A case report of Heidenhain variant Creutzfeldt-Jakob disease in a 49-year-old male with repeated negative magnetic resonance imaging and electroencephalogram findings

Introduction

Creutzfeldt-Jakob disease (CJD) is a rare, transmissible prion disease with a rapid progression that resolves in death (1). Sporadic cases of CJD (sCJD) arise from the spontaneous generation of misfolded prion proteins without an apparent trigger and constitute a majority of CJD cases (85%) (2). However, other subtypes of CJD include genetic CJD (10–15%) and infectious CJD (>1%) (2). Although classically described in older patients, about 4% of cases occur before the age of 50 years (3).

The diagnosis of CJD can be challenging due to the rarity of the disease, variability in clinical presentation, and the precautions necessary to minimize risk to others and healthcare providers (4). While immunohistochemistry is the definitive method for diagnosis, it is only possible to perform postmortem (5). As such, other modalities are employed to diagnose the patient earlier and enroll them in experimental therapies. These include magnetic resonance imaging (MRI), electroencephalogram (EEG), and cerebrospinal fluid (CSF) studies for 14-3-3 protein and real-time quaking-induced conversion (RTQuIC). While MRI findings for CJD, including the cortical ribbon sign, have a 91% sensitivity, they can be missed in up to half of cases (6). EEG patterns showing periodic sharp wave complexes (PSWCs) are considered a hallmark of CJD, present in approximately two-thirds of patients, and dependent on the clinical stage of the disease (7).

The symptomatology of CJD is variable and can be masked by comorbidities (8). However, pathognomonic symptoms and supportive diagnostic findings can be used to build a probable clinical diagnosis. These features include neuropsychiatric disorders, rapidly progressive dementia, myoclonus, visual defects, cerebellar signs, pyramidal or extrapyramidal signs, and akinetic mutism (9).

In this case report, we will discuss a patient with decreased visual acuity as an initial manifestation of the Heidenhain variant of Creutzfeldt-Jakob disease (HvCJD). HvCJD is a rare variant of sporadic CJD that makes up between 3.7% to 4.9% of all cases (10). The rarity of the disease, along with the variation in clinical and diagnostic findings, makes HvCJD a challenging diagnosis particularly in a patient with repeated negative imaging studies as in this case. We present this case in accordance with the CARE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-96/rc).

Case presentation

A 49-year-old male presented to the emergency department (ED) with a 6-week history of malaise and vertigo. Other symptoms included polydipsia, which was attributed to a sour taste in his mouth, as well as polyuria, decreased visual acuity, and weight loss of approximately 10% of body weight (230 to 203 lbs). The patient was employed at a plant nursery which was near a cattle farm, and he had received several tick bites from deer approximately 6 weeks before admission and 2 weeks before his initial ED presentation. One week prior to his ED visit, he began having frontal headaches and periumbilical pain with a 2-day history of diarrhea. He had no relevant past medical, surgical, or familial history. His social history was significant for the consumption of several beers daily.

On initial assessment in the ED, the patient was well-appearing, in no acute distress, with stable vital signs. His best-corrected visual acuity was 20/50 in the right eye and 20/70 in the left eye. Electrocardiogram (EKG) showed sinus bradycardia with a heart rate of 56 bpm and no other abnormalities. Laboratory analysis included a complete blood count (CBC), complete metabolic panel (CMP), urinalysis, thyroid-stimulating hormone (TSH), magnesium, prothrombin time, troponin I, ethanol, and a drug screen. All labs were within normal hospital reference ranges. A chest X-ray and non-contrast head computed tomography (CT) showed no abnormalities. The patient was given intravenous (IV) administration of 300 mg of thiamine and a 1-L normal saline IV bolus. His headaches were attributed to age-related vision loss, and he was discharged with instructions to follow up with an ophthalmologist.

Four days later, the patient returned to the ED with persistent left-sided weakness, left-sided arm myoclonus, binocular diplopia, and an ataxic gait. He was admitted to the hospital and underwent extensive diagnostic testing for over 13 days. After a more detailed history questioning, the patient revealed to have sustained multiple tick bites approximately 6 weeks prior, however, the tick bites occurred in East Texas where Lyme disease is uncommon. Additionally, the patient had no systemic features indicative of Rocky Mountain spotted fever (RMSF)/Ehrlichia or southern tick-associated rash illness (STARI)/Heartland/Bourbon viruses. Lyme serology, human immunodeficiency virus (HIV), rapid plasma reagin (RPR), Venereal Disease Research Laboratory (VDRL) were negative. Fungal culture, Coccidioides, and cryptococcal antigens were negative. Heavy metals were within normal limits. Autoimmune disease was considered unlikely due to normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, along with negative antinuclear antibody (ANA), cardiolipin, beta-2 glycoprotein antibodies, and lupus anticoagulant but remained the most likely differential due to insufficient support for other diagnoses and the subacute course of the disease. West Nile virus immunoglobulin G (IgG) was positive; however, this was likely attributed to a past infection due to a negative immunoglobulin M (IgM).

All neuroimaging, including magnetic resonance angiography (MRA) head and neck, MRI of the brain with and without contrast, MRI orbits, MRI of the cervical spine, and magnetic resonance venography (MRV), showed no abnormalities. CSF analysis showed a trace elevation in protein 51 mg/dL, as well as a white blood cell count (WBC) of 1 cells/µL and glucose of 52 mg/dL with negative cytology. Physical exam findings were significant for slowed eye movements, especially to the right, and mildly reduced muscle strength in the left lower extremity. Bilateral eye erythema was thought to be due to contact irritation and was treated with eye drops. On day 10, he started having intermittent facial spasms and left upper extremity twitching. Initial therapy with IV corticosteroids failed to provide relief, but a course of intravenous immune globulin (IVIG) moderately alleviated symptoms. An EEG recording on the patient’s twelfth day in the hospital did not find any abnormalities other than a muscle artifact due to myoclonic movement. After completing IVIG, the patient was suspected to have an autoimmune condition with unclear etiology and was discharged with instructions to follow up with his primary care physician (PCP) and neurologist.

Nine days later, the patient presented to a different ED with refractory, bilateral myoclonic jerking, and left gaze preference, as well as decreased sensation on the left side of his body. He was alert and oriented but showed impaired eye tracking. Soon after arrival, he had a seizure with right gaze deviation that lasted approximately 30–45 seconds. He was given IV ativan 2 mg and levetiracetam 1,000 mg and started on an antiepileptic regimen consisting of levetiracetam 1,500 mg, vimpat 100 mg, and valproate 500 mg twice daily. The patient was started on IV doxycycline and was evaluated by neurology and infectious disease. Neurology’s initial investigation found that the patient had decreased left extremity sensation, speech changes characterized by long pauses and a stutter in addition to previous findings. Given the patient’s myoclonus combined with a subacute presentation and visual disturbances, the diagnosis of the Heidenhain variant of CJD (HvCJD) was suspected. CSF analysis showed a WBC of 12 cells/µL (98% lymphocytes), glucose 70 mg/dL, and protein 34 mg/dL. Additionally, his CSF was positive for 14-3-3 protein and had elevated t-tau protein (15,249 pg/mL), suggesting a prion disease. Repeat MRI showed subtle evidence of a cortical ribbon sign involving bilateral frontoparietal lobes, but more extensively on the left frontoparietal lobe. Although the EEG continued to show non-specific wave patterns, the patient was diagnosed with CJD which was supported by a positive result for RTQuIC and a 14-3-3 gamma >2,000 AU/mL (54,597 AU/mL). The palliative care service was consulted, but the patient rapidly deteriorated and died 12 days after diagnosis.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report was not obtained from the patient due to his passing away and the rejection of the surviving relatives after all possible attempts were made.

Discussion

Diagnosing CJD is challenging as its symptom profile is largely heterogeneous—featuring but not limited to myoclonus, rapidly progressing dementia, akinetic mutism, cerebellar ataxia, extrapyramidal signs, and visual signs. Thus, the role of high-performing biomarkers is often a crucial factor in diagnosing CJD promptly (11). According to the Centers for Disease Control and Prevention (CDC), sporadic CJD can be definitively diagnosed via immunocytochemistry, Western blood-confirmed protease-resistant platelet-rich plasma (PrP), or standard neuropathological techniques. However, these tests can only be performed postmortem. Therefore, more useful diagnostic guidelines require either the presence of a neuropsychiatric disorder in addition to a positive RTQuIC in CSF or rapidly progressive dementia with at least 2 clinical symptoms. In addition to one of the requirements, there must be a positive result on EEG, 14-3-3 CSF assay, or high signaling in the dorsal striatum on MRI (9).

Due to the wide array of presentations, mimickers, and etiologies, CJD can be difficult to diagnose. The patient’s initial complaints of malaise, polyuria and polydipsia and injected conjunctiva suggested a viral etiology or a virus worsening the progression of CJD (12,13). These cases can be differentiated from CJD through CSF findings, which were normal during the initial presentation as well as the generally normal blood work and lack of fever (12,13). However, the patient’s normal temperature on admission as well as negative finding on CSF and rapid polymerase chain reaction (PCR) decrease the chances of a viral infection influencing his course. While the tick bites were interesting, the patient’s CSF was negative for antibodies against Borrelia burgdorferi which indicates that it was not a substantial factor for the patient’s disease course. Another mimic, which the patient was initially treated for, is autoimmune encephalitis. Autoimmune encephalitis is a non-infectious and immune regulated cause of brain inflammation with unclear etiology (14). However, CSF findings for CJD has drastically elevated t-tau proteins as was in the case with this patient and negative autoimmune encephalitis panel drastically lower its possibility (15). The HvCJD presents with visual disturbances, including deterioration of vision, visual hallucinations, diplopia, and metamorphopsia (16,17). Additionally, these patients develop rapidly progressive dementia that results in a comparatively shorter life expectancy (16). Due to the presence of blurred vision at the onset of symptoms, it is likely that this patient had sporadic HvCJD. One study by Kong et al., found that only 55.6% (10/18) of their HvCJD cases met the requirements for World Health Organization (WHO)’s criteria of CJD diagnosis based on initial imaging (9,17). Furthermore, only 64.3% (9/14) of their patients had a positive CSF 14-3-3 result and PSWCs were identified in only 61.1% (11/18) of their patients who underwent serial EEGs (17). This showcases the limited application of standard imaging protocol used in CJD diagnosis required to promptly identify the Heidenhain variant. This case’s imaging is interesting as MRI findings did not indicate involvement of the posterior lobe despite the patient initially and consistently reporting visual disturbances which continued and worsened throughout his disease course. This reduces the chances of another mimic called posterior reversible encephalopathy syndrome. This syndrome has a similar presentation to HvCJD with headaches, visual disturbances, and neurological defects on a background of hypertension (18,19). However, this patient’s MRI findings, when it did eventually have the cortical ribbon sign was isolated to the frontoparietal lobes and generally normal to moderately elevated blood pressures, made this differential unlikely. In existing literature, there was a similar patient who had MRI findings limited to the parietal and temporal regions of the brain who was diagnosed with HvCJD and had visual disturbances despite MRI not demonstrating occipital involvement (20). The frontal lobe involvement could explain the patient’s developing resistance to cooperation with treatment and neurological examination.

While rapidly progressive dementia is pathognomonic for prion disease, this case demonstrates the need to consider HvCJD when presented with visual disturbances, multiple cerebellar deficits, and myoclonus with dementia that arises later in the course of illness. Blurred vision can be easily attributed to the aging process, however, CJD most commonly arises in the elderly population (13).

Furthermore, this case is unusual due to the normal EEG and MRI findings. MRI findings usually show a cortical ribbon sign, although it can be missed in up to half of cases (6). EEG patterns of PSWCs, which are a hallmark of CJD, are present in around two-thirds of patients (7). Ultimately, our goal is to demonstrate that visual and neurological disturbances, despite normal EEG and MRI findings, may lead to a diagnosis of this particular variant of CJD.

CJD is an extremely rare disease with an annual global incidence rate of 1 per 1 million with approximately 350 cases occurring in the United States (2). Of these, HvCJD only accounts for approximately 4–20% of CJD cases (17,19). The pathophysiology of CJD is the accumulation of misfolded proteins (PRP^SC) from wild-type cellular form (PRP^C), which automatically catalyzes more wild-type proteins to misfold into the PRP^SC form. PRP^SC form is highly insoluble and causes aggregations to accumulate in the brain parenchyma, leading to neuronal death and respiratory and cardiac failure (5). This rare, predominantly sporadic, fatal neurodegenerative disease has a mean survival between 4 to 8 months with 90% dying within the year (19). Due to the terminal nature of this disease, CJD treatment options are largely palliative (19). However, there is promising work being done to develop monoclonal antibodies against PRP^C (20). While this case is limited in scope and new interventions; it thoroughly recounts the patient’s long course of illness and rapid decline. Therefore, demonstrating the importance of maintaining clinical suspicion for HvCJD palliative care despite negative imaging and ensuring access to appropriate resources such as palliative and hospice care.

Conclusions

We present a case of a rare variant of CJD, the Heidham variant, that manifests with visual disturbances as an initial symptom. This case highlights the diagnostic challenges associated with this disease due to its rapid onset, diverse symptom profile, and possible deviation from gold-standard imaging tests. In conclusion, it is important to maintain a suspicion of the diagnosis of HvCJD when symptoms align with the patient’s presentation even if MRI and EEG findings are normal.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-96/rc

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-96/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-96/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report was not obtained from the patient due to his passing away and the rejection of the surviving relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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