https://orcid.org/0000-0002-1375-048X
ABSTRACT
The Heidenhain variant Creutzfeldt-Jakob disease (CJD) is characterized by isolated visual symptoms at disease onset, which may mimic numerous ophthalmological disorders. Anti-recoverin autoantibody can be found in patients with autoimmune-related retinopathies. The presence of this antibody with visual symptoms might be confusing in the early stages of the Heidenhain variant CJD. We describe the first case of an anti-recoverin antibody found in the Heidenhain variant CJD who presented with progressive blurred vision then memory deterioration proceeded later. This presentation reinforces the concept that the presence of the anti-recoverin antibody could not exclude the possibility of the Heidenhain variant of CJD in highly suspicious patients with initial isolated visual disturbance.
Introduction
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease caused by the deposition of a prion protein (PrPSc) [Citation1]. The initial clinical presentation of sCJD includes a wide range of neurological signs of cortical, subcortical, and cerebellar origin [Citation2]. In particular, CJD involving initial symptoms as isolated visual disturbances, including poor vision, disturbed perception of colours, and optical distortions, is called the Heidenhain variant of CJD [Citation3]. Because visual symptoms can appear a few weeks before cognitive decline or motor signs, patients sometimes visit ophthalmologists first. We present a peculiar case of the Heidenhain variant of CJD with serum anti-recoverin antibody, which might imply autoimmune-related retinopathies (AIRs). The similar initial presentation of the Heidenhain variant and AIRs may be confusing to the physician when approaching this heterogeneous fatal disease.
Case presentation
A 53-year-old male patient who was a computer engineer presented with acute-onset progressive blurred vision monocularly in both eyes. He had no systemic or ophthalmological disorders, no animal contact history, and no family history. Initially, he reported ‘darkness over the entire visual field and blurred vision with objects overlapping or distortion change.’ He first visited an eye clinic, but no ophthalmic deficits were found. Two weeks after the onset of visual symptoms, he also complained of poor recent memory, frequent word-finding difficulty, stammering, and deteriorating calculation ability.
He was admitted to another hospital where nonconvulsive epilepsy secondary to autoimmune encephalitis was suspected after electroencephalography (EEG), so levetiracetam and low-dose prednisone were prescribed. However, during the next two months, his visual acuity rapidly deteriorated, and new visual hallucinations and afterimages developed. Because of the ineffective treatment described above, the patient presented at our institution.
On admission, the best-corrected visual acuity was only hand motion 10 cm in each eye with reduced colour vision according to the Ishihara test. Pupillary reactions and eye movements were normal, and the fundi were unremarkable. However, metamorphopsia, palinopsia, polyopia, and right homonymous hemianopia were observed in each eye. A high cortical function test on neurological examination showed dysgraphia, acalculia, and poor attention. Other neurologic examinations showed truncal titubation and mild ataxia, followed by auditory stimuli-induced myoclonus and action tremor in the later course but no specific sensory abnormality or full muscle power. A neuropsychological test showed learning and memory impairment, anomia, and agraphia with preserved orientation and verbal comprehension. The Mini-Mental Status Examination score was 19/30.
Results of laboratory tests, including routine biochemistry, electrolytes, tumour markers, and basic autoimmune profiles, were within normal limits. Cerebrospinal fluid analysis showed neither pleocytosis nor protein elevation and negative cytology. To detect neuro-immunological or paraneoplastic diseases involving brain or retina such as AIRs, the anti-recoverin autoantibody was assessed and found to be strongly positive (). Together, anti-recoverin antibody and visual symptoms may be strongly linked to AIRs, and other neurological deficits might explain by the autoimmune process to this curable disease.
Figure 1. Neuroimages, electroencephalographic findings and paraneoplastic panel of the subject. (A) Serum paraneoplastic panel showed a positive band in anti-recoverin autoantibody region. (B) Electroencephalography showing nearly continuous generalized quasiperiodic sharp slow or sharp-and slow waves at 1–2 Hz, 50–100 uV, with emphasis in posterior head areas. (C-D) Axial view of brain magnetic resonance imaging diffusion weighted imaging showing hyperintensity over bilateral parieto-temporo-occipital lobes (arrowheads) and bilateral putamen and caudate nuclei (arrow), but no contrast enhancement in T1-weighted image.
Therefore, several additional exams were conducted. Ophthalmological examinations including fundus scope, optical coherence tomography, and electroretinography, all showed negative findings, which implied preservation of retinal function. Visual-evoked potentials were also within normal limits. To screen for occult neoplasm, whole-body computed tomography was performed, but it showed only a benign hepatic haemangioma. Overall, the significance of anti-recoverin autoantibodies remained unknown.
A follow-up EEG study was performed 2 months after the previous one, which showed nearly continuous generalized quasiperiodic sharply contoured or blunt waves at 1–2 Hz and 50–100 µV, with emphases on posterior head areas and partial suppressibility by eye-opening (). Brain diffusion-weighted imaging – magnetic resonance imaging showed hyperintensity over both parieto-temporo-occipital lobes and both putamen and caudate nuclei(). A timeline of the clinical course is presented in . Based on the above clinical course and neurological examination results, CJD was a more possible diagnosis than AIRs. Despite the clinical diagnosis of CJD remained favourable, a salvage methylprednisolone pulse therapeutic trial for 3 days was administered; regrettably, no cognitive or visual improvement was noted.
Figure 2. Timeline of the clinical manifestations and the results of examinations of the present case. Ab, antibody; CSF, cerebrospinal fluid DWI, diffusion-weighted imaging; EEG, electroencephalography; MRI, magnetic resonance imaging; WNL, within normal limit.
Later, positive findings for the 14-3-3 cerebrospinal fluid protein was confirmed by the Taiwan Centers for Disease Control (CDC); thus, the criteria for probable sporadic CJD were met with high diagnostic confidence. The diagnosis was confirmed through a formal committee hosted by the Taiwan CDC according to national policy. The patient became bedridden 3 months after the onset of his visual symptoms and soon passed away. No autopsy was performed based on the national policy, and no specific genetic or immunocytochemical test for CJD were available in Taiwan at that time.
Discussion
The Heidenhain variant, a more furiously deteriorating form of sCJD [Citation4], accounts for approximately 5% of the total sCJD cases [Citation3], characterized by isolated visual disturbance as the first symptom at onset, reflecting the early and prominent involvement of the occipital cortex. Although approximately 42% of sCJD cases show visual signs and symptoms at some point during the disease course, only 19% of patients presented visual symptoms as the only manifestation at disease onset, without cognitive change or motor signs [Citation5]. The common complaints of visual symptoms are progressive visual acuity deterioration without funduscopic changes, ocular problems including blurred vision and diplopia, homonymous hemianopia, cortical perceptual disturbance or visual hallucination, and, rarely, eye movement problems such as periodic alternating nystagmus [Citation6,Citation7]. The pathology of visual function in patients diagnosed with CJD is known to affect not only various areas of the brain involved in visual function as the primary visual cortex but also the eye and visual pathways [Citation6]. Because visual symptoms could persist in isolation for weeks before other symptoms, 77% of the patients initially visited an ophthalmologist [Citation7], and it is not uncommon for them to receive an ophthalmology diagnosis eventually.
Autoantibody screening tests are frequently considered in suspected CJD cases to differentiate neuroimmunological disorders such as autoimmune encephalitis, which are amenable to treatment. Recoverin, a 23kDa protein, can be detected in the photoreceptor cells of the retina, but it can also serve as a paraneoplastic antigen in some patients with cancer, especially small cell lung cancer [Citation8]. Anti-recoverin autoantibody can be found in patients with AIRs, such as cancer-related retinopathies or melanoma-associated retinopathy [Citation9], which eventually induces retinal degeneration through a pro-apoptotic pathway [Citation10]. Other antigenic targets in the retina, such as anti-retinal antibodies, have also been implicated in the aetiology of AIRs. These antibodies could be observed several weeks or months before the underlying tumour was detected, which may hint the physician to conduct a complete survey and follow-up of occult cancer. As in lung cancer patients, the presence of antibodies against recoverin in the serum is highly specific (98%) and moderately sensitive (20%) [Citation8].
In our case, a positive report of anti-recoverin antibody may confuse physicians during the approaching of the visual symptoms if there were limited neurological manifestation in early stage Heidenhain variant of sCJD. The association between the anti-recoverin antibody and Heidenhain variant is not clear. One hypothesis is that the anti-recoverin antibody might be associated with degenerative retinal changes induced by CJD. A selective reduction in the amplitude of the β-wave in the electroretinograms was found in some CJD patients, and the magnitude was correlated with CJD progression. This abnormality may result from degenerative changes in the outer plexiform layer of the retina and Müller cells, implying damage to bipolar cells [Citation6,Citation11]. It is possible that the anti-recoverin antibody plays a role in the degeneration of bipolar cells as well as photoreceptors in CJD patient, which is similar to the pathogenesis of melanoma-associated retinopathy [Citation8], and eventually result in clinical visual disturbance. Therefore, anti-recoverin may be a potentially adjunctive test in cases of suspected visual-onset CJD.
On the other hand, anti-retinal antibodies can be incidental and unrelated [Citation9]. The pathogenetic significance of these antibodies must be doubted, and the interpretation should be cautious in patients without any documented visual loss or typical symptoms. Likewise, Urriola et al. reported a case of Heidenhain variant sporadic CJD diagnosed as atypical autoimmune encephalitis due to a false-positive GAD autoantibody, who showed no response to intravenous immunoglobulin (IVIg) [Citation12]. Moreover, the presence of reactivity against recoverin could be only a false-positive result under the evidence of no detectable electroretinogram changes, no discovered cancer by a detailed imaging study, and poor response to steroids. In fact, the inefficacious immune-modifying treatment with IVIg or steroid may provide unrealistic outcome expectations or even worsen cognitive deterioration.
In our patient, whether anti-recoverin truly takes part in the pathogenesis of Heidenhain variant or it is just a coincidental finding remains uncertain. The overlapping visual symptoms in anti-recoverin-related retinopathy and early stages of the Heidenhain variant lead the clinical approach to become more challenging. More importantly, our report reinforces the concept that the presence of the anti-recoverin antibody could not exclude the possibility of the Heidenhain variant of CJD in highly suspicious patients with initial isolated visual disturbance. Detailed neurological and ophthalmological examinations with close follow-up strategies are essential. To the best of our knowledge, this is the first presentation of an anti-recoverin antibody found in the Heidenhain variant. Further cases and investigations are necessary to clarify the role of the anti-recoverin antibody in the Heidenhain variant CJD.
Authors’ contributions
Study conception and design: TJ and JJS. Acquisition of data: CTC and TJ. Analyzed and interpreted the data: CTC. Drafted the manuscript for intellectual content: CTC. Revised the manuscript for intellectual content: TJ and JJS. All authors read and approved the final manuscript.
Statement of ethics
The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study was approved by the Research Ethics Committee of National Taiwan University Hospital (NTUH-REC). The committee’s reference number: (NTUH-REC No: 202203082RINB). Written and signed informed consent was obtained from the patient’s next of kin for publication of the details of their medical case and any accompanying images.
Acknowledgments
We would like to thank the patient and his sister for their participation and consent in relation to this presentation.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The complete data are available from the corresponding author on reasonable request.
Additional information
Funding
References
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