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Man referred for acute onset of distortions, decreased vision

The patient was then sent for neuro-ophthalmic testing because his symptoms were out of proportion to the exam findings.

Issue: October 25, 2014

ByGeetha Athappilly, MD

ByKristen E. Dunbar, MD

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A 53-year-old man was referred for cataract evaluation at Lahey Medical Center. Over the previous month, he noticed a gradual decrease in vision to the point where he had difficulty driving and functioning in his career as a mailman. His primary complaint was “difficulty focusing” at far and near despite a recent prescription for new glasses.

The patient denied any alleviating or aggravating factors. His medical history was significant for poorly controlled insulin-dependent diabetes and multiple prior deep venous thromboses. He was a glaucoma suspect based on optic nerve asymmetry. His family history was noncontributory.

Examination

The patient’s best corrected visual acuity was 20/50 in the right eye and 20/30-3 in the left eye. IOPs and pupil exam were normal. Anterior segment exam showed 2+ nuclear sclerosis. Posterior segment exam was normal with the exception of mild cup-to-disc asymmetry.

Because the patient’s symptoms were out of proportion to the exam findings, he was referred for neuro-ophthalmic testing. He demonstrated bilateral color desaturation. He had difficulty initiating pursuit and saccades. Pursuit was saccadic, and saccades were hypometric. Ocular motility was overall full, but he had esotropia of 10 ∆D to 12 ∆D on exam. Humphrey visual field showed a right homonymous field defect. The optic nerve and macula were both normal on optical coherence tomography. A brain MRI without gadolinium, ordered by his outside family physician, was read as normal.

When questioned regarding personality or cognitive changes, the patient’s family reported he recently had occasional outbursts that were uncharacteristic for him, which were thought to be due to frustration with his vision.

What is your diagnosis?

Symptoms out of proportion to exam

Given the patient’s symptoms out of proportion to his ophthalmic exam, homonymous field defect, and potential personality and cognitive changes, there was a strong suspicion his symptoms were due to an intracranial process. A second brain MRI was initially read as normal by a neuroradiologist, but after discussion of the pertinent exam findings and potential cognitive changes, further evaluation revealed mild cortically based diffusion signal abnormalities within the occipital lobes, posterior temporal lobe, left hippocampus and caudate heads (Figure 1).

Figure 1. Brain MRI diffusion-weighted images revealing cortically based diffusion signal noted within the occipital lobes.

Source: Dunbar K, Athappilly G

At this point, due to the concern for possible prion disease, the patient was admitted to the neurology service for further evaluation and confirmation. EEG showed generalized cerebral dysfunction, right greater than left, but was thought to be nonspecific. Cerebrospinal fluid returned positive for tau (2,463 pg/mL; normal less than 500), 14-3-3 protein and RT-QuIC; the remainder of the analysis was normal, including white blood cell count, protein, ACE, Lyme, Gram stain and electrophoresis. Thyroid studies, vitamin B12 level, C-reactive protein, HIV, Lyme antibody and ANA were all within normal limits.

During the patient’s hospitalization, his vision began to worsen and he complained of visual hallucinations, palinopsia and macropsia. Neurology evaluation at that time, however, did not reveal overt abnormalities, and it was thought that his neurologic status was normal.

After his discharge, there was a rapid decline in the patient’s vision, cognitive and neurologic status. He demonstrated cortical blindness, anosognosia, language disturbance, gait ataxia, myoclonus, increased emotional lability and confusion. Roughly 1 month after presentation of his visual symptoms, he died.

Given our patient’s initial presentation of primarily ocular findings and later cortical blindness, subtle neuroimaging findings, positive 14-3-3 and rapid deterioration, the diagnosis was Heidenhain variant of Creutzfeldt-Jakob disease (CJD).

Discussion

Prion diseases, or transmissible spongiform encephalopathies, are a group of encephalopathies that present as a rapidly progressive dementia and are uniformly fatal. After symptom onset, patient lifespan is short, usually less than 8 months. It is extremely rare, with an incidence of one case per 1 million people per year. Prions are formed from misfolded cell surface proteins that, when bound to other proteins, cause the propagation of the abnormal form. This causes accumulation in the brain, inhibiting normal neuronal function and resulting in significant neurologic symptoms.

The types of human prion disease include variant CJD, sporadic CJD, inherited prion disease, kuru and iatrogenic prion disease. The most common form is sporadic, which comprises 85% of all cases of CJD.

The classic clinical features of CJD include dementia, ataxia and myoclonus. Workup includes MRI, EEG and lumbar puncture; ultimately, brain biopsy may be needed to confirm the diagnosis. MRI findings are subtle and include cortical changes most often noted on FLAIR and DWI sequences in the occipital cortex and basal ganglia. EEG findings in prion disease are characterized by periodic sharp wave complexes. The protein 14-3-3 has been shown to be sensitive and specific for the diagnosis of CJD but is not diagnostic because it can be elevated with other intracranial disease processes.

In 1929, Heidenhain described a disease course that was characterized by visual problems and an even more rapid progression than that of CJD. This variant, called the Heidenhain variant, manifests with primarily ocular symptoms at disease onset and may lack the full clinical triad of symptoms and characteristic EEG changes.

Typical ocular symptoms consist of homonymous field loss, cortical blindness, visual hallucinations and palinopsia. Ophthalmologists therefore should consider this disease in the differential of patients with significant visual symptoms or field defects out of proportion to ophthalmic and neuro-imaging findings. An MRI often will initially be read as normal and requires careful evaluation of the cortex and basal ganglia on FLAIR and DWI sequences for subtle abnormalities. The Heidenhain variant has a more rapid course. Unfortunately, there is no cure or treatment for this uniformly fatal disease.