Punctate Diffuse Cortex Signals in Creutzfeldt-Jakob Disease.

This case report describes 2 patients with genetic Creutzfeldt-Jakob disease with atypical changes on diffusion-weighted imaging.

Sensory disturbances in Creutzfeldt-Jakob disease.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease characterized by rapidly progressive dementia, motor impairments, and psychiatric symptoms. Sensory disturbances were occasionally reported as well. The study aims to describe the sensory symptoms of the disease. METHODS: The CJD Israeli National Database was screened for patients who presented sensory symptoms throughout the disease course. Symptoms, characteristics, and distribution were reviewed and the demographic and clinical data (sex, etiologies of the disease, age of onset, disease duration, neurological exam finding, tau protein level, EEG and MRI findings) were compared with the demographics and clinical data of CJD without sensory symptoms. Then, the patients with sensory symptoms were divided into patients with symptom distribution consistent with peripheral nervous system (PNS) involvement and central nervous system (CNS) involvement. The demographics and clinical data of the 2 groups were compared. RESULTS: Eighty-four CJD patients with sensory symptoms and 645 CJD patients without sensory symptoms were included in the study. Sensory symptoms were more common in genetic E200K CJD patients (14.6% vs. 5.6% respectively, p = 0.0005) (chi-squared test). Numbness and neuropathic pain were the most common symptoms and distribution of symptoms of "stocking gloves" with decreased deep tendon reflexes suggesting peripheral neuropathy in 44% of the patients. In these patients, the classical EEG findings of Periodic Sharp Wave Complexes were less often found (58% vs. 22%, p = 0.02) (chi-squared test). CONCLUSIONS: Sensory symptoms are more common in E200K patients and often follow peripheral neuropathy distribution that suggests PNS involvement.

Sporadic Creutzfeldt-Jakob Disease Initially Presenting With Posterior Reversible Encephalopathy Syndrome: A Case Report.

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal neurodegenerative condition caused by prion proteins. Cortical and subcortical diffusion-weighted imaging restriction on magnetic resonance imaging (MRI) is associated with sCJD. Posterior reversible encephalopathy syndrome (PRES) results from impaired vessel autoregulation due to an identifiable trigger, which is associated with subcortical fluid-attenuated inversion recovery changes on MRI. We report a case of sCJD initially presenting with PRES. CASE REPORT: A 70-year-old woman presented to an outside hospital with progressive confusion and difficulty in managing activities of daily living. Initial examination revealed stuporous mental state and stimulus-induced myoclonus. MRI revealed bilateral subcortical occipital lobe T2-fluid-attenuated inversion recovery hyperintensities without contrast enhancement suggestive of PRES. Electroencephalogram (EEG) revealed frequent generalized periodic discharges meeting criteria for nonconvulsive status epilepticus. Clinical examination and EEG did not improve despite escalating antiseizure medications. Initial lumbar puncture was unremarkable. She was transferred to our hospital with a presumptive diagnosis of PRES, although there was no clear trigger. Continuous EEG revealed ongoing generalized periodic discharges with myoclonic activity meeting criteria for myoclonic seizures that were refractory to multiple antiseizure medications. Repeat MRI showed resolution of PRES but revealed subtle diffuse cortical diffusion-weighted imaging restriction. Repeat lumbar puncture was performed and 14-3-3 and real-time quaking-induced conversion returned positive, confirming sCJD. CONCLUSIONS: This case reports highlights that sCJD can present with neuroimaging consistent with PRES. The diagnosis of sCJD should be considered in patients with PRES who continue to show neurological decline despite optimal management and radiographic improvement of PRES on MRI. Further research is needed to identify a pathophysiological relationship between these clinical phenotypes.

Personalized brain MRI revealed distinct functional and anatomical disruptions in Creutzfeldt-Jakob disease and Alzheimer's disease.

AIMS: Creutzfeldt-Jakob disease (CJD) is a lethal neurodegenerative disorder, which leads to a rapidly progressive dementia. This study aimed to examine the cortical alterations in CJD, changes in these brain characteristics over time, and the differences between CJD and Alzheimer's disease (AD) that show similar clinical manifestations. METHODS: To obtain reliable, subject-specific functional measures, we acquired 24 min of resting-state fMRI data from each subject. We applied an individual-based approach to characterize the functional brain organization of 10 patients with CJD, 8 matched patients with AD, and 8 normal controls. We measured cortical atrophy as well as disruption in resting-state functional connectivity (rsFC) and then investigated longitudinal brain changes in a subset of CJD patients. RESULTS: CJD was associated with widespread cortical thinning and weakened rsFC. Compared with AD, CJD showed distinct atrophy patterns and greater disruptions in rsFC. Moreover, the longitudinal data demonstrated that the progressive cortical thinning and disruption in rsFC mainly affected the association rather than the primary cortex in CJD. CONCLUSIONS: CJD shows unique anatomical and functional disruptions in the cerebral cortex, distinct from AD. Rapid progression of CJD affects both the cortical thickness and rsFC in the association cortex.

MRI abnormalities in Creutzfeldt-Jakob disease and other rapidly progressive dementia.

OBJECTIVE: To investigate brain MRI abnormalities in a cohort of patients with rapidly progressive dementia (RPD) with and without a diagnosis of Creutzfeldt-Jakob disease (CJD). METHODS: One hundred and seven patients with diagnosis of prion disease (60 with definite sCJD, 33 with probable sCJD and 14 with genetic prion disease) and 40 non-prion related RPD patients (npRPD) underwent brain MRI including DWI and FLAIR. MRIs were evaluated with a semiquantitative rating score, which separately considered abnormal signal extent and intensity in 22 brain regions. Clinical findings at onset, disease duration, cerebrospinal-fluid 14-3-3 and t-tau protein levels, and EEG data were recorded. RESULTS: Among patients with definite/probable diagnosis of CJD or genetic prion disease, 2/107 had normal DWI-MRI: in one patient a 2-months follow-up DWI-MRI showed CJD-related changes while the other had autopsy-proven CJD despite no DWI abnormalities 282 days after clinical onset. CJD-related cortical changes were detected in all lobes and involvement of thalamus was common. In the npRPD groups, 6/40 patients showed DWI alterations that clustered in three different patterns: (1) minimal/doubtful signal alterations (limbic encephalitis, dementia with Lewy bodies); (2) clearly suggestive of alternative diagnoses (status epilepticus, Wernicke or metabolic encephalopathy); (3) highly suggestive of CJD (mitochondrial disease), though cortical swelling let exclude CJD. CONCLUSIONS: In the diagnostic work-up of RPD, negative/doubtful DWI makes CJD diagnosis rather unlikely, while specific DWI patterns help differentiating CJD from alternative diagnoses. The pulvinar sign is not exclusive of the variant form.

[Review of a series of cases of Creutzfeldt-Jakob disease in a tertiary care hospital]. / Revisión de una serie de casos de enfermedad de Creutzfeldt-Jakob en un hospital de tercer nivel.

INTRODUCTION: We analysed a series of patients with sporadic Creutzfeldt-Jakob disease in our setting. AIM: The aim of this study is to describe the characteristics of our sample using the new diagnostic tools based on the most recently published criteria. MATERIAL AND METHODS: A descriptive, retrospective study was conducted using a digitalised hospital register. We identified 20 cases of the sporadic type, in the period 2012-2022: eight with a pathological diagnosis and 12 with high probability. The variables sex, age at onset, time of evolution, clinical phenotype, magnetic resonance imaging (MRI) findings, 14.3.3 protein, electroencephalogram (EEG), real-time quaking-induced prion protein conversion (RT-QuIC), autopsy, pathological phenotype and genetic diagnosis were recorded. RESULTS: Of those affected, 50% were men and 50%, women, with an age at onset of 67 years (30-83) and a mean survival time of eight months (1-11 months). Cognitive impairment was the most frequent onset symptom, followed by gait ataxia. All MRI scans with long time-lapse sequences (FLAIR and DWI) were pathological, and the pattern of diffuse cortical and basal ganglia involvement was the most frequent. Altogether, 55% of the sample had an EEG with characteristic triphasic complexes. Sixty-five per cent were positive for 14.3.3 protein in cerebrospinal fluid. Four RT QuIC studies were carried out (in 2020) and all were positive. In 40% of them a confirmatory autopsy was performed, with the MM/MV1 pattern being the most frequent. CONCLUSIONS: MRI with DWI sequences is a particularly sensitive test for the diagnosis of the disease, although its sensitivity decreases in the early stages. The high specificity and sensitivity of RT-QuIC, together with a characteristic clinical diagnosis and radiological pattern, are proposed as an alternative to the pathological definitive diagnosis.

TITLE: Revisión de una serie de casos de enfermedad de Creutzfeldt-Jakob en un hospital de tercer nivel.Introducción. Analizamos en nuestro medio una serie de pacientes con enfermedad de Creutzfeldt-Jakob esporádica. Objetivo. Describir las características de nuestra muestra haciendo uso de las nuevas herramientas diagnósticas según los últimos criterios publicados. Material y métodos. Realizamos un estudio descriptivo y retrospectivo mediante registro hospitalario digitalizado. Identificamos 20 casos del tipo esporádico, en el período 2012-2022, ocho con diagnóstico anatomopatológico y 12 con alta probabilidad. Se registraron las variables sexo, edad de inicio, tiempo de evolución, fenotipo clínico, hallazgos en la resonancia magnética (RM), proteína 14.3.3, electroencefalograma (EEG), conversión de proteína priónica inducida por agitación en tiempo real (RT-QuIC), autopsia, fenotipo anatomopatológico y diagnóstico genético. Resultados. Registramos un 50% de hombres y un 50% de mujeres afectos, con una edad de inicio de 67 años (30-83) y un tiempo de supervivencia medio de ocho meses (1-11 meses). El deterioro cognitivo fue el síntoma de inicio más frecuente, seguido de la ataxia de la marcha. Todas las RM con secuencias de tiempo de repetición largo (FLAIR y DWI) fueron patológicas, y el patrón de afectación cortical difusa y de los ganglios basales fue el más frecuente. El 55% de la muestra tuvo un EEG con complejos trifásicos característicos. El 65% mostró positiva la proteína 14.3.3 en el líquido cefalorraquídeo. Se realizaron cuatro estudios de RT-QuIC (en 2020) y todos fueron positivos. En un 40% se realizó una autopsia confirmatoria, con el patrón MM/MV1 como el más frecuente. Conclusiones. La RM con secuencias de DWI constituye una prueba especialmente sensible para el diagnóstico de la enfermedad, aunque su sensibilidad disminuye en estadios precoces. La alta especificidad y la alta sensibilidad de la RT-QuIC, junto con un diagnóstico clínico y patrón radiológico característico, se plantean como alternativa al diagnóstico de certeza anatomopatológico.

Rapid progression of probable Creutzfeldt-Jakob disease with concomitant COVID-19 infection.

A previously healthy man in his 80s was admitted to a district general hospital with rapidly progressing dementia, gait abnormalities and myoclonus alongside COVID-19 infection. Investigations showed mild elevation of C-reactive protein and neutrophils, unremarkable CT head and mildly raised protein in cerebrospinal spinal fluid (CSF). Brain MRI revealed bilateral cortical and striatal diffusion restriction and electroencephalogram (EEG) findings showed diffuse activity slowing with high amplitude sharp/slow-wave complexes. He was diagnosed with probable sporadic Creutzfeldt-Jakob disease (CJD) and management prioritised comfort and care. He passed away two weeks following admission and a mere 8 weeks after the first onset of symptoms.We present the first documented case of probable CJD with concomitant COVID-19 infection in the UK. We identified six other cases worldwide identified in our literature review. These cases suggest a role of COVID-19 in the rapid progression of CJD and add to the growing evidence of its neuroinflammatory role in other forms of neurodegenerative diseases.

Two Chinese patients of sporadic Creutzfeldt-Jacob disease with a S97N mutation in PRNP gene.

Worldwide, 10-15% human prion disease are genetic and inherited, due to the special mutations or insertions in PRNP gene. Herein, we reported two Chinese patients with rapidly progressive dementia who were referred to the national Creutzfeldt-Jacob disease (CJD) surveillance as suspected CJD. Those two patients displayed sporadic CJD (sCJD)-like clinical phenotype, e.g. rapidly progressive dementia, visional and mental problems, sCJD-associated abnormalities in MRI. A missense mutation was identified in one PRNP allele of these two patients, resulting in a change from serine to asparagine at codon 97 (S97N). RT-QuIC of the cerebrospinal fluid samples from those two cases were positive. It indicates that they are very likely to be prion disease.

[Sporadic Creutzfeldt-Jakob Disease With Slow Progression:Report of One Case].

Sporadic Creutzfeldt-Jakob disease(sCJD)is a prion-caused degenerative disease of the central nervous system,with the typical clinical manifestation of rapidly progressive dementia.The course of disease is less than 1 year in most patients and more than 2 years in only 2% to 3% patients.We reported a case of sCJD with expressive language disorder and slow progression in this paper.By summarizing the clinical manifestations and the electroencephalograhpy,MRI,and pathological features,we aimed to enrich the knowledge about the sCJD with slow progression.

Diagnostic accuracy of diffusion-weighted imaging in variant Creutzfeldt-Jakob disease.

PURPOSE: This study sought to investigate the diagnostic sensitivity of diffusion-weighted imaging (DWI) in variant Creutzfeldt-Jakob disease (vCJD), a prion disease with significant public health implications on account of its transmissibility. The importance of this research stemmed from the first neuropathologically confirmed vCJD case in a PRNP heterozygous individual in 2016, which displayed DWI features typical of sporadic CJD (sCJD). The case was classified as 'probable' sCJD in life, predominantly based on these imaging findings. While DWI has proven valuable in diagnosing sCJD, its utility in vCJD diagnosis remains unclear. METHODS: DWI and Fluid-attenuated inversion recovery (FLAIR) images from probable and definite vCJD cases referred to the National CJD Research and Surveillance Unit (NCJDRSU) were independently analysed by an expert neuroradiologist. Scans were reviewed within a mixed cohort of CJD cases including definite sCJD and non-CJD controls. RESULTS: FLAIR sequences demonstrated greater sensitivity in identifying the pulvinar sign in vCJD compared to DWI (73% vs 41%, p-value <0.001). Basal ganglia hyperintensities were more prevalent in DWI (84%) than FLAIR (64%), and cortical hyperintensities were exclusive to DWI (24%). The pulvinar sign showed a specificity of 98% for vCJD and was rare in sCJD. CONCLUSION: DWI showed reduced sensitivity compared to FLAIR imaging in detecting the pulvinar sign in vCJD. Conversely, DWI can more distinctively identify basal ganglia and cortical hyperintensities, thus leading to imaging patterns more characteristic of sCJD. Therefore, DWI should be cautiously interpreted in vCJD diagnosis, with axial FLAIR potentially providing a more precise evaluation of the pulvinar sign.

Metabolic Brain Changes Can Predict the Underlying Pathology in Neurodegenerative Brain Disorders: A Case Report of Sporadic Creutzfeldt-Jakob Disease with Concomitant Parkinson's Disease.

The co-occurrence of multiple proteinopathies is being increasingly recognized in neurodegenerative disorders and poses a challenge in differential diagnosis and patient selection for clinical trials. Changes in brain metabolism captured by positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) allow us to differentiate between different neurodegenerative disorders either by visual exploration or by studying disease-specific metabolic networks in individual patients. However, the impact of multiple proteinopathies on brain metabolism and metabolic networks remains unknown due to the absence of pathological studies. In this case study, we present a 67-year-old patient with rapidly progressing dementia clinically diagnosed with probable sporadic Creutzfeldt-Jakob disease (sCJD). However, in addition to the expected pronounced cortical and subcortical hypometabolism characteristic of sCJD, the brain FDG PET revealed an intriguing finding of unexpected relative hypermetabolism in the bilateral putamina, raising suspicions of coexisting Parkinson's disease (PD). Additional investigation of disease-specific metabolic brain networks revealed elevated expression of both CJD-related pattern (CJDRP) and PD-related pattern (PDRP) networks. The patient eventually developed akinetic mutism and passed away seven weeks after symptom onset. Neuropathological examination confirmed neuropathological changes consistent with sCJD and the presence of Lewy bodies confirming PD pathology. Additionally, hyperphosphorylated tau and TDP-43 pathology were observed, a combination of four proteinopathies that had not been previously reported. Overall, this case provides valuable insights into the complex interplay of neurodegenerative pathologies and their impact on metabolic brain changes, emphasizing the role of metabolic brain imaging in evaluating potential presence of multiple proteinopathies.

Toward an early clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: To assess the proportion of clinically diagnosed MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) in a Chinese cohort, describe the clinical features of MM2-cortical (MM2C) and MM2-thalamic (MM2T) type sCJD to improve the early detection of MM2-type sCJD. METHODS: A total of 209 patients with sCJD admitted to the Xuanwu Hospital between February 2012 and August 2022 were reviewed. The patients were classified into probable MM2C, MM2T-type sCJD, and other types of sCJD according to current clinical diagnostic criteria. Clinical and ancillary data were compared between the groups. RESULTS: Fifty-one (24.4%) patients were clinically diagnosed with MM2-type sCJD, of which 44 were diagnosed with MM2C-type sCJD and 7 with MM2T-type sCJD. In the absence of RT-QuIC, 27 (61.3%) patients of MM2C-type sCJD did not meet the US CDC sCJD criteria for possible sCJD on admission, even though the mean period from onset to admission was 6.0 months. However, all of these patients had cortical hyperintensity on DWI. Compared to the other types of sCJD, MM2C-type sCJD was associated with slower disease progression and the absence of the typical clinical features of sCJD; the MM2T-type sCJD group had a higher proportion of males, earlier age of onset, longer duration of disease, and a higher incidence of bilateral thalamic hypometabolism/hypoperfusion. INTERPRETATION: In the absence of multiple typical sCJD symptoms within 6 months, the presence of cortical hyperintensity on DWI should raise concerns for MM2C-type sCJD after excluding other etiologies. Bilateral thalamic hypometabolism/hypoperfusion may be more helpful in the clinical diagnosis of MM2T-type sCJD.

Spectrum and Pattern of Movement Disorders in Patients with Sporadic Creutzfeldt-Jakob Disease.

Background: Creutzfeldt-Jakob disease (CJD) is a rare neuro degenerative disease that is mainly characterized by rapidly progressive dementia along with a varying combination of myoclonus, visual, cerebellar, pyramidal/extrapyramidal and akinetic mutism. Several movement disorders phenomenologies can occurs either at onset, as presenting symptom or during the course of illness. Present study aims to characterize the clinical, radiological features and the outcome of patients with CJD with movement disorders as the forthcoming manifestation. Methods: Chart review of patients with CJD with movement disorders. Demographic, clinical and radiological details of the patients were reviewed. Results: 25 patients (13 males) of sCJD with median age at presentation of 58 years and median duration of illness of 5 months were included in the study. According to revised CDC diagnostic criteria 1 patient was classified as definite sCJD, 20 as probable and 2 as possible CJD. Myoclonus, ataxia and parkinsonism were the most common movement disorder and chorea was the least common. Magnetic resonance imaging of brain was performed in all and basal ganglia abnormality and cortical ribboning was seen in more than two-third of cases. Electroencephalographic abnormality was noted in 21 patients with triphasic waves and periodic sharp waves seen in 7 and 6 patients respectively. Cerebrospinal fluid 14-3-3 assay was abnormal in 2 out of 4 patients. Atypical presentations were noted in the form of ataxic presentation, CBS like presentation and choreiform presentation. Conclusion: Myoclonus, ataxia and parkinsonism are the most frequent movement disorders phenomenology observed in patients with sCJD.

The epidemiological and clinical characteristics of patients with young-onset genetic Creutzfeldt-Jakob disease.

OBJECTIVES: The onset of Creutzfeldt-Jakob disease (CJD) is usually around the age of 60, but younger patients have been described as well. Our study characterizes the demographic and clinical features of young-onset CJD patients. METHODS: The CJD Israeli National Database was reviewed, and the patients were divided into groups of young (<40-year-old) (Y|) and older disease onset (>40-year-old) (O). Each group was further divided into sporadic (sCJD) and genetic (gCJD) patients. Clinical and demographic parameters were compared between the groups. RESULTS: The study included 731 patients (Y- 18 patients, O- 713 patients). MRI showed classical features more often in the older population (O-76.9%, Y-36%, p = 0.006). Rapidly progressive dementia as a presenting feature was more common in the older group (O = 58%, Y = 27.7%, p = 0.019) whereas cerebellar onset (gait instability, dysarthria) was more common in the younger group (O = 6.7%, Y = 27.7%, p = 0.036)). Among gCJD patients, rapidly progressive dementia was commonly seen in older patients (O = 54%, Y = 21% p = 0.008) whereas cerebellar symptoms were seen in young patients (O = 7%, Y = 30% p = 0.01) Typical MRI findings were seen in 37% of young people compared to 87% of older patients (p = 0.002). No significant differences were between young and older patients in the sCJD group. CONCLUSION: Young-onset gCJD patients have unique disease features including less typical brain MRI changes, a lower prevalence of dementia, and a higher prevalence of cerebellar signs at disease onset.

Cerebral cortex swelling in V180I genetic Creutzfeldt-Jakob disease: comparative imaging study between sporadic and V180I genetic Creutzfeldt-Jakob disease in the early stage.

The most common genetic Creutzfeldt-Jakob disease (gCJD) in Japan is caused by a point mutation in which isoleucine replaces valine at codon 180 of the prion protein (PrP) gene (V180I gCJD). Evidence suggests that cerebral cortex swelling, which appears as abnormal hyperintensities on diffusion-weighted imaging (DWI), is a characteristic magnetic resonance imaging (MRI) finding of V180I gCJD. However, no study has directly compared the MRI findings between V180I gCJD and sporadic CJD (sCJD). The current study, therefore, aims to clarify the imaging features of V180I gCJD, which would lead to prompt genetic counselling and analysis of the PrP gene, particularly focusing on cerebral cortex swelling. We included 35 patients with sCJD (n = 23) or V180I gCJD (n = 12). Cerebral cortex swelling on T2-weighted imaging (T2WI) or fluid-attenuated inversion recovery (FLAIR) wherein abnormal cortical hyperintensities were observed on DWI, and the distribution of grey matter hyperintensities on DWI were visually evaluated. V180I gCJD patients had significantly more cerebral cortex swelling (100% vs. 13.0%, p < 0.001), an overall correct classification of 91.4%, and parahippocampal gyrus hyperintensities on DWI (100% vs. 39.1%, q = 0.019) than sCJD patients. Cerebral cortical hyperintensities on DWI with swelling on T2WI or FLAIR are characteristic imaging findings of V180I gCJD and are useful for differentiating it from sCJD.

Bilateral tonic-clonic seizure and focal cortical hyperexcitability in familial Creutzfeldt-Jakob disease with E200K mutation of the prion protein.

Convulsive epileptic seizures are rare in Creutzfeldt-Jakob disease (CJD), and their clinical and EEG features have not been reported in detail. We describe a case of familial CJD with an E200K mutation of the prion protein who presented with bilateral tonic-clonic seizures (BTCS) during long-term video-EEG monitoring. Semiologically, BTCS showed focal clinical signs such as head turning and eye deviation to the left. The ictal EEG started with generalized polyspikes. Interictal EEG showed generalized periodic discharges with right fronto-temporal predominance (larger amplitude and earlier onset compared with other regions). MRI showed high-intensity signals persistently in the right temporo-parietal region on diffusion-weighted images (DWI). Interictal single-photon emission computed tomography (SPECT) showed hyperperfusion in the same region. Brain pathology revealed typical spongiform changes in CJD without other pathological findings of rapidly progressive dementia. Our case demonstrates that CJD can cause BTCS with generalized EEG changes and focal semiological/imaging abnormalities, suggesting that diffuse and inhomogeneous cortical and subcortical epileptic networks may develop in familial CJD.

Defining the phenotypic spectrum of sporadic Creutzfeldt-Jakob disease MV2K: the kuru plaque type.

The current classification of sporadic Creutzfeldt-Jakob disease identifies six major subtypes mainly defined by the combination of the genotype at polymorphic codon 129 (methionine/M or valine/V) of the prion protein gene and the type (1 or 2) of misfolded prion protein accumulating in the brain (e.g. MM1, MM2, MV1, MV2, etc.). Here, we systematically characterized the clinical and histo-molecular features associated with the third prevalent subtype, the MV2 subtype with kuru plaques (MV2K), in the most extensive series collected to date. We evaluated neurological histories, cerebrospinal biomarkers, brain MRI and EEG results in 126 patients. The histo-molecular assessment included misfolded prion protein typing, standard histologic staining and immunohistochemistry for prion protein in several brain areas. We also investigated the prevalence and topographic extent of coexisting MV2-cortical features, the number of cerebellar kuru plaques and their effect on clinical phenotype. Systematic regional typing revealed a western blot profile of misfolded prion protein comprising a doublet of 19 and 20 kDa unglycosylated fragments, with the former more prominent in neocortices and the latter in the deep grey nuclei. The 20/19 kDa fragment ratio positively correlated with the number of cerebellar kuru plaques. The mean disease duration was exceedingly longer than in the typical MM1 subtype (18.0 versus 3.4 months). Disease duration correlated positively with the severity of pathologic change and the number of cerebellar kuru plaques. At the onset and early stages, patients manifested prominent, often mixed, cerebellar symptoms and memory loss, variably associated with behavioural/psychiatric and sleep disturbances. The cerebrospinal fluid prion real-time quaking-induced conversion assay was positive in 97.3% of cases, while 14-3-3 protein and total-tau positive tests were 52.6 and 75.9%. Brain diffusion-weighted MRI showed hyperintensity of the striatum, cerebral cortex and thalamus in 81.4, 49.3 and 33.8% of cases, and a typical profile in 92.2%. Mixed histotypes (MV2K + MV2-cortical) showed an abnormal cortical signal more frequently than the pure MV2K (64.7 versus 16.7%, P = 0.007). EEG revealed periodic sharp-wave complexes in only 8.7% of participants. These results further establish MV2K as the most common 'atypical' subtype of sporadic Creutzfeldt-Jakob disease, showing a clinical course that often challenges the early diagnosis. The plaque-type aggregation of the misfolded prion protein accounts for most of the atypical clinical features. Nonetheless, our data strongly suggest that the consistent use of the real-time quaking-induced conversion assay and brain diffusion-weighted MRI allows an accurate early clinical diagnosis in most patients.

Repeated falls as onset of Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease is the most common prion disease in humans. Neuropsychiatric symptoms are common, and objective findings are myoclonus, pyramidal and extrapyramidal including cerebellar dysfunction. This is a case report of a 77-year-old woman with gradual onset of repeated falls due to cerebellar dysfunction. She had severe visuospatial difficulties, and she was unaware of her problems. Her MRI showed increased diffusion restriction in the caudate and lentiform nuclei. Her cerebrospinal fluid real-time quaking-induced conversion test was positive, fulfilling criteria for probable sporadic Creutzfeldt-Jakob disease.