Parkinsonism hyperpyrexia syndrome

Parkinsonism hyperpyrexia syndrome (PHS), otherwise known as neuroleptic malignant-like syndrome, akinetic crisis, or dopaminergic malignant syndrome, is a rare, potentially fatal complication of Parkinson's disease. It is characterised clinically by hyperthermia, autonomic dysfunction, altered level of consciousness, muscle rigidity, and increased serum creatine phosphokinase (CPK) levels. The syndrome is most frequently triggered by the withdrawal or sudden dose reduction of antiparkinsonian drugs. Favourable outcomes require timely diagnosis and appropriate treatment (with levodopa and dopamine agonists).

Clinical case

The patient was a 60-year-old man with an 8-year history of Parkinson's disease, and associated dyslipidaemia; he was receiving pramipexole at 2.1 mg/day, levodopa at 800 mg/day, rasagiline at 1 mg/day, and simvastatin at 20 mg/day. Family members brought the patient to the emergency department due to a 6-day history of fever (reaching 39 °C), sleepiness, disorientation in time and space, visual hallucinations, increased limb rigidity, and increased tremor and bradykinesia, which caused gait instability and frequent falls. Because of these symptoms, the patient was considerably limited in many activities of daily living. One week prior to admission, the patient decided to stop taking all medication, including antiparkinsonian drugs, following symptoms of depression. Physical examination showed a fever of 38.5 °C; pronounced rigidity in all 4 limbs, scoring 3/4 on the Unified Parkinson's Disease Rating Scale (UPDRS); resting and postural tremor in both hands; and generalised bradykinesia (finger taps, foot taps, pronation-supination, leg agility), scoring 3/4 on the UPDRS. Examination of the abdomen and thorax yielded normal results. The patient was admitted to the emergency department, where studies were performed to analyse the fever of unknown origin, and empirical treatment was administered. A complete blood count revealed mild leukocytosis (11 300 leukocytes/mm³) and high levels of CPK (5000 IU/L); urine analysis, thoracic radiography, and urine and blood cultures all returned normal results. Transoesophageal echocardiography was performed due to suspicion of endocarditis, with no findings. Despite treatment, all initial symptoms persisted. At this point, the neurology department was asked to assess the patient. Upon observing that infection had been ruled out, and suspecting PHS, neurologists decided to restart dopaminergic medication at the original, pre-admission dose. Two days thereafter, rigidity, bradykinesia, and the patient's level of consciousness improved significantly, and fever resolved. The diagnostic suspicion of PHS was confirmed by the positive response to treatment; the patient was discharged several days later.

Discussion

PHS occurs in patients with Parkinson's disease who suddenly withdraw or reduce doses of antiparkinsonian drugs, particularly levodopa. The condition was first described in 1981.¹ The syndrome has also been reported in patients with Lewy body dementia following withdrawal of cholinesterase inhibitors,² amantadine,³ and subthalamic deep brain stimulation.⁴ Other precipitating factors include co-prescription of neuroleptics, dehydration, very hot climates,⁵ and the wearing-off phenomenon.

The syndrome typically manifests with rigidity, fever, altered level of consciousness, and autonomic dysfunction, with onset usually occurring between 18 hours and 7 days after the withdrawal of dopaminergic drugs. After 72 to 96 hours, patients usually develop fever (the most frequent symptom) due to impaired dopaminergic transmission in the lateral hypothalamus, which is essential in controlling heat dissipation. Rhabdomyolysis increases CPK levels, which also contributes to fever due to the release of pyrogens from skeletal muscle; these substances stimulate the hypothalamic region responsible for thermoregulation.⁶

Rigidity, the main cause of disability, is caused by central dopaminergic hypofunction in the nigrostriatal pathway due to the increased release of calcium from the sarcoplasmic reticulum of the skeletal muscle. Patients may also experience altered levels of consciousness due to dopaminergic hypofunction in the mesocortical pathway.⁶

Autonomic dysfunction may manifest as tachycardia, labile blood pressure, and diaphoresis. These symptoms result from suppressed central dopaminergic activity, changes in central/peripheral sympathetic discharge, and alterations in central serotonin metabolism.⁷

Blood analysis may reveal mild leukocytosis, high CPK levels (although this is not a necessary condition for diagnosis), and abnormal levels of liver enzymes. The literature also includes reports of reduced levels of homovanillic acid (a dopamine metabolite) in the cerebrospinal fluid of patients undergoing sudden withdrawal of dopaminergic drugs.⁸

The main condition to be considered in the differential diagnosis of PHS is neuroleptic malignant syndrome; the main difference is that the latter is induced by exposure to dopamine receptor blockers. Other conditions to be considered are serotonin syndrome,⁹ malignant hyperthermia,¹⁰ malignant catatonia,¹¹ and dyskinesia-hyperpyrexia syndrome.¹²

The most common complications of PHS are respiratory insufficiency, sepsis, seizures, disseminated intravascular coagulation, and renal insufficiency; the latter 2 complications indicate poor prognosis. The condition has a mortality rate of 10%-30%, with prognostic markers including advanced age, high Hoehn and Yahr scale score, and the absence of the wearing-off phenomenon prior to onset.⁵

The main approach for treating PHS is promptly resuming the dopaminergic drug, either orally or by nasogastric tube; if these options are not viable, apomorphine may be administered.⁵ Dantrolene is another alternative if the patient presents high CPK levels and a risk of renal insufficiency, or if rigidity causes respiratory failure. Some authors have reported treatment with electroconvulsive therapy¹³ and steroid pulse therapy.¹⁴

These patients often require intensive care with respiratory support and central venous pressure monitoring; antipyretics, water replacement, and physical measures are also recommended in patients presenting hyperthermia.

Funding

The authors have received no private or public funding for this case report.