Levodopa, methylmalonic acid, and neuropathy in idiopathic Parkinson disease

Toth, Cory; Breithaupt, Kim; Ge, Shaohua; Duan, Yanjun; Terris, Joan M.; Thiessen, Anita; Wiebe, Samuel; Zochodne, Douglas W.; Suchowersky, Oksana

doi:10.1002/ana.22021

Cited by 172 publications

(161 citation statements)

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“…Cobalamin deficiency as a potential cause of neuropathy in IPD has been investigated extensively, but with conflicting results: in levodopa‐treated IPD patients, cobalamin has been shown to be lower in those with neuropathy than in those without it (Ceravolo et al., 2013; Mancini et al., 2014); some researchers have found an association between cobalamin levels and levodopa doses (Rajabally & Martey, 2013; Toth et al., 2010), but this finding could not be confirmed by others (Mancini et al., 2014). Also folate deficiency (Rajabally & Martey, 2013) and levodopa itself, especially LCIG and its ingredients or its way of resorption (Jugel et al., 2013), have been suspected to be involved in the development of neuropathy in IPD.…”

Section: Introductioncontrasting

confidence: 63%

“…It was predominantly axonal in nature. This proportion was much vaster than previously reported prevalences, which range from 5% to ~40% (Ceravolo et al., 2013; Jugel et al., 2013; Merola et al., 2014, 2016; Rajabally & Martey, 2011; Shahrizaila et al., 2013; Toth, Brown, Furtado, Suchowersky, & Zochodne, 2008; Toth et al., 2010). The frequency in our LCIG group was 100% (6 of 6), in the oral group 73% (8 of 11).…”

Section: Discussionmentioning

confidence: 99%

“…Looking at our results, this is exactly the case—cobalamin and folate were low in both groups, but still within normal range, homocysteine was high above upper limit. This result is in line with previous findings (Ceravolo et al., 2013; Mancini et al., 2014; Merola et al., 2014; Rajabally & Martey, 2011; Santos‐Garcia, Macias, Llaneza, Grande, & Fuente‐Fernandez, 2011; Toth et al., 2010). All three values did not significantly differ between LCIG and orally treated patients.…”

Section: Discussionmentioning

confidence: 99%

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Effects of levodopa/carbidopa intestinal gel versus oral levodopa/carbidopa on B vitamin levels and neuropathy

et al. 2017

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ObjectivesTo determine the possible interactions between levodopa therapy and plasma levels of B vitamins in patients with advanced idiopathic Parkinson's disease (IPD) in the context of either oral levodopa therapy or levodopa/carbidopa intestinal gel (LCIG). Secondly, to determine the prevalence of neuropathy and its relation to plasma levels of B vitamins and homocysteine.MethodsMedication doses, neurographies, and serum levels of pyridoxine, cobalamin, folate, and homocysteine of eight LCIG and 13 orally treated advanced IPD patients matched for age, Hoehn & Yahr stage, and UPRDS III were collected. This data was analyzed for correlation with daily levodopa dose (LDD).Results LICG patients had a longer disease duration and higher LDD. All LCIG patients and most orally treated patients had sensorimotor axonal polyneuropathy. Of all plasma vitamin levels, pyridoxine was decreased most and significantly lower in the LCIG group. Cobalamin and folate, however, were within the lower reference range, and homocysteine highly elevated, all without any significant difference between both groups. LDD correlated significantly with pyridoxine deficiency (p = .02) irrespective of the route of application and with hyperhomocysteinemia in the LCIG group (p = .03). At LDDs above 2,000 mg, pyridoxine deficiency was almost always detectable.ConclusionsPyridoxine deficiency and hyperhomocysteinemia are dependent on the daily levodopa/carbidopa dose, while levels of cobalamin and folate are not. The mode of application of levodopa/carbidopa has no impact on B‐vitamin levels. Neuropathy is very frequent in advanced IPD; however, it remains to be investigated further whether neuropathy is more frequent in LCIG than in orally levodopa/carbidopa‐treated advanced IPD patients.

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Section: Introductioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of levodopa/carbidopa intestinal gel versus oral levodopa/carbidopa on B vitamin levels and neuropathy

et al. 2017

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“…The mechanism underlying this neuropathy is not known. Several case reports and series have proposed that the neuropathy is related to levodopa, administered orally 35 or intestinally, 36 and that the neuropathy is due to vitamin deficiency (particularly vitamins B 12 and B 6 ). 35,37 However, a peripheral neuropathy may be present in some subjects without prior levodopa exposure.…”

Section: Figurementioning

confidence: 99%

α-Synuclein in cutaneous autonomic nerves

et al. 2013

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Objective: To develop a cutaneous biomarker for Parkinson disease (PD).Methods: Twenty patients with PD and 14 age-and sex-matched control subjects underwent examinations, autonomic testing, and skin biopsies at the distal leg, distal thigh, and proximal thigh. a-Synuclein deposition and the density of intraepidermal, sudomotor, and pilomotor nerve fibers were measured. a-Synuclein deposition was normalized to nerve fiber density (the a-synuclein ratio). Results were compared with examination scores and autonomic function testing.Results: Patients with PD had a distal sensory and autonomic neuropathy characterized by loss of intraepidermal and pilomotor fibers (p , 0.05 vs controls, all sites) and morphologic changes to sudomotor nerve fibers. Patients with PD had greater a-synuclein deposition and higher a-synuclein ratios compared with controls within pilomotor nerves and sudomotor nerves (p , 0.01, all sites) but not sensory nerves. Higher a-synuclein ratios correlated with Hoehn and Yahr scores (r 5 0.58-0.71, p , 0.01), with sympathetic adrenergic function (r 5 20.40 to 20.66, p , 0.01), and with parasympathetic function (r 5 20.66 to 20.77, p . 0.01). Conclusions:We conclude that a-synuclein deposition is increased in cutaneous sympathetic adrenergic and sympathetic cholinergic fibers but not sensory fibers of patients with PD. Higher a-synuclein deposition is associated with greater autonomic dysfunction and more advanced PD. These data suggest that measures of a-synuclein deposition in cutaneous autonomic nerves may be a useful biomarker in patients with PD. Accumulating evidence suggests that a-synuclein deposition occurs early in the course of PD and may antedate the appearance of the clinical features of the disease.2 This has provided the rationale for the use of a-synuclein as a biomarker in PD. 3Skin punch biopsy could provide a simple means to measure a-synuclein deposition in the peripheral nervous system; however, preliminary studies used techniques optimized for CNS tissue, relied on small tissue volumes, and did not systematically study autonomic substructures, and therefore detected a-synuclein in only a minority of subjects with PD. [4][5][6][7][8] We recently reported novel methods to study the cutaneous autonomic innervation in skin biopsies of patients with peripheral nerve disease.9,10 We hypothesized, based on the prominent autonomic manifestations of PD, that a-synuclein deposition would be elevated in cutaneous structures with autonomic innervation.The aims of the study were to determine 1) whether a-synuclein was present in cutaneous sensory and autonomic nerves, 2) the relationship between cutaneous a-synuclein deposition and *These authors contributed equally to this work.

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“…A few cases of acute inflammatory demyelinating polyneuropathy have been reported, one associated with encephalopathy. 56 The causality is so far not established because neuropathy may be very common in PD patients 57 and there is no clear relationship between levodopa and neuropathy. 58 However, it is well-known that levodopa is involved in the metabolism of vitamin B12 and causes hyperhomocysteinaemia.…”

Section: Safety With Levodopa/carbidopa Intestinal Gel Infusionmentioning

confidence: 99%

Long-term Efficacy and Safety with Continuous Dopaminergic Stimulation Pump Treatments in Parkinson’s Disease

Busk¹,

Johansson²,

Nyholm³

2011

European Neurological Review

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Continuous dopaminergic stimulation (CDS) is important for symptom control in advanced stages of Parkinson's disease (PD). The most efficacious approaches are pump treatments with dopaminergic drugs: subcutaneous infusion of the dopamine receptor agonist apomorphine and intestinal infusion of levodopa/carbidopa gel. Both methods decrease motor fluctuations in long-term follow-ups, including parkinsonian and dyskinetic states, when compared to conventional optimised oral therapy. Also non-motor symptoms may be improved. Adverse drug reactions are usually less pronounced although high levodopa doses, which are common with levodopa/carbidopa infusion, may cause hyperhomocysteinaemia and cobalamin deficiency. Technical complications are specific for each infusion strategy. Formation of subcutaneous nodules is the most common problem with apomorphine infusion. Dislocation of the intestinal tube is the most common problem with levodopa/carbidopa infusion. Both pump treatments may be used for 24-hour infusion in selected patients. The long-term experience is reviewed. To conclude, CDS pump treatments may be successfully used for several years in advanced PD. KeywordsApomorphine, continuous dopaminergic stimulation, infusion, levodopa/carbidopa, Parkinson's disease, pump The background is a combination of a number of findings, mainly that:• striatal dopaminergic stimulation is fairly constant in a healthy brain;• striatal dopaminergic stimulation in PD is pulsatile when oral levodopa is used; • pulsatile dopaminergic stimulation causes motor fluctuations and dyskinesias; and • continuous administration of dopaminergic agents may decrease motor fluctuations and reverse dyskinesias.PD is associated with a more widespread pathology than nigro-striatal degeneration and CDS is not the remedy for all problems. But there is firm evidence that continuous dopaminergic drug delivery, probably providing CDS, produces a significant benefit compared to conventional therapy in patients with advanced PD. The evidence mainly stems from studies of levodopa and apomorphine infusions.

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Levodopa, methylmalonic acid, and neuropathy in idiopathic Parkinson disease

Cited by 172 publications

References 27 publications

Effects of levodopa/carbidopa intestinal gel versus oral levodopa/carbidopa on B vitamin levels and neuropathy

Effects of levodopa/carbidopa intestinal gel versus oral levodopa/carbidopa on B vitamin levels and neuropathy

α-Synuclein in cutaneous autonomic nerves

Long-term Efficacy and Safety with Continuous Dopaminergic Stimulation Pump Treatments in Parkinson’s Disease

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