Multiple system atrophy
Encyclopedia
Multiple system atrophy (MSA) is a degenerative
neurological disorder
. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance and other autonomic functions of the body such as bladder control or blood pressure regulation. The cause of MSA is unknown and no specific risk factors have been identified. Around 55% of cases occur in men, with typical age of onset in the late 50s to early 60s.
The overall prevalence
of MSA is estimated at 4.6 cases per 100,000 people.
When autonomic
failure predominates, the term Shy-Drager syndrome is sometimes used, although this term is no longer current, given the terminology changes which are explained below. This syndrome was named after Dr Milton Shy and Dr Glenn Drager, who identified it in 1960, but the American Autonomic Society and the American Academy of Neurology redefined it as multiple system atrophy with autonomic phenomena in 1996.
A variant with combined features of MSA and Lewy body dementia may also exist.
) 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). 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 suffer a fall in their first year of disease.
These common first signs are the same as those of subacute combined degeneration of the spinal cord, which is caused by vitamin B12 deficiency:
Patients present with weakness of legs, arms, trunk, tingling and numbness that progressively worsens. Vision changes and change of mental state may also be present. Bilateral spastic paresis may develop and pressure, vibration and touch sense are diminished. A positive Babinski sign may be seen. Prolonged deficiency of vitamin B12 leads to irreversible nervous system damage
Vitamin B12 should be tested directly; it cannot be ruled out by a complete blood count. In the age of folic acid fortification, patients will not have macrocytic anemia. http://jnnp.bmj.com/content/65/6/822.abstract
These are:
Other symptoms such as double vision can occur.
Not all patients experience all of these symptoms.
Some patients (20% in one study) experience significant cognitive impairment as a result of MSA.
O’Sullivan and colleagues (2008) identified early autonomic dysfunction to be the most important early clinical prognostic feature regarding survival in MSA. Patients with concomitant motor and autonomic dysfunction within 3 years of symptom onset had a shorter survival duration, in addition to becoming wheelchair dependent and bed-ridden at an earlier stage than those who developed these symptoms after 3 years from symptom onset. Their study also showed that when patients with early autonomic dysfunction develop frequent falling, or wheelchair dependence, or severe dysphagia, or require residential care, there is a shorter interval from this point to death.
A definitive diagnosis can only be made pathologically on finding abundant glial cytoplasmic inclusions in the central nervous system.
Ongoing care from a neurologist specialized in "movement disorders" is recommended 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 thus injury from falling) often responds to fludrocortisone
, a synthetic mineralocorticoid
. Another common drug treatment is midodrine
(an alpha-agonist.) 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 (e.g. hot weather, alcohol
, dehydration) are crucial.
Hospice/homecare services can be very useful as disability progresses.
Levodopa
(L-Dopa), a drug used in the treatment of Parkinson's disease
, fails to improve the parkinsonian symptoms of most MSA patients. A recent trial reported that only 1.5% of MSA patients experienced a less than 50% improvement when taking levodopa, and even this 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 recent study conducted in Europe failed to find an effect for the drug riluzole
in treating MSA or PSP.
Physiotherapy can help to maintain the patient’s mobility and will help to prevent contractures. Instructing patients in gait training
will help to improve their mobility and decrease their risk of falls. A physiotherapist may also prescribe mobility aids
such as a cane or a walker in order to increase the patient’s safety. Other ways a physiotherapist can help to improve the patient’s safety is to teach them to move and transfer from sitting to standing slowly to decrease risk of falls and limit the effect of postural hypotension. Instruction in ankle pumping helps to return blood in the legs to the systemic circulation
.
In order to further control the postural hypotension, raising the head of the bed by 8 inches (20.3 cm) while sleeping may be indicated as well as the use of elastic compression garment
s.
Social workers can also help with coping with disability and access to health care services, both for the person with MSA as well as his/her family caregivers.
are visible. When brain tissue of a person with MSA is examined under a microscope, these glial structures are visible, confirming the diagnosis. The presence of these inclusions (also known as Papp-Lantos bodies) in the movement, balance and automatic control centres of the brain are the defining histopathologic hallmark of MSA. Recent studies have shown that major fillamentous component of glial and neuronal cytoplasmic inclusions is alpha-synuclein
. Mutations in this substance may play a role in the disease.
Tau proteins have been found in some GCIs
These terms and their distinctions have been dropped in recent (1996 onwards) medical usage and replaced with MSA subtype naming, but are helpful to understanding the older literature about this disease:
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."
The Second Consensus Statement defines two categories of MSA, based on the predominant symptoms of the disease at the time of evaluation. These are:
Sophie's Search for a Cure ( 64 min., color, documentary, 2007; DVD ) chronicles one woman's struggle with Multiple System Atrophy (MSA). DVD available from the SDS/MSA Support Group, Inc. www.shy-drager.org/ http://www.shy-drager.org/
Degenerative disease
A degenerative disease, also called neurodegenerative disease, is a disease in which the function or structure of the affected tissues or organs will progressively deteriorate over time, whether due to normal bodily wear or lifestyle choices such as exercise or eating habits...
neurological disorder
Neurological disorder
A neurological disorder is a disorder of the body's nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or in the nerves leading to or from them, can result in symptoms such as paralysis, muscle weakness, poor coordination, loss of sensation, seizures,...
. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance and other autonomic functions of the body such as bladder control or blood pressure regulation. The cause of MSA is unknown and no specific risk factors have been identified. Around 55% of cases occur in men, with typical age of onset in the late 50s to early 60s.
The overall prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of MSA is estimated at 4.6 cases per 100,000 people.
Symptoms
MSA is characterized by a combination of the following, which can be present in any combination:- autonomic dysfunction
- parkinsonismParkinsonismParkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
(muscle rigidity +/ tremorTremorA tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
and slow movement) - ataxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
(Poor coordination / unsteady walking)
When autonomic
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
failure predominates, the term Shy-Drager syndrome is sometimes used, although this term is no longer current, given the terminology changes which are explained below. This syndrome was named after Dr Milton Shy and Dr Glenn Drager, who identified it in 1960, but the American Autonomic Society and the American Academy of Neurology redefined it as multiple system atrophy with autonomic phenomena in 1996.
A variant with combined features of MSA and Lewy body dementia may also exist.
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 diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
) 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
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
(inability to achieve or sustain an erection). 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 suffer a fall in their first year of disease.
These common first signs are the same as those of subacute combined degeneration of the spinal cord, which is caused by vitamin B12 deficiency:
Patients present with weakness of legs, arms, trunk, tingling and numbness that progressively worsens. Vision changes and change of mental state may also be present. Bilateral spastic paresis may develop and pressure, vibration and touch sense are diminished. A positive Babinski sign may be seen. Prolonged deficiency of vitamin B12 leads to irreversible nervous system damage
Vitamin B12 should be tested directly; it cannot be ruled out by a complete blood count. In the age of folic acid fortification, patients will not have macrocytic anemia. http://jnnp.bmj.com/content/65/6/822.abstract
Symptoms as disease progresses
As the disease progresses three groups of symptoms predominate.These are:
- ParkinsonismParkinsonismParkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
(slow, stiff movement, writing becomes small and spidery) - Cerebellar dysfunction (difficulty coordinating movement and balance)
- Autonomic dysfunction (impaired automatic body functions) including:
- postural or orthostatic hypotensionOrthostatic hypotensionOrthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
, resulting in dizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
or fainting upon standing up - urinary incontinenceUrinary incontinenceUrinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
or urinary retentionUrinary retentionUrinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications... - impotence
- constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
- vocal cord paralysis
- dry mouth and skin
- trouble regulating body temperature due to abnormal sweatingSweatingPerspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
- abnormal breathing or inspiratory stridorStridorStridor is a high pitched wheezing sound resulting from turbulent air flow in the upper airway. Stridor is a physical sign which is produced by narrow or obstructed airway path. It can be inspiratory, expiratory or biphasic . Inspiratory stridor is common...
during sleep - other sleep disorders including sleep apneaSleep apneaSleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing, during sleep. Each pause in breathing, called an apnea, can last from a few seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low...
, REM Behavior Disorder
- postural or orthostatic hypotension
Other symptoms such as double vision can occur.
Not all patients experience all of these symptoms.
Some patients (20% in one study) experience significant cognitive impairment as a result of MSA.
Prognosis
MSA usually progresses more quickly than Parkinson's disease. There is no remission from the disease. The prevalence of MSA varies by study from between 3 and 20 in 100,000 people. The remaining lifespan after the onset of symptoms in patients with MSA is between 7.3 and 9.3 years. This disease is more common in men than women, with studies showing ratios ranging from between 1.4:1 to ratios as high as 1.9:1. Some believe that the higher ratio may be due to greater environmental exposure to putative toxins in men, or difference in endogenous protective factors (hormonal) in women. Almost 80% of patients are disabled within 5 years of onset of the motor symptoms, and only 20% survive past 12 years. Rate of progression differs in every case and speed of decline may vary widely in individual patients.O’Sullivan and colleagues (2008) identified early autonomic dysfunction to be the most important early clinical prognostic feature regarding survival in MSA. Patients with concomitant motor and autonomic dysfunction within 3 years of symptom onset had a shorter survival duration, in addition to becoming wheelchair dependent and bed-ridden at an earlier stage than those who developed these symptoms after 3 years from symptom onset. Their study also showed that when patients with early autonomic dysfunction develop frequent falling, or wheelchair dependence, or severe dysphagia, or require residential care, there is a shorter interval from this point to death.
Diagnosis
Diagnosis of MSA can be challenging because there is no test that can definitively make or confirm the diagnosis in a living patient. Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.A definitive diagnosis can only be made pathologically on finding abundant glial cytoplasmic inclusions in the central nervous system.
Treatment
There is no discovered cure for MSA, so treatment involves treating the symptoms.Ongoing care from a neurologist specialized in "movement disorders" is recommended 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 thus injury from falling) often responds to fludrocortisone
Fludrocortisone
Fludrocortisone is a synthetic corticosteroid with moderate glucocorticoid potency and much greater mineralocorticoid potency. The brand name in the U.S. and Canada is Florinef.-Uses:...
, a synthetic mineralocorticoid
Mineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
. Another common drug treatment is midodrine
Midodrine
Midodrine is a vasopressor/antihypotensive agent. Midodrine was approved in the United States by the Food and Drug Administration in 1996 for the treatment of orthostatic hypotension...
(an alpha-agonist.) 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 (e.g. hot weather, alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
, dehydration) are crucial.
Hospice/homecare services can be very useful as disability progresses.
Levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
(L-Dopa), a drug used in the treatment of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, fails to improve the parkinsonian symptoms of most MSA patients. A recent trial reported that only 1.5% of MSA patients experienced a less than 50% improvement when taking levodopa, and even this 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
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
A recent study conducted in Europe failed to find an effect for the drug riluzole
Riluzole
Riluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months....
in treating MSA or PSP.
Rehabilitation
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. Instructing patients in gait training
Gait training
In its most general form, Gait training is the act of learning how to walk. However, the term is more often used in reference to a person learning how to walk again after injury or with a disability...
will help to improve their mobility and decrease their risk of falls. A physiotherapist may also prescribe mobility aids
Mobility aids
Mobility aids are devices designed to assist walking or otherwise improve the mobility of people with a mobility impairment.There are various walking aids which can help with impaired ability to walk and wheelchairs or mobility scooters for more severe disability or longer journeys which would...
such as a cane or a walker in order to increase the patient’s safety. Other ways a physiotherapist can help to improve the patient’s safety is to teach them to move and transfer from sitting to standing slowly to decrease risk of falls and limit the effect of postural hypotension. Instruction in ankle pumping helps to return blood in the legs to the systemic circulation
Systemic circulation
Systemic circulation is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart. This physiologic theory of circulation was first described by William Harvey...
.
In order to further control the postural hypotension, raising the head of the bed by 8 inches (20.3 cm) while sleeping may be indicated as well as the use of elastic compression garment
Compression garment
Compression garments are pieces of clothing such as socks, pantyhose, sleeves, etc, that provide support that is especially useful for people who have to stand for long periods, or people with poor circulation. The garments can come in varying degrees of compression. The higher degrees require a...
s.
Social workers can also help with coping with disability and access to health care services, both for the person with MSA as well as his/her family caregivers.
Histopathology
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. Currently, a confirmed diagnosis of MSA can only be made post-mortem as glial cytoplasmic inclusion bodiesInclusion bodies
Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins...
are visible. When brain tissue of a person with MSA is examined under a microscope, these glial structures are visible, confirming the diagnosis. The presence of these inclusions (also known as Papp-Lantos bodies) in the movement, balance and automatic control centres of the brain are the defining histopathologic hallmark of MSA. Recent studies have shown that major fillamentous component of glial and neuronal cytoplasmic inclusions is alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...
. Mutations in this substance may play a role in the disease.
Tau proteins have been found in some GCIs
Terminology
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).These terms and their distinctions have been dropped in recent (1996 onwards) medical usage and replaced with MSA subtype naming, but are helpful to understanding the older literature about this disease:
| Name | Characteristics | Abbreviation >- | Striatonigral degeneration |
predominating Parkinson's Parkinson's disease Parkinson's disease is a degenerative disorder of the central nervous system... -like symptoms |
>- | 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 |
| characterized by Parkinsonism plus a more pronounced failure of the autonomic nervous system Autonomic nervous system The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,... . This subtype was referred to in the 1996 Consensus Statement as MSA-a, "a" = autonomic dysfunction subtype. |
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."
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.
Genomics
A possible link has been identified with the gene (Src homology 2 domain containing) transforming protein 2 located in the distal 350-kb subtelomeric region of chromosome 19 (19p13.3)Living with MSA
Carlos Cristos, a Spanish physician who died of MSA in 2008, is the subject of an inspiring documentary film about his coping with the disease, Las Alas de la Vida [The Wings of Life] (2007).Sophie's Search for a Cure ( 64 min., color, documentary, 2007; DVD ) chronicles one woman's struggle with Multiple System Atrophy (MSA). DVD available from the SDS/MSA Support Group, Inc. www.shy-drager.org/ http://www.shy-drager.org/
External links
- Autonomic Dysfunction Center at Vanderbilt UniversityVanderbilt UniversityVanderbilt University is a private research university located in Nashville, Tennessee, United States. Founded in 1873, the university is named for shipping and rail magnate "Commodore" Cornelius Vanderbilt, who provided Vanderbilt its initial $1 million endowment despite having never been to the...
- The Multiple System Atrophy Trust founded by Sarah Matheson, a UK registered charity providing information about MSA.
- The European MSA Study Group, an Innsbruck based European MSA Study Group comprising 25 academic centres of excellence dedicated to MSA research
- The SDS/MSA Support Group, Inc., A US-based non-profit for people with MSA
- March has been designated as Multiple System Atrophy Awareness Month http://www.MSAawareness.org
- October 3 has been designated at World MSA Day http://www.World-MSA-Day.org