When a Stroke Is Not a Stroke: MRI and Spinal Fluid Biomarkers Untangle Fatal Prion Disease Masquerading as Ischemic Attack

A 76-year-old man in China walked into a hospital feeling dizzy and unsteady on his feet. Within weeks he was diagnosed with a stroke. Within months he was dead from something far rarer and far more sinister: sporadic Creutzfeldt-Jakob disease, a uniformly fatal brain infection caused not by a virus or bacterium but by a misfolded protein that corrupts the very fabric of the brain. His case, published in Frontiers in Cellular Neuroscience, is a stark reminder that even in the age of advanced neuroimaging, one of medicine’s most feared pathogens can hide in plain sight, wearing the mask of a much more common disease.

Sporadic Creutzfeldt-Jakob disease, or sCJD, accounts for roughly 85 percent of all human prion disorders and strikes approximately one to two people per million each year. It occurs when the normal cellular prion protein, PrP^C, spontaneously refolds into an abnormal, self-propagating shape called PrP^Sc. These misfolded proteins then template the same corruption onto their healthy neighbors, spreading through brain tissue like a molecular contagion. The result is rapidly progressive dementia, myoclonus, cerebellar dysfunction, and eventually akinetic mutism, with no treatment currently able to halt the decline.

What makes this case particularly instructive is how convincingly the early presentation mimicked cerebrovascular disease. The patient, a Han Chinese man with more than a decade of hypertension, developed dizziness, gait instability, and progressive right-sided weakness. Initial brain MRI was interpreted as showing a presumed left parietal subcortical ischemic lesion alongside chronic white matter changes consistent with small vessel disease. Cerebral angiography subsequently confirmed stenosis of the left middle cerebral artery and severe stenosis of the A1 segment of the anterior cerebral artery, seemingly sealing the diagnosis of ischemic stroke secondary to intracranial atherosclerosis.

But the clinical course refused to cooperate. Despite antiplatelet therapy with aspirin, lipid-lowering medication, and circulation-oriented treatment, the patient continued to deteriorate. Rather than stabilizing or following the stepwise pattern typical of recurrent cerebrovascular events, he developed rapidly progressive cognitive impairment, psychiatric disturbances, aphasia, and worsening right hemiparesis. Neurological examination revealed reduced responsiveness, increased upper limb tone, bilateral ankle clonus, and right-sided weakness graded at Medical Research Council level III. This trajectory, the authors note, was fundamentally atypical for a stabilized ischemic stroke.

The diagnostic turning point came from serial neuroimaging. A follow-up MRI performed approximately one month before admission revealed subtle abnormal diffusion-weighted imaging hyperintensity involving the left insular and parietal cortices, initially dismissed as possible ischemic change in the context of pre-existing white matter disease. But a repeat MRI after admission told a very different story: extensive gyriform hyperintensity along the left frontal, parietal, temporal, and insular cortices, with corresponding low signal on apparent diffusion coefficient maps, confirming true diffusion restriction rather than T2 shine-through. This pattern, known as cortical ribboning, does not conform to vascular territories and is characteristic of sCJD.

Cerebrospinal fluid analysis provided the molecular confirmation the imaging had suggested. Total tau protein measured 4,553.50 picograms per milliliter, more than eleven times the laboratory cutoff of less than 399. Phosphorylated tau reached 66.93 picograms per milliliter against a cutoff of less than 50. Most strikingly, the 14-3-3 gamma protein, a marker of rapid neuronal destruction, measured 50,515 arbitrary units per milliliter against a threshold of less than 20,000. Autoimmune encephalitis antibodies were negative, as was metagenomic next-generation sequencing for infectious pathogens. Genetic testing of the PRNP gene in both the patient and his son detected no pathogenic variant, ruling out a hereditary prion disorder.

Applying the 2017 International CJD Surveillance Network criteria, the team classified the case as probable sCJD based on rapidly progressive cognitive impairment, two clinical features including documented cerebellar ataxia and pyramidal signs, characteristic MRI abnormalities showing restricted diffusion in at least two qualifying cortical regions, and positive CSF 14-3-3 within a disease duration under two years. Notably, the electroencephalogram showed only diffuse slowing without the periodic sharp wave complexes often seen in sCJD, and the real-time quaking-induced conversion assay, or RT-QuIC, could not be performed because it was unavailable at the institution despite efforts to arrange external testing.

The absence of RT-QuIC represents an important limitation, the authors acknowledge. Without this highly specific prion-seeding assay or neuropathological confirmation, the diagnosis remains probable rather than definite. Still, the convergence of clinical progression, non-territorial cortical diffusion restriction, and markedly elevated CSF biomarkers within the established diagnostic framework provides a compelling picture. Total tau and phosphorylated tau served as supportive markers of neuronal injury rather than core diagnostic criteria, but their magnitude, particularly total tau exceeding 4,500 picograms per milliliter, strongly supported prion-mediated damage.

The case also illuminates broader patterns in prion disease epidemiology across Asia. Chinese national surveillance has documented more than 2,100 diagnosed prion disease cases, with sCJD representing approximately 88.7 percent and genetic forms about 11.3 percent. An analysis of 1,970 referred cases from 2006 to 2019 across 344 hospitals in 29 provincial-level administrative divisions revealed substantial geographic variation in referral and case recognition, partly attributable to differences in surveillance coverage. These disparities underscore the ongoing challenge of recognizing a rare disease that can present deceptively as something far more common.

For clinicians, the lessons are clear. Coexisting vascular pathology does not exclude neurodegenerative disease. Rapid multidomain neurological decline despite adequate stroke management should prompt diagnostic reassessment rather than continued vascular optimization. Subtle unilateral cortical ribboning may be overlooked or misattributed to ischemic change at an early stage. And CSF biomarker testing, interpreted alongside clinical course, MRI, EEG, and exclusion of alternative diagnoses, can provide the critical evidence needed to redirect care. In this case, timely recognition came too late to alter the outcome, but the diagnostic pathway the authors describe offers a template for catching the next case earlier, before precious weeks are lost pursuing the wrong disease.

Subject of Research: Misdiagnosis of sporadic Creutzfeldt-Jakob disease as ischemic stroke and biomarker-based diagnostic clarification

Article Title: Case Report: Sporadic Creutzfeldt–Jakob disease initially misdiagnosed as ischemic stroke: a diagnostic challenge and biomarker-based clarification

Article References: Hao, W., Zhou, X., Wang, M., Yang, W., & Cheng, T. (2026). Case Report: Sporadic Creutzfeldt–Jakob disease initially misdiagnosed as ischemic stroke: a diagnostic challenge and biomarker-based clarification. Frontiers in Cellular Neuroscience, 20, Article 1938627. https://doi.org/10.3389/fncel.2026.1938627

Image Credits: AI Generated

DOI: 10.3389/fncel.2026.1938627

Keywords: Creutzfeldt-Jakob disease, prion disease, ischemic stroke, cortical ribboning, CSF biomarkers, 14-3-3 protein, tau protein, diffusion-weighted MRI, rapidly progressive dementia, misdiagnosis, RT-QuIC, neurodegeneration