Hyperdopaminergic crises in familial dysautonomia

Abstract

Objective: The purpose of this study was to determine whether carbidopa (Lodosyn), an inhibitor of dopa-decarboxylase that blocks the synthesis of dopamine outside the brain, is an effective antiemetic in patients with familial dysautonomia (FD) and hyperdopaminergic nausea/retching/vomiting attacks. Methods:We enrolled 12 patients with FD in an open-label titration and treatment study to assess the safety of carbidopa. We then conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate its antiemetic efficacy.Results: Previous fundoplication surgery in each patient studied prevented vomiting, but all of the subjects experienced severe cyclical nausea and uncontrollable retching that was refractory to standard treatments. Carbidopa at an average daily dose of 480 mg (range 325-600 mg/day) was well tolerated. In the double-blind phase, patients experienced significantly less nausea and retching while on carbidopa than on placebo ( p , 0.03 and p , 0.02, respectively). Twenty-fourhour urinary dopamine excretion was significantly lower while on carbidopa (147 6 32 mg/gCr) than while on placebo (222 6 41mg/gCr, p , 0.05).Conclusions: Carbidopa is a safe and effective antiemetic in patients with FD, likely by reducing the formation of dopamine outside the brain. Recurrent bouts of nausea, retching, and vomiting accompanied by tachycardia and hypertension following emotional or physiologic stresses are a common disabling feature of familial dysautonomia (FD) (Riley-Day syndrome or hereditary sensory and autonomic neuropathy type III).1,2 Standard antiemetics have little effectiveness during these episodes. Traditionally, patients with FD were advised to manage their episodes with benzodiazepines.3 Many quickly become tolerant and require increasing doses, which have been associated with respiratory depression. The central sympatholytic agent, clonidine, has been used with some success, but its use is limited by the unwanted side effects of sedation and hypotension.3 Metoclopramide has also been used, but it is frequently associated with tardive dyskinesia, and is therefore not suitable as a long-term therapy. 4 Newer agents like pregabalin are only moderately effective. 5Because of a developmental abnormality in the afferent neurons of the baroreflex, patients with FD are unable to restrain sympathetic outflow.6 Vomiting/retching attacks occur during sympathetic activation when dopamine spills over into the circulation. 2 We hypothesize, therefore, that vomiting is due to activation of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier. The purpose of this study was to determine whether carbidopa (Lodosyn, Merck & Co., Inc., Whitehouse Station, NJ), an inhibitor of dopa-decarboxylase that blocks the synthesis of dopamine outside the brain, 8 is an effective antiemetic in patients with FD. We present the results of a randomized, placebo-controlled trial conducted in patients with FD.

Current treatments in familial dysautonomia

“…Carbidopa blocks dopamine synthesis and was administered at a dose of 200 mg three times daily. 10 Since it does not cross the blood-brain barrier, its effects are confined to the periphery. Unlike previous treatment options, carbidopa is not associated with sedation or respiratory depression, making it suitable as a long-term pharmacotherapy to prevent the vomiting attacks.…”

“…28 In keeping with this finding, therapeutic focus is on pharmacological strategies that reduce catecholamine surges without producing sedation or respiratory depression. 10 Unfortunately, management of the hyperadrenergic crises is still suboptimal and many patients rely on sedative medications (diazepam and clonidine) with the risk of respiratory depression.…”

“…Controlled clinical trials in FD are possible, although difficult, as the cases are rare and the population is fragile. 10 Table 1 summarizes the current pharmacologic treatments for FD.…”

Dexmedetomidine for refractory adrenergic crisis in familial dysautonomia

“…In our study, the majority of patients presented with extremely high BP and HR indicating sympathetic hyper-activation, although these varied from patient to patient. In FD crises, there is also a significant component of plasma dopaminergic overload leading to retching and vomiting [20, 23]. Unfortunately, the retrospective design and the electronic medical record documentation did not provide adequate information regarding retching/vomiting incidences and therefore this could not be evaluated.…”

Cyclic vomiting syndrome: the nervous system has the guts

“…1) [7] can present with disabling nausea and vomiting. In the case of familial dysautonomia, the mechanism of nausea is related to massive dopamine release [5]. Of note, in patients with Parkinson disease treatment with L-dopa also triggers nausea, which can be relieved by blocking the peripheral conversion of L-dopa to dopamine with carbidopa, a dopadecarboxylase inhibitor.…”