Lithium Intoxication and Nephrogenic Diabetes Insipidus in a Bipolar Patient Case Report

CASE REPORT Lithium Intoxication and Nephrogenic Diabetes Insipidus in a Bipolar Patient Case Report Fang-Ju Tsai, Cha-Shun Wu 1, Susan Shur-Fen Gau 1,2 Department of Psychiatry, En Chu Kong Hospital, Taipei, Taiwan; Department of Psychiatry 1, National Taiwan University Hospital, Taipei, Taiwan; Department of Psychiatry 2, College of Medicine, National Taiwan University, Taipei, Taiwan ABSTRACT Nephrogenic diabetes insipidus has been reported to increase the risk for lithium intoxication. We report on a 52-year-old woman with bipolar disorder who had been treated with lithium regularly for twenty years. She had developed polyuria and polydipsia one year previously, and a depressive episode with psychotic features one month before this admission. She had not had a manic or a depressive episode for three years. Lithium was discontinued and supportive treatment was provided when lithium intoxication was diagnosed on the first day of hospitalization. Despite the disappearance of symptoms of intoxication on the 12th day of her 22 day hospitalization, she still suffered from polyuria, polydipsia, and mild cognitive impairment when she was discharged. This case report emphasizes the importance of early identification and treatment of nephrogenic diabetes insipidus and lithium intoxication in lithium-treated patients to prevent irreversible sequelae from a combination of these two conditions. (Tzu Chi Med J 2005; 17: 181-185) Key words: bipolar disorder, nephrogenic diabetes insipidus, lithium intoxication INTRODUCTION Despite solid evidence showing that lithium is effective in the acute treatment and prevention of relapse of bipolar disorder, the high probability of lithium intoxication due to its narrow safety margin has limited its long-term use in patients with bipolar disorder [1]. It has been estimated that 75% to 90% of patients under long-term maintenance therapy with lithium develop signs and symptoms of lithium intoxication at some time [2]. The manifestations of mild intoxication include fine tremor, apathy, fatigue, muscle weakness, hyperreflexia, restlessness, distractibility, increased muscle tone, and rigidity with impaired motor coordination. These symptoms might be mistaken for common side effects of lithium at a therapeutic level [1-3]. Hence, regular monitoring of the lithium level is a basic practice in psychiatric management. However, there have been several case reports of severe symptoms and signs of lithium intoxication among patients with therapeutic lithium levels, suggesting that there is not a dose-response relationship between the lithium level and the severity of symptoms [1-3]. In addition, neurological side effects are common during regular treatment. Irreversible neurological sequelae might develop after lithium intoxication [4]. In short, the lithium level may not reflect the severity of lithium intoxication [2]. Lithium administration is the most common causes of nephrogenic diabetes insipidus (NDI), which is characterized by polyuria and polydipsia due to renal insensitivity to antiuretic hormone (ADH) [5,6] Central DI, however, is due to a lack of ADH. The rates for polydipsis, polyuria, and NDI are 40%, 35%, and 5%-30%, Received: September 20, 2004, Revised: November 17, 2004, Accepted: December 29, 2004 Address reprint requests and correspondence to: Dr. Susan Shur-Fen Gau, Department of Psychiatry, National Taiwan University Hospital, 7, Chung Shan South Road, Taipei, Taiwan Tzu Chi Med J 2005 17 No. 3 NUN

F. J. Tsai, C. S. Wu, S. S. F. Gau respectively, in patients receiving lithium treatment [5, 6]. The water deprivation test is used to diagnose DI and to differentiate the nephrogenic form from the central form of DI. DI is suggested in dehydrated patients with increased serum osmolarity and decreased urine osmolarity. In NDI, the ADH level is inappropriately high. The desmopressin acetate (DDAVP) test is also used to confirm the status of DI [5]. Urine osmolarity does not increase in NDI patients when they are given ADH, but it does in central DI patients. Studies have shown that lithium-treated patients who have a negative water balance and lithium intoxication tend to have difficulty concentrating urine [2]. Therefore, early identification of NDI and lithium intoxication in lithiumtreated patients is important. We report on a patient with bipolar disorder, who developed lithium intoxication, NDI, and mild cognitive problems. To our knowledge, this is the first report of a patient with a combination of these conditions in Taiwan. CASE REPORTS This 52-year-old married woman was admitted to the inpatient psychiatric ward of a medical center in Taipei with the chief problems of increased water intake up to 1,500 ml/d over the past year and up to 2,000 ml/d for one month and manifestations of low mood, guilty feelings, low self-esteem, visual and auditory hallucinations, ideas of reference, and sleep disturbance for one month. Her daily medications prior to this admission were lithium 600 mg, propranolol 80 mg, lorazepam 1 mg, zotepine 50 mg, and estazolam 2 mg. The tentative diagnosis on admission was bipolar II disorder, with the most recent episode a depressive phase. This patient was a college graduate and had been a junior high school teacher with poor to fair functioning for 28 years until she retired at the age of 48. When she was a teacher, she often took naps during class and could not discipline her students. Her social interaction was mostly limited to her family and a few friends. She got married at the age of 30 and often quarreled with her mother-in-law. She suffered from episodic mood swings mixed with elation and low moods. She had pressured speech and sang songs continuously. Between the ages of 20 and 30, she experienced distractibility, insomnia, and social withdrawal, and had suicidal ideas, irritability, and destructive behaviors for two weeks prior to menstruation. These symptoms disappeared after the onset of menstruation. However, those episodes did not cause obvious impairment in her daily functioning. Since age 32 she has suffered from depression with clinical manifestations of low mood, suicidal thoughts, insomnia, impulsivity, and elementary auditory hallucinations. She was diagnosed with bipolar disorder, and received lithium 600 mg/d. In recent years, her lithium levels were sometimes up to the range of 1.09-1.20 meq/l. In addition, after the age of 40, she had four suicide attempts with impulsiveness under various stressors and was admitted to the psychiatric ward immediately after each attempt. She was treated with fluoxetine 20 mg/d at age 48. She received sulpiride 200-600 mg/d in addition to lithium at age 49 after a suicide attempt. Thereafter, she had been clinically stable with good drug compliance. In addition, she was diagnosed with hyperlipidemia, and hyperuricemia half a year before this admission. She received daily dipyridamole 50 mg, aspirin 100 mg, conjugated estrogenic 0.625 mg, fluvastatin 20 mg, and benzbromarone 50 mg. On admission, mental status examination revealed she spoke very little and had a drowsy consciousness level, distracted attention, restricted affect, psychomotor retardation, poverty of thought, ideas of reference, auditory and visual hallucinations, disorientation, impaired recent memory (recalling only 1 out of 3 objects) and impaired performance in the serial 7s test. Physical examination showed a masked face, dysarthria, ataxia, hand tremors, and self-reported generalized weakness. On arrival in the psychiatric ward, her vital signs did not reveal any abnormal findings (blood pressure, 102/60 mmhg; heart rate, 76 beats/min; respiratory rate, 18/min; body temperature, 36.2 C). Abnormal laboratory findings included sodium 154 mmol/l, chloride 116 Table. 1. Desmopresssin Acetate (DDAVP) Test DDAVP concentration test Urine osmolarity Serum osmolarity Na (mmol/l) K (mmol/l) Urine output 0 min 172 322 148 4.5 0 30 min 154 308 146 3.7 400 60 min 175 306 147 4.0 600 120 min 185 307 146 4.4 870 The serum sodium concentration did not increase after DDAVP 2 µg injection two hours later NUO Tzu Chi Med J 2005 17 No. 3

5,000 4,000 3,000 2,000 were up to the range of 1.09 to 1.20 meq/l in recent years. On admission, she presented moderate signs of toxicity such as drowsiness, distracted attention, psychomotor retardation, ideas of reference, auditory hallucinations, disorientation, impairment of recent memory, dysarthria, ataxia, masked face, and her subjective report of generalized weakness [2] with a lithium level of 0.74 meq/l. 1,000 Intake (cc) Output (cc) DISCUSSION 0 Fig. 1. Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 The patient had urine output above 3L/d during most of her hospitalization. mmol/l, creatine kinase 439 mmol/l, creatinine 1.4 mg/ dl, uric acid 9.9 mg/dl, triglycerides 406 mg/dl, total cholesterol 310 mg/dl, and serum osmolarity 322 osm/ kg. Complete blood count / differential count, Hb (11.1 g/dl), urinalysis, stool occult blood, and electroencephalography revealed normal findings. Despite a therapeutic lithium level (0.74 meq/l), she still presented typical signs of lithium intoxication such as delirium (disturbed consciousness with drowsiness, disorientation, ideas of reference, auditory and visual hallucinations, inatt-entiveness, and a fluctuating course), extrapyramidal syndrome, and ataxia. Lithium was discontinued immed-iately. This patient received fluid replacement therapy from hospital day 5 to day 16. She had urine output above 3 liters per day with input around 4 liters per day (Fig. 1) and was diagnosed with DI. Nephrogenic DI was diagnosed because the urine osmolarity did not increase after the DDAVP test (Table 1). Indeed, she might have had comorbid lithium intoxication, NDI, and mild dehydration. She was under intensive physical monitoring subsequently. Serum sodium became normal on hospital day 10, and the level of consciousness became clear on hospital day 12. She had stable vital signs, and was free of neurological symptoms except for hand tremors, but had persistent psychomotor retardation, episodic ideas of reference, polydipsia, polyuria, and mild cognitive problems (i.e., decreased full intelligence quotient from 106 to 84 for the past 4 years) when she was discharged after a 22 day hospitalization. In summary, this patient had several hypomanic and depressive episodes with psychotic features and was diagnosed with bipolar disorder II with depression as the most recent episode. She had received continuous lithium therapy 600 mg/d for 20 years and her lithium levels Several reports suggest that the lithium level may not be clearly related to the severity of intoxication [1-3], which was supported by observations in this case. Furthermore, some researchers have suggested that emphasis be placed on the patient s clinical status rather than the serum lithium level because there is no clearcut relationship between the serum lithium level, severity of symptoms and the patient s prognosis. This might also be explained by (1) a possible lag between the occurrence of symptoms and assay of the lithium level, or (2) delayed disappearance of symptoms of lithium intoxication despite normalization of the lithium level. The latter explanation needs further enquiry. Unfortunately, we had no information about the lithium level prior to this hospitalization. Tremor is the most common side effect of lithium. It may subside spontaneously after a decrease in the lithium dosage, or treatment with beta-adrenergic blocker drugs [4,7]. However, mild hand tremors may persist even after discontinuation of lithium [4], as in this patient. After admission, her extrapyramidal symptoms subsided. However, the presentation of extrapyramidal symptoms might also be the effects of drug-drug interaction between lithium and antipsychotics (sulpiride, zotepine, and risperidone) although there was no evidence to support a possible drug interaction. Fortunately, she did not have symptoms of irreversible cerebellar syndrome such as ataxia, which has been reported in a patient with a therapeutic lithium level [4]. There are three possible risk factors which cause lithium intoxication: a high serum lithium concentration or load, increased duration of exposure to an increased load, and decreased tolerance to the load [2]. With NDI, this patient would have been susceptible to lithium intoxication if water was not accessible. In addition, she had received combined treatment with the antipsychotic sulpiride 200 to 600 mg/d for the past three years and the antidepressant fluoxetine 20 mg/d for the past four years and this might have enhanced lithium neurotoxicity at a therapeutic level [1,2,4]. Tzu Chi Med J 2005 17 No. 3 NUP

F. J. Tsai, C. S. Wu, S. S. F. Gau Lithium might have some interaction with Selective Serotonin Reuptake Inhibitor (SSRI) due to possible increased lithium concentrations and/or an increased risk of SSRI-related serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes) [4]. This patient did not have symptoms of serotonin syndrome. Her age and mild cognitive problems may have been other factors explaining lithium toxicity [2]. In addition, a lithium-induced reduced renal concentrating ability might have increased the risk of intoxication. Although more data obtained from follow-up are necessary to understand the underlying mechanism of her cognitive problems, the findings in this case study provide evidence to support permanent deficits in recent memory following lithium intoxication [4,8] and neurological sequelae after lithium intoxication such as dementia [4,9]. Simply put, this patient might have comorbid conditions for her presentation of delirium. On admission, she might have had a mild electrolyte imbalance (sodium 154 mmol/l, chloride 116 mmol/l). After fluid replacement treatment, the serum sodium became normal on hospital day 10. Another possible contribution to delirium could be GI bleeding, but there was no evidence of this (such as anemia, coffee ground or bloody emesis, melena or hematochexia, hypotension, tachycardia, decreased pulse rate) in this patient despite her marginal Hb level (11.1 g/dl). Furthermore, she might have had mild dehydration due to polyuria and suspected poor water intake, but she did not have dry skin or shock on admission. During hospitalization, her clinical condition improved with fluid replacement therapy, one of the standard treatments for lithium intoxication. Accordingly, although we cannot completely exclude the possibility of a comorbid condition for delirium, lithium intoxication was probably the main cause of delirium in this patient. This patient would have been susceptible to lithium intoxication for the following reasons: long term antipsychotic medication exposure, her age, mild cognitive problems, lithium-induced reduced renal concentrating ability, acute water loss (such as polyuria) without increased water intake, a high serum lithium concentration or load, and increased duration of exposure to an increased load. Treatment of lithium intoxication involves supportive treatment and an immediate decrease in the lithium load. This patient received fluid replacement therapy on hospital day 5 to day 16 and her urine output was above 2 ml/kg/hr. Supportive treatment stabilized her clinical condition effectively. This patient had complained of thirst, nocturia, and increased urine output in the range of 3 to 18 liters per day. Laboratory findings revealed low urine specific gravity (1.005), low urine osmolarity (200 mosm/kg), and high serum osmolarity (300 mosm/kg). Based on these findings, we suspected DI initially [5] and the diagnosis of NDI was confirmed by the evidence provided by the results of the DDAVP test. ADH cannot increase water permeability among patients with NDI despite the presence of an adequate osmotic gradient. An assessment for DI should be done in patients with polyuria. According to the algorithm for the diagnosis of DI, Adam (1997) suggested that a water deprivation test is indicated when patients have polyuria (24 hour urine output >30 ml/kg/d), polydypsia, nocturia, urine specific gravity <1.005 and urine osmolarity < 200 mosm/kg, and a normal fasting glucose. A slight elevation in urine osmolarity, a urine-to-serum osmolarity less than 1, ADH greater than 5 pg per ml, and an increased urine osmolarity below 50 percent after ADH is given are diagnostic criteria for NDI [5]. Renal disease, sickle cell disease, myeloma, sarcoidosis, a decreased potassium level, an increased calcium level, and medications are also possible underlying causes [5]. The etiologies of NDI include genetic factors, which are inherited as an X-linked trait; exposure to drugs such as lithium, demeclocycline and methoflurane; metabolic problems; renal disease and idiopathic causes [5]. Exposure to lithium is the most common cause of acquired NDI. Most studies have confirmed that lithium can inhibit the activation of ADH-sensitive adenylate cyclase, resulting in decreasing intracellular cyclic AMP formation [6]. Although most cases of lithium-induced NDI resolve within three weeks following discontinuation of lithium, persistent NDI has also been documented [2]. The risk factors for persistent impairment are a long duration of lithium treatment, high average serum lithium level, and total lithium dose [2]. The signs and symptoms associated with NDI usually disappear after discontinuing lithium but they can last up to one year [2]. In conclusion, findings in this case report have implied that (1) intensive monitoring of the lithium level should be employed among patients on long-term treatment because it is not easy to detect the signs and symptoms of mild or even moderate lithium intoxication; (2) early intervention is important because lithium intoxication might cause irreversible neurological sequelae; (3) lithium-induced NDI might increase the likelihood of vulnerability to lithium intoxication and should be diagnosed and treated early; and (4) the first steps in treating a patient with lithium intoxication are to discontinue lithium immediately and to give supportive treatment. NUQ Tzu Chi Med J 2005 17 No. 3

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