Radoslav Matěj

Genetic Creutzfeldt–Jakob disease with R208H mutation presenting as progressive supranuclear palsy†‡§

Department of Pathology and Molecular Medicine, Thomayer Teaching Hospital, Prague, Czech Republic Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic Institute of Neurology, Medical University of Vienna, Vienna, Austria Department of Neurology, Thomayer Teaching Hospital and Institute for Postgraduate Education in Medicine, Prague, Czech Republic Department of Radiology, Na Homolce Hospital, Prague, Czech Republic Department of Neurology, District Hospital, Krnov, Czech Republic

Unusual association of seronegative, nonparaneoplastic limbic encephalitis and relapsing polychondritis in a patient with history of thymectomy for myasthenia: a case study

Limbic encephalitis (LE) associated with other autoimmune disorders is relatively rare. There is an evidence of LE with relapsing polychondritis [1, 2] or Sjogren’s syndrome [3], and also with myasthenia gravis [6]. We present a case of LE with an unusual association of different autoimmune conditions. A 73-year-old man developed headache and fever over 2 weeks and a transitory loss of consciousness. His wife reported episodes of confusion over the previous 2 months. He had a medical history of seropositive myasthenia gravis in 1996 requiring artificial ventilation, plasmapheresis, immunotherapy and thymectomy. Removed thymus showed atrophy without histopathological finding of thymoma or thymic hyperplasia. After 2 years, the patient was asymptomatic and decided to stop all treatment and follow up. His medical history also included acute myocarditis in 1972, asthma, gastric ulcer. He was followed up for bladder carcinoma without signs of activity since the operation in 1994 and recent biopsy revealed prostatic microcarcinoma. On admission, he was disoriented in place and person and was confabulating. He had painful erythema of his right auricle, which he had experienced in the past. Neurological examination was unremarkable except for slight gait instability. Laboratory results showed mild inflammatory changes (hyperleucocytosis, higher erythrocyte sedimentation rate 20 mm/h, and raised C reactive protein 20.3 mg/l). Thyroid function was normal. Serum auto-antibodies ANA, ANCA, GBMi and dsDNA were negative; only anti-striatal muscle antibodies were slightly positive. Cerebrospinal fluid analysis showed mild protein-cytological association (hyperproteinorachia 0.657 g/l and 89 mononuclear cells). Serology for HIV, Borrelia, HSV1,2, CMV, EBV, VZV and neurosyphilis was negative. Onconeural antibodies anti-Yo, Hu, Ri, anti-VGKC antibodies, anti-GAD, antiamphiphysin and anti-NMDA receptor antibodies were negative in serum and cerebrospinal fluid. MRI showed FLAIR and T2 hippocampal temporal hyperintensities, vascular white matter lesions and moderate atrophy (Fig. 1). EEG repeatedly showed slow waves in the temporal regions. Whole body PET scan was negative. Progressively, myoclonic jerks, cerebellar signs, aphasia and hallucinations appeared with worsening of cognitive impairment. Bilateral auricle swelling occurred with softening and loss of cartilage contour. Biopsy revealed nonspecific cartilage inflammation without signs of an acute vasculitis (Fig. 2b), compatible with criteria for relapsing chondritis. Parenteral bolus of methylprednisolone 1,500 mg over 3 days led to partial and transitory improvement, therefore a month later bolus of 3,500 mg was repeated followed by permanent treatment with oral methylprednisolone 24 mg daily. Painful swelling extended to elbows and knees, and partial complex seizures with orofacial automatisms developed. A third bolus of 1,500 mg methylprednisolone was administered and four cycles of plasmapheresis were performed with only limited effect, moreover, massive eruptions of herpes labialis required intravenous acyclovir. Finally, IVIG was added. The patient’s condition worsened K. Storey (&) R. Rusina Department of Neurology, Thomayer Teaching Hospital and Institute for Postgraduate Education in Medicine, Videňska 800, 14059 Prague 4, Czech Republic e-mail: katerina.storey@gmail.com

PAR-2, IL-4R, TGF-β and TNF-α in bronchoalveolar lavage distinguishes extrinsic allergic alveolitis from sarcoidosis.

Sarcoidosis (SARC) and extrinsic allergic alveolitis (EAA) share certain markers, making a differential diagnosis difficult even with histopathological investigation. In lung tissue, proteinase-activated receptor-2 (PAR-2) is primarily investigated with regard to epithelial and inflammatory perspectives. Varying levels of certain chemokines can be a useful tool for distinguishing EAA and SARC. Thus, in the present study, differences in the levels of transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin-4 receptor (IL-4R) and PAR-2 in bronchoalveolar lavage fluid (BALF) were compared, using an ELISA method, between 14 patients with EAA and six patients with SARC. Statistically significant higher levels of IL-4R, PAR-2 and the PAR-2/TGF-β1 and PAR-2/TNF-α ratios were observed in EAA patients as compared with SARC patients. Furthermore, the ratios of TNF-α/total protein, TGF-β1/PAR-2 and TNF-α/PAR-2 were significantly lower in EAA patients than in SARC patients. The results indicated a higher detection of PAR-2 in EAA samples in association with TNF-α and TGF-β levels. As EAA and PAR-2 in parallel belong to the Th2-mediated pathway, the results significantly indicated an association between this receptor and etiology. In addition, the results indicated that SARC is predominantly a granulomatous inflammatory disease, thus, higher levels of TNF-α are observed. Therefore, the detection of PAR-2 and investigated chemokines in BALF may serve as a useful tool in the differential diagnosis between EAA and SARC.

Higher TGF-β with lower CD124 and TSLP, but no difference in PAR-2 expression in bronchial biopsy of bronchial asthma patients in comparison with COPD patients.

Chronic obstructive pulmonary disease (COPD) and bronchial asthma (BA) are 2 severe respiratory disorders with different predominated immunopathologies. There are several “novel molecules” from different families that are proposed as part of the etiopathogenesis of COPD and BA. Proteinase-activated receptor 2 (PAR-2), thymic stromal lymphoprotein (TSLP), interleukin-4 and its receptor (CD124), Yin-Yang 1 (YY1), and transforming growth factor beta (TGF-&bgr;) have been previously shown to be involved in the pathophysiology of both these diseases. We investigated PAR-2, TSLP, CD124 (interleukin-4R), TGF-&bgr;, and YY1 immunohistochemical expression in endobronchial and transbronchial biopsies from 22 BA patients and 20 COPD patients. Immunostaining for the above-mentioned antigens was quantified using a modified semiquantitative scoring system and statistically evaluated. The values of TGF-&bgr; in the epithelial cells (P=0.0007) and TGF-&bgr; in the submucosa (P=0.0075) were higher in the BA samples, whereas values of CD124 (P=0.0015) and TSLP (P=0.0106) were higher in the COPD samples. No statistically significant differences between the groups were recorded for PAR-2 and YY1. Airway inflammatory reaction diversity in BA and COPD seems to be disease specific; however, there are also shared mechanisms involved in the pathophysiology of both diseases.

Pick and Alzheimer diseases: a rare comorbidity presenting as corticobasal syndrome.

We describe a patient with corticobasal syndrome in whom neuropathological examination on autopsy revealed Pick and Alzheimer diseases in comorbidity. Corticobasal degeneration is a tauopathy usually associated with asymmetric parkinsonism, parietal lobe involvement, and cognitive impairment. Corticobasal syndrome is the clinical presentation of corticobasal degeneration without neuropathological confirmation. A 66-year-old right-handed man slowly developed speech difficulties, right-hand clumsiness, and forgetfulness. His speech apraxia progressed to mutism with preserved comprehension, and his clumsiness progressed to severe apraxia involving both hands. He developed behavioral changes and severe amnesia. All of these features were consistent with corticobasal syndrome. His loss of episodic, verbal, and visuospatial memory suggested Alzheimer disease; however, beyond his frontotemporal neuropsychological profile, he had few symptoms characteristic of frontal lobe dementia. Magnetic resonance imaging scans showed worsening temporal, frontal, and parietal atrophy, predominant in the left hemisphere. Neuropathological examination at autopsy revealed abundant neuritic plaques and neurofibrillary tangles consistent with fully developed Alzheimer disease, as well as numerous intraneuronal Pick bodies in the frontotemporal lobes. Our findings confirm the importance of clinical and neuropathological correlations in patients with atypical neurodegenerative dementias.

Use of fuzzy edge single-photon emission computed tomography analysis in definite Alzheimer's disease - a retrospective study

BackgroundDefinite Alzheimers disease (AD) requires neuropathological confirmation. Single-photon emission computed tomography (SPECT) may enhance diagnostic accuracy, but due to restricted sensitivity and specificity, the role of SPECT is largely limited with regard to this purpose.MethodsWe propose a new method of SPECT data analysis. The method is based on a combination of parietal lobe selection (as regions-of-interest (ROI)), 3D fuzzy edge detection, and 3D watershed transformation. We applied the algorithm to three-dimensional SPECT images of human brains and compared the number of watershed regions inside the ROI between AD patients and controls. The Students two-sample t-test was used for testing domain number equity in both groups.ResultsAD patients had a significantly reduced number of watershed regions compared to controls (p < 0.01). A sensitivity of 94.1% and specificity of 80% was obtained with a threshold value of 57.11 for the watershed domain number. The narrowing of the SPECT analysis to parietal regions leads to a substantial increase in both sensitivity and specificity.ConclusionsOur non-invasive, relatively low-cost, and easy method can contribute to a more precise diagnosis of AD.

Gerstmann–Sträussler–Scheinker syndrome with the P102L pathogenic mutation presenting as familial Creutzfeldt–Jakob disease: a case report and review of the literature

Gerstmann–Sträussler–Scheinker syndrome is a rare autosomal dominant disease caused by a mutation in the prion gene, usually manifesting as progressive ataxia with late cognitive decline. A 44-year-old woman with a positive family history developed early personality and behavior changes, followed by paresthesias and ataxia, later associated with memory problems, pyramidal signs, anosognosia and very late myoclonus, spasticity, and severe dysexecutive impairment. Magnetic resonance showed caudate, mesio-frontal, and insular hyper-intensities, electroencephalography revealed generalized triphasic periodic complexes. A pathogenic P102L mutation in the prion gene was detected. Our case differed from classical Gerstmann–Sträussler–Scheinker syndrome by rapid progression, severe dementia, abnormal electroencephalography and magnetic resonance findings, which were highly suggestive of familial Creutzfeldt–Jakob disease.

Progressive supranuclear palsy phenotype mimicking synucleinopathies

BACKGROUND Atypical parkinsonian syndromes are currently divided into two groups based on their pathological appearance: synucleinopathies and tauopathies. Based on recent clinico-pathological studies it is increasingly clear, that some pathological characteristics are shared by both groups. STUDY OBJECTIVE To describe two pathologically proven cases of tauopathy manifesting in vivo in two typical synucleinopathy phenotypes: multiple system atrophy and dementia with Lewy bodies. PATIENTS AND METHODS There were 67-year-old woman with a phenotype of multiple system atrophy and a 70-year-old man with a phenotype of dementia with Lewy bodies. The clinical diagnosis was based on the commonly used clinical diagnostic criteria. A detailed neuropathological examination of the brain was conducted post-mortem in both cases. RESULTS The overall pathological picture corresponded with a rare combination of two neurodegenerative entities: 4R tauopathy (meeting the diagnostic criteria for typical progressive supranuclear palsy) and neocortical stage of Alzheimers disease. CONCLUSION The interesting feature in both our cases was the presence of dual pathology: diffuse tauopathy and Alzheimers pathology. We believe, that our two unique cases should serve as an evidence that tauopathies such as CBS and PSP might mimic practically anything from the family of atypical parkinsonian syndromes, particularly when another concomitant neurodegenerative disease is present.

Evaluation of Inflammatory Cells (Tumor Infiltrating Lymphocytes) in Solid Tumors

BACKGROUND The tumor microenvironment plays an important role in tumorigenesis and the tumor-host relationship. An important part of the tumor microenvironment is inflammatory infiltration. Its evaluation in solid tumors has prognostic meaning and appears also to be predictive of outcome, which is particularly important for predicting responses to immune checkpoint inhibitors. However, the methodology used to assess inflammatory infiltration is problematic, because it has been standardized only for certain types of tumors. OBJECTIVE The present study provides an overview of current issues related to the evaluation of inflammatory cells (tumor infiltrating lymphocytes) in solid tumors, specifically in tumors of the breast, lung, head and neck, gastrointestinal tract, female genital tract, urogenital tract, brain, malignant mesothelioma, and malignant melanoma. Various methodologies for evaluation are mentioned, including the efforts that are being made to standardize these methodologies and the importance of immunophenotyping inflammatory infiltrates. With regard to clinical meaning, prognostic and predictive significance are also discussed. CONCLUSION The evaluation of TILs in solid tumors often has predictive value; however, the results have been equivocal. There is also ambiguity about the predictive use of this marker. Despite all the methodological developments, which have resulted in the implementation of complicated technologies (image analysis, multiplex fluorescence immunohistochemistry, and mass spectrometry) for the evaluation of the various aspects of inflammatory infiltrates present in tumors, including their functional characteristics, there is still a need for standardization and development of inexpensive and universally available methodologies to enable the wide use of TIL evaluations in clinical settings. The recently proposed unified methodology may be used in all solid tumors and could help resolve one of the main limitations of the routine use of TIL, i.e., the inconsistent approach to assessment.Key words: solid tumors - tumor-infiltratig lymphocytes - inflammatory cells This work was supported by program of the Czech Ministry of Health No. RVO-VFN 64165 and AZV project No. 16-30954A, Charles University and OPPK (CZ.2.16/3.1.00/24509). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 24. 9. 2017Accepted: 3. 10. 2017.

Genetic Alzheimer Disease and Sporadic Dementia With Lewy Bodies: A Comorbidity Presenting as Primary Progressive Aphasia

We report a 44-year-old woman, with a family history of early-onset dementia, presenting with primary progressive aphasia. This clinically variable syndrome has multiple underlying pathologies, and correlations between clinical manifestations and postmortem neuropathologic findings are controversial. Our patient suffered worsening language impairment with major word-finding difficulties but preserved comprehension. She also developed episodic memory impairment. Her condition progressed to dementia with behavioral changes. Magnetic resonance imaging showed early left perisylvian and bitemporal atrophy. The patient died shortly afterward from colon cancer. Neuropathologic examination revealed advanced early-onset Alzheimer and Lewy body disease, plus a clinically nonrelevant metastasis of her colon cancer in her left parietal lobe. Genetic examination revealed a p.Glu184Asp mutation in the presenilin1 gene. Our findings confirm the importance of a thorough appreciation for the clinical and neuropathologic correlations in patients with atypical neurodegenerative dementias.