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Sporadic Creutzfeldt-Jacob disease: an 8-year experience from a single center in Turkey/Sporadik Creutzfeldt-Jacob Hastaligi: Turkiye'den bir merkezin sekiz yillik tecrubesi.

Introduction

Creutzfeldt-Jacob disease (CJD) is a neurodegenerative disease with sporadic (sCJD) (85%), familial (10%-15%), iatrogenic (1%), and new variant forms. The incidence of sCJD is estimated to be 0.5 to 1.5 cases per million people per year (1).

According to the accepted case definition criteria for sCJD, three subgroups are defined: possible, probable, and definite (2). Classic CJD, Heidenhain, Oppenheimer-Brownell, cognitive, and affective phenotypes have all been described as variants of sCJD (3), and there is still the possibility of encountering additional phenotypes of sCJD. The wide spectra of the disease's signs and symptoms make its diagnosis challenging.

This is the first case series of sCJD reported in Turkey. We report the clinical, electrophysiological, and imaging analyses of 10 patients diagnosed with sCJD during the last 8 years and draw conclusions about the applicability of the various tools in establishing an accurate diagnosis of sCJD.

Method

We screened all patients older than 18 years of age consecutively admitted to the Neurology Department of our university hospital between January 2000 and December 2008. A total of 10 patients (5 female and 5 male) of 8.259 hospitalized patients were diagnosed with sCJD. On the basis of the clinical information, the neurological examination, electroencephalography (EEG), radiological findings, and the presence of protein 14.3.3 in the cerebrospinal fluid (CSF), the patients were classified as clinically probable, possible, or "not" CJD based on the accepted case definition criteria for sCJD (2).

The classic CJD included patients with cognitive symptoms and ataxia but without visual impairments and affective symptoms during the first week of illness. Cases presenting with dementia, memory impairment, executive dysfunction, language impairment, and/or confusion in the absence of visual, cerebellar, and mood symptoms within the first week of illness were classified as the cognitive variant. Cases were classified as the Heidenhain variant if visual disturbances such as cortical blindness, oculomotor impairment, and/or visual hallucinations were documented within the first week of illness.

The Oppenheimer-Brownell variant included cases that had ataxia within the first week of illness in the absence of cognitive and visual impairments. Patients who were reported as having symptoms of depression, mood lability, mania, hypomania, and/ or anxiety within the first week of illness were classified as having the affective variant if they did not meet inclusion criteria for the Heidenhain group. Cases that could not be classified into one of the aforementioned groups were designated as indeterminate (3).

Standardized magnetic resonance imaging (MRI), which included T2-weighted axial, T1-weighted sagittal, T1-weighted sagittal with gadolinium, and proton density axial images, was performed for all patients.

Results

Eight patients had clinically probable CJD, and two showed the characteristic spongy changes in the brain associated with definite CJD (4). According to different sCJD phenotypes determined by Appleby et al. (3), four cases of classic CJD (cases 5, 6, 7, and 10) and four cases of the affective variant (cases 1, 3, 8, and 9) were diagnosed. One (case 4) was classified as the cognitive variant, and one (case 2) was in the indeterminate group. None of the patients were placed in the Oppenheimer-Brownell or the Heidenhain phenotype group.

The clinical, radiological, EEG, and CSF characteristics are presented in Table 1. The most common signs and symptoms were behavioral disturbances (n=4), cognitive decline (n=4), myoclonus (n=4), movement disorders (n=3), psychosis (n=3), aphasia (n=3), and focal neurological deficits (n=1). The number of female patients was equal to males.

The mean age at disease onset was 55 years. Four patients were hospitalized within 1 month, and three patients were hospitalized 1 to 3 months after the onset of complaints. The remaining three patients were hospitalized 3 months after the onset of complaints. Three patients died within 3 months of diagnosis, six died after 4 to 10 months, and one patient died 24 months after being diagnosed.

The investigative methods (EEG, CSF analysis, and cranial MRI) were carried out as soon as the patients were hospitalized (four patients within 1 month, three patients within 1 to 3 months, and three patients at 3 to 6 months of the disease). Nine patients (90%) had periodic sharp wave complexes (PSWCs) on their EEGs.

The pulvinar sign was present on the T2-weighted images in 5 of the 10 cases. Diffusion-weighted (DW) imaging, which was performed in two cases, also showed hyperintensities in the supratentorial gray matter (Figures 1,2).

With the exception of the two patients with increased CSF protein (20%), cytological and biochemical analysis of the CSF revealed no abnormalities. Seven patients, who underwent CSF analysis, tested positive for the protein 14.3.3.

The relatives of all the patients were offered brain biopsies. Only two patients' (Case 1 and 5) relatives accepted the biopsy procedure. The pathological specimens were evaluated both at the pathology department of our hospital and at the Institute of Neurology at the Medical University of Vienna, Austria.

Discussion

The presenting features of our patients were behavioral disturbances, cognitive decline, myoclonus, movement disorders, psychosis, aphasia, and focal neurological deficits. They were all similar to features of CJD reported in the literature (5).

CJD has been found to affect males and females equally, with a mean age at onset of 65 years (1). The mean age at disease onset in our patients was 55 years. Cases before 40 or after 80 years have been rarely reported (6,7). Age at symptom onset differed significantly between sCJD phenotypes (3). Among our cases, the ages at symptom onset for case 2 (the indeterminate group), case 4 (the cognitive variant), and case 7 (classic variant) were 44, 40, and 46 years, respectively.

Classic CJD cases were admitted to the hospital shortly after symptom onset (3). They also had the shortest median survival time. Cases 5, 6, 7, and 10 were admitted to the hospital 1 to 6 weeks after symptom onset, and they died within 1 to 4 months after symptom onset.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

EEGs were performed in all the patients, and 90%had PSWCs on their first EEG; this has been accepted as one of the World Health Organization's (WHO's) diagnostic criteria of CJD. PSWCs may be generalized, lateralized, or focal. Nine of our patients had PSWCs on their EEGs. Patients with cortical hyperintensities in diffusion MRI also had PSWCs on their EEGs. In patients with striatal involvement, PSWCs may not be seen on EEG (8). The cranial MRI in case 10 revealed hyperintensity in the basal ganglia bilaterally. The EEG in this case showed generalized slow wave discharges without PSWC. Lateralized periodical epileptic discharges (PLEDS) have been reported at the end stages of the disease (6). However, none of our patients showed PLEDS on their EEGs. The reason for this may be the early recoding time of the EEGs during the disease progression.

Routine analysis of CSF is normal and shows no evidence of inflammation. Slight elevation of protein is common, but this is usually below 100mg/dl (9,10). Two patients (cases 3 and 7; 20%) had increased CSF protein.

The protein 14.3.3 test provided a useful adjunct to the clinical and EEG data. The sensitivity and specificity of this protein, which is a reliable marker of rapid neuronal destruction, are about 93%and 84%, respectively (11). Some work has suggested that the specificity of the marker increases to 99%in definitively diagnosed cases (12). CSF 14.3.3 analyses of seven of our patients were positive.

Cranial MRI increases the sensitivity of the antemortem diagnosis of CJD. In most sCJD cases, MRI shows hyperintense signal changes in the caudate nucleus, putamen, globus pallidus, thalamus, and cerebral cortex on T2-weighted, fluid-attenuated inversion recovery, proton density, and DW images. The pulvinar sign has diagnostic value for vCJD, but studies have also reported it in sCJD cases where it was accompanied by signal changes in other regions of the brain (13,14). A true pulvinar sign (consistent with variants of CJD) must be considered only if the high signal in the pulvinar is greater than the hyperintensity in the caudate and putamen nucleus.

Studies have also suggested that DW MRIs are more sensitive to changes specific to CJD, such as ribbon-like hyperintensities in the cerebral cortex (15,16,17,18). Hyperintense signals in the basal ganglia and the cortex observed bilaterally on cranial MRIs are the result of spongiosis and degeneration. We detected these hyperintensities in 2 of the 10 patients who had undergone DW imaging (cases 3 and 4). These changes showed up as abnormal metabolism and perfusion in positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively (19,20). In case 6, global hypometabolism was performed in PET, and in case 7, decreased Tc-99 uptake in the right frontal interhemispheric region was performed in SPECT. Only two of our patients (cases 2 and 6) had cortical atrophy on their MRI without accompanying hyperintensities in the basal ganglia and the cortex. These patients had PSWCs on their EEGs, and their CSF analyses were positive for the protein 14.3.3 test.

Prions, before neuroinvasion, are assumed to replicate in the lymphoreticular tissue. Positive staining of abnormal prion protein in the tonsillar biopsy has been reported only in variants of CJD. However, our patients were diagnosed as having sCJD, thus, we did not perform a tonsillar biopsy, the use of which for antemortem diagnosis is still questionable. Tonsillar biopsy is not recommended routinely in cases with EEG appearances typical of sCJD, but it is useful in suspected cases whose clinical features are compatible with vCJD and when MRI does not show a bilateral pulvinar high signal (9,21).

A definitive diagnosis requires microscopic examination of the brain tissue (cerebral cortex, putamen, caudate nuclei, thalami, and molecular layer of the cerebellum) to detect the characteristic spongy changes associated with the disease (4). Two patients' relatives accepted the brain biopsy, and their brain specimens were compatible with a CJD diagnosis.

According to the WHO, clinical criteria for CJD depend on the number of symptoms a patient has. Clinical diagnosis may be probable or possible. Based on these clinical and microscopic criteria, eight of our patients had clinically probable CJD, and two had definite CJD. These two patients also met clinically probable CJD criteria. Considering the lack of history of traveling to age at the onset of symptoms, the rapid progression of the disease, results of investigations, and the short survival times, all of the patients were classified as having the sporadic form of CJD.

According to the different CJD phenotypes determined by Appleby et al. (3), case 2 might be classified as a cognitive variant of sCJD or as indeterminate. Admission to the hospital 3 months after symptom onset, a prolonged interval between illness onset and diagnostic testing, and more than 4 months of survival time were compatible with cognitive variants. However, a focal neurological deficit (left hemiparesis) is not a common feature of CJD, therefore, we classified this patient as indeterminate.

Case 10 had no PSWC on the EEG. This meant that Oppenheim-Brownel diagnosis was possible, but the presence of hyperintensity in the basal ganglia excluded this diagnosis. Absence of visual symptoms at onset made the Heidenhain variant diagnosis also impossible. The absence of PSWC on the EEG could be explained by the cranial lesion being localized only to the striatum (22).

The diagnosis of this rapidly progressing mortal disease is challenging. Based on our experience with ten patients with sCJD, we wish to emphasize the importance of clinical and laboratory investigations in the diagnosis of sCJD and of focusing on the different phenotypes of sCJD in light of the recent literature.

CJD should be considered in the differential diagnosis of patients with rapidly progressive dementia and neuropsychiatric symptoms. It is important to note the stage of the disease the when patient's symptoms begin. EEG and cranial MRIs are easily accessible methods in the hospitals in Turkey. However, CSF analyses of the 14.3.3 protein, the molecular analysis, and brain biopsies may need to be performed at specific centers. Considering all these factors will help in diagnosing a patient in the context of the wide spectra of CJD.

All patients suspected of having CJD in Turkey are reported to the Ministry of Health. However, there are no data regarding the analysis of these patients. Instead, knowledge of CJD is dependent on case reports (8,23,24,25). Our study is the first to review and report on the diagnosis and analysis of patients with sCJD in Turkey. This study may serve as the first step toward a nationwide review of the data of all patients referred to the Ministry of Health and the establishment of an investigative protocol for suspected CJD cases in Turkey.

DOI: 10.4274/Npa.y5903

Acknowledgments

The authors would like to thank the family members of the patients who made this study possible and Professor Herbert Budka at the Institute of Neurology, Medical University of Vienna, Austria, who examined two patients' brain specimens.

References

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Ozlem TASKAPILIOGLU [1], Meral SEFEROGLU [1], Sukran YURTOGULLARI [1], Bahattin HAKYEMEZ [3], Sevda ERER [1], Necdet KARLI [3], Mustafa BAKAR [1], O. Faruk TURAN [1], Mehmet ZARIFOGLU [1], Sahsine TOLUNAY [3], Ibrahim BORA [1]

[1] Uludag University Faculty of Medicine, Department of neurology, Bursa, Turkey

[2] Uludag University Faculty of Medicine, Department of Radiology, Bursa, Turkey

[3] Uludag University Faculty of Medicine, Department of Pathology, Bursa, Turkey
Table 1. Characteristics and clinical and laboratory findings of
the patients

Patient   Age      Signs &           Duration of    Presentation
          (Year)   Symptoms at       Symptoms       and
                   Onset             (Months) and   Neurological
                                     Outcome        Findings

Case 1    57       Cognitive         7              No cooperation,
(MT)               decline,                         agitated,
                   behavioral                       Myoclonus (+)
                   disturbances,
                   psychosis

Case 2    44       Headache,         8              Cooperation
(KC)               dizziness, left                  possible; right
                   hemiparesis,                     hemiparesis,
                   disturbed                        Babinski sign,
                   consciousness                    and
                                                    myoclonus(+)

Case 3    57       Cognitive         24             Noncooperated,
(SC)               decline,                         agitated
                   behavioral
                   disturbances

Case 4    40       Behavioral        6              Noncooperated,
(AY)               disturbances,                    spasticity in
                   aphasia                          all the
                                                    extremities
                                                    (+), increased
                                                    DTRs with
                                                    bilateral
                                                    Babinski sign
                                                    (+)

Case 5    57       Not conscious     1              No cooperation,
(GS)               of                               myoclonus (+)
                   surroundings,
                   aphasia,
                   movement
                   disorders

Case 6    67       Not conscious     2              No cooperation
(HB)               of
                   surroundings,
                   agitation

Case 7    46       Movement          4              Cooperation
(MT)               disorders, gait                  possible,
                   problems,                        increased tonus
                   psychosis                        in all
                                                    extremities,
                                                    bilateral
                                                    Babinski sign
                                                    (+)

Case 8    56       Cognitive         7              No cooperation,
(FC)               decline                          no motor
                   incoherent                       lateralization.
                   speech,                          Bilateral
                   movement                         Babinski (+)
                   disorders,
                   psychosis

Case 9    63       Echolaly,         10             Disorientation,
(MHS)              increased                        echolaly (+),
                   reaction time                    increased DTRs
                                                    with bilateral
                                                    Babinski sign
                                                    (+)

Case 10   62       Aphasia, gait     3              Disorientation,
(SO)               problems,                        no cooperation,
                   psychosis                        increased DTRs
                                                    with bilateral
                                                    Babinski sign
                                                    (+)

Patient   Cranial MRI       EEG               CSF

Case 1    Pulvinarsign      PSWCs             Normal
(MT)                                          microscopic and
                                              biochemical
                                              findings,
                                              14.3.3 not
                                              performed

Case 2    Diffuse           PSWCs             Normal
(KC)      cortical                            microscopic and
          atrophy                             biochemical
                                              findings,
                                              14.3.3 (+)

Case 3    Hyperintensity    PSWCs             Normal
(SC)      in the right                        microscopy,
          limbic system                       slightly
          predominant in                      increased
          the parietal                        protein level,
          and temporal                        14.3.3 (+)
          regions

Case 4    Gyral             PSWCs             Normal
(AY)      hyperintensity                      microscopic and
          extending to                        biochemical
          both cerebral                       findings,
          hemispheres                         14.3.3 (+)

Case 5    Pulvinarsign      Suppression       Normal
(GS)                        burst activity,   microscopic and
                            PSWCs             biochemical
                                              findings,
                                              14.3.3 (+)

Case 6    Cortical          PSWCs             Normal
(HB)      atrophy                             microscopic and
                                              biochemical
                                              findings,
                                              14.3.3 (+)

Case 7    Pulvinarsign      PSWCs             Increased
(MT)                                          protein and
                                              LDH, 14.3.3 not
                                              performed

Case 8    Pulvinarsign      PSWCs             Normal
(FC)      cortical                            microscopic and
          atrophy, and                        biochemical
          hyperintensity                      findings,
                                              14.3.3 not
                                              performed

Case 9    Hyperintensity    PSWCs             Normal
(MHS)     in the caudate                      microscopic and
          nucleus                             biochemical
          bilaterally                         findings,
                                              14.3.3 (+)

Case 10   Pulvinarsign in   Slow wave         Normal
(SO)      the basal         discharges        microscopic and
          ganglia           consistent        biochemical
          bilaterally       with severe       findings,
                            encephalopathy    14.3.3 (+)

Patient   Functional
          Imaging (PET or
          SPECT)

Case 1    Not performed
(MT)

Case 2    Not performed
(KC)

Case 3    Not performed
(SC)

Case 4    Not performed
(AY)

Case 5    Not performed
(GS)

Case 6    PET: Global
(HB)      hypometabolism
          in cerebrum and
          cerebellum

Case 7    SPECT:
(MT)      Decreased Tc-99
          uptake in the
          right frontal
          interhemispheric
          region

Case 8    Not performed
(FC)

Case 9    Not performed
(MHS)

Case 10   Not performed
(SO)

Table legend: MRI: Magnetic resonance imaging, EEG:
Electroencephalography, CSF: Cerebrospinal fluid, PET: Positron
emission tomography, SPECT: Single photon emission computed
tomography, PSWCs: Periodic sharp wave complexes
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Title Annotation:Research Article/Arastirma Makalesi
Author:Taskapilioglu, Ozlem; Seferoglu, Meral; Yurtogullari, Sukran; Hakyemez, Bahattin; Erer, Sevda; Karli
Publication:Archives of Neuropsychiatry
Article Type:Report
Date:Dec 1, 2013
Words:3362
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