First case on successful management of manganism with renal transplantation.

With Renal Transplantation Manganese (Mn) has recently been detected in patients undergoing maintenance hemodialysis with deposition in the brain causing a clinical syndrome with parkinsonian features (1). We present a patient with end-stage renal disease on maintenance dialysis and manganism successfully managed with renal transplantation. This is, to our knowledge, the first case reporting the complete clinical and radiologic resolution of manganism with renal transplantation. A 49-year-old housewife with endstage renal disease secondary to diabetes was referred for renal transplantation while on irregular hemodialysis for approximately 1 year elsewhere. She presented to us with uremic features and chronic headache. There was no history suggestive of vasculitis, connective tissue disorders, indigenous medication use, well water consumption, or addictions. There was no exposure to industrial toxins or wastes and stainless steel utensils were used at home for cooking. The headache was bifrontotemporal, sharp, continuous, and severe enough to interfere with daily activities as well as to wake her up from sleep. There was no associated aura, photophobia, phonophobia, or vomiting and improved marginally with analgesic use. She did not give any history of giddiness or hearing impairment. She had features of depression, reduced social interaction, and conversation. Her blood pressure was well controlled. On examination, her blood pressure was 110/70 mm Hg. She had mask-like facies, bradykinesia, and slow speech. Signs suggestive of distal symmetrical sensory polyneuropathy involving both small and large fibers were elicited. Proliferative diabetic retinal changes without features of chronic hypertension or papilledema were observed on fundoscopy. She was evaluated for the chronic headache with magnetic resonance imaging (MRI) of the brain, which revealed symmetrical hyperintensity in the globus pallidii on T1-weighted sequences (Fig. 1A). The T2-weighted MR images were normal. These features were consistent with Mn deposition. Blood Mn level was 48.70Kg/L (normal, 6.70Y10.40Kg/L). She had anemia with iron overload (hemoglobin 9.1 g/dL [91 g/L], MCV 94 fl, transferrin saturation 51.3%, and ferritin 1455.7 ng/mL [1455.7 Kg/L]) and normal liver function tests. She was maintained on thrice a week hemodialysis thereafter until she underwent renal transplantation 6 months later. She was not started on any antiparkinsonism drugs. Many of her neurologic features, especially cognitive abnormalities and neuropathy, improved after renal transplantation. MRI of the brain done 15 months after renal transplantation showed normal appearance of the globus pallidii (Fig. 1B) with complete resolution of the clinical symptoms and the bilateral hyperintensities that were seen in the pretransplantation MRI study of the brain. She is doing well with normal allograft function on last follow-up 15 months after transplantation with blood Mn level of 10.45 Kg/L (normal, 6.70Y10.40 Kg/L). Once absorbed, Mn either complexes as Mn 3+ with transferrin or albumin or exists as Mn free ions. Glial cells have a capacity to concentrate Mn up to 200 times the extracellular concentration and the basal ganglia have abundant transferrin receptors, resulting in increased deposition of Mn. This leads to neuronal injury and gliosis resulting in dopaminergic dysfunction. This process seems accentuated in patients on hemodialysis. Urinary excretion of Mn is only 0.1% to 2%. Thus, anuric chronic kidney disease patients do not routinely manifest with high Mn levels (1). Symmetrical high signals in T1weighted images have also been noted in deposition of other paramagnetic substances such as iron in neurodegeneration with brain iron accumulation and calcium (previous radiation/chemotherapy, hyperparathyroidism, and Fahr’s disease), methemoglobin (hemorrhage), melanin, and as atypical MRI features of Wilson’s disease. The combination of clinical details and imaging helps to identify the underlying cause as in this case. Our patient did not receive any parenteral nutrition and had normal liver function tests and normal serum calcium. Unremarkable T2-weighted images and high serum ferritin level excludes neurodegeneration with brain iron accumulation and Wilson’s disease does not improve with dialysis or renal transplantation. The clinical scenario, symmetric MRI appearance, normal signal in T2-weighted images makes hemorrhage unlikely. Differentiation from Parkinson’s disease that is asymmetrical, has resting tremors and festinant gait, and responds to L-DOPA is important (2, 3). Our patient had high blood levels of Mn without any obvious exposure. Health supplements in hemodialysis patient (Chlorella extract) have been reported previously to cause manganism (4), but no such intake was disclosed. The absence of details regarding water source and treatment while on hemodialysis for nearly a year before presentation led us to consider Mn transfer during hemodialysis, possibly as a result of water contamination, especially in the absence of excessive Mn intake in diet or as supplements (2). Treatment options for Mn toxicity are limited.