Inflammation as a Bridge Between Rhabdomyolysis and Acute Kidney Injury in Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS) is a rare but potentially fatal condition associated with dopamine D2 receptor antagonism. It manifests as hyperthermia, generalized rigidity, autonomic instability, and altered consciousness. Rhabdomyolysis is a frequent complication and can lead to AKI, although not in all cases. Emerging evidence suggests that inflammation may act as a critical co-factor in precipitating AKI following rhabdomyolysis. We report a case of a 23-year-old woman with NMS induced by risperidone and later carbamazepine, in whom AKI developed only during the second episode when complicated by systemic inflammation due to aspiration pneumonia. This case underscores the critical role of inflammation in bridging rhabdomyolysis and AKI.

A 23-year-old woman underwent craniotomy for treatment of a third ventricular tumor. Postoperatively, the patient developed hydrocephalus necessitating ventriculoperitoneal shunt placement and was diagnosed with panhypopituitarism for which hormone replacement therapies were initiated. After being transferred to a rehabilitation hospital, she developed a persistent high fever and a marked elevation in creatine kinase (CK) levels, leading to readmission to our university hospital on day -20. From day 1, she exhibited severe generalised rigidity, with her body temperature rising to 41·5 °C and her heart rate reaching 156 bpm. Laboratory findings included a WBC count of 12,800/μL, platelet count of 191,000/μL, serum sodium of 161 mEq/L, potassium of 3·0 mEq/L, creatinine of 0·51 mg/dL, and C-reactive protein (CRP) of 0·76 mg/dL. CK levels spiked to 66,529 IU/L and myoglobinuria was prominently observed; however, renal function remained largely preserved. Blood and urine cultures were negative, and cerebrospinal fluid findings were normal. As a result, a diagnosis of neuroleptic malignant syndrome (NMS)(1) associated with rhabdomyolysis due to risperidone was made and dantrolene therapy (60 mg/day) was initiated on day 6, resulting in significant reductions in body temperature and CK levels. Dantrolene could be gradually tapered and discontinued. Although the patient was transferred back to the rehabilitation hospital on day 59, the patient exhibited uncontrollable agitation, leading to the administration of carbamazepine. This was followed by high fever and circulatory shock, prompting readmission to our hospital on day 61. Her clinical presentation, including fever, tachycardia, generalized rigidity, altered consciousness, and agitation, was similar to that of previous episodes. Laboratory findings revealed a WBC count of 15,300/μL, platelet count of 38,000/μL, serum sodium of 106·3 mEq/L, potassium of 6·4 mEq/L, creatinine of 2·34 mg/dL, CRP of 8·13 mg/dL, and procalcitonin levels exceeding 100 ng/mL. CK levels peaked at 91,192 IU/L, with a strongly positive urinary myoglobin level. Blood and urine cultures were negative; however, chest computed tomography (CT) showed pronounced findings consistent with pneumonia. This was diagnosed as a recurrence of NMS triggered by carbamazepine administration and complicated by aspiration pneumonia. Endotracheal intubation was performed, and treatment was initiated with dantrolene re-administration on day 61, rapid fluid resuscitation, and antibiotics. Subsequently, the patient exhibited marked defervescence, resolution of pneumonia, recovery from acute kidney injury (AKI). In contrast to the first episode, she suffered from AKI induced by rhabdomyolysis and myoglobinuria during the second admission. Subsequently, systemic inflammation associated with aspiration pneumonia recurred, but renal function remained normal in the absence of rhabdomyolysis.

This case represents a valuable example demonstrating that inflammation caused by pneumonia modified the drug-induced adverse event of neuroleptic malignant syndrome (NMS)(1), triggering acute kidney injury (AKI). Despite significant rhabdomyolysis and myoglobinuria, AKI did not develop during the first NMS episode. However, during the second episode, in addition to pronounced rhabdomyolysis and myoglobinuria, the patient presented with AKI and hyperkalaemia. This represents a key pathological difference from the first episode, and it is highly likely that the systemic inflammation associated with aspiration pneumonia contributed to this outcome. Although drug induced rhabdomyolysis does not frequently lead to AKI, the exact reason remains unclear. In contrast, in crush syndrome, muscle damage and ischaemia-reperfusion injury cause localized inflammation in the muscles, which subsequently propagates systemically. This systemic inflammation is recognized as a factor that accelerates AKI in addition to myoglobinaemia (2).  Our research using a crush syndrome animal model has demonstrated that not only systemic inflammation, but also intraperitoneal inflammation and the phenomenon of macrophage extracellular traps (METs) are critical factors that promote the development of AKI following rhabdomyolysis (3). The present case aligns with our hypothesis that, although rhabdomyolysis is severe, AKI does not develop in the absence of systemic inflammation (4).  AKI occurs only when inflammation is superimposed. Risk factors for AKI in the context of NMS or drug-induced rhabdomyolysis have been proposed, including genetic predisposition, severity, and dehydration(5); however, the detailed mechanisms remain poorly understood. Our hypothesis that coexisting inflammation may act as a trigger or accelerator of AKI in patients with NMS warrants further investigation. Furthermore, identifying the clinical settings in which AKI develops in other cases of drug-induced rhabdomyolysis is another crucial area for future research.

References １．Wijdicks EFM et al. Neuroleptic Malignant Syndrome. N Engl J Med. 2024;391(12):1130-1138 ２．Tu H et al. Li YL. Inflammation balance in skeletal muscle damage and repair. Front Immunol. 2023;14:1133355. ３. Okubo K et al. Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury. Nat Med. 2018;24(2):232-238. ４．Miyauchi H et al. Multiple site inflammation and acute kidney injury in crush syndrome. Front Pharmacol. 2024;15:1458997.  ５．Modi S et al. Neuroleptic Malignant Syndrome: Complications, Outcomes, and Mortality. Neurocrit Care. 2016;24(1):97-103. 

This report illustrates the pivotal role of systemic inflammation in mediating AKI during drug-induced rhabdomyolysis. Clinicians should be alert to inflammatory triggers such as pneumonia in managing NMS and consider them as co-factors in AKI development. Further studies are needed to elucidate inflammatory mechanisms underlying AKI in this context.