether intravenous immunoglobulin and cyclophosphamide would have enhanced the benefit of plasma exchange remains unclear but these also remain additional treatment options.

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References: [1] Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with

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diseases of the CNS: new developments and future challenges. Lancet

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Neurol 2011;10:759-772.

[2] Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol

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2010;67:470-478.

[3] Matà S, Muscas GC, Naldi I, Rosati E, Paladini S, Cruciatti B, et al. Nonlimbic

encephalitis

associated

with

anti-glutamic

acid

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paraneoplastic

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decarboxylase antibodies. J Neuroimmunol 2008;199:155-159.

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[4] Ishida K, Mitoma H, Wada Y, Oka T, Shibahara J, Saito Y, et al. Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase

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antibody-associated cerebellar ataxia. J Neurol Neurosurg Psychiatry 2007;78:190-192.

[5] Rakocevic G, Raju R, Semino-Mora C, Dalakas MC. Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology 2006;67:1068-1070.

[6] Lehmann HC, Hartung HP, Hetzel GR, Stüve O, Kieseier BC. Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of

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inflammatory central nervous system disorders. Arch Neurol 2006;63:930-

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935.

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[7] Matsumoto S, Kusuhara T, Nakajima M, Ouma S, Takahashi M, Yamada

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T. Acute attacks and brain stem signs in a patient with glutamic acid decarboxylase autoantibodies. J Neurol Neurosurg Psychiatry 2002;73:345-

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[8] Alexopoulos H, Dalakas MC. A critical update on the immunopathogenesis

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of Stiff Person Syndrome. Eur J Clin Invest 2010;40:1018-1025.

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[9] Matà S, Muscas GC, Cincotta M, Bartolozzi ML, Ambrosini S, Sorbi S. GAD antibodies associated neurological disorders: incidence and phenotype

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distribution among neurological inflammatory diseases. J Neuroimmunol

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2010;227:175-177.

[10] Manto MU, Hampe CS, Rogemond V, Honnorat J. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet J Rare Dis 2011;6:3.

[11] Sloviter RS. The functional organization of the human dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy. Ann Neurol 1994;35:640-654

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[12] Lega BC, J Jacobs J, Kahana M. Human hippocampal theta oscillations

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and the formation of episodic memories. Hippocampus 2012;22:748-761.

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Figure legends

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Figure 1. Magnetic resonance imaging studies of the patient. A. Transverse FLAIR image showing swelling and T2 prolongation in medial temporal lobes within 6 months of symptom onset. B. Single-voxel NMR proton spectra

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acquired from the left mediotemporal region within 6 months of symptom

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onset. The affected brain displays increased myoinositol (mI) to creatine (Cr), choline (Cho) to creatine (Cr) and decreased N-acetyl aspartate (NAA) to

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creatine (Cr) ratios. The above spectral pattern is usually suggestive of low-

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grade glioma and diffuse gliomatosis; this possibility was however excluded with brain biopsy. C. Subsequent study performed after the revision of

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diagnosis and the administration of immunomodulatory treatment. An axial

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FLAIR image demonstrates significant atrophy of medial temporal lobes.

Figure 2. Immunofluorescent staining of mouse cerebellum with patient’s CSF showed a characteristic GAD reactivity pattern, which was more prominent in the granular layer. (A): CSF from patient, (B): CSF from control subject. The patient’s anti-GAD antibodies co-localised with a commercial anti-GAD antibody (rabbit-anti-GAD polyclonal, AB1511, Chemicon). (C) Patient’s CSF Goat-anti-human Alexa 488 (D) Anti-GAD polyclonal - Goat-anti-rabbit Alexa 568 (E) Overlap

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GAD is a recently described target of humoral autoimmunity in a

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Highlights



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subgroup of NPLE.

A patient with anti-GAD NPLE was treated with long-term plasma exchange.

Treatment led to complete seizure remission and to cognitive

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Intense and prolonged immunotherapy may be indicated in anti-GAD

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NPLE.

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improvement.

Immunotherapy-responsive limbic encephalitis with antibodies to glutamic acid decarboxylase.

Glutamic acid decarboxylase (GAD) has been recently identified as a target of humoral autoimmunity in a small subgroup of patients with non-paraneopla...
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