Drug-Induced Parkinsonism

Case Presentation

History of Present Illness: A 35-year-old male patient with no known significant past medical history presents to the ED complaining of palpitations after using an illicit substance. He is admitted to the hospital for persistent altered mental status and elevated serum troponin (i.e., NSTEMI). Three days after hospital admission, he is noted to have a flat affect along with increased tone; a medical toxicology consultation is requested by the medical team. Past Medical History: None

Medications: None

Social History: Admits to using “K2”; denies using other substances including ethanol or smoking cigarettes

ED Vital Signs: BP, 120/84; HR, 108 beats/min; RR, 18 breaths/minute; T, 35.6 degrees C; O2 Sat, 99% (RA); Point of care glucose, 119 mg/dL

ED Physical Examination: HEENT Normocephalic, atraumatic Pupils Equal, round, reactive to light CV Tachycardia, no murmurs rubs or gallops Lungs No distress, normal effort Abdomen Soft, non-tender, normal bowel sounds MSK No gross deformities Neurological Alert to person, place, and time Psychiatric Flat affect Skin Warm, diaphoretic, intact

Initial Laboratory Testing, Imaging and Diagnostic Testing:

High Sensitivity Troponin: 200.20 ng/L (normal reference range: 0.00-36.0 ng/L) ECG: Sinus tachycardia, rate of 126 bpm, QT 322 ms, no ST elevations or T wave inversions

Hospital Course

The patient was admitted to the hospital for an elevated serum troponin after reportedly recently using a suspected synthetic cannabinoid and presenting to the emergency department complaining of palpitations. He denied chest pain or shortness of breath. He was noted to have a flat affect and this persisted during his initial hospital stay. His serum troponin decreased to 15 ng/L and his initial tachycardia improved. A medical toxicology consultation was requested due to his flat affect and increased muscle tone of both his upper and lower extremities that were noted on hospital day three. His inpatient vital signs and physical examination at the time of medical toxicology consultation are listed below.

Inpatient Vital Signs: BP, 150/103; HR, 95 beats/min; RR, 20 breaths/minute; T, 36.4 degrees C; O2 Sat, 97% (RA)

Inpatient Physical Exam:

Constitutional Flat affect, alert, oriented x3, slow to respond but answering questions appropriately Eyes: PEERL, no nystagmus noted ENT: Moist mucous membranes CV: Regular rate/rhythm, no murmurs rubs or gallops Abdomen: Normal bowel sounds, non-tender, no palpable bladder Skin: Diaphoretic forehead, no rash noted MSK: Holding bilateral upper extremities at flexed position at elbows approximately 90 degrees. Neuro: Bilateral upper extremities held in flexion at 90 degrees but able to flex/extend elbow without rigidity; no clonus; gait - slow and small steps without broad based shuffle; orientated to person, place, and time Psych evidence: Flat affect, logical content of thoughts, paucity of language with responses; no of visual or auditory hallucinations

The patient’s chart and outside medical records were reviewed; he only had one other previous visit for agitation in the setting of suspected synthetic cannabinoid use. The patient was shelter- domiciled and denied any other medical history. Psychiatry, neurology and medical toxicology were consulted. After multiple weeks in the hospital, the patient had improvement in his affect along with gait. His MRI several days after admission showed: Mild symmetric diffusion abnormality involving the bilateral caudate. While this may be partially artifactual secondary to technique, underlying toxic/metabolic abnormality is not excluded, especially given patient's reported history. The patient was eventually discharged from the hospital back to his shelter. Based on his clinical course in the hospital and absence of any other identifiable etiology, the patient was diagnosed with Drug-Induced Parkinsonism (DIP).

Discussion

DIP is caused by changes to dopamine in the brain’s nigrostriatal pathway. Dopamine is a neurotransmitter derived from tyrosine. Tyrosine is converted by tyrosine hydroxylase to dopa which is then converted by aromatic L-amino acid decarboxylase, undergoing decarboxylation, to dopamine. 1, 5, 9

Tyrosine hydroxylase Aromatic L-amino acid decarboxylase Tyrosine Dopa Dopamine

There are two types of dopamine receptors in the brain, D1-like receptors (D1 and D5), and dopamine D2-like receptors (D2, D3, D4). These receptors are coupled to G proteins and are found throughout the brain but are highly present in the basal ganglia and limbic system. Dopamine is released from presynaptic neurons and interacts with the postsynaptic D2 receptor. It is theorized that too much dopamine in the mesolimbic area is responsible for the positive symptoms (e.g., hallucinations, psychosis, delusions, paranoia) of schizophrenia while the negative manifestations (e.g., apathy, anhedonia, and cognitive blunting) are the result of too little dopamine in the mesocortical areas of the brain. While 60% of postsynaptic D2 blockade by antipsychotics is efficacious in decreasing the positive symptoms of schizophrenia, more than 80% postsynaptic D2 blockade results in in a variety of extrapyramidal syndromes (EPS). These include DIP from D2 blockade in the nigrostriatal dopamine pathway; other EPS from dopamine deficiency include akathisia and dystonia. It is presumed that neuroleptic malignant syndrome is also related to dopamine blockade or abrupt dopamine withdrawal in the nigrostriatal pathway and elsewhere.

Meanwhile acute hyperactivity in the nigrostriatal pathway results in dyskinesias and rarely, when the D2 receptors are chronically blocked for a prolonged period of time, they are upregulated as the brain attempts to overcome the blockade resulting in tardive dyskinesia. Drug-Induced Parkinsonism and other EPS are typically thought to be due to the previously described dopamine antagonism, however, it should be noted that drugs which cause dopamine depletion (e.g., reserpine, tetrabenazine) can also lead to these effects. 1, 9, 10

The occurrence of EPS is modified and reduced by muscarinic M1 cholinergic blockade and serotonin 5HT2A antagonism. Drugs with additional antimuscarinic activity (e.g., first-generation conventional antipsychotics like chlorpromazine and thioridazine) produce less EPS. It is also the reason why antimuscarinic agents like benztropine and diphenhydramine are used to treat DIP and dystonic reactions.

The newer atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, risperidone, ziprasidone) produce less EPS and less hyperprolactinemia because they modulate serotonin receptors. Serotonin regulates dopamine release and antagonism of 5HT2A receptors ultimately allows more dopamine to be available in the striatal and tuberinfundibular dopamine pathways. Partial 5HT1A agonism, a trait some antipsychotic agents possess (e.g., aripiprazole, clozapine, quetiapine) to a meaningful degree, also increases dopamine in the striatal area. Stahl characterizes 5HT2A blockade as “releasing the brakes on dopamine release” and 5HT1A agonism as “stepping on the accelerator” for dopamine release.9

Drug-Induced Parkinsonism is often difficult to differentiate from Parkinson’s Disease (PD) itself. Both conditions exhibit a resting tremor (less often exhibited in DIP), paucity of movement with loss of arm swing with walking, rigidity, and an expressionless face (i.e., masked facies). Drug-Induced Parkinsonism is usually symmetric while in PD, one side of the body is usually affected more than the other. The onset of symptoms usually occurs within one month of drug exposure with DIP; sometimes after only one dose. Interestingly non-motor symptoms like hyposmia (loss of smell) and sleep disturbances occur more often in PD. Therefore, it is important to obtain a thorough medication history in these patients. In general, DIP is treated by stopping the offending substance (which should have been recently started or had a recent dosage increase) or treating with an antimuscarinic drug like benztropine or diphenhydramine. Some reports indicate that 10-50% of patients may still have motor symptoms even after drug cessation. This is most likely to occur in patients with undiagnosed PD who already have decreases in dopamine stores. There are also rare cases in which the dopamine containing cells in the basal ganglia have been destroyed by a xenobiotic. 1, 5, 11

Symptom/Treatment Drug-Induced Parkinsonism Parkinson’s Disease Resting Tremor + ++ Rigidity ++ ++ Loss of arm swing with ++ ++ ambulation Expressionless face ++ ++ Non-motor symptoms + ++ (Anosmia, constipation, urinary and sexual dysfunction) Reversibility ++ 0 Table 1. Comparison of Drug-Induced Parkinsonism to Parkinson’s Disease11,12

The development of irreversible DIP been associated with the contaminants in a substance and not the actual substance itself. In the late 1970s and early 1980’s, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) was a contaminant identified in clandestine laboratories attempting

to synthesize meperidine. This contaminant was converted in the brain by the enzyme monoamine oxidase B (MAO-B) to N-methyl-4-phenylpyridinium (MPP+) and resulted in dopamine depletion in the striatum. Consequently, a Parkinson’s Disease-like condition of cogwheel rigidity, shuffling gait and pill rolling tremor occurred in several people. This particular pathophysiology was elucidated when use of the MAO-B inhibitor selegiline as pretreatment in a nonhuman primate model of MPTP-induced PD, prevented the formation of MPP+ and protected against the development of PD. People who used this contaminated drug were found to have significant degeneration in the substantia nigra which was severe and irreversible; death was reported in a few cases. 3, 9

Xenobiotics Associated with Drug-Induced Parkinsonism

Typical antipsychotics and some atypical antipsychotics

Metoclopramide Prochlorperazine Reserpine

Tetrabenazine

Cocaine (suggested)

Phenytoin, valproate (rare)

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+) from MPTP (protoxin and contaminant) Lithium (rare) Table 2. Xenobiotics associated with DIP. Most agents are believed to be causes of DIP due to either dopamine antagonism or dopamine depletion. A few of the rare causes (e.g., phenytoin, valproic acid and lithium) have unclear mechanisms.1, 2, 4, 5, 6, 12, 13

Our patient stated he used “K2,” an illicit substance known to have contained various synthetic cannabinoids. Synthetic cannabinoids are laboratory created substances sprayed onto plant material and can individually differ in chemical structure. Although there was no confirmatory testing sent for this patient, his symptoms resolved with “K2” discontinuation in the hospital. Synthetic cannabinoids have been associated with the development of neurologic symptoms including seizures, ischemic cerebrovascular accidents, and hallucinations. They have also been associated with tachycardia and myocardial infarctions. This patient had an elevated troponin (but not a myocardial infarction) and tachycardia. It is possible that the patient used a synthetic cannabinoid xenobiotic alone or more probably in addition to a xenobiotic with dopamine blocking activity, but without formal confirmatory testing, this is merely conjecture. 7, 8

This case highlights the thorough medical work-up required to diagnose DIP and the significant complexity of the pathogenesis of DIP.

References

1. Shin, H. W., & Chung, S. J. (2012). Drug-induced parkinsonism. Journal of clinical neurology (Seoul, Korea), 8(1), 15–21. https://doi.org/10.3988/jcn.2012.8.1.15 2. Lowe, T. L., Cohen, D. J., Detlor, J., Kremenitzer, M. W., & Shaywitz, B. A. (1982). Stimulant medications precipitate Tourette's syndrome. JAMA, 247(8), 1168–1169. 3. Langston, J. W., Ballard, P., Tetrud, J. W., & Irwin, I. (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science (New York, N.Y.), 219(4587), 979–980. https://doi.org/10.1126/science.6823561 4. Hermida AP, et al. A case of lithium-induced parkinsonism presenting with typical motor symptoms of Parkinson’s disease in a bipolar patient. Int Psychogeriatr. 2016;28:2101– 2104 5. Curry S.C., & O’Connor A.D., & Graeme K.A., & Min Kang A.A. (2019). Neurotransmitters and neuromodulators. Nelson L.S., & Howland M, & Lewin N.A., & Smith S.W., & Goldfrank L.R., & Hoffman R.S.(Eds.), Goldfrank's Toxicologic Emergencies, 11e. McGraw-Hill. https://accessemergencymedicine-mhmedical- com.ezproxy.med.nyu.edu/content.aspx?bookid=2569§ionid=210258698 6. Stephen, P. J., & Williamson, J. (1984). Drug-induced parkinsonism in the elderly. Lancet (London, England), 2(8411), 1082–1083. https://doi- org.ezproxy.med.nyu.edu/10.1016/s0140-6736(84)91516-2 https://www.cdc.gov/mmwr/preview/mmwrhtml/00000360.htm 7. Robert J. Tait, David Caldicott, David Mountain, Simon L. Hill & Simon Lenton (2016) A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment, Clinical Toxicology, 54:1, 1-13, DOI: 10.3109/15563650.2015.1110590 https://health.ny.gov/professionals/narcotic/synthetic_cannabinoids/ 8. Le Boisselier R, Alexandre J, Lelong-Boulouard V, Debruyne D. Focus on cannabinoids and synthetic cannabinoids. Clin Pharmacol Ther. 2017 Feb;101(2):220-229. doi: 10.1002/cpt.563. Epub 2016 Dec 20. PMID: 27861784. 9. Stahl, Stephan M. “Antipsychotic Agents.” Stahl's Essential Psychopharmacology, 4th ed., Cambridge University Press, 2013, pp. 129–238. 10. Aminoff M.J. (2017). Pharmacologic management of parkinsonism & other movement disorders. Katzung B.G.(Ed.), Basic & Clinical Pharmacology, 14e. McGraw- Hill. https://accessmedicine-mhmedical- com.ezproxy.med.nyu.edu/content.aspx?bookid=2249§ionid=175219763 11. https://www.parkinsons.org.uk/sites/default/files/2018- 09/FS38%20Drug%20induced%20parkinsonism_0.pdf 12. Blanchet P, Kivenko V. Drug-induced parkinsonism: diagnosis and management. Journal of Parkinsonism and Restless Legs Syndrome. 2016:83–91.

13. Dhopesh VP, Yagnik PM, Weddington WW. Can cocaine abuse cause parkinsonism? Am J Addict. 1997 Spring;6(2):177-9. PMID: 9134080.