Case series of Creutzfeldt-Jakob disease in a third-level hospital in Quito

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder that affects humans. The pathophysiological mechanism of the disease consists of the formation of an abnormal isoform of the prion protein (PrP) called scrapie (PrPSc) which accumulates in the gray matter of the brain and is partially resistant to the action of proteases [1‐7].

The estimated incidence of the disease in the United States is 0.5 to 1 per million inhabitants per year. The age of onset is between 55 and 75 years, both sexes are equally affected [3, 4, 6, 8, 9]. There are 4 subtypes of CJD: sporadic, genetic, iatrogenic and variant. Sporadic CJD (sCJD) is the most common form of the disease, accounting for 85–90% of all CJD cases, followed by genetic subtypes such as Gertsmann-Sträussler-Scheinker, fatal familial insomnia and familial CJD (fCJD) which are present in 10–15% of cases. Variant and iatrogenic CJD subtypes are the least frequent, representing 5% of cases [2, 7, 9]. The prognosis of the disease is fatal because 90% of patients die within the first year of symptom onset [9].

Clinical presentation of CJD is highly variable; most cases have a subacute course. Frequent manifestations include: rapidly progressive dementia associated with neuropsychiatric manifestations, cerebellar ataxia, visual symptoms, myoclonus, akinetic mutism, and pyramidal and/or extrapyramidal signs [8‐10]. Atypical manifestations have also been described, which at their onset, resemble cerebrovascular disease, depression or supranuclear palsy [10]. Pre-mortem diagnosis is based on 5 types of paraclinical tests: electroencephalogram (EEG), cerebrospinal fluid (CSF) biomarkers, brain magnetic resonance imaging (MRI), positive real-time quaking-induced conversion (RT-QuIC) in CSF or other tissues and brain biopsy [11‐14]. The gold standard for definitive diagnosis Of CJD is histopathological confirmation through a brain biopsy or autopsy [12‐16].

Ecuador has an approximate population of 16 million inhabitants of which 9,271,362 are affiliated with social security [17, 18]. The Carlos Andrade Marín Hospital (CAMH) in the city of Quito is a third-level hospital and a reference center in the country that attends nearly 600,000 patients each year [18]. One thousand two hundred patients with dementias were treated between 2012 and 2016, 60% (720 patients) were for Alzheimer’s disease and 8.58% (103 patients) for rapidly progressive dementias (DRP). Of the DRP 1.9% (2/103) were autoimmune encephalopathies, 12.6% (13/103) infectious, 48.53% (50/103) metabolic, 2.9% toxic (3/103), 8.7% vascular (9/103), 6.8% neoplastic (7/103), 4.85% primary dementias with atypical onset and 5.85% (6/103) with CJD.

In Ecuador, there are no studies of the prevalence or incidence of CJD so far, and one clinical case-report of CJD has been described [19]. We present 6 case reports of CJD diagnosed between January 2012 and June 2016 at CAMH.

This series of cases demonstrates the variety of clinical manifestations that may occur at the onset or during the course of this disease. The age of presentation of sCJD is around 61 years. It is rare in patients younger than 40 years of age [12]. In our series of cases, the average age of symptom onset was 58.8 years, very similar to that reported in the case series of Torres-Ramírez et al., and in the case series of Lolekha et al. The first study reported an average age of onset of 55.8 years in patients with a definitive diagnosis, and 59.6 years in patients with a probable diagnosis [20]. The second study reported an average age of onset of 57 years [21]. The male to female ratio in our patients was 1:1, similar to that reported in other cases reports [9, 12, 13].

Regarding the presentation of disease, it is known that 30% of sCJD cases begin with cognitive or behavioral changes, and 30% begin with focal neurological signs, such as vision loss, cerebellar ataxia, aphasia and motor deficit [8, 9, 12]. In our cohort, 2 cases (33%) started with cognitive/behavioral symptoms, while 4 (66.6%) started with focal neurological signs; 1 case with ataxia, 2 with gait disorders and 1 with vertigo and headache.

Myoclonus represent one of the most common signs of sCJD [15]. Gao et al., showed that they were present in 74.2% of cases when the diagnosis of CJD was probable and in 56.3% when possible [22]. This contrasts with what was found in our patients where myoclonus were present in all patients in advanced stages of the disease. Depression in patients with CJD has also been described in the literature [22]. In our patients, one patient had depression.

Pre-mortem clinical diagnosis of sCJD has been modified over time. The most commonly used diagnostic criteria are the ones proposed by the World Health Organization (Table 2). Those criteria do not take in consideration MRI findings [13]. The most recent criteria have taken into account the great contribution that cerebral MRI has provided in the diagnosis of sCJD. According to current criteria proposed by Zerr and The University of Edinburgh [13, 23, 24] a diagnosis of probable CJD requires the presence of rapidly progressive cognitive impairment and at least 2 of the following 4 characteristics: myoclonus, visual or cerebellar disturbances, pyramidal or extrapyramidal signs, and akinetic mutism. In addition, these clinical criteria must be accompanied by at least one of four paraclinical studies. For diagnosis of possible CJD, rapidly progressive cognitive impairment, at least 2 clinical criteria and a duration of disease less than 2 years are required. Definitive diagnosis is made through histopathological study (Table 3) [23, 24]. According to the study by Zerr et al., the combination of the results of the paraclinical tests reaches a sensitivity of 98% and specificity of 71% [23]. In our series of cases, all of the patients met the clinical criteria established by World Health Organization in 1998, Zerr et al., in 2009 and The University of Edinburgh in 2017. In addition, the whole cohort was positive for 14–3-3 protein in CSF, and 6 out of 6 patients had a high signal abnormalities in caudate and putamen nuclei.

EEG typically shows periodic sharp wave complexes that repeat every 0.5 to 2 s. These alterations occur in only 60% to 70% of patients and are usually present in advanced stages of the disease [7, 12, 15, 25]. Gao et al., demonstrated in their study that these periodic sharp wave complexes are present in 63.5% of cases and reached 90% in those cases in which myoclonus existed [22]. Zerr et al., have determined that the periodic sharp wave complexes have a sensitivity and specificity of 66% and 74%, respectively [26‐28].

The tau protein is released after neuronal damage. Its presence reaches a sensitivity of 81% and a specificity of 85% for the diagnosis of CJD. However, the presence of tau protein, together with the 14–3-3 protein has a positive predictive value of 91% [29]. Wook reported that the specificity of the 14–3-3 protein along with the ratio of total and phosphorylated tau protein (phosphorylated-t/total-t) was 90.62% [30]. On the other hand, it appears that the diagnostic accuracy of tau protein depends on the levels of this protein in CSF [31, 32]. Thus, the LR+ of levels of tau protein > 3000 pg/ml is 10.2 for diagnosis of CJD but with levels of tau protein > 10,000 pg/ml the LR+ is 56.4 [31]. Hamlin et al., studied 420 patients with CJD. They demonstrated that tau protein was superior to 14–3-3 protein as a marker in the diagnosis of CJD [32]. A study by Coulthart et al., included 127 patients with definitive diagnosis of sCJD. They demonstrated that protein levels above 2130 pg/ml allowed for the differentiation of CJD from Alzheimer’s dementia with a sensitivity of 93% and a specificity of 100%. When we studied these markers in the CSF of our patients, we found that three of our patients (50%) had tau protein levels above 10,000 pg/ml and three patients had levels close to or above 3000 pg/ml. All patients had positive 14–3-3 protein in their CSF [31].

Shiga et al. have evaluated the usefulness of DWI MRI in CJD. They studied 36 patients with CJD. Brain DWI MRI abnormalities were found with 92.3% of patients. Moreover, brain DWI MRI abnormalities had a 93.8% specificity [33‐36]. Young et al., studied a cohort of patients with probable or defined CJD and the presence of abnormalities in brain DWI and FLAIR MRI. Abnormalities, including the presence of cortical ribboning and alterations in the deep gray matter were present in 68% of patients, affectation of the only cerebral cortex in 24% and of the deep substance of the brain in 5%. In this study, the findings in brain DWI and FLAIR MRI had a sensitivity and specificity of 91% and 95%, respectively [37]. In order to differentiate CJD from other rapidly progressive dementias (RPD) Vitali et al. [34] conducted a study by DWI and FLAIR MRI in 83 patients with CJD. This study showed that the hyperintensity of the gray matter was present in all cases of sCJD with certain regions preferentially involved, but never only limbic regions and rarely in the precentral gyrus. In all sCJD cases with basal ganglia or thalamic DWI hyperintensities, there was associated restricted diffusion. This restriction in diffusion was not seen in the other cases of RPD, in which the hyperintensities of the limbic system were common. The sensitivity and specificity of this study to differentiate sCJD from other RPDs was 96% and 93%, respectively. In our cohort of patients, we found the presence of hyperintensity in the basal ganglia in all patients and the presence of cortical ribboning in 4 of 6 patients.

RT-QuIC is a recently described laboratory technique that provides definitive diagnosis of CJD from CSF samples by detecting PrPSc [15, 38] Orru et al., used RT-QuIC with nasal brushings and showed a sensitivity of 97% and a specificity of 100%. This method is even less invasive than lumbar puncture, which only had 77% sensitivity but 100% specificity when the CSF was tested in the same patients [39]. Therefore, this modern technique should be part of the standard initial testing for CJD. However, this technique is not available in Ecuador.

Definitive diagnosis of CJD is only achieved by histopathological study. A cerebral biopsy gives us adequate histopathological information and is considered the cornerstone in the diagnosis of CJD. However, the frequency of positive test results for the disease in the biopsy is surprisingly low [15]. Brain biopsy should be reserved for cases in which the non-invasive studies have not shown positive results for the disease and the cause of symptoms is not found [15]. The neuropathological characteristics of sCJD at the macroscopic level include different degrees of cerebral and cerebellar atrophy and at a microscopic level the presence of intracytoplasmic vacuolization (spongiform changes) in the gray matter, along with marked neuronal loss and astrocytic gliosis. About 10% of the affected patients present deposition of amyloid plaques [40, 41]. In our cohort, we performed a histopathological analysis in one patient, which demonstrated intracytoplasmic vacuolization, neuronal depopulation and astrocytic gliosis, in which a definitive diagnosis of CJD could be established. The remaining patients were diagnosed with probable CJD.

Ninety percent of patients with prion disease die within the first year of disease onset [9]. The average time from the onset of the symptoms to death in this group was 13 months. The mainstay of treatment is symptomatic and supportive, for example, using clonazepam for the treatment of myoclonus. Otto et al., showed a statistically significant improvement in cognitive function in a group of 28 patients with CJD treated with flupirtine, but this is the only study in the literature to report any symptom improvement with the use of this medication [42]. Future targets of therapy involve preventing the conversion of PrPC to PrPSc [15].

In conclusion, these are the first case reports of CJD in Ecuador from a third level hospital of Quito. Only in one case, we reach a definitive diagnosis through a pathological study. All other cases had a probable diagnosis. This disease should be considered in individuals older than 50 years of age, with a rapidly progressive dementia associated with myoclonus, visual symptoms, and ataxia accompanied by signs of pyramidal and extrapyramidal dysfunction. Although definitive diagnosis must be histopathological, there are ancillary tests currently available that have allowed us to obtain a diagnosis of the disease.