Sporadic fatal insomnia in a young woman: A diagnostic challenge: Case Report

Human prion diseases are rare, transmissible, invariably fatal neurodegenerative diseases that are characterized by the accumulation of a misfolded host protein, the prion protein, in brain tissue. They are classified into three main groups: sporadic, acquired, and genetic. Sporadic cases, with no known environmental source of infection, include sporadic Creutzfeldt - Jakob disease (CJD), the most common human prion disease, and sporadic fatal insomnia (sFI), one of the least common [1]. Acquired cases include iatrogenic CJD, acquired by medical or surgical procedures, and variant CJD, usually acquired from consuming beef products contaminated with the agent of bovine spongiform encephalopathy [1]. Genetic or familial cases are linked to a mutation on the prion protein gene, and include several subtypes of Gerstmann Sträussler Scheinker syndrome, familial CJD, and fatal familial insomnia (FFI) [2]. sFI shares a very similar phenotype to FFI, but is not associated with a mutation in the prion protein gene [3]. FFI is linked to the presence of a D (aspartic acid) to N (asparagine) variation at codon 178 (D178N) coupled with the methionine at codon 129 (129M) on the mutant allele of the prion protein gene (PRNP) [4]. The presence of valine at codon 129 (129V) coupled with the same D178N mutation is associated with a very different phenotype reminiscent of CJD [4]. sFI lacks the D178N PRNP mutation but appears to be invariably associated with methionine homozygosity at codon 129 of the PRNP, suggesting that 129M, either coupled with the D178N mutation or present in both alleles in the absence of the mutation is a requirement for the phenotypic expression of fatal insomnia [4].

Although Kawasaki and colleagues described a probable case of sFI in 1997, the disease was definitively established in 1999 by both Mastrianni et al and Parchi et al utilizing the term sporadic fatal insomnia [3, 5, 6]. Parchi and colleagues reported five such cases in subjects between the ages of 36 and 70 years (mean 50) with duration of illness ranging from 15 to 24 months (mean 17.8) [3]. An additional ten patients have been reported in the literature as sFI, expanding the age range to 30-74 and the disease duration to 13-73 months [6‐13].

Like FFI, sFI is characterized pathologically by thalamic atrophy and clinically by disrupted sleep, autonomic dysfunction, and motor abnormalities including myoclonus, ataxia, dysarthria, dysphagia, and pyramidal signs [3]. Other clinical features consist of peculiar behaviors that can be mistaken for psychotic signs. Because the patients are deprived of sleep they may display drowsiness during the day which may be described as hypersomnolence unless the abnormal nocturnal sleep pattern is recognized by electroencephalogram (EEG) and/or polysomnography (PSG). The rarity of the disease can make the diagnosis of sFI challenging. To make clinicians more aware of an unusual presentation of prion disease and to demonstrate the importance of pursuing a thorough sleep history when prion disease is being considered, we describe the clinical and pathological details of a patient whose sFI diagnosis had not been considered antemortem.

The clinical diagnosis of prion disease in patients with signs of neurodegenerative diseases can be aided by paying particular attention to aspects of the patient history, including the patient's travels, past surgery, neurodegenerative illnesses in the family, and to possible changes in the patient's sleep pattern. Ancillary tests for suspected prion disease often include an EEG, MRI, and the measurement of CSF 14-3-3 protein, but these tests are typically unrevealing in cases of sFI. They also include genetic testing to detect possible PRNP mutations and to determine the genotype at codon 129 of the PRNP. Either valine or methionine can normally occur at the codon 129 of the PRNP and this polymorphism can strongly influence many aspects of human prion disease, including the disease phenotype and the susceptibility of a host to a prion infection. If FI is a diagnostic consideration, potentially helpful additional tests include PSG and nuclear imaging to demonstrate reduced tracer uptake in the thalamus [15, 16]. Finally, pathological examination of brain tissue at autopsy is the definitive way to confirm the presence and type of prion disease.

For the patient described in this report, her long duration of illness and young age at onset are unusual for the most common subtype of prion disease, sporadic CJD [17]. Other forms of CJD were considered but determined to be extremely unlikely. Although this young patient showed signs of psychiatric illness at the beginning of her disease consistent with variant CJD (vCJD), these signs did not precede her noticeable deficits in attention and memory and she had not traveled to any country where transmission of vCJD was known to occur.

Iatrogenic CJD has been associated with a number of medical procedures. However, it is not known to be linked with receipt of a bone transplant. Furthermore, the donor of the bone transplant received by our patient had been pre-screened providing greater assurance of the absence in the donor of an infectious or neurological illness [18]. This patient also had no family history of neurodegenerative illness.

The history of insomnia was not in the medical chart nor was a sleep study or nuclear imaging study performed [7]. The neuropathological studies of the brain tissue demonstrated atrophy of the patient's thalamus, the neuropathological signature of both FFI and sFI, which then prompted the interview with a family member about the patient's sleep patterns. The diagnosis of sFI was made at autopsy based on the pathological evidence and the results of the genetic testing indicating the absence of a PRNP mutation. The history of progressively worsening insomnia is characteristic of sFI and underscores the importance of taking a careful history of possible changes in the patient's sleep pattern when evaluating an illness suggestive of a prion disease, particularly if the illness exceeds 12 months in duration.

The consistency of the association of sleep-wake disturbances with FFI and sFI has been recently challenged. Zarranz et al have examined the sleep disorder in 23 symptomatic carriers of the D178N mutation both homozygous for methionine (D178N-129MM) and methionine/valine heterozygous (D178N-129MV) [19]. Eleven of these patients were reported not to have insomnia. However, only two of these patients had a PSG study that is essential to rule out the presence of insomnia often difficult to detect clinically especially in the D178N-129MV patients. In both these patients PSG examination did reveal a severe sleep disorder compatible with FFI. The authors also claim that the clinicopathological phenotype was that of CJD rather than FFI in eleven of these 23 patients. However, autopsy examination of the brain essential to exclude the thalamic atrophy characteristic of FFI was carried out in only four of these eleven subjects and the histology of the thalamus is not described.

Combined, the studies of Landolt et al, Taratuto et al and La Morgia et al raise the issue of a wider prevalence of sleep disorder in prion diseases that deserves further study [20‐22]. Landolt et al reported the presence of sleep-wake symptoms in all of seven patients with proven sCJD. However, the histology of the thalamus was examined in only four of the seven subjects and in a semi-quantitative fashion which regrettably did not include the assessment of the neuronal loss and the study of the thalamus in cases of sFI and FFI as positive controls of degree of thalamic atrophy. Furthermore, impairment of the autonomic system, a prominent component of the FFI phenotype, was not investigated in these cases [20]. These considerations are relevant also to the report of Taratuto et al of the presence of sleep impairment similar to that of FFI in a subject with the E200K-129MM mutation [21]. However, in this case the thalamus was fairly severely involved with gliosis and neuronal loss. Finally, La Morgia et al observed a sleep disorder similar to that of FFI and sFI in a case of sCJDVV2 with severe thalamic involvement by H-MR spectroscopy and detectable neuronal loss at histological examination [22].

Compared to the previous reports of sFI, the present case shows at least four major similarities: i) the presence of type 2 PrP^res; ii) greater amount of PrP^res in the cerebral cortex compared to that in the sub cortical regions [3, 10]; iii) glycoform ratios in the cerebral cortex and pulvinar that differ from that reported in FFI; and iv) no detectable PrP^res in the cerebellum. These findings along with the prominent thalamic atrophy and clinical evidence of sleep impairment definitely justify the classification of the present case as sFI.

Recently a case of alleged sFI has been reported showing the presence of PrP^res type 1 (rather than type 2 as in the present and other cases of sFI); the largest amount of PrP^res in the mediodorsal thalamic nucleus, and a glycoform ratio characterized by the relative prevalence of the diglycosylated PrP^res isoform similar to that of FFI [23]. If confirmed, this case indicates that, as in sCJD in general, occasional and unexplained phenotypic variations have to be expected in sFI. Finally, the severe neuronal loss of the anterior ventral and mediodorsal thalamic nuclei which contained relatively low amounts of PrP^res raises the issue of whether other isoforms of neurotoxic PrP such as protease-sensitive PrP are present in the thalamic nuclei in sFI.

Written informed consent was obtained from the patient's next of kin for publication of this case report. A copy of the written consent is available for review by the Editor-In-Chief of this journal.