scholarly journals Current experimental disease-modifying therapeutics for multiple system atrophy

2021 ◽  
Author(s):  
Miguel Lemos ◽  
Gregor K. Wenning ◽  
Nadia Stefanova
Keyword(s):  
Multiple System Atrophy ◽  
Clinical Presentation ◽  
Clinical Course ◽  
Neurodegenerative Disorder ◽  
Rapid Progression ◽  
Cytoplasmic Inclusions ◽  
Disease Modifying ◽  
Aggressive Clinical Course ◽  
Preclinical And Clinical Studies ◽  
Variable Clinical Presentation

AbstractMultiple system atrophy (MSA) is a challenging neurodegenerative disorder with a difficult and often inaccurate early diagnosis, still lacking effective treatment. It is characterized by a highly variable clinical presentation with parkinsonism, cerebellar ataxia, autonomic dysfunction, and pyramidal signs, with a rapid progression and an aggressive clinical course. The definite MSA diagnosis is only possible post-mortem, when the presence of distinctive oligodendroglial cytoplasmic inclusions (GCIs), mainly composed of misfolded and aggregated α-Synuclein (α-Syn) is demonstrated. The process of α-Syn accumulation and aggregation within oligodendrocytes is accepted one of the main pathological events underlying MSA. However, MSA is considered a multifactorial disorder with multiple pathogenic events acting together including neuroinflammation, oxidative stress, and disrupted neurotrophic support, among others. The discussed here treatment approaches are based on our current understanding of the pathogenesis of MSA and the results of preclinical and clinical therapeutic studies conducted over the last 2 decades. We summarize leading disease-modifying approaches for MSA including targeting α-Syn pathology, modulation of neuroinflammation, and enhancement of neuroprotection. In conclusion, we outline some challenges related to the need to overcome the gap in translation between preclinical and clinical studies towards a successful disease modification in MSA.

scholarly journals Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy

2020 ◽  
Vol 21 (8) ◽  
pp. 2775 ◽  
Author(s):  
Lisa Mészáros ◽  
Alana Hoffmann ◽  
Jeanette Wihan ◽  
Jürgen Winkler
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Autonomic Failure ◽  
Neuronal Loss ◽  
Symptomatic Treatment ◽  
Alpha Synuclein ◽  
Rapid Progression ◽  
Cytoplasmic Inclusions ◽  
Atypical Parkinsonian Syndrome ◽  
Disease Modifying

Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy.

scholarly journals Spontaneous Remission in an Older Patient with RelapsedFLT3ITD Mutant AML

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Pankit Vachhani ◽  
Jason H. Mendler ◽  
Andrew Evans ◽  
George Deeb ◽  
Petr Starostik ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Clinical Course ◽  
Spontaneous Remission ◽  
Rapid Progression ◽  
Older Patient ◽  
Internal Tandem Duplication ◽  
First Case ◽  
Short Overall Survival ◽  
Aggressive Clinical Course

Spontaneous remission (SR) of acute myeloid leukemia (AML) is a very rare phenomenon. AML characterized byFLT3internal tandem duplication (FLT3ITD) is typically associated with an aggressive clinical course with rapid progression, relapse, and short overall survival in the absence of transplantation. We report here the first case of SR ofFLT3ITD mutant AML in the literature. Our patient was an elderly woman with relapsedNPM1andFLT3ITD mutant AML whose disease underwent SR for a brief duration without precipitating cause. We review the potential immune mechanisms underlying SR in AML and discuss the implications for novel immunotherapeutic approaches forFLT3mutant AML.

scholarly journals Metastatic plasma cell leukemia to the skin: a case report with review of the literature

2021 ◽  
Author(s):  
Elena Pezzolo ◽  
Deborah Saraggi ◽  
Luigi Naldi
Keyword(s):  
Plasma Cell ◽  
Plasma Cells ◽  
Clinical Presentation ◽  
Clinical Course ◽  
Skin Lesions ◽  
Plasma Cell Leukemia ◽  
Cell Leukemia ◽  
Leukemia Cutis ◽  
Aggressive Clinical Course ◽  
New Skin

Plasma cell leukemia (PCL) is a rare variant of leukemia with an aggressive clinical course and a poor prognosis. The cutaneous involvement in PCL is very rare either at clinical presentation of leukemia, namely “leukemia cutis”, or in the metastatic PCL to the skin. We present a case of eruptive multiple cutaneous nodules in a 56-year-old man with metastatic PCL. Histologically, a diffuse dermal and subcutaneous infiltration of ovoid cells with amphophilic cytoplasm and eccentrically located nucleus consistent with plasmacytoid morphology was observed. Neoplastic cells showed strong immunoexpression for CD138 and CD38 consistent with plasma cells phenotype, and loss of expression of CD56. Kappa light chain restriction similar to the phenotype of his PCL was demonstrated. We suggest that the evaluation of new skin lesions in leukemic patients should include a histopathologic examination to establish the diagnosis as soon as possible and a correct management of the disease.

PEDIATRIC INTRADURAL EXTRAMEDULLARY SYNOVIAL SARCOMA

Neurosurgery ◽  
2006 ◽  
Vol 59 (6) ◽  
pp. E1339-E1339 ◽  
Author(s):  
Stephanie Greene ◽  
Douglas S. Hawkins ◽  
Joe C. Rutledge ◽  
Karen D. Tsuchiya ◽  
James Douglas ◽  
...  
Keyword(s):  
Synovial Sarcoma ◽  
Clinical Presentation ◽  
Clinical Course ◽  
Leptomeningeal Metastasis ◽  
Magnetic Resonance Imaging Scan ◽  
Rapid Progression ◽  
Resonance Imaging ◽  
Intracranial Metastases ◽  
Intradural Extramedullary ◽  
Resonance Imaging Scan

Abstract OBJECTIVE The diagnosis of intradural synovial sarcoma has not been previously published. This report provides a summary of the literature on this tumor and on tumors arising in this location, as well as a description of this patient's clinical course. CLINICAL PRESENTATION An 11-year-old girl presented with back pain and radiculopathy. A magnetic resonance imaging scan of the spine revealed a spinal intradural, extramedullary mass at L2–L4 and four additional nodules of enhancement. INTERVENTION The mass was nearly totally resected. Radiation and chemotherapy were administered. Intracranial metastases became evident during treatment. The patient died of the disease 14 months after diagnosis. CONCLUSION The rapid progression of leptomeningeal metastasis despite maximal treatment demonstrates the aggressive nature of the tumor and the need for further study.

scholarly journals Rare giant dermatofibrosarcoma protuberans with uncommon fibrosarcomatous transformation - case report and review of literature

2021 ◽  
Vol 8 (10) ◽  
pp. 3171
Author(s):  
Manisha Aggarwal ◽  
Dinesh Manchikanti ◽  
Sunayana Misra ◽  
Shaji Thomas ◽  
Ashish Arsia ◽  
...  
Keyword(s):  
Clinical Course ◽  
Dermatofibrosarcoma Protuberans ◽  
Distant Metastases ◽  
Metastatic Potential ◽  
Recurrence Risk ◽  
Skin Tumor ◽  
Rapid Progression ◽  
Split Skin Grafting ◽  
Aggressive Clinical Course ◽  
Slow Growing

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma with aggressive local behavior but with a low metastatic potential. Although slow growing and indolent, they rarely reach huge sizes. Very uncommonly, these locally invasive tumors undergo fibrosarcomatous transformation with a more aggressive clinical course, with higher rate of recurrence risk and distant metastases. A 32-years-old lady, presented with a gradually progressive lump in the upper central back for the past 6 years, with rapid progression in size during the last 6 months. On examination, she had a single lump of size 18×18 cm in the midline of the upper back, with prominent veins over its surface. Magnetic resonance imaging (MRI) showed no connection with the spinal canal and appeared flush with the paraspinal muscles. Core needle biopsy showed DFSP. The patient underwent a wide local excision with split skin grafting. The histopathology now showed a fibrosarcomatous transformation of DFSP. The patient again underwent a wide re-excision with a 3 cm margin. Histology reported no evidence of tumor cells in the specimen. The patient’s postoperative period was uneventful and she was referred for adjuvant radiotherapy. DFSP is a rare, slow-growing malignant fibroblastic mesenchymal skin tumor with low metastatic potential. However, in any patient with long standing DFSP with a recent increase in size, this fibrosarcomatous transformation must be kept in mind as it represents an uncommon form of DFSP that tends to follow a more aggressive clinical course, with higher rate of recurrence risk and distant metastases.

scholarly journals A historical review of multiple system atrophy with a critical appraisal of cellular and animal models

2021 ◽  
Author(s):  
David J. Marmion ◽  
Wouter Peelaerts ◽  
Jeffrey H. Kordower
Keyword(s):  
Animal Models ◽  
Multiple System Atrophy ◽  
Neurodegenerative Disorder ◽  
Rem Sleep Behavior Disorder ◽  
Alpha Synuclein ◽  
Motor Symptom ◽  
Olivopontocerebellar Atrophy ◽  
Prodromal Phase ◽  
Sleep Behavior ◽  
Cytoplasmic Inclusions

AbstractMultiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.

Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy

2017 ◽  
Vol 89 (2) ◽  
pp. 175-184 ◽  
Author(s):  
Shunsuke Koga ◽  
Dennis W Dickson
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Neurodegenerative Disorder ◽  
Cytoplasmic Inclusion ◽  
Olivopontocerebellar Atrophy ◽  
Cytoplasmic Inclusions ◽  
Cellular Origin ◽  
Recent Advances ◽  
Neuronal Cytoplasmic Inclusions ◽  
Variable Combination

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterised by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal symptoms. The pathological hallmark is the oligodendrocytic glial cytoplasmic inclusion (GCI) consisting of α-synuclein; therefore, MSA is included in the category of α-synucleinopathies. MSA has been divided into two clinicopathological subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia, which generally correlate with striatonigral degeneration and olivopontocerebellar atrophy, respectively. It is increasingly recognised, however, that clinical and pathological features of MSA are broader than previously considered.In this review, we aim to describe recent advances in neuropathology of MSA from a review of the literature and from information derived from review of nearly 200 definite MSA cases in the Mayo Clinic Brain Bank. In light of these new neuropathological findings, GCIs and neuronal cytoplasmic inclusions play an important role in clinicopathological correlates of MSA. We also focus on clinical diagnostic accuracy and differential diagnosis of MSA as well as candidate biomarkers. We also review some controversial topics in MSA. Cognitive impairment, which has been a non-supporting feature of MSA, is considered from both clinical and pathological perspectives. The cellular origin of α-synuclein in GCI and a ‘prion hypothesis’ are discussed. Finally, completed and ongoing clinical trials targeting disease modification, including immunotherapy, are summarised.

scholarly journals Towards Neurotransplantation in Multiple System Atrophy: Clinical Rationale, Pathophysiological Basis, and Preliminary Experimental Evidence

2000 ◽  
Vol 9 (2) ◽  
pp. 279-288 ◽  
Author(s):  
Gregor Karl Wenning ◽  
Francois Tison ◽  
Christoph Scherfler ◽  
Zoe Puschban ◽  
Regina Waldner ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Neurodegenerative Disorder ◽  
Experimental Studies ◽  
Substantia Nigra Pars Compacta ◽  
Functional Improvement ◽  
Future Research ◽  
Primate Model ◽  
Cytoplasmic Inclusions ◽  
Striatal Grafts ◽  
P Rat

Multiple system atrophy (MSA) is a neurodegenerative disorder that occurs sporadically and causes parkinsonism, cerebellar, autonomic, urinary, and pyramidal dysfunction in many combinations. Progressive L-dopa-unresponsive parkinsonism due to underlying striatonigral degeneration dominates the clinical syndrome in the majority of cases (MSA-P subtype). MSA-P is characterized pathologically by degenerative changes in somatotopically related areas of the substantia nigra pars compacta and of the putamen. Furthermore, oligodendroglial cytoplasmic inclusions (GCIs) are observed throughout the cortico-striato-pallido-cortical loops and may contribute to the basal ganglia dysfunction. Neurotransplantation strategies are of potential interest in this disease, which causes marked and early disability and dramatically reduces life expectancy. A number of experimental MSA-P models have been employed to evaluate neurotransplantation approaches. Sequential nigral and striatal lesions using 6-hydroxydopamine and quinolinic acid (double toxin–double lesion approach) indicate that apomorphine-induced contralateral rotation is abolished by a secondary striatal lesion. Intrastriatal injection of mitochondrial respiratory chain toxins produces secondary excitotoxic striatal lesions combined with retrograde nigral degeneration and therefore provides an alternative single toxin–double lesion approach. Neurotransplantation in MSA-P animal models has been used to improve functional deficits by replacing lost nigral and/or striatal circuitry (neuroregenerative approach). The available data indicate that embryonic mesencephalic grafts alone or combined with striatal grafts partially reverse drug-induced rotation asymmetries without improving deficits of complex motor function. The potential neuroprotective efficacy of embryonic striatal grafts against striatal excitotoxicity is presently under investigation in the double toxin–double lesion MSA-P rat model. Anecdotal clinical evidence in one MSA-P patient misdiagnosed as Parkinson's disease indicates that embryonic mesencephalic grafts produce incomplete clinical benefit. Striatal co-grafts may increase functional improvement. Further experimental studies are required prior to the clinical application of embryonic neurotransplantation in MSA-P. Future research strategies should explore the effect of neurotransplantation in partial MSA-P rat models with less severe nigral and striatal degeneration, the feasibility of a primate model closely mimicking the human disease, and the replication of oligodendroglial dysfunction.

scholarly journals Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy

2021 ◽  
Author(s):  
Nicole Campese ◽  
Alessandra Fanciulli ◽  
Nadia Stefanova ◽  
Johannes Haybaeck ◽  
Stefan Kiechl ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Neurodegenerative Disorder ◽  
Substantial Contribution ◽  
Olivopontocerebellar Atrophy ◽  
Striatonigral Degeneration ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Neurodegenerative Process ◽  
Disease Modifying Therapy ◽  
Current State

AbstractMultiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are α-synuclein rich glial cytoplasmic inclusions (GCIs). Neuropathologically, various degrees of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) can be observed. Since the original descriptions of this multifaceted disorder, several steps forward have been made to clarify its neuropathological hallmarks and key pathophysiological mechanisms. The Austrian neuropathologist Kurt Jellinger substantially contributed to the understanding of the underlying neuropathology of this disease, to its standardized assessment and to a broad systematical clinic-pathological correlation. On the occasion of his 90th birthday, we reviewed the current state of the art in the field of MSA neuropathology, highlighting Prof. Jellinger’s substantial contribution.

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