Ophthalmic Signs of Creutzfeldt-Jakob Disease

Key points at a glance

Key Points at a Glance

• CJD is a rare neurodegenerative disease caused by prions, with an annual incidence of 1 per million people.
• Heidenhain variant (HVCJD) accounts for 4–20% of CJD cases and presents with visual symptoms first.
• Initial symptoms often include blurred vision and diplopia, progressing to visual hallucinations and cortical blindness.
• MRI (DWI/FLAIR) and cerebrospinal fluid markers (14-3-3 protein, RT-QuIC) are useful for auxiliary diagnosis.
• Definitive diagnosis is made by histopathological evaluation of brain biopsy, but invasive procedures carry a risk of infection transmission.
• There is no proven treatment, and palliative care is chosen.
• The disease duration of HVCJD is on average 5.7 months, shorter than that of non-HVCJD (7.5 months).

1. What are the ophthalmic signs of Creutzfeldt-Jakob disease?

Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease associated with abnormal prion protein (PrPSc). It forms spongiform vacuoles in the brain and causes rapid cognitive decline. The annual incidence is estimated at 1 in 1 million people.

CJD is classified into four types based on the mode of onset.

• Sporadic (sCJD): Unknown cause. Most common.
• Familial (fCJD): Caused by mutations in the PRNP gene.
• Iatrogenic (iCJD): Transmitted through contaminated surgical instruments or grafted tissue.
• Variant (vCJD): Suspected to be associated with prions from infected cattle.

Heidenhain variant (HVCJD) is a form of sporadic CJD presenting with visual signs and symptoms. It accounts for 4–20% of all CJD cases and presents with isolated visual symptoms lasting 1–12 weeks [1,2]. It was first described in 1929 by Heidenhain in three patients with spongiform encephalopathy and cortical blindness.

Q What is Heidenhain variant (HVCJD)?

A

HVCJD is a form of sporadic CJD in which visual symptoms appear first. It accounts for 4–20% of CJD cases and is characterized by visual symptoms appearing weeks to months before other neurological symptoms.

2. Main symptoms and clinical findings

Subjective symptoms

Ocular symptoms may appear several weeks to months before the onset of other neurological symptoms.

• Blurred vision: One of the most common initial symptoms [3,4].
• Diplopia: Often appears as an initial symptom along with blurred vision [3].
• Visual hallucinations: Incidence increases with disease progression. May involve complex visual hallucinations [3].
• Cortical blindness: In advanced stages, cortical blindness occurs [3].

Specialist supplement

In patients with cerebral disorders, visual symptoms may go unnoticed due to dementia or decreased attention. Family members may notice the patient’s visual impairment and lead to a consultation.

Clinical findings

• Cortical blindness: A major finding in the advanced stage.
• Homonymous hemianopia: Visual field defect due to occipital lobe lesion. May reflect posterior cerebral artery occlusion. May be accompanied by macular sparing.
• Dyschromatopsia: May present as cerebral color vision abnormality. Caused by damage to the color center in the lingual gyrus and fusiform gyrus of the ventral occipital lobe. Bilateral, with relatively good visual acuity, and may be accompanied by prosopagnosia.
• Higher visual dysfunction: Bilateral parieto-occipital lobe lesions may cause Balint syndrome (optic ataxia, visual apraxia, simultanagnosia).
• Electroretinogram findings: Normal or decreased b-wave amplitude.
• OCT findings: Optic nerve temporal atrophy and retinal thinning have been reported in one case of HVCJD.

The following neurological symptoms are observed in CJD in general:

• Myoclonus, cerebellar ataxia, pyramidal and extrapyramidal symptoms.
• Delirium, confusion, cognitive decline
• Akinetic mutism, dystonia, aphasia
• Rigidity, athetosis, dysphagia

Q How do visual symptoms of CJD progress?

A

It begins with blurred vision or double vision, and as the disease progresses, it leads to visual hallucinations and cortical blindness. Visual symptoms often appear before other neurological symptoms. It may also be accompanied by higher-order visual dysfunction (such as Balint syndrome).

3. Causes and Risk Factors

The risk factors for CJD vary depending on the disease type. For sporadic CJD and HVCJD, no specific definitive risk factors have been established.

Known routes of infection:

• Contact with infected animal tissue: In variant CJD, an association with bovine-derived prions is suspected.
• Iatrogenic transmission via contaminated surgical instruments: Past reports have documented CJD transmission through corneal transplantation [6].
• Other transplanted tissues: There are case reports of CJD onset after implantation of bovine-derived bioprosthetic aortic valves.

Prevention and Daily Care

No specific preventive measures for CJD have been established. However, screening for CJD is important during surgeries including corneal transplantation. If a corneal donor candidate has or is suspected of having CJD, the Japanese criteria for eye donation (revised December 2023) exclude them from donation. Since CJD cannot be confirmed by testing, a detailed history of medical conditions and overseas travel is necessary.

Q Is it possible to contract CJD through corneal transplantation?

A

There have been past reports of CJD transmission from infected donors via corneal transplantation. The Japanese criteria for eye donation (revised December 2023) list CJD and suspected CJD as exclusion criteria for eye donation.

4. Diagnosis and Testing Methods

Definitive diagnosis of HVCJD is often difficult, and it is important to suspect HVCJD when visual field defects are present but conventional MRI is normal. Since Alzheimer’s disease and CJD have similar symptoms, careful differential diagnosis is necessary.

Gold Standard (Histopathological Evaluation)

Molecular biological and histopathological evaluation by brain biopsy is the standard for definitive diagnosis. Neuronal loss, gliosis, and spongiform vacuolation are observed in the occipital cortex and cerebellum. It is confirmed by immunostaining for PrPSc.

However, brain biopsy carries a risk of transmission via surgical instruments. Therefore, most patients tend to be definitively diagnosed by autopsy after death. Specimens from suspected cases are often sent to specialized facilities (in the US, the National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland).

Ancillary Tests

Imaging Tests

MRI (DWI/FLAIR): Hyperintensity in the posterior parietal lobe is observed in up to 80% of patients. It may be normal in the early stages. Signal enhancement in the basal ganglia and temporoparietal junction is also seen in some cases. Isolated atrophy of the occipital visual cortex may also be present.

SPECT/PET: Even when MRI shows only subtle changes, reduced blood flow in the parieto-occipital region can be detected.

Clinical Laboratory Tests (CSF)

14-3-3 protein / t-tau protein: Elevation suggests encephalopathy but is not specific to CJD. It may serve as an indicator approximately 2 weeks earlier than EEG findings.

NSE (neuron-specific enolase): Elevation is observed.

RT-QuIC method: A new test with high sensitivity and specificity. Sensitivity of approximately 95.8% and specificity of 100% have been reported for CSF samples [5]. Its clinical utility is attracting attention.

Western blotting: Used to confirm PrPSc.

Electrophysiological tests

EEG: Loss of normal posterior dominant rhythm, periodic sharp wave complexes (PSWC), 1 Hz spike-and-slow-wave in the occipital region, periodic triphasic wave complexes, and diffuse slowing.

Electroretinogram: Normal or reduced b-wave amplitude.

Molecular biological testing

Polymorphism analysis of codon 129 of the PRNP gene is performed. Methionine homozygosity has been observed in some cases of HVCJD [1,2].

Differential diagnosis

• Other causes of posterior cortical degeneration (PCD): Alzheimer disease, Pick disease, dementia with Lewy bodies
• Occipital lobe infarction: MRI DWI is useful for diagnosing hyperacute cerebral infarction. FLAIR images are useful for distinguishing from cerebrospinal fluid.
• Cataract: May be misdiagnosed as the initial visual change in HVCJD.
• Diabetic oculomotor nerve palsy, epilepsy, migraine
• In higher visual dysfunction, symptoms are often vague, and it is important to perform specific tests for symptoms predicted from the lesion location.

Q When CJD is suspected, what is the first test to perform?

A

The first step is to confirm hyperintensity in the parieto-occipital cortex on MRI (DWI/FLAIR). In CSF testing, 14-3-3 protein and RT-QuIC are useful as early supportive indicators. Definitive diagnosis requires brain biopsy, but caution is needed due to the risk of infection transmission.

5. Standard Treatment

There is no proven treatment for CJD. No large-scale controlled clinical trials have been conducted. Due to its rapidly progressive nature, palliative care is chosen for most patients.

Most patients die in an akinetic, mute, and blind state within weeks to months after symptom onset.

Prognostic data:

• In a case review of 169 CJD patients, the disease duration for HVCJD was an average of 5.7 months.
• The disease duration for non-HVCJD patients was 7.5 months, longer than for HVCJD.
• HVCJD patients with pathogenic PRNP mutations have significantly longer survival than those without mutations.

Infection control precautions

There have been reports of CJD transmission via intraocular pressure measurement alone, but this has not been scientifically proven. From an infection control perspective, caution is required when handling ophthalmic instruments used on CJD patients.

6. Pathophysiology and detailed pathogenesis

The main pathological factor in HVCJD is the abnormal prion protein (PrPSc). PrPSc acts on the normal prion protein (PrPC) and induces misfolding (abnormal folding).

HVCJD causes posterior cortical degeneration (PCD). Due to the activity of PrPSc, neurodegeneration occurs in the following areas.

• Parietal lobe, occipital lobe, temporal lobe, basal ganglia, thalamus: neuronal loss, gliosis, spongiform vacuolation.
• Compared to non-HVCJD patients, damage to the basal ganglia, cingulate gyrus, and limbic system is generally less.

An anatomical feature of the occipital lobe is that the visual cortex (V1) is located on the upper and lower lips of the calcarine sulcus, and higher-order visual areas spread around the primary visual cortex (V1). As posterior cortical degeneration progresses, these areas become extensively damaged.

Damage to the posterior cerebral artery causes homonymous hemianopia. Macular sparing may occur, which is thought to be due to dual blood supply to the occipital pole.

Polymorphism at codon 129 of the PRNP gene is also involved in disease susceptibility, and methionine homozygosity has been confirmed in some cases of HVCJD.

---

7. Latest Research and Future Prospects (Research Stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Research on the diagnosis and treatment of CJD is currently ongoing.

Research on new diagnostic markers:

Research is underway to identify new target markers for early diagnosis of CJD. In particular, the RT-QuIC (real-time quaking-induced conversion) method is attracting attention as a new biomarker with high sensitivity and specificity, and its clinical application for early diagnosis using CSF samples is expected.

At present, no treatment has been established, and further progress in basic and clinical research is awaited.

---

8. References

1. Cooper SA, Murray KL, Heath CA, Will RG, Knight RSG. Isolated visual symptoms at onset in sporadic Creutzfeldt-Jakob disease: the clinical phenotype of the “Heidenhain variant”. Br J Ophthalmol. 2005;89(10):1341-1342. PMID: 16170128. DOI: 10.1136/bjo.2005.074856
2. Baiardi S, Capellari S, Ladogana A, Strumia S, Santangelo M, Pocchiari M, Parchi P. Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings. J Alzheimers Dis. 2016;50(2):465-476. PMID: 26682685. DOI: 10.3233/JAD-150668
3. Armstrong RA. Creutzfeldt-Jakob disease and vision. Clin Exp Optom. 2006;89(1):3-9. PMID: 16430434. DOI: 10.1111/j.1444-0938.2006.00001.x
4. Hisata Y, Yamashita S, Tago M, Yoshimura M, Nakasima T, Nishi TM, Oda Y, Honda H, Yamashita S. Heidenhain Variant of Sporadic Creutzfeldt-Jakob Disease with a Variety of Visual Symptoms: A Case Report with Autopsy Study. Am J Case Rep. 2023;24:e938654. PMID: 36905109. DOI: 10.12659/AJCR.938654
5. Orrú CD, Groveman BR, Hughson AG, Zanusso G, Coulthart MB, Caughey B. Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid. mBio. 2015;6(1):e02451-14. PMID: 25604790. DOI: 10.1128/mBio.02451-14
6. Martheswaran T, Desautels JD, Moshirfar M, Shmunes KM, Ronquillo YC, Hoopes PC. A Contemporary Risk Analysis of Iatrogenic Transmission of Creutzfeldt-Jakob Disease (CJD) via Corneal Transplantation in the United States. Ophthalmol Ther. 2020;9(3):465-483. PMID: 32564338. DOI: 10.1007/s40123-020-00272-8