Multiple Systems Atrophy

Introduction:
Multiple systems atrophy (MSA) was formally called Shy-Drager syndrome. MSA shares many of the similar symptoms as Parkinson’s disease. For example, bradykinesia, rigidity, and having poor balance. [4] It is a rare progressive neurodegenerative disorder. It affects both the autonomic nervous system and movement. In America it affects 15,000 to 50,000 people. It affects all racial groups. Most symptoms will appear in the fifties. They symptoms will progress over a period of five to ten years. [3] There are also two types of MSA. The first type is MSA-P. MSA-P is associated with Parkinson’s like symptoms. The second type is MSA-C which is associated with loss of coordination and balance. [5]


Functional Anatomy:
With MSA there are three areas that experience degeneration.
  1. Basal Ganglia:
    • The basal ganglia is a collection of nuclei.The input nuclei are the caudate and putamen which are collectively called the striatum. The output nuclei are the substantial niagra para reticularis (SNr) and the globus palldius internus (GPi). Internal processing is done in the globus pallidus externus(GPe), subthalamic (STN), and substantial nigra para compacta (SNc).
basal ganglia.png


    • Direct and Indirect Pathways:
      • The basal ganglia have two motor pathways. The direct and indirect help to facilitate or inhibit movement. The direct and indirect pathway both get information from area 4, supplementary motor area, premotor cortex and the somatosensory cortex by glutamatergic axons that will excite the striatum. The direct pathway will then send inhibitory GABA projections to the GPi/SNr. The GPi and SNr are the output nucleus of the basal ganglia. From the output nuclei there will send inhibitory GABA projections to the ventral lateral portion of the thalamus. However, because of inhibitory projections to the output nuclei the output nuclei are not inhibiting the thalamus as much allowing for movement to occur. Instead of projecting directly to the output nuclei the indirect pathway will first project with inhibitory GABA cells to the GPe. From the GPe there are GABA cells projecting to the STN that are inhibiting the STN. The STN send excitatory glutamate cells to the output nucleus. The excitatory input onto the output nuclei will cause more inhibition the thalamus. This inhibition of the thalamus will inhibit unwanted movement. There are also two dopaminergic projections from the SNc. D1 receptors are found in the direct pathway and D2 receptors are found in the indirect pathway. D1 receptors will increase the activity of the direct pathway. This will allow for inhibition of neuronal firing in the output nuclei leading to disinhibition of their projections to the thalamus. The disinhibition will allow the cortex to become exited and allow for movement. The indirect pathway is associated with D2 fibers. The inhibition on the thalamus is going to be lower because there was less inhibition the GPe which inhibited the STN less, meaning the STN cannot excite the output nucleus as much resulting in less inhibition to the thalamus. Less inhibition means that it will also allow for movement. pathway.jpg
2. Cerebellum: coordinates voluntary movements and helps maintain balance [4]

brainstem.jpg
    • The cerebellum contains over 50% of the total number of the neurons in the brain and is located in the posterior fossa behind the brain stem. It is connected to the brain stem by three peduncles. They are the superior, inferior, and middle peduncles. It makes changes to the motor commands instead of initiating movement. It makes changes to the descending pathway to make the movements more accurate. The cerebellum helps with balance by input from the vestibular system and proprioceptors and using motor neurons to make changes to body position. It has two main components the cerebellar cortex and the cerebellar deep nuclei. These are the only output nuclei of the cerebellum.[1]
  • Cerebellar Cortex:
    • The cerebral cortex has three parts. First, you have the vestibulocerebellum it is the oldest part of the cerebellum. It contains the flocculus and nodules. Next, you have the spinocerebellum this developed after the vestibulocerebellum. It contains the vermis and intermediate hemisphere. Lastly, there is the cerebrocerebellum. This is the newest part of the cerebellum to develop. It contains the lateral hemisphere.
Image result for spinocerebellum
Image result for spinocerebellum
    • The cerebellar cortex is divided into three layers. The most superficial layer is molecular layer, the middle layer is purkinje cell layer and the deepest layer is the granule cell layer. The molecular layer contains dendrites from the purkinjie cells and axons from the granule layer.Granule cells are extremely small and are the most numerous type of cell in the cerebellum. These cells will get input from mossy cells and then send output to the Purkinje fibers. Purkinje cells have special dendrites that form a fan like structure.


external image cerebellar-cortex.jpg
    • The conduction of the cerebellar cortex has two different inputs. The first is through the mossy fibers. Mossy fibers are given there name due to their appearance. They have a tufted appearance meaning that they are like small dense clumps as they synapse onto the granule cells. Mossy fibers arises in the pontien nuclei, spinal cord, vestibular nuclei, and the brainstem reticular formation. These inputs will make excitatory connections into the cerebellar nuclei and then onto the granule cells. From there mossy fibers innervate hundreds of granule cells making a lot of divergence occurring. Once you make it to the molecular layer the axon splits and goes in different directions. The name of these fibers are parallel fibers. Like the name suggests the parallel fibers travel parallel to the folds of the cerebellar cortex. They will make excitatory synapses with Purkinje fibers. Parallel cells will synapse will hundreds of Purkinje cells. The second input comes from climbing fibers. Climbing fibers originate in the inferior olive and are called climbing fibers because of the way they wrap around the dendrites of Purkinje fibers. They have excitatory projections to the cerebellar nuclei and the Purkinje cells. The climbing cells have a more powerful input onto the Purkinje cells then mossy fibers or parallel fibers. This is because a single Purkinje fiber will recive an input from a single climbing fiber. Also, climbing fibers will only synapse on to the Puekinje cells around 300 times. [4]
  • Cerebellar Nuclei:
    • There are four cerebellum nuclei: the fastigial, interposed, denate, and vestibulr. The vestibular nuclei is not always considered apart of the cerebellar nuclei because it is located outside the cerebellum. The fastigial carries information from the somatosensory, vestibulr, auditory, and visual areas along with input from the virmis. It projects out the the vestibular nuclei and reticular formation. The next is interposed nuclei. Input comes from the inputs that are carrying spinal, somatosensory, auditory, and visual information. The interposed nuclei projects to contralateral red nucleus. The third is the dentate nucleus. This nucleus is the largest of all four. Input is received by the cerebral cortex and lateral hemisphere. Output goes to the ventrolateral thalamic nucleus and the contralateral red nucleus. The fourth nuclei is the vestibular nuclei. These are not strictly a cerebellar nuclei. This is because they are located outside of the cerebellum. Input is received from flocculonodular lobe and the vestibular labyrinth. Output to the motor nuclei.[4]
3. Areas that control autonomic nervous system: regulates involuntary body processes
    • Brain Stem:
      • midbrain
      • pons
      • medulla oblongata
    • Controls the information’s between the brain and the rest of the body. Also, it controls many body functions. For example, breathing, swallowing, heart rate, blood pressure, and consciousness. [5]
brainstemm.jpg
    • Midbrain:
      • Relay center for the visual, auditory, and motor system information. It regulates digestion, heart rate, and breathing rate.
    • Pons:
      • Controls breathing rate
      • Sensation of hearing, taste, and balance
      • Regulation of deep sleep
    • Medulla Oblongota:
      • Important in heart rate and blood pressure
      • Reflexes: Vomiting, sneezing and coughing

Causes:

There is not a clear reason for what causes multiple systems atrophy. Some scientists believe that there may be a component that is inferenced or that an environmental factor, but there is not a significant indication to that. MSA causes the degeneration of the cerebellum, basal ganglia and brainstem. [2] One cardinal feature of MSA is a build-up of alpha-synuclein. This build-up is found primarily in the glia and oligodendroglia. Another thought of a cause of MSA is with the synuclein gene SCNA. This gene holds the instructions to produce alpha-synuclein. The thought is that some individual have a different variation of the gene and that it may cause for an overproduction of alpha-synuclein [4]


Two Types of MSA [2]:
  1. Parkinsonian type (MSA-P): Symptoms similar to Parkinson’s disease, but individuals with MSA-P progress quicker.
    • Rigidity
    • Difficulty bending arms and legs
    • Brasykinesia
    • Tremors
    • Problems with posture and balance
2.Cerebellar type (MSA-C)
    • Ataxia
    • Difficulty swallowing
    • Speech abnormalities
    • abnormal eye movements

Diagnosis:
MSA is difficult to diagnose because of its similarity to other diseases like Parkinson's disease. Most people have been misdiagnosed when it comes to diagnosing MSA, but there has been increasing awareness of the disease making doctors better equipped to make diagnoses. When patients go into a doctors office the doctor will do a physical examination, medical history, and automatic tests. Some of the automatic tests that would be preformed are brain-imaging test, MRI, blood tests, and bladder test. MRI and other brain-imaging tests are done in order see if the brain has atrophied or if these is a lesions in the brain. Another test that might be done is a tilt table test. A tilt table test is done in order see how your body controls blood pressure. The patient is strapped onto a board and turned upside down. While in this position the doctors will monitor heart rate and blood pressure. [2] Another test that can be done is DaTscan. The DaTscan looks at dopamine transportation. This test is helpful, but can not tell the difference between Parkinson's and MSA. [4]

Symptoms [2,4]:
    • Parkinsonism: Parkinsonism is due to the degeneration of the basal ganglia. Movements become more difficult to perform. While walking people may have a festering gait and not swing their arms. Also, there is a feeling of unsteadiness which will cause the person more likely to fall. People with MSA are less likely to have tremors then other with Parkinson's disease.
    • Clumsiness or incoordination: Incoordination is due to degeneration of the cerebellum. With the degeneration of the cerebellum people will lose their balance and the eventually not be able to control movement of limbs. Because of the above factors walking will become difficult and they will be likely to take irregular steps.
    • Impaired speech download.jpg
    • Fainting or lightheadedness
    • Urinary and bowel dysfunction
    • Sweating abnormalities
    • Contractures in the hands or limbs
    • Pisa syndrome
    • Antecollis
    • Involuntary and uncontrollable sighing or gasping
    • Sleep disorders
    • Cardiovascular problems
    • Psychiatric problems


Treatment [5]:
    • There is no cure for MSA
    • Parkinson Symptoms:
      • Treatment with levodopa and carbidope to help improve motor function. However, this is not a treatment that is effective on all MSA patients and if they do work after a few years they will become less effective.
    • Autonomic Symptoms [3,4]:
      • Regulate blood pressure: One common medication that is prescribed is corticosteroid fludrocortisone. This medication is taken to increase blood pressure. It helps increase blood pressure by allowing your body to retain more salt. Another common blood pressure medication, pyridostigmine, will raise their standing blood pressure while not increasing their laying down blood pressure. One more treatment is a pacemaker. A pacemaker would be advised in order to keep your heart beating at a rapid pace. Some people also suffer from fainting and lightheadedness due to orthostatic hypotension. Most times this can be solved by wearing compression stockings, adding salt and more water to your diet and not eating heavy meals. In some cases the medications fludrocortisone and midodrine.
      • Controlling swallowing and breathing difficulties: The first step for treatment with swallowing is eating softer foods. If breathing and swallowing becomes increasingly difficult then a breathing and feeding tube will need to be inserted.
      • Bladder Control: At the initial stages of the disease anticholinergic medications like oxybutynin or tolteridine can be used in order to help with bladder control. However, as the disease progressing a catheter will need to be inserted in order to drain the bladder.
      • Dystonia: injections of botulinum toxin
      • Sleep Problems: A sleep study will be preformed and if needed some of the medications that can be prescribed are some antidepressants, melatonin, and clonazepam
      • Body fluids: Some people experience no or little sweating. People who experience these symptoms should avoid hot environments. Also, having regular dental check ups for dry mouth and an eye exams to deal with dry eyes.
    • Non-Drug Therapies:
      • Physical therapy
      • Occupational therapy
      • Speech therapy
      • Assistive devices
      • Social workers
      • Support groups
      • Home health or hospice services

Conclusion:

Multiple system atrophy is a rare degenerative neurological disorder. There are two types of MSA, Parkinsonian type and cerebellar type. It affects the basal ganglia, cerebellum, and brain stem. Degeneration occurs in those area due to an accumulation of the protein alpha-synuclein. Life expectancy with someone with MSA is about seven to ten years after symptoms first appear. However, survival rate does vary from person to person. Most people with MSA will die due to respiratory issues. There is no cure to the disease and only ways to mange the symptoms of the disease. [3]



Key Terms:
    • Gila: the cell that supports nerve cells in the brain [4]
    • Oligodendroglia: a type of cell that makes myelin [4]
    • Contractures: chronic shortening of muscles or tendons around joints.[4]
    • Antecollis: neck bends forward and the head drops down[4]
    • Ataxia: the loss of a full control of bodily movements [7]
    • Pisa syndrome: an abnormal posture in which the body appears to be leaning to one side [4]
    • Parkinsonism: any condition that causes a combination of the movement abnormalities seen in Parkinson’s [6]

Quiz:
1.What protein is thought to be the cause of MSA?
a. Amyloid beta
b.Tau Protein c. Presenitin d.Alpha-Synuclein
2. What are the three main parts affected by MSA? a. Cerebellum b. Brain Steam c. Basal Ganglia d a and c e All of the above
3. What are the output nuclei of the Basal Ganglia? a. Substantial niagra para reticularis b. Globus palldius internus c. Striatum d. A and C e A and B
4. What type of MSA is associated with rigidity, tremors, and bradykinesia? a MSA-P b MSA-C c MSA-N d MSA-I
5. T/F The function of the Cerebellum is to control the autonomic nervous system?


Short Answer:
1. Compare and contrast the two types of MSA?2. Explain how the basal ganglia functions?3. What would be the best treatment plan for a person with MSA?


Suggested Readings and Videos:


The story of Dr. James Wark and his family with their journey with MSA.


A simple explanation of what MSA is.


https://www.multiplesystematrophy.org/

This website will give you information about the disease, what research is being done, fundraising, and advocacy.



References:
[1](n.d.). Retrieved November 24, 2017, from http://neuroscience.uth.tmc.edu/s3/chapter05.html
[2]Multiple system atrophy (MSA). (2017, June 17). Retrieved November 24, 2017, from https://www.mayoclinic.org/diseases-conditions/multiple-system-atrophy/symptoms-causes/syc-20356153
[3]Multiple System Atrophy - Brain, Spinal Cord, and Nerve Disorders. (n.d.). Retrieved November 24, 2017, from http://www.merckmanuals.com/home/brain,-spinal-cord,-and-nerve-disorders/autonomic-nervous-system-disorders/multiple-system-atrophy
[4]Multiple System Atrophy Fact Sheet. (n.d.). Retrieved November 24, 2017, from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Multiple-System-Atrophy
[5]Non-Drug Therapies & Medications for Treatment of Multiple System Atrophy. (n.d.). Retrieved November 24, 2017, from https://www.multiplesystematrophy.org/about-msa/treatment
[6]Parkinsonism: What causes it? (2017, August 10). Retrieved November 24, 2017, from https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/expert-answers/parkinsonism/faq-20058490
[7]What is Ataxia? (n.d.). Retrieved November 24, 2017, from https://ataxia.org/what-is-ataxia/

Photo Links:

http://neurology.mhmedical.com/Content.aspx?bookId=1049&sectionId=59138673
https://basicmedicalkey.com/treatment-of-central-nervous-system-degenerative-disorders-
http://serendip.brynmawr.edu/exchange/brains/definitions/def-cerebellum

https://neuroticbody.weebly.com/spinocerebellum.html

https://www.stevemallory.org/brainstem/

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(11)70067-9/fulltext




Quiz Answers:
D,E,E, A,False

1) Parkinsonian type. Similar to Parkinson's disease, but individuals with MSA-P progress quicker. The symptoms are rigid muscles, difficulty bending arms and legs, bradykinesia, tremors, and problems with posture and balance. Cerebella type symptoms ataxia, difficulty swallowing, speech abnormalities, abnormal eye movements.2)
The basal ganglia have two motor pathways. The direct and indirect help to facilitate or inhibit movement. The direct and indirect pathway both get information from area 4, supplementary motor area, premotor cortex and the somatosensory cortex by glutamatergic axons that will excite the striatum. The direct pathway will then send inhibitory GABA projections to the GPi/SNr. The GPi and SNr are the output nucleus of the basal ganglia. From the output nuclei there will send inhibitory GABA projections to the ventral lateral portion of the thalamus. However, because of inhibitory projections to the output nuclei the output nuclei are not inhibiting the thalamus as much allowing for movement to occur. Instead of projecting directly to the output nuclei the indirect pathway will first project with inhibitory GABA cells to the GPe. From the GPe there are GABA cells projecting to the STN that are inhibiting the STN. The STN send excitatory glutamate cells to the output nucleus. The excitatory input onto the output nuclei will cause more inhibition the thalamus. This inhibition of the thalamus will inhibit unwanted movement. There are also two dopaminergic projections from the SNc. D1 receptors are found in the direct pathway and D2 receptors are found in the indirect pathway. D1 receptors will increase the activity of the direct pathway. This will allow for inhibition of neuronal firing in the output nuclei leading to disinhibition of their projections to the thalamus. The disinhibition will allow the cortex to become exited and allow for movement. The indirect pathway is associated with D2 fibers. The inhibition on the thalamus is going to be lower because there was less inhibition the GPe which inhibited the STN less, meaning the STN cannot excite the output nucleus as much resulting in less inhibition to the thalamus. Less inhibition means that it was also allow for movement

4) Answer should include treatments for parkinsonism symptoms along with autonomic symptoms. Also, non-drug therapies.