Multiple System Atrophy: Difference between revisions

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== Introduction  ==
== Introduction  ==
[[File:Parkinson's man sketches.jpg|right|frameless|209x209px]]
Multiple System Atrophy (MSA)&nbsp;is defined as a sporadic, fatal, progressive, [[Neurodegenerative Disease|neurodegenerative]] (specifically a [[synucleinopathy]]) adult-onset disorder. It is the second most common neurodegenerative movement disorder with an average annual incidence rate of 3 per 100000 person-years after [[Parkinson's|Parkinson’s disease]] (PD)<ref name=":3">Dash S, Mahale R, Netravathi M, Kamble NL, Holla V, Yadav R, Pal PK. [https://www.cureus.com/articles/83909-cognition-in-patients-with-multiple-system-atrophy-msa-and-its-neuroimaging-correlation-a-prospective-case-control-study Cognition in Patients With Multiple System Atrophy (MSA) and Its Neuroimaging Correlation: A Prospective Case-Control Study]. Cureus. 2022 Jan 29;14(1). Available:https://www.cureus.com/articles/83909-cognition-in-patients-with-multiple-system-atrophy-msa-and-its-neuroimaging-correlation-a-prospective-case-control-study (accessed 14.3.2022)</ref>. It can affect the
* Autonomic system causing autonomic failure, causing eg.fainting spells and problems with [[Heart Arrhythmias|heart rate]], erectile dysfunction, and [[Urinary Incontinence|bladder control]].
* [[Basal Ganglia|Basal ganglia]] causing [[Parkinson's|parkinsonism]], causing eg tremor, rigidity, and/or loss of muscle coordination as well as difficulties with speech and [[gait]].
* [[Cerebellum]] causing [[ataxia]] <ref name="Lundy Eckman">Lundy-Eckman, L.  Neuroscience: Fundamentals for Rehabilitation.  3rd ed.  St. Louis: Saunders Elsevier, 2002.</ref>
The symptoms reflect the progressive loss of function and death of different types of nerve cells in the [[Brain Anatomy|brain]] and [[Spinal cord anatomy|spinal cord]].


Multiple System Atrophy (MSA)&nbsp;is defined as a sporadic, fatal, progressive, neurodegenerative adult-onset disorder that can affect the
Some of these features are similar to those seen in Parkinson’s disease, and early in the disease course it often may be difficult to distinguish these disorders. This 1 minute video is titled Differentiating Multiple System Atrophy From Parkinson's Disease.
* autonomic system causing autonomic failure, causing eg.fainting spells and problems with heart rate, erectile dysfunction, and bladder control.
{{#ev:youtube |FZlk8a064N4|width}}<ref>MSA coalition Differentiating Multiple System Atrophy From Parkinson's Disease (PSA) Available: https://www.youtube.com/watch?v=CD7UL12GSCM<nowiki/>(accessed 14.3.2022)</ref>
* basal ganglia causing parkinsonism, causing eg tremor, rigidity, and/or loss of muscle coordination as well as difficulties with speech and [[gait]].
* cerebellum causing ataxia <ref name="Lundy Eckman">Lundy-Eckman, L.  Neuroscience: Fundamentals for Rehabilitation.  3rd ed.  St. Louis: Saunders Elsevier, 2002.</ref>
The symptoms reflect the progressive loss of function and death of different types of nerve cells in the brain and spinal cord.
 
Some of these features are similar to those seen in [[Parkinson's|Parkinson’s]] disease, and early in the disease course it often may be difficult to distinguish these disorders.
The 2 minute video below gives a good introduction to MSA
{{#ev:youtube|https://www.youtube.com/watch?v=mVqiCgaLSf4&app=desktop|width}}<ref>MSA coalition. What is MSA available from:https://www.youtube.com/watch?v=mVqiCgaLSf4&app=desktop (last accessed 17.1.2020)</ref>
=== Neuropathophysiology ===
[[File:Basal_ganglia.jpg|right|frameless]]
Neuropathologically, MSA is characterized by putaminal, pontine and cerebellar atrophy. 
 
The complexity of the neuropathological pattern correlates with the spectrum of the clinical phenotypes (several overlaps can be observed between MSA-P and MSA-C, each subtype is characterized by specific neuropathological features)
 
Subtypes
# MSA-P: denoted by severe striatonigral degeneration (part of the [[Basal Ganglia]], see image to R).The dorsolateral caudal putamen and the caudate nucleus are severely affected, with a selective involvement of GABAergic medium spiny neurons . Substantia nigra dopaminergic neurons are also remarkably involved in the degenerative process and a trans-synaptic degeneration of striatonigral fibers has been proposed. Globus pallidus and subthalamic nucleus are also implicated.
# MSA-C: this subtype is more severely characterized by the involvement of cerebellar vermis and hemispheres, dentate nucleus, inferior olive nuclei, pontine basis and cerebellopontine fibers. see image to R: Cerebellum[[Image:Cerebellum1.png|right|frameless]]
Both MSA-P and MSA-C are characterized by the involvement of other regions of the nervous system, including intermediolateral column of the spinal cord, dorsal nucleus of vagus and Onuf’s nucleus<ref name=":0">Compagnoni GM, Di Fonzo A. [https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives.] Acta neuropathologica communications. 2019 Dec;7(1):113. AVAILABLE FROM: https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6 (last accessed 16.1.2020)</ref>. Motor and supplementary motor cortices are also implicated.


=== Etiology ===
=== Etiology ===
The causes of MSA are unknown; however, as for other neurodegenerative diseases, a complex interaction of genetic and environmental mechanisms seems likely.<ref name=":1" />
The causes of MSA are unknown; however, as for other neurodegenerative diseases, a complex interaction of genetic and environmental mechanisms seems likely.<ref name=":1">Jellinger KA. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870010/ Multiple system atrophy: an oligodendroglioneural synucleinopathy]. Journal of Alzheimer's Disease. 2018 Jan 1;62(3):1141-79 Available from.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870010/ (last accessed 16.1.2020)</ref><br>Research has suggested that MSA is characterized by a progressive loss of neuronal and oligodendro[[Glial Cells|glial cells]] (myelin producing cells in CNS) in numerous sites in the CNS (basal ganglia, cerebellum). This damage is said to occur from the formation of glial cytoplasmic inclusions (GCI’s).<ref name="Diedrich">Diedrich A, Robertson D.  Multiple System Atrophy.  Vanderbilt University School of Medicine 2009. http://emedicine.medscape.com/article/1154583-overview (accessed on 24 Jan 2010).</ref>


Hypotheses include<ref name=":0" /> (from 2019 review)
== Classification ==
* alpha-synuclein accumulation in oligodendrocytes, including ''SNCA'' expression, neuron-oligodendrocyte protein transfer, impaired protein degradation and alpha-synuclein spread mechanisms.
MSA is classified by the most dominant symptom exhibited by the patient.
* mitochondrial biology defects, including the role of ''COQ2'' mutations, Coenzyme Q10 reduction, respiratory chain dysfunction and altered mitochondrial mass.
* alternative pathogenic mechanisms, including inflammation and impaired autophagy.
<br>Research has suggested that MSA is characterized by a progressive loss of neuronal and oligodendroglial cells (myelin producing cells in CNS) in numerous sites in the CNS (basal ganglia, cerebellum). This damage is said to occur from the formation of glial cytoplasmic inclusions (GCI’s).<ref name="Diedrich" />
 
*GCI’s are thought to be similar to neurofibrillary tangles that are present in movement disorders.
*Tangles are pathological protein groups found within neurons that slowly cause damage to neurons in the CNS.


Gliosis is also a contributor to MSA:
# Parkinsonian type (MSA-P): this includes symptoms similar to Parkinson's disease eg tremors at rest, rigidity of muscles, and slow movements, including gait
*Once damage has occurred to the CNS (from the formation of GCI's), glial cells come in to repair the damage.<ref name="Diedrich" /> Image is of Gliosis[[File:Gliosis.jpg|border|right|frameless]]
# Cerebellar type (MSA-C): involves difficulty walking (ataxia), issues maintaining [[balance]], and trouble [[Coordination Exercises|coordinating]] voluntary movements<ref name=":0">Very well health MSA Available: https://www.verywellhealth.com/multiple-system-atrophy-2860862<nowiki/>(accessed 14.3.2022)</ref>.
*A glial scar is then formed in order to protect and begin healing the damaged CNS. It is efficient in suppressing further damage, but it also halts neuroregeneration. Many neurological development inhibitor molecules are secreted by cells of the scar, which prevent complete physical and functional recovery of the CNS.<ref name="Diedrich" />
*This becomes a repetitive cycle of damage (from the GCI's) and ineffective healing (through gliosis), which will lead to increasingly poor control of the ANS and CNS.<ref name="Hardy">Hardy, Joanne. Multiple System Atrophy: Pathophysiology, Treatment and Nursing Care. Nursing Standard 2008;22:50-6.</ref>&nbsp;
While the above process is a current thought among many researchers, the etiology of the process of the initial cell loss is still unknown.<ref name="Diedrich" />


=== Epidemiology ===
=== Epidemiology ===
MSA is an orphan disease with a<ref name=":1">Jellinger KA. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870010/ Multiple system atrophy: an oligodendroglioneural synucleinopathy]. Journal of Alzheimer's Disease. 2018 Jan 1;62(3):1141-79 Available from.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870010/ (last accessed 16.1.2020)</ref>
[[File:MSE Dementia pic.jpg|thumb]]
# '''prevelance''': estimates range from 1.9 to 4.9 and may reach up to 7.8 after the age of 40. Wenning et al. completed an analysis of 100 patients with MSA and measured their disability. Results showed that patients with MSA become disabled at a faster rate than patients with Parkinson's.<ref name="Wenning">Wenning GK, Braune S.  Multiple System Atrophy: Pathophysiology and Management.  CNS Drugs 2001;15:839-48.</ref>
MSA is an orphan disease with an incidence of up to 2.4 cases per 100 000 persons per year, while the prevalence may reach up to 7.8 patients per 100 000 population over the age of 40. The MSA‐P variant seems to be more common in the western hemisphere, whereas MSA‐C appears to be more frequent in Asia<ref name=":4">Virtual strategy Multiple System Atrophy Epidemiology Forecast to 2030 Available: https://virtual-strategy.com/2020/07/16/multiple-system-atrophy-epidemiology-forecast-to-2030/ (accessed 14.3.2022)</ref> .
# '''incidence:'''
* of 0.6–0.7 cases per 100,000 person-years, with a range of 0.1 to 3.0 cases per 100,000 person-years. Studies from Russia and Northern Sweden reported incidences of 0.1 and 2.4 per 100,000 person-years, respectively.
* increases with age up to 12/100,000 above 70 years.
* In the Western hemisphere, MSA-P involves about 70 to 80%
* MSA-C is more frequent in Asian populations accounting for about 67–84%.
* The motor symptom onset is 56±9 years, with both sexes equally affected. However, like PD, 20 to 75% of MSA cases have a prodromal/preclinical phase with non-motor symptoms including cardiovascular autonomic failure, urogenital and sexual dysfunction, orthostatic hypotension, REM sleep behavior disorder, and respiratory disorders, which may precede the motor presentation by months to years 
* MSA is found more often in men than in women (Diedrich).<ref name="Diedrich">Diedrich A, Robertson D.  Multiple System Atrophy.  Vanderbilt University School of Medicine 2009. http://emedicine.medscape.com/article/1154583-overview (accessed on 24 Jan 2010).</ref>


=== Characteristics/Clinical Presentation ===
There is about 1 living case of MSA in the population for every 40 cases of Parkinson’s disease, but because survival in MSA is shorter than for PD, about 1 new MSA case presents every year for about every 20 who present with PD.<ref name=":4" />
MSA is classified by the most dominant symptom exhibited by the patient.


'''MSA-A:'''
=== Symptoms ===
The symptoms reflect the progressive loss of function and death of different types of [[Neurone|nerve cells]] in the brain and spinal cord. The initial symptoms of MSA are often difficult to distinguish from the initial symptoms of Parkinson’s disease and include: slowness of movement, tremor, or rigidity (stiffness); clumsiness or incoordination; impaired speech, a croaky, quivering voice; fainting or lightheadedness due to [[Orthostatic Hypotension|orthostatic hypotension]]; bladder control problems, eg a sudden urge to urinate or difficulty emptying the bladder<ref name=":4" />.


*Autonomic dysfunction, primarily orthostatic hypotension, is present in approximately 75% of people with MSA.<ref name="Wedge">Wedge F.  The Impact of Resistance Training on Balance and Functional Ability of a Patient with Multiple System Atrophy.  Journal of Geriatric Physical Therapy 2008;31:79-83.</ref>
The 2 minute video below gives a good introduction to MSA
*Autonomic dysfunction commonly appears as postural/[[Orthostatic Hypotension|orthostatic hypotension]] associated with impaired or absent reflex tachycardia upon standing, bowel and bladder incontinence, thermoregulatory dysfunction, impotence, and hypohydrosis.<ref name="Swan">Swan L, Dupont J.  Multiple System Atrophy.  Journal of Physical Therapy 1999;79:488-94.</ref>,<ref name="Diedrich" />
{{#ev:youtube|https://www.youtube.com/watch?v=mVqiCgaLSf4&app=desktop|width}}<ref>MSA coalition.  
[[File:ANS.gif|right|frameless|377x377px]]
 
&nbsp;&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;'''Figure 3''': Autonomic Nervous System
 
'''MSA-P:'''
 
*When a parkinson-like movement dysfunction is the prominent feature, the disease is categorized as MSA-P. [[Parkinsons Disease|Parkinsonism]] has been identified as the initial feature in 46% of patients with MSA, but eventually over 80% of patients with MSA will develop parkinsonian features.<ref name="Wedge" />
*Characteristics of parkinsonism include bilateral involvement, bradykinesia, impaired writing, slurred speech, rigidity,<ref name="Swan" />postural and rest tremor disequilibrium, and gait unsteadiness.<ref name="Diedrich" />
 
'''MSA-C:'''
 
*When cerebellar dysfunction is more prominent, the disease is labeled as MSA-C. &nbsp;Over 50% of individuals with MSA will present with cerebellar dysfunction.<ref name="Wedge" />
*Cerebellar features that are characteristic of MSA initially manifest in the trunk and lower extremities, leading to disturbances in gait.<ref name="Swan" />. These patients also display limb kinetic ataxia and scanning dysarthria, as well as cerebella ataxia.<br>
 
'''Additional Symptoms:'''
 
*Dysfunction to the pyramidal/[[Corticospinal Tract|corticospinal]] tracts can also occur. &nbsp;However, this symptomatic component does not own &nbsp;a subtype.<ref name="Wedge" />
*&nbsp;Signs of corticospinal tract dysfunction ([[Reflexes|hyperreflexia]], impaired muscle performance, spasticity, and a positive Babinski sign) are features characteristic of MSA, but are not used as criteria for diagnosis.<ref name="Swan" />
 
=== Associated Co-morbidities/Systemic Involvement ===
# Level of cognition:  
*Generally an absence of marked cognitive impairment, emotional instability may occur later in the progression of the disease.<ref name="Wedge" />
*Patients with MSA can have great difficulty switching attention from one stimulus to another,<ref name="Swan" />&nbsp;with a&nbsp;decrease in goal-oriented cognitive ability.
*Patients with MSA may experience depression. &nbsp;In one study of 15 patients with MSA, 28.6% had moderate to severe depression compared to 3%-4% of healthy individuals.<ref name="Hemingway">Hemingway J, Franco K, Chmelik E. Shy-Drager Syndrome: Multisystem Atrophy With Comorbid Depression.  Psychosomatics.  2005;46:73-6.</ref>
 
2. Bowel and Bladder Dysfunction:
*Genitourinary dysfunctions are common symptoms (may include frequency, urgency, incontinence, and retention).<ref name="Swan" />
*Men may experience erectile difficulties early in the course of the disease.<ref name="Swan" />
*Constipation a common problem.<ref name="Swan" />
 
3. Symptoms Occurring as the Disease Progresses:
 
4. Dysphagia and dysarthria are symptoms late in the disease<ref name="Swan" /> and should be treated by speech therapy.
 
=== Diagnostic Tests/Lab Tests/Lab Values ===
At this time, there are no specific symptoms, blood tests or imaging studies that distinguish MSA. Instead, doctors rely on a combination of symptom history, physical examination, and laboratory tests to evaluate the motor system, coordination, and autonomic function to arrive at a probable diagnosis<ref name=":2">MSA Coalition. [https://www.multiplesystematrophy.org/wp-content/uploads/2019/09/What-You-Need-to-Know-9.4.19-DSC-AM-NV-Edits2.pdf MSA what you need to know] 4.4.2019. Available from: https://www.multiplesystematrophy.org/wp-content/uploads/2019/09/What-You-Need-to-Know-9.4.19-DSC-AM-NV-Edits2.pdf (last accessed 17.1.2020)</ref>.
* Medical technology such as functional MRI (fMRI) measures activity levels in the brain and can demonstrate areas of impaired brain function. See MRI image below.
* By applying sensitive pattern recognition techniques to certain MRI studies, medical science is increasingly differentiating the early signs of MSA from Parkinson's disease and other neurologic conditions with greater accuracy.
* New studies are also finding that a particular type of lipid-transporting molecule important for production of myelin might be faulty in MSA patients and that evaluating this molecule, known as ABCA8, could provide a causative explanation and a screening tool for MSA.
Some atrophic changes are visible upon use of [[MRI Scans|MRI]]. &nbsp;
 
[[Image:MSA.jpg]]
 
'''Figure 4''': MRI showing visible atrophy of the pontine (A) and cerebellar (B) regions.
 
=== Diagnostic Challenge ===
It is important to differentiate MSA from PAF (Pure Autonomic Failure) and pure parkinsonism. As there is no “typical” presentation for this disorder, and MSA can often be masked by other diagnoses, it is important if one has a patient with pure Parkinson’s, PAF, etc to keep a watchful eye of any suspicious S/S that are not associated with that diagnosis alone. This is pertinent so that these patients do not go misdiagnosed.
*Patients with MSA are most commonly misdiagnosed with [[Parkinsons Disease|Parkinson’s Disease]]. About 1/3 of people with MSA die while still misdiagnosed.<ref name="Lundy Eckman" />
*Only 25% of patients with MSA are correctly diagnosed at their first neurological visit. The correct diagnosis is usually established on an average of 4 to 5 years after the disease onset.<ref name="Wenning" />
*The distinction between MSA and parkinsonism&nbsp;is made by exclusion. If no autonomic or cerebellar signs are present, then the patient most likely has pure parkinsonism.<ref name="Lundy Eckman" />
 
*90% of patients with MSA-P treated with [[Levodopa in the treatment of Parkinson's|Levodopa]] (L-Dopa) fail to show a sustained, long-term response.<ref name="Wenning" /> This is a sign that this patient does not have pure parkinsonism, as L-Dopa is not effective.
*Orthostatic hypotension, difficulty urinating, rapid progression of functional limitations, loud breathing,and impotence indicate that MSA is a more likely Dx than Parkinson’s Disease.<ref name="Wenning" />
*A patient most likely has PAF if ANS S/S (such as orthostatic hypotension) are present, but signs of parkinsonism or ataxia are not.<ref name="Lundy Eckman" />
=== Medical Management ===
MSA must be diagnosed on the basis of probability from the clinical presentation.<ref name="Hardy" />
 
To date there are no causative or disease-modifying treatments available and symptomatic therapies are limited. There is a strong need to clarify the pathogenic mechanisms in MSA in order to develop new therapeutic strategies options<ref name=":1" />.
* Levodopa responsiveness has been reported initially in 83% of MSA-P patients, but the effect is usually transient, and only 31% showed a response for a period of 3.5 years. In some patients, motor fluctuations with wearing-off phenomena or off-bound dystonia were observed. 
* Deep brain stimulation could not be recommended for MSA
* Active immunization against αS and combination with anti-inflammatory treatment may be promising therapeutic strategies. New strategies targeting αS are in progress, based on completed or ongoing interventional trials by the MSA Coalition.
Clinical presentation is not only important for diagnosis of MSA, but is also helpful in treatment. &nbsp;Since MSA is a variable condition, the most effective medical management is symptomatic treatment.<ref name="Hardy" /> &nbsp;Current medical management includes pharmacological treatment. &nbsp;Medication is prescribed according to the subtype of MSA and the symptoms that are present.
 
Since MSA is a variable disorder and can present in many different ways. &nbsp;Therefore, treatment is symptomatic.<br>Pharmacological Treatment:


'''MSA-A'''
What is MSA available from:https://www.youtube.com/watch?v=mVqiCgaLSf4&app=desktop (last accessed 17.1.2020)</ref>
=== Cognition ===
[[File:Cerebrum animation small2.gif|thumb|150x150px|Frontal lobe red Temporal lobe green]]
[[Cognitive Impairments|Cognitive deficits]] occur in all cognitive domains. The impaired cognitive domains had a significant correlation with atrophy of frontotemporal [[Cerebral Cortex|cortical]] areas, [[Basal Ganglia|basal ganglia]], [[thalamus]], and [[cerebellum]]<ref name=":3" />. Cognitive impairment, particularly seen in executive function, may occur in up to 75% of patients The [[Mini-Mental State Examination]], or MMSE, yielded 3% of participants showing signs of cognitive decline while a test called the Frontal Assessment Battery (FAB) categorized 41% of participants as being cognitively impaired. The FAB is a cognitive test that incorporates several clinical assessments to screen for [[Frontotemporal Dementia|frontotemporal dementia]] (FTD)


To manage autonomic symptoms, patients may consider options such as increasing salt intake or taking steroid hormones or other drugs that raise blood pressure. [[Sleep Apnea-Hypopnea Syndrome|Sleep apnea]] devices known as CPAP (continuous, positive airway pressure) machines can help with breathing difficulties.<ref name=":2" />  
* Emotional instability may occur later in the progression of the disease
* Depression, anxiety, panic attacks, and suicidal ideation may present in MSA
* Patients with MSA can have great difficulty switching attention from one stimulus to another,<ref name="Swan">Swan L, Dupont J.  Multiple System Atrophy.  Journal of Physical Therapy 1999;79:488-94.</ref>&nbsp;with a&nbsp;decrease in goal-oriented cognitive ability.


*To treat [[Orthostatic Hypotension|orthostatic hypotension]]: (is defined as a fall in BP on standing of more than 20mmHg in SBP or 10 mmHg in DBP)<ref name="Hardy" /> Drugs can be prescribed to enhance vasoconstriction and increase the blood volume, which will increase the blood pressure (''[http://www.drugs.com/pro/fludrocortisone.html Fludrocortisone]'' and ''[http://www.drugs.com/pro/midodrine.html Midodrine]'').<ref name="Lundy Eckman" />
== Diagnosis ==
*To treat constipation stool softener medications are effective.<ref name="Hardy" />
At this time, there are no specific symptoms, blood tests or imaging studies that distinguish MSA<ref name=":2">MSA Coalition. [https://www.multiplesystematrophy.org/wp-content/uploads/2019/09/What-You-Need-to-Know-9.4.19-DSC-AM-NV-Edits2.pdf MSA what you need to know] 4.4.2019. Available from: https://www.multiplesystematrophy.org/wp-content/uploads/2019/09/What-You-Need-to-Know-9.4.19-DSC-AM-NV-Edits2.pdf (last accessed 17.1.2020)</ref>. It can take a while to receive an MSA diagnosis because of the similarities between MSA and other conditions, eg Parkinson's disease. MSA is usually diagnosed around 50 years of age and is seen in people of all ethnic backgrounds. Once symptoms begin, the disease tends to progress quite rapidly.
*To treat urinary dysfunction pharmacological intervention do not adequately reduce post-void residual volume in patients with MSA, but anticholinergic agents like ''[http://www.drugs.com/pro/oxybutynin.html Oxybutynin]'' can improve symptoms of hyper-reflexia.<ref name="Wenning" />  
*To treat impotence:&nbsp;''Sildenafil'' (25 to 75mg) may be successful in treating erectile failure.<ref name="Wenning" />


'''MSA-C'''
The Mini-Mental State Examination, or MMSE, yielded 3% of participants showing signs of cognitive decline while a test called the Frontal Assessment Battery (FAB) categorized 41% of participants as being cognitively impaired<ref>MAS coalition Depression and Cognitive Impairment in MSA Available:https://www.multiplesystematrophy.org/about-msa/depression-cognitive-impairment/ (accessed 14.3.2022)</ref>. The FAB is a cognitive test that incorporates several clinical assessments to screen for frontotemporal dementia (FTD),


*There are no currently established pharmacological treatment strategies for cerebellar ataxia and pyramidal dysfunction.<ref name="Wenning" />
'''Diagnostic Challenge''' There is no “typical” presentation for this disorder, and MSA can often be masked by other diagnoses. Patients with MSA are most commonly misdiagnosed with [[Parkinsons Disease|Parkinson’s Disease]]. About 1/3 of people with MSA die while still misdiagnosed.<ref name="Lundy Eckman" /> Only 25% of patients with MSA are correctly diagnosed at their first neurological visit. The correct diagnosis is usually established on an average of 4 to 5 years after the disease onset.<ref name="Wenning">Wenning GK, Braune S.  Multiple System Atrophy: Pathophysiology and Management.  CNS Drugs 2001;15:839-48.</ref>
=== Management ===
Currently, there is no cure for MSA, nor are there any treatments specifically designed to reverse or stop disease progression.


'''MSA-P'''
* Movement disorders can be treated with levodopa and carbidopa (Sinemet), but this usually has limited results.
 
* Other medications such as trihexyphenidyl (Artane), benztropine mesylate (Cogentin), and amantadine (Symmetrel), may also offer some symptom relief. Several medications exist to treat orthostatic hypertension.
*Drugs used for Parkinson's disease may provide relief of muscle rigidity, slowness, and other motor symptoms for some MSA patients, though only in the earlier stages and with less effectiveness than for Parkinson's patients. Parkinson's drugs also can lower blood pressure and may worsen NOH symptoms, dizziness, and fainting episodes.<ref name=":2" />
* Physical and occupational therapy, eg aqua therapy, can help maintain muscle function, and speech therapy can help improve any difficulties swallowing or speaking<ref name=":0" />.


=== Physical Therapy Management ===
=== Physical Therapy Management ===
Physical therapies offer drug-free tools for keeping muscles strong and flexible, helping prevent [[falls]] and other incidents that hasten disability. Encouraging mobility also lowers the risk of [[Pulmonary Embolism|pulmonary embolism]] which can be fatal<ref name=":2" />.
[[File:Man-walker dementia.jpg|thumb|Walking Aid]]
Physical therapies offer drug-free tools to maintain their function for as long as possible, by helping keep muscles strong and flexible and helping prevent [[falls]]. Encouraging mobility also lowers the risk of [[Pulmonary Embolism|pulmonary embolism]] which can be fatal<ref name=":2" />.


There is very little published literature on physical therapy or exercise intervention for patients with MSA.<ref name="Wedge" /><br>There is the most evidence concerning patients with MSA-A.<ref name="Wedge" />
Ideally a neurological physiotherapist will assess the client and then make a tailored program. It incorporates a combination of progressive fitness, balance, movement and strength training and stretching, as well as education on how to manage symptoms. Make PT goals realistic.  Base the goals upon current function and take into consideration the activities most important to the patient.  


Since majority of patients with MSA-A seem to experience [[Orthostatic Hypotension|orthostatic hypotension]] (OH), this is a main focus during a treatment session.<ref name="Swan" /><ref name="Lundy Eckman" /> For effective strategies for [[Orthostatic Hypotension|OH]] see link.
[[Gait]]/Mobility Training:


Bowel and Bladder Treatment:
# Fit the patient for the most appropriate [[Walking Aids|walking aids]] in order to gain independent mobility. &nbsp;This will depend upon the patient’s level of function and safety.
*Begin a urinary incontinence program if appropriate. &nbsp;Introducing exercises for the [[Pelvic Floor Dysfunction|pelvic floor]] musculature in order to gain control/suppress urge, etc.
# If a [[Wheelchair Assessment - Assessment Interview|wheelchair]] is most appropriate, ensure the chair is one that will best benefit their posture and mobility based upon the function of patient.&nbsp;As a PT, the need to promote independent functional mobility and optimal posture with safety in mind is most important.


[[Gait]]/Mobility Training:
*Fit the patient for the most appropriate assistive device in order to gain independent mobility. &nbsp;This will depend upon the patient’s level of function and safety.
*If a [[Wheelchair Assessment - Assessment Interview|wheelchair]] is most appropriate, ensure the chair is one that will best benefit their posture and mobility based upon the function of patient.&nbsp;
*As a PT, the need to promote independent functional mobility and optimal posture with safety in mind is most important.
[[File:Hip exercise 6.png|right|frameless]]
[[File:Hip exercise 6.png|right|frameless]]
Therapeutic Exercise/Activities:
Therapeutic Exercise/Activities:
*According to a study by Wedge, et al., [[Gait Re-education in Parkinson's|gait]] training, transfer training, [[balance]] activities, and conditioning are necessary in reaching the goal of&nbsp;minimizing fatigue and risk for falling (safe transfers, etc.)<ref name="Wedge" />  
*[[Moving and Handling|Transfer training]]  
*Resistance training has been proven to be effective in patients with MSA.<br>• Knee extensors and flexors, hip abductors and adductors, and ankle plantarflexors were targeted for resistance training. &nbsp;These muscle groups are chosen because of their importance to balance.<ref name="Wedge" /><br>• Following resistance training interventions, marked improvements are noted in the patient's gait pattern (increased consistency in maintaining good step height and length even when fatigued). &nbsp;Reduces festinating gait and other functional changes achieved. &nbsp;The patients improve transfer technique and  posture (ie good head and trunk alignment in both sitting and standing). Also less frequency of [[Falls|fall]]<nowiki/>ing.<ref name="Wedge" />  
*[[Balance]] activities<ref name="Wedge">Wedge F.  The Impact of Resistance Training on Balance and Functional Ability of a Patient with Multiple System Atrophy.  Journal of Geriatric Physical Therapy 2008;31:79-83.</ref>eg [[Otago Exercise Programme|Otago balance porogram]]
*[[Strength Training|Strength training]] focusing  on  [[Knee Extensors|knee extensors]] and [[Knee Flexors|flexors]], [[Hip Abductors|hip abductors]] and [[Hip Adductors|adductors]], and ankle plantar flexors .These muscle groups are chosen because of their importance to balance.<ref name="Wedge" /> Can lead to improvements in the patient's gait pattern (better at maintaining good step height and length even) and reduces festinating gait.
*Postural muscle strengthening to improve eg head and trunk alignment in both sitting and standing).<ref name="Wedge" />


Additional Physical Therapy Advice:
Education


Research reinforces the fact that since MSA is a variable disorder. &nbsp;Each patient with MSA will present differently, so it is difficult to give clear PT advice.
*Based upon a patient’s level of mobility and function, PT's should use their skills and knowledge to promote a safe and optimal environment for the patient.
*As a PT, maintaining strength and physiologic fitness as long as possible will be most valuable to the patient.<ref name="Lundy Eckman" />
*Education of the patient and family on benefits of PT is important for patient/family knowledge and compliance.  
*Education of the patient and family on benefits of PT is important for patient/family knowledge and compliance.  
*Make PT goals realistic. &nbsp;Base the goals upon current function and take into consideration the activities most important to the patient.&nbsp;
*Since this is a progressive disorder, PT's must make sure to re-evaluate goals often to make sure they are appropriate.


=== Differential Diagnosis ===
=== Differential Diagnosis ===
MSA often presents as the following disorders:  
MSA often presents as the following disorders: Pure [[Parkinson's|Parkinsonism]]<ref name="Hardy">Hardy, Joanne.  Multiple System Atrophy: Pathophysiology, Treatment and Nursing Care.  Nursing Standard 2008;22:50-6.</ref>; Pure Autonomic Failu<nowiki/>re (PAF)<ref name="Hardy" />; [[Progressive Supranuclear Palsy]]<ref name="O'Sullivan">O'Sullivan SS, Massey LA, Williams DR, Silveira-moriyama L, Kempster PA, Holton JL, Revesz T,  Lees, AJ.  Clinical Outcomes of Progressive Supranuclear Palsy and Multiple System Atrophy.  Brain.  2008;131:1362-72</ref>; Corticobasal Ganglionic Degeneration<ref name="Hain">Hain TC.  Multiple System Atrophy.  2010.  http://www.dizziness-and-balance.com/disorders/central/movement/msa.html (accessed on 5 april 2010).</ref>
 
*Pure [[Parkinson's|Parkinsonism]]<ref name="Wedge" />,<ref name="Swan" />,<ref name="Wenning" />,<ref name="Hardy" />  
*Pure Autonomic Failure (PAF)<ref name="Wedge" />,<ref name="Swan" />,<ref name="Hardy" />,<ref name="Wenning" />
*[[Progressive Supranuclear Palsy]]<ref name="O'Sullivan">O'Sullivan SS, Massey LA, Williams DR, Silveira-moriyama L, Kempster PA, Holton JL, Revesz T,  Lees, AJ.  Clinical Outcomes of Progressive Supranuclear Palsy and Multiple System Atrophy.  Brain.  2008;131:1362-72</ref>  
*Corticobasal Ganglionic Degeneration<ref name="Hain">Hain TC.  Multiple System Atrophy.  2010.  http://www.dizziness-and-balance.com/disorders/central/movement/msa.html (accessed on 5 april 2010).</ref>


=== Prognosis and Outlook ===
=== Prognosis and Outlook ===
Prognosis is currently guarded, with most MSA patients passing away from the disease or its complications within 6-10 years after the onset of symptoms. Nonetheless, there is reason for hope for MSA research goes on. Since the biology of MSA may be related to other neurodegenerative diseases like Parkinson's disease, it is possible that therapies designed for other conditions will also prove helpful for patients with MSA.<ref name=":2" />
Prognosis is currently guarded, with most MSA patients passing away from the disease or its complications within 6-10 years after the onset of symptoms. Nonetheless, there is reason for hope for MSA research goes on. Since the biology of MSA may be related to other neurodegenerative diseases like Parkinson's disease, it is possible that therapies designed for other conditions will also prove helpful for patients with MSA.<ref name=":2" />
== Case Reports  ==
'''Wedge F. The Impact of Resistance Training on Balance and Functional Ability of a Patient with Multiple System Atrophy. Journal of Geriatric Physical Therapy 2008;31:79-83.'''<br>The following case report documents the impact of a resistance-training program on a 68 year-old-female patient with a 2-year history of MSA.&nbsp;<br>
'''Hemingway J, Franco K, Chmelik E. Shy-Drager Syndrome: Multisystem Atrophy With Comorbid Depression. Psychosomatics. 2005;46:73-6.'''
The following case report discusses the some of the struggles in the diagnostic process of a 48 year old man with MSA. &nbsp;
'''Mashidori T, Yamanishi T, Yoshida K, Sakakibara R ,Sakurai K, Hirata K. Continuous Urinary Incontinence Presenting as the Initial Symptoms Demonstrating Acontractile Detrusor and Intrinsic Sphincter Deficiency in Multiple System Atrophy. International Journal of Urology. 2007;14:972-74. '''<br> The following case report demonstrates how urinary incontinence can be the first symptoms of MSA in a 66-year-old female.
'''Goto K, Ueki A, Shimode H, Shinjo H, Miwa C, Morita, Y. Depression in Multiple System Atrophy: A Case Report. Psychiatry and Clinical Neurosciences. 2000;54:507-11.''' The following case report demonstrates how depression can be the first symptoms of MSA in a 56-year-old female.&nbsp;
=== Resources ===
'''WE MOVE''': Worldwide Education and Awareness for Movement Disorders.
http://www.wemove.org
'''SDS/MSA Support Group'''
http://www.shy-drager.org/
== References  ==
== References  ==


Latest revision as of 11:15, 17 February 2023

Original Editors - Emily Nicklies from Bellarmine University's Pathophysiology of Complex Patient Problems project.

Top Contributors - Emily Nicklies, Lucinda hampton, Admin, Kim Jackson, Dave Pariser, Wendy Walker, Elaine Lonnemann, Naomi O'Reilly, WikiSysop and Amrita Patro  

Introduction[edit | edit source]

Parkinson's man sketches.jpg

Multiple System Atrophy (MSA) is defined as a sporadic, fatal, progressive, neurodegenerative (specifically a synucleinopathy) adult-onset disorder. It is the second most common neurodegenerative movement disorder with an average annual incidence rate of 3 per 100000 person-years after Parkinson’s disease (PD)[1]. It can affect the

The symptoms reflect the progressive loss of function and death of different types of nerve cells in the brain and spinal cord.

Some of these features are similar to those seen in Parkinson’s disease, and early in the disease course it often may be difficult to distinguish these disorders. This 1 minute video is titled Differentiating Multiple System Atrophy From Parkinson's Disease.

[3]

Etiology[edit | edit source]

The causes of MSA are unknown; however, as for other neurodegenerative diseases, a complex interaction of genetic and environmental mechanisms seems likely.[4]
Research has suggested that MSA is characterized by a progressive loss of neuronal and oligodendroglial cells (myelin producing cells in CNS) in numerous sites in the CNS (basal ganglia, cerebellum). This damage is said to occur from the formation of glial cytoplasmic inclusions (GCI’s).[5]

Classification[edit | edit source]

MSA is classified by the most dominant symptom exhibited by the patient.

  1. Parkinsonian type (MSA-P): this includes symptoms similar to Parkinson's disease eg tremors at rest, rigidity of muscles, and slow movements, including gait
  2. Cerebellar type (MSA-C): involves difficulty walking (ataxia), issues maintaining balance, and trouble coordinating voluntary movements[6].

Epidemiology[edit | edit source]

MSE Dementia pic.jpg

MSA is an orphan disease with an incidence of up to 2.4 cases per 100 000 persons per year, while the prevalence may reach up to 7.8 patients per 100 000 population over the age of 40. The MSA‐P variant seems to be more common in the western hemisphere, whereas MSA‐C appears to be more frequent in Asia[7] .

There is about 1 living case of MSA in the population for every 40 cases of Parkinson’s disease, but because survival in MSA is shorter than for PD, about 1 new MSA case presents every year for about every 20 who present with PD.[7]

Symptoms[edit | edit source]

The symptoms reflect the progressive loss of function and death of different types of nerve cells in the brain and spinal cord. The initial symptoms of MSA are often difficult to distinguish from the initial symptoms of Parkinson’s disease and include: slowness of movement, tremor, or rigidity (stiffness); clumsiness or incoordination; impaired speech, a croaky, quivering voice; fainting or lightheadedness due to orthostatic hypotension; bladder control problems, eg a sudden urge to urinate or difficulty emptying the bladder[7].

The 2 minute video below gives a good introduction to MSA

[8]

Cognition[edit | edit source]

Frontal lobe red Temporal lobe green

Cognitive deficits occur in all cognitive domains. The impaired cognitive domains had a significant correlation with atrophy of frontotemporal cortical areas, basal ganglia, thalamus, and cerebellum[1]. Cognitive impairment, particularly seen in executive function, may occur in up to 75% of patients The Mini-Mental State Examination, or MMSE, yielded 3% of participants showing signs of cognitive decline while a test called the Frontal Assessment Battery (FAB) categorized 41% of participants as being cognitively impaired. The FAB is a cognitive test that incorporates several clinical assessments to screen for frontotemporal dementia (FTD)

  • Emotional instability may occur later in the progression of the disease
  • Depression, anxiety, panic attacks, and suicidal ideation may present in MSA
  • Patients with MSA can have great difficulty switching attention from one stimulus to another,[9] with a decrease in goal-oriented cognitive ability.

Diagnosis[edit | edit source]

At this time, there are no specific symptoms, blood tests or imaging studies that distinguish MSA[10]. It can take a while to receive an MSA diagnosis because of the similarities between MSA and other conditions, eg Parkinson's disease. MSA is usually diagnosed around 50 years of age and is seen in people of all ethnic backgrounds. Once symptoms begin, the disease tends to progress quite rapidly.

The Mini-Mental State Examination, or MMSE, yielded 3% of participants showing signs of cognitive decline while a test called the Frontal Assessment Battery (FAB) categorized 41% of participants as being cognitively impaired[11]. The FAB is a cognitive test that incorporates several clinical assessments to screen for frontotemporal dementia (FTD),

Diagnostic Challenge There is no “typical” presentation for this disorder, and MSA can often be masked by other diagnoses. Patients with MSA are most commonly misdiagnosed with Parkinson’s Disease. About 1/3 of people with MSA die while still misdiagnosed.[2] Only 25% of patients with MSA are correctly diagnosed at their first neurological visit. The correct diagnosis is usually established on an average of 4 to 5 years after the disease onset.[12]

Management[edit | edit source]

Currently, there is no cure for MSA, nor are there any treatments specifically designed to reverse or stop disease progression.

  • Movement disorders can be treated with levodopa and carbidopa (Sinemet), but this usually has limited results.
  • Other medications such as trihexyphenidyl (Artane), benztropine mesylate (Cogentin), and amantadine (Symmetrel), may also offer some symptom relief. Several medications exist to treat orthostatic hypertension.
  • Physical and occupational therapy, eg aqua therapy, can help maintain muscle function, and speech therapy can help improve any difficulties swallowing or speaking[6].

Physical Therapy Management[edit | edit source]

Walking Aid

Physical therapies offer drug-free tools to maintain their function for as long as possible, by helping keep muscles strong and flexible and helping prevent falls. Encouraging mobility also lowers the risk of pulmonary embolism which can be fatal[10].

Ideally a neurological physiotherapist will assess the client and then make a tailored program. It incorporates a combination of progressive fitness, balance, movement and strength training and stretching, as well as education on how to manage symptoms. Make PT goals realistic.  Base the goals upon current function and take into consideration the activities most important to the patient.

Gait/Mobility Training:

  1. Fit the patient for the most appropriate walking aids in order to gain independent mobility.  This will depend upon the patient’s level of function and safety.
  2. If a wheelchair is most appropriate, ensure the chair is one that will best benefit their posture and mobility based upon the function of patient. As a PT, the need to promote independent functional mobility and optimal posture with safety in mind is most important.
Hip exercise 6.png

Therapeutic Exercise/Activities:

Education

  • Education of the patient and family on benefits of PT is important for patient/family knowledge and compliance.

Differential Diagnosis[edit | edit source]

MSA often presents as the following disorders: Pure Parkinsonism[14]; Pure Autonomic Failure (PAF)[14]; Progressive Supranuclear Palsy[15]; Corticobasal Ganglionic Degeneration[16]

Prognosis and Outlook[edit | edit source]

Prognosis is currently guarded, with most MSA patients passing away from the disease or its complications within 6-10 years after the onset of symptoms. Nonetheless, there is reason for hope for MSA research goes on. Since the biology of MSA may be related to other neurodegenerative diseases like Parkinson's disease, it is possible that therapies designed for other conditions will also prove helpful for patients with MSA.[10]

References[edit | edit source]

  1. ↑ 1.0 1.1 Dash S, Mahale R, Netravathi M, Kamble NL, Holla V, Yadav R, Pal PK. Cognition in Patients With Multiple System Atrophy (MSA) and Its Neuroimaging Correlation: A Prospective Case-Control Study. Cureus. 2022 Jan 29;14(1). Available:https://www.cureus.com/articles/83909-cognition-in-patients-with-multiple-system-atrophy-msa-and-its-neuroimaging-correlation-a-prospective-case-control-study (accessed 14.3.2022)
  2. ↑ 2.0 2.1 Lundy-Eckman, L. Neuroscience: Fundamentals for Rehabilitation. 3rd ed. St. Louis: Saunders Elsevier, 2002.
  3. ↑ MSA coalition Differentiating Multiple System Atrophy From Parkinson's Disease (PSA) Available: https://www.youtube.com/watch?v=CD7UL12GSCM(accessed 14.3.2022)
  4. ↑ Jellinger KA. Multiple system atrophy: an oligodendroglioneural synucleinopathy. Journal of Alzheimer's Disease. 2018 Jan 1;62(3):1141-79 Available from.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870010/ (last accessed 16.1.2020)
  5. ↑ Diedrich A, Robertson D. Multiple System Atrophy. Vanderbilt University School of Medicine 2009. http://emedicine.medscape.com/article/1154583-overview (accessed on 24 Jan 2010).
  6. ↑ 6.0 6.1 Very well health MSA Available: https://www.verywellhealth.com/multiple-system-atrophy-2860862(accessed 14.3.2022)
  7. ↑ 7.0 7.1 7.2 Virtual strategy Multiple System Atrophy Epidemiology Forecast to 2030 Available: https://virtual-strategy.com/2020/07/16/multiple-system-atrophy-epidemiology-forecast-to-2030/ (accessed 14.3.2022)
  8. ↑ MSA coalition. What is MSA available from:https://www.youtube.com/watch?v=mVqiCgaLSf4&app=desktop (last accessed 17.1.2020)
  9. ↑ Swan L, Dupont J. Multiple System Atrophy. Journal of Physical Therapy 1999;79:488-94.
  10. ↑ 10.0 10.1 10.2 MSA Coalition. MSA what you need to know 4.4.2019. Available from: https://www.multiplesystematrophy.org/wp-content/uploads/2019/09/What-You-Need-to-Know-9.4.19-DSC-AM-NV-Edits2.pdf (last accessed 17.1.2020)
  11. ↑ MAS coalition Depression and Cognitive Impairment in MSA Available:https://www.multiplesystematrophy.org/about-msa/depression-cognitive-impairment/ (accessed 14.3.2022)
  12. ↑ Wenning GK, Braune S. Multiple System Atrophy: Pathophysiology and Management. CNS Drugs 2001;15:839-48.
  13. ↑ 13.0 13.1 13.2 Wedge F. The Impact of Resistance Training on Balance and Functional Ability of a Patient with Multiple System Atrophy. Journal of Geriatric Physical Therapy 2008;31:79-83.
  14. ↑ 14.0 14.1 Hardy, Joanne. Multiple System Atrophy: Pathophysiology, Treatment and Nursing Care. Nursing Standard 2008;22:50-6.
  15. ↑ O'Sullivan SS, Massey LA, Williams DR, Silveira-moriyama L, Kempster PA, Holton JL, Revesz T, Lees, AJ. Clinical Outcomes of Progressive Supranuclear Palsy and Multiple System Atrophy. Brain. 2008;131:1362-72
  16. ↑ Hain TC. Multiple System Atrophy. 2010. http://www.dizziness-and-balance.com/disorders/central/movement/msa.html (accessed on 5 april 2010).
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