Neuroleptic malignant-like syndrome causing thrombocytopaenia: a rare association

Abstract

Neuroleptic malignant-like syndrome is a rare but potentially fatal complication of sudden withdrawal of dopaminergic drugs. Clinical features are similar to that of neuroleptic malignant syndrome (NMS) like hyperthermia, autonomic dysfunction, altered sensorium, muscle rigidity; but instead of history of neuroleptic use, there is history of withdrawal of dopaminergic drugs. Laboratory examination generally show elevated creatine phosphokinase levels and may show elevated total leucocyte count. Thrombocytopaenia has been very rarely reported with NMS but it has not been reported with NM-like syndrome. Here, we discuss a case of Parkinson’s disease which presented with typical clinical features and risk factors of NM-like syndrome associated with thrombocytopaenia and type 1 respiratory failure. He was treated with bromocriptine and supportive care. Thrombocytopaenia and respiratory failure resolved with above treatment. The patient improved clinically and was successfully discharged on day 12 of admission.

Background

Neuroleptic malignant-like syndrome or parkinsonism hyperpyrexia syndrome is a rare but potentially fatal complication of sudden withdrawal of anti-Parkinson medication.^1–3 Clinical features are similar to neuroleptic malignant syndrome (NMS) like hyperthermia, autonomic dysfunction, altered sensorium, muscle rigidity and increased serum creatine phosphokinase (CPK) levels.^{4 5} These may be complicated by acute renal failure, aspiration pneumonia, deep vein thrombosis and disseminated intravenous coagulation.^{5 6} Thrombocytopaenia in absence of disseminated intravascular coagulation has rarely been reported with NMS,^{7 8} but its association with NM-like syndrome has not been reported. Here, we present a case of Parkinson’s disease with NM-like syndrome associated with thrombocytopaenia along with type 1 respiratory failure and also narrate the likely pathophysiological mechanism.

Case presentation

A 62-year-old-man, known case of hypertension (on telmisartan and hydrochlorothiazide) since 8 years and Parkinson’s disease (on levodopa, carbidopa, amantadine, entacapone, rasagiline, pramipexole) since 10 years, presented with raised body temperature since 3 days, muscle rigidity since 2 days and altered sensorium since 1 day. He had one episode of generalised tonic-clonic seizure on the morning of presentation. There is also history of non-compliance to therapy since 3 days prior to admission when he was on a tour in the peak of summers during which he purportedly drank very little fluids. There was no history of cough, burning micturition, rash, headache, photophobia or active bleeding manifestation. On examination, the patient was in state of altered sensorium with Glasgow Coma Scale (GCS) of 7, blood pressure of 165/95 mm Hg, pulse rate of 110/min. He had generalised rigidity with bilateral mute bilateral planter reflex. Rest of the systemic examination was normal. He was intubated on arrival for airway protection.

Investigations

On evaluation, the patient was found to have thrombocytopaenia (platelet count 21x10⁹/L), hyponatraemia (serum sodium 115 mEq/L), deranged renal function (creatinine of 1.5 g/dL) and elevated serum CPK levels (4375 IU/L). Urine examination with chest radiograph was normal with sterile blood and urine cultures.

Differential diagnosis

He had hyperthermia, muscle rigidity, altered mental status and elevated CPK. Since there was no history of intake of neuroleptics but discontinuation of dopaminergic drugs a diagnosis of NM-like syndrome was considered. He was found to have fluctuating blood pressure and heart rate suggestive of autonomic dysfunction and also had type 1 respiratory failure.

Treatment

All the anti-Parkinson medications were reintroduced. Hydration was maintained with intravenous fluids and temperature by cold sponging while continuing ventilatory support.

Bromocriptine (17.5 mg in four divided doses) was added 36 hours after initiation of therapy when encephalopathy and respiratory failure did not improve to the above treatment.

Outcome and follow-up

Hyponatraemia and renal functions improved after adequate hydration. The patient improved gradually; there was reduction in rigidity, improvement of GCS to E₄V_1tM₆, reduction in CPK levels and resolution of hypoxia (table 1). The patient was successfully extubated on day 4 of admission and later weaned off oxygen. Contrast-enhanced CT of chest was done for evaluation of respiratory compromise but was normal. Thrombocytopaenia also improved gradually after starting treatment of NM-like syndrome without any specific intervention. The patient was discharged on day 12 of admission in haemodynamically stable condition.

Table 1.

Serial laboratory parameters

	Day 1	Day 4	Day 6	Day 10
CPK (IU/L)	4376	1280	926	640
Platelet (per liter)	21 x 109	50 x 109	100 x 109	111 x 109
WCC (per liter)	9x 109	15 .4x 109	7.4x 109	7.6x 109
Urea (mg/dL)	31	52	23	26
Creatinine (mg/dL)	1.3	1.1	0.7	0.8
Sodium (mEq/L)	115	130	128	132
P/F ratio*	373	321	348	368
A-a gradient† (mm Hg)	283	71	41	29.7

*PaO₂/FiO₂-ratio of PaO₂ of arterial oxygen to fractional inspired oxygen.

†Alveolar-arterial gradient-difference between alveolar and arterial concentration of oxygen.

CPK, creatine phosphokinase; WCC, white cell count.

Discussion

NMS is a life-threatening illness with clinical features of altered mental status, rigidity, fever and dysautonomia associated with use of typical and atypical neuroleptic drugs.^{9 10} It occurs due to blockage of D2 dopamine receptors by these drugs. Dopamine receptor blockage in hypothalamus causes hyperthermia and autonomic dysfunction; while that in nigrostriatal pathways causes rigidity and tremors.¹¹ Similar disease can also occur in a patient with Parkinson’s disease due to sudden withdrawal of anti-Parkinson dopaminergic drugs and is called NM-like syndrome.^1–3 It is believed to have better prognosis than NMS.³ The most common risk factor for NM-like syndrome is sudden withdrawal of dopaminergic drugs but other contributing factors are reportedly similar to NMS which include dehydration, physical exhaustion, exposure to heat, hyponatraemia, alcohol, psychoactive substances and presence of a structural or functional brain disorder such as encephalitis, tumour, delirium or dementia.^{12 13}

NM-like syndrome is diagnosed by presence of typical clinical features and associated sudden withdrawal of dopaminergic drugs in absence of other possible cause. Creatine kinase levels are elevated (generally more than 1000 IU/L) which signify muscle injury but may be normal.¹⁴ Brain CT or MRI and lumbar puncture may be required to exclude alternate diagnosis.¹² Leucocytosis is the only frequent abnormality in haemogram although rarely thrombocytopaenia has been reported with NMS.^{7 8} However, thrombocytopaenia has yet not been reported with NM-like syndrome.

Mechanism of thrombocytopaenia in NMS is unclear. Human platelets express D3 and D5 dopamine receptors.¹⁵ In vitro studies have demonstrated that effect of dopamine on platelet aggregation depends on its concentration; low-dose potentiates platelet aggregation while high concentration inhibits thrombin-induced platelet aggregation.¹⁶ In vitro study done by Emerson et al to assess the effect of dopamine on platelet aggregation in cerebral and pulmonary circulation showed that in cerebral circulation dopamine potentiates thrombin-induced platelet aggregation at lower dose but inhibits it in higher dose, while in pulmonary circulation dopamine reduces platelet accumulation in higher dose but has no effect at lower dose.¹⁷

Case described above had parkinsonism and had developed NM-like syndrome after sudden discontinuation of anti-Parkinson drugs. He had risk factors like dehydration, physical exhaustion, exposure to heat and hyponatraemia. Apart from altered sensorium due to presumed encephalopathy, he also had thrombocytopaenia and type 1 respiratory failure. Respiratory compromise including pulmonary oedema and acute respiratory distress syndrome have been reported in NMS, with aspiration as possible cause.^{18 19} But cause of the same in case described above is not clear. Thrombocytopaenia and hypoxia improved gradually as underlying NM-like syndrome was treated, probably implicating NM-like syndrome to be the cause of both these abnormalities. We hypothesise that thrombocytopaenia in peripheral blood is due to accumulation and aggregation of platelet in cerebral and pulmonary circulation. Platelet aggregation in pulmonary circulation with resultant ventilation perfusion mismatch was the cause of hypoxia. The prompt reversal of thrombocytopaenia and type 1 respiratory failure with dopaminergic drugs would further support our hypothesis.

Learning points.

• A patient with Parkinson’s disease with clinical features of altered mental status, rigidity, fever and dysautonomia; neuroleptic malignant syndrome (NMS) should be suspected. In patient without history of neuroleptics but that of sudden withdrawal of dopaminergic drugs diagnosis of NM-like syndrome should be considered.

• NM-like syndrome can lead to respiratory failure and thrombocytopaenia, probably due to intravascular aggregation of platelets. Other causes of thrombocytopaenia should be ruled out before attributing it to NM-like syndrome.

• Thrombocytopaenia associated with NM-like syndrome does not require any specific therapy and responds well with treatment of NM-like syndrome. Likewise type 1 respiratory failure also responds to dopaminergic drugs along with supportive care.