Ophthalmic Signs in Fatal Familial Insomnia

Key points at a glance

Key Points at a Glance

• Fatal familial insomnia (FFI) is a hereditary prion disease caused by the D178N mutation in the PRNP gene, with a penetrance exceeding 90%.
• Saccadic intrusions (involuntary saccadic eye movements during fixation) are the most consistent neuro-ophthalmologic finding in FFI.
• Fluctuating diplopia may appear as one of the earliest symptoms of FFI.
• Ophthalmological findings reflect selective thalamic degeneration and can serve as early indicators of thalamic damage.
• FFI cannot be ruled out even if MRI, EEG, and CSF are normal. Genetic testing is the gold standard for definitive diagnosis.
• Currently, there is no effective curative treatment; symptomatic therapy and palliative care are the mainstays of management.
• Common sleep medications, including benzodiazepines, are ineffective for insomnia in FFI.

1. What are the ophthalmic signs in fatal familial insomnia?

Fatal Familial Insomnia (FFI) is a hereditary prion disease caused by a substitution of aspartic acid to asparagine at codon 178 (D178N mutation) of the PRNP gene. It is inherited in an autosomal dominant manner, with a lifetime risk of developing the disease exceeding 90%. ¹⁾

First reported by Lugaresi et al. in 1986, FFI is an extremely rare disease, with approximately 70 families worldwide and 25 cases of sporadic fatal insomnia (sFI) reported. ²⁾

The polymorphism at codon 129 (Met-Met or Met-Val type) influences the disease phenotype. In Han Chinese, the gene frequency of Met-Met (M/M) homozygosity is higher than in Europeans, potentially indicating higher susceptibility. ³⁾ Age of onset ranges widely from 12 to 89 years, with an average of approximately 50–51 years. Disease duration is reported to be 8 to 72 months. ¹⁾

The three main symptoms of FFI are sleep disturbance, motor dysfunction, and autonomic hyperactivity. Ophthalmic signs (saccadic intrusions, fluctuating diplopia) may appear early in the disease.

Sporadic fatal insomnia (sFI) presents with a clinical picture similar to FFI but is not associated with PRNP mutations.

Q How rare is fatal familial insomnia?

A

Only about 70 families with FFI and 25 cases of sFI have been reported worldwide, making it an extremely rare prion disease. ²⁾ It is said to be more common in families with specific ethnic backgrounds, such as Han Chinese.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Fluctuating diplopia: One of the earliest symptoms that can appear in FFI. In the first case reported by Lugaresi et al., transient diplopia occurred 6 months after the onset of insomnia.
• Blurred vision: Patients may experience a sensation of blurred vision.
• Sleep disturbance: progressive insomnia, dream enactment behavior (vivid dream-like behavior), sleep-disordered breathing. This is a core symptom of FFI.
• Hypersomnia/daytime sleepiness: Insomnia and hypersomnia may coexist. ²⁾
• Psychiatric symptoms: visual and auditory hallucinations, depression, anxiety, aggression, disinhibition. ¹⁾²⁾³⁾
• Cognitive decline: progresses from attention deficit and memory impairment to progressive dementia. ¹⁾

Clinical Findings (Findings Confirmed by Physician Examination)

Neuro-ophthalmological findings are important as characteristic early findings of this disease.

• Saccadic intrusions: The most prominent and consistent eye movement abnormality in FFI. Involuntary saccadic eye movements are inserted during fixation. This was observed in all six early FFI patients reported by Mastrangelo et al.
• Saccade-like eye movements: In the case reported by Lugaresi et al., these appeared 7 months after the onset of insomnia.
• Parasympathetic hyperactivity of the pupil: Confirmed by pupillary dilation testing with 4% cocaine and 5% homatropine.
• Ocular convergence spasm: Observed in a 54-year-old female FFI case reported by Patel et al. This was identified during ophthalmologic evaluation in the same patient who presented with diplopia. ²⁾
• Decompensated esophoria: Confirmed during ophthalmologic evaluation in the same case. ²⁾

Other systemic clinical signs are as follows:

• Autonomic dysfunction: hypertension, tachycardia, tachypnea, fever, hyperhidrosis, increased lacrimation, erectile dysfunction, sphincter incontinence.
• Movement abnormalities: dysphagia, dysarthria, ataxia, spasticity, myoclonus, gait apraxia.
• Differences in disease type by codon 129 polymorphism: Met-Met type presents with dream-like behavior, periodic confusion, and prominent autonomic signs, with a rapid course averaging 9–10 months. Met-Val type presents with severe somatic motor disturbances and incontinence from early stages, and the disease duration is 2–3 times longer than the Met-Met type.

Q At what stage of FFI do ophthalmic symptoms appear?

A

Saccadic intrusions and fluctuating diplopia can appear early in FFI. In Mastrangelo et al.’s study, saccadic intrusions were observed in all early-stage FFI patients, potentially serving as an early indicator of thalamic damage. Diplopia may also be the first symptom prompting a medical visit. ²⁾

3. Causes and Risk Factors

FFI is caused by the D178N mutation (codon 178: GAC→AAC) in the PRNP gene (chromosome 20). This mutation leads to misfolding of normal prion protein (PrP) into an abnormal isoform (PrPSc), causing accumulation of insoluble PrP in neural tissue and subsequent degeneration.

• Codon 178 mutation (D178N): Substitution of aspartic acid to asparagine. It forms the disease type specific to FFI. ¹⁾
• Interaction with codon 129 polymorphism: The methionine residue at codon 129 without mutation interacts with D178N to form an abnormal PrP isoform specific to FFI. When codon 129 is a valine residue (Val-Met type), it results in a different disease phenotype such as GSS.
• Met-Met (homozygous) type: More common in East Asians and may be associated with faster progression. The frequency of the 129 M/M genotype in Chinese (Han) is significantly higher than in Europeans. ³⁾
• Penetrance: The lifetime risk of developing the disease with the D178N mutation exceeds 90%. Predicting the age of onset between parent and child is difficult, and there is no systematic trend toward earlier onset across generations. ¹⁾
• Sporadic FFI (sFI): Does not involve a PRNP mutation but presents with clinical and pathological findings similar to FFI. The mechanism of onset is thought to be different.

Genetic Testing and Family Information

FFI is an autosomal dominant disorder, meaning that first-degree relatives of a patient have a 50% chance of inheriting the D178N mutation. Through genetic counseling, it is important to provide appropriate information and support to at-risk family members.

4. Diagnosis and Testing Methods

Diagnosis of FFI is challenging and often delayed. MRI, EEG, and CSF tests may be normal, so a high index of suspicion is necessary for clinical diagnosis.

Definitive Diagnosis and Key Tests

• Genetic testing: Gold standard for definitive diagnosis. Identifies the GAC→AAC mutation (D178N) in the PRNP gene. ¹⁾
• Polysomnography (PSG): Characteristic loss of sleep spindles and K-complexes is useful for diagnosis. In Tan et al.’s case, approximately 1 hour of effective sleep, short-latency REM, respiratory obstruction, and excessive REM sleep were recorded. ³⁾

Imaging Tests

• Brain MRI: In FFI, the diffusion restriction changes typical of CJD are usually not seen. Mild cerebral cortical atrophy or high signal in gray matter areas may be present. A normal MRI does not exclude FFI. ²⁾ In the case by Tan et al., frontotemporal atrophy and hippocampal atrophy were observed. ³⁾
• FDG-PET: Hypometabolism in the thalamus is characteristic of FFI. As the disease progresses, hypometabolism spreads to the cingulate gyrus, limbic system, and cerebral cortex (especially the frontal lobe). In the study by Cortelli et al., serial PET scans in the same patient showed progressive increase in hypometabolic areas, consistent with PrPSc distribution. ¹⁾

EEG and CSF Tests

The table below summarizes the main tests and findings.

Test	Findings/Sensitivity
EEG	Excessive theta and delta waves. Typically no periodic sharp wave complexes characteristic of CJD
CSF 14-3-3 protein	Abnormal only in 50% of FFI patients2)
CSF RT-QuIC	Positive in 83% of FFI and 50% of sFI2)
CSF T-Tau >284 pg/ml	Sensitivity 78%, specificity 80% for FFI diagnosis1)

• DaT scan: Decreased uptake in the basal ganglia (positive in Patel et al.’s case).²⁾
• Brain biopsy: Usually negative in FFI. PrPSc may be difficult to detect by routine immunohistochemistry; PET blot analysis is useful.²⁾
• Postmortem brain examination: 50–80% loss of large neurons in the anterior and dorsomedial thalamic nuclei, and astrogliosis (2–3-fold increase in reactive astrocytes) are confirmed. ²⁾

Clinical Diagnostic Criteria

A clinical diagnosis of “probable” requires either progressive autonomic dysfunction or somatic motor signs, in addition to sleep-related changes.

Differential Diagnosis

• CJD (Creutzfeldt-Jakob disease): Shorter disease duration than FFI, with widespread spongiform changes. Sleep disturbances and autonomic abnormalities are less prominent than in FFI.
• GSS (Gerstmann-Sträussler-Scheinker syndrome): Slow progression. Progressive loss of motor control occurs first, followed by cognitive decline.
• Autoimmune encephalitis: Differentiated by antibody testing and response to immunotherapy. ¹⁾²⁾
• Dementia with Lewy bodies (DLB): May present with similar psychiatric symptoms and visual hallucinations. ²⁾

Q Can FFI be diagnosed without genetic testing?

A

Genetic testing is the gold standard, and a definitive diagnosis without genetic testing is difficult. MRI, EEG, and CSF tests (14-3-3 protein, RT-QuIC) may all be normal and do not rule out FFI. ²⁾ PSG showing loss of sleep spindles and FDG-PET showing thalamic hypometabolism provide strong diagnostic evidence.

5. Standard Treatment

Currently, there is no effective curative treatment for FFI. Management focuses on symptomatic treatment and palliative care.

• Symptomatic treatment: Symptomatic management of autonomic, motor, and psychiatric symptoms.
• Palliative care: Given the irreversible nature of the disease, comprehensive care aimed at maintaining quality of life and alleviating suffering is important. ²⁾
• GHB (gamma-hydroxybutyric acid): One case reported a stimulating effect on slow-wave sleep, but its impact on disease duration is unknown.
• Genetic counseling: Support and information provision for at-risk families are important. ¹⁾²⁾

Points to note in treatment

• Benzodiazepines and common sedatives are ineffective for insomnia in FFI. In the case of Tan et al., multiple psychotropic drugs including risperidone, olanzapine, alprazolam, and clonazepam were all ineffective. ³⁾
• In the early diagnosis of FFI, autoimmune encephalitis may be suspected, and steroid pulse therapy or high-dose immunoglobulin therapy may be administered, but in the case of Wang et al., it was ineffective. ¹⁾
• Currently, there is no curative treatment, and it is important to carefully explain this to the patient and family.

Q Are sleeping pills effective for insomnia in FFI?

A

Common sleeping pills and sedatives, including benzodiazepines, are ineffective for insomnia in FFI. ³⁾ This is thought to be because FFI insomnia is due to thalamic neurodegeneration, making drug-induced sleep difficult. One case report described induction of slow-wave sleep with GHB, but no improvement in prognosis has been confirmed.

6. Pathophysiology and Detailed Mechanism of Onset

The central pathology of FFI is selective degeneration of the thalamus. Normal PrP protein misfolds into an abnormal isoform (PrPSc), which acts as a template for self-propagation, leading to accumulation of protease-resistant insoluble PrP and progression of neurodegeneration.

Thalamic degeneration and eye movement abnormalities

Thalamic degeneration

Anterior and dorsomedial thalamic nuclei: 50–80% of large neurons are lost. Reactive astrocytes increase 2–3 times (astrogliosis).

FDG-PET findings: Metabolism in the thalamic region is significantly reduced. This is a major cause of sleep disorders and autonomic dysfunction.

Lesions in other brain regions

Cerebral cortex, cerebellar cortex, and olivary nucleus: Reactive gliosis occurs. Rarely, spongiform changes in the cerebral cortex are present, but they are relatively mild and infrequent.

Correspondence with PrPSc distribution: The progression pattern of hypometabolism has been shown to match the intracerebral distribution of PrPSc. ¹⁾

Mastrangelo et al. suggested that the thalamus is the first region to be damaged even before clinical symptoms appear. Since the thalamus plays a crucial role in eye movement control, fixation instability with saccadic intrusions may serve as an indicator of early thalamic damage in FFI.

Temporal changes on PET-CT

Cortelli et al. observed in serial FDG-PET scans of the same FFI patient that initial thalamic hypometabolism gradually extended to the cingulate gyrus, limbic system, and cerebral cortex (basal frontal cortex and lateral frontal cortex). This distribution is consistent with the intracerebral spread of PrPSc. ¹⁾

Detection of PrPSc

• Conventional immunohistochemistry: Detection of PrPSc is often difficult in FFI. ²⁾
• PET blot analysis: PrPSc can be detected in the medial temporal lobe even in cases where detection is difficult with conventional IHC. In the case reported by Patel et al., a partially protease-resistant fragment (type 2B) was confirmed by Western blot. ²⁾

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7. Latest Research and Future Perspectives (Research-stage Reports)

For patients: Please be sure to read

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.

Diagnostic Limitations of RT-QuIC and Research Trends

Patel et al. reported a case of FFI confirmed by postmortem examination despite negative CSF RT-QuIC. ²⁾ RT-QuIC achieves 97% sensitivity and 100% specificity in sCJD, but sensitivity decreases in hereditary and atypical prion diseases such as FFI, GSS, and sFI (FFI: 83%, sFI: 50%). It has limitations as an antemortem biomarker for FFI diagnosis, and improved assays are needed.

CSF Biomarker Research

Schmitz et al. evaluated the accuracy of CSF biomarkers for genetic prion diseases and reported that in FFI patients, T-Tau >284 pg/ml yielded a sensitivity of 78% and specificity of 80%.¹⁾ Additionally, in a Chinese cohort study of genetic prion diseases by Chen et al., 41.47% of FFI patients showed T-Tau <2000 pg/ml, and cases with myoclonus had relatively higher T-Tau levels.¹⁾

Significance of CSF Pleocytosis

Wang et al. reported an FFI case presenting with CSF pleocytosis (initial 36.60×10⁶/L) during the COVID-19 pandemic.¹⁾ Although CSF pleocytosis is rare in prion diseases, it has been reported (mild elevation in 5 of 26 genetic CJD cases and 3 of 298 sporadic CJD cases), suggesting a mechanism different from classical inflammatory reactions. Pleocytosis can be mistaken for infectious or autoimmune encephalitis, leading to diagnostic delay.

Therapeutic Development Targeting the Causal Prion

The development of therapies targeting PrPSc formation with the D178N mutation is considered the ultimate goal of research. Since the penetrance exceeds 90%, future preventive intervention trials for asymptomatic mutation carriers are also being considered. Challenges remain in designing prevention trials due to the difficulty in predicting the age of onset between parents and children. ¹⁾

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8. References

1. Wang Z, Huang Y, Wang S, et al. A case report of fatal familial insomnia with cerebrospinal fluid leukocytosis during the COVID-19 epidemic and review of the literature. Prion. 2024;18(1):1-10.

2. Patel D, Ibrahim H, Rankin J, et al. Fatal insomnia: the elusive prion disease. BMJ Case Rep. 2021;14:e241289.

3. Tan Y, Liang J, Li X, et al. A fatal familial insomnia patient newly diagnosed as having depression: A case report. Medicine. 2021;100:41(e27544).