Updated 5.23.2016
Multiple System Atrophy(MSA) is a complex neurodegenerative disorder that affects multiple areas of the brain. Autonomic or urogenital dysfunction are the hallmark symptoms accompanied by either cerebellar ataxia or parkinsonism or both. There are two categories or MSA known as MSA-C (cerebellar) and MSA-P (parkinsonism). Previously the term MSA-A (autonomic) was used but this has been discontinued since autonomic or urinary symptoms are required for a diagnosis of probable MSA. As of 2014 there is no reliable biomarker to diagnose MSA with 100% certainly. Brain autopsy within 24 hours of death is currently the only method of diagnosing definite MSA.
Excellent sources of information on MSA with links to other articles and support organizations world wide can be found here:
http://www.MSAawareness.org
See also:
http://www.Multiple-System-Atrophy.org
http://www.msatrust.org.uk/living-with-msa/
http://surfcoastwombat.com/
http://www.emsa-sg.org/index.php?id=8
http://www.World-MSA-Day.org
You may also know MSA as Shy-Drager Syndrome(SDS), Striatonigral
Degeneration(SND) or Sporadic Olivopontocerebellar
Atrophy(OPCA). These three disorders have now been lumped
together and are considered one disorder by the MSA research
experts. By definition, MSA is a sporadic (non-hereditary) disorder. There are
some hereditary forms of cerebellar ataxia known as SCA1 thru SCA21
these disorders do not fall under the MSA umbrella but it is recommended that
anyone with ataxia symptoms be screened genetically to rule these out.
If you need more information on Hereditary Ataxia please contact the National
Ataxia Foundation. http://www.ataxia.org
MSA RESEARCH:
There is now a World MSA Study Group led by Professor Gregor Wenning made up of MSA researchers from around the globe. There goal is to work towards uncovering the exact cause and finding effective treatments and ultimately a cure. You can read their mission statement here:
http://www.movementdisorders.org/MDS/About/Committees--Other-Groups/Study-Groups/Multiple-System-Atrophy.htm
If you have a question for Professor Gregor Wenning please feel free to write him via this site:
http://www.msaawareness.org/?page_id=26
See also the European Multiple System Atrophy Study Group(EMSA-SG)
http://www.emsa-sg.org
Current research articles on MSA can be found by searching Pubmed at:
http://www.ncbi.nlm.nih.gov/pubmed/
Clinical trials accepting MSA patients can be found by searching:
http://www.clinicaltrials.gov
SUPPORT ORGANIZATIONS:
Multiple System Atrophy is recognized by several charitable
organizations. Their support groups all welcome people with
MSA, their caregivers and relatives.
The Multiple System Atrophy Coalition (USA)
http://www.Multiple-System-Atrophy.org
Their toll free lines are staffed 24 hours a day for personal support.
From Canada or USA call 1-866-737-5999 or 1-866-737-4999
See this list of local area support groups for MSA (US and Canada)
http://www.Multiple-System-Atrophy.org/local-support-groups
The Multiple System Atrophy Trust (UK)
http://www.msaweb.co.uk
ARAMISE - Association for Research on MSA, Information, Help to patients
in Europe (French Language Site)
http://asso.orpha.net/ARAMISE/cgi-bin/index.php
The Danish MSA Society, Landsforeningen Multipel System Atrofi (Danish Language site)
http://www.msa-danmark.dk
Benelux support group for people with MSA(Multi-lingual site)
http://www.msa-ams.be
The National Ataxia Foundation in the US
(They recognize MSA as a form of sporadic ataxia)
http://www.ataxia.org
The National Dysautonomia Research Foundation in the US
(They recognize MSA as a dysautonomia - disorder of the
autonomic nervous system).
http://www.ndrf.org
FACEBOOK:
Become a fan of "Miracles for MSA" and invite your friends. Some small miracles are already happening, let's see if we can make more. Miracles for MSA is spreading around the world. Regardless of which particular MSA charity you support or which MSA discussion board you participate in regularly, we are all in this together. Let's get these miracles going!
http://www.facebook.com/Miracles-for-MSA
SIMILAR DISORDERS:
Various Parkinson Disease Societies and Foundations
worldwide recognize MSA as a "Parkinson-Plus" Disorder.
Many people with MSA are first diagnosed with Parkinsons
Disease(PD) or with another of the Parkinson-Plus(PD+)
disorders which all have similar symptoms as MSA.
Parkinson-Plus (PD+) disorders include Progressive Supranuclear
Palsy(PSP), Corticobasal Ganglionic Degeneration(CBDG) and
Lewy Body Dementia(LBD)
Do check out support groups for PD and PD+ disorders as well
as they also usually welcome people with MSA.
ONLINE SUPPORT:
IN ENGLISH:
There is an online support group "mailing list" for MSA at
http://groups.yahoo.com/group/shydrager
Join the group online and read messages there or subscribe
and receive daily emails by sending a blank email to
shydrager-subscribe@yahoogroups.com
IN FRENCH:
For those who can converse in the French language there is
another group located at:
http://fr.groups.yahoo.com/group/shydragers
Regards,
Pam
Moderator, "shydrager" Multiple System Atrophy Online Support Group
pbower@accesscable.net
http://groups.yahoo.com/group/shydrager
Multiple System Atrophy(MSA) is a complex neurodegenerative disorder that affects multiple areas of the brain. Autonomic or urogenital dysfunction are the hallmark symptoms accompanied by either cerebellar ataxia or parkinsonism or both. There are two categories or MSA known as MSA-C (cerebellar) and MSA-P (parkinsonism). Previously the term MSA-A (autonomic) was used but this has been discontinued since autonomic or urinary symptoms are required for a diagnosis of probable MSA. As of 2014 there is no reliable biomarker to diagnose MSA with 100% certainly. Brain autopsy within 24 hours of death is currently the only method of diagnosing definite MSA.
Excellent sources of information on MSA with links to other articles and support organizations world wide can be found here:
http://www.MSAawareness.org
See also:
http://www.Multiple-System-Atrophy.org
http://www.msatrust.org.uk/living-with-msa/
http://surfcoastwombat.com/
http://www.emsa-sg.org/index.php?id=8
http://www.World-MSA-Day.org
You may also know MSA as Shy-Drager Syndrome(SDS), Striatonigral
Degeneration(SND) or Sporadic Olivopontocerebellar
Atrophy(OPCA). These three disorders have now been lumped
together and are considered one disorder by the MSA research
experts. By definition, MSA is a sporadic (non-hereditary) disorder. There are
some hereditary forms of cerebellar ataxia known as SCA1 thru SCA21
these disorders do not fall under the MSA umbrella but it is recommended that
anyone with ataxia symptoms be screened genetically to rule these out.
If you need more information on Hereditary Ataxia please contact the National
Ataxia Foundation. http://www.ataxia.org
MSA RESEARCH:
There is now a World MSA Study Group led by Professor Gregor Wenning made up of MSA researchers from around the globe. There goal is to work towards uncovering the exact cause and finding effective treatments and ultimately a cure. You can read their mission statement here:
http://www.movementdisorders.org/MDS/About/Committees--Other-Groups/Study-Groups/Multiple-System-Atrophy.htm
If you have a question for Professor Gregor Wenning please feel free to write him via this site:
http://www.msaawareness.org/?page_id=26
See also the European Multiple System Atrophy Study Group(EMSA-SG)
http://www.emsa-sg.org
Current research articles on MSA can be found by searching Pubmed at:
http://www.ncbi.nlm.nih.gov/pubmed/
Clinical trials accepting MSA patients can be found by searching:
http://www.clinicaltrials.gov
SUPPORT ORGANIZATIONS:
Multiple System Atrophy is recognized by several charitable
organizations. Their support groups all welcome people with
MSA, their caregivers and relatives.
The Multiple System Atrophy Coalition (USA)
http://www.Multiple-System-Atrophy.org
Their toll free lines are staffed 24 hours a day for personal support.
From Canada or USA call 1-866-737-5999 or 1-866-737-4999
See this list of local area support groups for MSA (US and Canada)
http://www.Multiple-System-Atrophy.org/local-support-groups
The Multiple System Atrophy Trust (UK)
http://www.msaweb.co.uk
ARAMISE - Association for Research on MSA, Information, Help to patients
in Europe (French Language Site)
http://asso.orpha.net/ARAMISE/cgi-bin/index.php
The Danish MSA Society, Landsforeningen Multipel System Atrofi (Danish Language site)
http://www.msa-danmark.dk
Benelux support group for people with MSA(Multi-lingual site)
http://www.msa-ams.be
The National Ataxia Foundation in the US
(They recognize MSA as a form of sporadic ataxia)
http://www.ataxia.org
The National Dysautonomia Research Foundation in the US
(They recognize MSA as a dysautonomia - disorder of the
autonomic nervous system).
http://www.ndrf.org
FACEBOOK:
Become a fan of "Miracles for MSA" and invite your friends. Some small miracles are already happening, let's see if we can make more. Miracles for MSA is spreading around the world. Regardless of which particular MSA charity you support or which MSA discussion board you participate in regularly, we are all in this together. Let's get these miracles going!
http://www.facebook.com/Miracles-for-MSA
SIMILAR DISORDERS:
Various Parkinson Disease Societies and Foundations
worldwide recognize MSA as a "Parkinson-Plus" Disorder.
Many people with MSA are first diagnosed with Parkinsons
Disease(PD) or with another of the Parkinson-Plus(PD+)
disorders which all have similar symptoms as MSA.
Parkinson-Plus (PD+) disorders include Progressive Supranuclear
Palsy(PSP), Corticobasal Ganglionic Degeneration(CBDG) and
Lewy Body Dementia(LBD)
Do check out support groups for PD and PD+ disorders as well
as they also usually welcome people with MSA.
ONLINE SUPPORT:
IN ENGLISH:
There is an online support group "mailing list" for MSA at
http://groups.yahoo.com/group/shydrager
Join the group online and read messages there or subscribe
and receive daily emails by sending a blank email to
shydrager-subscribe@yahoogroups.com
IN FRENCH:
For those who can converse in the French language there is
another group located at:
http://fr.groups.yahoo.com/group/shydragers
Regards,
Pam
Moderator, "shydrager" Multiple System Atrophy Online Support Group
pbower@accesscable.net
http://groups.yahoo.com/group/shydrager
Multiple System Atrophy Information
Many Faces, Same Disease – A patient primer from the University of Florida Center for Movement Disorders & Neurorestoration
What is MSA?
MSA, or Multiple System Atrophy, is a form of parkinsonism with many features that overlap with those of classic Parkinson disease and make it confusing to diagnose clinically. In fact, early symptoms may appear just like Parkinson disease (PD) and standard treatments, such as carbidopa/levodopa (Sinemet), can initially be helpful only to wane later in effectiveness as the disease progresses. As the disorder’s name alludes, MSA is a multisystem neurodegenerative disease that is characterized by a combination of symptoms including parkinsonism, cerebellar and pyramidal tract signs, and autonomic dysfunction. Parkinsonism is a descriptive term and includes tremor (usually resting), stiffness or rigidity, bradykinesia (slowed movements), and postural and gait instability. Cerebellar signs in contrast refer to problems with coordination and may include tremor with activity, past pointing (when reaching for objects), slurred speech, and an unstable “drunk-like” gait. Autonomic problems are non-motor features that involve failure of the automatic nervous system which controls things like heart rate, blood pressure, bowel, bladder and sexual functions. These are things you don’t often think about and are “automatically” controlled by the brain. In MSA people develop problems with this system and may present with lightheadedness/dizziness (related to changes in position, such as standing, and referred to as orthostatic hypotension), fainting spells, urinary retention or urgency (even incontinence), erectile dysfunction in men, constipation, and abnormal heat/cold intolerance and problems with sweat production. Additional features that are closely linked to MSA (and other parkinsonian syndromes) include REM sleep behavior disorder—characterized by yelling or thrashing about during dream sleep—periodic limb movements or restless legs, and respiratory stridor (harsh, strangled breathing). Importantly, it is possible for these other symptoms to precede motor symptoms by months to years.
What are the “faces” of MSA?
Given the multitude of features in MSA, clinical presentation is varied resulting in many “faces” of the disease. Since its first description in the 1960s the disease has been given different names—Shy-Drager syndrome, striatonigral degeneration (SND), and olivopontocerebellar atrophy (OPCA)—depending on the predominant presenting symptoms. However, it was later discovered that each of these syndromes shared a similar pathology characterized by the presence of abnormal protein deposits in the brain, called glial cytoplasmic inclusions or GCI’s. These inclusions are similar to “Lewy bodies” seen in PD, but unlike PD they are not found in neurons but rather in supporting glial cells. In the brain these glial cells are important for making myelin, a substance that “insulates” nerve fibers. The finding of this common pathological feature regardless of the clinical presentation (or “face” of the disease) led to the terminology used today, multiple system atrophy or MSA. Two clinical variants are generally still distinguished by clinicians based on the predominant presenting symptoms: parkinsonism (MSA-P, also known as Shy Drager or SND) or cerebellar ataxia (MSA-C, or OPCA). Both variants include autonomic dysfunction and as the disease progresses the features of these variants increasingly overlap.
Who does MSA affect?
MSA affects men and women equally and median age of onset is about 58 years-old. Although not as prevalent as PD, MSA affects about 4 per 100,000 individuals. In North America and Europe the parkinsonian variant of MSA (MSA-P) predominates, whereas the cerebellar variant (MSA-C) is more frequent in Asian populations. Disease progression unfortunately is usually more rapid than in PD and reflects a more widespread neurodegeneration in the brain. The combination of autonomic and motor symptoms, particularly if early in onset, can be fraught with more complications and shorter survival. Therefore early disease identification is critical. Referral to a movement disorders neurologist is recommended for proper diagnosis and symptom management.
How is MSA diagnosed?
Although the diagnosis of MSA is primarily based on clinical criteria (possible vs. probable disease; definitive diagnosis is made only at autopsy), several diagnostic studies may be helpful to support the diagnosis or to rule out other disease. So far there is no one blood test to identify MSA from other parkinsonian syndromes. Biomarkers such as alpha-synuclein, a protein abundantly found in Lewy body disorders, are being explored but remain controversial. The ability to distinguish MSA from PD and other parkinsonian syndromes is key and further study is still needed to increase the sensitivity and specificity of any blood or CSF (spinal fluid) test. On the other hand, brain imaging such as MRI is frequently used and can be helpful, particularly in cases that present with “atypical” parkinsonian features as in MSA. Brain MRI is often performed to evaluate for other potential causes of parkinsonism like stroke, inflammation, or hydrocephalus (“fluid on the brain”). In MSA a brain MRI can show atrophy or degeneration of specific brain region that are characteristic—including brainstem (pons, olivary nuclei), cerebellum, and basal ganglia—and lend support to the diagnosis. These classic signs are not always seen though, so repeat imaging may be needed as the disease progresses and if concern regarding diagnosis remains.
Newer imaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) are actively being explored, including major efforts here at the University of Florida. Functional MRI has the ability to look at brain activity based on changes in regional blood flow, whereas DTI is used to examine changes in brain connectivity by measuring water diffusion along nerve fiber tracts in the brain. Research here at UF by Dr. Vaillancourt and colleagues has demonstrated promising findings using these imaging techniques that may one day help distinguish MSA from classic PD and other forms of parkinsonism. Another imaging technique of note is the DaTscan™ (125I-iofluane SPECT), recently approved by the FDA, which measures the integrity of the dopamine system in the brain. Although touted as able to diagnose PD, it is not specific for PD and is typically abnormal in MSA patients (and other parkinsonian syndromes). Thus, while a DaTscan™ is not specific, it may also be helpful in supporting the diagnosis of MSA.
Testing for “non-motor” symptoms in MSA can also be useful. Patients that describe sleep disturbance including restlessness, jerking, dream-enactment (yelling, flailing), breathing issues (snoring and apnea), or just plain insomnia and excessive daytime fatigue should ask their physician to order a sleep study, or polysomnography. Restless leg syndrome (RLS), periodic limb movements of sleep (PLMS), and REM-sleep behavior disorder (RBD) can all be treated and improve sleep quality. If stridor or sleep apnea is identified, then the use of a machine that provides continuous positive airway pressure, or CPAP, may be indicated. Evaluation of autonomic symptoms can also be done, but may require specialized equipment and expertise. Simple lying, sitting, standing blood pressure check can be used to diagnose orthostatic hypotension. More detailed examination may include tilt-table testing that monitors changes in heart rate and BP with gradual incline. To measure sweat response, a variety of tests can be performed that stimulate or gently heat a portion of skin and assess sweat output—a part of the sympathetic or “flight/fight” response. Gastrointestinal motility can also be tested. If one experiences early satiety, or feeling of fullness or nausea after eating just small portions, a gastric emptying study may be in order. Urinary symptoms such as frequency, urgency, and incontinence should be evaluated by a urologist. Measurement of post-void residual (urine) and urodynamic testing are some of the things that may be done and helpful to determine cause of problems.
How is MSA treated?
Treatment of MSA remains largely supportive. About 30-60% of patients respond to typical Parkinson’s medications such as carbidopa/levodopa (Sinemet), and dose trial of up to 1 gram/day of levodopa for a few months is recommended. Benefit seen early in disease often fades though, or becomes fraught with complications. Two major complications include exacerbation of orthostatic symptoms (lightheadedness, dizziness, or fainting on standing) and dyskinesias, or abnormal involuntary movements that often involve the jaw or face. These symptoms can result in limiting the dose of medication tolerated, and thus also the effectiveness of drug treatment. More advanced motor symptoms, such as muscle spasm or fixed postures (dystonia), can be treated with “muscle relaxants” and sometimes by injection of botulinum toxin (i.e., Botox). Deep brain stimulation (DBS), however, is generally not recommended as poor outcomes have been reported. Physical and occupational therapies for gait and balance, range of motion and mobility, and help with activities of daily living are critical and require staff familiar with Parkinsonian patient needs. For those with progressive speech and swallowing issues therapy with a specialist is also highly recommended and includes regular swallow testing. Prevention of falls and aspiration (pneumonia) are major goals as these frequently lead to worsening disability and even death.
Although there is often focus on motor symptoms, the non-motor symptoms of MSA can also be just as disabling. Orthostatic symptoms, dizziness and even fainting, can become very limiting and lead to the wheelchair or recliner-bound patient. Treatment initially begins with “conservative” therapies including increased fluid intake, salt in diet (considering of course any concomitant heart disease), and wearing pressure stockings or binder. If these are not enough, drug treatment may be necessary. Options include “blood volume increasers” (fludrocortisone) or “pressor agents” (e.g., midodrine). Both increase BP thereby reducing episodes of low BP, but the later can also cause excessive high BP usually when lying down. Careful monitoring of BP is needed, avoiding ups and downs, and a happy medium found for each individual. Urinary and bowel symptoms likewise can be treated with select agents depending on the issue. Sleep disturbance can also be successfully treated depending on cause.
Conclusion
DRUG CLASS AND MECHANISM: Carbidopa-levodopa is a combination of two drugs, levodopa and carbidopa. Carbidopa-levodopa is used in the treatment of Parkinson's disease. Parkinson's disease is believed to be caused by low levels of dopamine in certain parts of the brain. When levodopa is taken orally, it crosses into the brain through the "blood- brain barrier." Once it crosses, it is converted to dopamine. The resulting increase in brain dopamine concentrations is believed to improve nerve conduction and assist the movement disorders in Parkinson disease. Carbidopa does not cross the blood-brain barrier. Carbidopa is added to the levodopa to prevent the breakdown of levodopa before it crosses into the brain. The addition of carbidopa allows lower doses of levodopa to be used. This reduces the risk of side effects from levodopa such as nausea and vomiting. This combination medicine was approved by the FDA in 1988.
PRESCRIBED FOR: Carbidopa-levodopa is used for the management of Parkinson's disease.
Levodopa and carbidopa are used in combination to treat the symptoms of Parkinson's disease or Parkinson-like symptoms (e.g., shakiness, stiffness, difficulty moving). Parkinson's disease is thought to be caused by too little of a naturally occurring substance (dopamine) in the brain. Levodopa changes into dopamine in the brain, helping to control movement.
Carbidopa prevents the breakdown of levodopa in the bloodstream so more levodopa can enter the brain. This can reduce some of levodopa's side effects such as nausea and vomiting, and it may also allow your doctor to increase your levodopa dose more quickly to find the best dose for you. This combination may be used alone or with other drugs for Parkinson's disease.
How to use carbidopa-levodopa
Take this medication by mouth, usually 3 to 4 times a day or as directed by your doctor. If you have been taking levodopa without any carbidopa and are taking this combination for the first time, wait at least 12 hours after your last levodopa dose before starting this medication. You may want to start your first dose in the morning. Your doctor will usually reduce your levodopa dose when starting this combination to prevent side effects from too much dopamine. Be sure to follow your doctor's instructions closely.
This combination comes in different strengths with different amounts of carbidopa and levodopa in each tablet. Be sure you have the correct strength of both drugs. Your doctor may also prescribe carbidopa alone to be taken with this combination.
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Multiple System Atrophy Information
Many Faces, Same Disease – A patient primer from the University of Florida Center for Movement Disorders & Neurorestoration
What is MSA?
MSA, or Multiple System Atrophy, is a form of parkinsonism with many features that overlap with those of classic Parkinson disease and make it confusing to diagnose clinically. In fact, early symptoms may appear just like Parkinson disease (PD) and standard treatments, such as carbidopa/levodopa (Sinemet), can initially be helpful only to wane later in effectiveness as the disease progresses. As the disorder’s name alludes, MSA is a multisystem neurodegenerative disease that is characterized by a combination of symptoms including parkinsonism, cerebellar and pyramidal tract signs, and autonomic dysfunction. Parkinsonism is a descriptive term and includes tremor (usually resting), stiffness or rigidity, bradykinesia (slowed movements), and postural and gait instability. Cerebellar signs in contrast refer to problems with coordination and may include tremor with activity, past pointing (when reaching for objects), slurred speech, and an unstable “drunk-like” gait. Autonomic problems are non-motor features that involve failure of the automatic nervous system which controls things like heart rate, blood pressure, bowel, bladder and sexual functions. These are things you don’t often think about and are “automatically” controlled by the brain. In MSA people develop problems with this system and may present with lightheadedness/dizziness (related to changes in position, such as standing, and referred to as orthostatic hypotension), fainting spells, urinary retention or urgency (even incontinence), erectile dysfunction in men, constipation, and abnormal heat/cold intolerance and problems with sweat production. Additional features that are closely linked to MSA (and other parkinsonian syndromes) include REM sleep behavior disorder—characterized by yelling or thrashing about during dream sleep—periodic limb movements or restless legs, and respiratory stridor (harsh, strangled breathing). Importantly, it is possible for these other symptoms to precede motor symptoms by months to years.
What are the “faces” of MSA?
Given the multitude of features in MSA, clinical presentation is varied resulting in many “faces” of the disease. Since its first description in the 1960s the disease has been given different names—Shy-Drager syndrome, striatonigral degeneration (SND), and olivopontocerebellar atrophy (OPCA)—depending on the predominant presenting symptoms. However, it was later discovered that each of these syndromes shared a similar pathology characterized by the presence of abnormal protein deposits in the brain, called glial cytoplasmic inclusions or GCI’s. These inclusions are similar to “Lewy bodies” seen in PD, but unlike PD they are not found in neurons but rather in supporting glial cells. In the brain these glial cells are important for making myelin, a substance that “insulates” nerve fibers. The finding of this common pathological feature regardless of the clinical presentation (or “face” of the disease) led to the terminology used today, multiple system atrophy or MSA. Two clinical variants are generally still distinguished by clinicians based on the predominant presenting symptoms: parkinsonism (MSA-P, also known as Shy Drager or SND) or cerebellar ataxia (MSA-C, or OPCA). Both variants include autonomic dysfunction and as the disease progresses the features of these variants increasingly overlap.
Who does MSA affect?
MSA affects men and women equally and median age of onset is about 58 years-old. Although not as prevalent as PD, MSA affects about 4 per 100,000 individuals. In North America and Europe the parkinsonian variant of MSA (MSA-P) predominates, whereas the cerebellar variant (MSA-C) is more frequent in Asian populations. Disease progression unfortunately is usually more rapid than in PD and reflects a more widespread neurodegeneration in the brain. The combination of autonomic and motor symptoms, particularly if early in onset, can be fraught with more complications and shorter survival. Therefore early disease identification is critical. Referral to a movement disorders neurologist is recommended for proper diagnosis and symptom management.
How is MSA diagnosed?
Although the diagnosis of MSA is primarily based on clinical criteria (possible vs. probable disease; definitive diagnosis is made only at autopsy), several diagnostic studies may be helpful to support the diagnosis or to rule out other disease. So far there is no one blood test to identify MSA from other parkinsonian syndromes. Biomarkers such as alpha-synuclein, a protein abundantly found in Lewy body disorders, are being explored but remain controversial. The ability to distinguish MSA from PD and other parkinsonian syndromes is key and further study is still needed to increase the sensitivity and specificity of any blood or CSF (spinal fluid) test. On the other hand, brain imaging such as MRI is frequently used and can be helpful, particularly in cases that present with “atypical” parkinsonian features as in MSA. Brain MRI is often performed to evaluate for other potential causes of parkinsonism like stroke, inflammation, or hydrocephalus (“fluid on the brain”). In MSA a brain MRI can show atrophy or degeneration of specific brain region that are characteristic—including brainstem (pons, olivary nuclei), cerebellum, and basal ganglia—and lend support to the diagnosis. These classic signs are not always seen though, so repeat imaging may be needed as the disease progresses and if concern regarding diagnosis remains.
Newer imaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) are actively being explored, including major efforts here at the University of Florida. Functional MRI has the ability to look at brain activity based on changes in regional blood flow, whereas DTI is used to examine changes in brain connectivity by measuring water diffusion along nerve fiber tracts in the brain. Research here at UF by Dr. Vaillancourt and colleagues has demonstrated promising findings using these imaging techniques that may one day help distinguish MSA from classic PD and other forms of parkinsonism. Another imaging technique of note is the DaTscan™ (125I-iofluane SPECT), recently approved by the FDA, which measures the integrity of the dopamine system in the brain. Although touted as able to diagnose PD, it is not specific for PD and is typically abnormal in MSA patients (and other parkinsonian syndromes). Thus, while a DaTscan™ is not specific, it may also be helpful in supporting the diagnosis of MSA.
Testing for “non-motor” symptoms in MSA can also be useful. Patients that describe sleep disturbance including restlessness, jerking, dream-enactment (yelling, flailing), breathing issues (snoring and apnea), or just plain insomnia and excessive daytime fatigue should ask their physician to order a sleep study, or polysomnography. Restless leg syndrome (RLS), periodic limb movements of sleep (PLMS), and REM-sleep behavior disorder (RBD) can all be treated and improve sleep quality. If stridor or sleep apnea is identified, then the use of a machine that provides continuous positive airway pressure, or CPAP, may be indicated. Evaluation of autonomic symptoms can also be done, but may require specialized equipment and expertise. Simple lying, sitting, standing blood pressure check can be used to diagnose orthostatic hypotension. More detailed examination may include tilt-table testing that monitors changes in heart rate and BP with gradual incline. To measure sweat response, a variety of tests can be performed that stimulate or gently heat a portion of skin and assess sweat output—a part of the sympathetic or “flight/fight” response. Gastrointestinal motility can also be tested. If one experiences early satiety, or feeling of fullness or nausea after eating just small portions, a gastric emptying study may be in order. Urinary symptoms such as frequency, urgency, and incontinence should be evaluated by a urologist. Measurement of post-void residual (urine) and urodynamic testing are some of the things that may be done and helpful to determine cause of problems.
How is MSA treated?
Treatment of MSA remains largely supportive. About 30-60% of patients respond to typical Parkinson’s medications such as carbidopa/levodopa (Sinemet), and dose trial of up to 1 gram/day of levodopa for a few months is recommended. Benefit seen early in disease often fades though, or becomes fraught with complications. Two major complications include exacerbation of orthostatic symptoms (lightheadedness, dizziness, or fainting on standing) and dyskinesias, or abnormal involuntary movements that often involve the jaw or face. These symptoms can result in limiting the dose of medication tolerated, and thus also the effectiveness of drug treatment. More advanced motor symptoms, such as muscle spasm or fixed postures (dystonia), can be treated with “muscle relaxants” and sometimes by injection of botulinum toxin (i.e., Botox). Deep brain stimulation (DBS), however, is generally not recommended as poor outcomes have been reported. Physical and occupational therapies for gait and balance, range of motion and mobility, and help with activities of daily living are critical and require staff familiar with Parkinsonian patient needs. For those with progressive speech and swallowing issues therapy with a specialist is also highly recommended and includes regular swallow testing. Prevention of falls and aspiration (pneumonia) are major goals as these frequently lead to worsening disability and even death.
Although there is often focus on motor symptoms, the non-motor symptoms of MSA can also be just as disabling. Orthostatic symptoms, dizziness and even fainting, can become very limiting and lead to the wheelchair or recliner-bound patient. Treatment initially begins with “conservative” therapies including increased fluid intake, salt in diet (considering of course any concomitant heart disease), and wearing pressure stockings or binder. If these are not enough, drug treatment may be necessary. Options include “blood volume increasers” (fludrocortisone) or “pressor agents” (e.g., midodrine). Both increase BP thereby reducing episodes of low BP, but the later can also cause excessive high BP usually when lying down. Careful monitoring of BP is needed, avoiding ups and downs, and a happy medium found for each individual. Urinary and bowel symptoms likewise can be treated with select agents depending on the issue. Sleep disturbance can also be successfully treated depending on cause.
Conclusion
DRUG CLASS AND MECHANISM: Carbidopa-levodopa is a combination of two drugs, levodopa and carbidopa. Carbidopa-levodopa is used in the treatment of Parkinson's disease. Parkinson's disease is believed to be caused by low levels of dopamine in certain parts of the brain. When levodopa is taken orally, it crosses into the brain through the "blood- brain barrier." Once it crosses, it is converted to dopamine. The resulting increase in brain dopamine concentrations is believed to improve nerve conduction and assist the movement disorders in Parkinson disease. Carbidopa does not cross the blood-brain barrier. Carbidopa is added to the levodopa to prevent the breakdown of levodopa before it crosses into the brain. The addition of carbidopa allows lower doses of levodopa to be used. This reduces the risk of side effects from levodopa such as nausea and vomiting. This combination medicine was approved by the FDA in 1988.
PRESCRIBED FOR: Carbidopa-levodopa is used for the management of Parkinson's disease.
Levodopa and carbidopa are used in combination to treat the symptoms of Parkinson's disease or Parkinson-like symptoms (e.g., shakiness, stiffness, difficulty moving). Parkinson's disease is thought to be caused by too little of a naturally occurring substance (dopamine) in the brain. Levodopa changes into dopamine in the brain, helping to control movement.
Carbidopa prevents the breakdown of levodopa in the bloodstream so more levodopa can enter the brain. This can reduce some of levodopa's side effects such as nausea and vomiting, and it may also allow your doctor to increase your levodopa dose more quickly to find the best dose for you. This combination may be used alone or with other drugs for Parkinson's disease.
How to use carbidopa-levodopa
Take this medication by mouth, usually 3 to 4 times a day or as directed by your doctor. If you have been taking levodopa without any carbidopa and are taking this combination for the first time, wait at least 12 hours after your last levodopa dose before starting this medication. You may want to start your first dose in the morning. Your doctor will usually reduce your levodopa dose when starting this combination to prevent side effects from too much dopamine. Be sure to follow your doctor's instructions closely.
This combination comes in different strengths with different amounts of carbidopa and levodopa in each tablet. Be sure you have the correct strength of both drugs. Your doctor may also prescribe carbidopa alone to be taken with this combination.
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- Now that I have been dealing directly with this MSA disease head on, I have thought about some of the early warning signs that may have led to this ugly disease. Back in 1996 I had disks C5-6 & C-6-7 fused. Inearly 1996 1997 I was living in Colorado and was having trouble with erectile dis-function (ED). It was very hard to discuss this issue with my doctor but I did. He prescribed "Viagra". To my surprise, it worked for a while. Then I was forced to try the other medicines like Cialis. Then I was having issues with pre-syncopy and syncopy. By my Mid-Fifties my ED was worse. I continued to have issues with syncopy, dizzyiness, light headedness, low blood pressure. Then the leg movement starting at night, Rem sleep ddidlegs hurting at night, right arm and hand always hurting, fatigued most of the time.
- It seems all these issues have slowly accumulated to a point where I believe; is has a much earlier start point than what common physicians think.
- Jul 22 2014
People with Parkinson’s disease (PD) who take dopaminergic medications show enhanced creativity, according to a study published in the June issue of theAnnals of Neurology.
Over the years, there have been anecdotal accounts of people living with Parkinson’s disease who experience a sudden emergence of artistic creativity after being treated with dopaminergic therapy. Examples include a person who within a month of starting treatment for PD, suddenly began writing poetry, and went on to become an award-winning poet. Yet it has been unclear whether medications lead to creativity directly or more indirectly, as part of side effectscalled impulse control disorders (ICDs), which are pathological in nature, and include unhealthy levels of gambling, shopping, eating and sexual activity.
Researchers led by Rivka Inzelberg, M.D., of the Joseph Sagol Neuroscience Center at Sheba Medical Center at Tel Aviv University in Israel were interested in learning more. The researchers assessed the creative skills of 27 people with Parkinson’s disease who were taking dopaminergic medications (average age 62, who had a high school education or higher) with a matched control group of 27 people without Parkinson’s disease. Participants took a series of tests that assessed skills such as verbal fluency, word association and original thinking. To determine if ICD was a factor in enhancing creativity, participants were also assessed for impulsive behavior, such as gambling and shopping.
Results
· Participants with PD, all of whom were treated with dopaminergic drugs, demonstrated enhanced verbal and visual creativity as compared to the neurologically healthy control group.
· Higher scores on a test of visual creativity were correlated with higher doses of dopaminergic medications, but also with decreased verbal fluency.
· Enhanced creativity was not correlated with the presence of impulse control disorders.
What Does It Mean?
In recent years, researchers have become increasingly interested in the relationship between dopaminergic drugs commonly used to treat Parkinson’s disease, such as levodopa and dopamine agonists, and enhanced artistic creativity.
Using an array of psychological testing, this study demonstrated that people with PD taking dopaminergic medications do, in fact, have increased measures of creativity compared to participants who do not live with Parkinson’s disease. More importantly, it found that enhanced creativity was not associated with impulse control disorders, potential complications of certain PD medications.
As the authors indicate, the good news is that if people with PD do show artistic abilities, creativity has potential to improve quality of life with PD. For example, the authors recommend that creativity could be integrated into occupational therapy. PDF also invites those with PD to join the already more than 400 artists contributing to its Creativity and Parkinson’s Project, which initially arose from feedback in the community about the link between creativity and the disease.
The study does have limitations. For example, it only evaluated a small sample of participants for a short period of time. It did not examine the relationship between duration of dopaminergic treatment and creative ability.
It is still not known exactly why dopaminergic medications boost creativity. One possible explanation is that dopaminergic drugs lower inhibition, which may expand a person’s creativity and “outside the box” thinking. Additionally, people with PD exhibit more impulsivity as measured in a laboratory setting – even off medication. It is possible that a subset of people with PD may have a greater creative capacity as a result of their disease, which can be the case in other neurodegenerative diseases, such as frontotemporal dementia.
Further research is needed to increase understanding of the relationship between PD, dopamine and creative thinking. Evaluating people with PD using functional neuroimaging may provide more valuable information regarding neurophysiological mechanisms underlying the creative thinking process.
Learn More
The Creativity and Parkinson's Project exists to explore, support and encourage the therapeutic value of creativity in Parkinson's. Browse our online gallery or submit creative works (painting, photography, poetry and more) atwww.pdf.org/creativity.
Browse Creativity and PD Gallery
Reference: Faust-Socher, A, Kenett, YN, Cohen, OS, Hassin-Baer, S, Inzelberg, R (2014) Enhanced Creative Thinking under Dopaminergic Therapy in Parkinson Disease. Annals of Neurology 75: 935-942. Published online before print June 10, 2014. DOI: 10.1002/ana.24181 http://dx.doi.org/10.1002/ana.24181
Summary of Multiple System Atrophy
Multiple System Atrophy (MSA, also known a Shy-Drager Syndrome) is a rare neurological condition that causes Parkinson's-like symptoms, however MSA patients have more widespread autonomic nerve damage than typical Parkinson's patients. Since MSA can cause widespread nerve damage, it may cause diverse symptoms throughout the body. MSA is one of three conditions of primary autonomic failure, the other two being PAF (Pure Autonomic Failure) and Parkinson's Disease.
Physicians often classify MSA as either MSA-P or MSA-C. MSA-P patients have predominantly Parkinsonian-like symptoms: tremors, muscle rigidity and slowness of voluntary movements. MSA-C patients predominantly show signs of cerebellar dysfunction: gait and limb ataxia (ataxia being a lack of control of muscle movements).1
Symptoms
Not every patient has every symptom of MSA. Each patient is unique.
Some of the early symptoms of MSA may include:
-Neurogenic Orthostatic Hypotension (a drop in blood pressure upon standing that can result in lightheadedness, dizziness and even fainting)
-headaches
-dry eyes, dry mouth, dry skin
-abnormally dilated pupils
-impotence
-loss of bladder control
Some of the later stage symptoms may include:
-sleep apnea
-stridor (a loud noise during inhalation)
-heart arrhythmias
-difficulty eating, swallowing or chewing food
-difficulty speaking
-monotone voice
-slow speaking
-low volume of voice
Symptoms that may be seen at varying times during the course of the illness:
-unusual or reduced ability to make facial expressions
-staring with the eyes
-loss of fine motor skills
-muscle aches and rigidity
-loss of balance
-movement difficulties
-difficulty sleeping
-cognitive impairment
-loss of bowel control
-loss of sweating in areas of the body
-nausea
-difficulty digesting foods
-unstable or stooped/slumped posture
-unsteady gait
-difficulty bending arms and legs
-difficulty starting any voluntary movement
-tremors, which may worsen with excitement, stress or fatigue
-finger-thumb rubbing (pill rolling tremor)
-vision changes, decreased or blurry vision
-confusion
-dementia
-depression
Who Develops MSA?
MSA is most often seen in persons over the age of 50, with a slightly higher incidence in men. However, women and younger patients can develop it. Estimates are that approximately 25,000 to 100,000 Americans have MSA at any given time.
What Causes MSA?
It is not known what causes MSA. Researchers are currently investigating this.
How is MSA Diagnosed?
MSA can be a challenge to diagnose. MSA is frequently confused with Parkinson's Disease, Pure Autonomic Failure (PAF), or Progressive Supranuclear Palsy. The top practitioners and researchers in the field have prepared a Consensus Statement on the Diagnosis of Multiple System Atrophy.1 The work-up may include autonomic testing, EMG testing, blood tests, sleep studies, catecholamine testing, and biopsies. Often, MSA can only be confirmed during an autopsy.
Treatment
There is currently no cure for MSA and no treatments proven to slow the neurological degeneration associated with MSA. However, there are treatments to help manage some of the symptoms, and to help the patient live the fullest life possible. Current therapeutic strategies are primarily based on dopamine replacement and improvement of autonomic failure.6Physicians may prescribe medications to help control the patient's blood pressure, gastric motility, sleeping difficulties, tremors, depression, pain and other symptoms. Medications such as Florinef, Midodrine and Sinemet are commonly prescribed.
Prognosis
Unfortunately, MSA usually progresses rapidly over a period of 7 to 10 years, with the mean survival rate of 9.3 years from the time of the first symptom. About 80% of patients are disabled within 5 years of the onset of motor symptoms. It is estimated that only 20% of MSA patients survive beyond 12 years. Patients continue to experience neurological degeneration until they lose motor skills, become confined to bed, and eventually pass away. Many MSA patients succumb to pneumonia and other respiratory infections, choking or cardiac arrest.2 MSA does not go into remission and there is no cure at this time.1-6 There are considerable genetic research and clinical investigations taking place to improve quality of life and treatment options for MSA patients at this time. 5
Sources
1. Consensus statement on the diagnosis of multiple system atrophy. Journal of the Neurological Sciences. S. Gilman, P.A. Low, N. Quinn, A. Albanese, Y. Ben-Shlomo, C.J. Fowler, H. Kaufmann, T. Klockgether, A.E. Lang, P.L. Lantos, I. Litvan, C.J. Mathias, E. Oliver, D. Robertson, I. Schatz, G.K. Wenning; Volume 163, Issue 1; Pages 94-98; 1 February 1999
2. National Institutes of Health Autonomic Disorders Consortium
3. J Neurol Sci. 012 Mar 13. [Epub ahead of print]
The role of autonomic testing in the differentiation of Parkinson's disease from multiple system atrophy. Kimpinki K, Iodice V, Burton DD, Camilleri M, Mullan BP, Lipp A, Sandroni P, Gehrking TL, Sletten DM, Ahlskog JE, Fealey RD, Singer W, Low PA.
4. Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1327-35. Epub 2010 Jul 26. Autonomic innervation in multiple system atrophy and pure autonomic failure. Donadio V, Cortelli P, Elam M, DiStasi V, Montagna P, Holmberg B, Giannoccaro MP, Bugiardini E, Avoni P, Baruzzi A, Liguori R.
5. Neurobiol Aging. 2011 Oct;32(10):1924.e5-14. Epub 2011 May 24. Genetic players in multiple system atrophy: unfolding the nature of the beast. Stemberger S, Scholz SW, Singelton AB, Wenning GK.
6. Ther Adv Neurol Discord. 2010 Jul;3(4):249-63. Multiple system atrophy: current and future approaches to management. Flabeau O, Meissner WG, Tison F.
Multiple System Atrophy (MSA, also known a Shy-Drager Syndrome) is a rare neurological condition that causes Parkinson's-like symptoms, however MSA patients have more widespread autonomic nerve damage than typical Parkinson's patients. Since MSA can cause widespread nerve damage, it may cause diverse symptoms throughout the body. MSA is one of three conditions of primary autonomic failure, the other two being PAF (Pure Autonomic Failure) and Parkinson's Disease.
Physicians often classify MSA as either MSA-P or MSA-C. MSA-P patients have predominantly Parkinsonian-like symptoms: tremors, muscle rigidity and slowness of voluntary movements. MSA-C patients predominantly show signs of cerebellar dysfunction: gait and limb ataxia (ataxia being a lack of control of muscle movements).1
Symptoms
Not every patient has every symptom of MSA. Each patient is unique.
Some of the early symptoms of MSA may include:
-Neurogenic Orthostatic Hypotension (a drop in blood pressure upon standing that can result in lightheadedness, dizziness and even fainting)
-headaches
-dry eyes, dry mouth, dry skin
-abnormally dilated pupils
-impotence
-loss of bladder control
Some of the later stage symptoms may include:
-sleep apnea
-stridor (a loud noise during inhalation)
-heart arrhythmias
-difficulty eating, swallowing or chewing food
-difficulty speaking
-monotone voice
-slow speaking
-low volume of voice
Symptoms that may be seen at varying times during the course of the illness:
-unusual or reduced ability to make facial expressions
-staring with the eyes
-loss of fine motor skills
-muscle aches and rigidity
-loss of balance
-movement difficulties
-difficulty sleeping
-cognitive impairment
-loss of bowel control
-loss of sweating in areas of the body
-nausea
-difficulty digesting foods
-unstable or stooped/slumped posture
-unsteady gait
-difficulty bending arms and legs
-difficulty starting any voluntary movement
-tremors, which may worsen with excitement, stress or fatigue
-finger-thumb rubbing (pill rolling tremor)
-vision changes, decreased or blurry vision
-confusion
-dementia
-depression
Who Develops MSA?
MSA is most often seen in persons over the age of 50, with a slightly higher incidence in men. However, women and younger patients can develop it. Estimates are that approximately 25,000 to 100,000 Americans have MSA at any given time.
What Causes MSA?
It is not known what causes MSA. Researchers are currently investigating this.
How is MSA Diagnosed?
MSA can be a challenge to diagnose. MSA is frequently confused with Parkinson's Disease, Pure Autonomic Failure (PAF), or Progressive Supranuclear Palsy. The top practitioners and researchers in the field have prepared a Consensus Statement on the Diagnosis of Multiple System Atrophy.1 The work-up may include autonomic testing, EMG testing, blood tests, sleep studies, catecholamine testing, and biopsies. Often, MSA can only be confirmed during an autopsy.
Treatment
There is currently no cure for MSA and no treatments proven to slow the neurological degeneration associated with MSA. However, there are treatments to help manage some of the symptoms, and to help the patient live the fullest life possible. Current therapeutic strategies are primarily based on dopamine replacement and improvement of autonomic failure.6Physicians may prescribe medications to help control the patient's blood pressure, gastric motility, sleeping difficulties, tremors, depression, pain and other symptoms. Medications such as Florinef, Midodrine and Sinemet are commonly prescribed.
Prognosis
Unfortunately, MSA usually progresses rapidly over a period of 7 to 10 years, with the mean survival rate of 9.3 years from the time of the first symptom. About 80% of patients are disabled within 5 years of the onset of motor symptoms. It is estimated that only 20% of MSA patients survive beyond 12 years. Patients continue to experience neurological degeneration until they lose motor skills, become confined to bed, and eventually pass away. Many MSA patients succumb to pneumonia and other respiratory infections, choking or cardiac arrest.2 MSA does not go into remission and there is no cure at this time.1-6 There are considerable genetic research and clinical investigations taking place to improve quality of life and treatment options for MSA patients at this time. 5
Sources
1. Consensus statement on the diagnosis of multiple system atrophy. Journal of the Neurological Sciences. S. Gilman, P.A. Low, N. Quinn, A. Albanese, Y. Ben-Shlomo, C.J. Fowler, H. Kaufmann, T. Klockgether, A.E. Lang, P.L. Lantos, I. Litvan, C.J. Mathias, E. Oliver, D. Robertson, I. Schatz, G.K. Wenning; Volume 163, Issue 1; Pages 94-98; 1 February 1999
2. National Institutes of Health Autonomic Disorders Consortium
3. J Neurol Sci. 012 Mar 13. [Epub ahead of print]
The role of autonomic testing in the differentiation of Parkinson's disease from multiple system atrophy. Kimpinki K, Iodice V, Burton DD, Camilleri M, Mullan BP, Lipp A, Sandroni P, Gehrking TL, Sletten DM, Ahlskog JE, Fealey RD, Singer W, Low PA.
4. Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1327-35. Epub 2010 Jul 26. Autonomic innervation in multiple system atrophy and pure autonomic failure. Donadio V, Cortelli P, Elam M, DiStasi V, Montagna P, Holmberg B, Giannoccaro MP, Bugiardini E, Avoni P, Baruzzi A, Liguori R.
5. Neurobiol Aging. 2011 Oct;32(10):1924.e5-14. Epub 2011 May 24. Genetic players in multiple system atrophy: unfolding the nature of the beast. Stemberger S, Scholz SW, Singelton AB, Wenning GK.
6. Ther Adv Neurol Discord. 2010 Jul;3(4):249-63. Multiple system atrophy: current and future approaches to management. Flabeau O, Meissner WG, Tison F.
Multiple system atrophy (MSA) is a rare neurodegenerative disorder without any effective treatment in slowing or stopping disease progression. It is characterized by poor levodopa responsive Parkinsonism, cerebellar ataxia, pyramidal signs and autonomic failure in any combination. Current therapeutic strategies are primarily based on dopamine replacement and improvement of autonomic failure. However, symptomatic management remains disappointing and no curative treatment is yet available. Recent experimental evidence has confirmed the key role of alpha-synuclein aggregation in the pathogenesis of MSA. Referring to this hypothesis, transgenic and toxic animal models have been developed to assess candidate drugs for MSA. The standardization of diagnosis criteria and assessment procedures will allow large multicentre clinical trials to be conducted. In this article we review the available symptomatic treatment, recent results of studies investigating potential neuroprotective drugs, and future approaches for the management in MSA.
Introduction
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder leading to more severe disability and impairment in quality of life than in Parkinson’s disease (PD) [Schrag et al. 2006; Tison et al. 2002]. MSA is characterized by a variable combination of poor levodopa responsive Parkinsonism, cerebellar ataxia and autonomic failure [Gilman et al. 2008]. MSA-Parkinsonism type (MSA-P) predominates in the Western Hemisphere and MSA-cerebellar type (MSA-C) is the major phenotype in the Eastern Hemisphere [Watanabe et al. 2002]. There is no recognized efficient treatment for cerebellar ataxia whereas levodopa may transiently improve Parkinsonism in one third of the patients [Constantinescu et al. 2007; Wenning et al. 1997]. Since autonomic failure strongly correlates with poor quality of life [Schrag et al. 2006], therapeutic management focuses on symptomatic therapy of orthostatic hypotension (OH), constipation, genitourinary and breathing disorders. Mean survival is about 9–10 years after symptom onset [Schrag et al. 2008] with nocturnal sudden death being a major cause of death [Shimohata et al. 2008]. Hitherto, no treatment has been shown to improve survival in MSA, creating a strong need for new therapeutic approaches.
Abnormal aggregation of alpha-synuclein in oligodendrocytes is the pathological hallmark of MSA and may trigger the progressive cell loss in widespread brain areas [Jellinger and Lantos, 2010; Wenning et al. 2008, 1997]. Advances in therapeutics have been achieved during the past 10 years through the development of transgenic animal models and experimental strategies against alpha-synuclein accumulation and for neuroprotection [Stefanova et al. 2009]. This progress may provide a testbed for future candidate drugs discovery and multicentric clinical trials.
Here we review potential neuroprotective drugs, current symptomatic treatment and future approaches in the management of MSA.
Available symptomatic treatment for multiple system atrophy (MSA). Almost all of the therapeutics currently used are based on expert experience and do not meet scientific evidence standards. Double-blind, placebo-controlled trials are indicated in references. ...
Parkinsonism
A poor levodopa response is one of the consensus criteria for the diagnosis of MSA [Gilman et al. 2008] and helps to differentiate MSA from PD [Wenning et al. 2000]. Although there are no controlled clinical trials on the efficacy of levodopa in MSA, about one third of patients may experience a benefit, more often in the MSA-P subtype than in MSA-C [Constantinescu et al. 2007]. In series with pathological confirmation, the positive levodopa responsiveness is reported in 28–65% of the patients [Colosimo et al. 1995; Wenning et al. 1997, 1995; Hughes et al. 1992; Fearnley and Lees, 1990; Rajput et al. 1990]. However, this effect persists for several years (as in PD) in only 13% of all patients [Wenning et al.1994]. Although levodopa induces less delirium and hallucinations in MSA than in PD [Wenning et al. 2000], it can lead to adverse effects such as worsening of OH or pathological hypersexuality [Klos et al. 2005; Wenning et al. 1994]. Moreover, early orofacial levodopa induced dyskinesias may occur in half of MSA patients often in the absence of any motor benefit [Boesch et al. 2002; Wenning et al.1994]. According to consensus criteria, levodopa unresponsiveness should only be accepted after a treatment with at least 1 g of levodopa per day for at least 3 months [Gilman et al. 2008]. However, some patients report a subjective benefit that may not be apparent in a standardized motor examination, while others convey subsequent motor degradation after levodopa discontinuation [Wenning et al.1994]. To date, there is no evidence suggesting that such high doses of levodopa accelerate the neurodegenerative process in transgenic animal models of MSA [Stefanova et al. 2007]. As in PD, domperidone can be added to prevent dopaminergic side effects such as nausea and vomiting.
There are no controlled studies that have tested the efficacy of dopamine agonists in MSA so far. In a retrospective case record analysis, only 10% of the patients experienced a benefit with dopamine agonists [Wenning et al. 1994]. Thus, dopamine agonists cannot be recommended as a first-line treatment given their high rate of side effects compared with levodopa, particularly worsening of OH. Amantadine may be an alternative symptomatic treatment. While a double-blind, placebo-controlled crossover trial failed to demonstrate any significant motor benefit in eight MSA patients [Wenning, 2005], a retrospective study disclosed good or excellent responsiveness in 15% [Wenning et al. 1994].
Although serotonergic involvement in MSA remains unclear, postmortem studies disclosed clear evidence for serotonergic depletion in brainstem nuclei [Tada et al.2009; Benarroch, 2007]. The selective serotonin reuptake inhibitor paroxetine has been assessed for 2 weeks in a small trial including 19 MSA patients [Friess et al.2006]. In this double-blind, placebo-controlled, randomized study, motor improvement was slight but significant in comparison with placebo. Further investigations are needed before any conclusion can be drawn on the efficacy of selective serotonin reuptake inhibitors in MSA. A double-blind, multicentre trial with fluoxetine is currently underway in France.
Cerebellar ataxia
Physiotherapy remains the best therapeutic option for cerebellar ataxia in MSA [Jain et al. 2004]. When intentional cerebellar tremor predominates, off-label use of low doses of clonazepam may sometimes help in our hands. Off-label use of propanolol, baclofen or amantadine have shown modest and transient efficacy in a retrospective data analysis [Wenning et al. 2003]. Buspirone (off-label) improved upper limb ataxia in an open-label trial including nine MSA-C patients [Heo et al.2008]. Gabapentin (off-label) may have symptomatic benefits on ataxia, oscillopsia and dysarthria according to a limited report in two MSA-C patients [Gazulla and Benavente, 2005]. Finally, protirelin tartrate (off-label) has been used for ataxic diseases in Japan, but without any apparent effect in MSA [Takei et al.2009].
Autonomic failure
Orthostatic hypotension
OH is one of the major criteria for MSA diagnosis [Gilman et al. 2008]. Spreading of the neurodegenerative process to the intermediolateral cell column [Wenning et al. 1997] underlies earlier and more severe autonomic failure in MSA compared with PD [Lipp et al. 2009]. First-line treatment should always include nonpharmacological advice: use of custom-fitted elastic stockings, raising the head of the bed by 20–30° when sleeping, performing isotonic exercises, as well as increasing intake of fluid, salt and frequency of small meals [Freeman, 2008]. Drinking more than 350 ml of water a day reduces both OH and orthostatic symptoms but long-term effects and acceptance are unknown [Deguchi et al. 2007; Young and Mathias, 2004].
A broad range of drugs has been assessed in OH, such as fludrocortisone, midodrine, ephedrine or octreotide [Wenning et al. 2003]. Only midodrine has been investigated with a strong, double-blind, placebo-controlled procedure in three studies including few patients with MSA and labelled in the indication of neurogenic OH [Wright et al. 1998; Low et al. 1997; Jankovic et al. 1993]. This α1-adrenoceptor agonist alleviated moderate to severe OH with oral doses that ranged from 2.5 to 30 mg daily. Blood pressure should be regularly monitored in patients receiving midodrine to detect supine hypertension which may be prevented by taking the last pill more than 4 hours before bedtime [McClellan et al. 1998]. By enhancing sympathetic activity, pyridostigmine modestly but significantly improved OH without supine hypertension in a double-blind, randomized, crossover study [Singer et al. 2006]. Although almost exclusively used in Japan, droxidopa seems to be effective and well tolerated to treat OH in patients with MSA [Kaufmann, 2008; Mathias, 2008; Kaufmann et al. 2003;Mathias et al. 2001; Freeman et al. 1999].
Neurogenic lower urinary tract dysfunction
Urinary urgency, frequency or incomplete bladder emptying, and urinary incontinence remain key features of the consensual diagnosis criteria [Gilman et al. 2008]. Urinary disorders severely affect the quality of life in MSA patients and may lead to lower urinary tract and kidney infection as major causes of morbidity in MSA [Ito et al. 2006]. Clean intermittent self-catheterization (CISC) is recommended as the first-line treatment when the postvoid residual is above 100 ml [Fowler and O’Malley, 2003]. Thus, the residual volume should be regularly monitored, for example with a portable ultrasound device. The critical threshold of 100 ml is reached in a mean of 2 years after disease diagnosis [Ito et al. 2006]. If the postvoid residual is below 100 ml, drugs acting on the detrusor may be used [Papatsoris et al. 2008]. Bladder-oriented anticholinergic agents are often prescribed for detrusor hyperactivity symptoms (e.g. urinary urgency, frequency and urge incontinence) but with a risk of worsening urinary retention. Urethra-orientated α-adrenergic antagonists may reduce the residual urine volume but exacerbation of OH is likely to occur [Sakakibara et al. 2000]. If urge incontinence still persists, third-line treatments may be considered. Synthetic antidiuretic hormone desmopressin (off-label) decreases urinary volumes. Taken just before bedtime, desmopressin reduces nocturia and improves morning hypotension. Regular monitoring of drug safety is necessary since it may induce water intoxication [Sakakibara et al. 2003]. Injection of botulinum toxin A in the detrusor muscle may be an alternative treatment for detrusor overactivity given the positive results in two MSA patients [Giannantoniet al. 2009], as well as urethral sphincter injections for urethral hypertonia when alpha-blockers are not tolerated [Apostolidis et al. 2009]. Botulinum toxin injections (off-label) seem to be safe and effective but further trials with larger samples are needed in MSA. To reduce the risk of infection due to permanent catheterization, surgery such as sphincterotomy or sphincteric wall stenting can be considered as a last option in MSA [Ito et al. 2006; Fowler and O’Malley, 2003].
Constipation
In addition to exercise, high fluid and fibre intake, laxative therapy is often necessary to relieve constipation in MSA. As in PD, classical laxative treatment may be used. Two small open trials have demonstrated the efficacy of polycarbophil [Sakakibara et al. 2007] and mosapride citrate [Liu et al. 2005] to reduce the time of transit in MSA patients. Moreover, macrogol 3350 has been reported to be subjectively efficient in two MSA patients [Eichhorn and Oertel, 2001].
Erectile dysfunction
Intracavernosal injection of papaverine or prostaglandin E1 may be used for erectile dysfunction in MSA [Papatsoris et al. 2008]. Subcutaneous apomorphine administration may also induce erections in PD [O’Sullivan, 2002; O’Sullivan and Hughes, 1998]. Although its use has not been assessed in this indication in MSA patients, apomorphine is easier to handle than papaverine. The use of sildenafil in MSA often faces the problem of its cardiovascular side effects, mainly the risk of a severe blood pressure drop. Efficiency and safety of the latter was assessed in a randomized, double-blind, placebo-controlled, crossover study [Hussain et al. 2001]. Sildenafil enhanced erectile function in the six MSA patients studied, but half of them experienced a severe drop in blood pressure 1 hour after drug ingestion. The pre-existing severity of OH may be predictive for a further decrease in blood pressure and the appearance of clinical signs of orthostatism.
Breathing disorders
MSA may manifest with obstructive and central sleep apnoea, dysrhythmia, dyspnoea, hypoxaemia, inspiratory sighs and laryngeal stridor [Meissner et al. 2010; Gilman et al. 2008; Shimohata et al. 2007; Geser et al.2005; Vetrugno et al. 2004; Chokroverty et al. 1978]. These breathing disorders reflect the extension of the neurodegenerative process to the pontomedullary respiratory nuclei [Benarroch, 2007]. Since respiratory disorders may manifest in the early stages of MSA [Glass et al. 2006], and may explain sudden death [Tadaet al. 2009], they should be considered as a primordial aspect of management in MSA. Stridor is usually the consequence of vocal cord dystonia [Vetrugno et al.2007; Merlo et al. 2002] but cases with vocal cord abduction muscle denervation have been documented [Hayashi et al. 1997; Bannister et al. 1981]. Its occurrence is known to be associated with poor outcome [Yamaguchi et al. 2003; Silber and Levine, 2000]. Invasive procedures should be considered after the failure of noninvasive ventilation. Tracheostomy may be discussed with the patient for life-threatening and/or daytime stridor, or when abnormal vocal cord mobility is diagnosed on laryngoscopic examination [Silber, 2008; Silber and Levine, 2000]. However, the latter do not seem to prevent sudden death [Shimohata et al. 2008;Jin et al. 2007]. The use of laryngeal surgery or botulinum toxin therapy is sometimes performed with contrasting effects in limited reports [Iranzo, 2005;Merlo et al. 2002].
Concerning obstructive sleep apnoea, treatment with continuous positive air pressure may reduce the apnoea/hypopnoea index and desaturation [Iranzo et al.2004, 2000], but we found the acceptability to be low when disease progresses [Ghorayeb et al. 2005b]. Moreover, the mean survival does not seem to be modified according to retrospective and/or uncontrolled data [Shimohata et al.2008; Ghorayeb et al. 2005b]. Finally, recent clinical evidence suggests that adaptive servoventilation may reduce the apnoea index in MSA patients with central sleep apnoea [Suzuki et al. 2010].
Movement disorders
Orofacial dystonia, antecollis and camptocormia are features supporting the consensual diagnosis of MSA and constitute ‘red flags’ for the differential diagnosis with PD [Gilman et al. 2008; Kollensperger et al. 2008].
Dystonia
In a prospective trial including 24 levodopa-naive patients with probable MSA, dystonia occurred in 46% [Boesch et al. 2002]. Botulinum toxin injection is the most commonly used treatment for focal dystonia [Papapetropoulos et al.2008]. Although no controlled studies with any other drug are yet available, symptomatic relief with anticholinergics, amantadine, dopamine agonists, muscle relaxants or tetrabenazine has been reported in some MSA patients when used off-label [Papapetropoulos et al. 2008; Azher and Jankovic, 2005].
Camptocormia
Camptocormia (CC) is an abnormal forward flexion of the trunk that manifests when standing or walking and relieves in the supine position [Azher and Jankovic, 2005]. Whether CC is a dystonic posture, a consequence of axial rigidity or a focal myopathy is still debated [Margraf et al. 2010; Diederich et al.2006; Slawek et al. 2006; Azher and Jankovic, 2005]. The levodopa responsiveness is generally poor [Bloch et al. 2006; Diederich et al. 2006; Azher and Jankovic, 2005], but some patients reported fair relief [Song et al. 2008;Slawek et al. 2006]. In a single case report, protirelin tartrate (off-label use) improved CC dramatically, presumably by enhancing motoneuronal excitability of the paraspinal muscles [Takei et al. 2009]. As in focal dystonia, botulinum toxin injections may be effective [Azher and Jankovic, 2005]. Despite the lack of placebo-controlled trials, injections may be more appropriate in rectus abdominus muscles than in lumbar paraspinal muscles because of the risk of transient aggravation of CC. Finally physiotherapy in combination with specific orthosis may improve CC and quality of life [de Seze et al. 2008]. Recent clinical evidence suggests that wearing a backpack may also alleviate CC in PD [Gerton et al.2010]. Although the efficacy has not been specifically tested in MSA, such noninvasive options should be considered.
Rapid eye movement sleep behaviour disorder
Rapid eye movement sleep behaviour disorder (RBD) may be the presenting symptom of MSA [Tison et al.1995] and is observed in 69–100% of systematic polysomnography recordings in MSA patients [Vetrugno et al. 2004; Plazzi et al. 1997; Manni et al. 1993]. Although no therapeutic strategy has been validated, the off-label use of clonazepam is consensually and by experience considered as the first-line treatment [Ghorayeb et al. 2005a]. Clonazepam may aggravate existing obstructive sleep apnoea, but alternative treatments are sparse. Sodium oxybate, temazepam, zopiclone, gabapentin and pramipexole were effective when used off-label in limited and uncontrolled single case reports [Anderson and Shneerson, 2009]. Donepezil, a centrally acting reversible acetylcholinesterase inhibitor, is expected to alleviate RBD (off-label use) [Ringman and Simmons, 2000], but its reported clinical efficacy is variable [Boeve et al. 2003]. Melatonin may restore RBD-related desynchronization of the circadian rhythms without major side effects [Boeve et al. 2003], but these data await confirmation.
Nonspecific therapies
Depression
Depression is more prevalent in MSA than in PD [Tison et al. 2006] and correlates with poor quality of life [Schrag et al. 2006]. Selective serotonergic reuptake inhibitors are the most prescribed antidepressive treatment, with less expected risk of inducing OH than tricyclic drugs. Electroconvulsive therapy may be considered in MSA patients with melancholia [Shioda et al. 2006]. Repetitive transcranial magnetic stimulation may also have antidepressant efficacy in PD but the effects in MSA are unknown [Fregni et al. 2004]. Psychological support is necessary, as well as nursing care and family education [Hardy, 2008]. Finally, levodopa may slightly improve mood disorders in MSA [Fetoni et al. 1999].
Cognitive impairment
MSA patients may have impaired visuospatial and constructional function, verbal fluency and executive function compared with control subjects [Kitayama et al. 2009; Kawai et al. 2008]. No specific cognition enhancement treatment has been assessed in MSA.
Medical rehabilitation
For cerebellar ataxia and Parkinsonism, medical rehabilitation seems to improve balance and motor impairment [Landers et al.2009; Wedge, 2008; Jain et al. 2004] as does the practice of tai chi [Venglar, 2005]. Speech therapy may be necessary to improve communication because of severe dysarthria.
Drooling
Excessive drooling may be a problem in later disease stages. Anticholinergic drugs may be efficient but adverse effects are frequent, including dry mouth, cognitive impairment, constipation, blurred vision or urinary retention. Injection of botulinum toxin type A into the salivary glands is the treatment of choice in excessive drooling as central side effects can be avoided [Mancini et al.2003]. However, it may aggravate swallowing problems which may require transient nasogastric tube feeding.
Neuroprotective strategies
Although recent advances in basic science have given some clues for neuroprotective strategies in MSA patients, all clinical trials failed to show any disease-modifying properties (Table 2). Experimental evidence in a rodent model of MSA suggested that the antiglutamate drug riluzole may delay neuronal loss [Diguet et al. 2005]. No positive effect was noted in two prospective trials performed in MSA, using validated clinical scales and survival time as outcomes [Bensimon et al. 2009; Seppi et al. 2006].
Neuroprotective drugs for multiple system atrophy (MSA): study failures and ongoing trials.
To test the hypothesis that minocycline inhibits microglial activation, which is supposed to contribute to the progressive cell death in MSA, a 48-week prospective study was performed in 63 MSA-P patients [Dodel et al. 2010]. Although a subgroup analysis of eight patients revealed a nonsignificant decrease in [11C](R)-PK11195-PET binding, a tracer of glial cells including microglia, astrocytes and infiltrating macrophages, there was no change in clinical measures of motor impairment or health-related quality of life.
Since growth hormone (GH) may also act as a neuronal ‘survival factor’ in MSA, a randomized, double-blind, placebo-controlled trial has been designed with 22 MSA patients receiving recombinant human growth hormone (r-hGH) injection during 1 year and 21 receiving placebo [Holmberg et al. 2007]. Although this study disclosed no significant effect, there was a trend to a smaller increase in Unified Parkinson’s Disease Rating Scale (UPDRS) and Unified Multiple System Atrophy Rating Scale (UMSARS) scores over time as well as in OH and cardiovascular variability. Since the use of r-hGH appears to be safe, further trials with higher doses and more patients are needed.
Finally, in MSA-C patients, the hypothesis that oestrogen could have neuroprotective properties has not been confirmed in a recent trial [Heo et al.2008].
Deep brain stimulation
Although bilateral subthalamic stimulation may have beneficial effects in a few MSA patients [Visser-Vandewalle et al. 2003], a recent review of the literature highlights the poor efficacy of deep brain simulation (DBS) [Shih and Tarsy, 2007]. Moreover, more than a quarter of patients died within 7 months of surgery. Owing to the limited number of reports, the poor outcome and the possibility of a harmful effect, DBS is currently not recommended in MSA [Wenning and Stefanova, 2009; Lambrecq et al. 2008; Shih and Tarsy, 2007; Santens et al. 2006;Talmant et al. 2006; Tarsy et al. 2003].
Neuroprotective strategies
Although the exact mechanisms of the neurodegenerative process in MSA remain unclear, the aggregation of alpha-synuclein in oligodendrocytes has been identified as a critical step in the pathogenesis [Jellinger and Lantos, 2010; Ubhi et al. 2010;Stefanova et al. 2009; Wenning et al. 2008]. Based on the key role of alpha-synuclein aggregation in MSA, transgenic animal models and genetic strategies have been developed. Transgenic animal models allow the expression of alpha-synuclein in oligodendrocytes under control of specific promoters [Shults et al.2005; Yazawa et al. 2005; Kahle et al. 2002]. The growing number of MSA animal models [Fernagut et al. 2005; Stefanova et al. 2005] opens up the possibility to create a basis for drug screening in human trials. The efficacy of neuroprotective drugs is assessed in rodent models before translation to clinical trials. Furthermore, transgenic models may be used to understand the alpha-synuclein aggregation process and allow screening for candidate drugs before further assessment in clinical trials [Waxman and Giasson, 2010; Ono et al. 2007].
Lithium is a first-line treatment for bipolar mood disorders [Beaulieu and Caron, 2008]. The set of evidence has grown to suggest that lithium may also have also some neuroprotective properties [Ferrucci et al. 2010; Beaulieu and Caron, 2008;Feng et al. 2008; Fornai et al. 2008]. In human pathology, lithium has been tried in amyotrophic lateral sclerosis [Bedlack et al. 2008; Fornai et al. 2008; Vanacore and Galeotti, 2008]. The safety, tolerability and efficacy of lithium are being assessed in MSA in a prospective phase 2 trial (ClinicalTrials.gov Identifier: NCT00997672).
The results of a recent trial suggest that rasagiline may have ‘disease-modifying’ properties of still uncertain clinical significance in PD patients [Olanow et al.2009b]. Positive effects of rasagiline on clinical motor scores and neuronal loss have also been suggested in a transgenic model of MSA [Stefanova et al. 2008]. Rasagiline is currently being assessed in MSA-P patients in a randomized, placebo-controlled, multicentre study (ClinicalTrials.gov Identifier: NCT00977665).
Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce alpha-synuclein fibril formation in vitro [Hirohata et al. 2008] and may lower the risk of developing PD [Samii et al. 2009; Chen et al. 2005]. To date, the potential therapeutic benefit of NSAIDs has not been assessed in symptomatic alpha-synucleinopathies such as MSA [Hirsch and Hunot, 2009]. However, the harmful adverse effects of long-term use may limit their evaluation until the development of safer drugs. No clinical trials have yet been conducted or planned in MSA.
An open trial testing intravenous immunoglobulins for 6 months is currently in phase 2 (ClinicalTrials.gov Identifier: NCT00750867). However, a former clinical report does not support any therapeutic effect in MSA [Nanri et al. 2009].
Since rifampicin avoids alpha-synuclein fibril formation in vitro [Ono and Yamada, 2006] and reduces neuronal loss in a rodent model of MSA [Ubhi et al.2008], this drug may be a candidate neuroprotective agent in MSA. However, to the best of the authors’ knowledge, no human trial has been yet planned.
Neurorestorative approach
Although experimental and open trials may support transplantation of foetal dopaminergic cells into the striatum in PD [Hauser et al. 1999; Kordower et al.1998; Freeman et al. 1995; Widner et al. 1992; Lindvall et al. 1994, 1990], two double-blind, sham-controlled trials assessing transplantation of foetal nigral cells in PD failed to demonstrate any significant effect of the graft considering the primary outcome [Olanow et al. 2003; Freed et al. 2001]. Moreover, off-medication dyskinesia may occur in half of the transplanted patients [Olanow et al.2009a], and the set of evidence has grown to suggest that Lewy body pathology may affect graft cells [Apostolidis et al. 2009; Kordower et al. 2008a, 2008b]. Despite these shortcomings, recent evidence in animal models of MSA-P may provide the rationale for human trials in MSA [Kollensperger et al. 2009;Puschban et al. 2005]. The use of autologous stem cells has recently been assessed in an open trial with MSA-C patients during 1 year [Lee et al. 2008]. Parenteral injection of bone marrow mesenchymal stem cells seem to slow UMSARS progression and increase cerebellar and frontal glucose metabolism on positron emission tomography (PET) scans compared with nontreated MSA patients. These preliminary results are still to be taken with caution. The underlying mechanisms of action, in particular how graft cells pass the blood–brain barrier from the arterial or venous peripheral circulation, remain unclear and need more preclinical explanation [Whone and Scolding, 2009; Quinn et al. 2008]. A double-blind, placebo-controlled, randomized clinical trial with initial arterial and subsequent venous administration of autologous mesenchymal stem cells has been launched in MSA patients in May 2009 (ClinicalTrials.gov Identifier: NCT00911365).
At the same time, a stem cell boosting strategy with injection of granulocyte colony stimulating factor (GCSF) has been launched in an open uncontrolled trial in four MSA patients [Pezzoli et al. 2010]. No major side effect was noted except for bone pain. However, given the small sample size, it is currently impossible to draw any conclusions about the efficacy of this approach.
Unexplained sudden death
For Schrag and collaborators, therapeutic management should concentrate on autonomic dysfunction, motor impairment and depression, because these features are associated with poor quality of life in MSA [Schrag et al. 2006]. In addition to symptomatic management and neuroprotective strategies, sudden death does not yet represent a major target for therapeutic intervention and there is no trial designed for such a strategy. Occurrence of sudden death is a common cause of mortality in MSA and may happen in the early stages while disability remains acceptable [Shimohata et al. 2008]. The origin of sudden death in MSA remains unknown, although clinical reports [Shimohata et al. 2007, 2008; Glass et al.2006; Cormican et al. 2004], experimental [Tsuda et al. 2002] and neuropathological evidence [Tada et al. 2009; Benarroch, 2007] suggest that respiratory dysfunction may be the leading cause. Future preclinical studies should help to determine the underlying mechanisms before testing specific treatment strategies.
Considerations for future clinical trials
MSA is a rare neurodegenerative disease, with an estimated prevalence ranging from 1.9 [Tison et al. 2000] to 5 cases per 100,000 persons [Vanacore et al. 2001;Schrag et al. 1999]. The long-term follow up is limited by the rapid neurodegenerative process leading to reduced life expectancy. Rapid progression may also explain the high rate of drop out in MSA trials [Dodel et al. 2010]. Therefore, prospective trials with large sample sizes are challenging. The development of multicentric network trials in the framework of the European Multiple System Atrophy-Study Group (EMSA-SG) [Geser et al. 2005] or the North American Multiple System Atrophy Study Group (NAMSAS-SG) in the United States [Gilman et al. 2005] may help to overcome this problem. For a better comparison of outcome results, clinical trials should apply consensus criteria for the diagnosis of MSA [Gilman et al. 2008] and assess disease severity by the validated UMSARS [Wenning et al. 2004].
As in other neurodegenerative disorders, a putative neuroprotective drug should be given as early as possible. Therefore, sensitivity and specificity for the diagnosis of MSA have to be improved in early disease stages. In an ideal world, patients at risk of developing MSA should be identified before the onset of core features. However, even when using recent consensual criteria [Gilman et al. 2008] current diagnostic accuracy at the first neurological evaluation remains poor [Osaki et al.2009]. Early autonomic symptoms or preceding RBD may be useful for early MSA detection [Gaig et al. 2008; Plazzi et al. 1997; Tison et al. 1995], but whether a patient with RBD will develop MSA, PD or no neurodegenerative disorder remains unpredictable [Schenck et al. 1996].
More sensitive progression biomarkers are also needed to assess the small effect of a putative neuroprotective drug in trials. To date, cerebrospinal fluid or blood biomarkers, even in combination, are still not specific enough or need further evidence-based studies before they can be employed in routine use for the clinical diagnosis of MSA [Constantinescu et al. 2010; Mollenhauer and Trenkwalder, 2009]. Promising biomarkers may consist of structural and functional neuroimaging abnormalities [Brooks and Seppi, 2009]. While routine MRI techniques are not sensitive enough to assess disease progression in clinical trials, the use of diffusion-weighted imaging, voxel-based morphometry or scales that rate the progression of brain atrophy may be better quantitative markers for the assessment of disease-modifying properties of a neuroprotective drug [Kollensperger and Wenning, 2009].
Conclusion
Current symptomatic management in MSA should target motor impairment, autonomic failure and depression, as these features are associated with a poor quality of life [Schrag et al. 2006]. Owing to the low number of randomized and controlled trials, practical management is currently based on empirical evidence. Levodopa remains the main treatment for MSA, despite its modest and nonsustained effect. Among the several treatments available for OH, only midodrine meets the criteria of evidence-based medicine [Wright et al. 1998; Lowet al. 1997; Jankovic et al. 1993]. Strategies for urinary disorders are well standardized, while other symptoms such as breathing disorders, RBD, depression or dystonia remain out of consensus.
Although there have been major advances in our understanding of the cellular pathology and in performing prospective trials designed for putative neuroprotective drugs, no curative treatment is yet available. The results from clinical trials assessing the disease-modifying potential of rasagiline and lithium will soon be available. Recent advances in genetic models and neurotransplantation may stimulate further clinical trials in MSA. Finally, the growing number of multicentric networks in Europe and North America combining preclinical and clinical research strategies provide some hope for future advances.
NEED STATEMENT
Multiple system atrophy, or MSA, is a rare, degenerative neurological condition that affects both men and women of all races. Potentially affecting 15,000 to 50,000 Americans, the disease affects the autonomic system and movement.
MSA symptoms include fainting spells, problems with heart rate, sudden dramatic changes in blood pressure, tremor, rigidity, slowness of movement and difficulty speaking or swallowing. While some of the symptoms of MSA can be treated with medications, currently there are no drugs that are able to slow disease progression and there is no cure. While MSA is similar to the better known Parkinson’s disease, MSA progresses much more rapidly, with most MSA patients passing away within 7.9 years of diagnosis. Quality of life decreases as the disease progresses, as the patient’s ability to perform daily activity becomes more limited. 80% of MSA patients are disabled within 5 years.
It is the difficult to diagnose MSA, since its symptoms are easily confused with Parkinson’s or other more prevalent neurological disorders. The only way a definitive diagnosis of MSA can be made is during autopsy after death. While specialized testing by a neurologist can rule out other types of rare neurological disorders, many patients are in advanced stages of the disease before being diagnosed.
Because there is a much higher incidence of MSA in the United Kingdom and Japan, most of the research and clinical trials are conducted in those countries. This fact, coupled with the advanced stage of the disease at the time of diagnosis make it difficult for MSA patients in the United States to participate in the clinical trials.
The rarity of the disease, the rapid and debilitating progression of MSA, the level of knowledge of and research on MSA can lead to patients and caregivers feeling isolated and frustrated.
PROGRAM STATEMENT
The Multiple System Atrophy Coalition develops programs to address four areas; support for patients and caregivers affected by MSA, education of patients, caregivers and healthcare professionals, encouragement and financial support of meaningful research toward identifying a cause and finding a cure for MSA, avocation for issues important to the MSA community, including creating greater awareness of MSA.
We have developed a website that provides information the disease, support groups, patient and caregiver forums, fundraising and advocacy. The website, coupled with our annual conference and webcast, allows us to provide support to both patients and caregivers, provide up to date information on the disease, offers several methods for individual fundraising, and promote grassroots advocacy. Because of the number of MSA patients, the debilitating nature of the disease and the fact those affected are spread throughout the United States, an online presence is critical to our reaching our objectives in all four areas.
The establishment of more, improved fundraising tools, along with developing partnerships with other like -minded organizations has enabled us to award 5 MSA research grants totaling $219,000. We seek to widen the awareness of our grant program by attending relevant medical conferences and partnering with National Institute of Health consortiums.
Multiple system atrophy, or MSA, is a rare, degenerative neurological condition that affects both men and women of all races. Potentially affecting 15,000 to 50,000 Americans, the disease affects the autonomic system and movement.
MSA symptoms include fainting spells, problems with heart rate, sudden dramatic changes in blood pressure, tremor, rigidity, slowness of movement and difficulty speaking or swallowing. While some of the symptoms of MSA can be treated with medications, currently there are no drugs that are able to slow disease progression and there is no cure. While MSA is similar to the better known Parkinson’s disease, MSA progresses much more rapidly, with most MSA patients passing away within 7.9 years of diagnosis. Quality of life decreases as the disease progresses, as the patient’s ability to perform daily activity becomes more limited. 80% of MSA patients are disabled within 5 years.
It is the difficult to diagnose MSA, since its symptoms are easily confused with Parkinson’s or other more prevalent neurological disorders. The only way a definitive diagnosis of MSA can be made is during autopsy after death. While specialized testing by a neurologist can rule out other types of rare neurological disorders, many patients are in advanced stages of the disease before being diagnosed.
Because there is a much higher incidence of MSA in the United Kingdom and Japan, most of the research and clinical trials are conducted in those countries. This fact, coupled with the advanced stage of the disease at the time of diagnosis make it difficult for MSA patients in the United States to participate in the clinical trials.
The rarity of the disease, the rapid and debilitating progression of MSA, the level of knowledge of and research on MSA can lead to patients and caregivers feeling isolated and frustrated.
PROGRAM STATEMENT
The Multiple System Atrophy Coalition develops programs to address four areas; support for patients and caregivers affected by MSA, education of patients, caregivers and healthcare professionals, encouragement and financial support of meaningful research toward identifying a cause and finding a cure for MSA, avocation for issues important to the MSA community, including creating greater awareness of MSA.
We have developed a website that provides information the disease, support groups, patient and caregiver forums, fundraising and advocacy. The website, coupled with our annual conference and webcast, allows us to provide support to both patients and caregivers, provide up to date information on the disease, offers several methods for individual fundraising, and promote grassroots advocacy. Because of the number of MSA patients, the debilitating nature of the disease and the fact those affected are spread throughout the United States, an online presence is critical to our reaching our objectives in all four areas.
The establishment of more, improved fundraising tools, along with developing partnerships with other like -minded organizations has enabled us to award 5 MSA research grants totaling $219,000. We seek to widen the awareness of our grant program by attending relevant medical conferences and partnering with National Institute of Health consortiums.