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Abnormal Movements
Professional in charge: Dr. Marcelo Merello
A. Abnormal Movements
* 1. Parkinson's disease
* 2. Dystonias
* 3. Chorea - Huntington's disease
* 4. Gilles de la Tourette syndrome
* 5. Ataxias
* 6. Abnormal movements induced by drugs
* 7. Parkinson Plus - Progressive Supranuclear Palsy
B. New Treatments
* 1. Thalamotomy
* 2. Thalamic stimulation
* 3. Pallidotomy
* 4. Pallidal stimulation
* 5. Subthalamotomy
* 6. Subthalamic stimulation
* 7. Tables
* 8. References
C. More Information
D. Medical Team
A. Abnormal Movements
A. 1. Parkinson's disease
This work is intended to provide general information on Parkinson's disease to those who suffer this pathology and to their family. Nevertheless, your physician will be able to give you more details on your case in particular and on the doubts you may have.
What is Parkinson's disease?
It is a slowly progressive chronic disorder that affects a small area of the brain called substantia nigra, which is responsible of the production of a chemical compound called dopamine. When the substantia nigra is involved, the quantity of dopamine in the brain
diminishes markedly causing the appearance of the classic signs of Parkinson's disease: tremor, bradykinesia (slowness in movements), rigidity and impairment of postural balance. It is possible that initially all these signs are not presented or that some of them are almost imperceptible.
Tremor is generally one of the first manifestations, and usually begins in a hand and diminishes or disappears when carrying out movements or during sleep; on the contrary, it is intensified in situations of emotional tension and stress.
Bradykinesia is the difficulty and slowness to execute movements, especially the so-called automatic movements, that is to say those that habitually we carry out without intervention of our will (walking, speaking, and so on). Because of this illness a voluntary effort is required to perform them, so that the patient is forced to think about the movement to be made.
What other signs can appear in the course of this disease?
To a variable degree, some of the following signs can appear:
· Micrography: it is the reduction in letter size when writing.
· Hypomimia: refers to the decrease in facial expression.
· Dysarthria/Hypophonia: difficulty to articulate words and/or decrease in the volume of the voice.
· Sensation of depression or anxiety.
· Difficulty in walking: when walking, there may be episodes of the sensation of being attached to the floor and difficulty to start stepping.
· Seborrhea: greasy or oily skin.
· Sialorrhea: increase in the quantity of saliva.
Occasionally there may be difficulty in deglutition, that is to say on swallowing.
Is a rare illness?
No. It is a relatively frequent illness, as it affects 2% of people over 55 years of age, and it is not a mortal disease.
What is known about the origin of this illness?
The first scientific description of this disease was made in 1817 by an English physician called James Parkinson, to whom it owes its name. Although the origin of this illness remains unknown even today, we know that it is neither hereditary nor contagious. Many people who develop symptoms of the disease are afflicted by what is called idiopathic Parkinson's disease (idiopathic means that the cause is unknown) or Parkinson's disease proper, while the rest of the patients present parkinsonism, that is to say some or all the classic symptoms of the illness but with a specific cause that has made it appear, generally medications (drugs that cause this symptomatology as an adverse effect) and in other cases to problems secondary to cerebral circulation. Although it is certain that there are isolated cases in which there is a high incidence of this illness within the same family, nevertheless the relationship of the disease to a certain gene has not yet been identified, despite the susceptibility of a family to suffer it.
Is there a definitive cure for this disease?
There is neither prevention nor definitive cure for this pathology, but there are numerous medical and surgical options to control it.
For this reason it is very important that the patient should be treated by a neurologist who is a specialist in this illness.
How does this illness progress?
Generally it starts with transient episodes of tremor in a hand, then it can extend to other parts on the same side of the body and later on to the other side. The tremor that initially is slight can increase, ending up by interfering with some abilities. The tremor is usually accompanied by rigidity on the same side of the body, and over time will extend toward the rest of the body. As a result of the above, there will be difficulty to carry out fine and coordinated movements such as fastening buttons or brushing the teeth. Walking may slow down and even become hindered, with increasing shorter steps or due to freezing (the sensation of being attached to the floor) and often difficulty to cross doors or corridors, or to traverse restricted areas. The volume of the voice can diminish slowly until in some cases it becomes unintelligible.
Later on there are problems of balance postural. In the advanced stage of the illness it is common that l-dopa has a smaller beneficial effect on symptomatology than at the beginning and causes involuntary movements called dyskinesias. These movements can present in a limb, on one side of the body or generalise, and can be of variable degree, whether involving daily activities or not. Undoubtedly, the course of the illness varies widely according to the patient, and correctly established treatment helps to slow down its progression.
Are there coadjuvant therapies?
Yes. It is very important that another type of therapies should be carried out together with medical treatment.
Kinesiology is one of these options and it not only favours walking but also maintains mobile the diverse corporal segments.
Occupational therapy allows better training for performing activities of daily life, by simplifying them, such as the use of small tricks to facilitate washing, dressing, feeding, and so on.
Phonoaudiology is an important tool in patients who begin the illness with difficulties in diction, favouring better communication with those surrounding the patient and improving his/her well-being, being able to carry requirements correctly.
Psychological support should always be available, not only for the patient but also for those who live with him/her and are in direct contact, due to the fact that tensions, anxiety or depression are often generated that cause mutual problems within the family.
Which is the medical treatment?
Currently, there are a great quantity of effective therapeutic means to combat the symptomatology of this disease, and work is underway world-wide in order to improve these resources and to achieve a definitive cure or, if possible, prevention.
The most well-known and used drug is l-dopa (a synthetic version of the dopamine lacking in the body) whose trade name is Sinemet or Madopar. Nevertheless, there is a group of more modern drugs that act at the same bodily site as l-dopa without being identical and provide an effect relieving not only symptoms but probably preventive in nature.
There are other drugs commonly used in combination with l-dopa such as amantadine or akatinol (antiviral drugs with antiparkinsonian effect) and selegiline.
There are drugs that belong to the so-called group of anticholinergic agents that markedly improve certain symptoms but that involve a great risk in elderly patients.
There are also medications that prolong the duration of l-dopa effect (therefore used in combination form), but extreme precaution should be taken in the control of hepatic function, since these medications many times cause alterations when passing through the liver.
On the other hand, there is a drug called apomorphine, which although of short duration and of subcutaneous application, has a very fast action, that favours the management of patients who abruptly lose the effect of medication. This medication can also be used in continuous infusion through a small pump for portable administration, (approximately 12 x 5 cm).
Those above enumerated are at the present time some of the drugs in existence, while day by day new treatment options appear. A good indication of this medication is essential for a proper use of resources and to an alternative drug always at hand.
Does a definitive surgical treatment exist?
A surgical treatment exists, but it is not a definitive cure. There are two classes of surgical treatments: the so-called ablative one or of lesioning, and the placement of intracerebral stimulators (that are like small cerebral pacemakers regulated from outside and can be programmed as many times as the physician believes convenient without need of new interventions, thus opening a wide spectrum of possibilities).
Regarding this topic, it is very important to bear two things in mind: one is that surgery is not for any patient at any time during the course of the disease, but rather that symptomatology should afford certain features according to which the appropriate type of surgery may be chosen. The other important aspect is the choice of the surgical equipment because an electrophysiological recording of the brain should be performed to determine the exact site where surgery should be carried out, which is not something all surgical groups have available. If this means of information of the "brain map" were not available, we would be carrying out surgeries without success, as those made at the beginning of the last century, a time regrettably long before the technological advances we possess nowadays, which led to the discontinuance of these surgeries.
Suggestions for daily life
As you already know the features of the illness that afflicts you and you are aware that
although it can be improved there is no definitive cure up to now, it is necessary to learn how to live with it. And believe me, one can! Patience is needed. Probably the established treatments they show no improvement immediately or, if they do, perhaps in time some setbacks arise, which is normal, as it is a progressive disease and medication also undergoes changes in its absorption at digestive tract level. In other words, there are many variables at work, but your physician will know how to regulate the dosage and to vary the therapy if necessary, so have patience. Learn how to live with yourself.
Regarding gait, when one tries to walk, there are little tricks that will help to overcome the state of immobility and to avoid falling. If you drag your feet, stops walking, and make sure you separate your feet by roughly the shoulders’ width and to stand up as straightly as you can, try to make your steps as long as possible, imagining that you have to overcome an object in your way, raising the knees well and supporting first your heels on the floor. At the same time, swing your arm, taking the right arm and left leg forward, then the left arm and right leg. To bend, walk forward toward the curve and carry out a semicircle or turn in “U”, maintaining your feet at a distance similar to the shoulders’ width. Avoid to rotating or crossing a leg over the other one.
As clothes choose garments that are easy to put on such as those without small buttons or difficult zip fasteners. Try to use some accessory to get dressed, to reach the clothes or to put on the trousers. A shoehorn with a long handle will be able to help you put on your shoes. Place the overhead bar for the clothes in the clothier so that there is no need to make an effort to reach it. If your balance is impaired, sit down on the border of the bed when you get dressed. Get dressed by yourself while you can, because it is an excellent exercise and very good for your self-esteem.
A. 2. Dystonias
Dystonia is the name of a group of neurological illnesses, as well as of their symptoms, that consist in sustained contractions of muscles in one or more parts of the body. It often originates writhing or torsion of the affected parts. The disorder is secondary to dysfunction of the central nervous system (basal ganglia). Initially, dystonia without complications fails to functions related with the conscience, whether sensory or intellectual. Dystonia can be
associated with slight tremor or with a tremor featuring irregular and strong contractions. Dystonia can be classified, depending on the affected regions of the body, by its cause, although it is sometimes unknown (primary or idiopathic), or secondary to lesions, toxins or other illnesses of the central nervous system.
Idiopathic torsion dystonia (ITD) (deforming dystonia of the musculature, widespread distonía) begins in a certain part of the body, usually in a foot. After walking or performing other exercise, the foot can rotate toward another axis. It usually begins in childhood and frequently extends to other parts of the body, as the back, neck or arms. It is inherited in autosomal dominant form, or else in some cases its appearance is sporadic. Other inherited dystonias includes the dopa-responsive dystonias and dystonias responding to L - dopa and dystonias X-associated to parkinsonism. It begins in childhood or in young adults and is frequently accompanied by rigidity and clumsiness similar to that of patients with Parkinson’s disease. Treatment with l-dopa can totally suppress symptomatology and the drug is effective indefinitely. Dystonia X-associated to parkinsonism is a form found in males in the Philippines. It presents certain parkinsonian symptoms and has a tendency to progress with the result of severe disabilities.
Secondary Dystonias: This dystonia type is secondary to damage to small areas of the brain. It can be caused by lack of oxygen before, during or immediately after birth (cerebral paralysis), due to encephalic injury, particularly in childhood, or due to small blows. It can also be secondary to small damaged areas related with multiple sclerosis, encephalitis, or secondary to a great number of disorders that affect the nervous system, including Wilson’s disease (hepato-lenticular degeneration).
Focal dystonias include writer's cramp, blepharospasm, spasmodic torticollis, orofacial-buccal dystonia and laryngeal dystonia. Writer's cramp is a focal dystonia of the hand with contraction of hand and arm muscles, during the act of writing. The hand can contract so strongly that it cannot move. As soon as the writing instrument is abandoned, it relaxes. Under this denomination are included dystonias in musicians of different instruments that require delicate movements with the fingers (occupational). In blepharospasm the eyes close strongly during minutes or even hours. It can be precipitated by exposure to solar light, contact with the eyelids or by a state of anxiety. Spasmodic torticollis (cervical dystonia) is a focal form in which the contracted neck muscles rotate the head toward one side or tilt it downward or backward. It is sometimes accompanied by abrupt head movements. Quite often, it is partly alleviated with a soft contact on the chin or other parts of the face. In orofacial-buccal dystonia, called Meige syndrome, the muscles of the lower part of the face they contract in an irregular way. Sometimes the muscles of the jaw act on the mouth opening it or closing it and similarly the superficial muscles of the neck contract. Generally, blepharospasm also manifests. Laryngeal dystonia or dysphonia is a focal form of dystonia that affects the laryngeal muscles or voice box. In adductor muscle dystonia, the vocal chords are tense and joined, particularly when trying to speak. The voice is forced, hoarse and interrupted. There is sometimes difficulty in breathing. In abductor type dystonia the vocal chords are forcibly separated and the voice has an encouraging sound, while phonation is sometimes impossible. Hemifacial spasm is not strictly speaking a form of dystonia. In this disorder the muscles on one side of the face contract irregularly. It is often secondary to a previous inflammation or damage to the facial nerve.
Which is the prognosis?
To prognosticate the progress of dystonia is uncertain. One can say that if the dystonia affects other members of the family, and it begins in childhood, it tends to worsen over the years. However, cases are known in which there is no worsening and partial or even complete recovery may take place.
If the illness begins in childhood and is secondary to brain paralysis or another lesion during childbirth, the dystonia usually remains static during many years. There are few cases of dystonia secondary to brain paralysis in which there has been worsening in mature age.
When the dystonia begins in mature age, it is generally focal and tends to remain restricted to the affected part of the body.
Is dystonia hereditary?
In many cases the aspects related to the inheritance of dystonia are quite clear. One can say that there are hereditary factors in the dystonia in Ashkenazi Jewish families and in a number of non-Jewish families. It is inherited in autosomal dominant form with variable penetrance.
Dominant means that every son of a father who bears the corresponding anomalous gene, has 50% chances of inheriting the disease.
Diagnosis and treatment of dystonia
As dystonia is a relatively rare illness, the best advice is to consult to a neurologist with experience in movement disorders to perform the diagnosis.
As regards diagnosis, the first thing is to review minutely the family tree, searching for a history of focal or generalised dystonia. Even the smallest case of torticollis should be written down, as well as type of tremor. This information will be crucial to carry out the genetic test, a procedure that will be possible in the near future.
Second in rank, the type of therapy will be considered. A neurologist with considerable experience in dystonias will be the best guide. There are many medications but only a few can be useful to a given individual.
Some of the medications regarded as useful are as follows: Artane (trihexiphenidyl), Valium (diazepam), Rivotril (clonazepam), Lioresal (baclofen), Tegretol (carbamazepine), Sinemet or Madopar (Levodopa), Parlodel (bromocriptine), Virosol (amantadine), Nitoman (tetrabenazine), Thorazine (chlorpromazine) and Halopidol (haloperidol). Other medications of the phenothiazine group or butyrophenone can help but with the risk of a secondary effect called late dyskinesia, so that they should be used with great caution.
For the focal dystonias, including blepharospasmo, Meige syndrome, spasmodic torticollis and laryngeal dystonia, a very effective treatment is the injection of botulimun toxin, which is very useful when the dystonia affects a limited group of muscles. The treatment needs
to be repeated every three or four months and must be carried out by professionals with considerable experience in its use.
Several types of surgical operations will only be considered if medications are not effective and the dystonia is severe.
A. 3. Chorea - Huntington's disease
What is Huntington's disease?
Huntington's disease is a hereditary neurodegenerative disorder caused by an expansion in IT-15, in chromosome 4, which is responsible for the protein huntingtine.
Who can suffer this illness?
It is transmitted in autosomal dominant form, so that every child with a father affected by the illness will 50% chances of developing it.
At what age is this pathology manifested?
Most people who develop the symptoms generally do so between the fourth or fifth decade of life although some symptoms can manifest earlier. Around 10% of patients begin their illness before 20 years of age (Juvenile Huntington's disease) and 10% after age 60.
How is it manifested?
The illness is manifested by a triad of motor, cognitive and psychiatric symptoms with an insidious and progressive onset during several years, up to the individual's death.
Which are the features of the illness?
The movement disorder that characterises this illness is the presence of involuntary or so-called choreic movements and ineffective voluntary movements. These movements slowly disable the patient by reducing manual dexterity and clarity of speech and cause
difficulties to swallow, problems of balance postural and falls.
Later on, the patient remains rigid longer and longer and unable to perform voluntary movements. In advanced stages, these patients are unable to carry out their basic personal activities by themselves.
The cognitive disorder is characterised initially by a loss of speed in thinking. With the passage of time the cognitive deterioration becomes much more severe.
The most common psychiatric dysfunction is depression although patients can also suffer a maniac or obsessive-compulsive disorder. Although not so characteristic, others symptoms can appear as irritability, anxiety, agitation, impulsiveness, apathy and impairment in social adaptability.
The course of disease may be divided into three stages. The early stage is the one in which the patient continues his/her daily activities without problems and can live independently. Symptoms presenting in this stage can include some slight involuntary movement, difficulty in the coordination of some movements, difficulty to decipher complex problems and maybe depression or an irritable mood.
In the second stage, the patient is no longer able to live alone and requires help. He/She is no longer qualified to work or to drive, or to manage his/her own finances, although with help their own washing, dressing and feeding may be performed. Chorea is usually severe disabling for carrying out voluntary movements. There is usually difficulty in balance and gait, with frequent falls, difficulty to swallow and loss of weight.
In the advanced stage of the illness, the patient requires attention for all the activities of daily life. He/she can have difficulty in understanding. Choreic movements become severe and end up being replaced by rigidity, slowness in movements (bradykinesia), dystonia (involuntary and painful muscular contractures) and sometimes tremor.
Does it presented similarly in children?
When it presents in children, this disease shows some differences, as the choreic movements are milder or absent, with difficulty in attention, disorders of behaviour, failure at school, dystonia, bradykinesia and on occasion tremor. While uncommon in the mature patient, convulsions can occur in the juvenile form. The onset of the juvenile form is faster, with a survival less than 15 years.
How is the diagnosis made?
The clinical diagnosis of the illness is made on the basis of family history, the presence of the characteristics of the pathology and confirmation by means of a genetic test (especially if the symptoms are atypical or the family history is unknown). This confirmation is important in case it is necessary to provide genetic advice.
Which is the treatment?
Because it is a progressive disease, initially it may not be necessary to establish treatment and later on it may become complicated. An example of this is the treatment with neuroleptics that initially are very effective to control the choreic movements but then they can exacerbate rigidity and bradykinesia. The medication indicated should be re-evaluated every now and then, because on occasion it is suitable to suspend it during certain periods.
How does the illness evolve?
The average survival after diagnosis is around 15 to 20 years but there are patients who end up living 30 or 40 years with the illness.
The evolution is progressive and varies from one patient to another.
A. 4. Gilles de la Tourette syndrome
It is a chronic and familial neurobiological illness of fluctuating course that manifests by a triad consisting in behavioural disorders, multiple tics (motor and audible) and obsessive-compulsive behaviours (TOC).
It was described by the French neurologist Georges Gilles de la Tourette in 1885 when he reported the presence of these symptoms in 9 children. It affects men with an incidence three times greater than women and has its onset in childhood with evident improvement in the mature age. It has a good long-term prognosis and although its etiology is still uncertain, this pathology is known to feature an alteration of the neuronal pathways in the frontal-subcortical region.
CLINICAL PICTURE: Its diagnosis is based on the observation of the above mentioned triad it begins in childhood associated to a strong family history of similar behaviour.
A tic is an involuntary, quick, repetitive and stereotyped movement that involves an individual muscular group. Tics are the distinctive clinical feature characteristic of the Tourette Syndrome, and are abrupt, brief and intermittent. They can be both MOTOR (involuntary and repetitive), and AUDIBLE (phonic or verbal).
MOTOR TICS can be SIMPLE or COMPLEX. SIMPLE TICS can be 1) CLONIC, that are characteristically brief and of the shaking type as for example blinking, nostril movements, head shaking and limb shaking; 2) DYSTONIC, that are slow and lead to adopt abnormal postures as for example sustained blinking or blepharospasmo, ocular deviation, bruxism, buccal opening and torticollis; 3) TONIC, that are manifested by sustained tension of a stretching muscle. COMPLEX TICS are slower, more apparent and involve several muscular groups: the main ones are trunk twisting, repetitive palpation, repeated jumps, kicks, obscene expressions and genital palpation (copropraxia) and imitation of expressions (echopraxia).
AUDIBLE TICS can be SIMPLE or COMPLEX. The SIMPLE ones consist of such repetitive noises as throat clearing, nasal noises, repetition of phonemes and coughing. The COMPLEX ones include verbalisation with linguistic content such as insults, obscenities and repetitive sentences.
Both motor and audible tics are preceded by premonitory sensations of disconfort that calm down partially after execution of the tic. The tic can be suppressed by the patient, which differentiates it from other illnesses and the presence of the tic diminishes when the patient
is concentrated on some type of activity either physical as mental. In contrast, tics increase in stress situations, anxiety and fatigue. They can also be exacerbated when there has been a prolonged time of relaxation (children who to school and tics begin). The presence of tics is a restrictive factor in the life of these patients since it interferes in the activities of their social life.
Diagnostic criteria defined for the illness include:
a) multiple motor tics with at least one associated audible tic that have occurred simultaneously at some time;
b) tics have to be present several times per day and should last a minimum of one year, with the patient not having been free of symptoms for more than three months in the year;
c) that these tics cause disorders in the patient's social life;
d) age at onset less than 18 years; and
e) they are not due to medication or to other illnesses that feature tics.
BEHAVIOURAL DISORDERS: especially the presence of the attention deficit (ADD) syndrome with hyperkinesia (ADHD), bad behavior, impairment in learning and difficulty to relate with people.
OBSESSIVE-COMPULSIVE DISORDERS (OCD): they are defined as thoughts, images or impulses that are consciously introduced and that are involuntary, very stressful and hardly perceived, cannot be abolished and that lead to carrying out such rituals as hand washing, self-aggresion, tooth and hair brushing, phobias, fears, smelling all nearby objects, outbursts of anger and insults.
Their greater incidence of appearance of symptoms occurs from 3 to 8 years of age, with a maximum peak of symptoms around 11 years, with an evident decrease after age 18 years that can reach 50% of patients free of symptoms.
PATHOGENESIS: it is known to be a hereditary type of disorder with alteration of synaptic neurotransmission that leads to disinhibition of the cortico-striato-thalamic-cortical circuit mainly affecting the basal ganglia and the prefrontal cortex. MRI studies disclose asymmetry of the basal ganglia with an increase in volume on the right side and functional MRI shows a decrease in neuronal activity at the level of the pale pallidus, putamen and thalamus, with increased activity at the level of the prefrontal, parietal and temporal cortices.
At EEG there is absence of premotor potentials, which indicates that tics are involuntary movements due to decreased of motor inhibition. From the neurochemical point of view, there is a decrease in serotonin, glutamate and AMPc with dopaminergic hyperfunction at the level of the striate nucleus and the limbic system.
It is known to be a hereditary illness in which there is a strong family history of tics and behavioural disorders. In 20-40% of cases there is genetic transmission of the illness. Immunological as well as infectious type causes have been postulated, but there are no conclusive studies in this regard.
TREATMENT: The main objective is the appropriate education of people who surround the patient, such as the parents, teachers and family. In most cases therapy is suggested for the patient and his/her family environment. The administration of medication begins when
symptoms interfere with the social, academic life and the daily activity of the patient. Due to the wide range of signs and symptoms of the illness, treatment should be adjusted to each patient in particular, the main target being the treatment of the most distressing symptom.
Tics cannot be eliminated, but only alleviated to allow to the patient to control them in order to follow a normal daily life. Drugs of choice are dopaminergic receptor blockers such as neuroleptics. Those most used are Haloperidol and Pimozide. Risperidona thioridazine, tiapride and others can also be prescribed. No improvement has been observed with such atypical neuroletics as clozapine, olanzapine or quetiapine. Neuroleptics can cause sedation, depression, weight increase, phobias and hepatic damage.
Tetrabenzine is a depressor of dopaminergic receptors, thus providing a potent anti-tic drug with the advantage that it does not develop late dyskinesias as can occur with the conventional neuroleptics. Other drugs used for the handling of tics are clonazepam, pergolide, metoclopramide, calcium blockers and clonidine.
In the case of severe focal tics, botulinum toxin can be used, but it should be clarified that its effect lasts from 3 to 4 months, so that it should be re-injected with this frequency.
For BEHAVIOURAL DISORDERS, teachers' and parents' training is essential for the appropriate management of these patients. In the case of those presenting ADD or ADHD, central nervous system stimulants are used such as methylphenidate, dextranfetaminas and
pemoline, but they can cause edginess, irritability, insomnia, anorexia and migraines. Other drugs used are clonidine patches, but they can cause marked arterial hypotension.
In the case of TOC, inhibitors of serotonin reuptake, such as fluoxetine, fluvoxamine, clomipramine, paroxetine, sertraline and citalopram are used. In more severe cases, these drugs may be associated with buspirone, clonazepam, lithium and conventional neuroleptics.
A. 5. Ataxia
The term ataxia designates a clinical picture characterised by incoordination of voluntary movements of the limbs and of the trunk, together with alterations in speech articulation,
involving posture and gait. The ataxias are classified into two groups:
· ACQUIRED
· HEREDITARY
The acquired ataxias are those secondary to diverse causes, such as: alcoholism, vitamin deficiencies (Vitamin B1), primary tumors or metastasis, paraneoplasic syndromes (ovary, breast, and lung carcinoma; tests available to dose Anti-Hu, Anti-Ro and Anti-Ri antibodies that guide diagnosis), hypothyroidism, medication intoxication (Phenobarbital, Diphenylhydantoin, Neuroleptics), amyloidosis, cerebrovascular accident, multiple sclerosis, viral cerebellitis, polyneuropathies (Anti-MAG syndrome, Sensory Polyneuropathy), vestibular apparatus illnesses (vestibular Neuronotis, Labyrinthitis). The importance of the acquired ataxias resides in the possibility of treatment of some of them.
Hereditary ataxias comprise a group of heterogeneous syndromes, where the main characteristics are slowly progressive ataxia and cerebellar atrophy evidenced at neuroimaging. They are classified according to clinical and genetic criteria:
1. Ataxia syndromes related with innate errors of metabolism.
2. Congenital ataxias
3. Progressive cerebellar ataxia of early onset (before 20 years of age)
- Friedreich's Ataxia
- Syndromes other than Friedreich's Ataxia
4. Episodic ataxia
5. Progressive cerebellar ataxia with autosomal dominant inheritance (ADCA)
- ADCA-I: cerebellar syndrome plus other neurological signs (SCA-1-4, SCA-8, SCA13,14 AND DRPLA)
- ADCA-II: as for SCA-I and retinitis pigmentosa (SCA-7)
- ADCA-III: with pure cerebellar syndrome (SCA-5, 6, SCA-10, 11, 12, 6)
6. Sporadic and idiopathic adult's progressive cerebellar ataxia.
7. Hereditary spastic paraplegia
- Pure form
- Complicated form
- With atrophy of hand muscles (AD)
- With phenotype of atrophy of peroneal muscles (AD)
- With phenotype of amyotrophic lateral sclerosis (AR)
- Charlevoix-Saguenay syndrome (ataxia, dysarthria and abnormal ocular movements) (AR)
- Troyer syndrome (pseudobulbar paralysis and athetosis) (AR)
- With macular degeneration and mental delay (Kjellin syndrome) (AR)
- With optic atrophy (AR / AD)
- With athetosis / dystonia (AR / AD)
- With appendicular ataxia and dysarthria (AR)
- With sensory neuropathy (AR / AD)
- With cutaneous pigmentation dysfunction (AR / AD)
- Sjögren-Larsson syndrome (oligophrenia and congenital ichthyosis) (AR)
- With tetraparesis and oligophrenia (AR)
SCA: spinocerebellar ataxia; DRPLA: jagged-rubropallidoluysian atrophies; AD: autosomal dominant; AR: autosomal recessive.
Congenital ataxias are not very frequent, their inheritance pattern is Autosomal Recessive and they are due to alterations in the development of cerebellum and the brainstem. The most frequent clinical manifestations are oligophrenia, ataxia, delay in motor development and nystagmus.
Friedreich's Ataxia (FA) it is the most frequent form of the hereditary ataxias with a prevalencia of 4.7 cases per 100,000 inhabitants.
The inheritance is Autosomal Recessive and it manifests before 20 years of age.
Gene x25 is located in chromosome 9p; the genetic mutation consists in an intriónica and homozygous expansion of triplete GAA. Under normal conditions the number of repetitions is between 8 and 22, while in the AF the expansion ranges from 200 to 1700. The product of the gene is Frataxine, a protein that is believed to be responsible for the
degenerative changes of the FA.
Clinically, it begins with gait ataxia that progresses slowly, upper limb ataxia, dysarthria, tendinous arreflexia (the masseter reflex is preserved), hypopalesthesia and oculomotor alterations. Among the systemic manifestations it is necessary to mention, cyphoscoliosis, myocardiopathy (effort dyspnoea or palpitations), and in 10% of diabetes mellitus patients.
At the present time, the essential test for diagnosis is the detection of the dynamic mutation GAA. Genetic studies have allowed identifying a group of patients: 25% with the homozygous mutation of FA that either presents an atypical picture beginning after 20
years of age (late onset Friedreich's ataxia) or preservation of myotatic reflexes (Friedreich's ataxia with retained reflex). The progressive course leads to the need of a wheelchair at 15 years' evolution.
There is no specific treatment, only supportive measures.
Episodic Ataxia comprises two syndromes:
- Episodic Ataxia type 1, caused by point mutations in the potassium channel gene (KCNA1) located in the chromosome 12p. The clinical picture consists on brief attacks, between seconds and minutes, of ataxia, dysarthria, vertigo and nystagmus, triggered by exercise and by alarm. It begins in adolescence or later and its course is not
progressive. It responds to treatment with acetazolamide or phenytoin.
- Episodic Ataxia type 2, the mutation is located in the gene of subunit a1A in the calcium dependent voltage channel (CACNLIA4), located in chromosome 19p. Different mutations of this gene are responsible for Familial Hemiplegic migraine and SCA-6 (Spinocerebellar ataxia type 6). The duration of the attacks ranges from hours to days, and they are precipitated by emotional stress and exercise. Treatment is with acetazolamide.
The current classification of the Autosomal Dominant Cerebellar Ataxia syndromes is based on clinical (ADCA-I-II-III) and genetic criteria (SCA-1-16).
Clinically they are characterised by:
- ADCA-I: progressive cerebellar ataxia with oophthalmoplegia, dementia, optic atrophy, extrapyramidal signs or amyotrophy. SCA 1,2,3,4,,8,13, 14, DRPLA belong to this group.
- ADCA-II: a clinical picture superimposed to the previous one plus pigmentary degeneration of the retina. SCA-7 is found in this group.
- ADCA-III: pure cerebellar ataxia of late onset. It includes SCA 5,6,10,11,12,16.
The denomination SCA refers to the 15 loci that have been found in molecular genetic studies; a particular locus corresponds to dentate-rubropallidoluysian atrophy (DRPLA). The molecular basis of SCA-1,2,3,6,7,12 and DRPLA is a dynamic mutation by expansion of the CAG triplete that codes polyglutamine tracts; this leads to alterations in the structure and in the function of proteins that contain polyglutamine. A feature of the ataxias that have
A repetition of the CAG triplete, particularly SCA-7 and DRPLA, is the Anticipation phenomenon; this consists in that as the illness is transmitted to the descendant, it appears at an earlier age and is of greater severity. In SCA-6 the dynamic mutation is located in the gene of subunit 1A in the calcium dependent voltage channel, which originates dysfunction of this channel mainly affecting to the Purkinje cells of the cerebellum. In SCA-12, the dynamic mutation CAG is located in the region promoter of PPP2R2B of a gene that codes a subunit regulating protein phosphatase 2A that is specific of the brain.
SCA-8 is produced by a dynamic mutation by expansion of the CTG / CTA (CR) triplete in chromosome 13q21.
For the diagnosis of these entities it is necessary to keep in mind the clinical picture, the age at onset, the family history, the neurological examination, the complementary methods of diagnosis as neuroimaging (magnetic resonance, where atrophy of the cerebellum, brainstem and spinal cord will be observed), neurophysiological studies (electromyogram,
evoked potentials) and genetic studies, by means of which the mutation that causes the illness can be identified. These studies allow carrying out carrier diagnosis (individual who possesses the mutation without manifesting disease), prenatal diagnosis,
presymptomatic diagnosis (it estimates the risk of suffering the illness with onset in the mature age), and confirmation of the diagnosis in patients with symptoms.
Currently, genetic tests are available for the diagnosis of SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, DRPLA, Friedreich's Ataxia, Ataxia Telangiectasia and Ataxia with vitamin E deficiency.
With the obtained information, the Genetic Council should inform the patient and his/her family of the diagnosis or the risk of suffering one of the illnesses mentioned.
Sporadic or idiopathic progressive cerebellar Ataxia in the adult begins after 20 years of age and can present as a pure cerebellar syndrome (Cerebellar Cortical Atrophy) or as a
cerebellar plus syndrome (sporadic Olivopontocerebellar Atrophy), in which case a parkinsonian syndrome and autonomic disorders are added to the cerebellar picture.
In he case of such patients, a series of diagnoses differential should be carried out, whose most frequent causes are medication intoxication, paraneoplasic syndrome and hypothyroidism.
A. 6. Abnormal movements induced by drugs
There is a series of drugs capable of produce involuntary movements, among which are neuroleptics, antiparkinsonian agents (levodopa, dopaminergic and anticholinergic agonists), anticonvulsants (hydantoin and carbamazepine), calcium antagonists (flunarizine,
cinnarizine, nifedipine, diltiazem), noradrenergic stimulators (amphetamines, xanthines and pemoline), steroids and opiates.
How long do the effects induced by neuroleptics last?
These collateral effects (dysfunctions of tone and of posture and abnormal movements) are on occasion self-limited in time, while others disappear when the neuroleptic is discontinued and, lastly, some can be persistent or even permanent in spite of the
interruption of treatment.
Which are the features of these undesirable effects?
Through the blockade of postsynaptic dopaminergic receptors or by depletion of dopaminergic vesicles, neuroleptics can lead to a picture similar to that of Parkinson's disease, characterised by tremor, rigidity, slowness and alteration of postural reflexes. The susceptibility is greater in women, especially when postmenopausal.
Another complication of long-term therapy with neuroleptics is that called late dyskinesia, featuring involuntary movements (not tremor) that develop insidiously during treatment or when discontinuing it and mainly involve orofacial musculature. They often affect neck, trunk and limbs. Such symptoms disappear during sleep. These movements can be slight
and fail to inconvenience the patient or intense and extremely annoying, or even disabling.
When starting neuroleptic treatment, sustained muscular spasms can present involving the face, neck, eyes, throat and at times they are generalised affecting the trunk. The picture sometimes can present later on or before an increase in dose or a switch in neuroleptic. It is more frequent and severe in children, in whom dystonia is usually generalised, while in adults it tends to be focal.
Some 40% of patients who receive neuroleptics present acathysia during the first hours of treatment and up to 75% in the first week. This symptomatology consists in a sensation of permanent restlessness, with the possibility to remain motionless only during limited periods and at the cost of great effort. Acathysia is limited in time but sometimes becomes persistent.
Should this type of medication be used?
Certainly, but only by medical prescription, because there are precise indications for its use. There are benign pictures and others that can be potentially fatal. Treatment is not always effective, so that prevention is very important.
A. 7. Parkinson Plus - Progressive Supranuclear Palsy (PSP)
It is most unlikely that any of the 3,000 or 4,000 people in the United States diagnosed as afflicted with Progressive Supranuclear Palsy has ever heard about that illness before. Furthermore, attending neurologists probably thought that the diagnosis was of Parkinson's disease up to several years after onset of the illness. Recently, in the medical literature information has increasingly appeared in this regard to foster its awareness. This information was written to help the patients and their families to understand the illness and to adapt better to it.
Why has nobody heard about PSP?
The PSP is unknown because it is a rare disease, because even when it appears, it is often underdiagnosed. However, this is changing gradually. The more people are acquainted with PSP, the better it will be diagnosed. Nobody even knew that it existed up to 1964, when several patients were described at a national American neurology research meeting and the illness received its name. At least 13 cases of PSP appeared in the medical literature as from 1904, but nobody recognised them as PSP up to 1960. Another name given to the illness refers to the three scientists who discovered it, Steele, Richardson and
Olszewski, although this name is much less used.
Which are the more common early symptoms of PSP?
In most cases the first most common symptom, manifesting on the average, at 60 years of age, is loss of balance when walking. This can take the form of unexplained falls or of rigidity and clumsiness when walking, that can resemble Parkinson's disease. The falls are sometimes described by the person who experiences them as attacks of "vertigo", which often incites the physician to suspect an inner ear problem or hardening of the arteries that provide blood to the brain. Other common early symptoms are forgetfulness and changes in personality. The latter can present as loss of interest in pleasant daily activities or increased irritability. These mental changes are mistakenly interpreted as depression or as senility. The less common early symptoms are sight and speech problems, as well as hand tremor. There is also difficulty in driving a car, with several accidents or the risk of same. The exact reason for this illness is not clear.
What happens later?
The term "progressive" was included in the name of the disease because, unfortunately, early symptoms worsen later on and new symptoms develop. As a rule, imbalance and rgidity worsen to make walking very difficult or impossible after 7 to 9 years' of illness. If the sight problem was not present initially, it is developed in the future in almost all cases and sometimes can influence the performance of movements. The difficulty in speech and when swallowing are additional important features of the illness, that are added later on in most patients. The good news is that nobody dies from PSP. If general health and nutrition are maintained appropriately, most people with PSP live well at 70 years of age and even more.
What does the name "supranuclear palsy" mean?
In general, a palsy or paralysis is the loss of strength of a part of the body. The term "supranuclear" refers to the nature of the ocular problem presented in PSP. The problem with the eyes is quite disabling, due to blurred vision, difficulty to mobilise the eyes appropriately because of paralysis of the muscles. These muscles are controlled by nerve cells located in nuclei near the base of the brain.
Is the visual problem an important part of the disease?
In most cases the visual problem is at least as important as the difficulty to walk, although if it is not present initially it appears before 3 to 5 years after the gait problem. Therefore, as the major visual problem is to direct sight appropriately, to read is difficult. The patient is hindered to direct the gaze automatically to the following line when finishing the first line.
This is quite different from the need of using glasses. Another common visual problem is the inability to maintain visual contact during a conversation, which can cause the erroneous impression that the patient is hostile, disinterested or senile. The same movement problem can cause a symptom called "tunnel vision" which interferes mainly in driving a car. The most common problem in ocular mobilisation is the impossibility to direct the eyes up and down, which is not easily detected by the family or by the patient him/herself. Among other things, this interferes with feeding and climbing up and down stairs. In other pathologies, as in Parkinson's disease, at some time it can have problems to move the eyes up, but here the problem is mainly to mobilise them down. Another problem that can present with regard to the eyes is their abnormal movements. Some patients present involuntary closing of the eyes called blepharospasm. Others have difficulty to open the eyes, although the lids are relaxed, so that they try to help themselves with the muscles of the face or the fingers: this effort to try to open the eyes is called apraxia of ocular opening. Around 20% of patients can develop this symptomatology. Other patients have decreased blinking; thus, around 15 to 25 blinks per minute is considered as normal, but these patients only blink 3 or 4 times per minute. This is the cause of irritated eyes and the need to apply many times artificial tears.
Which are the speech problems?
The same area of the brain that regulates the ocular movements, also coordinates the movements of the mouth, tongue and throat, so that these movements are also weakened in the illness. In most patients this problem begins 3 or 4 years after the first symptom of the illness is established. In Parkinson's disease the problem of speech is characterised by a decrease in the volume of the voice, as well as difficulty in diction and speed. In PSP, however, the voice is irregular, of the plosive type (called spastic) or of the "drunkard" type (ataxic), or a combination of both.
Which are the difficulties when swallowing?
This difficulty is presented both for solids and liquids and it is due to muscular weakness and lack of coordination. This tends to occur after the gait, visual or speech problems but becomes very distressing because the patient is liable to choke when trying to eat. This is one of the most risky complications that may present, due to the possibility of food aspiration and its passage along airways. The repetition of several episodes, even in small amounts, of food or liquid aspiration toward the lung causes pneumonia and this
it is the most common cause of death of patients with PSP.
Is PSP able to lead to a demential picture or Alzheimer's disease?
Although the mental confusion in patients with PSP is more apparent than true, many patients can possibly develop slight or moderate mental deterioration. Some have developed Alzheimer's disease, but is unlike the situation in Parkinson's disease. In PSP, when there is insanity it is characterised by slow thought and difficulty to synthesise different ideas into a single one. These cerebral functions are regulated by the frontal lobe, while in Alzheimer's disease the problem is related to loss of memory and the ability to concentrate, which is governed by the temporal lobe.
In the Alzheimer's disease there is also difficulty in speech (for example, to remember the name of common objects) or difficulty to recognise familiar places. Fortunately, this never happens in PSP.
Which are the differences between PSP and Parkinson's disease?
Initially it can be very difficult to distinguish one illness from the other, because PSP is an important cause of parkinsonism. Both diseases cause rigidity, slowness and motor clumsiness. However, the tremor may be more marked in patients with Parkinson's disease
than in those with PSP; when presents in the latter, it is more irregular and appears in activity, not at rest. Patients with PSP walk erect or leaning backward, which usually causes
falls toward that side, unlike parkinsonian patients who present the trunk flexed forward and fall forward.
Finally another difference is the response to treatment: the medication used for the treatment of Parkinson's disease, l-dopa, is much less effective in patients with PSP. This happens because in Parkinson's disease a dopamine deficiency is the cause of the illness, whereas in PSP there is deficiency of several neurotransmitters besides dopamine, so that it is enough to replace this one alone.
Is there any treatment for the illness?
There are different medications that help to treat the illness but there is no definitive cure yet.
· L-dopa: it is a medication that was revolutionary at the end of the 1960s for the treatment of Parkinson's disease and even today it is still used. It has a more modest effect on PSP. It help to reduce slowness, rigidity and imbalance. Some patients require very high doses
(1,500 mg or more per day) to achieve a positive effect. Generally, it loses the effect at two or three years' treatment.
· Antidepressants: The drug that has shown in this respect more benefit has been amitriptiline. The initial daily dose is usually 25mg. once a day before bedtime, or possibly in two daily takes if the dose is greater. This medication also brings benefit by favouring sleep.
· Experimental drugs: Over the last few years many drugs have been investigated, such as physostigmine or eserine, idaxosan, and metisergide, which have not shown benefits that justify their use. Investigating new drugs permanently continues.
· Botox: it is used with success in cases of blepharospasmo. This substance is produced by a bacterium and its effect takes place by inducing muscular weakness when injected into the ocular muscles that cause involuntary palpebral occlusion.
What resources are there for feeding in patients with advanced disease?
In patient with extreme difficulty to swallow and great risk of aspirative pneumonia a small operation can be performed in which a tube is placed to passes through skin of the abdomen toward the stomach (gastrostomy) or toward the jejunum (jejunostomy) and through which the food is sent. This allows that without any suffering or risk patients keep well fed and hydrated, essential to maintain their general state.
What else may be done for the patient?
Probably one of the most important points is that the family should be aware of the pathology and can thus understand the patient's difficulties and that they are part of the illness. It is also important to take into account that many of the disabilities are fluctuating and get worse with anxiety. Help when walking is important to avoid back falls; also the placement of handles in bathrooms and avoiding small furniture, as occasional tables that the patients cannot see due to their difficulty to look downward. Exercise affords psychological benefits and in to maintain abilities.
Are there surgeries for PSP?
No, regrettably.
Which is the cause of PSP?
The symptoms of the illness are caused by gradual deterioration of the cells at the base of the brain. A very important area, called substantia nigra, is affected both in this illness and in Parkinson's disease, causing the symptoms that these illnesses have in common. However, there are many areas that are not affected in this pathology and affected in the other one and vice versa.
Which is the cause of cellular degeneration?
It is unknown. No associations with occupation, toxins or geographical region have been found. Experimentally, material from brains with PSP has been injected to chimpanzees to determine whether an infection was possible, but this was not so. This demonstrates that it is not a transferable person-to-person disease or due to contact with animals. There is no evidence that indicates family transmission.
Which are the perspectives for a patient with this illness?
Although currently there is no curative treatment for this illness, there are palliative treatments and that help to improve the quality of life, besides multiple therapies under investigation, so that it is important to consult your physician and to follow his/her recommendations.
B. New Treatments
B. 1. Thalamotomy
Despite the impossibility of evaluating objectively the response to thalamotomy in old series, these reports and anecdotal experience indicated that unilateral thalamotomy was an effective treatment for Parkinson's disease. According to these series, there was improvement in limb tremor and rigidity contralateral to the lesion side in over 90% of patients.
Kelly and Gillingham reported that 90% of 57 patients subjected to thalamotomy were free of tremor 2 years after surgery, a figure that diminished to 57% at 10 years.
Kelly also observed the abolition of tremor in 86% of 36 patients, with an average follow-up of 33 months. Nagasaki et al. found a minimal recurrence of tremor in 27 parkinsonian patients after an average of 6.6 years' follow-up. Jankovic et al. reported the non-
recurrence of tremor in 36 patients followed up by an average of 60 months. Piederich et al. examined a group of patients treated 10 to 15 years before with unilateral lesion of the thalamus and found that tremor at the time of evaluation was significantly better on the side contralateral to surgery, thus disclosing a long-term effect of thalamotomy. Other parkinsonian symptoms as bradykinesia and tremor ipsilateral to the lesion were reported in previous series as progressive symptoms after surgery, as developing in non-operated patients.
In all the series reported, the complications of bilateral thalamotomy were greater than 25%, speech difficulty and neuropsychological changes proving the most marked. Due to this high index of adverse effects, the bilateral procedure is not recommended.
The mechanism of action of thalamotomy is not very well known, but it is believed to be attributable to the destruction of the neural activity characteristic of the nucleus.
B. 2. Thalamic stimulation
From the beginnings of thalamotomy it was observed that during ots performance the stimulation of the surgical target, usually the VIN nucleus, produced the same effect as its destruction. This procedure can be used effectively as an alternative to lesion treatment
in parkinsonian and non-parkinsonian tremors. The main advantage of this procedure is its reversibility, the capacity to change stimulus parameters.
The limitations of this technique include essentially the cost, the fact of an implant and the future necessity of replacing the stimulator battery. The complications of implanting pulse generators are uncommon and the duration of the battery for the implanted generator is,
on the average, from 4 to 5 years.
Reports on thalamic stimulation in Parkinson's disease (Table 2) indicate a marked effectiveness in the reduction of tremor, similar to that obtained with thalamotomy. Tremor would seem to be the only cardinal symptom of Parkinson's disease influenced by thalamic stimulation, since the effect on rigidity and bradykinesia in the series is insignificant.
As complications of stimulation electrode placement, there have occurred sporadic haematomas, postoperative convulsions; however, adverse reactions related to stimulation are slight and transient, such as contralateral parestesias, dystonia contralateral to the stimulator, disequilibium and slight dysarthria.
In conclusion, both thalamotomy and stimulation of the thalamus are effective techniques in the reduction of parkinsonian tremor, but not on other symptoms associated to Parkinson's disease.
B. 3. Pallidotomy
The long term complications of levodopa use together with the advances in stereotaxis and neuro-imaging have allowed great precision and a significant decrease in surgical morbility, so that Laitinen et al. re-explored the old posteroventral pallidotomy of Leksell in 38 patients with Parkinson's disease and reported significant improvement in bradykinesia, rigidity, tremor, gait, speech and involuntary movements induced by drugs.
According to Dogalli et al., patients improved 65% in the UPDRS scale, in 38.2% subtests contralateral to surgery and 24.2% ipsilateral to surgery. Walking speed improved 45%. Later, Lozano et al. also studied the effect of posteroventral pallidotomy in 14 patients and reported results at 6 months' fo
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