Abstract
We report a patient with neuroleptic malignant syndrome (NMS) who developed acute renal failure and was successfully treated by hemodialysis. A 60-year-old man with a 26-year history of schizophrenia had been treated with thioridazine and sulpiride. He was admitted to our hospital for muscular rigidity and oliguria. After the diagnosis of NMS with acute renal failure was established, thioridazine and sulpiride were discontinued and hemodialysis was instituted. Renal function gradually improved and hemodialysis was discontinued after 17th treatment. We also reviewed 57 cases of NMS with acute renal failure reported in the literature. To our knowledge, 26 years is the longest latency between initiation of neuroleptic drug treatment and onset of NMS. Our review of reported NMS cases with acute renal failure identified those risks for poor prognosis as high level of BUN, age and female gender.
INTRODUCTION
Neuroleptic malignant syndrome (NMS) was defined as “the most serious but also the rarest known complication of neuroleptic chemotherapy.” by Delay et al. in 1968.Citation[[1]] However, NMS is known to cause many complications, the most serious being renal failure,Citation[[2]] which occurs in 16% of the cases.Citation[[3]] Over the past several years, several groups reported cases of NMS however, there is no review of NMS-related acute renal failure. Here we report a case of acute renal failure complicating NMS, and review 57 reported cases of NMS with acute renal failure.
CASE REPORT
A 60-year-old man with a 26-year history of schizophrenia had been treated with 200 mg/day thioridazine and 200 mg/day sulpiride orally since June 1973. He had no past history of abnormal urinalysis or renal dysfunction. Family history was negative. Subsequently, he suddenly developed muscular rigidity and oliguria and was admitted to our hospital on January 29, 1999 for further management.
On admission, arterial blood pressure was 134/78 mmHg, and pulse was 78 bpm. Body temperature was 38.0°C. Chest and abdominal examinations were not remarkable and no anemia or icterus was evident. Tremor was observed in the upper extremities. Neurological examination showed weakness of the muscles of lower extremities and muscular rigidity of the upper extremities. No signs of meningeal involvement or pathological reflex were found. Biochemical data showed high serum GOT (1539 IU/L), LDH (3489 IU/L), myoglobin (19 000 ng/mL), CPK (164 620 mg/dL), UA (17.3 mg/dL), potassium (6.13 mEq/L), creatinine (15.69 mg/dL) and BUN (129.3 mg/dL). Arterial blood gas analysis under room air showed PaO2 of 86.0 mmHg, PaCO2 of 32.5 mmHg, and pH 7.271. Urinalysis could not be performed because of anuria on admission.
A diagnosis of NMS was made based on treatment with neuroleptic drugs, fever, extrapyramidal signs and elevated CPK level. Thioridazine and sulpiride were discontinued following the diagnosis of NMS. Since anuria persisted and the level of serum creatinine increased to 15.69 mg/dL, hemodialysis was commenced 2 days after hospitalization and was performed almost on a daily basis. Urinary output resumed on day 18 and renal function gradually improved. Hemodialysis was discontinued after 17th treatment, 25 days after hospitalization. All laboratory tests returned to normal levels during recovery, and the patient was discharged from the hospital 53 days after admission.
DISCUSSION
We reported here a 60-year-old man with schizophrenia treated with thioridazine and sulpiride for 26 years, who developed NMS-related acute renal failure, and reviewed 57 cases of NMS with acute renal failure.
Since various types of drugs are used for the treatment of psychiatric disorders, it is important to identify those drugs that are commonly associated with NMS. The majority of cases with NMS complicated with acute renal failure were treated by a single or combined treatment of haloperidol. This finding was not different to those patients with NMS who had no acute renal failure. Thirty-seven of 57 (65%) cases received more than two neuroleptic drugs. To our knowledge, our patient is the first case with NMS-related acute renal failure treated with thioridazine and sulpiride.
To establish a correct diagnosis of NMS, it is also important to know the exact time of development of NMS during treatment of psychiatric disorders. The duration of neuroleptic therapy prior to onset of NMS varied considerably. About half of cases developed NMS within one week of treatment and 85% cases within one month, however, four cases (8%) developed NMS more than one year after the induction of therapy. Since development of NMS at 26 years after the start of neuroleptic drug therapy in our patient is the longest reported duration, it is important to exclude other diseases causing rhabdomyolysis characterized by elevation of CPK and serum myoglobin. In our case, no other condition known to cause rhabdomyolysis and NMS could be identified. Our case suggests that any patient taking any neuroleptic drugs may develop NMS at any time.
The mean, maximum, and minimum levels of serum CPK, BUN, Cr, and myoglobin, and urinary myoglobin varied widely in reported cases of NMS-related acute renal failure (). Acute renal failure in NMS is generally considered to be the result of rhabdomyolysis and myoglobinemia,Citation[[4]] although renal failure is not always accompanied by rhabdomyolysis. Hydration and hypotension may also induce circulatory insufficiency, leading to acute renal failure.Citation[[2]], Citation[[3]] CPK, serum myoglobin, and urine myoglobin were elevated in almost all reported cases, but among the 57 cases, 2 had normal serum level of CPK; in one case the level of serum myoglobin was normal, and in the other the level of urine myoglobin was normal. Comparison of laboratory data between NMS patients with and without acute renal failure revealed a greater rise of CPK, serum myoglobin, and urine myoglobin in NMS with acute renal failure than in NMS without acute renal failure. In the review of Kellam,Citation[[5]] among 90 cases of NMS, CPK was 100–999 IU/L in 45 (50%) cases, 1000–9999 IU/L in 31 (34%) cases, and > 10 000 IU/L in 14 (16%) cases. In comparison, among patients of NMS with acute renal failure reviewed in the present study, CPK was 100–999 IU/L in 8 (15%) cases, 1000–9999 IU/L in 15 (27%) cases, and > 10 000 IU/L in 32 (58%) cases. Because there is a strong relationship between CPK level and the severity of NMS,Citation[[3]] acute renal failure may develop when NMS is more severe; i.e., high CPK levels.
Table 1. Laboratory Findings
Eleven (21%) of 52 cases with NMS-related acute renal failure died during hospitalization. This rate is lower than 56% and 50% previously reported by Shalev et al.Citation[[6]] and Teo et al.,Citation[[7]] respectively. While it is difficult to explain the differences of mortality in these reports, early application of dialysis as well as other dialysis techniques may improve prognosis in such patients. Further studies aimed at identifying those factors that could predict prognosis of patients with NMS-related acute renal failure are important.
We also compared the clinical features of patients with good and poor prognosis using paired Student's t-test (). Such analysis showed significantly high BUN levels in the poor-prognosis group compared to good-prognosis group (p < 0.01). The rise in BUN may not only be due to renal failure but also to increased protein catabolism and dehydration, which should be reflected on the general condition of the patient compared to CPK and Cr. Our analysis also showed a significant difference between the two groups with regard to age; the mean age of patients who died as a result of acute renal failure was 55.5 ± 12.2 years compared to 42.1 ± 11.9 years in the alive group (p<0.01). Furthermore, the mortality rate was higher among women (30%) than men (16%). Although our patient showed some poor prognosis factors; high level of BUN and old age, hemodialysis treatment was introduced in the early stages of acute renal failure, which probably explains the improved prognosis.
Table 2. Laboratory Findings in Patients with NMS-Related Acute Renal Failure with Good (Alive Patients) and Poor (Deceased Patients) Prognosis
CONCLUSION
Though the development of renal failure in NMS confers a poor prognosis, early and aggressive treatment should improve the prognosis and lower the mortality rate. Physicians should always pay attention to the early signs of acute renal failure in NMS; correct diagnosis and prompt treatment are essential for good prognosis.
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