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.

Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration?

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 (COVID-19). Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient's prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.

Rare histotype of sporadic Creutzfeldt-Jakob disease, clinically suspected as corticobasal degeneration.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disease that can mimic other neurological disorders. We present a case of sCJD in a 64-year-old man that presented with corticobasal syndrome and survived for 3 years. He presented initially with dementia, hemiparkinsonism and alien limb phenomenon and was diagnosed with corticobasal degeneration, ultimately progressing to immobility and akinetic mutism. With a normal MRI 1 year before onset, his neuroimaging 1 year later revealed abnormal DaTscan, cortical and hippocampal atrophy with ventricular dilatation on MRI, and diffusion-weighted cortical ribboning and thalamic hyperintensity. Postmortem, the patient's brain was collected by the Parkinson's UK Tissue Bank. Prion protein immunohistochemistry revealed widespread diffuse microvacuolar staining without kuru-type plaques. Hyperphosphorylated tau was only found in the entorhinal cortex and hippocampus. This case highlights the clinical heterogeneity of sCJD presentation and the important inclusion of CJD in the differential diagnosis of atypical presentations of neurodegenerative disease.

A patient with a 'typical presentation' of Wernicke encephalopathy was found to have sporadic Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) has a significant degree of clinical heterogeneity that is especially found in the features at onset. Here we present a patient with the sporadic form of CJD mimicking Wernicke encephalopathy. We first treated him with a high dose of thiamine; however, the vitamin B1 levels proved to be normal, which ruled out Wernicke encephalopathy. Meanwhile, his clinical condition progressively worsened and he developed a rapidly progressive cognitive disorder, mutism and myoclonus of the muscles. At this point, the diagnosis of CJD was most likely. The patient died two months after the first symptoms. Autopsy showed prion-protein depositions in several regions. Genetic analysis was negative for familial CJD. Those findings confirmed the diagnosis of 'sporadic Creutzfeldt-Jakob disease'. CJD presents in a wide range of sequences and clinical symptoms. Therefore, recognition in the early stage can be difficult.

Insights from Therapeutic Studies for PrP Prion Disease.

Although an effective therapy for prion disease has not yet been established, many advances have been made toward understanding its pathogenesis, which has facilitated research into therapeutics for the disease. Several compounds, including flupirtine, quinacrine, pentosan polysulfate, and doxycycline, have recently been used on a trial basis for patients with prion disease. Concomitantly, several lead antiprion compounds, including compound B (compB), IND series, and anle138b, have been discovered. However, clinical trials are still far from yielding significantly beneficial results, and the findings of lead compound studies in animals have highlighted new challenges. These efforts have highlighted areas that need improvement or further exploration to achieve more effective therapies. In this work, we review recent advances in prion-related therapeutic research and discuss basic scientific issues to be resolved for meaningful medical intervention of prion disease.

[Carboplatin plus irinotecan induced partial response in a patient with small cell carcinoma of the prostate; a case report].

An 80-year-old man with prostate cancer receiving hormone therapy presented with urinary retention. The computed tomographic scan showed metastases to the lung, liver, and lymph nodes, as well as increased prostate volume. Transurethral resection of the prostate (TURP) was performed, and the resected specimen was pathologically found to be a small cell carcinoma of the prostate. The patient was treated with a combination of carboplatin and irinotecan, and achieved a partial response : size reduction of the prostate and the metastatic lesions, and decreased neuron specific enolase (NSE) level. The chemotherapy with carboplatin and irinotecan is reported to have fewer serious adverse effects, and equivalent efficacy to the cisplatin/etoposide chemotherapy. Therefore, this regimen could also be a treatment option for the patients with small cell carcinoma of the prostate.

Veterans health administration information systems as a resource for rare disorders research: Creutzfeldt-Jakob disease as a paradigm.

OBJECTIVE: To illustrate the application of Veterans Health Administration (VHA) information systems in both clinical and epidemiologic investigations of a rare disease, our specific aims were: (1) to determine the number and incidence of Creutzfeldt-Jakob disease (CJD) diagnoses in the VHA from fiscal year (FY) 1997 through FY 2010 and (2) to describe the relevant clinical features associated with those diagnoses. METHODS: The VHA Medical SAS Datasets were queried for all unique, incident CJD diagnoses between FY 1997 and 2010. Electronic health records were then reviewed to validate diagnoses using modified criteria. RESULTS: During the study period, 115 CJD diagnoses (43 definite, 27 probable, 19 possible, and 26 suspected) were identified. Annual incidence ranged between 0.8 per million (95% CI, 0.3-1.7) in FY 2009 and 3.7 per million (95% CI, 2.1-6.4) in FY 1997. Dementia was documented in 111 cases (96.5%) and myoclonus in 73 (63.5%). Discharges consistent with CJD were noted in 31 of 78 patients (39.7%) with documented electroencephalography. CONCLUSIONS: For certain rare diseases, VHA information systems can be used to assemble a substantive case series for clinical study. However, the VHA's distinctive demographic characteristics and population dynamics may limit the external validity of epidemiologic investigations.

Once upon a cataract surgeon.

A 60-year-old man presented with diplopia and neurocognitive deficits, which progressed rapidly over several months. Magnetic resonance imaging of the head revealed bilateral signal abnormalities and diffusion-weighted imaging restriction in bilateral basal ganglia, thalami, mesial temporal regions, and periaqueductal gray matter. Cerebrospinal fluid analysis was positive for 14-3-3 and tau proteins. The patient developed progressive neurocognitive decline followed by sleep disturbance and myoclonic jerking consistent with probable Creutzfeldt-Jakob disease.

Regulating factors of PrP glycosylation in Creutzfeldt-Jakob disease--implications for the dissemination and the diagnosis of human prion strains.

OBJECTIVE: The glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease. METHODS: PrP(res) glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrP(res). RESULTS: The regional distribution of PrP(res) glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrP(res) glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrP(res) in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrP(res) was undistinguishable from that observed in variant CJD. INTERPRETATION: Regulations leading to variations of PrP(res) pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrP(res) may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD.

Patología del sueño en las enfermedades priónicas / Sleep disorders in prion diseases

Las enfermedades priónicas son un grupo de encefalopatías con cambios neurodegenerativos causados por una proteína alterada denominada prión cuyo dato característico es la transmisibilidad. Ocurren la mayoría de las veces de forma esporádica aunque un grupo de ellas son familiares asociadas a mutaciones en el gen de la proteína priónica. El polimorfismo genético parece determinar las diferentes variantes familiares. Una de las más enigmáticas e inhabituales es el Insomnio Letal Familiar (ILF), trastorno hereditario caracterizado por pérdida del sueño fisiológico con estupor onírico, hiperactividad autonómica y motora, y anomalías motoras. La polisomnografía de esta entidad refleja la incapacidad para producir un patrón fisiológico del sueño NREM y REM, así como de las fluctuaciones circadianas hormonales y vegetativas; la transición de vigilia a sueño está marcadamente alterada con desaparición precoz de los husos de sueño. La hipótesis del origen de estos trastornos es la pérdida neuronal talámica, especialmente en los núcleos anterior y dorsomedial, descrita en la neuropatología de estos pacientes; además la PET revela hipofunción de núcleos talámicos, centros responsables del control vigilia-sueño. En la enfermedad de Creutzfeldt-Jakob las alteraciones de sueño-vigilia no se han considerado características, no obstante, se han encontrado frecuentes alteraciones en los registros electroencefalográficos de sueño. Además de la neurodegeneración talámica puede haber mecanismos etiopatogénicos comunes en las enfermedades priónicas en relación con la función biológica de la proteína priónica

Prion diseases are a group of encephalopathies with neurodegenerative changes caused by an altered protein named prion whose characteristic datum is transmissibility. In most cases they occur in a sporadic form although a group of them are familial associated with mutations in the gene of the prion protein. Genetic polymorphism seems to determine the different family variants. One of the most enigmatic and unusual is Fatal Familial Insomnia (FFI), a hereditary disorder characterised by loss of physiological sleep with oneiric stupor, autonomic and motor hyperactivity, and motor anomalies. The polysomnography of this entity reflects an inability to produce the physiological pattern of NREM and REM sleep, as well as hormonal and vegetative circadian fluctuations; the transition from wakefulness to sleep is markedly altered with the early disappearance sleep spindles. The hypothesis of the origin of these disorders is thalamic neuronal loss, especially in the anterior and dorsomedial nuclei, described in the neuropathology of these patients; besides PET reveals hypofunction of thalamic nuclei, centres responsible for controlling wakefulness-sleep. In Creutzfeldt-Jakob disease the wake-sleep disorders are not considered characteristic; nonetheless, frequent alterations have been found in the electroencephalographic registers of sleep. Besides thalamic neurodegeneration, there could be common etiopathogenic mechanisms in prion diseases in relation to the biological function of the prion protein

Creutzfeldt-Jakob disease: comparative analysis of MR imaging sequences.

BACKGROUND AND PURPOSE: MR imaging has played an increasingly important role in the diagnosis of Creutzfeldt-Jakob disease (CJD) since basal ganglia abnormalities on T2-weighted images have been described; thus, the aim of our study was to compare the value of different MR images in the diagnosis of CJD. METHODS: One hundred fifty-seven patients with CJD underwent MR imaging examinations. Ninety-two patients were neuropathologically confirmed, and 65 were clinically classified as having CJD through the CJD Surveillance Unit (probability of 95%). There was no standardized MR imaging protocol; thus, the examinations included 143 T2-weighted, 43 proton attenuation (PD)-weighted, 84 fluid-attenuated inversion recovery (FLAIR), and 44 diffusion-weighted images (DWI). The MR images were reviewed for pathologic changes of the basal ganglia, thalamus, and cerebral cortex. RESULTS: Cortical abnormalities were present in 70 patients (45%) and were visible in 80% (35/44) of all available DWI examinations. The basal ganglia were affected in 94 patients (60%), in particular in the caudate nucleus; the most sensitive sequences were DWI (64%) and PD-weighted (63%). A thalamic involvement was more frequently diagnosed on PD-weighted images (19%) and DWI (14%) than on FLAIR or T2-weighted images. CONCLUSION: PD-weighted images and DWI showed better results in the diagnosis of signal intensity changes in the basal ganglia compared with T2-weighted or FLAIR images; however, in the diagnosis of cortical changes, DWI was clearly superior. Our data suggest that DWI is the most sensitive MR imaging technique in the diagnosis of CJD.

The "pulvinar sign" in a case of paraneoplastic limbic encephalitis associated with non-Hodgkin's lymphoma.

This paper reports a 59 year old woman with paraneoplastic limbic encephalitis associated with diffuse large B cell lymphoma. Her brain magnetic resonance imaging scan showed bilateral posterior thalamic hyperintensities, similar to the "pulvinar sign". Her symptoms included progressive psychiatric disturbance and resembled the initial symptoms of variant Creutzfeldt-Jakob disease (vCJD). Clinicians should consider this treatable disorder in the differential diagnosis of vCJD.

Cerebroventricular infusion of pentosan polysulphate in human variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy believed to be caused by the bovine spongiform encephalopathy agent, an abnormal isoform of the prion protein (PrP(sc)). At present there is no specific or effective treatment available for any form of CJD. Pentosan polysulphate (PPS), a large polyglycoside molecule with weak heparin-like activity, has been shown to prolong the incubation period of the intracerebral infection when administered to the cerebral ventricles in a rodent scrapie model. PPS also prevents the production of further PrP(sc) in cell culture models. These properties of PPS prompted its cerebroventricular administration in a young man with vCJD. Long-term continuous infusion of PPS at a dose of 11 microg/kg/day for 18 months did not cause drug-related side effects. Follow-up CT scans demonstrated progressive brain atrophy during PPS administration. Further basic and clinical research is needed in order to address the issue of efficacy of PPS in vCJD and in other prion diseases.

Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease.

BACKGROUND: No method for the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) has been established except for pathologic examination. OBJECTIVE: To identify a reliable marker for the clinical diagnosis of MM2-type sCJD. METHODS: CSF, EEG, and neuroimaging studies were performed in eight patients with MM2-type sCJD confirmed by neuropathologic, genetic, and western blot analyses. RESULTS: The eight cases were pathologically classified into the cortical (n = 2), thalamic (n = 5), and combined (corticothalamic) (n = 1) forms. The cortical form was characterized by late-onset, slowly progressive dementia, cortical hyperintensity signals on diffusion-weighted imaging (DWI) of brain, and elevated levels of CSF 14-3-3 protein. The thalamic form showed various neurologic manifestations including dementia, ataxia, and pyramidal and extrapyramidal signs with onset at various ages and relatively long disease duration. Characteristic EEG and MRI abnormalities were almost absent. However, all four patients examined with cerebral blood flow (CBF) study using SPECT showed reduction of the CBF in the thalamus as well as the cerebral cortex. The combined form had features of both the cortical and the thalamic forms, showing cortical hyperintensity signals on DWI and hypometabolism of the thalamus on [18F]2-fluoro-2-deoxy-d-glucose PET. CONCLUSION: For the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, cortical hyperintensity signals on diffusion-weighted MRI are useful for the cortical form and thalamic hypoperfusion or hypometabolism on cerebral blood flow SPECT or [18F]2-fluoro-2-deoxy-d-glucose PET for the thalamic form.

Thalamic involvement in sporadic Creutzfeldt-Jakob disease: a diffusion-weighted MR imaging study.

BACKGROUND AND PURPOSE: Recent neuropathologic research suggests thalamic involvement in sporadic Creutzfeldt-Jakob disease (sCJD), which has been disregarded in imaging studies. Diffusion-weighted (DW) MR imaging has the highest sensitivity for the detection of signal intensity (SI) abnormalities in CJD. We hypothesized that pathologic changes in the thalamus in sCJD can be detected by using a subtle analysis of DW MR imaging. METHODS: Six sCJD patients and nine healthy controls were examined with a 1.5-T system by using DW single-shot spin-echo echo planar (b = 0, 1000 s/mm(2)), T2-weighted turbo spin-echo, and fluid-attenuated inversion recovery sequences. One patient was examined serially (3, 4, and 8 months after onset of symptoms). MR images were reviewed for SI changes in the striatum, hippocampus, mediodorsal thalamic nucleus (MD), and pulvinar thalami. Apparent diffusion coefficients (ADCs) were measured in these areas. RESULTS: All sCJD patients showed increased SI on DW images in the striatum bilaterally. ADCs in these areas were significantly reduced. Four of six sCJD patients showed increased SI on DW images in the pulvinar thalami, whereas ADCs were significantly reduced in all patients (mean ADC +/- SEM: in patients with SI changes, 701 +/- 38; in patients without SI changes, 684 +/- 37; in controls, 853 +/- 15 [P <.0001]). No patient showed SI changes in the MD on DW images, whereas ADCs were significantly reduced in all (664 +/- 28 as compared with 800 +/- 24 in controls [P =.0011]). Serial measurements in one sCJD patient showed ADC reduction in the pulvinar thalami preceding the SI changes on DW images. CONCLUSION: A quantitative analysis of DW images with ADC measurements shows slight MR imaging changes in the thalamus in sCJD when abnormal SI may not be present.

Magnetic resonance spectroscopic abnormalities in sporadic and variant Creutzfeldt-Jakob disease.

AIM: To study the proton MR spectroscopic findings in Creutzfeldt-Jakob disease (CJD) (sporadic and variant). MATERIALS AND METHODS: MR imaging and proton MR spectra were acquired in two patients with sporadic CJD (biopsy proven) and one patient with variant CJD. RESULTS: The two patients with sporadic CJD demonstrated MR signal change within the basal ganglia and thalami and reduced N-acetylaspartate (NAA):creatine ratios. The patient with variant CJD showed characteristic signal change within the pulvinar of the thalami and a markedly reduced N-acetylaspartate:creatine ratio. CONCLUSION: All three patients with CJD demonstrated evidence of reduced N-acetylaspartate: creatine ratios on MR spectroscopy. These changes imply that neuronal loss and/or dysfunction is a consistent finding in established CJD.

Enfermedad de Creutzfeldt-Jakob esporádica: a propósito de un caso

La enfermedad de Creutzfeldt-Jakob pertenece al grupo de las encefalopatías espongiformes de los seres humanos. Es una enfermedad rara con una incidencia de 1 a 2 casos por millón de habitantes y año. Aparece en la edad adulta. El cuadro clínico se caracteriza por demencia rápidamente progresiva, ataxia y mioclonías. No tiene tratamiento y la muerte se produce en la mayoría de los casos en menos de un año. Presentamos un caso de probable encefalopatía espongiforme (enfermedad de Creutzfeldt-Jakob esporádica) de inicio atípico con síntomas psiquiátricos (más característico de la nueva variante). En cualquier caso, no fue posible realizar la necropsia ante la negativa de la familia (AU)

Diffusion-weighted sequence on mri for the diagnosis of Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) is a progressive and fatal dementing illness caused by a virus like agent called prion. Currently, the definitive diagnosis can only be made through brain biopsy. Given its potential transmissibility, it is paramount to have noninvasive and reliable means to detect the disease. The present case reports on a 63 year-old man with biopsy proven CJD, and evaluates the dependability of diffusion-weighted MRI in this condition, stressing the importance of this particular sequence to its diagnosis