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I read with interest the article by Yoshikawa and colleagues.1 The authors reported the case of a 44 year old woman with hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease) involving the liver, who had raised serum concentrations of manganese, hyperintense areas in the basal ganglia on T1 weighted magnetic resonance images, and levodopa unresponsive parkinsonism. Naturally, I agree that the parkinsonism in this case is most probably related to portal-systemic (portal-venous) shunts. There are, however, two points that deserve clarification.
First, it is not entirely clear whether their fig 2 (left panel) shows portal-systemic or arteriovenous shunts. The authors say that the figure shows a selective angiogram of the superior mesenteric artery. If that were the case, there should not be a “feeding artery” involved in the intrahepatic shunts (as they state in the legend to fig 2). Instead, the figure would show the portal vein and portal-systemic shunts (that is, portal phase of the angiogram). If, on the other hand, the catheter were in the coeliac artery (as they mention in the text), then the figure would probably correspond to the arterial phase of the angiogram and show a feeding artery (the hepatic artery) and arteriovenous (not portal-systemic) shunts. Interestingly, there is evidence to suggest that both types of shunt may be necessary for the development of neurological complications in the presence of an intact (or mostly preserved) hepatic parenchyma.2 Thus excessive quantities of potentially toxic substances (for example, ammonia, manganese) passing directly from the gut to the systemic circulation through portal-systemic shunts could be rapidly cleared by a normal liver as long as the hepatic arterial blood flow is adequate.
Second, Yoshikawa and colleagues claim that the parkinsonism of their patient was induced by manganese. While this is a reasonable working hypothesis, the authors provide no direct evidence supporting such a statement. The fact that serum manganese was raised does not necessarily imply that manganese played a key role in the pathogenesis of parkinsonism. Indeed, their patient lacked various clinical features often seen in cases of manganese induced parkinsonism3 (for example, cock walk and propensity to fall backwards).
Levodopa unresponsive parkinsonism is a well known manifestation of chronic non-Wilsonian hepatocerebral degeneration.4 Although blood concentrations of ammonia were within the normal range in the case reported by Yoshikawa and colleagues, the possibility of transient abnormal increases of ammonia occurring particularly after meals was not investigated.
We are pleased to have an opportunity to comment on the important issues raised by Dr de la Fuente-Fernández regarding a case of hereditary haemorrhagic telangiectasia with parkinsonism. Raised serum manganese combined with the abnormal findings in cranial magnetic resonance imaging and abdominal angiography were the rationale for our conclusion that the parkinsonism in our patient was induced by manganese that had accumulated because of portal-systemic shunting.
About the angiogram: the angiogram of the superior mesenteric artery presented in our manuscript showed a dilated feeding artery, a dense mottled hepatogram, and early filling of the hepatic vein. These findings concerned the arterial phase. The intrahepatic arteriovenous shunts were definite diagnostic evidence of hereditary haemorrhagic telangiectasia but not of portal-systemic shunts. We therefore agree with Dr de la Fuente-Fernández that we should have presented another angiogram in the portal phase showing a hypoplastic portal vein with abnormal vessels between the mesenteric and inferior vena cava to confirm the portal-systemic shunt.
About the parkinsonism: after the failure of treatment by levodopa, we took other measures to relieve the parkinsonism; for example, we persuaded the patient to avoid manganese-rich foods such as blueberries. Fortunately, her serum manganese gradually decreased below the normal upper limit during the next six months, and her neurological symptoms became less prominent. Alleviation of parkinsonism in inverse proportion to serum manganese concentrations suggests that the parkinsonism in this case may have been caused by manganese accumulation, and that the patient was in the early stage of manganese intoxication in which neurological symptoms were incomplete and partially reversible.
About transient hyperammonaemia: we searched for cases of hyperammonaemia related parkinsonism, and finally found a case with portal-systemic encephalopathy and parkinsonism which disappeared after treatment of the portal-systemic shunting.1 The mechanism of parkinsonism in that case is certainly open to debate, as hyperammonaemia is generally thought to cause disturbance of consciousness or negative myoclonus rather than parkinsonism. We do not deny the possibility that our patient may have had a transient increase in serum ammonia, though it seems unlikely when there had never been a disturbance of consciousness.