show evolution of signal changes with degeneration and regeneration following nerve injury.6,7 Magnetic resonance tractography, by visualizing growing nerve fibers, may allow distinction between axonotmetic and neurotmetic injuries earlier, thereby expediting necessary surgeries while reducing the need for exploratory nerve surgery. *These authors contributed equally to this work as senior authors. From the University of California (N.G.S., J.N., T.C., J.W.R., J.W.E., M.K., C.C.), San Francisco; and GE Health Care (S.B.), Menlo Park, CA. Dr. Kliot is currently with the Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL. Author contributions: Dr. Simon: study design, data acquisition, analysis and interpretation, drafting and revision of the manuscript. Dr. Narvid: data acquisition and analysis, critical revision of the manuscript for important intellectual content. Dr. Cage: critical revision of the manuscript for important intellectual content. Dr. Banerjee: study design and data acquisition, critical revision of the manuscript for important intellectual content. Dr. Ralph: data acquisition and analysis, critical revision of the manuscript for important intellectual content. Dr. Engstrom: data acquisition and analysis, critical revision of the manuscript for important intellectual content. Dr. Kliot: study design, data acquisition, analysis and interpretation, critical revision of the manuscript for important intellectual content. Dr. Chin: study design, data acquisition, analysis and interpretation, critical revision of the manuscript for important intellectual content. Study funding: National Health and Medical Research Council of Australia and the Motor Neurone Disease Research Institute of Australia (grant 1039520) (N.G.S.). Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Harald Prüss, MD Marcus Rothkirch, PhD Ute Kopp, PhD Hajo M. Hamer, MD Mareike Hagge, MD Phillipp Sterzer, MD Sandra Saschenbrecker PhD Winfried Stöcker, MD Lutz Harms, MD Matthias Endres, MD
Supplemental data at Neurology.org
LIMBIC ENCEPHALITIS WITH mGluR5 ANTIBODIES AND IMMUNOTHERAPYRESPONSIVE PROSOPAGNOSIA
In 1982, Dr. Ian Carr described personality changes and memory loss in his 15-year-old daughter, who had limbic encephalitis and Hodgkin lymphoma (HL).1 He assumed “a circulating neurotransmitter-like molecule produced by the neoplasm” causing the brain disease, and noted that it “may be reversible and can be remembered as the Ophelia syndrome.” Almost 30 years later, Lancaster et al.2 identified antibodies against the metabotropic glutamate receptor 5 (mGluR5) as Carr’s neurotransmitter-like molecule in 2 patients with limbic encephalitis and HL. Encephalitis was reversible in both patients receiving tumor treatment. The clinical spectrum is largely unknown and the role of immunotherapy is unclear. Case report. A 30-year-old woman complained of night sweats, low-grade fever, fatigue for weeks, and 15-kg weight loss over 8 months. She had acute onset of progressive personality and mood changes, headaches, memory problems, disorientation, and affective incontinence. Lumbar puncture revealed Neurology 83
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Received January 23, 2014. Accepted in final form May 19, 2014. Correspondence to Dr. Kliot: [email protected]
© 2014 American Academy of Neurology 1.
Saritas EU, Cunningham CH, Lee JH, Han ET, Nishimura DG. DWI of the spinal cord with reduced FOV single-shot EPI. Magn Reson Med 2008;60:468–473. Zaharchuk G, Saritas EU, Andre JB, et al. Reduced field-ofview diffusion imaging of the human spinal cord: comparison with conventional single-shot echo-planar imaging. AJNR Am J Neuroradiol 2011;32:813–820. West GA, Haynor DR, Goodkin R, et al. Magnetic resonance imaging signal changes in denervated muscles after peripheral nerve injury. Neurosurgery 1994;35:1077–1085; discussion 1085–1086. Takagi T, Nakamura M, Yamada M, et al. Visualization of peripheral nerve degeneration and regeneration: monitoring with diffusion tensor tractography. Neuroimage 2009;44: 884–892. Meek MF, Stenekes MW, Hoogduin HM, Nicolai JP. In vivo three-dimensional reconstruction of human median nerves by diffusion tensor imaging. Exp Neurol 2006; 198:479–482. Dailey AT, Tsuruda JS, Filler AG, Maravilla KR, Goodkin R, Kliot M. Magnetic resonance neurography of peripheral nerve degeneration and regeneration. Lancet 1997;350:1221–1222. Aagaard BD, Lazar DA, Lankerovich L, et al. High-resolution magnetic resonance imaging is a noninvasive method of observing injury and recovery in the peripheral nervous system. Neurosurgery 2003;53:199–203.
increased cell counts (25/mL) and intrathecal immunoglobulin G (IgG) synthesis; protein was normal. Extensive tests for infectious encephalitis or metabolic encephalopathy remained negative; repeated head MRIs were unremarkable. Diagnosis of limbic encephalitis of unknown etiology was established. The condition improved in the following weeks; however, deficits in attention and marked impairment of visuoconstructive abilities persisted. The patient complained about prosopagnosia and sleep-associated episodes of enuresis and involuntary movements. Video-EEG evaluation 3 months later showed frequent episodes of complex abrupt movements out of waking state, tossing and turning in bed, and reduced responsiveness and vocalizations (video on the Neurology® Web site at Neurology.org). The episodes were not associated with seizure patterns on EEG, reminiscent of psychogenic nonepileptic seizures. However, the patient reported improvement under levetiracetam and worsening after discontinuation. Serum and CSF showed IgG antibodies against mGluR5 in indirect immunofluorescence using mGluR5-transfected HEK293 cells and rat brain sections (figure). The specific antibody index (ratio
Detection of metabotropic glutamate receptor 5 (mGluR5) antibodies and immunotherapy-responsive prosopagnosia
(A) Patient’s serum (green, Alexa Fluor 488, Jackson ImmunoResearch, Suffolk, UK) shows the typical mGluR5 distribution pattern in rat cerebellum, (B) rat hippocampus, and (C) mGluR5-transfected HEK293 cells, but not (D) control-transfected cells. Red nuclear stain was performed with TO-PRO-3 iodide (Invitrogen, Karlsruhe, Germany). For transfection, mGluR5 cDNA (GenBank accession no. BC096533) was amplified from mouse cDNA clone IRAKp961P03205Q (BioScience, Nottingham, UK) by PCR using primers for sense (59-ATAGGTCTCTCATGGTCCTTCTGTTGATTCTGTCAG-39) and antisense (59-ATAGGTCTCCTCGAGCTATCCCAGGGATGTTTCCAGTGG-39) with appropriate restriction sites. Resulting fragments were digested (Eco31I) and ligated into linearized (NcoI/XhoI) pTriEx-1 (Merck Biosciences, Darmstadt, Germany) to create pTriEx-1-GRM5. (E) Recognition of faces (family, friends, famous persons such as politicians and actors) was impaired, while recognition of objects (buildings, nonhumans such as Mickey Mouse, car brands) was preserved. To quantify prosopagnosia, neural responsiveness to faces was tested in 3 fMRI sessions. Stimuli of faces and houses were presented within a 1-back task paradigm and neural responsiveness to face stimuli in the right face-selective fusiform face area (FFA) quantified (see reference 7 for further details). The patient’s face-related FFA responses were low before immunotherapy (timepoint T1), but showed a progressive improvement under immunotherapy with steroids, plasma exchange (T2), and rituximab (T3) (red circles in E, showing activation maps thresholded at p , 0.001, uncorrected). (F) Our patient’s face-specific neural response at timepoint T1 was very low (7.6th percentile, left red line) compared to the FFA activity distribution curve from 44 healthy participants (black curve). Face processing increased toward the middle range of the healthy distribution between timepoints T2 (29.7th percentile) and T3 (54.8th percentile).
between CSF/serum quotient for mGluR5-IgG antibodies, and CSF/serum quotient for total IgG) was 43.5, verifying intrathecal synthesis of mGluR5 antibodies. Other antibodies against neural antigens (NMDAR, AMPAR, GABABR, GABAAR, mGluR1, GlyR, LGI1, CASPR2, AQP4, DNER[Tr], GAD65, Hu, Yo, Ri, Ma/Ta, amphiphysin, MAG, myelin) were absent. Positive mGluR5 antibodies and absence of GABAAR/mGluR1 antibodies were confirmed in Prof. Josep Dalmau’s laboratory (Barcelona, Spain).
PET scan showed 2 hypermetabolic inguinal lymph nodes that were excised and did not show evidence of a tumor. Similarly, no lymphoma cells were found in a bone marrow specimen. Immunosuppressive therapy with methylprednisolone and plasma exchange resulted in marked improvement of fatigue, alertness, movement episodes, and general activity. Memory improvement was particularly evident; however, prosopagnosia persisted initially (figure) and 2 doses of 1,000 mg Neurology 83
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rituximab were administered, followed by further improvement of anterograde amnesia and prosopagnosia. mGluR5 serum antibody titer declined from 1:320 to 1:32 over 12 months. A gradual increase of functional MRI responses to face stimuli over 3 scanning sessions corroborated the improvement of prosopagnosia (figure). Discussion. The present case of mGluR5 antibody– positive limbic encephalitis markedly extends the known clinical spectrum. So far, mGluR5 antibodies were detectable either in serum2 or CSF.3 This is the first case in which both serum and CSF were available demonstrating that patients can have intrathecal synthesis of mGluR5 antibodies, similar to other autoimmune encephalitides.4 All previous cases were associated with HL.1–3,5,6 Indeed, our patient had low-grade fever, night sweats, and weight loss suggestive of lymphoma. However, extensive tumor search including whole-body PET, examination of hypermetabolic lymph nodes, and bone marrow aspiration could not demonstrate a malignancy over a follow-up of 17 months. Thus, it is possible that mGluR5 antibody–positive encephalitis can also occur as nonparaneoplastic disease, although careful follow-ups remain needed given that Ophelia syndrome usually precedes the identification of HL and patients may start to improve before tumor treatment.2,5 The neuropsychiatric abnormalities can be diverse, ranging from mood and personality changes to anterograde amnesia, disorientation, headaches, and involuntary movements. The present case adds immunotherapy-responsive prosopagnosia to the spectrum. In previous cases, the main therapy consisted of tumor treatment, leaving the importance of immunotherapy an open question. The profound improvement of neuropsychiatric abnormalities, prosopagnosia, and anterograde amnesia in our patient suggests that immunosuppression with steroids, plasma exchange, and rituximab can be beneficial. Finally, while all previous cases showed various degrees of MRI abnormalities,2,3 mGluR5-positive encephalitis can present with normal brain PET and MRI, similar to related autoimmune encephalitides. Based on the growing clinical spectrum related to mGluR5 antibodies, we recommend considering testing
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for these antibodies in serum and CSF of patients with unexplained noninfectious encephalitis, even if there is no HL or other tumor detectable. From the Klinik und Hochschulambulanz für Neurologie, Charité– Universitätsmedizin Berlin (H.P., U.K., L.H., M.E.), Department of Psychiatry, Charité–Universitätsmedizin Berlin (M.R., P.S.); German Center for Neurodegenerative Diseases (DZNE) Berlin (H.P., M.E.), Berlin; the Epilepsy Center (H.M.H., M.H.), Universitätsklinikum Erlangen; and the Institute for Experimental Immunology (S.S., W.S.), affiliated with Euroimmun, Lübeck, Germany. Author contributions: Dr. Prüss, Dr. Endres: design or conceptualization of the study. Dr. Prüss, Dr. Rothkirch, Dr. Kopp, Dr. Hamer, Dr. Hagge, Dr. Sterzer, Dr. Saschenbrecker, Dr. Stöcker, Dr. Harms, Dr. Endres: analysis or interpretation of the data. Dr. Prüss, Dr. Rothkirch, Dr. Kopp, Dr. Hamer, Dr. Hagge, Dr. Sterzer, Dr. Saschenbrecker, Dr. Stöcker, Dr. Harms, Dr. Endres: drafting or revising the manuscript. Study funding: No targeted funding reported. Disclosure: H. Prüss, M. Rothkirch, U. Kopp, H.M. Hamer, M. Hagge, and P. Sterzer report no disclosures relevant to the manuscript. S. Saschenbrecker is an employee of Euroimmun AG. W. Stöcker is shareholder and member of the board of Euroimmun AG. L. Harms and M. Endres report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. Received March 4, 2014. Accepted in final form June 3, 2014. Correspondence to Dr. Prüss: [email protected]
© 2014 American Academy of Neurology 1. 2.
Carr I. The Ophelia syndrome: memory loss in Hodgkin’s disease. Lancet 1982;1:844–845. Lancaster E, Martinez-Hernandez E, Titulaer MJ, et al.
Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 2011;77:1698–1701. Mat A, Adler H, Merwick A, et al. Ophelia syndrome with
metabotropic glutamate receptor 5 antibodies in CSF. Neurology 2013;80:1349–1350. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;
13:167–177. Shinohara T, Kojima H, Nakamura N, et al. Pathology of pure hippocampal sclerosis in a patient with dementia and
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Hodgkin’s lymphoma with Ophelia syndrome. J Clin Oncol 2007;25:1802–1803. Rothkirch M, Schmack K, Schlagenhauf F, Sterzer P. Implicit motivational value and salience are processed in distinct areas of orbitofrontal cortex. Neuroimage 2012;62: 1717–1725.
Limbic encephalitis with mGluR5 antibodies and immunotherapy-responsive prosopagnosia Harald Prüss, Marcus Rothkirch, Ute Kopp, et al. Neurology 2014;83;1384-1386 Published Online before print September 5, 2014 DOI 10.1212/WNL.0000000000000865 This information is current as of September 5, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/15/1384.full.html
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/09/05/WNL.0000000000 000865.DC1.html
This article cites 7 articles, 3 of which you can access for free at: http://www.neurology.org/content/83/15/1384.full.html##ref-list-1
This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology Autoimmune diseases http://www.neurology.org//cgi/collection/autoimmune_diseases Encephalitis http://www.neurology.org//cgi/collection/encephalitis
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