Ophthalmologic Manifestations in Fatal Familial Insomnia
Fatal Familial Insomnia (FFI) is an inherited prion disease produced by a genetic variant of the prion-protein (PrP) gene (PRNP). First described by Lugaresi et al. in 1986, this disorder causes intractable insomnia, dysautonomia and motor system abnormalities. The sporadic form, termed sporadic fatal insomnia (SFI), presents with similar clinical features as FFI.
FFI affects both male and females equally with onset typically occurring between the third through sixth decades of life. The mean age of onset is about 50 years old. An increased number of FFI cases have been reported in Han Chinese, more so that other Asian regions (including Japan and Korea).
While details of the physiological role of PrP remains unclear, this protein is highly expressed in the nervous system. Loss of wild type function due to misfolding and aggregation of insoluble PrP triggers inevitable neurodegeneration and plays a central role in prion disease.
In FFI, a missense mutation at codon 178 of the PRNP gene located on chromosome 20 results in the substitution of asparagine for aspartic acid (D178N). This uniformly fatal illness is passed from parent to offspring in an autosomal dominant fashion with high phenotypic penetrance. 
The substituted amino acid at position 178 interacts with a nonmutated methionine residue at the polymorphic position 129 to form the abnormal PrP isoform responsible for this distinct disease. The homozygous presence of methionine (Met-Met), most common in East Asians, may shorten the duration of disease or hasten the onset of disease. Therefore, heterozygosity for the methionine residue (Met-Val) at codon 129 may provide a protective effect against developing FFI.
A conformational change in the normal PrP protein results in a deviant isoform that acts as a template for self-propagation. This proliferation allows for the accumulation of insoluble PrP, which is resistant to degradation by proteases.
As FFI progresses specific neurodegenerative changes occur. Autopsy examination of brain specimens reveals microscopic abnormalities in the anterior and dorsomedial thalamic nuclei bilaterally. These lesions are characterized by a significant loss in the number of large neurons and astrogliosis. This selective reduction in neural cells can range from over 50% to almost 80% and corresponds with a two to three-fold increase in reactive astrocytes. [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) imaging confirms a substantial decrease in metabolism, most notably in these particular thalamic regions.
Neuropathological analysis of other areas of the brain may find reactive gliosis in the cerebral cortex, cerebellar cortex and olives as well as rare spongiosis of the cerebral cortex. However, these latter changes are not as severe and less often described.
Molecular analysis can identify the GAC to AAC genetic variant of PRNP and atargeted PRNP gene test can confirm FFI.
Imaging modalities including brain magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) reflect mild cortical atrophy and hyperintense signals in gray matter areas. PET may show hypometabolism of the thalamus and other affected areas.
Polysomnography is remarkably useful, showing a loss of sleep spindles and K-complexes. In addition, electroencephalogram (EEG) depicts surplus theta and delta frequencies and cerebrospinal fluid (CSF) analysis may demonstrate increased protein levels.
Of the clinical signs discussed in detail below, sleep-related changes plus either progressive autonomic dysfunction or somatomotor manifestations must be present for a diagnosis of probable FFI.
Neuro-ophthalmic Symptoms and Signs
One of the earliest symptoms of FFI is fluctuating diplopia. Lugaresi et al. described a 52-year-old male with transient diplopia six months after the onset of nocturnal insomnia and saccadic ocular movements another month later. In addition, administration of mydriatic agents including 4% cocaine and 5% homatropine demonstrated parasympathetic hyperactivity of the pupils. 
Mastrangelo et al. analyzed neuro-ophthalmological manifestations in six patients with early FFI, with early stage defined as within six months of onset of insomnia. All patients experienced disturbance in vision, including binocular horizontal diplopia and blurred vision, as well as irregular eye movements. The most prominent and consistent findings were saccadic intrusions. As the thalamus has been shown to exhibit damage first, even before clinical symptoms surface, the authors speculate that this brain structure plays a paramount role in motor control of the eyes. Therefore, a patient demonstrating disruption of fixation with saccadic intrusions could be an indication of thalamic injury due to early FFI.
Other Symptoms and signs
The most common presenting symptom of FFI is profound disturbance of sleep. This includes insomnia, irregularities in sleep respiration patterns, stuporous episodes of confusion and physically acting out vivid dreams. Manifestations of autonomic dysfunction include hypertension, tachycardia, tachypnea, pyrexia, diaphoresis, increased lacrimation, impotence and sphincter incontinence. Motor abnormalities tend to worsen gradually, exhibiting progressive signs such as dysphagia, dysarthria, ataxia, spasticity, myoclonus, and gait disturbance. Evolution of gait abnormalities appears to parallel the path of neuronal degeneration as it spreads from the thalamus to other areas of the brain involved in relay of motor signals.
Of note, patients homozygous for methionine at codon 129 tend to engage in oneiric behaviors and display periodic confusion at the onset of disease. These patients also exhibit more significant autonomic signs. On the other hand, patients heterozygous for methionine often show severe somatomotor disturbances and bowel and bladder incontinence close to disease onset.
Neuropsychological changes involve decreased vigilance, frequent dream-like states and impaired attention early on. Finally, psychiatric symptoms may present later in the disease course such as cognitive impairment, visual hallucinations and changes in personality which may include depression, anxiety, increased aggression and disinhibition.
FFI should be distinguished from other prion diseases by their differing clinical and pathological hallmarks. In contrast to Creutzfeldt-Jakob disease (CJD) FFI patients tend to have longer duration of illness and more prominent sleep disruption and autonomic system aberrations. While CJD is caused by multiple mutations FFI is only caused by one. In addition, typical neuropathological findings of each disease are different, with CJD producing widespread spongiform changes.
Another prion disease with overlapping clinical signs is Gerstmann Sträussler Scheinker disease. This disorder is more acute in nature than FFI and manifests first with progressive loss of motor control then later cognitive deterioration.
Ultimately, effective treatment must target the prion culprit but currently management consists of symptomatic relief and palliative measures.
Pharmacologics typically used to induce sleep, including benzodiazepines and sedatives, are not effective in FFI subjects. Gamma-hydroxybutyrate (GHB) was found to stimulate short-wave sleep (SWS) in a patient with FFI, though the effects of this medication on disease duration could not be determined.
Duration of disease ranges from 8 months up to 6 years, with a mean of approximately 1.5 years. The evolution of FFI for Met-Met patients is faster, averaging between 9 and 10 months. The duration of illness for Met-Val individuals is 2-3 times longer than their homozygous counterparts.
This triad of loss of sleep, motor dysfunction and autonomic hyperactivity should prompt consideration for FFI and saccadic intrusions and fluctuating diplopia may be early neuro-ophthalmic symptoms and signs –.
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