Dyskinesia‐Hyperpyrexia Syndrome in Parkinson's Disease: A Heat Shock–Related Emergency?

Dyskinesia hyperpyrexia syndrome (DHS) has been reported as a medical emergency in patients with advanced Parkinson's disease (PD). The few previously published cases have emphasized the role of high dopaminergic daily dose and complex concomitant polytherapy as a risk factor for DHS. We report three patients with advanced PD and Levodopa‐Carbidopa intestinal gel (LCIG) who developed DHS during a seasonal heatwave. In this context of climate warming, advanced PD patients, especially when treated with high dopaminergic daily dose (i.e. under LCIG), are a cohort at risk for DHS. In the event of heatwaves, onset of fever and appearance/worsening of severe dyskinesia must be evaluated with the utmost care in order to prevent a DHS emergency in PD.

Nonphysiological dopaminergic stimulation can cause Dyskinesia‐Hyperpyrexia syndrome (DHS), a rare medical emergency associated with Parkinson's Disease (PD).1, 2, 3, 4, 5 DHS is characterized by severe continuous dyskinesia, rhabdomyolysis, and hyperthermia that may progress to mental state alteration, renal and cardiac failure, and death. Here, we report on 3 patients with advanced PD and optimal control of motor fluctuations under levodopa‐carbidopa intestinal gel (LCIG) infusion. They all developed DHS during summer heatwaves (Fig. S1).

Case 1 (July 2015, Second Decade, External Temperature 38–40°C, Max Average Temperature ≥34°)

A 77‐year‐old man with a 17‐year history of PD underwent LCIG infusion in 2012 because of severe motor fluctuations. Before LCIG, he had mild dyskinesia, which did not worsen after the infusion. He also suffered from orthostatic hypotension and hyperhidrosis episodes. In the year preceding DHS, motor fluctuations had been fully controlled with LCIG (1,500 mg/day) and dyskinesia were minimal (UPDRS IV, items 32–33 = 2). His treatment also included pramipexole (1.05 mg/day), amantadine (200 mg/day), and sertraline (50 mg/day). During a heatwave in July 2015, at age 80, he developed severe continuous generalized choreodystonic dyskinesia (UPDRS IV_32–33 = 8) followed by confusion and lethargy.

At admission in the intensive care unit (ICU), his temperature was 42°C, he had leucocytosis (14,200 per mm³), iperCKemia (16,040 U/L), elevated liver enzymes (aspartate aminotransferase = 389 U/L; alanine aminotransferase = 450 U/L), renal failure (creatine = 2.1 mg/dL), and high plasma osmolality (309 mEq/L). He had increased C‐reactive protein (6.8 mg/dL; normal value, < 0.3) and procalcitonin (4.1 ng/mL; normal value, < 0.5). A total body CT scan revealed cholecystitis and pericholecystic effusion. Cerebrospinal fluid examination was negative, including bacteriological cultures.

Treatment was started with intravenous fluids, antipyretics, and antibiotic (piperacilline and tazobactam). Because of severe diurnal continuous dyskinesia persisting at a milder intensity when stopping the infusion at night, LCIG was tapered and pramipexole was gradually suspended (Table 1; Fig. S1). This action did not produce remission of dyskinesia. His clinical conditions worsened over the following days because of right basal pneumonia and renal failure. Switching to meropenem and colistine antibiotic therapy was unsuccessful. Laboratory investigations revealed 18,100 leukocytes, creatinine = 3.78 mg/dL, myoglobin > 900 ng/mL, and creatinine kinase (CK) = 2,747 U/L. He died of multiple organ failure at 5 days after being admitted to the hospital.

Table 1.

Clinical features of our cases with dyskinesia‐hyperpyrexia syndrome and previously reported cases

Case	Age/ Sex	Season	PD Duration (Years)	Suspected Trigger	Medication (Daily Dose)	Treatment	Outcome
Case 1	80/M	Summer	17	Infection/summer heatwave	LCIG = 1,500 mg Pramipexole = 1 mg Amantadine = 200 mg Sertraline = 50 mg	Pramipexole and AMA withdrawn LCIG dose reduction = 700 mg Antibiotics	Death
Case 2	76/F	Summer	18	Infection/summer heatwave	LCIG = 1,200 mg Pramipexole = 1 mg Clozapine = 25 mg Venlafaxine = 75 mg Zolpidem = 10 mg	Antibiotics	Death
Case 3	79/F	Summer	30	Infection/summer heatwave	LCIG = 1,250 mg	LCIG reduction (675 mg) Rehydration Antibiotics	Recovered
Gil‐Navarro et al., 2010	68/F	NA	12	NA	Levodopa = 750 mg Pramipexole = 4 mg Amantadine = 200 mg	Pramipexole tapered off Quetiapine 25 mg	Recovered
Taguchi et al., 2015	70/F	Fall	13	Drug change (pramipexole IR→ER)	Levodopa = 600 mg Pramipexole = 3 mg Selegiline = 5 mg	Reduction of dopaminergic drugs	Recovered
Herreros‐Rodriguez et al., 2016	83/F	Three consecutive summers	25	Summer heatwave	Levodopa = NA	LCIG = 1,310 mg	Recovered
Acebrón Sánchez‐ Herrera et al., 2017	66/F	Summer	16	Trauma/recent medication change (ropinirole for RLS)	LCIG = 1,450 mg Amantadine = 200 mg Ropinirole = 8 mg Safinamide = 100 mg	LCIG reduced Amantadine, ropinirole and safinamide stopped Midazolam i.v.	Recovered
Baek et al., 2017	74/F	Spring	23	Trauma (rib fracture)	Levodopa = 375 mg Amantadine = 200 mg Pramipexole = 1 mg	Pramipexole stopped l‐dopa reduced to 300 mg	Recovered

ER, extended release; F, female; IR, immediate release; i.v., intravenous; LCIG, levodopa‐carbidopa intestinal gel; M, male; NA, not available; PD, Parkinson's disease.

Case 2 (July 2016, First Decade, External Temperature 36–38°C, Max Average Temperature ≥34°)

On July 2016, a 76‐year‐old woman with advanced PD and chronic ischemic heart disease developed a fever (38°) requiring antibiotic treatment. Over the year preceding DHS, she had been treated with LCIG (1,200 mg/day), pramipexole (1.05 mg/day), venlafaxine (75 mg/day), and zolpidem (10 mg/day). LCIG provided full control of motor fluctuations and minimal dyskinesia occurring for few hours in the evening (UPDRS IV_32–33 = 1). She also suffered from orthostatic hypotension and nocturnal visual hallucinations (successfully treated with clozapine 25 mg/day). At day 3 after the onset of fever, her temperature reached 41°C and she developed uncontrollable continuous dyskinesia persisting also at night and causing admission to the ICU. At examination, she had stupor and severe generalized choreodystonic dyskinesia (UPDRS IV_32–33 = 8) with only a mild bilateral akinetic‐rigid syndrome. She also had severe respiratory distress and tachycardia. Her blood test revealed severe dehydration, leukocytosis (18,000/mm³), hyperCKemia (2,967 U/L), and hypernatremia (160 mEq/L). Later that day, she developed acute pulmonary edema and died, before any change in her PD medications would have been done.

Case 3 (August 2017, First Decade, External Temperature 38–40°C, Max Average Temperature ≥33°)

A 79‐year‐old woman with a 30‐year history of PD was successfully treated with LCIG (1,250 mg/day) for 9 years because of disabling motor fluctuations. She also suffered from postprandial orthostatic hypotension. Her UPDRS IV_32–33 on LGCI was 2 because of mild dyskinesia affecting facial muscles, especially in the evening. She was hospitalized on August 2017 because of a 4‐day history of fever associated with pharyngodynia, hyporexia, dehydration, and generalized severe choreodystonic dyskinesia. Involuntary movements mildly persisted also at night. She had two febrile episodes in the previous 2 months, successfully treated with antibiotics. At admission, her temperature was 39.5°C and she had the following laboratory findings: 11,900 leucocytes, CK = 1,967 U/L, creatinine = 1.97 mg/dL, serum sodium = 159 mEq/L, C‐reactive protein = 3.1 mg/dL, and procalcitonin = 2.3 ng/mL. Chest x‐rays, blood, and urine cultures were negative. She was hydrated with 5% dextrose solution (2,000 mL/day), treated with ceftriaxone 2 g/day, and LCIG dose was progressively reduced (around 50%), because of severe dyskinesia (UPDRS IV_32–33 = 8). Over the following days, body temperature, CK levels, serum creatinine, sodium, and kidney function returned to normal levels. Severity of dyskinesia was also greatly reduced (UPDRS IV_32–33 = 2). She was discharged after 6 days of hospitalization.

Discussion

PD patients may experience severe acute complications often associated to change of their medications or systemic diseases. The most common described emergency is Parkinsonism‐hyperpyrexia syndrome (also known as acute akinesia),6 which may be caused by dopaminergic drugs withdrawal or abrupt reduction, interruption of DBS, traumatic injury, and infectious or gastrointestinal diseases. PD patients experiencing Parkinsonism‐hyperpyrexia syndrome develop severe akinetic state with transient unresponsiveness to dopaminergic treatment.

DHS is a poorly described and under‐reported acute complication in PD patients with an opposite clinical spectrum (dyskinesia), but under similar precipitating systemic factors (infectious diseases, trauma, and dehydration). In all reported cases,1, 2, 3, 4, 5 including ours (Table 1, n = 8 patients), DHS occurred in patients with long duration PD and was associated with a trigger event. Most of the subjects were treated with high doses of dopaminergic drugs (half of them with LCIG). A distinctive feature of DHS is the relationship with high ambient temperature, described in a patient with recurrent DHS over three summers2 and in our 3 cases. All our patients, suffering from DHS during summer, showed the same sequence of clinical‐pathological events: sustained hyperthermia and impaired thermoregulation, dehydration, dyskinesia, rhabdomyolysis, and alteration of mental state. In all cases, ambient temperature was much higher than the seasonal average. A clear source of infection was only demonstrated in case 1 from our series, pointing out the additional role of other factors for DHS, such as impaired thermoregulation and dehydration.

Considering the few data available on this rare emergency, we can just speculate on a pathophysiological mechanism for DHS. Here, we propose that DHS is a multifactorial phenomenon in which hyperpyrexia (caused by systemic diseases or trauma), high ambient temperature, and impaired thermoregulation (further worsened by dehydration during summer heatwaves) may contribute to full development of the clinical picture. In addition, a high daily dose of l‐dopa, as used in advanced PD under LCIG, might sustain this vicious circle.

Preclinical studies have suggested that ambient temperature strongly influences dopaminergic transmission and dopamine receptor sensitivity. Over 32°C, systemic injection of apomorphine fails to elicit any significant fall in core temperatures.7 Furthermore, rats exposed to heat stress (ambient temperature = 45 ± 0.5°C) demonstrate a significant increase of dopamine and glutamate in the systemic circulation and hypothalamus, along with signs of hypothalamic inflammation.8 Moreover, abnormal thermoregulation,9 which is part of the spectrum of dysautonomia in PD, might trigger DHS, further enhancing the effect of high ambient temperature on dopaminergic receptors. This hypothesis is further supported by the presence of autonomic impairment in our cohort of PD patients with DHS.

Exposure to high ambient temperature is a natural risk that continues to increase with the rising of global temperature, and 30% of the world population is currently exposed to potentially deadly heat for 20 days or more per year.10 In the context of global climate warming, PD patients with a long disease duration and a high daily dopaminergic dose should be considered a high‐risk cohort for DHS. We suggest that, over heatwaves, onset of fever and appearance/worsening of severe dyskinesia should be a red flag for DHS. Timely treatment with rehydration, antipyretic measures, and circulatory support, together with a reduction of antiparkinsonian drugs, might be crucial for a favourable outcome.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

M.S.: 1B, 1C, 3A

M.M., M.D., R.A., M.M.: 1C, 3B

F.M.: 1B, 3B

G.C.: 1A, 1B, 1C, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. We also guarantee that patients or their legal representatives have given their consent to anonymously report their clinical reports in accordance with current ethical standards.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: F.M. declares the following: consultancies with Medtronic, Merz, and Bial; honoraria from UCB Pharma, Medtronic, Chiesi, AbbVie, Bial, Merz, and Zambon; and royalties from Springer.

Supporting information

Supporting information may be found in the online version of this article.

FIG. S1. UPDRS items 32 and 33 for dyskinesia in each of the 3 reported patients, before dyskinesia‐hyperpyrexia syndrome (T0), at the time of dyskinesia‐hyperpyrexia syndrome (T1), and after recovering from it (T2; only in patient 3 who survived). Cutaneous temperature (CT), ambient temperature (AT), and levodopa and daily dosage of and levodopa‐carbidopa intestinal gel (LCIG) are shown.