1. MEDICATION-INDUCEDMOVEMENT DISORDERSOLADAPO SAMSON OLUWABUKOLA 9TH JULY, 2012

2. Definition of terms Medication-inducedmovementdisorder(Extra-Pyramidal Side Effects, EPSE) occurs due to treatmentwith antipsychotic medications. It can also be defined as physical symptoms, includingtremor, slurredspeech, akathesia, dystonia, anxiety, distress, paranoia, and bradyphrenia, that are primarily associated with improperdosing of or unusual reactions to neuroleptic (antipsychotic)medications. Though they are commonly caused by the typicalantipsychotics, but can also be caused by the atypical. The adverse consequences of these syndromes can beminimized by vigilant clinicians who systematically examinepatients at risk for these disorders and who manage themproperly when discovered. The best management is, of course, prevention, whichstarts with the judicious prescription of neuroleptics, and anawareness of the potential for certain nonpsychiatric 3. Incidence Though the true incidence and prevalence of drug- induced movement disorders is unknown and likely vastly underappreciated because of lack of recognition, but studies and epidemiological evidence have shown that one in 500 people who take metoclopramide are likely to develop Extra-Pyramidal Side Effects (EPSE). The risk for the development of EPSE is highest in infants and children and adults younger than 30 years of age. The risk of developing EPS or Tardive Dyskinesia ,TD and the likely irreversibility of TD are related to the length of exposure and total accumulative exposure to the drug. 4. Incidence Other factors influencing the correlation of Medicationinduced Movement Disorder, MIMD and the use ofantipsychotic drugs include: age of the population, the drug being used and the dose, the definition of the movement being employed in the study, design of the study. MIMD related to exposure to antipsychotic drugs isestimated to occur in 19% and 42% of patientsreceiving atypical (second-generation) and typical(first-generation) antipsychotic drugs, respectively. 5. Risk Factors This is a function of the exposure and the dosage ofantipsychotics taken. The following populations are considered to be atincreased risk of Medication Induced MovementDisorder.Populations at High Risk for Developing Potential ReasonsMIMDElderlyDecreased functional reserveElderly womenDecreased Estrogen levelsPatients who have used Dopamine Receptor Increased exposure to DRBDsBlocking Drugs, DRBDs for more than 3 monthsDiabetics, independent of their use of DRBD, Impaired glucose metabolismalthough the risk increases with the use ofDRBDPersons with phenylketonuria Increased level of 6. Etiology The etiology of Medication Induced Movement Disorders, MIMD, is largely of biological origin: 7. Etiology Biological The most common antipsychotic associated with EPSE ishaloperidol used especially in schizophrenia. Other antidopaminergic drugs like the antiemetic such asmetoclopramide or the tricyclic antidepressantamoxapine can also cause extrapyramidal side-effects. Another common cause are Selective Serotonic ReuptakeInhibitors (SSRIs), which decrease dopamine andnorepinephrine neurotransmission in the Substantia Nigra. Others include: Perphenazine (Trilafon) Thiothixene HCl (Navane) Fluphenazine HCl (Prolixin) Trifluoperazine (Stelazine) Risperidone (Risperdal) 8. PathogenesisExtrapyramidal system,EPS: collateral pathways separate from the pyramidal tract; plays a role in voluntary movement whereas the pyramidal tract is the motor areas of the cerebral cortex to the anterior motor neurons of the spinal cordThe extra-pyramidalsystemincludes all descending motor tracts other than corticospinal and corticobulbar tracts. Nerve impulses along this pathway follow a complex, polysynaptic circuit that involves the motor cortex, basal nuclei, limbic system, thalamus, cerebellum, reticular formation and nuclei in the brainstemEPS is contained in basal ganglia where bothNeurotransmitters that act on EPS include the following: sensory and motor information travels; information is integrated GABA relayed through thalamus to Inhibitory and Glutamate spinal cord. Acetylcholine Serotonin Dopamine 9. Pathophysiology Though the pathophysiology of MIMD has not been clearly elucidated yet, but certain theories and hypothesis suggest the interplay between: genetic predisposition, dopaminergicsystem hypersensitivity in the basal ganglia, decreased functional reserve, and over activation of the cholinergic system. 10. Postsynaptic Dopamine Receptor Hypersensitivity Theory The chronic blocking of presynaptic dopamine receptors enhances excitatory glutamatergic neurotransmission. The neurotoxic stress in the striatum, which is caused by increasing glutamate release and extracellular glutamate levels at corticostriatal terminals, ultimately destroys the output neurons, leading to dopaminergic hypersensitivity. Although this theory has been the long-held hypothesis as the cause of MIMD, it cannot completely account for the clinical findings, primarily because it does explain the fact that MIMD are not a universal phenomenon among people exposed to Dopamine Receptor Blocking Drugs, DRBDs 11. Neurotoxicity Theory Suggests that MIMD are caused by the neurotoxic effects of free radicals that are created as a byproduct of catecholamine metabolism because the use of DRBDs increases the turnover of neurotransmitters and because the basal ganglia are particularly vulnerable to the effects of membrane lipid peroxidation. Dopamine-GABA Hypothesis Dopamine has both inhibitory and excitatory effects on GABA neurons, determined by the location and type of the dopamine receptors in the brain. In this theory, which does not disregard the fact that dopamine receptors become increasingly sensitive to the effects of DRBD, the interaction between the dopamine and gamma-aminobutyric acid (GABA) neurons plays a greater role, likely accounting for the different, yet simultaneous, effects of the DRBD. Unfortunately, this theory has not been able to be converted into a treatment paradigm because of the toxicity of the agents 12. Clinical Features Though the presentation of the MIMD is in no way different frommovement disorder secondary to neurological diseasesaffecting the extrapyramidal motor system. Generally, based onthe features, there are 3 main groups: Druginducedmovementdisorders, such as:akathisia, akinesia, hyperkinesia, dyskinesias, extrapyramidalsyndrome, and tardive dyskinesia Movement disorders secondary to neurological diseasesaffecting the extrapyramidal motor system, such as:athetosis, chorea, dystonia, hemiballismus, myoclonus, tremor, tics and spasm Abnormal movements in psychiatric disorders, such as:mannerism, stereotyped behaviour and psychomotorretardation. It is of importance that the presentation of each of this disordersbe distinguished, based on their phenomena, which is believedto be of help to the medical fraternity in other to make quick 13. Akathisia Akathisia is a state of motor restlessness ranging from afeeling of inner disquiet to inability to sit still or lie quietly.Its subjective feeling of objective signs of muscle unrest,particularly in the lower extremities. Complaints of restlessness accompanied by movementssuch as fidgeting of the legs, rocking from foot to foot,pacing, or inability to sit or stand. Symptoms can developwithin a few weeks of starting or raising the dose oftraditional neuroleptic medications or of reducing the doseof medication used to treat extrapyramidal symptoms. Difficulty remaining seated, agitation, restlessness Difficult to recognize and may be misdiagnosed with apsychiatric disorder Can be treated with anti-parkinsonian agents in addition to benzodiazepines 14. Rigidity - Akinesia Rigidity develops without tremor in many patients. When a rigid joint ismoved, sudden, rhythmic jerks due to variations in the intensity of therigidity occur, producing a ratchet-like effect (cogwheel rigidity) Akinesia is a state of motor inhibition or reduced voluntary movement.It is also known to be the absence, poverty, or loss of control ofvoluntary muscle movements. Slow movements (bradykinesia) are typical as rigidity progresses.Movement also becomes decreased (hypokinesia) and difficult toinitiate (akinesia) Rigidity and hypokinesia may contribute to muscular aches andsensations of fatigue. The face becomes masklike definitive sign ofParkinsons Disease , with an open mouth, drooling, and reducedblinking. Patient may appear depressed because facial expression is lackingand movements are decreased and slowed. Speech becomes hypophonic, with characteristic monotonous,stuttering dysarthria. Hypokinesia and impaired control of distal musculature causemicrographia (writing in very small letters and makes activities of dailyliving increasingly difficult. 15. Dystonia Dystonia can be defined as dyskinetic movements due to disorderedtonicity of muscle. It is sustained involuntary muscle contractions, often distorting bodyposture. It can be primary or secondary, and often can be generalized,focal or segmental. Diagnosis is clinical. Treatment of generalizeddystonia is often with combination of anticholinergics, muscle relaxants,and benzodiazepines. Treatment of focal or segmental dystonia is oftenwith botulinum toxin; more generalized or refractory cases may benefitfrom surgery. Tonic muscular contractions localized to one or several muscle groups,particularly in the eyes, mouth, throat or neck. Eye manifestationsinclude spasm of extra ocular muscles (oculogyric crisis). Neckmanifestations include torticollis. Back manifestations includeopisthotonus. Pharyngeal muscle spasm or laryngospasm can be life-threatening. Canbetreatedwithdiphenhydramineorbenztropine (Cogentin) which are anti-parkinsonian agents Common drug causes of dystonia: Phenothiazines, Thioxanthenes, 16. Parkinsonism Parkinsonism refers to symptoms that are similar to those of Parkinsons Disease butcaused by another condition. Signs and symptoms include: Resting tremor of one hand, maximum at rest. It is often the first symptom Rigidity Slow movements Postural instability Dementia Sleep disorders are common. Insomnia may result from nocturia or from the inability to turn in bed Seborrheic dermatitis The mechanism is blockage of or interference with dopamines action in the basalganglia. The most common cause is ingestion of drugs that block dopamine receptors.Such drugs include: Phenothiazines Thioxanthenes Butyrophenones Antipsychotics can cause reversible parkinsonism Reserpine Metoclopramide can be dose dependent or related to the patients susceptibility (risk factors include older age and elderly women) Meperidine analoge can cause sudden, irreversible parkinsonism. This occurs in IV drug users. 17. Tardive Dyskinesia Tardive dyskinesia is a syndrome of abnormalinvoluntary muscle movements resulting fromprolonged neuroleptic exposure. The syndrome mayarise either during or following the cessation of long-term neuroleptic therapy. Raising the dose ofneuroleptics suppress the movement disorder acutely,while lowering the dose results in an exacerbation ofthe movements acutely. Known to manifest itself by oral buccal dyskineticmovements including chewing movements, protrusionof the tongue, lip smacking, puckering, and pursingthe lips, but it can consist of any hyperkineticmovement disorder of any part of the body, includingthe choreiform movements of the hands and feet,axial symptoms of pelvic thrusting, or even dyskinesia 18. Tardive Dyskinesia - Pathophysiology The dopamine supersensitivy hypothesis of tardivedyskinesia states that the hyperkinetic movements ofTD result from a super-sensitivity of the dopaminereceptor population in the striatum that is due tochronic dopamine receptor blockade. This is justifiesthe reason, why, TD improves acutely after increase indosage of neuroleptics, and why it is transientlyexacerbated by withdrawal of neuroleptics. The dopaine-acetycholine balance theory explicateswhy anticholinergics exacerbate TD that is improvedby cholinergics. The GABA hypothesis explains some of the preclinicalsubtleties of TD better than the older hypothesis but isnot as yet more clinically useful. 19. Other forms of Tardive movementdisorders Tardive dystonia a less common form of MIMD resultingfrom prolonged exposure to neuroleptics than tardivedyskinesia, but tend to be more disabling. The symptomsinclude the developemnt of dystonic movements followingprolonged neuroleptc exposure, primarily involving theface and neck and especially producing retrocollis -spasmodic torticollis in which the head is drawn back.Estimated prevalence among the psychiatric patients varywidely between 1.5% and 21%. Tardive dystonia differsfrom tardive dyskinesia not only in being moredisabling, but in being less likely to remit. Tardive akathisia generally associated with tardivedyskinesia and often responds well to treatment withdopamine depleting agents such as reserpine andtetrabenazine. Other forms of tardive movment disorders, thoughrare, includes Gilles de la Tourettes syndrome, tardivemyoclonus, and tardive tremor 20. Differential Diagnosis For the sake of simplicity, it is explicit to describe thedifferential diagnosis under the following heading: Medical Psychiatric 21. Differential diagnosis Medical Parkinsons Disease Benign childhood epilepsy Chorea Gravidarum Chorea in Adults Complex partial seizures Frontal lobe epilepsy Cortical Basal Ganglionic Disorder Wilson disease Huntington Disease dementia Tetanus Wilson Disease. Thyroid dysfunction SLE Polycythemia Rubra Vera 22. Differential diagnosis psychiatric Dopamine-responsive dystonia Psychogenic Nonepileptic Seizures Alcohol related psychosis Mania Stimulant drug intoxication Drug withdrawal Agitated emotional state One must be wary of missing akathisia, as it may be the cause for a paradoxical worsening of behavior in response to antipsychotic treatment. Equally important is the consideration of akathisia as a driving force for agitation in demented patients who receive antipsychotic drugs for psychiatric aspects of their dementias. If the response to an antipsychotic is worsened behavior, akathisia must be considered. Because the patients are often unable to communicate, a high index of suspicion must be maintained. Restless legs (Ekbom syndrome) is not associated with dopamine blockade although it is relieved by L-DOPA and dopamine agonists. Patients develop uncomfortable sensations in their legs that are relieved by walking. These sensations occur primarily at night and interfere with falling asleep but do not occur to a significant degree during the day. This syndrome has been associated with iron deficiency in some cases. Finally, tardive dyskinesia or "pseudo akathisia" can cause a constellation of fidgety looking choreic movement in which patients 23. Investigations Investigations and workup may include selected laboratorystudies, as well as imaging modalities such as CT scan,MRI, or Positron Emission Tomography (PET). Tardive blepharospasm should be evaluated withelectroencephalography(EEG)and acompleteophthalmologic evaluation, including slit-lamp examinationto rule out the Kayser-Fleischer rings of Wilson disease. In addition, the following tests may be appropriate: Thyroid function tests to exclude thyroid dysfunction Serum biochemistry, serum copper, serum ceruloplasmin,thyroid function tests, and syphilis serology to evaluate tardiveblepharospasm Connective tissue disease screening tests to excludesystemic lupus erythematosus and other vasculitides Red blood cell (RBC) counts to exclude polycythemia rubravera Serum calcium level 24. DSM IV Criteria for MIMDs 333.92 Neuroleptic Malignant Syndrome Severe muscle rigidity, elevated temperature, and other relatedfindings (e.g. diaphoresis, dysphagia, incontinence, changes in levelof consciousness ranging from confusion to coma, mutism, elevatedor labile blood pressure, elevated creatine phosphokinase [CPK])developing in association with the use of neuroleptic medication 333.7 Neuroleptic-induced Acute Dystonia Abnormal positioning or spasm of the muscles of the head, neck,limbs, or trunk developing within a few days of starting or raising thedose of a neuroleptic medication. 333.99 Neuroleptic-induced Acute Akathisia Subjective complaints of restlessness accompanied by observedmovements (e.g. fidgety movements of the legs, rocking from foodto food, pacing, or inability to sit or stand still) developing within afew weeks of starting or raising the dose of a neuroleptic medication(or after reducing a medication to treat extrapyramidal symptoms). 25. DSM IV Criteria for MIMDs contd 333.82 Neuroleptic-induced Tardive Dyskinesia Involuntary choreiform athetoid, or rhythmic movements (lasting at least a few weeks) of the tongue, jaw, or extremities developing in association with the use of neuroleptic medication for at least a few months (may be for a shorter period of time in elderly persons) 333.1 Medication-Induced Postural Tremor Fine tremor occurring during attempts to maintain a posture that develops in association with the use of medication(e.g. lithium, antidepressants, valporate) 26. DSM IV Criteria for MIMDs contd 333.90 Medication-induced Movement Disorder Not Otherwise Specified this category is for Medication Induced Movement Disorders not classified by any of the specific disorders listed above. Examples include: Parkinsonism, Acute Akathisia, Acute Dystonia, or Dyskinetic movement that is associated with a medication other than a neuroleptic A presentation that resembles neuroleptic malignant syndrome that is associatied with a meidcationother than a neuroleptic Tardive dystonia 27. Treatment Treatment modality of MIMD will be discussed under the following headlines: Biological psychological 28. Treatment - Biological Management of drug-induced movement disorders in the olderpatient requires careful consideration of the contraindicationsimposed by such agents as anticholinergics and -blockers. Atpresent, the use of second-generation antipsychotics such asclozapine, risperidone, olanzapine or quetiapine for reducing therisk of treatment-emergent movement disorders in the elderly havenot been published. However, open-label studies of atypicalantipsychotics demonstrate a markedly lower incidence of bothEPSE and TD compared with conventional antipsychotic treatmentin the elderly. Dopamine-depleting agents: the most effective medications arethose that deplete catecholamines (eg, reserpine, tetrabenazine). Atypical antipsychotics (eg, clozapine, risperidone, olanzapine)bind to dopamine D2 receptors and may improve tardive dystoniawhen lower doses are used. Recent trials have shown that they notonly may cause or aggravate tardive dystonia but ultimately mayprove to be highly useful therapeutic agents to treat dystonias.Long-term safety is not fully established for this indication. 29. Treatment Psychological Patients frequently experience adverse effects ofantipsychotics before clinical improvements ofpsychotic symptoms. High potency drugs are more likely to cause EPSEwhich can render a patient to poor compliance oftaking drugs. Hence start management of EPS by giving pre-information to patients about the drug, possibleside effects, duration, costs, and ways to minimizethese adverse effects. 30. Prognosis - overall The prognosis of patients with tardive dystonia is very poor.Unfortunately, once developed, this condition is usuallypersistent. The discontinuation of all dopamine receptor antagonists appears tobe the most important factor related to remission; patients whopermanently discontinue these agents increase their chance ofremission 4-fold compared with those patients who do not. Another factor related to remission is the total duration of dopaminereceptor antagonist therapy; patients taking dopamine receptorantagonists for less than 10 years have a 5-times higher chance ofremission than those with more than 10 years of exposure. Tardive dystonia is most likely permanent in patients who continueusing neuroleptic drugs for more than 10 years. The indication for long-term use of neuroleptic agents must be wellestablished. Patients must be evaluated repeatedly in hopes of earlydetection of tardive dystonia; once tardive dystonia is present, thecausative drug should be withdrawn if possible. If the patient is notdisabled by dyskinesia, observing and hoping for a spontaneousrecovery, rather than treating, is best. 31. Prognosis Patients who have previously experienced episodes ofneuroleptic malignant syndrome are at risk for recurrences. Therisk of neuroleptic malignant syndrome recurrence is stronglyrelated to the elapsed time between an episode of neurolepticmalignant syndrome and restarting antipsychotics. If patientsare rechallenged with antipsychotics within 2 weeks of anepisode of neuroleptic malignant syndrome, 63% will have arecurrence. If more than 2 weeks has elapsed, only 30% willhave a recurrence. 87% of patients who develop neuroleptic malignant syndromewill be able to tolerate another antipsychotic at some point in thefuture, which is very important because most patients takingneuroleptics require them to maintain a reasonable functionalstatus. Current practice is to switch to a different class ofantipsychotic when reintroducing these medications. Often, oneof the newer atypical antipsychotics is chosen because currentevidence suggests a lower incidence of neuroleptic malignant 32. Prevention Movement disorders may be aggravated by the administrationof dopamine-receptor blocking drugs. In vulnerable patients, theadministration of even a single dose of a dopamine-receptorblocking drug may lead to incapacitating movement disorders. Patients with developmental disabilities, fetal alcohol syndrome,schizophrenia, and other neuropsychiatric disorders may beexquisitely vulnerable to TD upon exposure to dopamine-receptor blocking drugs. If a patient exhibits a movementdisorder when given a drug, discontinuance of thecausative drug is generally wise. Advise the patient to avoidreceiving dopamine-receptor blocking drugs and warn againstthe administration of these drugs. In addition, advise all of the clinicians treating the patient torefrain from administering dopamine-receptor blocking drugs.Advise the patient to obtain a medical alert bracelet warningagainst the administration of dopamine-receptor blocking drugs. 33. References http://www.ncbi.nlm.nih.gov/pubmed/6627043 http://www.extrapyramidalsideeffects.com/ http://pediatrics.uchicago.edu/chiefs/documents/ExtrapyramidalSideEffects.pdf http://www.medmerits.com/index.php/article/acute_drug_induced_movement_disorders/P8 http://med.brown.edu/neurology/articles/sr55693.pdf http://emedicine.medscape.com/article/1151826-overview#a7 http://books.google.com/books?id=w_HajjMnjxwC&pg=PA735&lpg=PA735&dq=DSM+IV+333.99+criteria&source=bl&ots=i7PQbobJ1I&sig=bhwZwRtb6Mggd7sLyYozgbKpjLE&hl=en&sa=X&ei=Ceb5T_avEcL40gHv5YGEBw&ved=0CEwQ6AEwAw#v=onepage&q&f=false http://emedicine.medscape.com/article/288482-followup#a2650 Treatment of Extrapyramidal Side Effects of AntipsychoticsDrugs, Frank. A Dept of Psychiatry MUCHS