Multiple system atrophy

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Multiple system atrophy
MSA aSynuclein.jpg
Alpha synuclein immunohistochemistry showing many glial inclusions
SpecialtyNeurology Edit this on Wikidata

Multiple system atrophy (MSA), also known as Shy–Drager syndrome, is a rare neurodegenerative disorder[1] characterized by tremors, slow movement, muscle rigidity, and postural instability (collectively known as parkinsonism) due to dysfunction of the autonomic nervous system, and ataxia. This is caused by progressive degeneration of neurons in several parts of the brain including the substantia nigra, striatum, inferior olivary nucleus, and cerebellum.

Many people affected by multiple system atrophy 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.

The cause of MSA is uncertain and no specific risk factor has been identified,[2] although current research indicates that a modified form of the alpha-synuclein protein may cause the disease.[3] About 55% of MSA cases occur in men, with those affected first showing symptoms at the age of 50-60 years. [4] MSA often presents with some of the same symptoms as Parkinson's disease. However, those with MSA generally show little response to the dopamine medications used to treat Parkinson's disease, and only about 9% of MSA patients with tremor had a true parkinsonian pill-rolling tremor.[5]

MSA is distinct from multisystem proteinopathy, a more common muscle wasting syndrome. It should also not be confused with multiple organ dysfunction syndrome (sometimes referred to as multiple organ failure), or with multiple organ system failure (an often-fatal complication of septic shock or other very severe illnesses or injuries).

Classification[edit]

MSA, Parkinson's disease, the Lewy body dementias, and other more rare conditions make up the synucleinopathiesneurodegenerative diseases that are characterized by an abnormal accumulation of alpha-synuclein protein in the brain.[6]

Many terms have historically been used to refer to this disorder, based on the predominant systems presented. These include olivopontocerebellar atrophy (OPCA), Shy–Drager syndrome (SDS), and striatonigral degeneration (SND), which were once considered to be separate disorders.[7]

These terms and their distinctions have been dropped in recent (1996 onwards) medical usage[8] and replaced with MSA and its subtypes, but are helpful to understanding the older literature about this disease:

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.[9] No modern equivalent – this terminology fell out of favour[10] and was not specified in the 2007 consensus paper.[11] The earlier consensus of 1998[12] 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 on the disease and set forth in the "Second consensus statement on the diagnosis of multiple system atrophy."[11]

The 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). MSA-P is defined as MSA where extrapyramidal features predominate. The term striatonigral degeneration, parkinsonian variant, is sometimes used for this category of MSA.
  • MSA with cerebellar features (MSA-C). MSA-C is defined as MSA where cerebellar ataxia predominates. It is sometimes termed sporadic olivopontocerebellar atrophy.

Signs and symptoms[edit]

MSA is characterized by the following, which can be present in any combination:[13][14]

A variant with combined features of MSA and Lewy body dementia may also exist.[unreliable medical source?][15] There have also been occasional instances of frontotemporal lobar degeneration associated with MSA.[16]

Initial presentation[edit]

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 problems (9%). For men, the first sign can be erectile dysfunction (inability to achieve or sustain an erection). Women have also reported reduced genital sensitivity.[17] Both men and women often experience problems with their bladders including urgency, frequency, incomplete bladder emptying, or an inability to pass urine (retention). About 1 in 5 MSA patients will fall in their first year of disease.[18]

Progression[edit]

As the disease progresses one of three groups of symptoms predominate. These are:

  1. Parkinsonism (slow, stiff movement, writing becomes small and spidery)
  2. Cerebellar dysfunction (difficulty coordinating movement and balance)
  3. Autonomic nervous system dysfunction (impaired automatic body functions) including:

Other symptoms such as double vision can occur.[20] Not all patients experience all of these symptoms.

Some patients (20% in one study) experience significant cognitive impairment as a result of MSA.[21]

Genetics[edit]

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.[22] 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. (See Copy-number variation for a general discussion of gene copy deletion and the variation in the number of copies of one or more sections of the DNA.)

A follow-up study was unable to replicate this finding in American MSA patients.[23] The authors of the U.S. 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."

Pathophysiology[edit]

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.[24] The presence of these inclusions (also known as Papp–Lantos bodies) in the movement, balance, and autonomic-control centres of the brain are the defining histopathologic hallmark of MSA. Recent studies have shown that the major filamentous component of glial and neuronal cytoplasmic inclusions is alpha-synuclein.[25] Mutations in this substance may play a role in the disease.[26] Tau proteins have been found in some glial cytoplasmic inclusions (GCI)s.[27]

A study in 2018 suggests a post-translationally modified form of the protein called alpha-synuclein may be a causal agent for the disease.[3]

Diagnosis[edit]

Diagnosis of MSA can be challenging because there is no test that can definitively make or confirm the diagnosis in a living patient. Clinical diagnostic criteria were defined in 1998[12] and updated in 2007.[11] Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.[28][29][30]

Both MRI and CT scanning frequently show a decrease in the size of the cerebellum and pons in those with cerebellar features (MSA-C). The putamen is hypodense 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 has been identified; it reflects atrophy of the pontocerebellar fibers that manifest in T2 signal intensity in the atrophic pons.

A definitive diagnosis can only be made pathologically on finding abundant GCIs in the central nervous system.[31]

Management[edit]

There is no known cure for MSA and management is primarily supportive.

Ongoing care from a neurologist specializing in movement disorders is recommended[by whom?], as the complex symptoms of MSA are often not familiar to less-specialized health care professionals.

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.[32] Another common drug treatment is midodrine (an alpha-agonist).[32] 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.[33]

Hospice/homecare services can be very useful as disability progresses.

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.

A November, 2008 study conducted in Europe failed to find an effect for the drug riluzole in treating MSA or PSP.[18]

Rehabilitation[edit]

Management by rehabilitation professionals (physiatrists, physiotherapists, occupational therapists, speech therapists, and others) for problems with walking/movement, daily tasks, and speech problems is essential.

Physiotherapy can help to maintain the patient’s mobility and will help to prevent contractures.[24] Instructing patients in gait training will help to improve their mobility and decrease their risk of falls.[34] A physiotherapist may also prescribe mobility aids such as a cane or a walker to increase the patient’s safety.[34] Other ways a physiotherapist can help to improve the patient’s safety are to teach them to move and transfer from sitting to standing slowly to decrease risk of falls and limit the effect of postural hypotension.[34] Instruction in ankle pumping helps to return blood in the legs to the systemic circulation.[34] To further control the postural hypotension, raising the head of the bed by 8 in (20.3 cm) while sleeping may be indicated as well as the use of elastic compression garments.[13]

Speech and language therapists may assist in assessing, treating and supporting speech (dysarthria) and swallowing difficulties (dysphagia). 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 suggested. Speech changes mean that alternative communication may be needed, for example communication aids or word charts.

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.

Prognosis[edit]

The average remaining lifespan after the onset of symptoms in patients with MSA is 6-10 years. [4] Approximately 60% of patients require a wheelchair within five years of onset of the motor symptoms, and few patients survive beyond 12 years. [4] 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. [4] Those with predominantly cerebellar features and those who display autonomic dysfunction later have a better prognosis. [4]

Causes of Death[edit]

The most common causes of death are sudden death or death caused by infections, primarily urinary catheterization infections, feeding tube infection, and infections caused by Pulmonary aspiration, such as aspiration pneumonia. Some deaths are caused from Cachexia, also known as Wasting Syndrome, which manifests itself as loss of weight, muscle atrophy, fatigue, weakness and significant loss of appetite. [35]

Epidemiology[edit]

Multiple-system atrophy is estimated to affect approximately 4 per 100,000 people. [4] While some suggest that MSA is more likely to affect men than women, others suggest that the two sexes are equally likely to be affected. [4][24][13] The condition most commonly presents in persons aged 50-60. [4]

Notable Cases[edit]

  • Nikolai Andrianov was a Soviet/Russian gymnast who held the record for men for the most Olympic medals at 15 (7 gold medals, 5 silver medals, 3 bronze medals) until Michael Phelps surpassed him at the 2008 Beijing Summer Olympics.[37]

Research[edit]

A July, 2012, study suggested that mesenchymal stem cell therapy could delay the progression of neurological deficits in patients with MSA-cerebellar type, suggesting the potential of mesenchymal stem cell therapy as a treatment candidate of MSA.[39]

References[edit]

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  39. ^ Lee PH, Lee JE, Kim HS, Song SK, Lee HS, Nam HS, et al. (July 2012). "A randomized trial of mesenchymal stem cells in multiple system atrophy". Ann. Neurol. 72 (1): 32–40. doi:10.1002/ana.23612. PMID 22829267.

External links[edit]

Classification
External resources