International Urology and Nephrology32: 147–150, 2000.© 2000Kluwer Academic Publishers. Printed in the Netherlands.

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CLINICAL PHARMACOLOGY-PHYSIOLOGY CONFERENCE

Mental illness, muscle rigidity in tremors and renal failure

Joel Rich1, Alexander Del Castillo1, Abdel Gabr1, Henrique Kallas1,Cesar Quililan1 & David T. Lowenthal21Geriatric Research, Education and Clinical Center, VA Medical Center, University of Florida College of Medicine,Gainesville, Florida, USA;2Geriatric Research, Education and Clinical Center, VA Medical Center, and Divisionof Nephrology, Hypertension and Transplantation, University of Florida College of Medicine, Gainesville, Florida,USA

Key words: Acute renal failure (ARF), Neuroleptic malignant syndrome (NMS)

Clinical presentation

A 72 year old black male with a history of psy-chiatric illness is presented to the emergency roomwith a history of progressively worsening neurolo-gical status described by the family as drooling salivaand a decrease in communication. His food and fluidintake had likewise decreased substantially over a sev-eral week period. He had been receiving for severalyears depofluphenazine (Prolixinr) 50 mg intramus-cularly every two weeks, chlorpromazine 50 mg PO atbedtime and lithium 300 mg twice daily.

In the emergency room physical exam revealed hisblood pressure to be 90/76 mm Hg, afebrile with apulse of 104 and respiratory rate of 28. He had dif-fuse skeletal muscle rigidity, minimally responsiveto noxious stimuli including sternal rub. He madeno eye contact. His plantar reflexes were diminished.His chest was clear to auscultation and percussion;his heart was regular with no murmurs rubs or gal-lops; abdomen was negative except for wall musclerigidity. Rectal exam revealed prostate to be normalin size without any blood in the stool. Initial labora-tories revealed BUN 101 mg/dl, serum creatinine 4.3mg/dl, serum sodium 156 mEq/l, chloride 117 mEq/l,potassium 5.4 mEq/l and bicarbonate 24 mEq/l; totalCPK 5032 units with an MB fraction of 6.16 nano-grams (ng) per ml (0–5 normal); Troponin 0.04 (0–0.1

normal); serum lithium 0.9 mEq/l. Urine analysisshowed a pH 5 with a specific gravity of 1.022 andmultiple granular casts. Electrocardiogram revealednormal sinus rhythm with T-wave inversion anteriorly.Neurological and nephrologic consults were obtainedto elucide the cause(s) for this neurologic-nephrologicentity.

What is the differential diagnosis for the acute renalfailure (ARF) in this patient?

Rhabdomyolysis (pigment nephropathy) seems to bea highly likely cause of the acute renal failure dueto the high CPK along with high serum creatinine.Causes of rhabdomyolysis can be traumatic or non-traumatic. The history of present illness supports anontraumatic cause of rhabdomyolysis, which appearsto be not infrequent according to Koffler et al. [1].Potential etiologies of nontraumatic rhabdomyolysisin this patient include his medication of chlorpro-mazine (Thoraziner), fluphenazine (Prolixinr), andlithium. These medications have been associated withneuroleptic malignant syndrome (NMS) of which non-traumatic rhabdomyolysis is a possible complication.In addition the patient appeared dehydrated whichwould have exacerbated the rhabdomyolysis. Otherpossible etiologies of nontraumatic rhabdomyolysisin this patient could include a viral illness, seizure

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disorder, alcohol or heroin abuse, carbon monoxidepoisoning, strenuous exercise, diabetic ketoacidosis,or thyroid storm.

Prerenal azotemia could have contributed to theARF. The most common cause of prerenal azotemiais volume depletion. The patient reportedly had poororal intake for several days prior to admission and hishematocrit, sodium, and BUN where elevated whichsupport that he was dehydrated.

Acute tubular necrosis could have contributed tothe ARF as a result of renal ischemia. This couldhave resulted from the patient possibly being in shock.The patient had a mild leukocytosis with a left shift,hypotension, tachycardia, and soon after admissiondeveloped a fever up to 37.8◦C (101.8◦F).

Intrinsic renal disease could also have contributedto the ARF. The patient had been on lithium for severalyears and there are rare case reports of lithium causingnephrotic syndrome [2].

What drugs can contribute to the ARF with thisclinical picture?

The patient was only on three medications at thetime of admission. It appears the patient had beentaking these medications for many years at a stabledosage. However, as mentioned in the differentialdiagnosis, his three medications of chlorpromazine,fluphenazine, and lithium could all have contributedto his ARF. All three can be linked to NMS, espe-cially chlorpromazine and fluphenazine [3]. Rhab-domyolysis can occur due to extensive muscle con-tractions seen in NMS. Most clinicians are aware thatlithium can cause nephrogenic diabetes insipidus butthere are also rare case reports of lithium causingnephrotic syndrome. This occurs in the clinical settingof chronic use of lithium even though the lithium levelis in the therapeutic range [2]. In addition, lithium hasbeen known to cause chronic interstitial nephritis [4].

What is NMS and how does it differ from otherneuroleptic syndromes?

First described by Delay et al., in 1960 [5], NMSis a rare yet potentially fatal idiosyncratic drug reac-tion to neuroleptic drugs. These neuroleptic drugsinclude antipsychotic agents and major tranquilizers,are among the most common prescribed medicationsespecially in the elderly. The incidence of NMS is notcertain, but estimates from 0.02–3.2% have been sug-gested in patients exposed to neuroleptics [6]. NMS

has also been associated with tricyclic antidepress-ants, carbamazepine, withdrawal of Parkinson’s med-ication (levodopa and amantadine), prochlorperazine,metaclopromide, and lithium [3]. It has been estimatedthat about 10% NMS occurs within 24 hours of firstreceiving the medication and the other 90% usuallyoccurs within 2 weeks of the medication. Howeverthere are case reports of NMS occurring months toyears after being on a neuroleptic [7].

There are no standard diagnostic criteria for NMSyet the major or cardinal symptoms of NMS are fever(T > 37.2 ◦C) and rigidity which be diffuse or loc-alized, and leadpipe or cogwheel type that occur inthe setting of a neuroleptic agent. The other minorsymptoms and signs are change in mental status, auto-nomic instability (labile blood pressure), tachycardia,tachypnea, diaphoresis, tremor, incontinence, leuk-ocytosis, elevated CPK, and metabolic acidosis [8].Some clinicians believe one needs both major and 5minor criteria to support diagnosis of NMS [9]. Typi-cally one sees the symptoms of NMS evolve over24–72 hours yet it may take up to 10 days for a patientto manifest the full syndrome [7].

The pathophysiology of NMS is not fully under-stood yet appears to involve a depletion and/or dys-regulation of dopamine in the CNS. All neurolepticsare D2 dopamine receptor antagonists. This antag-onism seems to impair dopamine transmission inthe hypothalamus, corpus striatum, corticolimbic andcorticospinal pathways that result in the myriad orsymptoms and signs. Also indirectly, the dopamineblockade may increase prostaglandin synthesis andderange calcium homeostasis effecting muscle con-traction [10].

The major complications associated with NMS arecardiovascular collapse, pulmonary embolism, aspir-ation pneumonia, respiratory failure, and ARF. Theoverall mortality from NMS ranges from 11.6–25%yet increases to nearly 50% in the setting of ARF [9].

NMS is similar to several neuroleptic conditionsyet there are noticeable differences. Incatatonia(lethal catatonia), one does not see the degree of auto-nomic instability, muscle rigidity and elevated CPK asseen in NMS. Also, the initial symptom of catatoniais usually psychotic excitement and in NMS one seesextrapyramidal-induced rigidity. In theserotonin syn-dromeone does not see the degree of muscle rigidityas seen in NMS. Also, serotonin syndrome is associ-ated with serotonin substance reuptake inhibitor, tri-cyclic antidepressant, or monoamine oxidase inhibitormedications and one typically sees NMS associated

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with neuroleptic use. Incentral anticholinergic syn-dromeone does not see the autonomic instability anddiaphoresis as seen in NMS.

What is the best treatment for this patient?

Based on his symptoms and signs, it appears hehad NMS with rhabdomyolysis induced ARF. Thefirst step should be prompt supportive care for theNMS and rhabdomyolysis. Attempts to establish cir-culatory stability should be made with isotonic salineinfusion at 2.5 to 5 mg/kg per hour [7]. This willhelp in the treatment of patient’s dehydration andARF. One should closely monitor the patient’s elec-trolytes q 4 hours (especially hypokalemia and hypo-calcemia) and urine output. One can also alkalinizethe patient’s urine with IV NaHCO3 therapy (initialdose 1 mmol/kg body wt) with a goal to achieve anarterial pH = 7.45 and use IV mannitol infusion of 1mg/kg body wt over 30 minutes. These two methodshave been shown to improve renal function and urineoutput in rhabdomyolysis induced acute renal failure[7]. Antipyretics (acetaminophen) and cooling tech-niques should be used to lower his temperature. Onecan also consider using a dopamine agonist such asropinerole (Requipr) (0.5 mg po tid) or bromocriptine(5 mg po q4–6 hrs) and/or dantrolene sodium (1 mgto 8 mg/kg per day in four divided daily doses) thatmay help diminish extrapyramidal symptoms as wellas his fever [7]. Anticholinergic medications can beconsidered as needed to relieve the patient’s musclerigidity [7].

What was his clinical course?

All neuroleptic drugs were stopped. He was treatedwith intravenous fluids and supportive care. Spinal tapwas normal but a computerized tomogram of the headdemonstrated a pattern compatible with a subacuteCVA. The urine myoglobin was negative and urineprotein was 100 mg/dl. On the third hospital day therewere 38 red cells per high power field. The total CPKhad fallen to 4090 units per liter (5–180 normal); theMB had likewise fallen to 2.9. By the third hospitalday the BUN was 37 mg/dl and the serum creatinine1.2 mg/dl. With continued fluid administration, on thefourth hospital day, the BUN was 16 and serum creat-inine 0.9 and when he was finally discharged his BUNwas 12 and serum creatinine 0.8 mg/dl. In additionto the fluid management given intravenously the urinewas alkalinized and the calculated deficit of 3.5 litersof water had been replaced. As a result the patient’s

affect became brighter and he was more interactive.He was given a trial of ropinorole (Requipr) 0.5 mg3 times daily to treat the adverse effects from the longacting neuroleptic agents. By the third hospital day thepatient was much improved and there was plan for himto be transported to the rehabilitation unit for furthertreatment.

Conclusion

We encountered an elderly male patient with a PMHof psychiatric disease who had been on neurolepticsfor many years. He then experienced an acute changein his mental status. His symptoms and signs wereconsistent with the diagnosis of NMS with rhabdomy-olysis induced ARF. This is an unusual case due tothe fact that the patient had been on neuroleptics formany years without a problem. However, it has beennoted that NMS can occur after many years on neur-oleptics. The in-depth neurological evaluation of thispatient concluded that the patient might have had atransient ischemia attack (TIA) at the time of admis-sion. The TIA along with the patient being dehydratedmay have been the precipitants that caused the patientto develop NMS after being stable on neuroleptics formany years. This shows that one needs to be vigilantabout a patient’s temperature, mental status, renaland hydration status, and monitor for rigidity whilepatients are on neuroleptics, regardless of the durationof the medication.

References

1. Koffler A, Friedler R, Massry S. Acute renal failure due tonon-traumatic rhabdomyolysis. Ann Intern Med 1976; 85:23–28.

2. Bosquet S, Descombs E, Gaother T, Fillay C et al. Nephroticsyndrome during lithium therapy. Nephrol Dial Transplant1997; 12: 27–28.

3. Jacobs L. The neuroleptic syndrome: often an unrecognizedgeriatric problem. JAGS 1996; 44: 474.

4. Boton R, Gavinia M, Battle D. Prevalence, pathogenesis, andtreatment of renal dysfunction associated with chronic lithiumtreatment. Am J Kidney Dis 1987; 10: 329–345.

5. Delay J, Pinchot P, Lemperiere T, Ellisalde B, Peijne F.Un neuroleptique majeur non phenothiazine et non reserpi-nique, l’haloperidol dans le traitement des psychosis. An MedPsychol 1960; 118: 145–152.

6. Velamoor V. Neuroleptic malignant syndrome-recognition,prevalence, and management. Drug Safety 1978; 19: 73–81.

7. Becker BN, Ismail N. the neuroleptic syndrome and acuterenal failure. J Am Soc Nephrol 1994; 4: 1406–1412.

8. Bristow MF, Kohen D. Neuroleptic malignant syndrome. Br JHosp Med 1996; 55: 517–520.

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9. Korzets Z, Zelter E, Beinhem J. Acute renal failure in thesetting of the neuroleptic malignant syndrome. Nephrol DialTransplant 1996; 11: 885–886.

10. Sciavolino C, Racco A, Lieto T, Kleiner M. Severehyponatremia. Neuroleptic malignant syndrome, rhabdomy-olysis and acute renal failure: a case report. The Mt Sinai JMed 1998; 4: 284–288.

11. Guze B, Baxler L. Current concepts-neuroleptic malignantsyndrome. N Engl J Med 1985; 313: 163–166.

Address for correspondence:David T. Lowenthal, MD, PhD, Dir-ector Geriatric Research, Education and Clinical Center (182), VAMedical Center, 1601 SW Archer Road, Gainesville, FL 32608-1197, USAPhone: (352) 374-6077; Fax: (352) 374-6142