This article examines a clinical challenge faced by neurologists when a patient presenting with progressive visual and psychiatric disturbances was initially diagnosed with autoimmune encephalitis—an error rectified only upon autopsy. The potential of false-positive autoantibody results, importance of comprehensive differential diagnoses, and implications for treatment underline this exploration of a rare Heidenhain variant of sporadic Creutzfeldt-Jakob disease (CJD).
Keywords
1. Heidenhain Variant CJD
2. Autoimmune Encephalitis
3. GAD Autoantibodies
4. False-Positive Diagnosis
5. Progressive Neurological Disorders
Introduction
In an era where medicine continually evolves with discoveries that better explain the nuances of neurological disorders, the case of a 64-year-old man has surfaced to underline a diagnostic conundrum, examining the overlaps and distinctions between autoimmune encephalitis and sporadic Creutzfeldt-Jakob disease (CJD). Published in BMJ Case Reports in May 2019 (doi: 10.1136/bcr-2018-229018), the case narrated by Urriola et al. delves into a patient’s clinical journey, culminating in an autopsy-confirmed diagnosis of the Heidenhain variant of sporadic CJD, a rare subtype of a universally fatal prion disease, which was initially misdiagnosed as autoimmune encephalitis due to false-positive glutamic acid decarboxylase (GAD) autoantibodies.
Case Presentation
The patient’s odyssey into the labyrinth of neurological diagnostics began with subacute progressive visual field defects, illusions, and misperceptions. Preliminary investigations, including an MRI brain scan revealing a right occipital signal abnormality on diffusion-weighted imaging (DWI), presaged a medical misdirection when markedly elevated serum GAD autoantibodies ostensibly pointed to a diagnosis of autoimmune encephalitis. This was further cemented by a positive response to intravenous immunoglobulin therapy.
The Plot Thickens
A month post-discharge, the patient re-presented—this time with symptoms exacerbated to include frank and well-formed visual hallucinations, ataxia, and progressive cognitive impairment. The unfolding clinical picture, characterized by worsening neurological deficits, now painted a reminiscent tableau of a prion disease. Follow-up MRI scans displayed the telltale T2 ribboning on DWI and fluid-attenuated inversion recovery (FLAIR) sequences. This imaging hallmark, accompanied by periodic sharp wave complexes on EEG and a raised CSF protein 14-3-3, shifted the diagnostic needle towards sporadic CJD.
False-Positive Conundrum
The enigma further deepened as repeat serum and CSF GAD antibodies remained markedly elevated. However, a retrospective investigation using a more specific radioimmunoassay contradicted the earlier findings, revealing undetectable GAD autoantibodies in CSF samples from both the initial and subsequent presentations. This disparity beguiled physicians with a false-positive result potentially influenced by assay-related factors or non-specific bindings closely associated with inflammatory processes (Güven et al., 2014).
Autopsy and the Truth
The definitive diagnosis of the Heidenhain variant of sporadic CJD was only confirmed post-mortem. The autopsy provided irrefutable evidence, emphasizing the limitations of presumptive diagnostic criteria in life and the perils of false-positive serological markers.
Discussion
This clinical narrative is a stark portrayal of the complexities surrounding neurological diagnostics. The Heidenhain variant of CJD, characterized by initial visual disturbances, stands as a rarer phenotype within a rare group of disorders (Kropp et al., 1999). Under normal circumstances, the distinct pathologies of autoimmune encephalitis and CJD are discernible through classic clinical, radiological, and laboratory features. However, crossover symptoms and misguiding serology can confound even the most sagacious clinicians.
The Need for Diagnostic Vigilance
In the labyrinthine realm of rare neurological disorders, diagnostic vigilance remains paramount. The Zerr et al. (2009) updated clinical diagnostic criteria for sporadic CJD emphasize the need for integrated analysis of clinical presentation, DWI or FLAIR MRI findings, EEG readings, and CSF analyses including 14-3-3 protein detection. This specific case stresses the additional consideration of potential false-positive serological markers, which can mislead the clinical trajectory.
Treatment and Management Implications
The misdiagnosis and resultant treatment with intravenous immunoglobulin carried consequences for this patient. While appropriate for autoimmune encephalitis, such treatment regimens offer no benefit against CJD, and precious time is lost in providing supportive and palliative care essential in the management of confirmed CJD cases. Rossi et al. (2015) underscore the importance of evaluating neuronal antibodies in patients with suspected CJD, but our current understanding mandates practitioners be careful interpreters of this data.
The Differential Diagnosis Challenge
Autoimmune encephalitis presents as a spectrum of disorders in which the immune system erroneously targets synaptic receptors or neuronal cell surface proteins. The phenotypical similarities between the limbic form of autoimmune encephalitis and sporadic CJD have been reported (Yoo & Hirsch, 2014), stressing the importance of considering prion disease in the differential diagnosis of any rapidly progressive dementia-like illness.
The Significance of Autopsy
Urriola et al. (2019) accentuate the significance of autopsy in conclusively diagnosing sporadic CJD. Deemed the gold standard, post-mortem examination can provide clarity in ambiguous cases, contributing to the greater medical understanding and further refining diagnostic criteria. The underutilization of autopsy impedes the progress in this domain, a barrier that the medical community must strive to overcome.
Conclusion
This case study offers a poignant reminder of the intricate dance between clinical acumen and the reliance on laboratory investigations. In the event of a false-positive GAD antibody result, clinicians are urged to maintain a broad differential diagnosis and consider re-evaluating negative results through more specific assays when clinical suspicion of autoimmune encephalitis persists. As lamented by the tale of the misdiagnosed Heidenhain variant of sporadic CJD, a heightened awareness and attention to detail are the beacons that guide the path through the neurological thicket.
References
1. Urriola, N., Soosapilla, K., Herkes, G., & Nogajski, J. (2019). Heidenhain variant sporadic Creutzfeldt-Jakob disease diagnosed as an autoimmune encephalitis due to a false-positive GAD autoantibody. BMJ Case Reports, 12(5), e229018. https://doi.org/10.1136/bcr-2018-229018
2. Zerr, I., Kallenberg, K., Summers, D. M., et al. (2009). Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain, 132, 2659–2668. https://doi.org/10.1093/brain/awp191
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4. Rossi, M., Mead, S., Collinge, J., et al. (2015). Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease. Journal of Neurology, Neurosurgery & Psychiatry, 86, 692–694. https://doi.org/10.1136/jnnp-2014-308695
5. Yoo, J., & Hirsch, L. (2014). Limbic Encephalitis Associated With Anti–Voltage-Gated Potassium Channel Complex Antibodies Mimicking Creutzfeldt-Jakob Disease. JAMA Neurology, 71, 79–82. PMID: 24247910
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