Pisa syndrome and Parkinsonism secondary to valproic acid in Huntington's disease

Abstract

et al. 1 reported postural tremor in one patient with polycythaemia vera which was tentatively attributed to manganese deposits in the basal ganglia and improved after therapy with a chelating agent. Herein we report a patient with polycythaemia vera who developed persistent parkinsonism and in whom MRI showed features consistent with manganism.In 1998 a 47-year-old man employee began to complain of headache and arterial hypertension that led to the diagnosis of polycythaemia vera, which were treated with repeated blood-lettings. The next year he began to complain of dysesthesia to the feet, nocturnal leg cramps, and unsteady gait. His wife reported that he was slightly confused. The neurological examination showed masked face, monotonous voice, rigidity of the neck and of the right upper arm, slightly ataxic gait with forward bent of the trunk and diffusely brisk tendon reflexes. The blood examination revealed an increase of the hematocrit (50.2%), and transferrin (504 mg/dL; NV 290-390 mg/dL) and a decrease of the sideremia (33 lg/dL; NV 50-150 lg/dL). The serum magnesium, copper and ammonium were within normal range. Serum or urine manganese was not assessed. Hepatic biopsy was negative for increased hepatic copper content. Cranial CT was negative. T1 weighted MR imaging revealed a symmetric hyperintensity of the basal ganglia, cerebral peduncles, red nucleus, quadrigeminal bodies, superior cerebellar peduncles, and dentate nuclei. He started levodopa therapy (100 mg/die) which was unsuccessful and interrupted few months later. Seven years later the clinical condition was substantially stable and the score of the Unified Parkinson's Disease Rating Scale subscale 3 was 16. A control MRI showed progression of the T1 symmetric hyperintensity in the cerebral peduncels and evidence of the same signal change also in occipital white matter (Fig. 1). There was only a mild diffuse cerebellar atrophy. SPECT examination, obtained by injection of 111-185 MBq of [ 123 I]FP-CIT, showed only a mild decrease of dopamine transporter (DAT) density in the right putamen. Manganese level was finally assessed in blood and urine and it was within normal limits.The diagnosis of manganism in our patient was based on the clinical features, exclusion of Parkinson's disease and Wilson's disease, and on presence of the typical MRI appear-ance of symmetric hyperintensity in T1-weighted images of the basal ganglia and other brain structures caused by the paramagnetic properties of manganese. 1 Although a direct demonstration of increased manganese in the serum of our patient was not available, the normal manganese levels observed at follow-up do not exclude the diagnosis since it is well known that, serum or urine levels correlate with actual, but not previous, levels of exposure. 2 Manganese intoxication is usually caused by professional exposure as it typically occurs in miners, welders, and workers in steel industry, 3 but it can also be observed in acute or chronic hepatic diseases and anemia. 4,5 In particular, increased level of se...

Preclinical and Clinical Investigations of Mood Stabilizers for Huntington's Disease: What Have We Learned?

“…Another case study reported that VPA treatment caused a state of tolerance, however this was found in only one late-stage HD patient 168 . While VPA is generally a safe drug 169 , it is a known teratogen in both rodents 170 and humans 171 , and it should be noted that one case study reported that a single HD patient developed Pisa syndrome, an incredibly rare but dangerous neurological side effect 172 , after VPA treatment.…”

Targeting Huntington’s disease through histone deacetylases

“…It must be noted that there has also been one report linking valproic acid treatment with the development of Pisa syndrome in a patient with HD (Salazar et al 2008). …”

From Pathways to Targets: Understanding the Mechanisms behind Polyglutamine Disease

“…Furthermore, a combined treatment of lithium (induces autophagy and downregulates HDAC1) and VPA produced several beneficial effects and prolonged median survival in HD transgenic mice [ 230 ]. In HD patients, valproic acid is discussed to have beneficial effects on psychiatric symptoms [ 231 ] but was also shown to have side effects like developing Parkinson's syndrome with an axial dystonia [ 232 ]. The HDAC inhibitor sodium butyrate was shown to delay the onset, ameliorate the neurological phenotype, improve the survival in SCA 3 transgenic mice, and improve the survival of neurons in an ataxin-7 cell model [ 55 , 233 ].…”