Movement disordersinclude: Akathisia(inability to sit still) Akinesia(lack of movement) Associated Movements(Mirror Movements or Homolateral Synkinesis) Athetosis(contorted torsion or twisting) Ataxia(gross lack of coordination of muscle movements) Ballismus (violent involuntary rapid and irregular movements) Hemiballismus(affecting only one side of the body) Bradykinesia(slow movement) Cerebral palsy Chorea(rapid, involuntary movement) Sydenham's chorea Rheumatic chorea Huntington's disease Dyskinesia(abnormal, involuntary movement) Tardive dyskinesia Dystonia(sustained torsion) Dystonia muscularum Blepharospasm Writer's cramp Spasmodic torticollis(twisting of head and neck) Dopamine-responsive dystonia(hereditary progressive dystonia with diurnal fluctuation or Segawa's disease) Essential tremor Geniospasm(episodic involuntary up and down movements of the chin and lower lip) Myoclonus(brief, involuntary twitching of a muscle or a group of muscles) Metabolic General Unwellness Movement Syndrome (MGUMS) Mirror movement disorder(involuntary movements on one side of the body mirroring voluntary movements of the other side) Parkinson's disease Paroxysmal kinesigenic dyskinesia Restless Legs SyndromeRLS (WittMaack-Ekboms disease) Spasms(contractions) Stereotypic movement disorder Stereotypy(repetition) Tic disorders(involuntary, compulsive, repetitive, stereotyped) Tourette's syndrome Tremor(oscillations) Rest tremor (4-8Hz) Postural tremor Kinetic tremor Essential tremor(6-8 Hz variableamplitude) Cerebellar tremor (6-8 Hz variable amplitude) Parkinsonian tremors(4-8 Hz variable amplitude) Physiological tremor (10-12 Hz low amplitude) Wilson's diseaseTreatment[edit]How do we move?Movement, although seemingly simple like picking up a bit of paper, is actually a complex process that requires activities of several different parts of thebrainworking in tandem with muscles and nerves.The thought areas of the brain trigger or stimulate the motor area to send signals to the muscles that finally carry out the action.Throughout the action there is a constant to and from of information between the brain and the muscles via nerves of the spinal cord. This regulates the power, speed, coordination and balance necessary for a smooth action.Gait or normal locomotion or walking, running etc. is another complex area of movement that in addition requires maintenance of posture and balance. (1-5)What are movement disorders?Movement disorders are neurological syndromes where they may be excess of movement or a paucity of movement that is not connected to weakness,paralysisof spasticity of the muscles.They affect the speed, fluency or smoothness, quality, and ease of movement.Causes of movement disordersMost movement disorders are associated with pathological changes in the brain especially in an area of the brain called the basal ganglia. This region is part of thegrey matterthat lies deep within thebrain.The defects may also lie in the base of the brain or cerebellum. This leads to difficulty in walking, locomotion or maintenance of posture and normal body balance.Movement disorders are widely prevalent and many of them havegeneticsas the common cause.Impact of movement disordersThe impact can be enormous, with loss of employment, inability to drive and difficulties in performing activities of daily living including those of personal hygiene.Progression of movement disordersMost movement disorders begin slowly and progress to a more severe form if left untreated. Sometimes they begin as weakness or stiffness of muscles or there may be twitches and tics.How common are movement disordersGiven that movement and gait are complex phenomenon, problems with them are widespread since minor changes in the pathways and components of movement may affect smooth workings of motion.Essential tremorThe most common movement disorder is essential tremor. It affects one in 20 people under the age of 40 and one in five people over 65.The disorder is characterized by shaking of the hand or fingers when it attempts to perform a task.Restless leg syndromeAnother common condition is called restless leg syndrome and affects nearly one in 10 individuals.Parkinsons diseaseParkinsons disease is the best known movement disorder. It affects one in 500 individuals and in most cases is caused by genetic predisposition or exposure to certain drugs and toxins.Although less common than other movement disorders, Parkinsons disease can severely impair quality of life because they hamper regular movement and walking about and make the sufferer dependent on their carers.The disease is characterized by rigidity of muscles, tremors and shaking and a short shuffling gait which eventually becomes difficult.DystoniaDystoniais another type of movement disorder where there is excessive spasm of a group of muscles making them painful and difficult to move.This leads to abnormal postures or writhing, twisting movements of part of the body. Dystonias affect 0.4% of the population. (1-5)Reviewed byApril Cashin-Garbutt, BA HonsTypes of MDTremorThe most commonmovement disorderis essential tremor. It affects one in 20 people under the age of 40 and one in five people over 65.The disorder is characterized by shaking of the hand or fingers when it attempts to perform a task. The tremors are usually involuntary, rhythmic or pendulous movements of a part of the body.Physiological tremor means faint tremor that may be triggered by nervousness etc.Stress, exercise, weakness, or an overactive thyroid gland may lead to more persistent tremor.Essential tremor usually affects the hands and feet, but voice tremors and head tremors are also seen. It may lead to severe disability.Parkinsons diseaseParkinsons disease affects one in 500 individuals and in most cases is caused by genetic predisposition or exposure to certain drugs and toxins.Parkinsons disease is characterized by rigidity of muscles, tremors and shaking and a short shuffling gait.Eventually the patient may fail to perform his or her daily activities and may have to depend on their caregivers. Parkinsons disease is a severely debilitating disease.DyskinesiaThis is a symptom of an underlying movement disorder. Dyskinesia literally means abnormal (dys) movements (kinesia).This is characterized by spasms, tics and twitches or more complex slow writhing movements (athetosis), rapid, jerky movements (chorea) or spasm of a group of muscles (dystonia).There may be hypokinesia or paucity of movement or akinesia lack of movements and brady kinesia or slowing of movements. These are all commonly seen in Parkinsons disease.These complex abnormalities of movement may appear slowly or may appear suddenly and unpredictably with a rapid return to normal.Dyskinesia may be seen in Parkinsons disease and other similar conditions. They may be seen on intake of certain drugs like Levodopa for Parkinsons disease therapy or antipsychotic medications for psychiatric conditions.DystoniaDystonia is characterized by sustained spasm or contraction of a group of muscles. This may lead to painful writhing movements or abnormally held postures.Writer's cramp is an example of focal dystonia that affects the fingers of the writing hand. It is often sudden in onset and disappears by itself on rest.Similar dystonia may affect the eyelids leading to blepharospasm. This leads to increased blinking and involuntary closing of the eyes.Tired, stressed muscles are prone to dystonia.Anxietyand sharp emotions may also trigger dystonias.TicsThese are small movements or twitches that are repeated in a group of muscles.The movements include blinking, shrugging, grunting or grimacing.DysphoniaThere are abnormal movements of the muscles involved in voice production and speech. The voice as a result becomes quivery, jerky or strained and hoarse.AtaxiaThis affects regular movement of walking, running etc. There is a problem with posture maintenance and control of coordination and balance.Ataxiais usually a symptom of conditions such asmultiple sclerosisorcerebral palsyrather than being a disease in itself. It is caused due to diseases of the cerebellum or base part of the back of thebrain. Commonly alcohol consumption may lead to ataxia.Restless legs syndromeThis is a common movement disorder affecting one in 10 individuals. There are intensely uncomfortable sensations in the legs and sometimes arms typically seen during bedtime or at rest.It may be felt as tingling or creeping that is relieved by movement of the limbs. This leads to disturbed sleep andinsomnia.Huntingtons diseaseThis is a genetic condition that affects movements. There is chronic progressive chorea or rapid jerky purposeless movements of various groups of muscles. There is additional emotional, behavioral, and psychiatric abnormalities.Other movement disordersOther movement disorders include:- Myoclonus usually means rapid, uncontrolled, brief and irregular abnormalities of movement of a group of muscles. Affliction of multiple system leading to atrophies. This is called Shy Dragger syndrome Progressive supranuclear palsy (PSP) is a rare movement disorder that affects purposeful movements. Tourettes syndrome This is characterized by various tics and grunts. Wilsons disease This is caused by excess deposition of copper in the body leading to neurological and psychiatric symptoms along withliver disease Drug induced movement disorders Abnormal movements, tremor; anddystoniaand dyskinesias may be associated with intake of certain drugs. These could be due to antipsychotic medications or due to some anti-vomitingagents like metoclopramide etc.Reviewed byApril CCauses of MDre neurological syndromes where there may be excess of movement or a paucity of movement that is not connected to weakness,paralysisof spasticity of the muscles. Movement disorders commonly affect the speed, fluency or smoothness, quality, and ease of movement.Thepathologymore often than not lies in thebrainespecially in an area of the brain called the basal ganglia. This region is part of thegrey matterthat lies deep within the brain or cerebrum.The defects may also lie in the base of the brain or cerebellum. This leads to difficulty in walking, locomotion or maintenance of posture and normal body balance.Althoughgeneticsis the commonly implicated cause of abnormal movements there are other causes such as stress, drugs and so forth. (1-5)Stress, anxiety and emotional disturbancesi,These may lead to abnormalities of movements like tremors. Tremors are rhythmic movements of hands, feet, head or voice.They may be triggered by emotional components as well as stress. Older individuals commonly manifest essential tremors. Although the condition is not fatal, it may cause severe debility.Drugs as cause of movement disordersDyskinesias signify a range of abnormal movements that may include: hypokinesia (less movements) bradykinesia (slowing of movements) akinesia (absence of movements) chorea (rapid jerky movements) athetosis (slow writing movements) tics (rapid repeated twitches) dystoniasThese may be caused due to intake of certain drugs. Antipsychotic medications taken for psychiatric conditions likeSchizophreniaor anti-nauseaagents like Metoclopramide may lead to these movement disorders.Chronic diseases and movement disordersChronic disease like an over active thyroid gland can lead to abnormal movements like tremors.Alcohol consumptionAlcohol consumption may lead toataxia an abnormal movement or gait. There are problems with coordination and balance.There are many different types. Commonly the cerebellum is affected in this condition.Iron deficiencyIron deficiency is thought to be responsible for Restless leg syndrome although the exact cause of the condition is unknown.Excessnicotine, alcohol andcaffeinehas also been implicated.Restless legs syndrome affects nearly 20% of women during pregnancy and disappears after delivery. Those withrenal failuremay also develop symptoms.Some evidence exists that the use of antidepressants, lithium (mood stabilizer), and blood pressure lowering drugs likecalciumchannel blockers may aggravate the condition.Excess copper in the bodyCopper excess in the body leads to Wilsons disease characterized by abnormal movements, psychiatric andliver diseasemanifestations.There may be tremors, lack of coordination and abnormal movements. It affects 1 in 30,000 to 1 in 40,000 individuals.It affects all races but there is an increased incidence among European Jews, Italians, Sicilians, and Japanese.There may be a defect in the way the body handles excess copper leading to its deposition in the liver and brain. Usually the cause is genetic with the problem lying in the 13thchromosome.Neurodegenerative conditionsParkinsons disease is a neurodegenerative condition. There is a reduction of cells in the basal ganglia that produce a chemical messenger of thebraincalledDopamine.It has mainly genetics as a cause. There are other causes such as exposure to heavy metals, such as prolonged exposure to copper and manganese or exposure to pesticides and exposure to antipsychotic drugs like phenothiazines, prochlorperazine, thioridazine, chlorpromazine,haloperidoland anti-vomitingagent metoclopramide.Genetic causes of movement disordersHuntingtons disease is primarily caused by genetic defects that are inherited. The defect lies in the 4thchromosome and is transmitted to the offspring almost certainly (autosomal dominant trait).Reviewed byApril Cashin-GarbutBy Dr Ananya Mandal, MDMovement disordersare abnormalities of movements and gait. Movements that appear relatively simple liking picking up a bit of paper from the floor are actually quite complex.There are numerous to and from movement of signals from thebrainto the arm as well as other parts of the body to maintain balance and guarantee a smooth, rapid and fluent movement to pick up the object. Thus any problems at any part of this complex pathway can affect normal movements.Characteristic symptoms of movement disordersMovement disorders are usually characterized by excess movements or by paucity or lack of movements and rigidity and contraction of muscles.They may lead to severe disability and difficulty in leading a normal life. There is a huge effect on the society as these patients are unable to find and retain gainful employment and may need constant care and supervision for day to day activities including personal hygiene.Most movement disorders begin slowlyA co-worker or spouse may notice the problem before the patient realizes. There may be initial weakness and stiffness of the muscles and there is usually an onset of involuntary movements.These include twitches, tics, movements or flapping or writing of arms, head and abnormal sounds or grunts.The symptoms may persist throughout the day or may appear only when the sufferer tries to perform a task, walk or turn their heads.Changes in muscle toneThere may be increased or decreased muscle tone. Muscle tone refers to the resting activity of the muscles that prevents the limbs and torso from sagging and holds up the body even at rest.With movement disorders likedystoniathe muscle tone is increased as there is spasm or persistent contraction of a group of muscles.RigidityDue to increased muscle tone the limbs may be difficult to maneuver by the physician.Cogwheel rigidity is seen in patients with Parkinsons disease. In this there is a ratchet-y feel when passively moving a limb.Pain and spasmIncreased muscle tone may also be accompanied by pain and spasm of the muscles. This is also seen in dystonias.Types of movement disordersThere are a range of different types of movement disorders. Symptoms and signs of these disorders vary for different types. (1-5)BlepharospasmThis leads to contraction of eyelid muscles and closure of one or both eyes. This is a type of dystonia.DyskensiaDyskinesia is characterized by a series of abnormal movements. Tics and tremors are rhythmic or pendulous movements of the arms and legs.In tics there may repeated movements like twitches of facial muscles, shrugging, grimacing, grunting or sighing.Patients with dyskinesia may also have hypokinesia (less movements), bradykinesia (slow movements) or akinesia (complete lack of movements).There may be choreas (rapid jerky movements of the limbs) or athetosis (slow writhing movements) or myoclonus (rapid, purposeless movements of the limbs that appear suddenly and disappear on their own).Patients report that they feel an involuntary pulling or twisting of the muscles before the movement appears.TremorsTremors are the most common symptom. They appear in the head, face, especially the chin, voice or arms and legs. Tremors may occur at rest or may occur during attempts to perform a task.AsterixisAsterixis is another symptom characterized by sudden loss of tone while attempting to maintain a limb in a certain position.There is flapping of the hands as the patient holds out his or her arm.Symptoms affecting posture and balancePropulsion and retropulsion are symptoms affecting posture and balance. There is stooping, pull to one side while walking, short steps and easy falls while walking.This is seen in patients with Parkinsons disease.Ataxiacauses imbalance and difficulties in gait and walking.DysphoniaDysphonia refers to disorder of the voice caused by abnormal contraction of the muscles producing voice.There may be times when no sound can be made at all and times when the voice is quivery, strained, hoarse or jerky.Restless leg syndromeRestless leg syndrome is characterized by creeping, tingling or feeling of bugs over the legs or sometimes arms especially at bedtime or at rest. The feeling is relieved temporarily by movement of the limbs.Other problems include disrupted sleep,insomniaand daytime fatigue.Wilsons diseaseWilsons disease in addition manifests with symptoms ofliver diseaselikejaundiceetc.There may be psychiatric and behavioral disturbances like loss of concentration, cognitive decline,depressionetc. there are special KF rings that can be seen in the eyes on examination. Rarely seizures may be seen.Parkinsons diseaseParkinsons disease is characterized by tremor at rest, rigidity and bradykinesia. There is diminished postural stability with falls and a shuffling gait. There is a diminished arm swing while walking.There is a feature called festination while walking that refers to the symptom when the patient may lean forward and walk with fast, shortened steps which can result in an involuntary forward acceleration.Sometimes the patient may just freeze in their movements.There may be micrographia or progressive shortening of the letters written by the patient.Other symptoms that are commonly seen include: Anxiety depression andpsychosis constipation sexual dysfunction low blood pressure intolerance to heat and cold pain numbness burning or tingling swallowing difficultiesThe patient may present with a fixed, immobile, and expressionless face called masked facies with excessive drooling.Reviewed byApril Cashin-Garbutt, BA Hons (Cantab)Further ReadingBy Dr Ananya Mandal, MDMovement disorderscommonly affect normal fluency, speed and ease of movements and gait. Most of them are cause due to faultygenesthat may or may not be inherited.Movement disorders begin with thepathologywithin thebrainand there are drugs that may help in therapy of these conditions.The most common areas affected are the basal ganglia,thalamusand globus pallidum deep within the brain. The cerebellum at the back of the brain may be affected in abnormalities of gait.Treatment depends on type of movement disorderOutlining therapy of movement disorders it is important to note that there are a range of movement disorders and each need spate attention and diagnosis although most of them are treated with the same armament of medications.Parkinsons diseaseTreatment involves many types of specialists and primarily neurologists. Early stages respond well to medications. During mid- to late-stage disease additional surgery may be suggested.The primary problem is depletion of chemical messengerDopaminein the basal ganglia of the brain.Levodopa helps to restore this Dopamine and is the mainstay of drug therapy for Parkinsons disease. Carbidopa helps in the activity of Levodopa.There are other drugs like Amantadine, Selegiline, Ropinirole, Entacapone, Tolcapaone, and Pramipexole that help in treatment of Parkinsons disease by replacing or increasing the dopamine in the brain.Those with Parkinsons disease caused by certain drugs like antipsychotic agents need to be evaluated and the offending drug needs to be stopped. Drugs like Trihexyphenydyl help these patients. Neuroprotective agents help in protecting the damaged neurons of thebrain.Some surgeries like Deep brain stimulation (DBS), thalamotomy, Pallidotomy are other options for advanced cases. DBS surgery uses electrodes to cause stimulation of certain affected areas of the brain.Stem celltransplantation has also been tried in treatment of Parkinsons disease.Overall good nutrition is essential for treatment of Parkinsons disease. Good nursing care is vital.Exercise helps keep the patient with the disease from losing muscle mass and can improve mobility and diminish injury from falls.Psychotherapy is necessary for patients with concomitant psychiatric conditions.DystoniasDystonias are treated with anticholinergic drugs like trihexyphenidyl, Benzodiazepines like diazepam, lorazepam and Skeletal muscle relaxants like baclofen. Levodopa with carbiidopa, clozapine and tetrabenazine is also used in therapy.Botulinum toxin or botox may be used to relieve the muscle spasm.For patients with severedystoniawho have not responded to therapy surgery is considered to relieve the muscle spasm and pain. Brain surgery may also be performed as treatment.TremorsTremors, especially essential tremors, are treated with: betablockers like Propranolol other drugs like Primidone Benzodiazepines like alprazolam, clonazepam gaba analogues like gabapentin antipsychotics like Mirtazapine, clozapine botoxSurgery and DBS is recommended in severe cases.Tourettes syndromeTourette's syndromeis usually treated with antipsychotics likeHaloperidol. Clonidine a blood pressure lowering agent has been found useful in certain tic disorders.Botox is useful in facial spasms, blepharospasm and torticollis (dystonia of the neck muscles).Anti-seizuredrugs like carbamazepine, phenytoin, gabapentin, baclofen are also useful in the treatment of movement disorders.Phenytoin and Pramipexole (originally drug for Parkinsons disease) is useful in restless legs syndrome.Treatment of movement disorders caused by drugsCommon side effects of dopamine increasing drugs includenausea,headache, dizziness, and fatigue and rarely abnormal movements like dyskinesias.Beta blockerslike Propranolol may cause slowedheart rate, light-headedness,depressionand nausea.Benzodiazepines lead to drowsiness, and fatigue.Anti-seizure medications may cause lack of coordination and balance, nausea, dizziness and fatigue.Botox may cause temporary weakness in the group of muscles being treated and rarely, flu-like symptoms due toallergies. (1-4)Reviewed byApril CashixxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxMedscapeENERAL CLASSIFICATION PRINCIPLESGenerally speaking, two main categories of movement disorder phenomena can be distinguished, with several specific subdivisions (Box 1). The first category corresponds broadly to akinetic-rigid disorders, the second to hyperkinetic disorders. The hyperkinetic disorders are usually perceived as being more difficult to diagnose correctly. A helpful approach is to separate this group into two main subdivisions, one in which the movements have a jerky character, and a second in which this jerky character is absent. Few disorders feature a combination of both categories.Akinetic-rigid SyndromesThe literature uses the terms akinesia, bradykinesia and hypokinesia inconsistently. We define akinesia as an umbrella term for a symptom complex that can include bradykinesia (slowness of movement) and hypokinesia (poverty of movement, and movements that are smaller than intended), but alsocrucially and fundamentallythe progressive fatiguing and decrement of repetitive alternating movements seen during finger or foot tapping. We ask the patient to make large, regular, repetitive alternating movements of each extremity in turn: opposition of the thumb to the crease between the terminal phalanges of the index and third fingers, and repeatedly tapping the forefoot on the floor, keeping the heel on the ground. It is easy to seeor, at the ankle, to hearearly progressive reduction in amplitude or speed of the movements. Sometimes, however, the clinical question is not whether akinesia or bradykinesia is present, but whether they are absent. Demonstrating absence of these features is more time-consuming, and in order to be certain we recommend asking the patient to perform up to 64 repetitions in each extremity, if necessary. Sometimes severe tremor can intervene to 'hijack' the movements, thereby making this assessment difficult or even impossible.In the widely used Queen Square Brain Bank Criteria[7]for the diagnosis of parkinsonism, bradykinesia is defined as including fatiguing and decrement of repetitive alternating movements, which we would consider under the broader rubric of akinesia. The variability in terminology is not in itself important, provided that, whatever name one gives, fatiguing and decrement are defining features for untreated parkinsonism (note that signs of akinesia can be masked in treated patients). One must also recognize that slowness of movement, without fatiguing and decrement, is seen in pyramidal and cerebellar dysfunction (often with additional clumsiness or irregularity). This observation could explain why patients with an upper motor neuron presentation of amyotrophic lateral sclerosis (with pyramidal slowing, and increased tone due to spasticity) can, in rare cases, be misdiagnosed as having parkinsonism.[8]An additional component of akinesia is absence or poverty of automatic movements (we refer to this as hypokinesia), manifested by, for example, hypomimia with reduced blinking, or a reduced arm swing during walking. Care should be taken not to mistake depression for a masked face, and to recognize other possible causes for reduced arm swing, since this feature can be seen in individuals who are unsteady for any reason, in patients with dystonia, and in patients with musculoskeletal problems such as frozen shoulder (although the latter not uncommonly precedes the diagnosis of PD).Increased muscle tone across a joint due to rigidity or spasticity can be differentiated while examining the full range of motion of a joint at varying speeds. In rigidity, the resistance is more or less stable, and equal between flexion and extension movements, during the whole trajectory. In spasticity, the tone is preferentially increased in arm flexors and leg extensors, and sudden decreases of muscle resistance (the 'clasp-knife phenomenon') can be felt.Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

http://www.youtube.com/watch?v=ZBJeyk2GJws

aetiology of PDAlthough the etiology of Parkinson disease is still unclear, most cases are hypothesized to be due to a combination of genetic and environmental factors. Currently known genetic causes of Parkinson disease account for approximately 10% of cases.Environmental causesEnvironmental risk factors commonly associated with the development of Parkinson disease include use of pesticides, living in a rural environment, consumption of well water, exposure to herbicides, and proximity to industrial plants or quarries.[4]A meta-analysis of 89 studies, including 6 prospective and 83 case-control studies, found that exposure to pesticides may increase the risk for PD by as much as 80%.[5, 6]Exposure to the weed killer paraquat or to the fungicides maneb or mancozeb is particularly toxic, increasing the risk for PD about 2-fold. Many of the agents studied are no longer used in the United States and Europe; however, some are still found in developing parts of the world.[5, 6]In case-control studies, PD was associated with exposure to any type of pesticide, herbicide, insecticide, and solvent, with risks ranging from 33% to 80%.[5, 6]Increased PD risk was also associated with proxy conditions of exposure to organic pollutants, such as farming, well-water drinking, and rural living. In addition, risk seemed to increase with length of exposure.[5, 6]The National Institutes of Health-AARP Diet and Health Study, as well as a meta-analysis of prospective studies, found that higher caffeine intake was associated with lower risk of Parkinson disease in both men and women. A similar association was found for smoking and Parkinson disease risk.[7]The biological mechanisms underlying the inverse relationship between caffeine or smoking and Parkinson disease risk are not well elucidated.MPTPinterference with mitochondrial functionSeveral individuals were identified who developed parkinsonism after self-injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These patients developed bradykinesia, rigidity, and tremor, which progressed over several weeks and improved with dopamine replacement therapy. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B.[8]MPP+ accumulates in mitochondria and interferes with the function of complex I of the respiratory chain. A chemical resemblance between MPTP and some herbicides and pesticides suggested that an MPTP-like environmental toxin might be a cause of Parkinson disease, but no specific agent has been identified. Nonetheless, mitochondrial complex I activity is reduced in Parkinson disease, suggesting a common pathway with MPTP-induced parkinsonism.Oxidation hypothesisThe oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative metabolism, plays a role in the development or progression of Parkinson disease. The oxidative metabolism of dopamine by MAO leads to the formation of hydrogen peroxide. Normally, hydrogen peroxide is cleared rapidly by glutathione, but if hydrogen peroxide is not cleared adequately, it may lead to the formation of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage. In Parkinson disease, levels of reduced glutathione are decreased, suggesting a loss of protection against formation of free radicals. Iron is increased in the substantia nigra and may serve as a source of donor electrons, thereby promoting the formation of free radicals.Parkinson disease is associated with increased dopamine turnover, decreased protective mechanisms (glutathione), increased iron (a pro-oxidation molecule), and evidence of increased lipid peroxidation. This hypothesis has raised concern that increased dopamine turnover due to levodopa administration could increase oxidative damage and accelerate loss of dopamine neurons. However, there is no clear evidence that levodopa accelerates disease progression.Genetic factorsIf genetic factors are important in a particular disease, concordance in genetically identical monozygotic (MZ) twins will be greater than in dizygotic (DZ) twins, who share only about 50% of genes. Early Parkinson disease twin studies generally found low and similar concordance rates for MZ and DZ pairs.However, genetic factors in Parkinson disease appear to be very important when the disease begins at or before age 50 years. In a study of 193 twins, overall concordance for MZ and DZ pairs was similar, but in 16 pairs of twins in whom Parkinson disease was diagnosed at or before age 50 years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant.[9]The identification of a few families with familial Parkinson disease sparked further interest in the genetics of the disease. In one large family in Salerno, Italy, 50 of 592 members had Parkinson disease; linkage analysis incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G substitution at base 209 of the alpha-synuclein gene.[10]TermedPD-1, this mutation codes for a substitution of threonine for alanine at amino acid 53. These individuals were characterized by early age of disease onset (mean age, 47.5 years), rapid progression (mean age at death, 56.1 years), lack of tremor, and good response to levodopa therapy.[10]Five small Greek kindreds were also found to have thePD-1mutation.In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C for G at base 88, producing a substitution of proline for alanine at amino acid 30) confirmed that mutations in the alpha-synuclein gene can cause Parkinson disease.[11]A few additional familial mutations in the alpha-synuclein gene have been identified and are collectively calledPARK1. It is now clear that these mutations are an exceedingly rare cause of Parkinson disease.A total of 18 loci in various genes have now been proposed for Parkinson disease. Mutations within 6 of these loci (SNCA,LRRK2,PRKN,DJ1,PINK1, andATP 13A2) are well-validated causes of familial parkinsonism.[12]Inheritance is autosomal dominant forSNCAandLRRK2(althoughLRRK2mutations exhibit variable penetrance). Inheritance is autosomal recessive forPRKN,DJ1,PINK1, andATP13A2. In addition, polymorphisms withinSNCAandLRRK2, as well as variations inMAPTandGBA,are risk factors for Parkinson disease.[12](For more information on genes/loci underlying monogenic parkinsonism and susceptibility genes/loci for Parkinson disease, see Tables 1 and 2, respectively, inThe Genetics of Parkinson Disease.[12])In one study of 953 patients with Parkinson disease with age at onset of 50 years or younger, 64 patients (6.7%) had aPRKNmutation, 1 patient (0.2%) had aDJ1mutation, 35 patients (3.6%) had anLRRK2mutation, and 64 patients (6.7%) had aGBAmutation.[13]. Mutations were more common in patients with age at onset of 30 years or younger (40.6%) than in those with age at onset between 31 and 50 years (14.6%); more common in patients of Jewish ancestry (32.4%) than in non-Jewish patients (13.7%); and more common in patients reporting a first-degree family history of Parkinson disease (23.9%) than in those without such a family history (15.1%).[13]Although the mechanisms by which genetic mutations cause Parkinson disease is not known, evidence to date converges on mechanisms related to abnormal protein aggregation, defective ubiquitin-mediated protein degradation, mitochondrial dysfunction, and oxidative damage.Alpha-synuclein conformational changes and aggregationAbnormally aggregated alpha-synuclein is the major component of Lewy bodies and Lewy neurites, which are characteristic pathologic findings in Parkinson disease. Missense mutations and multiplications in theSNCAgene that encodes alpha-synuclein, although rare, cause autosomal dominant Parkinson disease. However, genome-wide association studies have also demonstrated a link betweenSNCAand sporadic Parkinson disease.Dysfunction of alpha-synuclein appears to play a central role in the pathogenesis of Parkinson disease, and understanding its relationship to the disease process holds major promise for the development of a cure.Alpha-synuclein is a 140-amino-acid protein that is unfolded at neutral pH. However, when bound to membranes or vesicles containing acidic phospholipids, it takes on an alpha-helical structure. Normally, alpha-synuclein is found mainly in neuronal presynaptic terminals and may play a role in assembly and function of SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) proteins that are involved in neurotransmitter release.Under certain conditions, alpha-synuclein aggregates into oligomers that are gradually converted to the betasheet-rich fibrillary structures that form Lewy bodies and neurites in Parkinson disease. Most evidence currently suggests that it is the intermediate soluble oligomers that are toxic to neurons.Multiple mechanisms have been suggested as to how abnormally aggregated alpha-synuclein could exert neurotoxicity.[14]One hypothesis suggests that oligomeric alpha-synuclein can promote formation of ion-permeable pores on neuronal membranes, leading to increased calcium influx. Aberrant pore formation could also lead to neurotransmitter leaks from synaptic vesicles into the cytosol. In addition, overexpression of alpha-synuclein has been demonstrated to impair mitochondrial complex I activity, and oligomeric alpha-synuclein may have a direct effect on mitochondrial membranes. Other lines of evidence suggest that oligomerization of alpha-synuclein could cause cytoskeletal disruption, possibly by an effect on the microtubule-stabilizing protein, tau.[15]Elevated levels of alpha-synuclein promote abnormal aggregation. levels are normally regulated by a balance between synthesis and degradation.SNCAmultiplications lead to increased synthesis of alpha-synuclein and can cause Parkinson disease. Alpha-synuclein appears to be degraded by the ubiquitin proteasome system and the autophagy-lysosome pathway. Several genetic mutations associated with Parkinson disease may lead to decreased alpha-synuclein degradation. For example, increased risk of Parkinson disease in carriers ofGBA(beta-glucocerebrosidase gene) mutations, which encode for the lysosomal enzyme glucocerebrosidase, may be due to lysosomal dysfunction and consequent alpha-synuclein accumulation and oligomerization.How the Parkinson disease process begins is not known. Once it is initiated, however, it may propagate by a prionlike process in which misconformed proteins induce the templated misfolding of other protein molecules. In Parkinson disease, synuclein pathology begins in the lower brainstem and olfactory bulb, ascends up the midbrain, and eventually affects the neocortex. One set of observations in support of a prionlike process comes from experience with fetal dopaminergic grafts transplanted into the striata of patients with Parkinson disease, because these grafts develop Lewy bodies, suggesting host-graft transmission of disease.[16]Preventing the propagation of abnormal alpha-synuclein aggregation may be the key to slowing or stopping Parkinson disease progression.PreviousMYOCLONUS ( MEDSACPE)Where is the Myoclonus Generated?Myoclonus can arise from several levels in the nervous system, ranging from cerebral cortex to peripheral nerve.Cortical MyoclonusCortical (or pyramidal) myoclonic jerks are mostly epileptic, brief (10 V). There may be a long-loop C-reflex at rest.The treatment of cortical myoclonus depends on its clinical context. Epileptic myoclonus is treated as part of the epileptic syndrome. Most patients with other seizure types need no specific treatment for the myoclonus. Where specific treatment is needed, there is class II evidence for piracetam (levetiracetam is an alternative) and class IV evidence for sodium valproate (remembering potential teratogenicity in women) and for clonazepam. There is only anecdotal evidence for other medications such as topiramate, zonisamide, primidone and phenobarbital.[4]Subcortical MyoclonusSubcortical myoclonus manifests as a typically bilateral, non-epileptic, flexor jerk, affecting axial or proximal limb muscles. Contractions are typically more prolonged than cortical myoclonus (up to 500 ms). The movement may be provoked by a stimulus (eg, noise, giving an exaggerated startle reflex = hyperekplexia) or by an action or intention (LanceAdams syndrome). Jerks may originate in various regions: diencephalic (thalamic, basal ganglia;[5]see figure 3) or brainstem (reticular reflex myoclonus). Multi-channel electromyogram (EMG)recording may indicate rostro-caudal recruitment, for example, activation of facial nerve before trigeminal nerve innervated muscles. Other conditions associated with subcortical myoclonus are shown inTable 2. Clonazepam is the recommended treatment for subcortical myoclonus.

(Enlarge Image)Figure 3.MR scan (A) and perfusion CT scan (B) of a 73-year-old man with left-sided myoclonic jerks of