sign in sign up
<<
Home , Ioflupane (123I), Levosulpiride, Serotonin syndrome

Drug Induced Movement Disorders Dr Kigocha Okeng’o Neurophysician Muhimbili National Hospital Dar Es Salaam Tanzania Introduction 44% of patients in Ethiopia, 5.67% in India • Therapeutic and illicit drugs can cause movement disorders • and antiemetics most commonly implicated

• Severity ranges from mild to severe and life-threatening

• Early recognition of a drug-induced is essential to allow for prompt intervention

• Tadesse Misgana,1 Niguse Yigzaw,2 Getachew Asfaw3Drug-Induced Movement Disorders and Its Associated Factors Among Patients Attending Treatment at Public Hospitals in Eastern Ethiopia https://doi.org/10.2147/NDT.S261272, • Nimisha et al Prevalence and pattern of induced movement disorders in a tertiary care teaching hospital in India - a cross-sectional study, Int J Clin Pract, 2018 Jun;22(2):101-108. INTRODUCTION…

• Symptomatology is often indistinguishable from that of idiopathic movement disorders • resemble that of several other medical conditions

• Careful drug history, recognition of a DIMD may be relatively straightforward

• As with idiopathic movement disorders, and stress will also exacerbate symptoms associated with DIMDs

• Patients may develop mixed DIMDs ( more than one type of DIMD)

Jack J. Chen, Drug-Induced Movement Disorders: A Primer US Pharm. 32(11)HS16-HS32 Drug induced movement disorders Movement disorder Implicated drugs blocking drugs Selective reuptake inhibitors Antiepileptics

Tremor Selective serotonin reuptake inhibitors Antiepileptics (e.g. ) Bronchodilators Immunosuppressive drugs (tacrolimus, ciclosporin) Serotonin syndrome (usually due to overdose or Selective serotonin reuptake inhibitors combinations of serotoninergic drugs) Serotonin noradrenaline reuptake inhibitors Tricyclic antidepressants inhibitors Lithium (, , propentadol) Antiepileptics (valproate, lamotrigine) St John’s wort Drug induced movement disorders Acute dystonic reaction blocking drugs (e.g. antipsychotics, ) Selective serotonin reuptake inhibitors Dopamine receptor blocking drugs (e.g. antipsychotics) Calcium channel antagonists (e.g. , cinnarizine) Antiepileptics (e.g. phenytoin, valproate, levetiracetam) Antidepressants (e.g. selective serotonin reuptake inhibitors, monoamine oxidase inhibitors) Lithium Chemotherapeutic drugs (e.g. cystosine arabinoside, cyclophosphamide, vincristine, adriamycin, doxorubicin, paclitaxel, etoposide) Immunosuppressive drugs (e.g. ciclosporin, tacrolimus) (e.g. 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), organophosphate pesticides, manganese, , , carbon monoxide and carbon disulphide) CLASSIFICATION OF DIMD

• Acute DIMD- Occur within minutes to days of drug ingestion – Neuroleptic malignant syndrome – Serotonin syndrome – Acute – Acute akathisia & acute - parkinsonism-hyperpyrexia disorder • Chronic reversible DIMD: occur within days to weeks of drug ingestion – – Myoclonus • Chronic potentially irreversible DIMD – Tardive syndromes Akathisia

• Common, under-recognised, drug-induced movement disorder that can occur as an acute, subacute or tardive reaction • Reportedly 39% in -treated patients, 45% with first generation antipsychotics

• A sense of internal restlessness, irritability & tension without necessarily manifesting with physical signs • unlike which is typically more severe and worse at night

• predominantly affects the lower extremities from the hips to the ankles, • predilection for the lower extremities distinguishes akathisia from other antipsychotic-induced syndromes

Sahoo S., Ameen S. Acute nocturnal akathisia induced by clozapine. J. Clin. Psychopharmacol. 2007;27(2):205. Akathisia

• Occur either after starting a dopamine receptor blocker, dose escalation, or when switching to an alternative drug

• Improves following cessation of the offending drug • , beta blockers, , , and clonidine have also been used with varying efficacy and with minimal evidence Akathisia

• Pathophysiology: • imbalance between and /noradrenergic systems

• overstimulation of the locus ceruleus leading to a mismatch between the core and the shell of the nucleus accumbens

• neuroinflammation, damage to the blood barrier, and/or impaired neurogenesis Drug-induced tremor

• Typically postural, kinetic, or both • Symmetrical and occurs acutely following drug ingestion or dose escalation • Exceptions include tremor secondary to valproate, which can appear at therapeutic or during stable treatment, or, rarely, tardive tremor • Can occur secondary to many drugs, including SSRIs, lithium, tricyclic antidepressants, antiepileptics (particularly valproate), bronchodilators, amiodarone and immunosuppressives. • Parkinson’s , or hyperthyroidism, needs to be excluded Drug-induced tremor

• Exact mechanism of DIT is unknown for most that cause tremor • In most cases physiological tremor is influenced by these medications • Epinephrine- lead to tremor by peripheral mechanisms in the muscle (β-adrenergic ) • Other drugs can cause tremor by blockade of dopamine receptors in the (dopamine-blocking agents) • amiodarone causes hyperthyroidism- Management Of Drug-induced tremor

• Altering the dose, stopping the offending drug

• Switching to an alternative drug

• Should the offending drug need to be continued • discuss the risks of the adverse effects versus the benefits of continuing to ensure the patient is informed • If the drug is continued, drugs typically used for essential tremor (for example, ) can occasionally be beneficial Serotonin syndrome Serotonin Syndrome

The most misdiagnosed MD emergency

• Clinical features:

– EPS (tremor and rigidity) – Dysautonomia – Altered consciousness

• Boyer EW & Shannon M, 2005 Serotonin Syndrome

• Associated features – Myoclonus – – • Much quicker than NMS -hours rather than days Serotonin Syndrome Serotonin Syndrome

• Implies exposure to a single serotonergic agent or more • commonly, exposure to two or more drugs w/ serotonergic properties NOT JUST ANTIDEPRESSANTS • • Metoclopramide • Valproate • Lithium • • • Tramadol • Phentanyl TREATMENT

All pts (even mild forms): • Removal of causal agent • Control of agitation w/ benzodiazepines • Supportive care w/ cardiovascular stabilisation – Moderately ill: • 5-HT2A (serotonin receptor) antagonists (Tabs. 12 mg stat then 2mg every 2 hours, 50-100 mg iv) till sx are controlled – Severely ill (body temp. ≥ 41.1 ºC): • Orotracheal intubation and immediate paralysis Serotonin syndrome Acute dystonic reactions

• Commonly occur in younger patients soon after taking dopamine receptor blocking drugs, including antiemetics (e.g. metoclopramide or ), antipsychotics • Young males more susceptible to dystonic reactions

• Acute sustained dystonic spasm of craniocervical muscles is typical, • oculogyric crises, truncal spasm causing opisthotonus, or limb dystonia can also occur

• Acute laryngeal dystonia can be life-threatening due to airway obstruction and requires emergency medical care Acute dystonic reactions

• Usually within 24h after starting/increasing/switching the drug, but 50% within 48h and 90% within 5 days

• Self-limited, but stressing and life threatening if airway compromised

• Kipps et al, 2005 • Mazurek, 1991,92,96 Medications likely to induce acute dystonia

• Anticonvulsivants • Antipsychotics -carbamazepine -Typical and atypical -gabapentine • Antibiotics • Antiemetics -erythromycin -foscarnet -metoclopramide, • (H2) -ranitidine -prochlorperazine -cetirizine • Antidepressants • Recreational -cocaine -SSRIs & SNRIs Acute dystonic reactions

• Older individuals carry less risk for the development of dystonia due to diminished numbers of D2 receptors with aging

• Agents that balance dopamine blockade with muscarinic M1 receptor blockade, like atypical antipsychotics, are less likely to elicit dystonic reactions Pathophysiology of Acute dystonic reactions

• Occasionally dose related, reactions are more often idiosyncratic and unpredictable • Arise from a drug-induced: • alteration of dopaminergic-cholinergic balance in the nigrostriatum (i.e, basal ganglia) • nigrostriatal dopamine D2 receptor blockade leading to excess of striatal cholinergic output

• High-potency D2 receptor antagonists are most likely to produce an acute dystonic reaction Management Of Acute dystonic reactions

• Acute episode • Prophylaxis after acute episode - Parenteral anticholinergics - Oral anticholinergics for 4-7 days - Benztropine 1-2 mg IV or IM, and then tapper slowly repeated in 20‘ - Avoid future exposure for - Biperiden IM or scopolamine precipitating drug - Parental diazepam (2-5 mg) or • Primary prophylaxis lorazepam (1-2 mg) - Controversial - Resolves within 15-20 minutes - High risk patient: 1 week of - Prolonged use: discouraged Parkinsonism-hyperpyrexia disorder

• Known as akinetic crisis • rare but potentially fatal complication of Parkinson’s disease(PD)

• syndrome of significantly worsening parkinsonism (with or without ), hyperpyrexia, autonomic instability and elevated creatine kinase. • seen in PD patients who have reduced or stopped their antiparkinsonian drugs • precipitated by an or other metabolic disturbance Parkinsonism-hyperpyrexia disorder

• Clinical features overlap with NMS • important to exclude an underlying infection, metabolic abnormalities, or • Recovery can take hours to weeks following treatment • Management • resuming anti-parkinsonian drugs, usually via nasogastric tube because of the dysphagia resulting from severe parkinsonism • Intermittent injections or a continuous infusion may be required in moderate– severe cases Neuroleptic Malignant Syndrome (NMS)

• Incidence 0.02 to 3.2 % of patients taking neuroleptics • Life threatening neurologic emergency: mortality 8-20% • Most affected: individuals 20-50 years • Onset: – 4-14 days after the start of therapy – mean 5 days – 90% of cases within 10 days – Slow progression, full blown in hours to 1-3 days Neuroleptic Malignant Syndrome (NMS) Cardinal features – Extrapyramidal features (severe rigidity) – (temperature >38°C) – Dysautonomia: • Diaphoresis • Sialorrhea • and tachypnea (respiratory distress in 31%) • Increased or labile • Hypoxemia – Change in mental status Neuroleptic Malignant Syndrome (NMS) • Systemic and lab changes: – & renal impairment – Increased CPK (> 2000; often 15.000-20.000) – Aspiration pneumonia – Increased liver – Leucocytosis – Low serum iron – Neuroleptic Malignant Syndrome (NMS) Predisposing factors – Antidepressants – Male sex – Dehydration – Young adult – Exertion – Quick up titration – Hot weather – Parenteric neuroleptics – Hypothyroidism – Affective disorder – Hyponatremia – Catatonia – Previous brain – Lithium lesion

Jain KK, 1996; Dressler D & Benecke R, 2005 Neuroleptic Malignant Syndrome (NMS) • Responsible agents Other agents without anti D2 effect have been reported to induce – All agents with anti D2 effect are prone to induce NMS: NMS: – All neuroleptics (either typical 1% or atypical 0.2%) – Antiemetics w/ anti D2 action (metoclopramide, – Other tricyclic agents (, amytriptiline) levosulpiride) – Amine depletors () – SSRI’s () – Antihistaminics – Antidepressants w/ anti D2 action ()

Shalev A, 1986; Caroff SN, 1993; Jain KK, 1996; Biller J, 1998 Neuroleptic malignant syndrome

Mechanism • Central D2 receptor blockade in the , nigrostriatal pathways, and leads to increased muscle rigidity and tremor via extrapyramidal pathways • Removing tonic inhibition from the sympathetic • resulting sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction • A genetic mechanism underlying this process has been suggested • DRD2 gene has been associated with low density of dopamine D2 receptors in the brain, mostly on the corpus on the caudate region. Carriers of the A1 allele have a 10.5 times higher risk of developing NMS than noncarriers • Direct muscle Treatment

• Immediate cessation of causal agent (enough for mild cases) • (2.5 mg tid, followed by 5 mg tid) • Dantrolene (severe forms; blocks release of calcium from muscle); 25 mg qd, titrated to ≥ 25 mg tid followed by oral dantrolene for several weeks • Benzodiazepines • Supportive care • ICU • Rest • Force diuresis and prevent dehydration • Prevent pulmonary embolism Drug-induced Parkinsonism

• Second leading cause of parkinsonism (24-35%) • 10-15% patients treated with neuroleptics • ↑risk: women, older age • Dose dependent • Predominant features: bradykinesia and rigidity • Tardive syndromes may be associated • DAT imaging with I-123 Ioflupane useful

• Ayd ,1961; Korczyn & Goldberg, 1976; Moleman et al, 1986; Miller & Jankovic, 1989; Marsden et al, 1975 Drug-induced Parkinsonism

• Onset: - days – years after drug onset - 50-70%: 1st month - 90% in the first 3 months • 3 scenarios after drug wash-out: – 60-70% remission up to 7 weeks – Some patients: 15-18 months – Irreversible in some patients: DIP unmasks previous nigro-striatal deficit • Elderly more prone Stephen & Williamson, 1984; Hardie & Lees, 1988; Ayd, 1961; Fleming et al 1970; Klawans et al 1973 Drug-induced Parkinsonism(DIP)

• Drugs • • Common: neuroleptics • • Less common: • • antiemetics: metoclopramide • • calcium-channel blockers: flunarizine, cinnarizine • • dopamine depletors: tetrabenazine and • • SSRIs • • valproate • • lithium • • amiodarone • • cyclophosphamide, cyclosporine, cytosine arabinoside • • amphotericine B • • Not to prescribe in PD: typical plus , TREATMENT OF DIP

• Prevention, prevention, prevention – Discontinuation of offending drug if possible or decrease dose – Switch to a drug with lower risk (clozapine; ) – Levodopa \ dopamine agonists: not recommended for typical cases TREATMENT OF DIP

• Primary prophylaxis – Controversial: anticholinergics – Reasonable approach: treat those at higher risk (AIDS and needing high potency typical antipsychotics) Tardive disorders

• Occur either during exposure or within weeks of stopping a drug, present for at least one month • Minimum duration of exposure to the drug is three months, or one month in adults aged over 60 >years • Elderly females are more susceptible • Include (typically orobuccolingual), stereotypies, akathisia, dystonia (focal, segmental or generalised), myoclonus, tremor, tics, tardive parkinsonism

• Withdrawal-emergent : occur on abrupt cessation of long- term antipsychotic treatment, particularly in children. • dyskinesia improves on resuming the drug, dose can then be gradually reduced Tardive disorders

• Commonly implicated drugs: - anticholinergic agents (ex. antipsychotics Procyclidine) - antiemetics (metoclopramide - antidepressants, and prochlorperazine) anticonvulsants, antihistamines, - calcium channel antagonists decongestants (ex. with dopamine receptor blocking and properties (cinnarizine and ) flunarizine) - antimalarials, antiparkinson agents, anxiolytics, biogenic amines, mood stabilizers, Mechanism Of Tardive Dyskinesia

• Exaggerated response by dopamine receptors due to a chronic dopamine blockade specifically at the basal ganglia

• oxidative stress, GABA depletion, cholinergic deficiency, altered synaptic plasticity, neurotoxicity and defective neuroadaptive signaling Management Of Tardive disorders

• Withdrawing the offending drug • Clonazepam for myoclonus • Resuming the offending drug or changing to an • In patients with a chronic psychotic disorder clozapine is preferred • Drugs used: - , , tetrabenazine, amantadine, propranolol, antioxidants, including , vitamin B6, Ginkgo biloba, - Caution with Ginkgo biloba due to its antiplatelet effects, especially in patients taking antiplatelet drugs or anticoagulants • Botulinum injections for focal manifestations of tardive dystonia • DBS targeting the globus pallidus, highly effective in severe cases Levodopa-induced dyskinesia

• Common cause of dyskinesia in PD • Occurs due to the relationship between dopaminergic loss and the resultant response to levodopa • rather than being due to excess levodopa ingestion only

• Risk factors : ↓ age at onset of PD, ↑levodopa dose, ↓ body weight, more severe disease

• Careful history is vital in establishing a pattern to the timing and duration of dyskinesias, which can then assist in altering the levodopa dose Levodopa-induced dyskinesia

• Depending on the duration of dyskinesia- reduce levodopa dose to a lower dose which still maintains efficacy

• mild dyskinesias are often not bothersome to the individual and do not interfere with their function • change in levodopa dose may not be required

• Amantadine can a be used

• DBS for patients with late-stage disease Illicit drugs INDUCED MOVEMENT DISORDERS

• usually acute and self-limiting • Can be life-threatening • Cocaine blocks dopamine reuptake thereby increasing dopaminergic drive. • cause more widespread catecholaminergic stimulation, chronic use results in dopamine depletion, and is associated with nigral damage • MDMA cause parkinsonism and a syndrome similar to serotonin syndrome Illicit drugs and associated movement disorders Drug Movement disorder Cocaine ( and dystonia, also known as ‘crack dancing’) Stereotypies Tremor Myoclonus

Amphetamines Punding (purposeless, repetitive behaviours) Tremor Dystonia Choreoathetosis Orolingual dyskinesia

3,4-methylenedioxymethamphetamine (MDMA) Serotonin syndrome Parkinsonism

Opioids Myoclonus THANK YOU