It has been suggested that Olivopontocerebellar atrophy be merged into this article. (Discuss) Proposed since May 2024. |
Multiple system atrophy | |
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Alpha-synuclein immunohistochemistry of the brain showing many glial inclusion bodies | |
Specialty | Neurology |
Symptoms | Parkinsonism, xerostomia, dysautonomia, ataxia |
Complications | Cardiac arrest, infections, aspiration pneumonia |
Usual onset | 50–60 years |
Duration | Long term |
Types |
|
Causes | Unknown |
Diagnostic method | MRI, CT scan, autopsy |
Treatment | Physical therapy, hospice care |
Medication | L-DOPA, fludrocortisone, midodrine |
Prognosis | Life expectancy 6–12 years after onset of symptoms |
Frequency | 5 per 100,000 people |
Multiple system atrophy (MSA) is a rare neurodegenerative disorder [1] characterized by tremors, slow movement, muscle rigidity, and postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progressive degeneration of neurons in several parts of the brain including the basal ganglia, inferior olivary nucleus, and cerebellum.
Many people affected by MSA experience dysfunction of the autonomic nervous system, which commonly manifests as orthostatic hypotension, impotence, loss of sweating, dry mouth and urinary retention and incontinence. Palsy of the vocal cords is an important and sometimes initial clinical manifestation of the disorder.
A prion of the alpha-synuclein protein within affected neurons may cause MSA. [2] About 55% of MSA cases occur in men, with those affected first showing symptoms at the age of 50–60 years. [3] MSA often presents with some of the same symptoms as Parkinson's disease. However, those with MSA generally show little response to the dopamine agonists used to treat Parkinson's disease and only about 9% of MSA patients with tremor exhibit a true parkinsonian pill-rolling tremor. [4]
MSA is distinct from multisystem proteinopathy, a more common muscle-wasting syndrome. MSA is also different from multiple organ dysfunction syndrome, sometimes referred to as multiple organ failure, and from multiple organ system failures, an often-fatal complication of septic shock and other severe illnesses or injuries.
MSA is characterized by the following: Autonomic and at least one Motor (clinically established MSA criteria 2022) [5] [6]
A variant with combined features of MSA and dementia with Lewy bodies may also exist.[ unreliable medical source? ] [7] There have also been occasional instances of frontotemporal lobar degeneration associated with MSA. [8]
The most common first sign of MSA is the appearance of an "akinetic-rigid syndrome" (i.e. slowness of initiation of movement resembling Parkinson's disease) found in 62% at first presentation. Other common signs at onset include problems with balance (cerebellar ataxia) found in 22% at first presentation, followed by genito-urinary symptoms (9%): both men and women often experience urgency, frequency, incomplete bladder emptying, or an inability to pass urine (retention). About 1 in 5 MSA patients experience a fall in their first year of disease. [9]
For men, the first sign can be erectile dysfunction. Women have also reported reduced genital sensitivity. [10]
As the disease progresses, one of three groups of symptoms predominates. These are: [11]
One study found a correlation between the deletion of genes in a specific genetic region and the development of MSA in a group of Japanese patients. The region in question includes the SHC2 gene which, in mice and rats, appears to have some function in the nervous system. The authors of this study hypothesized that there may be a link between the deletion of the SHC2 and the development of MSA. [25]
A follow-up study was unable to replicate this finding in American MSA patients. [26] The authors of the study concluded that "Our results indicate that SHC2 gene deletions underlie few, if any, cases of well-characterized MSA in the US population. This is in contrast to the Japanese experience reported by Sasaki et al., likely reflecting heterogeneity of the disease in different genetic backgrounds."[ clarification needed ]
Another study investigated the frequency of RFC1 intronic repeat expansions, a phenomenon implicated in CANVAS; a disease with a diagnostic overlap with MSA. [27] [28] The study concluded that these repeats were absent in pathologically confirmed MSA, suggesting an alternative genetic cause. [27]
Multiple system atrophy can be explained as cell loss and gliosis or a proliferation of astrocytes in damaged areas of the central nervous system. This damage forms a scar which is then termed a glial scar. [29] The presence of inclusion bodies known as Papp–Lantos bodies, in the movement, balance, and autonomic-control centres of the brain are the defining histopathologic hallmark of MSA. [30]
The major filamentous component of Papp-Lantos bodies, glial and neuronal cytoplasmic inclusions, is alpha-synuclein. [31] Mutations in this substance may play a role in the disease. [32] The conformation of the alpha-synuclein is different from that of alpha-synuclein in Lewy bodies. [2] The disease probably starts with an oligodendrogliopathy. [33] It has been proposed that the α-synuclein inclusions found in Oligodendrocytes result from the pruning and the engulfment of diseased axonal segments containing aggregated α-synuclein, i.e., of Lewy neurites [34]
Tau proteins have been found in some glial cytoplasmic inclusion bodies. [35]
Clinical diagnostic criteria were defined in 1998 [36] and updated in 2007 [37] and in 2022. [38] Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult. [39] [40] [41]
Both MRI and CT scanning may show a decrease in the size of the cerebellum and pons in those with cerebellar features (MSA-C). The putamen is hypointense on T2-weighted MRI and may show an increased deposition of iron in the Parkinsonian (MSA-P) form. In MSA-C, a "hot cross bun" sign is sometimes found; it reflects atrophy of the pontocerebellar tracts that give T2 hyper intense signal intensity in the atrophic pons.
MRI changes are not required to diagnose the disease as these features are often absent, especially early in the course of the disease. Additionally, the changes can be quite subtle and are usually missed by examiners who are not experienced with MSA.[ citation needed ]
Pathological diagnosis can only be made at autopsy by finding abundant GCIs on histological specimens of the central nervous system. [42]
Contrary to most other synucleinopathies, which develop α-synuclein inclusions primarily in neuronal cell populations, [43] MSA presents with extensive pathological α-synuclein inclusions in the cytosol of oligodendrocytes (glial cytoplasmic inclusions), with limited pathology in neurons. [44] MSA also differs from other synucleinopathies in its regional pathological presentation, with α-synuclein positive inclusions detected predominantly in the striatum, midbrain, pons, medulla and cerebellum, [45] [46] rather than the brainstem, limbic and cortical regions typically effected in Lewy inclusion diseases. [46] However, recent studies using novel, monoclonal antibodies specific for C-terminally truncated α-synuclein (αSynΔC) have now shown that neuronal α-synuclein pathology is more abundant than previously thought. [47] [48] One group revealed robust α-synuclein pathology in the pontine nuclei and medullary inferior olivary nucleus upon histological analysis of neurological tissue from MSA patients. [47] Histopathological investigation on six cases of pathologically confirmed MSA, using antibodies directed at a variety of α-synuclein epitopes, revealed substantial variation in α-synuclein protein deposition across both cases and brain regions within cases, providing evidence for 'strains' of aggregated conformers that may differentially promote pathological prion-like spread. [49]
In 2020, researchers at The University of Texas Health Science Center at Houston concluded that protein misfolding cyclic amplification could be used to distinguish between two progressive neurodegenerative diseases, Parkinson's disease and multiple system atrophy, being the first process to give an objective diagnosis of Multiple System Atrophy instead of just a differential diagnosis. [50] [51]
MSA is one of several neurodegenerative diseases known as synucleinopathies: they have in common an abnormal accumulation of alpha-synuclein protein in various parts of the brain. Other synucleinopathies include Parkinson's disease, the Lewy body dementias, and other more rare conditions. [52]
Historically, many terms were used to refer to this disorder, based on the predominant systems presented. These terms were discontinued by consensus in 1996 and replaced with MSA and its subtypes, [53] but awareness of these older terms and their definitions is helpful to understanding the relevant literature prior to 1996. These include striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and Shy–Drager syndrome. [54] A table describing the characteristics and modern names of these conditions follows:
Historical Name | Characteristics | Modern name and abbreviation |
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Striatonigral degeneration | predominating Parkinson's-like symptoms | MSA-P, "p" = parkinsonian subtype |
Sporadic olivopontocerebellar atrophy (OPCA) | characterized by progressive ataxia (an inability to coordinate voluntary muscular movements) of the gait and arms and dysarthria (difficulty in articulating words) | MSA-C, "c" = cerebellar dysfunction subtype |
Shy-Drager syndrome | characterized by Parkinsonism plus a more pronounced failure of the autonomic nervous system. [55] | No modern equivalent – this terminology fell out of favour [56] and was not specified in the 2007 consensus paper. [37] The earlier consensus of 1998 [36] referred to MSA-A, "a" = autonomic dysfunction subtype but this subtype is no longer used. |
The current terminology and diagnostic criteria for the disease were established at a 2007 conference of experts and set forth in a position paper. [37] This Second Consensus Statement defines two categories of MSA, based on the predominant symptoms of the disease at the time of evaluation. These are:
Ongoing care from a neurologist specializing in movement disorders is recommended,[ by whom? ] because the complex symptoms of MSA are often not familiar to less-specialized neurologists. Hospice/homecare services can be very useful as disability progresses.[ citation needed ]
Levodopa (L-Dopa), a drug used in the treatment of Parkinson's disease, improves parkinsonian symptoms in a small percentage of MSA patients. A recent trial reported that only 1.5% of MSA patients experienced any improvement at all when taking levodopa, their improvement was less than 50%, and even that improvement was a transient effect lasting less than one year. Poor response to L-Dopa has been suggested as a possible element in the differential diagnosis of MSA from Parkinson's disease. [57]
The drug riluzole is ineffective in treating MSA or PSP. [9]
Management by rehabilitation professionals including physiatrists, physiotherapists, occupational therapists, speech therapists, and others for difficulties with walking/movement, daily tasks, and speech problems is essential.[ citation needed ]
Physiotherapists can help to maintain the patient's mobility and will help to prevent contractures. [29] Instructing patients in gait training will help to improve their mobility and decrease their risk of falls. [58] A physiotherapist may also prescribe mobility aids such as a cane or a walker to increase the patient's safety. [58]
Speech therapists may assist in assessing, treating and supporting speech (dysarthria) and swallowing difficulties (dysphagia). Speech changes mean that alternative communication may be needed, for example, communication aids or word charts.[ citation needed ]
Early intervention of swallowing difficulties is particularly useful to allow for discussion around tube feeding further in the disease progression.[ citation needed ] At some point in the progression of the disease, fluid and food modification may be implemented.[ citation needed ]
One particularly serious problem, the drop in blood pressure upon standing up (with risk of fainting and thus injury from falling), often responds to fludrocortisone, a synthetic mineralocorticoid. [59] [60] Another common drug treatment is the alpha-agonist midodrine. [59]
Non-drug treatments include "head-up tilt" (elevating the head of the whole bed by about 10 degrees), salt tablets or increasing salt in the diet, generous intake of fluids, and pressure (elastic) stockings. Avoidance of triggers of low blood pressure, such as hot weather, alcohol, and dehydration, are crucial. [60] The patient can be taught to move and transfer from sitting to standing slowly to decrease risk of falls and limit the effect of postural hypotension. [58] Instruction in ankle pumping helps to return blood in the legs to the systemic circulation. [58] Other preventative measures are raising the head of the bed by 8 in (20.3 cm), and the use of compression stockings and abdominal binders. [5]
Social workers and occupational therapists can also help with coping with disability through the provision of equipment and home adaptations, services for caregivers and access to healthcare services, both for the person with MSA as well as family caregivers.[ citation needed ]
The average lifespan after the onset of symptoms in patients with MSA is 6–10 years. [3] Approximately 60% of patients require a wheelchair within five years of onset of the motor symptoms, and few patients survive beyond 12 years. [3] The disease progresses without remission at a variable rate. Those who present at an older age, those with parkinsonian features, and those with severe autonomic dysfunction have a poorer prognosis. [3] Those with predominantly cerebellar features and those who display autonomic dysfunction later have a better prognosis. [3]
The most common causes of death are sudden death and death caused by infections, which include urinary catheterization infections, feeding tube infections, and aspiration pneumonia. Some deaths are caused by cachexia, also known as wasting syndrome. [61]
Multiple system atrophy is estimated to affect approximately 5 per 100,000 people. At autopsy, many patients diagnosed during life with Parkinson's disease are found actually to have MSA, suggesting that the actual incidence of MSA is higher than that estimate. [3] While some suggest that MSA affects slightly more men than women (1.3:1), others suggest that the two sexes are equally likely to be affected. [3] [5] [29] The condition most commonly presents in persons aged 50–60. [3]
Mesenchymal stem cell therapy may delay the progression of neurological deficits in patients with MSA-cerebellar type. [62]
Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and regulation of automatic bodily functions. Memory loss is not always an early symptom. The disease worsens over time and is usually diagnosed when cognitive impairment interferes with normal daily functioning. Together with Parkinson's disease dementia, DLB is one of the two Lewy body dementias. It is a common form of dementia, but the prevalence is not known accurately and many diagnoses are missed. The disease was first described on autopsy by Kenji Kosaka in 1976, and he named the condition several years later.
Rapid eye movement sleep behavior disorder or REM sleep behavior disorder (RBD) is a sleep disorder in which people act out their dreams. It involves abnormal behavior during the sleep phase with rapid eye movement (REM) sleep. The major feature of RBD is loss of muscle atonia during otherwise intact REM sleep. The loss of motor inhibition leads to sleep behaviors ranging from simple limb twitches to more complex integrated movements that can be violent or result in injury to either the individual or their bedmates.
Dysautonomia, autonomic failure, or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly. This may affect the functioning of the heart, bladder, intestines, sweat glands, pupils, and blood vessels. Dysautonomia has many causes, not all of which may be classified as neuropathic. A number of conditions can feature dysautonomia, such as Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Ehlers–Danlos syndromes, autoimmune autonomic ganglionopathy and autonomic neuropathy, HIV/AIDS, mitochondrial cytopathy, pure autonomic failure, autism, and postural orthostatic tachycardia syndrome.
Lewy bodies are the inclusion bodies — abnormal aggregations of protein — that develop inside neurons affected by Parkinson's disease (PD), the Lewy body dementias, and some other disorders. They are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P).
Alpha-synuclein (aSyn) is a protein that, in humans, is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain. The condition leads to symptoms including loss of balance, slowing of movement, difficulty moving the eyes, and cognitive impairment. PSP may be mistaken for other types of neurodegeneration such as Parkinson's disease, frontotemporal dementia and Alzheimer's disease. The cause of the condition is uncertain, but involves the accumulation of tau protein within the brain. Medications such as levodopa and amantadine may be useful in some cases.
Parkinson-plus syndromes (PPS) are a group of neurodegenerative diseases featuring the classical features of Parkinson's disease with additional features that distinguish them from simple idiopathic Parkinson's disease (PD). Parkinson-plus syndromes are either inherited genetically or occur sporadically.
Corticobasal degeneration (CBD) is a rare neurodegenerative disease involving the cerebral cortex and the basal ganglia. CBD symptoms typically begin in people from 50 to 70 years of age, and typical survival before death is eight years. It is characterized by marked disorders in movement and cognition, and is classified as one of the Parkinson plus syndromes. Diagnosis is difficult, as symptoms are often similar to those of other disorders, such as Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and a definitive diagnosis of CBD can only be made upon neuropathologic examination.
Pure autonomic failure (PAF) is an uncommon, sporadic neurodegenerative condition marked by a steadily declining autonomic regulation. Bradbury and Eggleston originally described pure autonomic failure in 1925.
A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative tauopathy and Parkinson plus syndrome. FTDP-17 is caused by mutations in the MAPT gene located on the q arm of chromosome 17, and has three cardinal features: behavioral and personality changes, cognitive impairment, and motor symptoms. FTDP-17 was defined during the International Consensus Conference in Ann Arbor, Michigan, in 1996.
Beta-synuclein is a protein that in humans is encoded by the SNCB gene.
Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS) and sold under the brand names Northera and Dops among others, is sympathomimetic medication which is used in the treatment of hypotension and for other indications. It is taken by mouth.
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease of mainly the central nervous system that affects both the motor and non-motor systems of the body. The symptoms usually emerge slowly, and, as the disease progresses, non-motor symptoms become more common. Usual symptoms include tremors, slowness of movement, rigidity, and difficulty with balance, collectively known as parkinsonism. Parkinson's disease dementia, falls and neuropsychiatric problems such as sleep abnormalities, psychosis, mood swings, or behavioral changes may also arise in advanced stages.
Gregor Karl Wenning was a German neurologist best known for his clinical and scientific work in Parkinson's disease and atypical Parkinsonian disorders, particularly multiple system atrophy (MSA). In 2006 he was appointed Professor and Head of the Division of Clinical Neurobiology at the Medical University Innsbruck. Wenning died on 11 February 2024, at the age of 59.
Braak staging refers to two methods used to classify the degree of pathology in Parkinson's disease and Alzheimer's disease. These methods are used both in research and for the clinical diagnosis of these diseases and are obtained by performing an autopsy of the brain.
Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells. There are three main types of synucleinopathy: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Other rare disorders, such as various neuroaxonal dystrophies, also have α-synuclein pathologies. Additionally, autopsy studies have shown that around 6% of sporadic Alzheimer's Disease exhibit α-synuclein positive Lewy pathology, and are sub-classed as Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD/ALB).
The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.
Animal models of Parkinson's disease are essential in the research field and widely used to study Parkinson's disease. Parkinson's disease is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of the dopamine neurons in the brain, results in motor dysfunction, ultimately causing the four cardinal symptoms of PD: tremor, rigidity, postural instability, and bradykinesia. It is the second most prevalent neurodegenerative disease, following Alzheimer's disease. It is estimated that nearly one million people could be living with PD in the United States.
Rapid eye movement sleep behaviour disorder and Parkinson's disease is rapid eye movement sleep behavior disorder (RBD) that is associated with Parkinson's disease. RBC is linked genetically and neuropathologically to α- synuclein, a presynaptic neuronal protein that exerts deleterious effects on neighbouring proteins, leading to neuronal death. This pathology is linked to numerous other neurodegenerative disorders, such as Lewy body dementias, and collectively these disorders are known as synucleinopathies. Numerous reports over the past few years have stated the frequent association of synucleinopathies with REM sleep behaviour disorder (RBD). In particular, the frequent association of RBD with Parkinson's. In the general population the incidence of RBD is around 0.5%, compared to the prevalence of RBD in PD patients, which has been reported to be between 38% and 60%. The diagnosis and symptom onset of RBD typically precedes the onset of motor or cognitive symptoms of PD by a number of years, typically ranging anywhere from 2 to 15 years prior. Hence, this link could provide an important window of opportunity in the implementation of therapies and treatments, that could prevent or slow the onset of PD.
Parkinsonian syndromes are a group of movement disorders characterized by classical motor symptoms such as tremors, bradykinesia, and rigidity. They are most frequently due to primary neurodegenerative disease, resulting in the loss of dopaminergic nerve terminals along the nigrostriatal pathway, similar to idiopathic PD, MSA, PSP, CBD, and DLB.
Copy number loss of SHC2 strongly indicates a causal link to MSA.