Fatal insomnia: the elusive prion disease

A previously well 54- year-old woman presented with a short history of diplopia, cognitive decline, hallucinations and hypersomnolence. The patient had progressive deterioration in short-term memory, ocular convergence spasm, tremor, myoclonus, gait apraxia, central fever, dream enactment and seizures. Results of investigations were normal including MRI brain, electroencephalogram, cerebrospinal fluid (CSF, including CSF prion protein markers) and brain biopsy. The patient died from pneumonia and pulmonary embolus. Brain postmortem analysis revealed neuropathological changes in keeping with Fatal familial insomnia (FFI); the diagnosis was confirmed on genetic testing. FFI is caused by an autosomal dominant and highly penetrant pathogenic Prion Protein gene PRNP. Although usually familial, fatal insomnia (FI) also occurs in a rare sporadic form. FI is a rare human prion disease with prominent sleep disturbance, autonomic, motor, cognitive and behavioural involvement. Patient management is with best supportive care and early suspected diagnosis allows for timely palliation.


BACKGROUND
This report illustrates a difficult case of a patient with the presenting features and natural history of a prion disorder, in the face of negative familiar investigations and newer highly sensitive and specific cerebrospinal fluid (CSF) methods. We aim to highlight that difficult and rare neurological cases may present acutely to hospital, sometimes via other specialties. The case is likely to resonate with BMJ readers as our initial 'gut' diagnosis proved correct despite off-putting investigation results. We discuss the epidemiology, clinical features, investigations, neuropathology, neurogenetics and supportive management of patients with fatal insomnia (FI).

CASE PRESENTATION
A previously well 54-year-old woman developed new onset diplopia followed by hearing impairment and 'seashell' tinnitus over several weeks. Four months following symptom onset, ophthalmic assessment found decompensated esophoria and ocular convergence spasm. Her family told the ophthalmologist that she had been struggling with recent memory: her Acute Mental Test Score was reduced at 7/10. MRI brain with MR angiography showed non-specific deep white matter changes in keeping with known vascular risk factors.
A range of screening tests gave negative results (table 1). The patient's tinnitus improved with the provision of hearing aids. However, 2 months later she was admitted to hospital with rapid cognitive decline, such that she had forgotten the names of her relatives. The family reported auditory and visual hallucinations, involuntary movements, daytime somnolence and low mood.
The patient suffered from borderline diabetes mellitus and hypertension for which she took amlodipine. She had undergone gastric banding or a balloon procedure in Spain many years ago, was an ex-smoker and did not drink alcohol. She was 1 of 13 children, was separated from her partner and had five healthy children by two different partners. There was no neurological or otherwise relevant family history.
On examination, the patient had flattened affect, short-term memory impairment, ocular convergence spasm, tremor, myoclonus and severe gait apraxia. At times she appeared to have hypnopompic hallucinations. There were no pyramidal, extrapyramidal or cerebellar signs. Addenbrooke's Cognitive examination (ACE)-III revealed a score of 34/100, deficient in all domains, particularly memory and verbal fluency. Her clinical state deteriorated rapidly; she had multiple fevers of central origin and developed clinically apparent sleep apnea (although this could not be confirmed formally as she removed pulse oximetry leads). The patient had several probable seizures with eye rolling, unresponsiveness, posturing of the right arm and limb twitching. One month after admission to the hospital, her ACE score fell to 20/100.
The results of in-hospital radiographic and specialist investigations are summarised in table 2.

DIFFERENTIAL DIAGNOSIS
We initially considered differential diagnoses of Creutzfeldt-Jakob disease (CJD), autoimmune encephalitis, intravascular lymphoma and Dementia with Lewy Bodies (DLB). Serological tests of nutritional status were not performed, but in retrospect measures of vitamin B 1 for Wernicke's encephalopathy and vitamin E for ataxia, would have been appropriate additions to our test battery, in view of the possibility of malnutrition linked to past bariatric surgery.
Given a positive Dopamine active Transporter (DaT) scan result (figure 1) in the face of otherwise negative investigation including brain biopsy, atypical DLB was our working diagnosis.
Subsequent postmortem brain examination showed marked gliosis of the thalamic and inferior olivary nuclei ( figure 2A,B). However, immunohistochemistry showed no evidence of any spongiform change or convincing prion protein (PrP) accumulation in the brain (figure 2C). Subsequent paraffinembedded tissue (PET) blot analysis undertaken by Case report the National CJD Research and Surveillance Unit (NCJDRSU) in Edinburgh showed accumulation of the misfolded form of the prion protein (PrP Sc ) in the medial temporal lobe (figure 2D).
Frontal cortex (FC) and cerebral cortex (CC) samples were selected for biochemical analysis. The tissue samples were homogenised and precipitated with sodium phosphotungstic acid (NaPTA) followed by proteolytic digestion with proteinase K     (PK) and high-sensitivity Western blotting. 1 Western blot analysis showed detectable levels of partially protease-resistant fragments in brain samples (FC and CC) using the monoclonal antibody 3F4, typed as 'type 2B' (figure 2E). Genetic analysis revealed the D178N (aspartic acid to arginine) pathogenic variant in the PRNP gene (c.532G>A p.(Asp178Asn)), in combination with methionine homozygosity at codon 129 (MM) of the same gene in keeping with a diagnosis of Fatal familial insomnia (FFI).

TREATMENT
Treatment with rivastigmine for atypical DLB was unhelpful. No immunotherapy was tried on the basis that the aetiology was unknown but was presumed to be a neurodegenerative process. Family members were subsequently offered counselling by our clinical genetics team.

OUTCOME AND FOLLOW-UP
The patient was discharged to a nursing home but readmitted 48 hours later with hospital-acquired pneumonia and pulmonary embolus. She died 2 days later, 6-7 months after first symptom onset.

DISCUSSION
FI is a rare human prion disease, which occurs in both sporadic (sFI) and familial forms (FFI). It typically presents with prominent sleep disturbance, and is usually inherited. 2 As a group, the transmissible spongiform encephalopathiesprionopathies or prion diseases-occur in sporadic, inherited and acquired forms. All involve the accumulation of an aggregated and partially protease-resistant form (PrP Sc ) of the PrP with the capacity to drive the further conversion of normal PrP molecules (PrP c ) into the misfolded, protease-resistant and disease-associated isoform. 2 Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common human prion disease, with a worldwide incidence of around 1-2 cases per million population/year. FI is much rarer: only 70 known affected kindreds and 25 typical cases of sFI have been reported world-wide. 2 Age of onset in FFI varies between 36 and 72 years affecting males and females equally. sFI has been reported in a handful of cases with similar clinical and neuropathological features to the familial phenotype. 3 The clinical features of FI involve sleep, autonomic, motor, behavioural and cognitive disturbance. However, although titled FI, insomnia is not a defining feature of the disease. Involvement of the thalamus, hypothalamus and higher brainstem can affect sleep in a variety of ways. Insomnia is the most frequently observed sleep disturbance, but Rapid Eye Movement (REM) sleep behaviour disorder and dream enactment may also be seen. Early clinical manifestations include altered vigilance, fluctuating diplopia, disrupted circadian rhythm, apathy and executive dysfunction. Nocturnal sleep disturbance can lead to daytime somnolence. Autonomic features may then ensue with hypertension, central fever, perspiration, lacrimation, salivation and impotence. Gait apraxia, ataxia, myoclonus and other motor signs (table 3) may emerge as the disease progresses. Occasional convulsive seizures have been reported. 3 Patients may die as a result of secondary pneumonia. 3 Other forms of human prion disease, atypical parkinsonism, DLB disease, autoimmune encephalitis and intravascular lymphoma should all be considered when investigating for FI. 1 As this case illustrates, standard investigations in life may be normal. The following investigations may assist in the suspected diagnosis of FI; MRI of the brain may show non-specific changes of cortical, cerebral and cerebellar atrophy. 2 3 Cortical ribboning seen in sCJD and diffusion restriction changes on diffusionweighted MRI brain, are not seen in FI. 2 Periodic complexes on an EEG of the kind seen in CJD, are not typically present but may develop in patients with a long duration of illness. Abnormality of CSF 14-3-3 protein occurs in only 50% patients with FI. 2 CSF Real-Time Quaking-induced Conversion is positive in 83% of FFI cases but only in 50% of patients with sFI. Positron emission tomography fluorodeoxyglucose scans have shown hypometabolism in the thalamus, basal ganglia and limbic system in some cases. 2 3 Polysomnography may show disruption of the sleep wake cycle, 2 with sleep state dissociation (loss of the normal boundaries between non-REM sleep, REM sleep and wakefulness). Total duration of sleep is often reduced and slow wave sleep may be lost entirely. Hypercortisolaemia and low melatonin levels have been reported. 3 4 FI is caused by the highly penetrant, autosomal dominant, pathogenic PrP gene (PRNP) variant c.532G>A p.(Asp178Asn) on chromosome 20, previously called the D178N mutation. 5 The codon 129 variant on the same allele modifies the phenotype expressed at codon 178; with p.Met129 the phenotype is usually FI whereas with p.Val129 it is usually typical CJD. 5

Case report
Neuropathological assessment at postmortem remains the definitive means of confirming a diagnosis of FI. Neuropathological changes in FI include prominent thalamic, 4 and inferior olivary neuronal loss and astrogliosis. 2 Cortical and subcortical gliosis may be seen to a milder degree as well as spongiform degeneration later in the course of disease, with more extensive changes observed as the disease progresses. PET blot analysis may be useful in the detection PrP Sc when standard immunohistochemical methods fail to detect evidence of the PrP. 6 The management of FI is currently supportive, with genetic counselling for at risk family members.

CONCLUSION
We initially suspected a diagnosis of a prion disease in this case of rapidly progressive dementia with prominent somnolence, gait apraxia and myoclonus. We were discouraged from the diagnosis by negative investigations including CSF examination and brain biopsy. Formal polysomnography might have suggested the diagnosis, but was difficult to perform in this agitated patient. A neuropathological postmortem of the patient's brain eventually provided the crucial clue to the correct diagnosis, of FFI, with confirmation by further specialised neuropathological and genetic assessment by the NCJDRSU. We have since offered genetic counselling to at risk family members. For those wishing to learn more of the human dimension of FFI, a moving documentary, Dying to Sleep, is available online (https://www. youtube. com/ watch? v= AxjNay_ TRRg).