Authors: Anita S. Bahbah, Esra’a O. Kurdi, Darwish M. Mosameh, Baraa M.M. Sharawi, Mohammed Damrah
Categories: Case Report, Creutzfeldt–Jakob disease, Neurodegenerative, Sporadic
Source: BMC Neurology
Authors: Anita S. Bahbah, Esra’a O. Kurdi, Darwish M. Mosameh, Baraa M.M. Sharawi, Mohammed Damrah
Creutzfeldt–Jakob disease (CJD) is a rare and fatal neurodegenerative disorder caused by misfolded prion proteins. It progresses inexorably to death once clinical symptoms emerge. Early manifestations are often nonspecific and may mimic other neurological conditions, making diagnosis particularly challenging.
We report the case of a 54-year-old Palestinian male who initially presented with dysarthria, vertical gaze nystagmus, dizziness, and gait ataxia while maintaining preserved cognition. Over the following month, he developed short-term memory loss, hallucinations, and disorientation. Extensive workup excluded infectious, toxicological, autoimmune, metabolic, and paraneoplastic causes. Cerebrospinal fluid (CSF) analysis revealed markedly elevated tau protein, a decreased Aβ42/40 ratio, and positive 14-3-3 protein. Although the initial Magnetic Resonance Imaging (MRI) was unremarkable, a follow-up scan demonstrated bilateral thalamic and basal ganglia abnormalities. Trials of plasmapheresis and corticosteroids were administered without clinical improvement. The patient's condition deteriorated rapidly, culminating in death within seven months of symptom onset. This case of CJD was considered the first to be documented in Palestine.
Creutzfeldt–Jakob disease (CJD) is a rare, degenerative brain disorder with a global incidence of 1–2 cases per million annually. It affects multiple species and results from the accumulation of a pathological isoform (PrP^Sc) of the prion protein, leading to brain damage and variable clinical manifestations, such as rapidly progressive dementia, myoclonus, ataxia, and extrapyramidal symptoms. CJD exists in several forms, including sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD), and variant (vCJD) cases, with sporadic CJD accounting for 85–90% of all cases [1, 2].
Diagnosing sCJD is challenging and should be considered in any patient with rapidly progressive dementia [1]. Diagnostic workup includes brain MRI, electroencephalography (EEG), CSF testing for protein 14-3-3, and Real-time Quaking-Induced Conversion (RT-QuIC) testing. Despite these findings, brain autopsy remains the gold standard [3], and no curative treatment exists for CJD, which is uniformly fatal [4].
This case highlights a sporadic CJD presentation that lacked early cognitive symptoms. We aim to emphasize the importance of including CJD in differential diagnoses, even without early dementia, and repeating diagnostic tests when initial results are inconclusive. Additionally, reporting this case contributes valuable documentation, as no cases have previously been formally reported from Palestine.
A 54-year-old man presented with a two-month history of progressive gait ataxia, dizziness, and dysarthria. He first exhibited gait unsteadiness with frequent falling downs, with a heavy speech, and later progressed to inability to walk independently. The patient’s medical history was unremarkable, with no surgeries, blood transfusions, or travel. He did not smoke or use alcohol or drugs. The family history was noncontributory.
One month after symptom onset, he developed headaches and short-term memory loss. Initial brain MRI revealed no abnormalities (Fig. 1), and CSF analysis was unremarkable. He was discharged with symptomatic treatment only, and no further investigation was pursued at that time.
Fig. 1Initial Brain MRI without IV contrast. 1-a. Normal Axial FLAIR (Fluid-Attenuated Inversion Recovery) image demonstrating no focal areas of abnormal high signal intensity in the periventricular or deep white matter regions. 1-b. Normal Diffusion-Weighted Imaging (DWI), showing no evidence of restricted diffusion
Symptoms persisted, and a second MRI one month later again revealed no changes. Over the following weeks, memory worsened. CSF results remained normal. During this period, he was treated empirically with antipsychotic and antidepressant medications for presumed psychiatric symptoms with his reported mood changes and memory complaints, although no clear psychiatric diagnosis could be established. These medications were later discontinued due to lack of benefit and the emergence of neurological signs.
At his next visit, he was found to have developed vertical gaze nystagmus (predominantly the right eye), prompting hospital admission for extensive workup. On admission, he was alert and oriented. A neurological exam revealed no patellar reflexes but preserved strength, tone, and sensation. Cranial nerves exam was normal, and there were no signs of meningeal irritation, myoclonus, or behavioral abnormalities.
Based on the initial presentation of gait ataxia, dizziness, dysarthria, and normal early MRI and CSF findings, the early differential diagnosis included cerebellar or brainstem inflammatory disorders, metabolic or toxic causes, autoimmune encephalitis, and - less likely at that early stage-neurodegenerative diseases.
Blood work, including metabolic panel, thyroid function, B12, folate, lactate, ceruloplasmin, and infectious screening—was normal (Table 1). The absence of fever, infection, toxic exposure, or systemic disease made infectious and metabolic etiologies unlikely.
Table 1Lab resultsTestResultNormal rangeCreatinine, serum0.74 mg/dL0.6–1.2 mg/dLBlood Urea Nitrogen (BUN)14.2 mg/dL6–20 mg/dLAlbumin3.72 g/dL3.5 to 5.5 g/dLAmmonia40 µ/dL15 to 45 µ/dLINR1.00.8 to 1.1Ceruplasmin22 mg/dL14 to 40 mg/dLCopper, 24 urine2320–50 mgTSH1.3 mIU/L0.4–4.0 mIU/LVitamin B12455 pg/mL200–900 pg/mLFolate8.6 ng/mL2.7–17.0 ng/mLHBsAg screeningNonreactiveNonreactive: < 0.9Borderline: 0.9–1.0Reactive: > 1.0HCVNonreactivateLess than 15 IU/mLHIV (CD4 cell count)980600–1200Ca+8.44 mEq/L8.4–10 mg/dLNa+137.8 mEq/L135–145 mEq/LLactate2.4 mmol/L0.5–2.2 mmol/LPCo23835–45Glucose161 mg/dL< 100 mg/dL
As his cognitive status deteriorated rapidly, with apathy, hallucinations, inappropriate emotional responses, and Coordination impairment in daily tasks (buttoning, feeding, writing), autoimmune encephalitis became a leading consideration, prompting repeat CSF testing and autoimmune/paraneoplastic screening. Empirical treatment (methylprednisolone, plasmapheresis) for autoimmune encephalitis was initiated, pending autoimmune antibody panel results, but yielded no improvement.
The new CSF analysis revealed positive 14-3-3 protein, elevated tau protein (> 1120 pg/mL), low β-amyloid 1–42 (108.4 pg/mL), and a low Aβ42/Aβ40 ratio (0.088), with near-normal phospho-tau, which is consistent with a rapidly progressive neurodegenerative process. Autoimmune and paraneoplastic antibody panels returned negative after four weeks, and CSF culture was negative.
A third MRI with IV contrast one month after the previous MRI, revealed bilateral symmetrical hyperintensities in the thalami and, to a lesser extent, basal ganglia (Fig. 2). In the context of these MRI findings and the characteristic CSF biomarker profile, and after excluding inflammatory mimickers, prion disease—most consistent with sporadic Creutzfeldt–Jakob disease (CJD)—became the primary diagnosis.
Fig. 2New Brain MRI with IV contrast 3 months after symptoms onset. 2-a DWI showed hyperintense signal in the caudate heads and putamen, suggestive of prion-related pathology. 2-b DWI slice indicating bilateral symmetrical abnormal signal intensity involving both thalami and to a lesser extent both basal ganglia, bilateral caudate head, globus pallidus, putamen. 2-c FLAIR (Fluid-Attenuated Inversion Recovery) confirm high signal intensity in previously described regions
EEG revealed no epileptiform activity or triphasic waves. A full-body CT scan revealed no malignancy. After the clinical and laboratory evidence was reviewed, the family was informed that the findings strongly suggested CJD. He was discharged for palliative care.
Despite additional IVIG treatment sought by the family without documented indications, the patient’s cognitive impairment increased rapidly, to include most domains; in memory, language, behaviors, attention and executive function. He eventually lost all speech and mobility. This constellation of findings makes the diagnosis of Creutzfeldt–Jakob disease highly likely. Brain biopsy, for definitive diagnosis, was not performed due to family refusal. The patient died six months after initial presentation (Fig. 3).
Fig. 3Timeline of clinical case presentation
Creutzfeldt–Jakob disease is a fatal neurodegenerative disorder with a broad clinical spectrum. Typical symptoms include dementia, myoclonus, behavioral changes, bradykinesia, and ataxia. Early diagnosis is complicated by variable presentations. CJD can mimic other neurological disorders, such as Alzheimer’s disease or Lewy body dementia [5]. Therefore, up-to-date and comprehensive clinical knowledge, along with refined diagnostic skills, is essential for distinguishing CJD from other neurological disorders.
Dementia is commonly the earliest symptom [6]. However, in our patient, it appeared nearly two months after motor symptoms. Although rare, delayed cognitive impairment has been previously documented [7].
The neurological manifestations of CJD reflect widespread brain involvement. Our patient’s ataxia likely resulted from disruption of the cerebellar and proprioceptive pathways [8]. Vertical nystagmus suggests dysfunction in the vestibulo-ocular and vertical gaze pathways [9]. Rapid dementia and behavioral symptoms reflect diffuse cortical degeneration caused by PrP^Sc accumulation.
Risk factors vary by type. The genetic (gCJD) type results from inherited PRNP mutations. The variant (vCJD) type is linked to contaminated beef consumption and, rarely, blood transfusions. The iatrogenic (iCJD) type arises from exposure to infected medical instruments or human biological material, such as dura mater transplants or cadaver-derived human growth hormone [2, 10].
This case was classified as sporadic (sCJD) because of the absence of identifiable risk factors. This type is indeed the most common. The diagnosis was based on the WHO and CDC criteria, which were last updated in 2010 [10]. Our patient fulfilled the criteria for probable sCJD (Table 2): rapidly progressive dementia, ataxia, dysarthria, abnormal MRI, elevated CSF biomarkers (14-3-3, tau), and a fatal course within one year. Moreover, additional investigations did not suggest any alternative diagnoses.
Table 2Criteria for diagnosing the sporadic form of CJD according to the CDC, 2010Definite sCJD Criterion (at least one required)Present in Patient? Neuropathological confirmation (brain biopsy/autopsy)Not performed Immunocytochemical confirmation of PrPSc or Western blotNot performed Presence of scrapie-associated fibrilsNot performedProbable sCJD CriterionPresent in Patient? Rapidly progressive dementiaYes And at least 2 of the following 4 clinical 3/4 present • MyoclonusNo • Visual or cerebellar signs (e.g., ataxia, nystagmus)Yes • Pyramidal/extrapyramidal signs (e.g., falls, dysarthria)Yes • Akinetic mutismLate stage And at least one of the following positive lab 2/3 present • Typical EEG (periodic sharp wave complexes)No • Positive 14-3-3 protein in CSFYes • MRI with high signal abnormalities in caudate/putamen or ≥ 2 cortical regions (DWI or FLAIR)Yes And routine investigations do not suggest alternative diagnosisYes***Possible sCJD CriterionPresent in Patient? Progressive dementiaYes And at least 2 of the 4 clinical features aboveYes And no positive lab tests that would classify as “probable”Positive results present And duration of illness < 2 yearsYes (~ 6 months) And no routine investigations suggesting alternative diagnosisYes ***Excluded Forms CriterionPresent in Patient? Familial CJD (first-degree relative with CJD or PRNP mutation)No family history Iatrogenic CJD (history of cadaveric pituitary hormone or neurosurgery with dura)No exposure history
Initial imaging and CSF were unrevealing, which is consistent with the literature showing that early imaging may be normal [1]. Repeat MRI later revealed thalamic and basal ganglia changes, underscoring the value of serial neuroimaging.
EEG revealed no abnormalities. Periodic sharp wave complexes (PSWCs) are only observed in approximately two-thirds of sCJD cases and are often correlated with myoclonus, which is absent here. Thus, a normal EEG does not exclude CJD.
Although CJD is considered the most probable diagnosis, no definitive treatment currently exists for this disease [4]. Pending autoimmune panel results and the unclear picture, the patient was treated empirically for autoimmune encephalitis. The lack of response to immunomodulatory therapy supported the diagnosis of Creutzfeldt‒Jakob.
Another test is RT-QuIC, which is considered a highly sensitive and specific assay now widely used to detect misfolded proteins in CSF, primarily prions causing CJD [11]. Unfortunately, this test could not be performed in our patient due to its logistical and financial burdens, which represents a limitation to our report, and also in diagnosing future cases in Palestine.
Published data on CJD from Palestine are extremely limited, and to our knowledge, no prior cases have been formally reported. Beyond a series described among Libyan Jews in Israel, regional epidemiological information remains sparse [12]. This underrepresentation highlights the need for improved surveillance and further epidemiological studies in the region, and underscores the importance of documenting individual cases such as ours.
This case illustrates the diagnostic challenges of sporadic Creutzfeldt–Jakob disease, particularly when early cognitive symptoms are absent. These findings emphasize the importance of repeated imaging and CSF testing in patients with progressive neurological symptoms. Despite the absence of brain biopsy, the clinical, radiological, and laboratory features met the WHO criteria for probable sCJD. Clinicians should remain vigilant for the unusual CJD presentations and consider repeated evaluations when initial tests are inconclusive.