Introduction

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Dystonia is known as a movement disorder in which there is sustained or irregular muscle contractions which cause repetitive movements. These movements are
commonly seen as occurring in a twisting pattern and can also be accompanied by a tremor. These muscle contractions can be worsened by voluntary movements due to an abundance of muscle activation. There are many different kinds of dystonia that have been diagnosed with some types of dystonia linking with other diseases like Parkinson’s or Huntington’s disease. It is important to know that research is still being done on patients with dystonia and that the information included here is the most recent findings of the disorder.

Functional Anatomy

Basal Ganglia- The basal ganglia are a collection of structures that have roles in both motor as well as non-motor (cognitive and emotional) aspects. They are a collection of nuclei deep to the white matter of the cerebral cortex. These collection of nuclei include the caudate, putamen, substantia nigra, globus pallidus, and sub thalamic nuclei. They are responsible for modifying movement on a minute-to-minute basis by controlling the direct and indirect pathways. The striatum is responsible for choosing whether the direct or indirect pathway will be used. It does this by receiving input from the cortex which relays the desired movement which triggers the direct and indirect pathways depending on the movement. [2]

Cerebellum- The cerebellar tonsils sit right next to the foramen magnum where the brainstem exits the skull. It sits at the roof of the fourth ventricle and is located posterior to the brainstem at about the level of the pons. It is connected to the brainstem by the peduncles and receives information from the spinal cord to regulate motor movements. It is important in regulating posture, balance, coordination and speech. The flocculonodular lobe, vermis, intermediate hemispheres and lateral hemispheres make up the cerebellum. The cerebellum controls movement through error-detection and correction and is involved in maintaining postural control and smooth gait patterns.

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Input/output pathways:

Input pathway (afferent)- The excitatory afferents arise from the cerebral cortex and from the interlaminar nuclei of the thalamus. These inputs are directed toward the striatum, some going to the caudate and others to the putamen depending on their origin. However, we will be looking more in depth to the output pathway because this is where it is believed that dystonia can be caused when problems arise in the pathway.

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Output pathway (efferent)- The output structures of the basal ganglia are the globus pallidus internus and the substantia nigra pars reticulata. Both of
theseoutput structures produce GABA inhibitory connections on their targets. The globus pallidus internus projects to the thalamic structures by way of the ansa
lenticularis and the lenticular fasciculus tracts. The substantia nigra pars reticulata projects to the superior colliculus. The globus pallidus externus plays a role in the
indirect pathway but the pathway ends up making its way back to the output nuclei just mentioned.

Direct pathway- This pathway facilitates movement and starts with cells that make inhibitory connections to the globus pallidus internus and substantia nigra parsreticulata. In this pathway the sensorimotor cortex sends input to the striatum which in turn will send output to the output nuclei (globus pallidus internus and substantia nigra pars reticulata). The output nuclei then send output to the thalamus which will then send output back to the cortex in one big feedback loop. The cortex starts by sending glutamate to the striatum which excites it and causes it to send out more inhibitory signals to the output nuclei. Since the output nuclei are inhibiting the thalamus at rest then in this case when the striatum inhibits them it causes the output nuclei to send less inhibitory signals to the thalamus. Once the thalamus has been disinhibited it will be able to send excitatory signals to the cortex in order for movement to be produced.
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Indirect pathway- This pathway inhibits movement and starts with a different set of cells in the striatum which will make inhibitory connections with the globus pallidus externus. This pathway like the direct pathway is also a feedback loop and it begins in the cortex as well which sends output to the striatum, then the globus pallidus externus, sub thalamic nuclei, output nuclei, thalamus and then back to the cortex. The more excitatory signals that are sent to the striatum, the more
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inhibitory signals are sent to the globus pallidus externus. The globus pallidus externus is then being inhibited so therefor it will send less inhibitory signals to the sub thalamic nuclei. This decreased inhibition to the sub thalamic nuclei will cause them to send more excitatory input to the output nuclei. We know the function of the output nuclei is to inhibit the thalamus so if they are receiving excitatory signals then they will end up increasing the inhibition on the thalamus. This will then prevent the thalamus from sending excitatory signals to the cortex. This is the pathway that is believed to have issues in a patient with dystonia. It is important to note that there is strong evidence for this pathway playing a role in causing dystonia, however, there are patients with dystonia that don’t have lesions in these pathways. Research is still being conducted but it is believed that the indirect pathway is not working properly in patients with dystonia. The function of the indirect pathway as just described is to inhibit the thalamus, and therefor inhibit movement. If this pathway is not working properly then it would be difficult for any unwanted movements to be suppressed which would result in sustained or irregular muscle contractions. [3]

Cerebellum- The cerebellum is mostly associated with the coordination of muscle activity and figuring out if there are any errors associated with the movement. It can find out if there is an error with the movement in three ways. The cortex will send information to the cerebellum telling it what the intended movement was supposed to be. There is also ascending input coming from an interneuron in the spinal cord that tells the cerebellum what the muscle action being performed is at that level. Finally, it is also getting proprioception information coming up the dorsospinocerebellar tract which lets the cerebellum know what the executed movement ended up being. With all this information the cerebellum is allowed to see if it all matches up and if it doesn’t then it will send signals to the red nucleus or to the thalamus and cortex to correct for the movement. Recently there has been information to suggest that the cerebellum can contribute to the disorder of dystonia. If those pathways that were just described have lesions associated with them then it would make accounting for error more difficult and it would not be corrected. So the unwanted movements associated with dystonia would continue to happen without any error signal being sent back to the cerebellum. [4]


Presentation of topic issue:

Diagnosis- It is difficult to diagnose dystonia properly because there are so many different kinds of dystonia. It could be related with Parkinson’s or be confined to a particular part of the body.
Dystonia is classified clinically by identifying key features in the categories of the age of onset, body distribution, temporal pattern and associated features. The best way to diagnose a patient is to first rule out disorders that mimic dystonia. The next step is to narrow down the clinical syndrome according to these four categories used for clinical classification.
The age of onset ranges from infancy all the way to late adulthood. The age ranges for each of these are as listed,
Infancy: neonatal-2 years
Childhood: 3-12 years
Adolescence: 13-20 years
Early adulthood: 21-40 years
Late adulthood: greater than 40 years


Classification of the dystonias according to clinical features

Dimension for classification
Subgroups
Age at onset
Infancy (birth to 2 years)
Childhood (3–12 years)
Adolescence (13–20 years)
Early adulthood (21–40 years)
Late adulthood (40 years and older)
Body distribution
Focal (one isolated region)
Segmental (2 or more contiguous regions)
Multifocal (2 or more non-contiguous regions)
Hemidystonia (half the body)
Generalized (trunk plus 3 other sites)
Temporal pattern
Disease course (static vs progressive)
Short-term variation (persistent, action-specific, diurnal, paroxysmal)
Associated features
Isolated (with or without tremor)
Combined (with other neurological or systemic features)

Body distribution deals with classifications based off of the number of body parts affected and if they are contiguous. The classifications are as listed,
Focal: This is when one body part is affected by dystonia, an example of this we are all familiar with is writers cramp in the hand.
Segmental: This is when 2 contiguous body parts are affected and some examples are brachial (arm and trunk), crural (leg and trunk).
Multifocal: This is two non-contiguous body parts being affected, an example is called faciobrachial which is when dystonia is affecting both the arm/hand and the eyelids.
Generalized: This is when 3 or more body parts are affected which could be when the legs, trunk and arms are all affected at the same time.
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Temporal patterns deal with how often or when the dystonia arises throughout the day and it is broken up into these following categories,
Persistent: When dystonia is active at the same level throughout most of the day.
Action specific: When performing an action, the dystonia arises like with a writer’s cramp.
Diurnal fluctuations: As the day goes on the symptoms progress like in dopa-responsive dystonia.
Paroxysmal: This is when symptoms of dystonia appear suddenly due to a specific trigger. [1][5]

Associated features can be put into three separate categories,
Isolated: When dystonia is the only noticeable motor feature with the possibility of a tremor as well.
Combined: When dystonia is linked with another movement disorder like parkinson's disease or Huntington's.
Complex: When dystonia is not the most prominent disease, dystonia in these circumstances is an inconsistent feature.

Symptoms- The symptoms for dystonia vary depending on what type of dystonia the patient has. These are some general symptoms for most patients:
  • Involuntary muscle contractions that cause repetitive or twisting movements
  • Begins in a single area and tends to remain focal to that specific area
  • Occurs during a specific action like when writing
  • Can worsen with stress, fatigue or anxiety
  • Over time it becomes more noticeable
  • Areas of the body that can be affected include:
    • o Neck where there are contractions that cause turning and twisting of the head and it can pull side to side or forwards and backwards
    • o Eyelids can twitch which causes rapid blinking or spasms where it can make you functionally blind by not allowing the eyelids to relax
    • o Jaw or tongue can cause slurred speech and drooling with also difficulty with eating by affecting chewing and swallowing
    • o Hands and forearms can occur when trying to perform a movement like writing and it will begin to act up to the point where a fine movement like writing isn’t possible
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Treatment- There is currently no cure for dystonia but there are multiple treatment options to try and help suppress the symptoms of the disorder.
Education and counseling are important for the patients because they may be dealing with psychiatric problems or could have been misdiagnosed. Sometimes the onset of symptoms for someone who has been diagnosed can be up to 4-6 years. This will cause the patients to not believe that they are misdiagnosed and then will not want to listen to the doctor that diagnosed them. Allowing the patient to be properly educated on what the disorder is can be important when questions or doubts arise for them. It is important also for counseling so that the patient can be told the realistic expectations of treatment and life with the disorder.

Physical Therapy is also another option as far as treatment goes and can be done along with education and counseling. This is not a strong option as far as treatment goes because there have been systematic reviews that have came to the conclusion that there is not enough evidence to allow the therapist to use a particular strategy. The reported benefits have been small but for some this is an option if it helps but their mind more at peace or if they try it and find that going does improve their functioning throughout the week.

Some studies have found that oral medications can be helpful, however, none of the have been FDA approved for the treatment of dystonia. Some of these
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medications include acetylcholine-related drugs, dopamine-related drugs, GABA-related drugs and muscle relaxants. (See table 5 for examples)

Neuromodulation, also known as deep brain stimulation, has been an option with varying levels of success among patients. Some respond quite well while others receive no benefit and become discouraged with the treatment. Research has shown that patients with isolated generalized dystonia will respond the most positively and consistently with the deep brain stimulation treatment. The best possible outcomes usually occur in younger age patients. Those with isolated focal and segmental dystonia also respond well to treatment but research is still being done to figure out why this is. It is important to know that benefits from this can take weeks or even months to see and it requires frequent visits and adjustments of the treatment until the right outcomes are seen. The ideal target of the stimulation remains unknown (thalamus and sub thalamic nuclei are top candidates) because it could vary from patient to patient or dependent on the type of dystonia the patient has. [5] [6]


Conclusion:

Dystonia is a disorder that can be seen when there are twisting, irregular, and sustained muscle activity. This activity can take place in various areas of the body and is important to identify when diagnosing a patient’s type of dystonia. Dystonia is believed to effect the basal ganglia’s indirect pathway by not allowing the inhibition of the thalamus to suppress unwanted movements when trying to perform a separate movement. This is why sometimes dystonia is seen more when voluntary movements are trying to be performed. There are speculations that the cerebellum is also involved in dystonia but not enough research has been done to be sure of it. Dystonia is not curable but there are many courses of treatment that can be taken to better the lifestyle of a patient with this disorder.

Glossary:

  • Parkinson’s Disease- A disorder that arises from nerve damage where dopamine levels drop and affect the direct pathway in the basal ganglia. Symptoms include slow movement, stiffness and loss of balance with tremors.
  • Huntington’s Disease- A disorder where the basal ganglia area of the brain is affected and it results in the loss of functional abilities and with cognitive thinking.
  • Striatum- Made up of the caudate and putamen in the basal ganglia and is an important part in both the direct and indirect pathways when conducting movement.
  • Globus Pallidus Internus- Part of the basal ganglia as one of the output nuclei and is a major function of the direct pathway, its function is to inhibit the thalamus at rest.
  • Globus Pallidus Externus- Part of the basal ganglia and plays a major function in the indirect pathway, its function is to inhibit the sub thalamic nuclei at rest.
  • Substantia nigra- Consists of both the pars compacta and pars reticulata, both are parts of the basal ganglia. The function of the pars reticulata is important in dystonia because it is one of the output nuclei in the direct pathway. At rest it inhibits the thalamus.
  • GABA- Stands for gamma-aminobutyric acid and it is an inhibitory neurotransmitter that is important in the functions of the direct and indirect pathways in the basal ganglia

Quiz:

Multiple choice/True False

1. What pathway in the basal ganglia is associated with inhibiting movement?
a) Direct pathway
b) Input pathway
c) Output pathway
d) Indirect pathway

2. True or False, both glutamate and GABA are inhibiting neurotransmitters?

3. Which of the following is NOT used to classify a possible diagnosis of dystonia for the patient?
a) Age at onset
b) Years with disease
c) Temporal patterns
d) Body distribution

4. Which of the following is NOT a treatment technique used by patients with dystonia?
a) Physical Therapy
b) Become educated
c) Counseling
d) Deep Brain Stimulation
e) All of the above

5. True or False, the cerebellum deals with error control of muscle movements?

Essay/Short answer

1. What are the two of the three different ways that the cerebellum is able to account for error in a movement (where is it getting feedback or feedforward information from)?

2. Describe either the direct or indirect pathway in detail and explain what the overall function of the pathway is.

3. Would you suggest to a patient with dystonia to go to physical therapy or receive deep brain stimulation for treatment? What are the advantages and disadvantages of the treatment you suggest to them?

Quiz Answers:

Multiple choice/True False
1. D
2. False
3. B
4. E
5. True

Essays/Short answer
1. The three ways that the cerebellum is able to account for error in movement are as listed.
  • Motor cortex sends what the intended movement should be before it is executed
  • Interneurons in the spinal cord send information up to the cerebellum telling it what the movement is that is about to be performed
  • Proprioception of the limbs during movement send information via the dorsospinocerebellar tract and up to the cerebellum telling it what the movement is that is now being performed
2. The direct pathway is important in the decreased inhibition of the thalamus which allows for the execution of movement, in this pathway the output nuclei are inhibited by the striatum which ends up sending decreased inhibition to the thalamus which allows for movement. The indirect pathway is important in increasing the inhibition sent onto the thalamus which in turn allows for the suppression of movement that is unwanted. This pathway works by the output nuclei being excited due to the striatum having increased inhibition put onto it which will in turn inhibit the thalamus even more to suppress movement.
3. The answer could be either because both physical therapy and deep brain stimulation can have advantages based on the patient. The correctness of the answer depends on how they explain the advantages and disadvantages. Deep brain stimulation works overall better than physical therapy for most patients with isolated dystonia but for some patients it will have no effect at all so it would have to be a type of trial and error for patients going through deep brain stimulation. Physical therapy is less effective overall for patients but there are those who can find it effective through various stretching exercises. It is patient dependent due to so many different cases of dystonia.

Suggested Readings/Links

http://www.dystonia.org.uk/index.php/about-dystonia/what-happens-in-the-brain-to-cause-dystonia
This link is for various theories about spinal cord and cerebellar involvement in dystonia, it is not confirmed information but they give reasons for and against these ideas.
https://www.youtube.com/watch?v=mSwo28t5t3k
To get an idea for visually what dystonia looks like this is a good video to see a patient with cervical dystonia.
https://www.dystonia-foundation.org/about-us/newsletters-press-releases/dystonia-dialogue/articles/stanfahn
This is an interview with a dystonia expert that I found interesting to get some more detail on the disorder and to see frequently asked questions and future research ideas

References:

1. Klein, Christine. “Hereditary Dystonia Overview.” GeneReviews® [Internet]., U.S. National Library of Medicine, 22 June 2017, www.ncbi.nlm.nih.gov/books/NBK1155/.
2. Richardson, Emily. “The Basal Ganglia and Dystonia.” Home, www.dystonia.org.uk/index.php/about-dystonia/dystonia-and-the-basal-ganglia.
3. Neychev, Vladimir K., et al. “The Functional Neuroanatomy of Dystonia.” Neurobiology of Disease, U.S. National Library of Medicine, May 2011, www.ncbi.nlm.nih.gov/pmc/articles/PMC3478782/.
4. Manto, Mario, et al. “Consensus Paper: Roles of the Cerebellum in Motor Control—The Diversity of Ideas on Cerebellar Involvement in Movement.” Cerebellum (London, England), U.S. National Library of Medicine, June 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC4347949/.
5. Jinnah, H. A. “Diagnosis & Treatment of Dystonia.” Neurologic Clinics, U.S. National Library of Medicine, Feb. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4248237/.
6. “Coping Articles.” Coping Articles | Dystonia Medical Research Foundation | DMRF, www.dystonia-foundation.org/living-with-dystonia/coping-articles.