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Ethanol consumption remains a major concern at a world scale in terms of transient or irreversible neurological consequences, with motor, cognitive, or social consequences. Cerebellum is particularly vulnerable to ethanol, both during development and at the adult stage. In adults, chronic alcoholism elicits, in particular, cerebellar vermis atrophy, the anterior lobe of the cerebellum being highly vulnerable. Alcohol-dependent patients develop gait ataxia and lower limb postural tremor. Prenatal exposure to ethanol causes fetal alcohol spectrum disorder (FASD), characterized by permanent congenital disabilities in both motor and cognitive domains, including deficits in general intelligence, attention, executive function, language, memory, visual perception, and communication/social skills. Children with FASD show volume deficits in the anterior lobules related to sensorimotor functions (Lobules I, II, IV, V, and VI), and lobules related to cognitive functions (Crus II and Lobule VIIB). Various mechanisms underlie ethanol-induced cell death, with oxidative stress and endoplasmic reticulum (ER) stress being the main pro-apoptotic mechanisms in alcohol abuse and FASD. Oxidative and ER stresses are induced by thiamine deficiency, especially in alcohol abuse, and are exacerbated by neuroinflammation, particularly in fetal ethanol exposure. Furthermore, exposure to ethanol during the prenatal period interferes with neurotransmission, neurotrophic factors and retinoic acid-mediated signaling, and reduces the number of microglia, which diminishes expected cerebellar development. We highlight the spectrum of cerebellar damage induced by ethanol, emphasizing physiological-based clinical profiles and biological mechanisms leading to cell death and disorganized development.
Hiroshi Mitoma; Mario Manto; Aasef G. Shaikh. Mechanisms of Ethanol-Induced Cerebellar Ataxia: Underpinnings of Neuronal Death in the Cerebellum. International Journal of Environmental Research and Public Health 2021, 18, 8678 .
AMA StyleHiroshi Mitoma, Mario Manto, Aasef G. Shaikh. Mechanisms of Ethanol-Induced Cerebellar Ataxia: Underpinnings of Neuronal Death in the Cerebellum. International Journal of Environmental Research and Public Health. 2021; 18 (16):8678.
Chicago/Turabian StyleHiroshi Mitoma; Mario Manto; Aasef G. Shaikh. 2021. "Mechanisms of Ethanol-Induced Cerebellar Ataxia: Underpinnings of Neuronal Death in the Cerebellum." International Journal of Environmental Research and Public Health 18, no. 16: 8678.
Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient’s functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs.
Jan Cendelin; Marija Cvetanovic; Mandi Gandelman; Hirokazu Hirai; Harry T. Orr; Stefan M. Pulst; Michael Strupp; Filip Tichanek; Jan Tuma; Mario Manto. Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications. The Cerebellum 2021, 1 -30.
AMA StyleJan Cendelin, Marija Cvetanovic, Mandi Gandelman, Hirokazu Hirai, Harry T. Orr, Stefan M. Pulst, Michael Strupp, Filip Tichanek, Jan Tuma, Mario Manto. Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications. The Cerebellum. 2021; ():1-30.
Chicago/Turabian StyleJan Cendelin; Marija Cvetanovic; Mandi Gandelman; Hirokazu Hirai; Harry T. Orr; Stefan M. Pulst; Michael Strupp; Filip Tichanek; Jan Tuma; Mario Manto. 2021. "Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications." The Cerebellum , no. : 1-30.
Differential ultracentrifugation and subcellular fractionation historically helped to study the components of the cell, to discover new cellular organelles, and to decipher their morphological and molecular properties. In neuroscience, the technique has yielded important results on neuron biochemistry and the mechanisms of synaptic transmission. This Cerebellar Classic is devoted to the pioneering work of Manuel del Cerro, Ray S. Snider, and Mary Lou Oster-Granite, who isolated purified fractions after successive centrifugations of the rat cerebellum from birth to adulthood and studied them under the electron microscope.
Lazaros C. Triarhou; Mario Manto. Exploring Subcellular Cerebellar Fractions with the Electron Microscope. The Cerebellum 2021, 1 -3.
AMA StyleLazaros C. Triarhou, Mario Manto. Exploring Subcellular Cerebellar Fractions with the Electron Microscope. The Cerebellum. 2021; ():1-3.
Chicago/Turabian StyleLazaros C. Triarhou; Mario Manto. 2021. "Exploring Subcellular Cerebellar Fractions with the Electron Microscope." The Cerebellum , no. : 1-3.
The cerebellum is endowed with the capacity for compensation and restoration after pathological injury, a property known as cerebellar reserve. Such capacity is attributed to two unique morphological and physiological features of the cerebellum. First, mossy fibers that convey peripheral and central information run mediolaterally over a wide area of the cerebellum, resulting in the innervation of multiple microzones, commonly known as cerebellar functional units. Thus, a single microzone receives redundant information that can be used in pathological conditions. Secondly, the circuitry is characterized by a co-operative interplay among various forms of synaptic plasticity. Recent progress in understanding the mechanisms of redundant information and synaptic plasticity has allowed outlining therapeutic strategies potentiating these neural substrates to enhance the cerebellar reserve, taking advantage of the unique physiological properties of the cerebellum which appears as a modular and potentially reconfiguring brain structure.
Hiroshi Mitoma; Shinji Kakei; Kazuhiko Yamaguchi; Mario Manto. Physiology of Cerebellar Reserve: Redundancy and Plasticity of a Modular Machine. International Journal of Molecular Sciences 2021, 22, 4777 .
AMA StyleHiroshi Mitoma, Shinji Kakei, Kazuhiko Yamaguchi, Mario Manto. Physiology of Cerebellar Reserve: Redundancy and Plasticity of a Modular Machine. International Journal of Molecular Sciences. 2021; 22 (9):4777.
Chicago/Turabian StyleHiroshi Mitoma; Shinji Kakei; Kazuhiko Yamaguchi; Mario Manto. 2021. "Physiology of Cerebellar Reserve: Redundancy and Plasticity of a Modular Machine." International Journal of Molecular Sciences 22, no. 9: 4777.
The cerebellum is particularly vulnerable to neurotoxic agents and poisoning. People of all ages can be affected by cerebellar damage due to neurotoxicity, ranging from fetuses to the elderly. Elderly patients are more vulnerable to injury, as well as patients with silent cerebellar lesions, such as preexisting structural lesions. Purkinje neurons are a main target of cerebellotoxic substances. The main causes of TOICS (toxic-induced cerebellar syndrome) are acute and chronic ethanol ingestion, drugs, and environmental exposure. Cerebellar structures are among the most sensitive targets of the central nervous system (CNS) to ethanol intake. In addition to ethanol, drugs such as phenytoin, antineoplastics, lithium salts, and heroin can cause an irreversible cerebellar syndrome. Environmental causes of TOICS include chronic exposure to metals, benzene derivatives, and hyperthermia. Recently, deposits of Gadolinium, a heavy metal of the lanthanide group, have been reported in the cerebellum (dentate nuclei) and globus pallidus following repeated administration of linear Gd-based contrast agents (GBCAs). Both the mechanism of these deposits and their fate are unknown. As a general rule, cerebellar syndromes associated with toxic insults should not be underestimated. In particular, since patients may develop life-threatening edema of the posterior fossa in several circumstances, urgent management may be required. Preventative measures should be considered. The clinical significance of deposits of Gadolinium in the cerebellum is currently undetermined.
Mario U. Manto. Cerebellotoxic Agents. Handbook of the Cerebellum and Cerebellar Disorders 2021, 1 -46.
AMA StyleMario U. Manto. Cerebellotoxic Agents. Handbook of the Cerebellum and Cerebellar Disorders. 2021; ():1-46.
Chicago/Turabian StyleMario U. Manto. 2021. "Cerebellotoxic Agents." Handbook of the Cerebellum and Cerebellar Disorders , no. : 1-46.
Infections of the posterior fossa include bacterial infections, viral infections, and human prion diseases. Bacterial infections can present as abscesses involving the cerebellum and/or brainstem structures. About 8–18% of purulent brain abscesses are located in the cerebellum. Cerebellar abscesses are mainly associated with otogenic infections, cyanotic heart disease, congenital dermal sinus, trauma, and postoperative complications. Cerebellitis often presents with an acute or subacute cerebellar syndrome following an initial infection, often of viral origin, or a vaccination. The clinical picture may also manifest with combinations of cerebellar and brainstem deficits. Human prion diseases include Creutzfeldt-Jakob disease (CJD), variant CJD, and Gertsmann-Sträussler-Scheinker disease which is transmitted as an autosomal dominant disease. Sporadic CJD may have an iatrogenic origin following contamination. The main clinical presentation of sporadic CJD is a rapidly progressive dementia developing between the age of 60 and 65 years. The association of dementia, myoclonic jerks, parkinsonism, cerebellar ataxia, and seizures is suggestive. Prions are mainly composed of abnormal isoforms (PrPsc) of a host-encoded glycoprotein (prion protein PrPc). Infections of the posterior fossa (abscesses and cerebellitis) carry the risk of brainstem compression with tonsillar herniation and obstructive hydrocephalus. Antibiotics are used for abscesses but raised intracranial pressure may require urgent decompressive therapy. Early administration of steroids is recommended for the treatment of cerebellitis. Plasmapheresis and immunoglobulins are used in some immune-mediated forms of acute ataxia. There is still no cure for prion disorders.
Mario U. Manto; Patrice Jissendi. Infectious Diseases of the Posterior Fossa. Handbook of the Cerebellum and Cerebellar Disorders 2021, 1 -18.
AMA StyleMario U. Manto, Patrice Jissendi. Infectious Diseases of the Posterior Fossa. Handbook of the Cerebellum and Cerebellar Disorders. 2021; ():1-18.
Chicago/Turabian StyleMario U. Manto; Patrice Jissendi. 2021. "Infectious Diseases of the Posterior Fossa." Handbook of the Cerebellum and Cerebellar Disorders , no. : 1-18.
Since the first description of immune-mediated cerebellar ataxias (IMCAs) by Charcot in 1868, several milestones have been reached in our understanding of this group of neurological disorders. IMCAs have diverse etiologies, such as gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. The cerebellum, a vulnerable autoimmune target of the nervous system, has remarkable capacities (collectively known as the cerebellar reserve, closely linked to plasticity) to compensate and restore function following various pathological insults. Therefore, good prognosis is expected when immune-mediated therapeutic interventions are delivered during early stages when the cerebellar reserve can be preserved. However, some types of IMCAs show poor responses to immunotherapies, even if such therapies are introduced at an early stage. Thus, further research is needed to enhance our understanding of the autoimmune mechanisms underlying IMCAs, as such research could potentially lead to the development of more effective immunotherapies. We underscore the need to pursue the identification of robust biomarkers.
Hiroshi Mitoma; Mario Manto; Marios Hadjivassiliou. Immune-Mediated Cerebellar Ataxias: Clinical Diagnosis and Treatment Based on Immunological and Physiological Mechanisms. Journal of Movement Disorders 2021, 14, 10 -28.
AMA StyleHiroshi Mitoma, Mario Manto, Marios Hadjivassiliou. Immune-Mediated Cerebellar Ataxias: Clinical Diagnosis and Treatment Based on Immunological and Physiological Mechanisms. Journal of Movement Disorders. 2021; 14 (1):10-28.
Chicago/Turabian StyleHiroshi Mitoma; Mario Manto; Marios Hadjivassiliou. 2021. "Immune-Mediated Cerebellar Ataxias: Clinical Diagnosis and Treatment Based on Immunological and Physiological Mechanisms." Journal of Movement Disorders 14, no. 1: 10-28.
The terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, there is still no agreement on its pathophysiological mechanisms to date since its first clinical description by Babinski. We argue that impairment in the predictive computation for voluntary movements explains a range of characteristics accompanied by dysmetria. Within this framework, the cerebellum acquires and maintains an internal forward model, which predicts current and future states of the body by integrating an estimate of the previous state and a given efference copy of motor commands. Two of our recent studies experimentally support the internal-forward-model hypothesis of the cerebellar circuitry. First, the cerebellar outputs (firing rates of dentate nucleus cells) contain predictive information for the future cerebellar inputs (firing rates of mossy fibers). Second, a component of movement kinematics is predictive for target motions in control subjects. In cerebellar patients, the predictive component lags behind a target motion and is compensated with a feedback component. Furthermore, a clinical analysis has examined kinematic and electromyography (EMG) features using a task of elbow flexion goal-directed movements, which mimics the finger-to-nose test. Consistent with the hypothesis of the internal forward model, the predictive activations in the triceps muscles are impaired, and the impaired predictive activations result in hypermetria (overshoot). Dysmetria stems from deficits in the predictive computation of the internal forward model in the cerebellum. Errors in this fundamental mechanism result in undershoot (hypometria) and overshoot during voluntary motor actions. The predictive computation of the forward model affords error-based motor learning, coordination of multiple degrees of freedom, and adequate timing of muscle activities. Both the timing and synergy theory fit with the internal forward model, microzones being the elemental computational unit, and the anatomical organization of converging inputs to the Purkinje neurons providing them the unique property of a perceptron in the brain. We propose that motor dysmetria observed in attacks of ataxia occurs as a result of impaired predictive computation of the internal forward model in the cerebellum.
Pierre Cabaraux; Jordi Gandini; Shinji Kakei; Mario Manto; Hiroshi Mitoma; Hirokazu Tanaka. Dysmetria and Errors in Predictions: The Role of Internal Forward Model. International Journal of Molecular Sciences 2020, 21, 6900 .
AMA StylePierre Cabaraux, Jordi Gandini, Shinji Kakei, Mario Manto, Hiroshi Mitoma, Hirokazu Tanaka. Dysmetria and Errors in Predictions: The Role of Internal Forward Model. International Journal of Molecular Sciences. 2020; 21 (18):6900.
Chicago/Turabian StylePierre Cabaraux; Jordi Gandini; Shinji Kakei; Mario Manto; Hiroshi Mitoma; Hirokazu Tanaka. 2020. "Dysmetria and Errors in Predictions: The Role of Internal Forward Model." International Journal of Molecular Sciences 21, no. 18: 6900.
In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis.
Hiroshi Mitoma; Jerome Honnorat; Kazuhiko Yamaguchi; Mario Manto. Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias. International Journal of Molecular Sciences 2020, 21, 4936 .
AMA StyleHiroshi Mitoma, Jerome Honnorat, Kazuhiko Yamaguchi, Mario Manto. Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias. International Journal of Molecular Sciences. 2020; 21 (14):4936.
Chicago/Turabian StyleHiroshi Mitoma; Jerome Honnorat; Kazuhiko Yamaguchi; Mario Manto. 2020. "Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias." International Journal of Molecular Sciences 21, no. 14: 4936.
The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social “mirroring”) which is very close to its original role in motor learning, as well as in social understanding of other individuals’ mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social “mentalizing”). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions.
Frank Van Overwalle; Mario Manto; Zaira Cattaneo; Silvia Clausi; Chiara Ferrari; John D. E. Gabrieli; Xavier Guell; Elien Heleven; Michela Lupo; Qianying Ma; Marco Michelutti; Giusy Olivito; Min Pu; Laura C. Rice; Jeremy D. Schmahmann; Libera Siciliano; Arseny A. Sokolov; Catherine J. Stoodley; Kim Van Dun; Larry Vandervert; Maria Leggio. Consensus Paper: Cerebellum and Social Cognition. The Cerebellum 2020, 19, 833 -868.
AMA StyleFrank Van Overwalle, Mario Manto, Zaira Cattaneo, Silvia Clausi, Chiara Ferrari, John D. E. Gabrieli, Xavier Guell, Elien Heleven, Michela Lupo, Qianying Ma, Marco Michelutti, Giusy Olivito, Min Pu, Laura C. Rice, Jeremy D. Schmahmann, Libera Siciliano, Arseny A. Sokolov, Catherine J. Stoodley, Kim Van Dun, Larry Vandervert, Maria Leggio. Consensus Paper: Cerebellum and Social Cognition. The Cerebellum. 2020; 19 (6):833-868.
Chicago/Turabian StyleFrank Van Overwalle; Mario Manto; Zaira Cattaneo; Silvia Clausi; Chiara Ferrari; John D. E. Gabrieli; Xavier Guell; Elien Heleven; Michela Lupo; Qianying Ma; Marco Michelutti; Giusy Olivito; Min Pu; Laura C. Rice; Jeremy D. Schmahmann; Libera Siciliano; Arseny A. Sokolov; Catherine J. Stoodley; Kim Van Dun; Larry Vandervert; Maria Leggio. 2020. "Consensus Paper: Cerebellum and Social Cognition." The Cerebellum 19, no. 6: 833-868.
Aasef G Shaikh; Hiroshi Mitoma; Mario Manto. Cerebellar Scholars' Challenging Time in COVID-19 Pandemia. 2020, 19, 343 -344.
AMA StyleAasef G Shaikh, Hiroshi Mitoma, Mario Manto. Cerebellar Scholars' Challenging Time in COVID-19 Pandemia. . 2020; 19 (3):343-344.
Chicago/Turabian StyleAasef G Shaikh; Hiroshi Mitoma; Mario Manto. 2020. "Cerebellar Scholars' Challenging Time in COVID-19 Pandemia." 19, no. 3: 343-344.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the cause of the current pandemic coronavirus disease 2019 (COVID-19), primarily targets the respiratory system. Some patients also experience neurological signs and symptoms ranging from anosmia, ageusia, headache, nausea, and vomiting to confusion, encephalitis, and stroke. Approximately 36% of those with severe COVID-19 experience neurological complications. The virus may enter the central nervous system through the olfactory nerve in the nasal cavity and damage neurons in the brainstem nuclei involved in the regulation of respiration. Patients with cerebellar ataxia (CA) are particularly vulnerable to severe outcome if they contract COVID-19 because of the complexity of their disease, the presence of comorbidities, and their use of immunosuppressive therapies. Most CA patients burdened by progressive neurologic deficits have substantially impaired mobility and other essential functions, for which they rely heavily on ambulatory services, including rehabilitation and psychosocial care. Cessation of these interventions because of isolation restrictions places the CA patient population at risk of further deterioration. This international panel of ataxia experts provides recommendations for neurologists caring for patients with CA, emphasizing a pro-active approach designed to maintain their autonomy and well-being: continue long-term medications, promote rehabilitation efforts, utilize the technology of virtual visits for regular contact with healthcare providers, and pay attention to emotional and psychosocial health. Neurologists should play an active role in decision-making in those CA cases requiring escalation to intensive care and resuscitation. Multi-disciplinary collaboration between care teams is always important, and never more so than in the context of the current pandemic.
Mario Manto; Nicolas Dupre; Marios Hadjivassiliou; Elan D. Louis; Hiroshi Mitoma; Marco Molinari; Aasef G. Shaikh; Bing-Wen Soong; Michael Strupp; Frank Van Overwalle; Jeremy D. Schmahmann. Medical and Paramedical Care of Patients With Cerebellar Ataxia During the COVID-19 Outbreak: Seven Practical Recommendations of the COVID 19 Cerebellum Task Force. Frontiers in Neurology 2020, 11, 1 .
AMA StyleMario Manto, Nicolas Dupre, Marios Hadjivassiliou, Elan D. Louis, Hiroshi Mitoma, Marco Molinari, Aasef G. Shaikh, Bing-Wen Soong, Michael Strupp, Frank Van Overwalle, Jeremy D. Schmahmann. Medical and Paramedical Care of Patients With Cerebellar Ataxia During the COVID-19 Outbreak: Seven Practical Recommendations of the COVID 19 Cerebellum Task Force. Frontiers in Neurology. 2020; 11 ():1.
Chicago/Turabian StyleMario Manto; Nicolas Dupre; Marios Hadjivassiliou; Elan D. Louis; Hiroshi Mitoma; Marco Molinari; Aasef G. Shaikh; Bing-Wen Soong; Michael Strupp; Frank Van Overwalle; Jeremy D. Schmahmann. 2020. "Medical and Paramedical Care of Patients With Cerebellar Ataxia During the COVID-19 Outbreak: Seven Practical Recommendations of the COVID 19 Cerebellum Task Force." Frontiers in Neurology 11, no. : 1.
The current worldwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that causes coronavirus disease 2019 (COVID-19) has brought some medical systems to the brink of collapse. This crisis is also negatively impacting the care of patients with non-COVID-19 conditions, including those with cerebellar ataxia (CA). Older patients with CA and those with immune-mediated ataxias on immunosuppressive medication are potentially at high risk of developing serious complications of the infection, although it is also possible that immunosuppressive agents may provide a defense against cytokine storm. This has implications for even greater attention to preventing contracting the disease through physical distancing and/or isolation. The CA patient population is also at higher risk because of the neurological complexities of their underlying disorder and the comorbid medical illnesses that often accompany the genetic ataxias. As the disruption of social patterns and healthcare delivery in response to the crisis continues, interruption of rehabilitation, speech and language therapy, and face-to-face consultations threatens to have a negative impact on the course and well-being of CA patients. Mental and physical health is also potentially at greater risk because the prevailing uncertainty and anxiety may be superimposed upon cerebellum-specific neuropsychological challenges. We identify and review some of the short- and long-term consequences of this global pandemic for the community of ataxia patients and their families and for the clinical and academic neurologists/ataxiologists caring for these patients. This includes the recognition that telemedicine has emerged as a principle means of caregiver-patient contact and that neurological manifestations of COVID-19 including those specific to cerebellar neurobiology are increasingly recognized and will require close surveillance and monitoring. This COVID-19 Cerebellum Task Force consensus provides some guidance on how we may approach this uncertain time and consider preparing for the new realities we face in CA patient care once this acute crisis has passed.
Mario Manto; Nicolas Dupre; Marios Hadjivassiliou; Elan D. Louis; Hiroshi Mitoma; Marco Molinari; Aasef G. Shaikh; Bing-Wen Soong; Michael Strupp; Frank Van Overwalle; Jeremy D. Schmahmann. Management of Patients with Cerebellar Ataxia During the COVID-19 Pandemic: Current Concerns and Future Implications. The Cerebellum 2020, 19, 562 -568.
AMA StyleMario Manto, Nicolas Dupre, Marios Hadjivassiliou, Elan D. Louis, Hiroshi Mitoma, Marco Molinari, Aasef G. Shaikh, Bing-Wen Soong, Michael Strupp, Frank Van Overwalle, Jeremy D. Schmahmann. Management of Patients with Cerebellar Ataxia During the COVID-19 Pandemic: Current Concerns and Future Implications. The Cerebellum. 2020; 19 (4):562-568.
Chicago/Turabian StyleMario Manto; Nicolas Dupre; Marios Hadjivassiliou; Elan D. Louis; Hiroshi Mitoma; Marco Molinari; Aasef G. Shaikh; Bing-Wen Soong; Michael Strupp; Frank Van Overwalle; Jeremy D. Schmahmann. 2020. "Management of Patients with Cerebellar Ataxia During the COVID-19 Pandemic: Current Concerns and Future Implications." The Cerebellum 19, no. 4: 562-568.
Novel coronavirus, SARS-CoV2, has caused pandemic of highly contagious disease called coronavirus disease 2019 (COVID-19), with epicenters in China, Italy, Spain, and the USA. Primarily affecting the human respiratory system, SARS-CoV2 has some impact on the human brain, but apparently minimal on the cerebellum, at least so far. Neurological involvement in the acute phase appears to manifest with confusion, dizziness, impaired consciousness, propensity to develop acute strokes, anosmia, hypogeusia, ataxia, epilepsy, and neuralgia. Cerebellar scholars are facing a time of uncertainty. Telemedicine has suddenly emerged as an alternative to follow patients. There is an urgent need to develop novel platforms to assess and follow ataxic patients remotely, especially because cerebellar patients often require ambulatory care to maintain their autonomy.
Aasef G. Shaikh; Hiroshi Mitoma; Mario Manto. Cerebellar Scholars’ Challenging Time in COVID-19 Pandemia. The Cerebellum 2020, 19, 343 -344.
AMA StyleAasef G. Shaikh, Hiroshi Mitoma, Mario Manto. Cerebellar Scholars’ Challenging Time in COVID-19 Pandemia. The Cerebellum. 2020; 19 (3):343-344.
Chicago/Turabian StyleAasef G. Shaikh; Hiroshi Mitoma; Mario Manto. 2020. "Cerebellar Scholars’ Challenging Time in COVID-19 Pandemia." The Cerebellum 19, no. 3: 343-344.
Jordi Gandini; Mario Manto. How does editing the genome improve targeting DNA and RNA for cerebellar ataxias? Future Neurology 2020, 15, FNL37 .
AMA StyleJordi Gandini, Mario Manto. How does editing the genome improve targeting DNA and RNA for cerebellar ataxias? Future Neurology. 2020; 15 (1):FNL37.
Chicago/Turabian StyleJordi Gandini; Mario Manto. 2020. "How does editing the genome improve targeting DNA and RNA for cerebellar ataxias?" Future Neurology 15, no. 1: FNL37.
Posterior reversible encephalopathy syndrome (PRES) is a potentially severe disorder of the autoregulation of cerebral perfusion. The major clinical manifestations are headache, seizures, altered mental status, and visual loss. The typical radiological finding is vasogenic edema predominating in the white matter of occipital and parietal lobes. PRES is increasingly recognized as a clinico-radiological entity owing to improvements and fast availability of brain imaging, especially magnetic resonance imaging (MRI). We present the exceptional case of a 67-year-old female patient with a gastric adenocarcinoma at stage IIB (T3N0M0) treated by FLOT chemotherapy (5-fluorouracil, oxaliplatin, docetaxel, and folinic acid). Two months after the unique administration of FLOT regimen, she developed sudden posterior headache and visual loss. Blood pressure values were normal. Cerebral tomography showed ischemic-like occipital bilateral lesions, and angiographic sequences revealed breakdown of the blood–brain barrier (BBB). MRI revealed bilateral parieto-occipital T1 hypointensity and T2 hyperintensity, which demonstrated vasogenic edema. The rest of the parts of the lesions were T1 hyperintensity, T2 hyperintensity, and diffusion-weighted imaging (DWI) hyperintensity, which indicate cortical laminar necrosis. After injection of gadolinium, a linear enhancement of the cortex was observed. She was treated with oral nimodipine. Follow-up was characterized by permanent visual sequelae and tetraparesis. PRES represents an urgent neurological condition. Our observation highlights that PRES should be considered in patients under chemotherapy, even when their blood pressure remains within normal range. This is the first report of PRES triggered by FLOT chemotherapy and with a silent window of 2 months between chemotherapy and PRES, widening further the spectrum of chemotherapy-induced PRES. Our case highlights the potential role of FLOT regimen in the pathogenesis of PRES and the need for a novel approach in terms of prevention of this potentially fatal complication when patients receive chemotherapy.
Jordi Gandini; Mario Manto; Nicolas Charette. Delayed Posterior Reversible Leukoencephalopathy Syndrome Triggered by FLOT Chemotherapy. Frontiers in Neurology 2020, 10, 1405 .
AMA StyleJordi Gandini, Mario Manto, Nicolas Charette. Delayed Posterior Reversible Leukoencephalopathy Syndrome Triggered by FLOT Chemotherapy. Frontiers in Neurology. 2020; 10 ():1405.
Chicago/Turabian StyleJordi Gandini; Mario Manto; Nicolas Charette. 2020. "Delayed Posterior Reversible Leukoencephalopathy Syndrome Triggered by FLOT Chemotherapy." Frontiers in Neurology 10, no. : 1405.
Cerebellar ataxias (CAs) represent a heterogeneous group of sporadic or inherited disorders. The clinical spectrum of CAs is continuously expanding. Our understanding of the mechanisms leading to the clinical deficits has improved over these last decades, in particular thanks to progress in genetics, neuroimaging and the advent of relevant animal models allowing the identification of the pathophysiological pathways leading to CAs. The rationale behind treatments is now established for most of the CAs encountered during daily practice worldwide. In this update, we will discuss the symptomatic, physical and occupational therapies now being trialled along with individualized exercises, and present key emerging issues on immune-mediated cerebellar ataxias, hereditary cerebellar ataxias. Finally, we will discuss novel therapeutic approaches, including cerebellar non-invasive stimulation and treatments acting on RNA/proteins. So far, no state-of-the art randomized placebo-controlled clinical trial has shown a convincing clinically relevant efficacy of any drug, with the exception of 4-aminopyridine for the symptomatic treatment of episodic ataxia type 2 and downbeat nystagmus (placebo-controlled trials).
J. Gandini; Mario Manto; T. Bremova-Ertl; K. Feil; M. Strupp. The neurological update: therapies for cerebellar ataxias in 2020. Journal of Neurology 2020, 267, 1211 -1220.
AMA StyleJ. Gandini, Mario Manto, T. Bremova-Ertl, K. Feil, M. Strupp. The neurological update: therapies for cerebellar ataxias in 2020. Journal of Neurology. 2020; 267 (4):1211-1220.
Chicago/Turabian StyleJ. Gandini; Mario Manto; T. Bremova-Ertl; K. Feil; M. Strupp. 2020. "The neurological update: therapies for cerebellar ataxias in 2020." Journal of Neurology 267, no. 4: 1211-1220.
Chiari malformations designate a group of developmental disorders characterized by anatomical deformities of the posterior fossa. They are evident at birth, prenatally, or become symptomatic during adolescence or adulthood. Diagnosis relies mainly on MRI. Chiari type I is the most common form and is characterized by herniation of the cerebellar tonsils through the foramen magnum and consecutive forward compression of the lower brainstem. Symptoms include occipital headaches that last for a few minutes but may be exacerbated by Valsalva maneuver, cerebellar motor symptoms, and various pyramidal deficits and sensory disturbances. Deficits in cognitive operations involving the cerebellum have also recently been recognized. Chiari type II combines mainly a caudal herniation of the cerebellar vermis and brainstem, lumbar myelomeningocele, and supratentorial abnormalities of the corpus callosum. Chiari type III associates some intracranial defects of Chiari type II with a high cervical meningomyelocele. Chiari type IV is characterized by cerebellar hypoplasia with aplasia of the tentorium cerebelli. Syringomyelia is the most common spinal cord defect found in association with Chiari malformations. About 40–80% of patients with Chiari type I malformations have a syrinx. The central cavitation is usually located at the cervical level, but may extend cranially to the brainstem or caudally to the lower segments of the spinal cord. Asymptomatic patients diagnosed with Chiari type I in the absence of concomitant syringomyelia are not considered candidates for surgical therapy in most cases. Surgery of symptomatic malformations usually consists of decompression of the foramen magnum. Nonsurgical therapies include management of neuropathic pain, physical therapy, and rehabilitation.
Mario U. Manto; Christian Herweh. Chiari Malformations. Handbook of the Cerebellum and Cerebellar Disorders 2020, 1 -16.
AMA StyleMario U. Manto, Christian Herweh. Chiari Malformations. Handbook of the Cerebellum and Cerebellar Disorders. 2020; ():1-16.
Chicago/Turabian StyleMario U. Manto; Christian Herweh. 2020. "Chiari Malformations." Handbook of the Cerebellum and Cerebellar Disorders , no. : 1-16.
Various etiopathologies affect the cerebellum, resulting in the development of cerebellar ataxias (CAs), a heterogeneous group of disorders characterized clinically by movement incoordination, affective dysregulation, and cognitive dysmetria. Recent progress in clinical and basic research has opened the door of the ‘‘era of therapy” of CAs. The therapeutic rationale of cerebellar diseases takes into account the capacity of the cerebellum to compensate for pathology and restoration, which is collectively termed cerebellar reserve. In general, treatments of CAs are classified into two categories: cause-cure treatments, aimed at arresting disease progression, and neuromodulation therapies, aimed at potentiating cerebellar reserve. Both forms of therapies should be introduced as soon as possible, at a time where cerebellar reserve is still preserved. Clinical studies have established evidence-based cause-cure treatments for metabolic and immune-mediated CAs. Elaborate protocols of rehabilitation and non-invasive cerebellar stimulation facilitate cerebellar reserve, leading to recovery in the case of controllable pathologies (metabolic and immune-mediated CAs) and delay of disease progression in the case of uncontrollable pathologies (degenerative CAs). Furthermore, recent advances in molecular biology have encouraged the development of new forms of therapies: the molecular targeting therapy, which manipulates impaired RNA or proteins, and the neurotransplantation therapy, which delays cell degeneration and facilitates compensatory functions. The present review focuses on the therapeutic rationales of these recently developed therapeutic modalities, highlighting the underlying pathogenesis.
Hiroshi Mitoma; Mario Manto; Jordi Gandini. Recent Advances in the Treatment of Cerebellar Disorders. Brain Sciences 2019, 10, 11 .
AMA StyleHiroshi Mitoma, Mario Manto, Jordi Gandini. Recent Advances in the Treatment of Cerebellar Disorders. Brain Sciences. 2019; 10 (1):11.
Chicago/Turabian StyleHiroshi Mitoma; Mario Manto; Jordi Gandini. 2019. "Recent Advances in the Treatment of Cerebellar Disorders." Brain Sciences 10, no. 1: 11.
Sporadically advocated over the last two centuries, a cerebellar role in cognition and affect has been rigorously established in the past few decades. In the clinical domain, such progress is epitomized by the “cerebellar cognitive affective syndrome” (“CCAS”) or “Schmahmann syndrome.” Introduced in the late 1990s, CCAS reflects a constellation of cerebellar-induced sequelae, comprising deficits in executive function, visuospatial cognition, emotion–affect, and language, over and above speech. The CCAS thus offers excellent grounds to investigate the functional topography of the cerebellum, and, ultimately, illustrate the precise mechanisms by which the cerebellum modulates cognition and affect. The primary objective of this task force paper is thus to stimulate further research in this area. After providing an up-to-date overview of the fundamental findings on cerebellar neurocognition, the paper substantiates the concept of CCAS with recent evidence from different scientific angles, promotes awareness of the CCAS as a clinical entity, and examines our current insight into the therapeutic options available. The paper finally identifies topics of divergence and outstanding questions for further research.
Georgios P. D. Argyropoulos; Kim Van Dun; Michael Adamaszek; Maria Leggio; Mario Manto; Marcella Masciullo; Marco Molinari; Catherine J. Stoodley; Frank Van Overwalle; Richard B. Ivry; Jeremy D. Schmahmann. The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper. The Cerebellum 2019, 19, 102 -125.
AMA StyleGeorgios P. D. Argyropoulos, Kim Van Dun, Michael Adamaszek, Maria Leggio, Mario Manto, Marcella Masciullo, Marco Molinari, Catherine J. Stoodley, Frank Van Overwalle, Richard B. Ivry, Jeremy D. Schmahmann. The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper. The Cerebellum. 2019; 19 (1):102-125.
Chicago/Turabian StyleGeorgios P. D. Argyropoulos; Kim Van Dun; Michael Adamaszek; Maria Leggio; Mario Manto; Marcella Masciullo; Marco Molinari; Catherine J. Stoodley; Frank Van Overwalle; Richard B. Ivry; Jeremy D. Schmahmann. 2019. "The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper." The Cerebellum 19, no. 1: 102-125.