Multiple System Atrophy

Introduction

Parkinson's man sketches.jpg

Multiple System Atrophy (MSA) is defined as a sporadic, fatal, progressive, neurodegenerative adult-onset disorder that can affect the

  • autonomic system causing autonomic failure, causing eg.fainting spells and problems with heart rate, erectile dysfunction, and bladder control.
  • 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 [1]

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. The 2 minute video below gives a good introduction to MSA

[2]

Neuropathophysiology

Basal ganglia.jpg

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

  1. 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.
  2. 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
    Cerebellum1.png

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[3]. Motor and supplementary motor cortices are also implicated.

Etiology

The causes of MSA are unknown; however, as for other neurodegenerative diseases, a complex interaction of genetic and environmental mechanisms seems likely.[4]

Hypotheses include[3] (from 2019 review)

  • alpha-synuclein accumulation in oligodendrocytes, including SNCA expression, neuron-oligodendrocyte protein transfer, impaired protein degradation and alpha-synuclein spread mechanisms.
  • 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.


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]

  • 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:

  • Once damage has occurred to the CNS (from the formation of GCI's), glial cells come in to repair the damage.[5] Image is of Gliosis
    Gliosis.jpg
  • 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.[5]
  • 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.[6] 

While the above process is a current thought among many researchers, the etiology of the process of the initial cell loss is still unknown.[5]

Epidemiology

MSA is an orphan disease with a[4]

  1. 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.[7]
  2. 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).[5]

Characteristics/Clinical Presentation

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

MSA-A:

  • Autonomic dysfunction, primarily orthostatic hypotension, is present in approximately 75% of people with MSA.[8]
  • Autonomic dysfunction commonly appears as postural/orthostatic hypotension associated with impaired or absent reflex tachycardia upon standing, bowel and bladder incontinence, thermoregulatory dysfunction, impotence, and hypohydrosis.[9],[5]
ANS.gif

                      Figure 3: Autonomic Nervous System

MSA-P:

  • When a parkinson-like movement dysfunction is the prominent feature, the disease is categorized as MSA-P. 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.[8]
  • Characteristics of parkinsonism include bilateral involvement, bradykinesia, impaired writing, slurred speech, rigidity,[9]postural and rest tremor disequilibrium, and gait unsteadiness.[5]

MSA-C:

  • When cerebellar dysfunction is more prominent, the disease is labeled as MSA-C.  Over 50% of individuals with MSA will present with cerebellar dysfunction.[8]
  • Cerebellar features that are characteristic of MSA initially manifest in the trunk and lower extremities, leading to disturbances in gait.[9]. These patients also display limb kinetic ataxia and scanning dysarthria, as well as cerebella ataxia.

Additional Symptoms:

  • Dysfunction to the pyramidal/corticospinal tracts can also occur.  However, this symptomatic component does not own  a subtype.[8]
  •  Signs of corticospinal tract dysfunction (hyperreflexia, impaired muscle performance, spasticity, and a positive Babinski sign) are features characteristic of MSA, but are not used as criteria for diagnosis.[9]

Associated Co-morbidities/Systemic Involvement

  1. Level of cognition and mental health[10]
  • Generally an absence of marked cognitive impairment. Dementia is thought to be rare in MSA but may affect 12% to 18% of patients
  • Emotional instability may occur later in the progression of the disease.[8]
  • Depression, anxiety, panic attacks, and suicidal ideation may present in MSA. Some patients express inappropriate laughing or crying. Cognitive impairment, particularly seen in executive function, may occur in up to 75% of patients
  • Patients with MSA can have great difficulty switching attention from one stimulus to another,[9] with a decrease in goal-oriented cognitive ability.

2. Bowel and Bladder Dysfunction:

  • Genitourinary dysfunctions are common symptoms (may include frequency, urgency, incontinence, and retention).[9]
  • Men may experience erectile difficulties early in the course of the disease.[9]
  • Constipation a common problem.[9]

3. Symptoms Occurring as the Disease Progresses:

4. Dysphagia and dysarthria are symptoms late in the disease[9] 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[10].

  • 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.  

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 Parkinson’s Disease. About 1/3 of people with MSA die while still misdiagnosed.[1]
  • 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.[7]
  • The distinction between MSA and parkinsonism is made by exclusion. If no autonomic or cerebellar signs are present, then the patient most likely has pure parkinsonism.[1]
  • 90% of patients with MSA-P treated with Levodopa (L-Dopa) fail to show a sustained, long-term response.[7] 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.[7]
  • A patient most likely has PAF if ANS S/S (such as orthostatic hypotension) are present, but signs of parkinsonism or ataxia are not.[1]

Medical Management

MSA must be diagnosed on the basis of probability from the clinical presentation.[6]

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[4].

  • 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.  Since MSA is a variable condition, the most effective medical management is symptomatic treatment.[6]  Current medical management includes pharmacological treatment.  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.  Therefore, treatment is symptomatic.
Pharmacological Treatment:

MSA-A

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 devices known as CPAP (continuous, positive airway pressure) machines can help with breathing difficulties.[10]

  • To treat orthostatic hypotension: (is defined as a fall in BP on standing of more than 20mmHg in SBP or 10 mmHg in DBP)[6] Drugs can be prescribed to enhance vasoconstriction and increase the blood volume, which will increase the blood pressure (Fludrocortisone and Midodrine).[1]
  • To treat constipation stool softener medications are effective.[6]
  • To treat urinary dysfunction pharmacological intervention do not adequately reduce post-void residual volume in patients with MSA, but anticholinergic agents like Oxybutynin can improve symptoms of hyper-reflexia.[7]
  • To treat impotence: Sildenafil (25 to 75mg) may be successful in treating erectile failure.[7]

MSA-C

  • There are no currently established pharmacological treatment strategies for cerebellar ataxia and pyramidal dysfunction.[7]

MSA-P

  • 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.[10]

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 which can be fatal[10].

There is very little published literature on physical therapy or exercise intervention for patients with MSA.[8]
There is the most evidence concerning patients with MSA-A.[8]

Since majority of patients with MSA-A seem to experience orthostatic hypotension (OH), this is a main focus during a treatment session.[9][1] For effective strategies for OH see link.

Bowel and Bladder Treatment:

  • Begin a urinary incontinence program if appropriate.  Introducing exercises for the pelvic floor musculature in order to gain control/suppress urge, etc.

Gait/Mobility Training:

  • Fit the patient for the most appropriate assistive device in order to gain independent mobility.  This will depend upon the patient’s level of function and safety.
  • 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:

  • According to a study by Wedge, et al., gait training, transfer training, balance activities, and conditioning are necessary in reaching the goal of minimizing fatigue and risk for falling (safe transfers, etc.)[8]
  • Resistance training has been proven to be effective in patients with MSA.
    • Knee extensors and flexors, hip abductors and adductors, and ankle plantarflexors were targeted for resistance training.  These muscle groups are chosen because of their importance to balance.[8]
    • 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).  Reduces festinating gait and other functional changes achieved.  The patients improve transfer technique and posture (ie good head and trunk alignment in both sitting and standing). Also less frequency of falling.[8]

Additional Physical Therapy Advice:

Research reinforces the fact that since MSA is a variable disorder.  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.[1]
  • Education of the patient and family on benefits of PT is important for patient/family knowledge and compliance.
  • Make PT goals realistic.  Base the goals upon current function and take into consideration the activities most important to the patient. 
  • Since this is a progressive disorder, PT's must make sure to re-evaluate goals often to make sure they are appropriate.

Differential Diagnosis

MSA often presents as the following disorders:

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.[10]

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.
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. 

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.  

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.
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. 

Resources

SDS/MSA Support Group

http://www.shy-drager.org/

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Lundy-Eckman, L. Neuroscience: Fundamentals for Rehabilitation. 3rd ed. St. Louis: Saunders Elsevier, 2002.
  2. MSA coalition. What is MSA available from:https://www.youtube.com/watch?v=mVqiCgaLSf4&app=desktop (last accessed 17.1.2020)
  3. 3.0 3.1 Compagnoni GM, Di Fonzo A. 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)
  4. 4.0 4.1 4.2 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. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 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 6.2 6.3 6.4 6.5 6.6 Hardy, Joanne. Multiple System Atrophy: Pathophysiology, Treatment and Nursing Care. Nursing Standard 2008;22:50-6.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Wenning GK, Braune S. Multiple System Atrophy: Pathophysiology and Management. CNS Drugs 2001;15:839-48.
  8. 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 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.
  9. 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 Swan L, Dupont J. Multiple System Atrophy. Journal of Physical Therapy 1999;79:488-94.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 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. 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
  12. Hain TC. Multiple System Atrophy. 2010. http://www.dizziness-and-balance.com/disorders/central/movement/msa.html (accessed on 5 april 2010).