NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease

Abstract

Sporadic Creutzfeldt-Jakob disease (sCJD) and N-methylD-aspartate receptor antibody (NMDAR-Ab) encephalitis [1], share similar clinical features including prominent psychiatric symptoms, memory problems, and seizures (Table 1). Previously, other forms of autoimmune encephalitis have been misdiagnosed as CJD, including Hashimoto’s and voltage-gated potassium channel complex antibody-associated encephalopathies [2, 3]. Here, conversely, we describe two patients presenting with progressive cognitive impairment and NMDAR-Abs with confirmed sCJD at post mortem. A retrospective review of 100 pathologically confirmed cases of sCJD seen by the UK National CJD surveillance unit [4] over the past 2 years identified six tested for NMDAR-Abs at presentation in whom results were available: four were negative and two positive. Both NMDAR-Ab positive cases presented with subacute cognitive decline and behavioral disturbance leading to serum testing for the antibodies. Patient A progressed to an akinetic mute state over 3 months and patient B over 9 months. Both had basal ganglia high signal on MRI brain imaging, a positive 14-3-3 immunoassay and elevated S100b level. Patient A twice had positive serum NMDARAb levels at dilutions up to 1:80. He was given 3 days of intravenous methylprednisolone and continued to deteriorate, dying 9 days later. Patient B deteriorated over 9 months. Some months after discharge to palliative care, his earlier positive serum NMDAR-Ab titre of 1:80 was discovered. Both had sporadic CJD confirmed at post mortem. CSFs were negative for NMDAR-Abs in all six cases. The presentation and clinical evolution in these two cases was consistent with sCJD and the positive NMDARAb results were surprising. Detecting NMDAR-Abs involves the demonstration of autoantibodies binding to a cell line expressing the NR1 and NR2B subunits [5]. All positive sera (tested at 1:20 initially) are checked against cells expressing other antigens, and the cells alone, to exclude any false-positive results [5, 6]. Positive results in healthy individuals or other disease controls are very rare; not found in 160 neurological disease controls [5]. The existence of these antibodies in two out of six patients with confirmed CJD is therefore intriguing. The titres were low, but at a level seen in patients with NMDAR-Ab encephalitis. One possibility is that these antibodies occurred as a secondary event resulting from an immune response to NMDARs released from damaged neurons. An altered composition of NMDAR has been implicated in cell death Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6489-3) contains supplementary material, which is available to authorized users.