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Movement Disorder Dr.Ghayath Movement disorders Movement disorders: (sometimes called extrapyramidal disorders) impair the regulation of voluntary motor activity without directly affecting strength, sensation, or cerebellar function. They include hyperkinetic disorders associated with abnormal, involuntary movements and hypokinetic disorders characterized by poverty of movement. Hyperkinetic disorders of abnormal movements can be classified as tremor, chorea, athetosis or dystonia, ballismus, myoclonus, or tics. And example of Hypokinetic is Parkinson. Parkinson disease Parkinson's disease is one the commonest neurodegenerative disease. Parkinson’s disease (PD) is a neurodegenerative disorder associated with a loss of dopamine-producing neurons in the substantia nigra. The disease was described by James Parkinson in 1817. 1 Movement Disorder Dr.Ghayath Link to anatomy (ADDED BY THE STUDENTS NOT INCLUDED IN THE LECTURE) this will help you to understand the pathogenesis of all movement disorders: • The basal ganglia play important motor functions in starting and stopping voluntary motor functions and inhibiting unwanted movements. The basal ganglia consists of 3 nuclei masses deep in the cerebrum (caudate nucleus, putamen, and Globus pallidus), one nucleus in the midbrain (substantia nigra), and the sub thalamic nucleus of the diencephalon. The striatum combines the caudate nucleus and the putamen while the corpus striatum consists of these 2 nuclei plus the Globus pallid us. • There are 2 parallel circuits (direct and indirect) through the basal ganglia. These circuits receive extensive input from the cerebral cortex that project back to the motor cortex after a relay in the ventrolateral (VL) nucleus of the thalamus. Both of these pathways demonstrate disinhibition. The direct pathway increases the level of cortical excitation and promotes movement. The indirect pathway decreases the level of cortical excitation and suppresses unwanted movement. • The striatum is the major input center and the Globus pallidus is the major output center for the pathways through the basal ganglia. Critical to proper function of the striatum is dopamine production by the substantia nigra. Dopamine excites the direct pathway and inhibits the indirect pathway. • Lesions of the direct pathway result in an underactive cortex, which produces hypokinetic motor disturbances. The classic disorder caused by degeneration of dopaminergic neurons of the substantia nigra is Parkinson disease. • Hyperkinetic disorders result from lesions of the indirect pathway and cause an overactive motor cortex. These movements occur spontaneously at rest and cannot be controlled by the patient. Examples of these disorders include chorea (multiple quick movements), athetosis (slow serpentine movements), and hemiballismus (violent flinging movements). Hemiballismus results from hemorrhagic destruction of the contra lateral subthalamic nucleus. 2 Movement Disorder Dr.Ghayath PD slightly more common in men than women. The mean age of onset is about 60 years, but cases can be seen in patients in their 20s, and even younger. Diagnosis of a parkinsonian syndrome Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions) Muscular rigidity 4–6 Hz REST tremor Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction. This box was added by the student it is not included in the lecture: The muscular rigidity described as (cogwheel), and the resting tremor as (pill rolling) 3 Movement Disorder Dr.Ghayath Other Motor Features Micrographia Masked facies (hypomimia) Reduced eye blink Soft voice (hypophonia) Dysphagia Freezing Nonmotor Features Anosmia Pain Mood disorders (e.g. depression) Sleep disturbances Epidemiology and Pathogenesis Hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra. The studies suggest that environmental factors likely play the more important role in patients older than 50 years, with genetic factors being more important in younger patients. Epidemiologic studies suggest increased risk with exposure to pesticides, rural living, and drinking well water and reduced risk with cigarette smoking and caffeine. Differential diagnosis Secondary Parkinsonism Drug-induced (Dopamine-blocking agents such as the Antipsychotic ) Infection Vascular Normal-pressure hydrocephalus Trauma Liver failure Toxins (e.g., carbon monoxide, manganese, cyanide, hexane, methanol, carbon disulfide) 4 Movement Disorder Dr.Ghayath Other Neurodegenerative Disorders Wilson's disease Huntington's disease Treatment of Parkinson's disease A. Medical 1- Levo Dopa Dopamine does not cross the blood-brain barrier (BBB), so clinical trials were initiated with levodopa, a precursor of dopamine. Levodopa is routinely administered in combination with a peripheral decarboxylase inhibitor (carbidopa or benserazide) to prevent its peripheral metabolism to dopamine and the development of nausea and vomiting levodopa is still the most potent and effective symptomatic treatment for PD, and remain the ‘gold standard’. It is usual to start with half a tablet of 25/100 (PDI/levodopa) strength b.d. or t.d. for a couple of weeks, then doubling the dose and waiting to judge the effect over time with continued treatment, however, the duration of benefit following an individual dose becomes progressively shorter until it approaches the half-life of the drug. This loss of benefit is known as the wearing-off effect. At the same time, many patients develop dyskinesia, these tend to occur at the time of maximal clinical benefit and peak plasma concentration (peak-dose dyskinesia). In more advanced states, patients may cycle between "on" periods complicated by disabling dyskinesia and "off" periods in which they suffer severe Parkinsonism. Link to pharmacology and psychiatry (This box were added by the students it is not included in the lecture): One of the side effects of anti-Parkinson medications is Psychosis because it was hypothesized that psychosis is related to increase level of dopamine. While one of the side effects of anti-psychotic medications is Secondary Parkinsonism because they decrease the level of dopamine in the brain. 5 Movement Disorder Dr.Ghayath Strategies to treat motor fluctuations End-of-Dose Deterioration At night ‘‘Off ’’ Dystonia Peak-Dose Dyskinesia (1) Increase LD/CD from 3 to 4 times daily (2) Substitute sustained release LD/CD (3) Add dopamine agonist (4) Add COMT inhibitor (1) Add sustained-release LD/CD at bedtime (2) Add dopamine agonist at bedtime (1) Smaller doses of levodopa taken more frequently (2) Add dopamine agonist, decrease levodopa (3) Add amantadine 2-Dopamine agonists Dopamine agonists stimulate dopamine receptors directly. Six oral agonists (bromocriptine, lisuride, pergolide, cabergoline, ropinirole and pramipexole), one transdermal agonist (rotigotine) and Apomorphine administered SC are available, these agonist may be given before levodopa is introduced especially in young age, these drugs cause fluctuations and dyskinesia much less frequently. 3- Catechol-O-methyl transferase (COMT) inhibitors Entacapone (peripheral) and tolcapone (peripheral and central COMT inhibitor) block the conversion of levodopa to 3-O-methyldopa, its principal metabolite so increase the duration effect of levodopa.A combined tablet containing levodopa, carbidopa and entacapone (Stalevo) is available. 4-Monoamine oxidase B (MAO-B) inhibitors Selegiline and rasagiline are inhibitors of MAO-B, the iso-enzyme (MAO-B) responsible for catabolizing dopamine to homovanillic acid (HVA).lead to increase the duration effect of levodopa. 6 Movement Disorder Dr.Ghayath 5-Anticholinergics Anticholinergics often restricted to reducing tremor. E.g. trihexyphynidyl, procyclidin. 6-Amantadine This drug has several actions: an amphetamine-like effect (releasing presynaptic dopamine stores); a mild anticholinergic effect. B. Surgery for PD It was appreciated that lesions placed into the nucleus of the thalamus reduced contralateral tremor without inducing hemiparesis, but these lesions did not meaningfully help other more disabling features of PD. Lesions placed in the GPi (globus palidus interna) improved rigidity and bradykinesia as well as tremor. C. Deep brain stimulation (DBS) Most surgical procedures for PD performed today utilize deep brain stimulation (DBS). Here, an electrode is placed into the target area and connected to a stimulator inserted SC over the chest wall. DBS simulates the effects of a lesion without necessitating a brain lesion, Stimulation of thalamus lead to decrease tremor, stimulation of Globus Pallidus Interna lead to decrease rigidity and bradykinesia. 7 Movement Disorder Dr.Ghayath Tremor A tremor is a rhythmic oscillatory movement best characterized by its relationship to voluntary motor activity, i.e., according to whether it occurs at rest, during maintenance of a particular posture, or during movement so tremor can be classified to: rest and action tremor Action tremor is classified into: Note by the students: You can find a good summary of different types of tremor on YouTube video (The Approach to Tremor uploaded by Stanford medicine). Postural tremor Intention tremor Action tremor 1-Postural tremor Physiologic tremor Enhanced physiologic tremor causes are: Anxiety or fear Excessive physical activity or sleep deprivation Sedative drug or alcohol withdrawal Drug toxicity (lithium, bronchodilators, sodium valproate, tricyclic anti-depressants) Thyrotoxicosis Carbon monoxide poisoning Familial (autosomal dominant) or idiopathic (benign essential) tremor Wilson disease Asterixis 2-Intention tremor Cerebellar disorders Wilson disease Drug toxicity (e.g., alcohol, anticonvulsants, sedatives) 8 Movement Disorder Dr.Ghayath Rest tremor o Parkinsonism o Wilson disease Physiological tremor: An 8- to 12-Hz tremor of the outstretched hands is a normal finding. Its physiologic basis is uncertain. Enhanced physiological tremor Physiologic tremor may be enhanced by fear or anxiety. A more conspicuous postural tremor may also be found following excessive physical activity or sleep deprivation and other causes mentioned above. Benign essential tremor This is commonly inherited as an autosomal dominant trait. Most people with essential tremor (ET) have little or no disability ET is a 4-Hz to 12-Hz postural tremor, typically seen as adduction-abduction of the fingers or flexionextension of the wrist; pronation-supination of the wrist can occur, but it is more typical of PD. The tremor may start on one side, but as a rule it becomes bilateral with time. The handwriting remains large (unlike PD) but may often be severely affected and illegible. The head is the next most frequent area to be affected, with a vertical ‘‘yes-yes’’ or horizontal ‘‘no-no’’ tremor. The voice, tongue, and chin may all be involved as well. Criteria of essential tremor Core Criteria Bilateral action tremor of the hands and forearms (not rest tremor) Absence of other neurologic signs May have isolated head tremor 9 Movement Disorder Dr.Ghayath Secondary Criteria Long duration (>3 years) Positive family history Beneficial response to alcohol Treatment A) Medical: Propranolol About 50% of patients will experience relief with propranolol and other Badrenergic antagonists. Doses generally are rather large, with optimal response in the 240 mg to 320 mg range. Primidone Because the main side effect of primidone is sedation, it should be started at 25 mg at bedtime and increased very slowly by 25-mg increments. If needed, a low dose may be added in the morning. Doses above 250 mg to 350 mg are rarely needed. Topiramate Have suggested some improvement in ET B) Surgical treatment Stereotactic lesioning of the ventral intermediate Nucleus (VIM) of the thalamus has produced the greatest response in patients with severe tremor. Deep brain stimulation (DBS) of the VIM nucleus of the thalamus , has become the surgical procedure of choice Before treatment After treatment End 10 Movement Disorder Dr.Ghayath Note: the below appendix were added by the students (it’s not included in lecture): The diagnosis of Parkinson disease is a clinical one because there are no specific tests till this moment except at autopsy by the presence of specific neuropathological findings including Lewy bodies. (See the case below). A 64-year-old Caucasian male presents to your office because he has had two falls within the last month. He states that he loses his balance when he tries to turn or stop suddenly while walking. Recently, he says, it has been taking him quite a while to get himself out of bed. He also complains of hand tremors that started last year in his left hand, but that now have been affecting both hands. Which of the following is the best tool to confirm his diagnosis? A. B. C. D. Physical examination B. Lumbar puncture CT scan of the head Electroencephalography Explanation: This patient is most likely suffering from Parkinson disease (PO), a neurodegenerative disorder caused by accumulation of alpha-synuclein within the neurons of the substantia nigra pars compacta, which ultimately leads to the death of these neurons. The three cardinal signs of PO are rest tremor, rigidity and bradykinesia. The presence of two of these three signs suggests a clinical diagnosis of PO, which can be further confirmed by physical examination. To date, there are no imaging or laboratory tests that can be used to confirm this diagnosis with any greater accuracy than physical examination. The most common presenting sign of PO is an asymmetric resting tremor in the distal part of an upper extremity. To summarize, physical examination findings that contribute to a clinical diagnosis of PO include: Tremor: A resting 4 to 6 Hz tremor with a "pill rolling" quality • frequently first manifests in one hand, and may then slowly generalize to involve the other side of the body and the lower extremities. Rigidity: Baseline increased resistance to passive movement about a joint which may be uniform (lead pipe) or oscillating (cogwheel) Bradykinesia: Difficulty initiating movements, as when starting to walk or rising from a chair • Narrow-based, shuffling gait with short strides and without arm swing (festinating gait) • Micrographia (small handwriting) • Hypomimia (decreased facial expression) • Hypophonia (soft speech) Postural instability: • Flexed axial posture • Loss of balance during turning or stopping • Loss of balance when pushed slightly from a stationary bipedal stance • Frequent falls So the answer is A 11 Movement Disorder Dr.Ghayath A 53-year-old man complains of "shaking" of his right hand. He first noticed this shaking while resting in an armchair and watching lV. He reports that the shaking stopped when he reached for the remote to change the channel. On physical examination, his vital signs are within normal limits and all other organ systems appear normal. Which of the following is most likely responsible? A. B. C. D. E. F. Physiological tremor Essential tremor Cerebellar dysfunction Basal ganglia dysfunction Corticospinal tract lesion Peripheral neuropathy Explanation: This patient describes a resting tremor, based on its tendency to affect his hand while it is at rest and improve with activity. Resting tremor can be a manifestation of Parkinson's disease, and is often the presenting symptom. Parkinson's disease is caused by progressive loss of dopaminergic neurons in the basal ganglia. Its classic tetrad of symptoms includes: rigidity, tremor, bradykinesia, and postural instability. Patients typically present in late adulthood and their condition slowly deteriorates over several years. The resting tremor of Parkinson's disease is a 5 to 7 Hertz tremor that typically starts in one hand. The motion is often described as having a "pill rolling" quality. The tremor may progress to involve the other extremities, as well as the jaw, face, and lips. Unlike essential and cerebellar tremors, resting tremor will not involve the entire head. So the answer is D 12 Movement Disorder Dr.Ghayath A 73-year-old male presents to your office for evaluation of a tremor. He states that over the past several months he becomes tremulous when attempting to hold the newspaper and when drinking his morning cup of coffee. The tremor is not noticeably worse during any particular time of day. He denies any other medical problems other than hypertension, for which he takes hydrochlorothiazide. His vital signs are normal. Physical examination, including his gait, is normal. The patient did exhibit a tremor. Which of the following is the most likely diagnosis? A. B. C. D. E. Parkinson disease Huntington's chorea Side effect from caffeine Essential tremor Spinocerebellar ataxia Explanation: This patient's clinical history and visualized tremor is typical of essential tremor, which is diagnosed by the presence of an action tremor in the absence of additional neurologic signs. Essential tremor is typically suppressed at rest, but becomes noticeable when the patient attempts a task that requires fine motor movement. So the answer is D Which of the following is the next best step in the management of the previous patient? A. B. C. D. E. Carbidopa/levodopa Propranolol Genetic counseling Deep brain stimulation Advise him to stop drinking coffee Explanation: The treatment of essential tremor typically begins with the beta-blocker propranolol, which is especially helpful if the patient also has coexistent hypertension. Other treatment possibilities include anticonvulsants such as primidone and topiramate. Although benzodiazepines such as alprazolam are effective in reducing the symptoms of essential tremor, their use should be restricted due to the potential for dependence. So the answer is B Link to biochemistry: The black color of substantia nigra (in Latin: black substance) is due to presence of high levels of neuromelanin in dopaminergic neurons. This neuromelanin has a role in neuroprotection (neuromelanin can chelate metals and xenobiotics). Neuromelanincontaining neurons in the substantia nigra undergo neurodegeneration during Parkinson's disease that’s why it appears lighter in color. 13