A case of slow orthostatic tremor, responsive to intravenous immunoglobulin

We present two cases of parkinsonism secondary to adalimumab, a tumor necrosis factor a (TNF-a) inhibitor. Case 1: A 30-year-old woman with rheumatoid arthritis (RA) was started on adalimumab 40 mg monthly, which was increased to 40 mg weekly after 7 months. Within days, she developed gait disturbance, bradykinesia, and cognitive slowing. Brain magnetic resonance imaging (MRI) revealed increased signal in the globus pallidus, putamen, and internal capsule, extending into the subthalamic region (Fig. 1A) with faint putamenal enhancement (Fig. 1B), suggestive of toxic, metabolic or inflammatory causes. Cerebral angiogram showed no evidence of vasculitis. Cerebrospinal fluid examination was normal. The patient continued to deteriorate, and developed urinary incontinence, freezing of gait and falls. High-dose methylprednisone resulted in no improvement. Examination revealed prominent parkinsonian features, including bilateral rigidity and bradykinesia (Video Segment 1). She scored 50 on the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS). Adalimumab was discontinued and carbidopa/levodopa was started. She improved and was able to walk independently without freezing after 4 months. Her UPDRS motor score improved to 28 (Video Segment 2). L-dopa was ceased due to nausea, with no worsening of parkinsonism. A repeat brain MRI performed 8 months after the initial scan revealed significant resolution of the high signal changes (Fig. 1C,D). Her symptoms resolved over the next 3 years. Case 2: A 31-year-old woman with ankylosing spondylitis was referred for evaluation of arm and leg stiffness causing difficulties with hand dexterity and walking, which developed after treatment with adalimumab 40 mg every 2 weeks for 11 months. She experienced recurrent episodes of right-sided painful toe curling. Examination revealed predominantly right-sided cogwheel rigidity and bradykinesia. MRI of the brain was normal. Ceruloplasmin and copper levels were normal. Carbidopa/L-dopa was started. Although her symptoms have improved, reduction in medication resulted in worsening of bradykinesia and rigidity, and she has remained on L-dopa/ carbidopa 50/200 mg three times per day. Although the use of inhibitors against TNF-a has advanced the treatment of several inflammatory conditions, troublesome adverse effects associated with these drugs have emerged. We describe two women who developed parkinsonism following adalimumab use. The first case was associated with abnormal radiological findings. The second case was associated with dystonia. There was no significant family history. The cause-and-effect relationship between adalimumab and parkinsonism was supported by the onset after the introduction or increased dosages of the drug in both cases, improvement when the drug was discontinued (Case 1), and the unusual MRI findings (Case 1; Fig. 1A,B). These two cases represent the first reports of adalimumabinduced movement disorders. We acknowledge that youngonset Parkinson’s disease (PD) cannot be definitively excluded in the second case. Chorea in a patient with juvenile RA treated with infliximab for several months followed by adalimumab was previously described. This patient however, apparently had Sydenham’s disease, with clinical and serological evidence of streptococcal pharyngitis, which could have caused the observed chorea. Another report describes the development of parkinsonian features 1 week after the introduction of infliximab with rapid deterioration 12 months into the therapy, raising the possibility of infliximab-induced parkinsonism. (Table 1). TNF-a, regarded as a major regulator of physiological processes within the central nervous system, appears to exert modulating activity on dopaminergic neurons. Elevated levels of TNF-a were seen in postmortem brains of patients with PD and in animal models of PD. Increased density of A2A adenosine receptors were found in the putamen of patients with PD that significantly correlated with UPDRS scores and plasma TNF-a levels . Animal studies indicate that TNF-a causes dopaminergic loss by activating apoptotic transduction pathways. This selective loss may be related to their particular vulnerability to oxidative stress, as dopaminergic neurons produce abundant quantities of reactive oxygen species. These findings suggest that antagonism of TNFa should improve PD. However, similar to the observed worsening of multiple sclerosis seen with TNF-a antagonists, the mechanisms are likely to be more complex. TNFa plays both pathogenic and protective roles in the immune response against self-proteins. Whether altered TNF-a signaling is pathogenic in PD, or secondary to disease-related mechanisms is unclear. Further studies into the underlying pathophysiology, pharmacology, and radiological changes are needed to better understand the mechanisms of this newly described movement disorder induced by inhibitors of TNF-a.