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Dyskinesia-Hyperpyrexia Syndrome in
Parkinson’s Disease: A Heat Shock–Related
Emergency?
Marianna Sarchioto, MD,
1,2
Valeria Ricchi, MD,
3
Marta Melis, MD,
1,2
Marcello Deriu, MD,
4
Roberta Arca, MD,
1
Maurizio Melis, MD,
1
Francesca Morgante, MD, PhD,
5
Giovanni Cossu, MD
1,
*
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).
1–5
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
38–40C, 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 42C, he had leucocytosis (14,200 per mm
3
), iperCKemia
(16,040 U/L), elevated liver enzymes (aspartate aminotransfer-
ase = 389 U/L; alanine aminotransferase = 450 U/L), renal fail-
ure (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 pra-
mipexole 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 pneu-
monia and renal failure. Switching to meropenem and colistine
antibiotic therapy was unsuccessful. Laboratory investigations
revealed 18,100 leukocytes, creatinine = 3.78 mg/dL, myoglo-
bin > 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.
1
Neurology Service and Stroke Unit, AO Brotzu Hospital, Cagliari, Italy;
2
Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy;
3
Neurology Service, Sirai Hospital Carbonia, Italy;
4
Neurology Service, Nostra Signora della Mercede Hospital, S. Gavino Monreale, Italy;
5
Institute of Molecular and
Clinical Sciences, St George’s University of London, London, United Kingdom
*Correspondence to: Dr. Giovanni Cossu, Neurology Service and Stroke Unit, AO Brotzu Hospital, P.le Ricchi, 1, 09134 Cagliari, Sardinia, Italy;
E-mail: giovannicossu1@gmail.com
Keywords: Parkinson’s disease, levodopa/carbidopa intestinal gel, dyskinesia, hyperpirexia, heat.
Relevant disclosures and conflicts of interest are listed at the end of this article.
Received 6 March 2018; revised 9 July 2018; accepted 12 July 2018.
Published online 3 October 2018 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mdc3.12663
534 MOVEMENT DISORDERS CLINICAL PRACTICE 2018; 5(5): 534–537. doi: 10.1002/mdc3.12663
© 2018 International Parkinson and Movement Disorder Society
CASE SERIES
CLINICAL PRACTICE
Case 2
(July 2016, First Decade, External Temperature
36–38C, 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 mini-
mal 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 cloza-
pine 25 mg/day). At day 3 after the onset of fever, her tempera-
ture reached 41C 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 respi-
ratory distress and tachycardia. Her blood test revealed severe
dehydration, leukocytosis (18,000/mm
3
), 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
38–40C, Max Average Temperature 33)
A 79-year-old woman with a 30-year history of PD was success-
fully treated with LCIG (1,250 mg/day) for 9 years because of dis-
abling 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 39.5Candshehad
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.
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.
MOVEMENT DISORDERS CLINICAL PRACTICE 2018; 5(5): 534–537. doi: 10.1002/mdc3.12663 535
M. SARCHIOTO ET AL. CASE SERIES
Chest x-rays, blood, and urine cultures were negative. She was
hydrated with 5% dextrose solution (2,000 mL/day), treated with
ceftriaxone2g/day,andLCIGdosewasprogressivelyreduced
(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 asso-
ciated 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, interrup-
tion of DBS, traumatic injury, and infectious or gastrointestinal
diseases. PD patients experiencing Parkinsonism-hyperpyrexia syn-
drome develop severe akinetic state with transient unresponsive-
ness to dopaminergic treatment.
DHS is a poorly described and under-reported acute compli-
cation in PD patients with an opposite clinical spectrum (dyski-
nesia), but under similar precipitating systemic factors (infectious
diseases, trauma, and dehydration). In all reported cases,
1–5
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 fea-
ture of DHS is the relationship with high ambient temperature,
described in a patient with recurrent DHS over three summers
2
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 demon-
strated 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 con-
tribute 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 32C, systemic injection of apo-
morphine fails to elicit any significant fall in core tempera-
tures.
7
Furthermore, rats exposed to heat stress (ambient
temperature = 45 ± 0.5C) demonstrate a significant increase
of dopamine and glutamate in the systemic circulation and
hypothalamus, along with signs of hypothalamic inflamma-
tion.
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 dopaminer-
gic 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:Weconfirm that we have
read the Journal’spositiononissuesinvolvedinethicalpublica-
tion and affirm that this work is consistent with those guide-
lines. 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.
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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.
MOVEMENT DISORDERS CLINICAL PRACTICE 2018; 5(5): 534–537. doi: 10.1002/mdc3.12663 537
M. SARCHIOTO ET AL. CASE SERIES
