Permanent Lithium-Induced Cerebellar Toxicity in an Elderly Patient: Case Report and Review of the Literature
Acute lithium toxicity affects the central nervous system, including the cerebellum. The cerebellar toxicity is often transient and resolves once the lithium intoxication has been treated. Although uncommon, patients can develop a long-lasting cerebellar syndrome. We present a case of persistent lithium-induced cerebellar toxicity in an elderly patient.
Case Presentation
A 66-year-old woman is admitted to a geriatric psychiatry inpatient unit for depression. She has a 10-month history of gait ataxia, scanning dysarthria, bilateral dysmetria, and dysphagia. The patient—who is right-handed—has a long history of bipolar affective disorder and had taken lithium for nearly 15 years without any adverse effects, until 10 months ago when the drug was discontinued after an incident requiring hospitalization.
At that time, the patient experienced pain in her right leg when she tried to get out of bed in the morning and she fell to the ground. She was hospitalized at a medical facility for the acute condition, presenting with gait disturbance, weakness, confusion, and prominent cerebellar symptoms including dysarthria, ataxia, dysmetria, and dysphagia. On admission to the medical hospital, laboratory testing showed a white blood cell (WBC) count of 12,400/µL. Kidney function tests revealed elevated levels of blood urea nitrogen (26 mg/dL) and creatinine (1.5 mg/dL), and her serum lithium level was 2.0 mEq/L. A urinalysis, blood cultures, and a chest radiograph did not demonstrate any evidence of infection. A computed tomography (CT) scan of the patient’s brain revealed a small focus of decreased attenuation in the left periventricular white matter, but no acute intracranial pathology. Magnetic resonance imaging (MRI) of the brain, including her cerebellum, showed no acute infarctions. A modified barium swallow study (MBSS) revealed a prolonged oral phase and significant penetration of honey thick liquids to the level of the vocal cords, but no frank aspiration. As a result of these findings, her lithium was discontinued. Results of a second WBC count and repeated kidney function tests were normal. On re-examination, the patient’s lithium level had dropped to <0.3 mEq/L. Results of thyroid function tests were normal, too, as was her level of vitamin B12.
After a 2-week stay at the medical facility, during which she did not exhibit any change or improvement in her neurologic or cerebellar symptoms, the patient was discharged to a subacute rehabilitation unit at a skilled nursing facility. She was still not receiving lithium and took no other psychotropics, including no antipsychotics. At the rehabilitation unit, she was noted to be nonambulatory, depressed, and withdrawn, with prominent signs of cerebellar dysfunction.
The patient stayed at the rehabilitation facility for 5 months before being discharged home. She continued to have depression; needed assistance with eating, ambulation, and activities of daily living; and was essentially homebound. She received follow-up care for her neurologic symptoms on an outpatient basis. Examinations included a repeat CT scan of her brain, spinal tap, MRI/magnetic resonance angiography, MBSS, and laboratory testing for paraneoplastic antibodies that might indicate an autoimmune cerebellar illness, all of which were unrevealing.
At home, the patient was apathetic, tearful, and withdrawn, and her regular primary care physician started her on citalopram 10 mg per day to treat depression. Her depressive symptoms failed to improve, and her husband requested that she be admitted to the geriatric psychiatry unit for treatment after 1 month of being at home.
An examination on admission to the geriatric psychiatry unit revealed persistent and fixed cerebellar signs and symptoms and no tremor. She had slow scanning dysarthric speech and was dysprosodic, with explosive inflections. A finger-nose-finger test demonstrated bilateral dysmetria. She had persistent gait ataxia, with a broad-based, swinging gait. The patient received a course of electroconvulsive therapy for her depression and showed improvement in her depressive symptoms. Her neurological symptoms remained unchanged, however, and she was transferred to a long-term, skilled nursing facility.
Discussion
Since lithium was popularized in 1949 as a treatment for mania, its use in treating bipolar affective disorder has remained prevalent.1 Lithium has a narrow therapeutic and safety range, with toxicity occurring only slightly above the therapeutic levels of 0.6 to 1.2 mEq/L for maintenance therapy in patients with mania and of 1 to 1.5 mEq/L for individuals with acute mania. In a study of 10,615 elderly patients in Canada, 3.9% (413) were admitted to a medical facility for lithium toxicity over a 10-year period.2
Common neurologic adverse effects of lithium use include postural fine tremor, dysphoria, memory problems, slowed reaction time, peripheral neuropathy, and irritability (Table). The most common symptom of lithium toxicity is a rapid postural/action tremor. Encephalopathy can also develop and is characterized by altered mental status, lethargy, dysarthria, ataxia, and nystagmus. Neuromuscular effects include proximal muscle weakness and axonal neuropathy (Table). Although these neurologic manifestations are usually acute and reversible, they can become chronic and irreversible. Cerebellar toxicity due to lithium intoxication has long been recognized as an uncommon but potentially irreversible consequence of lithium toxicity.3
The irreversible syndrome of cerebellar toxicity due to lithium poisoning was first described in 1972 by Von Hartitzsch and colleagues,4 observed in two patients with elevated lithium levels and acute renal failure. Since then, there have been several other cases reported in the literature.5-7 The incidence of cerebellar syndrome secondary to lithium poisoning is unknown, but it appears to be extremely rare—even after severe lithium toxicity.8 One case series suggested a 1.25% prevalence of this syndrome.7 Lithium-induced cerebellar toxicity often occurs concomitantly with an acute illness involving fever or dehydration.1 Improvement may occur in the first 6 to 12 months after stopping lithium, but further recovery after this appears to be rare and it may be irreversible in some cases.9
The pathophysiology of the condition appears to be related to significant loss of Purkinje cells in the cerebellum, with sparing of the surrounding basket cells. Astrocytosis and vacuolation of the white matter and dentate nucleus are also seen.10 Lithium may act directly and indirectly on Purkinje cell calcium homeostasis and have excitotoxic effects.11
It is difficult to predict who might develop lithium-induced neurotoxicity,1 particularly since lithium toxicity and its permanent sequelae can occur in patients without elevated serum levels of lithium. Thus, patients who present with signs of lithium toxicity yet have normal lithium levels may need their lithium doses lowered. In cases of acute lithium toxicity, the lithium must be stopped and hydration initiated. In many cases, hemodialysis is often initiated.1 If persistent neurotoxicity occurs, physical therapy, speech therapy, and rehabilitation can sometimes improve its manifestations. In a few cases, lithium treatment has been restarted without aggravating the deficits.9 In other cases, resuming lithium use worsened the cerebellar deficits.1
We presented the case of a 66-year-old woman with a diagnosis of bipolar disorder who developed acute cerebellar symptoms in the context of lithium toxicity and was found to have a serum lithium level of 2.0 mEq/L. She had presented at the emergency department with dysarthria, ataxia, dysphagia, and dysmetria. Treatment of the lithium toxicity did not resolve or improve her cerebellar symptoms. An extensive medical workup—including a spinal tap, multiple MRI scans of the brain, immunological tests, and extensive blood work—did not reveal any other likely etiology for her cerebellar symptoms. One year later, she continues to demonstrate the same persistent neurological sequelae. The differential diagnosis of cerebellar toxicity is extensive and includes vascular (strokes), infectious, endocrine, autoimmune, and drug-induced causes, among others. Other possible causes were ruled out for the case patient, and was therefore believed that she manifested permanent lithium-induced cerebellar toxicity.
Conclusions
Although uncommon, lithium toxicity can lead to a cerebellar syndrome that is not reversible. Clinicians should be aware of this risk and monitor their patients’ lithium levels closely. This is especially important in elderly patients, who can develop lithium toxicity even at so-called therapeutic lithium levels.
The author reports no relevant financial relationships.
References
1. Niethammer M, Ford B. Permanent lithium-induced cerebellar toxicity: three cases and review of literature. Mov Disord. 2007;22(4):570-573.
2. Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc. 2004;52(5):794-798.
3. Grignon S, Bruguerolle B. Cerebellar lithium toxicity: a review of recent literature and tentative pathophysiology. Therapie. 1996;51(2):101-106.
4. Von Hartitzsch B, Hoenich NA, Leigh RJ, et al. Permanent neurological sequelae despite haemodialysis for lithium intoxication. Br Med J. 1972;4(5843):757-759.
5. Donaldson IM, Cunningham J. Persisting neurologic sequelae of lithium carbonate therapy. Arch Neurol. 1983;40(12):747-751.
6. Kores B, Lader MH. Irreversible lithium neurotoxicity: an overview. Clin Neuropharmacol. 1997;20(4):283-299.
7. Nagaraja D, Taly AB, Sahu RN, Channabasavanna SM, Narayanan HS. Permanent neurological sequelae due to lithium toxicity. Clin Neurol Neurosurg. 1987;89(1):31-34.
8. Arya DK. Lithium-induced neurotoxicity at serum lithium levels within therapeutic range. Aust N Z J Psychiatry. 1996;30(6):871-873.
9. Schou M. Long-acting neurological sequelae after lithium intoxication. Acta Psychiatr Scand. 1984;70(6):594-602.
10. Peiffer J. Clinical and neuropathological aspects of long-term damage to the central nervous system after lithium medication. Arch Psychiatr Nervenkr. 1981;231(1):41-60.
11. Dixon JF, Los GV, Hokin LE. Lithium stimulates glutamate “ release” and inositol 1,4,5-trisphosphate accumulation via activation of the N-methyl-D-aspartate receptor in monkey and mouse cerebral cortex slices. Proc Natl Acad Sci U S A. 1994;91(18):8358-8362.