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Huntington's disease, or Chorea disorder (HD) is an incurable neurodegenerative genetic disorder. A dominant mutation on either of the two copies of a specific gene, on the chromosome 4 causes this disease. The Huntingtin gene (HTT) is present in every human which codes for the protein Huntingtin (HTT). Huntington's disease is inherited in an autosomal dominant fashion. The probability of each offspring inheriting an affected gene is 50 %( B-17) . Inheritance is independent of gender, and the gene does not skip generations. The disease attacks cells in the part of the brain called the striatum. This thus results in uncontrollable movement, emotional disturbances and loss of mental ability. Diagram of a sideview of the brain and part of spinal cord, the front of the brain is to the left, in the centre are orange and purple masses about a quarter of the size of the whole brain, the purple mass largely overlaps the orange and has an arm that starts at its leftmost region and forms a spiral a little way out tapering off and ending in a nodule directly below the main massCloser view of neuron having a large central core with several tendrils branching out some of which branche again, the core of the contains an orange blob about a quarter of its diameter
Fig 1: Area of the brain damaged by Huntington's disease - striatum (shown in purple)
Fig 2: A microscopic image of a neurone with inclusion (stained orange) caused by HD, image width 250 Âµm
Jerky, random and uncontrollable movements are the most common physical symptoms exhibited by patients (B-17~20). Clear appearances of the symptom as the disease progresses include, rigidity, writhing motions and abnormal posturing. Psychomotor functions become impaired and any reaction that requires muscle control such as chewing, eating, swallowing and speaking are affected as well. Physical instability as well as abnormal facial expression too becomes prevalent (B-22). This disease is a fatal genetic disease and there is no cure but there are several drugs which have been tested and are used to alleviate and slow Huntington's progression. Therefore, what are the treatments available nowadays that can help in managing this disease? (256 words)
Since chorea is the most severe symptoms in Huntington's patients, three classes of medication are commonly used to suppress it, namely neuroleptics, such as haloperidol and fluphenazine; benzodiazepines, such as clonazepam and diazepam; and dopamine depleting agents, such as reserpine and tetrabenazine(B-5).
Each class has its advantages and disadvantages.The suppression of movement, regarded as a side effect when neuroleptics are used to treat psychosis, is the desired effect when they are used to treat chorea. Therefore the most popular neuroleptic agents are the high potency drugs, which can also induce the most Parkinsonism. Haloperidol and fluphenazine are most commonly prescribed (B-5). Haloperidol and fluphenazine interferes with the effects of neurotransmitters in the brain which are the chemical messengers that nerves manufacture and release to communicate with one another. It blocks receptors for the neurotransmitters (specifically the postsynaptic mesolimbic dopaminergic D1 and D2 and serotonin type 2 receptors) on the nerves (B-23). As a result, the nerves are not "activated" by the neurotransmitters released by other nerves. Haloperidol is useful in treatment of irregular spasmodic movements of limbs or facial muscles
Chemical structure of xenazineC:\Users\User\Pictures\800px-Fluphenazine_structural_formulae.pngC:\Users\User\Pictures\638px-Clonazepam.png
Clonazepam Tetrabenazine Fluphenazine
Figure 3: Chemical structures of a few antichorea drugs
Risperidone is a newer neuroleptic which does not cause as much Parkinsonism as the other high potency agents, but is still useful in suppressing chorea and may relieve agitation as well. Benzodiazepines, such as clonazepam and diazepam are also very useful in the treatment of chorea. Benzodiazepines generally act as a central nervous system depressant .Long acting varieties such as clonazepam and diazepam are favored because they require less frequent dosing, provide more even coverage of symptoms throughout the day, and are less likely to precipitate withdrawal symptoms if a dose is missed(B-2,5).
Dopamine depleting agents includes reserpine and tetrabenazine. Reserpine functions by depleting norepinephrine and epinephrine, which in turn depress sympathetic nerve functions (B-4, 22). Tetrabenazine helps reduce jerky movement of Huntington's disease by increasing the amount of dopamine available in the brain especially in the basal ganglia part of the brain which is responsible for movements.
Among all, tetrabenazine is found to be the most effective drug (B-1). The efficacy of tetrabenazine as a treatment for the chorea of Huntington's disease was established primarily in a randomized, double-blind, placebo-controlled multi-center trial (Study 1) conducted in ambulatory patients with a diagnosis of Huntington's disease.Figure 1. Mean +/- s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Subjects Treated with Tetrabenazine (n=54) or Placebo (n=30)
Figure 4. Mean +/- s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Subjects Treated with Tetrabenazine (n=54) or Placebo (n=30)
As shown in Figure 4, Total Chorea Scores for subjects in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. (B-3)
Tetrabenazine does not only help to alleviate chorea but at the same time can act as mood stabilizers. However it is not advisable to be used for any one in depression and those having suicidal thoughts which most of Huntington's patient more or less develop when the disease progresses (B,1). Nevertheless, not all patients respond the same way to tetrabenazine.
Huntington's is a chronic disorder and is incurable and thus will eventually lead to death. Treatments are just to alleviate symptoms and also slow the progress of the disease. Overtime, patients' survival rate decreases as the symptoms progress.
Figure 5: According to the study, the survival of HD decreases to below 50% after 18 years and reaches 0% survival by 39 years.
SOCIAL AND ECONOMIC IMPLICATIONS
The problem with Huntington's is that the symptom onset isn't until people are in their late 30's or early 40's. By that age, many of them have children, meaning they've passed this deleterious gene to the next generation already, condemning them to a slow death. The social problem here is that many children are condemned to watch their parents die a painful death and knowing that they are probably headed the same way in years to come. This is a harsh reality to many of them. Also some of these people who die of Huntington's are taken out of the workforce in the prime of their careers. These are due to the involuntary movements that they develop as the disease progresses and also due to the side effects of the drugs they take. Huntington's patients also gradually lose control of their emotions and they develop abnormal facial expression which normally affects their social life. For many sufferers and their families these symptoms are the most distressing aspects of the disease. Moreover, Huntington patients tend to be suicidal. Some commit suicide because they cannot accept the fact that they will be dying a slow, painful and humiliating death while some attempt suicide due to side effects from medications which are quite difficult to tolerate.(B-6)C:\Users\User\Pictures\jnnpsyc00128-0021.gif
Figure 5: increased rate of suicide among patients with Huntington's disease.(A-6)
Worse yet, their care later into the disease are expensive. Drugs such as clonazepam as well as tetrabenazine are very expensive. Patients too will be needing treatment due to other complications that arise as the disease progresses which might need hospitalization and also tender care. These involve high cost and cause a huge financial burden and economic impact.
BENEFITS AND RISKS
Combinations of drugs are effective as it delays the progress of the disease. These delays deaths as well as increases the qualities of life of Huntington patients as their symptoms are under control. (A-7) These are proven by the study which showed that combination of fluxetine and clonazepam decreased the level of depression as compared to using single drugs.C:\Users\User\Pictures\af7f1.jpg
Figure 6: Scores on the Hamilton Depression Rating Scale Over 8 Weeks for Patients Taking Clonazepam Plus Fluoxetine or Placebo Plus Fluoxetine
However, every treatment given always comes with a setback, the side effects. Drugs used to manage Huntington's can cause a lot of adverse effect The first is tardive dyskinesia, a syndrome of involuntary movements often first noted in the face and mouth, that develops in some patients taking neuroleptics. Tardive dyskinesia is of concern because the symptoms are usually permanent, and will likely be hard to recognize in someone with Huntington's disease. The other serious problem is
neuroleptic malignant syndrome, a rare, but life threatening reaction characterized by acute onset of delirium, rigidity, and fever, often accompanied by leukocytocis, and elevated CPK. Families should know about this so that the patient can be given prompt medical attention if it develops.
dystonia, akathisia ,hypotension, constipation,
dry mouth, weight gain
sedation, ataxia, apathy, withdrawal
Dopamine Depleting Agents
hypotension, sedation, depression
TABLE 1: Medications Used to Suppress Chorea and the Side Effects
Tetrabenazine treats Huntington's symptoms well and although considered safe when appropriately administered and monitored, TBZ does have potential side effects, such as drowsiness, slowness of movement (Parkinsonism), mood changes (depression), and nervousness/anxiety/ restlessness (akathisia). The labeling for the TBZ (Xenazine) draws
special attention to potential depression and suicidality. (B-7) The side effects of TBZ are reversible and are usually controlled by reducing the dose. Most importantly, there has been no documented TBZ-induced tardive dyskinesia, and, therefore, this dopamine depleting agent has a distinct advantage over the dopamine-blocking agents (typical neuroleptics) in the treatment of a variety of hyperkinetic movement disorders.
It is important that patients as well as their caregivers are well aware of the medications being administered as side effects may vary for individuals.
Huntington's disease can cause speech difficulties, affecting ability to express complex thoughts. Speech language therapist (SLP) can help to overcome communication difficulties. The SLP can be helpful at all stages of the disease. In early stages, they assist with problem solving and developing strategies to help persons with HD compensate for some of the problems they might be experiencing (A-1~3). As the disease progresses, the role of the SLP evolve into helping preserve and maintain the person's highest level of communication. The SLP can also evaluate a person's ability to use augmentative or alternative communication (AAC) devices and techniques, which can be as simple as an electronic device that speaks for the person and then they begin to focus on personalizing the technique or method of communication. (B-9)
Physical therapy can help keep your muscles strong and flexible, reducing the risk of injury by strengthening exercises for muscles involved in postural control.
General strengthening exercises for major muscle groups of the body.
Advanced balance activities
Aerobic activity to enhance cardiovascular function.
Beginning a fitness program early in the disease process not only serves to maintain physical function, but also helps to reduce some of the stress associated with catastrophic illness(A-6~7). A routine fitness program can also be very helpful in treating depression.
Mind, spirit and soul are aspects of every living body. A dead body has no mind, it has lost its spirit, and its soul has departed... When your body loses some of its aliveness...you tend to withdraw ... illness has [this] affect ... [you] sense the world as at a distance or see it as through a haze. (B-15)
Patients normally get depressed when they get to know about their disease. Psychologists help them to live through it as well as encourage them not to give up. Psychologist normally advise them on what to do when they have bad mood swings and also help the patients through the depression they are going through. Family members and caregivers too might be involved in the process as they are enlightened about patient's sensitivity. (B-12)
As the disease progresses, occupational therapy can aid you with carrying out everyday routines, such as eating and dressing. An occupational therapist helps the person with HD and family members develop compensatory strategies. By employing these strategies early in the disease process, the person with HD learns to have some control over the disease and is therefore less apt to feel helpless. Occupational therapy normally deals with memory strategies (e.g. Offer hints, aid in retrieval of information), sequencing tasks as well as concentration .Although some people with HD appear to be moving all the time, they are often not able to change position voluntarily, and therefore susceptible to skin breakdown from constant shearing movement. The occupational therapist can assist the caregivers by suggesting a routine of position changes. The OT can also assist in designing a protective environment for a person with a lot of choreic movement. Padding of hard furniture, wheelchair parts and sharp corners helps to prevent injury from falls. (B-10) (2107 words)
Tetrabenazine has been found to reduce choreic movements as well as reduce hypotension from reference to (B-19) and also other sources as well as the extracts
"Tetrabenazine was well tolerated and produced long-term improvement of motor symptoms in Huntington disease patients, although a slight reduction of benefit occurred during the course of treatment" by Marsha L. Miller, Ph.D.
"Neuroleptic drugs like haloperidol (Haldol) are currently in widespread use in the United States to suppress chorea, but the effect of these drugs on chorea has never been studied in a systematic way, and they have a number of troublesome side effects, such as blunting of personality, loss of voluntary movement, and hindering balance," lead author Frederick J. Marshall, MD, from the University of Rochester Medical Center in New York, said in a news release. "Our study showed that tetrabenazine, when appropriately dosed, can decrease chorea without causing those side effects. (B-21)
These articles have gone through all the stages ensuring that they are valid and address the complication with research progression. Besides the source was obtained from the study done by Huntington's Disease Society of America, the Hereditary Disease Foundation, the Huntington Society of Canada, and the High Q Foundation. The other resource that I found is in (B-3). It is very reliable and useful as it clearly indicates that the drug tetrabenazine reduces choreic movements very effectively. This too is supported by the fact in (A-7) "Tetrabenazine works by depleting dopamine levels in the brain," said Joseph Jankovic, M.D., Professor of Neurology and Director of the Parkinson Disease Center and Movement Disorder Clinic at BCM. "In 1979, I was granted special permission from the FDA to treat patients with the drug. Since that time, I've treated thousands of people with tetrabenazine and have seen amazing results that translated into marked improvement in the quality of life. . In December 2007, an independent advisory committee concluded that TBZ is effective and safe and unanimously recommended to the FDA an approval of TBZ (Xenazine) for the treatment of chorea associated with Huntington disease, which was finally granted on Aug. 15, 2008. (2457 words)