Disabling Parkinsonism following brief exposure to lithium carbonate in amyotrophic lateral sclerosis

Abstract

We report on a 46-year-old male patient affected by amyotrophic lateral sclerosis (ALS) with bulbar onset. His family and medical history was not relevant. In February 2008, a paper published by Fornai et al. [3] suggested that daily lithium administration at a serum level of 0.4–0.8 mEq/L delays ALS progression in both the animal model and in patients. The patient asked to try this new therapy and lithium was prescribed for compassionate use 4 years after disease onset. On neurological examination we found mild atrophy and fasciculations of the tongue, severe dysarthria, and mild dysphagia. Jaw jerk and glabellar tap were absent. Light lower limb muscle weakness, rare diffused fasciculations, and normal muscle tone were detected. Reflexes were brisk in the lower limbs. Babinski sign was bilaterally found. Functional status was good (ALS-FRS 34/40). The patient started lithium assumption at very low dose (150 mg lithium carbonate/day) for 1 week and then increased to 300 mg/day. Lithium blood level was tested every 2 weeks in order to keep it at the lower therapeutic range (0.3 mEq/L). Associated medications were riluzole 100 mg/day, a-tocopherol 900 mg/day, trihexyphenidyl 4 mg/day (symptomatic of sialorrhea). There was no history of additional medication such as antidepressants or antipsychotics, thiazide diuretics, NSAIDS, or ACE inhibitors. Three months later, the patient began to complain of gait instability and frequent falling. Neurological examination showed festinating gait, diffuse bradykinesia, severe stiffness, and positive cogwheel phenomenon both in the upper and lower limbs. No lithium-induced postural tremor was detected. The lithium value was 0.31 mEq/L, and blood count, electrolytes, and renal and thyroid function were all normal. The patient described no concomitant episode of fever and diarrhea. Lithium was immediately discontinued. A therapeutic attempt with L-dopa was unsuccessful. Eight months after lithium discontinuation, the extrapyramidal features significantly improved, only festinating gait persisted. However, spasticity severely worsened and functional status was largely impaired (ALS-FRS = 20/40). On the brain MRI scans, hyperintensities of the corticospinal tract were detected bilaterally (as expected in ALS). SPECT with 1231-ioflupano (DAT-scan) showed normal dopaminergic function in the basal ganglia. The patient also tested negative for SOD1, TDP-43, and FUS gene mutations. This was a very rare case of acute lithium neurotoxicity with low serum level and in the absence of other intoxication symptoms or association with antipsychotic drugs. Movement disorders have been reported during lithium treatment, and are usually associated with high serum levels. To our knowledge, in only one patient Parkinsonism manifested during lithium treatment alone [2, 4] and in one patient with therapeutic levels [4]. Lithium is known to decrease the amount of dopamine in rat striatum and limbic forebrain and act as an anticholinesterase able to increase central cholinergic activity. Because serum lithium levels do not always reflect L. Mazzini, G. D. Oggioni, N. Nasuelli, S. Servo, L. Testa, and F. Monaco contributed equally to the manuscript.