Multiple system atrophy

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Multiple system atrophy (MSA) is a rare neurodegenerative disorder<ref>Template:DorlandsDict</ref> characterized by tremors, slow movement, muscle rigidity, 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. MSA was first described in 1960 by Milton Shy and Glen Drager and was then known as Shy–Drager syndrome.<ref>Template:Cite web</ref>

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.<ref name="pmid29743672"/> About 55% of MSA cases occur in men, with those affected first showing symptoms at the age of 50–60 years.<ref name=":0" /> 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.<ref>Template:Cite web</ref>

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.

Signs and symptoms

MSA is characterized by the following: Autonomic and at least one Motor (clinically established MSA criteria 2022)<ref name="pmid10331752">Template:Cite journal</ref><ref name="pmid11724918">Template:Cite journal</ref>

  • autonomic dysfunction: Post-void urinary residual volume ≥100 mL (usually by ultrasound); Unexplained urinary urge incontinence; or Neurogenic orthostatic hypotension (≥20/10 mmHg blood pressure drop) within 3 minutes (usually by head‐up tilt)
  • parkinsonism (muscle rigidity +/ tremor and slow movement: MSA-P)
  • cerebellar ataxia (Poor coordination/unsteady walking: MSA-C)

A variant with combined features of MSA and dementia with Lewy bodies may also exist.Template:MEDRS<ref>Template:MEDRSTemplate:Cite journal</ref> There have also been occasional instances of frontotemporal lobar degeneration associated with MSA.<ref name="pmid25962793">Template:Cite journal</ref>

Initial presentation

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.<ref name="Bensimon">Template:Cite journal</ref>

For men, the first sign can be erectile dysfunction. Women have also reported reduced genital sensitivity.<ref name="pmid12671951">Template:Cite journal</ref>

Progression

As the disease progresses, one of three groups of symptoms predominates. These are:<ref>Template:Cite journal</ref>

  1. Parkinsonism - slow, stiff movement, writing becomes small and spidery<ref>Template:Cite book</ref><ref>Template:Cite journal</ref>
  2. Cerebellar dysfunction - difficulty coordinating movement and balance<ref>Template:Cite book</ref>
  3. Autonomic nervous system dysfunction - impaired automatic body functions, including one, some, or all of the following:<ref>Template:DorlandsDict</ref>

Genetics

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.<ref name=Sasaki2011>Template:Cite journal</ref>

A follow-up study was unable to replicate this finding in American MSA patients.<ref name="pmid24170347">Template:Cite journal</ref> 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."Template:Clarify

Another study investigated the frequency of RFC1 intronic repeat expansions, a phenomenon implicated in CANVAS; a disease with a diagnostic overlap with MSA.<ref name=":1">Template:Cite journal</ref><ref>Template:Cite journal</ref> The study concluded that these repeats were absent in pathologically confirmed MSA, suggesting an alternative genetic cause.<ref name=":1" />

Pathophysiology

The defining pathologic feature of multiple system atrophy is the presence of inclusion bodies (known as glial cytoplasmic inclusions or Papp-Lantos bodies) consisting of alpha-synuclein in oligodendrocytes.<ref name="pmid20309568">Template:Cite journal</ref><ref name="Stefanova 2016">Template:Cite journal</ref> In addition, neurons are lost in several regions of the nervous system, particularly in the basal ganglia, inferior olivary nuclei, cerebellum, pons, and spinal cord.<ref name="Krismer 2024">Template:Cite journal</ref> Reactive astrocytes and microglia are prominent in damaged areas of the central nervous system, especially in regions with abundant oligodendroglial inclusions.<ref name="Krismer 2024"/> Neuronal cytoplasmic inclusions also are present in MSA, although these are much less numerous than are oligodendroglial inclusions.<ref name="Krismer 2024"/> Inclusions sometimes occur in the cell nucleus of neurons and oligodendrocytes.<ref name="Jellinger 2018">Template:Cite journal</ref><ref name="Stefanova 2016"/> Outside of the central nervous system, alpha‐synuclein inclusions may be found in Schwann cells of cranial, spinal and autonomic nerves and in the enteric nervous system.<ref name="Stefanova 2016"/>

The major proteinaceous component of glial and neuronal inclusions in MSA is alpha-synuclein<ref name="pmid9829806">Template:Cite journal</ref><ref name="Jellinger 2018"/> that is phosphorylated at serine residue 129.<ref name="Krismer 2024"/> Mutations in the gene for alpha-synuclein may play a role in the disease,<ref name="pmid19771175">Template:Cite journal</ref> and a variety of other potential genetic and environmental risk factors have been proposed.<ref name="Jellinger 2018"/> The conformation of alpha-synuclein in MSA is different from that of alpha-synuclein in Lewy bodies, indicative of variant proteopathic strains.<ref name="pmid29743672">Template:Cite journal</ref><ref name="Walker LC 2016">Template:Cite journal</ref>

The origin of the alpha-synuclein that forms inclusions in oligodendrocytes is uncertain. Compared to neurons, oligodendrocytes produce little or no alpha-synuclein themselves, suggesting that these cells take up the protein that is generated by neurons.<ref name="Walker 2018">Template:Cite journal</ref> For example, it has been proposed that the α-synuclein inclusions found in oligodendrocytes result from the pruning and engulfment of diseased axonal segments containing aggregated α-synuclein, i.e., of Lewy neurites.<ref>Template:Cite journal</ref> Research has shown that the strain of the protein generated by oligodendrocytes causes a more aggressive type of disease than does the Lewy body strain.<ref name="Walker 2018"/> The factors in oligodendrocytes that induce the formation of especially potent alpha-synuclein seeds are not known.<ref name="Walker 2018"/>

In addition to the primary protein alpha-synuclein, glial cytoplasmic inclusions contain several other types of protein as well as lysosomes and peroxisomes.<ref name="Krismer 2024"/> Tau proteins (the main components of neurofibrillary tangles) have been found in some glial cytoplasmic inclusions.<ref name="pmid11307630">Template:Cite journal</ref>

Diagnosis

Clinical

Clinical diagnostic criteria were defined in 1998<ref name="Gilman 94–8">Template:Cite journal</ref> and updated in 2007<ref name="pmid18725592"/> and in 2022.<ref>Template:Cite journal</ref> Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.<ref>Template:Cite web</ref><ref>Template:Cite journal</ref><ref name="pmid26138942">Template:Cite journal</ref>

Features characteristic of OPCA include progressive cerebellar ataxia, leading to clumsiness in body movements, veering from midline when walking, wide-based stance, and falls without signs of paralysis or weakness.<ref name=Landers>Template:Cite journal</ref><ref name=Berciano>Template:Cite journal</ref> Clinical presentation can vary greatly between patients, but mostly affects speech, balance and walking.<ref>Template:Cite web</ref> Other possible neurological problems include spasmodic dysphonia, hypertonia, hyperreflexia, rigidity, dysarthria, dysphagia and neck dystonic posture.<ref name=Berciano/> Dysarthria is characterized by increased pauses of irregular duration, impaired coordination of vocal pitch, prolonged syllables and an overall irregular speech rhythm.<ref>Template:Cite journal</ref> Diagnosis may be based on a thorough medical exam; the presence of signs and symptoms; imaging studies; various laboratory tests; and an evaluation of the family history.<ref>Template:Cite web</ref>

Radiologic

An MRI finding that is seen commonly in Multiple System atrophy. This occurs on the Pons.
The "Hot Cross Bun" sign, found in MSA with MRI

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.Template:Citation needed

Pathologic

Pathological diagnosis can only be made at autopsy by finding abundant glial cytoplasmic inclusions (GCIs) on histological specimens of the central nervous system.<ref name="pmid2559165">Template:Cite journal</ref>

Olivopontocerebellar atrophy can be used as a pathological term to describe degeneration of neurons in specific areas of the brain – the cerebellum, pons, and inferior olivary nucleus.<ref name=nidsopca>Template:Cite web</ref> OPCA is present in several neurodegenerative syndromes, including inherited and non-inherited forms of ataxia (such as the hereditary spinocerebellar ataxia known as Machado–Joseph disease) and MSA, with which it is primarily associated.<ref name=nidsopca/>

Contrary to most other synucleinopathies, which develop α-synuclein inclusions primarily in neuronal cell populations,<ref>Template:Cite journal</ref> MSA presents with extensive pathological α-synuclein inclusions in the cytosol of oligodendrocytes (glial cytoplasmic inclusions), with limited pathology in neurons.<ref>Template:Cite journal</ref> 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,<ref>Template:Cite journal</ref><ref name="Converging Patterns of α-Synuclein">Template:Cite journal</ref> rather than the brainstem, limbic and cortical regions typically effected in Lewy inclusion diseases.<ref name="Converging Patterns of α-Synuclein"/> 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.<ref name="Robust α-synuclein pathology in sel">Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name="Robust α-synuclein pathology in sel"/> 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite news</ref><ref name="pmca">Template:Cite journal</ref>

Classification

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.<ref name=Goedert2017>Template:Cite journal</ref>

Old terminology

Template:Infobox medical condition (new) 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,<ref name="pmid8628505">Template:Cite journal</ref> 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.<ref name="Ahmed-2012">Template:Cite journal</ref> A table describing the characteristics and modern names of these conditions follows:

Historical Name Characteristics Modern name and abbreviation
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.<ref name="Shy GM, Drager GA 1960 511–27">Template:Cite journal</ref> No modern equivalent – this terminology fell out of favour<ref name="pmid8644992">Template:Cite journal</ref> and was not specified in the 2007 consensus paper.<ref name="pmid18725592"/> The earlier consensus of 1998<ref name="Gilman 94–8"/> referred to MSA-A, "a" = autonomic dysfunction subtype but this subtype is no longer used.

The term olivopontocerebellar atrophy was originally coined by Joseph Jules Dejerine and André Thomas.<ref>Template:WhoNamedIt - "Dejerine-Thomas atrophy"</ref><ref>J. J. Dejerine, A. Thomas. L'atrophie olivo-ponto-cérébelleuse. Nouvelle iconographie de la Salpêtrière, Paris, 1900, 13: 330-370. 1912, 25: 223-250.</ref> It was subdivided as:

Number OMIM Alt. name Inheritance
OPCA type 2 Template:OMIM Fickler<ref>Fickler, A. Klinische und pathologisch-anatomische Beitraege zu den Erkrankungen des Kleinhirns. Dtsch. Z. Nervenheilk. 41: 306-375, 1911.</ref>-Winkler<ref>Winkler, C. A case of olivo-pontine cerebellar atrophy and our conceptions of neo- and palaio-cerebellum. Schweiz. Arch. Neurol. Psychiat. 13: 684-702, 1923.</ref> type OPCA autosomal recessive
OPCA type 5 Template:OMIM OPCA with dementia and extrapyramidal signs autosomal dominant

Non-hereditary diseases formerly categorized as olivopontocerebellar atrophy have were reclassified as forms of MSA<ref>MeSH Result</ref> as well as to four hereditary types, that have been currently reclassified as four different forms of spinocerebellar ataxia:

Hereditary OPCA type OPCA name SCA # Gene OMIM
OPCA type 1 "Menzel type OPCA" SCA1 ATXN1 Template:OMIM
OPCA type 2, autosomal dominant "Holguin type OPCA" SCA2 ATXN2 Template:OMIM
OPCA type 3 "OPCA with retinal degeneration" SCA7 ATXN7 Template:OMIM
OPCA type 4 "Schut-Haymaker type OPCA" SCA1 ATXN1 Template:OMIM

Current terminology

The current terminology and diagnostic criteria for the disease were established at a 2007 conference of experts and set forth in a position paper.<ref name="pmid18725592">Template:Cite journal</ref> This Second Consensus Statement defines two categories of MSA, based on the predominant symptoms of the disease at the time of evaluation. These are:

  • MSA with predominant parkinsonism (MSA-P) - defined as MSA where extrapyramidal features predominate. It is sometimes termed striatonigral degeneration, a parkinsonian variant.Template:Citation needed
  • MSA with cerebellar features (MSA-C) - defined as MSA in which cerebellar ataxia predominates. It is sometimes termed sporadic olivopontocerebellar atrophy.Template:Citation needed

Management

Supervision

Ongoing care from a neurologist specializing in movement disorders is recommended,Template: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.Template:Citation needed

Drug therapy

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.<ref name="Calandra-BuonauraDoria2015">Template:Cite journal</ref>

The drug riluzole is ineffective in treating MSA or PSP.<ref name="Bensimon"/>

Rehabilitation

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.Template:Citation needed

Physiotherapists can help to maintain the patient's mobility and will help to prevent contractures.<ref name=Wenning04>Template:Cite journal
Template:Cite journal</ref> Instructing patients in gait training will help to improve their mobility and decrease their risk of falls.<ref name="Hardy">Template:Cite journal</ref> A physiotherapist may also prescribe mobility aids such as a cane or a walker to increase the patient's safety.<ref name="Hardy"/>

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.Template:Citation needed

Early intervention of swallowing difficulties is particularly useful to allow for discussion around tube feeding further in the disease progression.Template:Citation needed At some point in the progression of the disease, fluid and food modification may be implemented.Template:Citation needed

Avoidance of postural hypotension

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.<ref name="MayoMSA" /><ref name=":2">Template:Cite journal</ref> Another common drug treatment is the alpha-agonist midodrine.<ref name=MayoMSA>Multiple system atrophy (MSA) mayoclinic.org, accessed 20 May 2018</ref>

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.<ref name=":2" /> 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.<ref name="Hardy"/> Instruction in ankle pumping helps to return blood in the legs to the systemic circulation.<ref name=Hardy /> 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.<ref name="pmid10331752"/>

Supine hypertension

In addition to orthostatic hypotension, supine hypertension, where the BP is excessively high lying down, is a frequent problem in multiple system atrophy. Treatment of one symptom can easily aggravate the other, and supine hypertension in such patients has been linked to the same cardiovascular complications as essential hypertension.<ref>Template:Cite journal</ref>

Support

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.Template:Citation needed

Prognosis

The average lifespan after the onset of symptoms in patients with MSA is 6–10 years.<ref name=":0" /> Approximately 60% of patients require a wheelchair within five years of onset of the motor symptoms, and few patients survive beyond 12 years.<ref name=":0" /> 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.<ref name=":0" /> Those with predominantly cerebellar features and those who display autonomic dysfunction later have a better prognosis.<ref name=":0" />

Causes of death

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.<ref>Template:Cite journal</ref>

Epidemiology

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.<ref name=":0">Template:Cite journal</ref> 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.<ref name=":0" /><ref name="pmid10331752"/><ref name=Wenning04/> The condition most commonly presents in persons aged 50–60.<ref name=":0" />

Research

Mesenchymal stem cell therapy may delay the progression of neurological deficits in patients with MSA-cerebellar type.<ref name="Yonsei University study">Template:Cite journal</ref>

Notable cases

See also

References

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Template:Autonomic diseases Template:CNS diseases of the nervous system

ca:Síndrome de Shy-Drager es:Síndrome de Shy-Drager pt:Síndrome de Shy-Drager ro:Sindromul Shy-Drager sl:Shy-Dragerjev sindrom

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