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Prospective assessment of peripheral neuropathy in Duodopa-treated parkinsonian patients
Acta Neurologica Scandinavica
Abstract
Although peripheral neuropathies (PN) have been described in patients with Parkinson's disease (PD) treated with oral dopaminergic therapies, anecdotal reports of subacute severe PN have been reported during treatment with enteral levodopa/carbidopa infusion (Duodopa).
We prospectively assessed clinical and electrophysiological data of 15 consecutive patients with PD treated with Duodopa for a mean follow-up of 9 months.
Nerve conduction studies and a clinical evaluation with a standardized battery of peripheral neuropathy scales were performed at baseline and after a mean follow-up of 9 months.
At baseline, mild signs of PN were observed in three subjects, and vitamin B12 serum levels were found to correlate with the amplitude of sural sensory action potentials. Follow-up data were available for 10/15 subjects: one patient developed a subacute sensory-motor PN and three subjects with pre-existing PN showed a moderate worsening of electrophysiological and clinical features. Subclinical electrophysiological alterations of peripheral nerves were observed in two subjects. No significant changes were observed in vitamin B12, folate, homocysteine and methylmalonic acid levels.
In this consecutive series of patients treated with Duodopa, we observed one subacute sensory-motor PN and few length-dependent alterations of peripheral nerves, similar to those described during oral levodopa treatment.
... Ultimately, nine papers were identified (including one in Spanish) -four with prospective assessment [10,12,15,16] and five case reports [11,13,[17][18][19]. Publications were identified where such cases were only mentioned (providing an additional 33 cases) without any detailed information, and therefore they were not analysed [20][21][22][23][24]. Finally, the data of 15 patients was collected. ...
... Due to the heterogeneous and often incomplete NCS data presented, precise interpretation or comparative analysis was impossible. For prospective studies, either only the interpretation of the result [10,15] or average values [12,16] are available. Detailed NCS data in the context of a case report was available in 3/5 publications, but in the remaining 2/5 only the descriptive interpretation of the study was available. ...
... In most cases, data for the baseline NCS before the diagnosis of polyneuropathy was lacking. Only in one study did we have a complete comparative list of electrophysiological parameters [18], and in two others information was provided that an NCS study had been performed [15,16]. In the majority of cases, electrophysiological results consisted of a mixed pattern of axonal and demyelinating damage. ...
Polyneuropathy (PNP) is a known complication of levodopa-carbidopa intestinal gel (LCIG) therapy of advanced Parkinson's Disease (PD). The overall prevalence of PNP in PD is estimated to be 42.1% (as shown in a review by Romagnolo et al. 2018), and the most common type is chronic axonal polyneuropathy. There is a group of acute/subacute onset demyelinating polyneuropathies, which is far less common, although it seems to be an important factor leading to the rapid discontinuation of LCIG treatment. In this systematic review, we present data on demyelinating polyneuropathy with acute/subacute onset; we identified nine papers including prospective assessments and case reports, with detailed information on 15 patients. In all patients, despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) or plasma exchange (PE), the LCIG therapy was terminated. We also present a case of subacute demyelinating polyneuropathy with effective treatment and continuation of LCIG therapy.
... not really well estimated. [3][4][5][6][7][8][9][10][11][12][13] In LCIG-PD patients are described both acute/subacute and chronic forms of PN. ...
... 8,[11][12][13][14][15] Recent findings demonstrated an early small fibers (autonomic and nociceptive) involvement that could be related to PD itself instead of levodopa exposure. 28,29 The incidence of PN in LCIG patients, in few case series reported, [4][5][6]9,11,14,30,31 ranges from 20% to 71%, and the exact mechanism is still poorly understood: vitamin B12 deficiency/hyperhomocysteinemia, older age, and higher LD dosage are the primarily hypothesized causes. Indeed, the enteral LD formulation, with its To note, these patients remained asymptomatic throughout the whole follow-up, and we did not find any significant increase in plasma Hcy levels, pathological reduction in vitamin B12, and folate plasma level 7,14-16 or increased LEDD values as reported previously. ...
... In the group of pre-PN, no one showed a poorer outcome respect to the rest of patients. Furthermore, in none of these patients the presence of a new PN or the worsening of a pre-existing one was cause of discontinuation of therapy as reported in other studies.9,11,17 Our data suggest that, even if chronic treatment with vitamins B group is not able to prevent new cases of PN, probably it may stabilize the new onset PN and pre-existing ones. ...
Objectives:
Peripheral neuropathy (PN) is a significant concern and potential cause of withdrawal in patients with Parkinson's disease (PD) treated with Levodopa/Carbidopa Intestinal Gel (LCIG) infusion. Vitamin B deficiency and/or hyperhomocysteinemia levodopa-related are considered possible causative factors. In this study, we evaluated PN incidence in LCIG-PD patients treated since the beginning of infusion with vitamins B supplementation.
Materials & methods:
In this prospective open-label pilot study, 30 consecutive patients with PD on LCIG infusion were evaluated with clinical, neurophysiological, and biochemical assessments for a mean follow-up of 42.4 months (range 24-72). All evaluations were repeated every 6 months.
Results:
At baseline, 21 of 30 presented no signs or symptoms of PN, and 9 of 30 had pre-existing chronic PN. In whole population, a progressive worsening in nerve conduction studies of sural sensory and peroneal motor nerves was observed during the long-term follow-up. 4 of 21 patients, with normal clinical, electrophysiological assessment at baseline, developed distal symmetrical axonal polyneuropathy that remained asymptomatic during the long-term follow-up. Patients with pre-existing PN (9 of 30) showed a mild worsening of electrophysiological features during the period of observation. In none PN was cause of discontinuation of LCIG therapy. No incident cases of acute-subacute PN were documented. No correlation was found with age, sex, Levodopa dosage, duration of levodopa exposure, and homocysteine plasma levels.
Conclusion:
In this consecutive series of 30 patients with PD on LCIG infusion, with early and continuous vitamins B integration, we observed a low rate (19%) of new onset peripheral polyneuropathy that remained stable after long-term follow-up. Larger studies, controlled, with blinded evaluation, are needed to confirm these findings.
... Cases of peripheral neuropathy (PN) including cases of subacute Guillain-Barre like illness were reported during levodopa enteral infusion trials. [57][58][59][60][61][62][63] Reviewed reported cases of PN in those receiving carbidopa-levodopa intestinal infusion have more often shown a milder sensorimotor subtype and much less often, a severe acute or subacute axonal-demyelinating subtype of neuropathy. [64] There is a higher frequency of PN in clinical and/or electrophysiological testing of PD patients (38 -55%) compared with controls (8 -9%), correlating with levodopa dosage, duration of levodopa exposure, age of patients, low serum vitamin B 12 and high homocysteine levels with or without methylmalonic acidemia. ...
... In those with acute PN, the infusion should be discontinued and replaced by oral levodopa and treatment of PN as well as any vitamin deficiencies undertaken. [64] In a prospective study of 15 patients converting from oral to enteral infusion of carbidopa-levodopa, [62] baseline clinical evaluation for neuropathy and nerve conduction testing revealed 21.4% (3/14) with mild clinical neuropathy and sensory axonal changes on electrophysiological testing. These three patients did show mild worsening on repeat testing at an average 9 months follow-up. ...
... In conclusion, the authors noted a significant correlation of electrophysiological changes and lower vitamin B 12 levels and advise peripheral nerve clinical examination, electrophysiologic assessment and vitamin B 12 levels when treating patients with oral or infused levodopa therapy. [62] Mancini et al. observed that patients on oral or intestinal infusion of levodopa were more likely to have peripheral neuropathy than those on non-levodopa treatment for PD. [63] All patients with peripheral neuropathy in the oral levodopa and nonlevodopa groups presented as a subacute sensory neuropathy versus 71% in the levodopa infusion group. ...
Introduction:
The search for consistent, effective treatments in Parkinson's disease (PD) is ongoing. The importance of continuous dopaminergic stimulation (CDS) is understood to underlie best medical therapy for PD by providing closer replication of physiological patterns of dopamine release in healthy brains. Areas covered: An overview of interventions to improve motor fluctuations in PD is presented. Significant improvements in off-time are achieved by providing continuous therapy using targeted deep brain stimulation (DBS), subcutaneous apomorphine infusion and carbidopa/levodopa enteral suspension (Duopa). Duopa is a newly approved treatment in the US for advanced PD that delivers levodopa pumped to the intestinal tract through a percutaneous gastrostomy with jejunum tube extension (PEG-J tube). Trials with carbidopa/levodopa enteral suspension show improvement in motor fluctuations, reduction in plasma levodopa variation and improvement in overall "on" time compared with oral immediate release formulation of carbidopa/levodopa. Expert opinion: The degree of improvement in number of off hours per day on carbidopa/levodopa enteral suspension infusion rivals that seen with DBS and apomorphine infusion and makes this new treatment a valuable option in advanced fluctuating PD patients, especially those who are neither candidates for DBS or who do not have access to apomorphine infusion therapy or who have failed either or both therapies.
... Keywords Parkinson's disease Á Peripheral neuropathy Á Cobalamin (vitamin B12) Á Duodenal levodopa therapy Continuous jejunal levodopa infusion (cjLI) can improve motor fluctuations of patients with Parkinson's disease (PD) that are refractory to optimized oral medication (Nyholm et al. 2005;Antonini et al. 2007;Olanow et al. 2014). A number of recent case reports depicted the occurrence of peripheral neuropathy (PN) in patients undergoing this novel treatment approach (Urban et al. 2010;Meppelink et al. 2011;Santos-García et al. 2012;Klostermann et al. 2012;Müller et al. 2013;Jugel et al. 2013;Merola et al. 2014). As a large movement disorder centre we treated 31 patients with advanced PD during the years 2008-2013 with cjLI. ...
... All three patients had received high oral levodopa Subacute peripheral neuropathy is not a rare complication in patients receiving cjLI. A similar frequency as reported here was recently published in a prospective trial (Merola et al. 2014). Cumulative lifetime levodopa dosage was shown to be predictive for the risk of developing PN in orally treated Parkinson patients (Toth et al. 2010;Ceravolo et al. 2013), and enterally given levodopa even has a higher bioavailability compared to oral levodopa (Santos-García et al. 2012). ...
... However, PN in patients who ingested levodopa orally seems to differ from PN that follows cjLI in clinical presentation and electrophysiological findings (Jugel et al. 2013;Merola et al. 2014). The clinical course of the latter seems to be more acute and severe, and might resemble Guillain-Barré syndrome (Antonini et al. 2007;Klostermann et al. 2012;Merola et al. 2014). ...
Continuous jejunal levodopa infusion is an increasingly used therapy option in patients with Parkinson's disease who experience severe fluctuations from oral levodopa. In a number of recent reports polyneuropathy in patients receiving jejunal levodopa infusion was referenced to cobalamin (vitamin B12) deficiency. We describe one of three cases from our hospital with severe subacute polyneuropathy that developed during jejunal levodopa infusion, and occurred despite vitamin substitution therapy and normal vitamin B12 and holotranscobalamin serum levels.
... It is used in severe cases of PD for controlling the involuntary movements associated with the disease. The duodopa gel was pumped continuously into the gut of the patient through the abdominal wall via a tube that is attached to a small external pump at the end [78][79][80]. ...
... It also has an agonistic action on D3, D4, and 5-HT2 family of receptors. Cabergoline efficiently delays the outset of motor complexities with a single dose in a day because of its longer half-life [80]. Dizziness, nausea, dyspepsia, postural hypotension, peripheral edema, daytime sleepiness, and vomiting are the common side-effects reported for cabergoline [96]. ...
Parkinson’s disease is one of the most severe progressive neurodegenerative diseases which have a mortifying effect on the health of almost hundreds of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out which leads to symptoms like hypokinesia, rigidity, bradykinesia and rest tremor.Parkinsonism cannot be cured but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging, the blood brain barrier act as a highly selective semi permeable barrier which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease does not easily cross the blood barrier and further leads to a number of side effects. Recent advancements in drug delivery technologies have facilitated the drug delivery to the brain without flooding the blood stream and by directly targeting the neurons.In the era of Nanotherapeutics, liposomes can be an efficient drug delivery option for brain targeting.Liposomes can facilitate the passage of drugs across the blood brain barrier, enhances the efficacy of the drugs and minimises the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targetingParkinson’s disease.
... Recent data suggest an impairment of the peripheral nervous system as well, which takes the form of large-fiber neuropathy (PNP) in L-Dopa-treated patients [3][4][5][6][7][8][9][10][11][12][13][14]. Hyperhomocysteinemia, low plasma levels of B12, B6, and folic acid, along with disease duration, age, and L-Dopa daily intake are considered to be the key factors in PD patients developing PNP [3][4][5][6][7][8][9][10][12][13][14][15][16]. Small-fiber neuropathy is considered to be an intrinsic feature of PD, mainly because of alpha-synuclein deposits at the level of sensory nerve fibers and modifications of intradermal nerve fiber density [17][18][19][20][21]. ...
... Several studies found that PNP prevalence was higher in PD than in age-matched controls, ranging from 15% to 73% in patients treated orally with L-Dopa [5][6][7]12,13,15,16], depending on the ...
(1) Background: Increased attention has lately been given to polyneuropathy in Parkinson’s Disease (PD). Several papers postulated that large-fiber neuropathy (PNP) in PD is related to vitamin B12 deficiency and L-Dopa exposure. (2) Methods: Using a cross-sectional, observational study, we evaluated 73 PD patients without a previously known cause of PNP using clinical scores (UPDRS II and III and Toronto Clinical Scoring System), biological evaluation of vitamin B12 and folic acid, and nerve conduction studies to assess the prevalence and features of PNP. (3) Results: The prevalence of PNP was 49.3% in the study group. In the L-Dopa group, the frequency of PNP was 67.3% as compared to PNP in the non-L-Dopa group, where one subject had PNP (χ2 = 23.41, p < 0.01). PNP was predominantly sensory with mild to moderate axonal loss. Cyanocobalamin correlated with L-Dopa daily dose (r = −0.287, p < 0.05) and L-Dopa duration of administration (r = −0.316, p < 0.05). L-Dopa daily dose correlated with the amplitudes of sensory nerve action potentials of the superficial peroneal and radial nerves (r = −0.312, p < 0.05) (r = −0.336, p < 0.05), respectively. (4) Conclusions: PNP is more frequent in L-Dopa-treated patients than in L-Dopa-naïve patients. The results imply that longer exposure to high doses of L-Dopa may cause vitamin B12 and folate imbalance and PNP, secondarily.
... In this study, it was suggested that cumulative lifetime levodopa dosage and fasting MMA levels were associated with PN severity and concluded that PN in PD may either be associated with iatrogenic cobalamin metabolic abnormalities or be a peripheral nervous system manifestation of PD[23]. Increased Hcy and low B12 levels have been reported in smaller case series of patients with PD and PN[29][30][31][38][39][40][41][42][43]. Ceravolo et al. reported that the risk of neuropathy in PD is independently associated only to age and duration of exposure to levodopa and is not influenced by disease duration, disease severity, serum vitamin B12 or serum Hcy level[8]. ...
... No difference between the intestinal and oral levodopa groups was observed[37]. In a prospective study of assessment of PN during intestinal levodopa infusion, Merola et al. reported that intestinal levodopa infusion may worsen the neurophysiological and clinical features of pre-existing polyneuropathy, but these alterations are similar to those described during oral levodopa treatment[41]. The same group recently published their experience on 33 consecutive patients treated with intestinal levodopa infusion[47]. ...
Background:
Parkinson's disease (PD) has been associated with peripheral neuropathy (PN). PN has been demonstrated in some rare genetic forms of PD (e.g. PARK2 mutations) but has also been linked to levodopa exposure.
Objective:
The aim of this systematic review is to clarify any evidence of peripheral nervous system involvement in idiopathic PD.
Methods:
A systematic computer-based literature search was conducted on PubMed database.
Findings:
The pooled estimate of the prevalence of large fiber PN in PD was 16.3% (based on 1376 patients). The pooled estimate of the prevalence of biopsy-proven small fiber neuropathy was 56.9% (based on 72 patients). Large fiber PN in PD is in the majority of cases distal, symmetrical, axonal and predominantly sensory. There are, however, few reports of chronic idiopathic demyelinating polyneuropathy and very occasional cases of acute neuropathies. Although nerve conduction studies have been performed in the majority of the studies, they included only a limited number of nerves, mainly in the lower limbs. There is little evidence to support a direct link between levodopa treatment and the development of PN in idiopathic PD. In the majority of the cases PN has been linked to abnormalities in vitamin B12, methylmalonic acid or fasting homocysteine levels. Additional aetiological risk factors for PN may be responsible for any apparent link between PD and PN.
Conclusions:
Large-scale prospective studies with long-term follow-up with detailed baseline assessments are needed in order to understand the natural history of PN in PD, both on clinical and neurophysiological parameters.
... 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., 2014Merola et al., , 2016Rajabally & 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). ...
... 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. ...
Objectives
To 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.
Methods
Medication 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.
Conclusions
Pyridoxine 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.
... The authors recommend that all patients receiving L-DOPA substitution undergo follow-up examinations based on thorough clinical examination and laboratory tests, and also postulate the benefits of prophylactic treatment [43]. The working group led by Merola studied in depth the issue of peripheral neuropathy in LCIG-treated parkinsonan patients [30,65,66]. ...
... A limitation of the study was the small sample size and low-powered electrophysiology diagnosis. Noteworthy was also the fact that no significant changes were observed in vitamin B12, folate, homocysteine and methylmalonic acid levels [65]. ...
Introduction:
Levodopa is the most effective treatment for Parkinson's disease. After a number of years on treatment, fluctuations and dyskinesias may develop. Hence, invasive treatment measures are often needed (escalation therapy).
Areas covered:
Twenty years ago, a levodopa/carbidopa intestinal gel (LCIG) that can be infused directly into the jejunum was developed. This provides for continuous dopaminergic stimulation. For the past 10 years, LCIG has been licensed in some countries and its marketing approval is pending in the USA. It is endowed with very good efficacy, and in studies, it has proven to be superior to oral drug treatment. Continuous dopaminergic stimulation is also assured, and fluctuations and dyskinesias are significantly reduced. However, this technique involves an invasive procedure with percutaneous endoscopic gastrostomy and attendant surgical and postsurgical complications. Besides, there are problems related to the pump and tube. Vitamin deficiency and polyneuropathies are other drawbacks.
Expert opinion:
LCIG is a beneficial and very useful treatment option as escalation therapy for Parkinson's disease. While the side effects are not insignificant, they are justifiable in view of the severity of the disease. Attention must be paid, in particular, to malabsorption, with monitoring at baseline and in the course of treatment.
... Similarly, in an integrated safety analysis of prospective clinical trials which included 412 patients with a medi-an LCIG exposure of 911 days weight loss was reported for 14.0% of the treated patients and polyneuropathy for 5.5% of the treated patients (33). Polyneuropathy has been considered as a possible complication of lcig infusion, however, the etiology remains uncertain with hyperhomocysteinemia and low levels of vitamin B6, vitamin B12, folic acid among the presumed mechanisms involved in its development (34). It is important to note that this study did neither include formalized assessment of peripheral nerve conduction velocity to confirm diagnoses nor were laboratory assessments conducted for vitamin B12, folic acid or homocysteine evaluation. ...
Objectives. The aim of the Global Long-Term Registry on Efficacy and Safety of DUODOPA in Patients with Advanced Parkinson’s Disease in Routine Care (GLORIA) was to document 24-month efficacy, safety and the effect on patient’s quality of life (QoL) of long-term treatment with levodopa-carbidopa intestinal gel (LCIG) in advanced Parkinson’s disease (PD) in routine clinical care. Here we present the results for the patients enrolled in Romania in the GLORIA registry.
Material and methods. GLORIA registry is a multicenter, international, observational registry conducted between June 2010 and June 2015. In Romania, 39 patients with an indication for LCIG therapy were enrolled and followed for up to 24 months.
Outcomes. During the study period LCIG led to significant improvements in “Off” time, “On” time with dyskinesia, activities of daily living (ADLs), motor examination, non-motor symptoms, and QoL which maintained up to the end of follow-up. At 24 months, “Off” time had a mean reduction of -5.2±3.1 hours/day vs. baseline (p < 0.0001) and “On” time with dyskinesia had a mean reduction of -3.5±3.3 hours/day vs. baseline (p < 0.0001). Both ADLs and motor examination “On” scores showed a maximum improvement at 6 months and 12 months (p < 0.0001) and remained
significantly lower vs. baseline at 24 months (ADLs -6.6±8.7, p = 0.0023; motor examination -6.4±7.3, p = 0.0007). Non-motor symptoms scale (NMSS) total score had a mean reduction at 24 months of -18.29 as compared to baseline (p = 0.0011). QoL, as assessed by PDQ-8 significantly improved at 6 months as compared to baseline (p = 0.0141) and maintained its statistical significance until the 12 months evaluation (p = 0.0076). Adverse drug reactions possibly or probably related to the LCIG therapy were reported for 2.9% (1/35) of the patients during the temporary nasojejunal tube therapy and for 60.0% (21/35) of the patients during permanent tube phase. conclusions. LCIG treatment showed significant and clinically relevant long-term improvements in motor symptoms and QoL in advanced PD patients. The safety/tolerability data confirmed the established safety profile.
... Upon a follow-up, 9 of their participants expressed a mild axonal length-dependent PN akin to that arising from duodopa therapy. Three of the 9 participants already had PN at baseline relating to a previous L-DOPA regimen, though the symptoms of PN worsened with duodopa [31]. In an extension of the same protocol, 33 PD patients were given LCIG therapy and were followed for 24 months. ...
Peripheral neuropathy (PN) is a common neurological problem defined as a dysfunction of sensory, motor, and autonomic nerves. The presence of peripheral neuropathy has recently been noticed in Parkinson’s disease (PD) This comorbidity is concerning as it increases the burden on patients whose motor functions are previously compromised. A comprehensive computer-based literature review utilizing multiple peer-reviewed databases (e.g., Embase, PsycINFO, CINAHL, etc.) was conducted. There is evidence for the utility of robust diagnostic criteria to distinguish between large fiber neuropathy (LFN) and small fiber neuropathy (SFN). Some studies have established links between prolonged l-DOPA exposure and prevalence with increased levels of homocysteine (HCY) and methylmalonic acid (MMA) as pathological underlying mechanisms. PN in PD patients with relatively truncated exposure to l-DOPA therapy may have underlying mutations in the Parkin and MHTFR gene or separate mitochondrial disorders. Vitamin B12 and cobalamin deficiencies have also been implicated as drivers of PN. Accumulation of phosphorylated α-synuclein is another central feature in PN and deems urgent exploration via large cohort studies. Importantly, these underlying mechanisms have been linked to peripheral denervation. This review delves into the potential treatments for PN targeting B12 deficiencies and the use of COMT inhibitors along with other novel approaches. Avenues of research with powerful randomized controlled and long-term cohort studies exploring genetic mechanisms and novel treatment pathways is urgently required to alleviate the burden of disease exerted by PN on PD.
... Peripheral nerve fiber impairment in PD can take the form of large fiber neuropathy (PN) in L-Dopa treated patients (5)(6)(7)(8)(9)(10)(11)(12) or small fiber neuropathy (SFN) in all PD patients (13)(14)(15). A se-ries of data consider PN to be secondary to L-Dopa intake that determines the accumulation of homocysteine and methylmalonic acid, and cyanocobalamin, pyridoxine or folate plasma deficits (4,(6)(7)(8)11,(16)(17)(18). This imbalance in neuro-trophic vitamins and neuro-toxic metabolites is believed to be related to PN in PD (19)(20)(21). ...
Background. Recent studies described a higher prevalence of peripheral neuropathy (PN) in Parkinson’s disease that was linked to L-Dopa exposure. Peripheral neuropathies are known causes of a decreased health-related quality of life (HrQoL). Until now, no studies addressed the issue of how or if associated PN in PD affects HrQoL. Methods. In a cross-sectional, observational study, 73 non-demented PD patients, from which 36 with confirmed PN based on clinical (using the Toronto Clinical Neuropathy Scale-TCSS) and nerve conduction studies completed the Romanian version of PDQ-39. Results. Significant differences between mean scores in Motor (49.86 (27.61) vs. 31.50 (26.24), p = 0.005), Activities of daily living (49.86 (27.61) vs. 31.75 (30.10), p = 0.003) and body discomfort (52.54 (29.54) vs. 23.64 (18.48), p = 0.002) domains of PDQ-39 in the PN-PD group versus non-PN group were observed. TCSS significantly correlated to motor, emotional well-being and body discomfort domains (r = 0.406 p< 0.001; r = 0.316 p = 0.007; r = 0.356 p = 0.002, respectively). The multivariate linear regression model showed that motor impairment and PN correlated to motor domain (beta = 0.601, p = 0.000; beta = 0.211 p = 0.041, respectively) and PN significantly correlated to body discomfort domain (beta = 0.314, p = 0.020) of PDQ-39. Conclusions. The presence of associated PN in PD determines a further deterioration of HrQol in subjects with already a poorer HrQol.
... First, the sample size was too small to get statistical power and also detailed information on the effects of zinc deficiency. We have not experienced cases with peripheral neuropathy, but in previous studies, it has been reported to occur as a side effect of LCIG treatment, and homocysteine level and high dose L-dopa were correlated to chronic peripheral neuropathy (Merola et al., 2014(Merola et al., , 2016. Obviously, it is important to accumulate more number of cases in the future. ...
Objectives
Levodopa–carbidopa intestinal gel (LCIG) infusion is a useful therapy for the wearing‐off phenomenon of advanced Parkinson's disease (PD) patients. Recently, we found three PD patients that may have had a zinc deficiency after the LCIG infusion, possibly due to the zinc‐chelating action of levodopa. This study aims to evaluate changes in serum zinc levels in three patients that received LCIG treatment and to determine possible remedies for zinc deficiency during treatment.
Materials and Methods
We performed a prospective blood analysis of serum zinc levels before, when possible, and after LCIG treatment in our three PD patients.
Results
The serum zinc levels of the first patient before treatment and 4 months after beginning LCIG treatment were 69 and 58 μg/dl, respectively. For the second patient, serum zinc levels before treatment and two months after starting LCIG treatment were 87 and 46 μg/dl, respectively. The baseline serum zinc level for the third patient was not examined, but was 48 μg/dl 5 months after starting the LCIG infusion.
Conclusions
Levodopa–carbidopa intestinal gel infusion might have caused a zinc deficiency through levodopa zinc chelation. Zinc deficiency with LCIG infusion has not yet been reported, though preventing zinc deficiency may be an important factor in future LCIG treatment strategies.
... Vitamin B12 and B6 levels, adequate nutrition, and pre-existing 'red flag' signs of polyneuropathy ('red flags' include distal symmetrical parasthease, distal to proximal spreading numbness, slowly evolving distal weakness of arms and legs, peripheral cutaneous changes/discoloration) may influence development of these side effects. These side effects may be avoidable if adequate precautions or screening is done pre-IJLI therapy [16,17]. ...
Introduction:
Intrajejunal levodopa infusion (IJLI) therapy is one of the most influential therapies in moderate to late stage Parkinson's disease with documented effects on motor and non-motor symptoms and quality of life. The process of initiation and maintenance of therapy however, remains a challenge particularly in the long term. Areas covered: The authors reviewed "evidence base" for pathways and advice given to patients pre and post IJLI initiation. The authors found lack of patient, carer and clinician led "real life" advisory documents which need to be given to patients on IJLI. Expert commentary: Experience from centres engaged in IJLI therapy as well as feedback from carers and patients on IJLI suggest wide variability of practical advice given to patients. This is important as such tips could avoid termination of treatment or serious adverse events in some cases. In this review the authors provide a collection of pragmatic and practical tips for patients initiated on IJLI, both related to the short and long term and which we believe is a key unmet need. The paper is illustrated with two case reports.
... 68 Other case series supported a relationship between levodopa and neuropathy, presumably linked to a relative deficiency of vitamin B12 or an imbalance in vitamin B12 and homocysteine, which was thought to be responsible, at least, for the subacute to chronic form of axonal degeneration developing over several weeks to months. 69,70 More acute, Guillain-Barré-like phenotypes were assumed to reflect inflammatory damage, maybe triggered by vitamin deficiency or other, still not established factors. 69 Another severe incident has been reported in a patient with therapy-refractory epileptic seizures that have been linked to vitamin B6 deficiency suspected to be caused by malabsorption promoted by high-dose levodopa administration. ...
Sabine SkoddaDepartment of Neurology, Knappschaftskrankenhaus, Ruhr-University of Bochum, Bochum, GermanyAbstract: Parkinson's disease (PD) is characterized by a progression of symptoms in the course of time which typically leads to the occurrence of motor complications in the advanced stages of disease. In this stage of “motor complication”, conventional oral polypharmacotherapy often fails to preserve sufficiently stable motor function during the course of the day. Continuous infusions of levodopa/carbidopa gel (LCIG) delivered directly into the small intestine by a portable pump have been shown to stabilize levodopa plasma levels and to ameliorate motor fluctuations and troublesome dyskinesias in patients in the advanced stages of PD. Furthermore, there are also some first indications for beneficial effects on dopamine-related nonmotor symptoms of PD and an amelioration of overall quality of life. On the other hand, LCIG is an elaborate and expensive therapy, which requires the assured access to a medical team who are experienced with the management of adverse events and technical problems related to the tube and pump delivery system. This review focuses on the principle of LCIG infusion therapy and gives a comprehensive summary of the existing data on therapeutic effects and adverse events and possible complications.Keywords: motor complications, continuous dopaminergic stimulation, dyskinesia, nonmotor symptoms, quality of life
... On the other hand, neuropathological studies provided evi-dence of a peripheral nervous system intrinsic involvement in PD, with signs of small fibre neuropathies and alpha-synuclein peripheral deposits [10], and cases of PNP have also been reported with oral dopaminergic treatments, indicating a potential L-dopa neurotoxic effect [11][12][13]. Altogether these data confirm that PNP might represent an underestimated feature of advanced PD, particularly relevant in patients receiving LCIG, even though few prospective clinical-electrophysiological studies are currently available [7,14]. ...
Background and purpose:
Subacute and chronic peripheral neuropathies (PNP) have been reported in Parkinson's disease (PD) patients treated with levodopa/carbidopa intestinal gel infusion (LCIG), although several aspects of their incidence and pathogenesis still remain to be clarified. This study main objective is to prospectively report the 2-year incidence of PNP in patients treated with LCIG.
Methods and results:
The clinical, hematological, nutritional and electrophysiological assessments of 33 consecutive patients have been prospectively collected and evaluated. At baseline (before the start of LCIG therapy), 3/33 (9%) patients showed symptomatic PNP and 7/33 (21%) subclinical PNP. During a follow-up of 24.36 ± 12.18 months, 2/23 patients with normal baseline clinical-electrophysiological assessment developed a subacute PNP, 2/23 developed a chronic PNP and 7/23 developed a subclinical PNP. LCIG was immediately halted in the subacute cases, while the infusion therapy was not interrupted in chronic and subclinical forms. All PNP were supplemented with vitamin B1 and B12, showing a clinical improvement and/or substantial stability at the following evaluations. Higher levodopa-equivalent daily dose (P: 0.024) and homocysteine levels (P: 0.041) were found in chronic PNP, while no correlations were observed with vitamin B12, folate and UPDRS values. A trend towards BMI reduction was observed in both PNP and unaffected subjects and one patient developed a symptomatic PNP associated with a relevant weight loss.
Conclusions:
Serial clinical-electrophysiological evaluations are mandatory in patients treated with LCIG, given the possible risk of subacute and chronic PNP. No clear causative factors has been recognized in the subacute forms, whilst homocysteine-mediated neurotoxicity seems to underlie the pathogenesis of chronic forms.
... This medication comes as a gel that is continuously pumped into your gut through a tube inserted through your abdominal wall (tummy). There is a small external pump attached to the end of the tube, which you wear on your belt [84][85][86] . ...
Parkinson's disease (PD) is a type of movement disorder. It happens when nerve cells in the brain don't produce enough of a brain chemical called dopamine. Sometimes it is genetic, but most cases do not seem to run in families. Exposure to chemicals in the environment might play a role. Symptoms begin gradually, often on one side of the body. Later they affect both sides. They include Trembling of hands, arms, legs, jaw and face Stiffness of the arms, legs and trunk Slowness of movement, Poor balance and coordination. As symptoms get worse, people with the disease may have trouble walking, talking, or doing simple tasks. They may also have problems such as depression, sleep problems, or trouble chewing, swallowing, or speaking. There is no lab test for PD, so it can be difficult to diagnose. Doctors use a medical history and a neurological examination to diagnose it. PD usually begins around age 60, but it can start earlier. It is more common in men than in women. There is no cure for PD. A variety of medicines sometimes help symptoms dramatically. Surgery and deep brain stimulation (DBS) can help severe cases. With DBS, electrodes are surgically implanted in the brain. They send electrical pulses to stimulate the parts of the brain that control movement.
... Es gibt Fallberichte zur Entwicklung akuter sensomotorischer Polyneuropathien unter laufender Duodopa-Behandlung mit [33,34] und ohne [35,36] einhergehenden Mangel an Vitamin B6, B12 oder Folsäure. Der Zusammenhang zwischen der L-Dopa-Infusion und der Polyneuropathie ist noch unklar. ...
Bei der Parkinson-Erkrankung treten unter dopaminerger Therapie nach einigen Jahren Wirkfluktuationen in Form von kurzen Wearing-OFF-Phasen auf. Später können längere OFF-Phasen und Dyskinesien hinzukommen und nach zehn Jahren bestehen ausgeprägte Wirkschwankungen. Parenteral applizierbare Therapeutika wie Rotigotin-Pflaster, Apomorphin-Pen und -Pumpe sowie L-Dopa-Pumpen können hier eine sinnvolle Ergänzung und Fortführung der oralen medikamentösen Therapie sein.
... Although rare cases of acute PN in patients on high doses of oral LD were reported, such pattern seems far more frequent in patients on CLDII [27,44,54] (Table 2). ...
Background:
In recent years, non-motor features of Parkinson's disease (PD) have received increasing attention and PD is currently considered a systemic rather than a pure basal ganglia disorder. Among the systemic features, peripheral neuropathy (PN) is a recent acquisition since the first case-control study reporting increased frequency of PN in PD dates back to 2008.
Methods:
We reviewed available literature on peripheral nervous system (PNS) involvement in PD.
Results:
Evidence of α-synuclein deposition in the PNS and small nerve fiber deterioration in both drug-naïve and treated PD patients is becoming stronger. In addition, several recent reports documented a significant role of levodopa exposure together with group B vitamin deficiency in facilitating the development of PN and case reports suggested that treatment with continuous levodopa intestinal infusion may increase the risk of acute PN compared to both oral levodopa and other dopaminergic treatments.
Conclusion:
It is currently debated whether PN is an intrinsic disease-related feature, a consequence of levodopa treatment or both. In this review, we will discuss the different hypotheses, as well as our perspective on open issues and controversies.
... A recently performed observational study of patients treated with oral medication, compared with LCIG-treated patients, suggests a LCIG-specific neuropathy [89]. A prospective assessment study performed by Merola et al. [90] found moderate signs of neuropathy in 21.4 % of their subjects and observed a correlation between electrophysiological alterations and plasma vitamin B 12 levels. Recently, new cases involving development of polyneuropathy during LCIG treatment, but also during long-term high-dose oral levodopa treatment, have been reported [91,92]. ...
Development of motor and non-motor complications during the course of Parkinson's disease (PD) is a major challenge for therapeutic management. At advanced disease stages, patients frequently fluctuate between PD symptoms-such as bradykinesia-and dyskinesias, in response to fluctuations in drug concentrations. Continuous subcutaneous infusion of the dopamine agonist apomorphine or intestinal infusion of levodopa reduce such fluctuations in both pharmacokinetics and motor function. This is the basis for the concept of continuous drug delivery in PD, and the more theoretical concept of continuous dopaminergic stimulation. These expressions are sometimes used to describe a treatment that is more continuous in its pharmacokinetic profile or that produces more sustained effects, compared with immediate-release levodopa, i.e. not only pump treatments. For example, sustained-release formulations of levodopa or dopamine agonists, transdermal delivery of rotigotine, and addition of catechol-O-methyltransferase inhibitors or monoamine oxidase-B inhibitors have been developed with the aim to provide more continuous drug concentrations, sustained benefits and minimized side effects. Progress has been made, but there are still knowledge gaps regarding how these treatment alternatives can be optimally used. New treatments are currently being developed to provide the continuous drug delivery that is known to successfully alleviate motor and non-motor complications. Hopefully, although not yet proven, these new methods may also prevent or postpone some of the late-stage complications.
... LCIG treatment was not interrupted in these subjects, but vitamin B12 supplementation and strict clinical and electrophysiological monitoring was carried out. These cases are described in greater detail in a separate report on the prospective assessment of peripheral neuropathy in LCIG-treated patients recently published by our group [26]. ...
Levodopa/carbidopa intestinal gel (LCIG) infusion is nowadays becoming an established therapeutic option for advanced Parkinson's disease (PD) patients with fluctuating symptoms unresponsive to conventional oral treatment. As the implementation of LCIG therapy is increasing, there is a need for safety and efficacy data from current clinical practice.
All PD patients treated with LCIG at our centre over a 7-year period were analysed to determine the duration of treatment, retention rate, reasons for discontinuation, LCIG efficacy in motor complications, modifications of concomitant therapy and adverse events.
Of the 59 patients, seven subjects (12%) died of causes unrelated to LCIG infusion and 11 patients (19%) discontinued therapy prior to the cut-off date. Duodopa improved motor complications and over 90% of patients reported an improvement in their quality of life, autonomy and clinical global status. The most common adverse events were dislocation and kinking of the intestinal tube.
LCIG infusion is effective for the long-term treatment of advanced PD patients and exerts a positive and clinically significant effect on motor complications with a relatively low dropout rate.
Neuropathies associated with nutritional deficiencies are routinely encountered by the practicing neurologist. Though these neuropathies assume different patterns, most are length‐dependent, sensory axonopathies. Cobalamin deficiency neuropathy is the exception, often presenting with a non‐length‐dependent sensory neuropathy. Patients with cobalamin and copper deficiency neuropathy characteristically have concomitant myelopathy, whereas vitamin E deficiency is uniquely associated with a spinocerebellar syndrome. In contrast to those nutrients for which deficiencies produce neuropathies, pyridoxine toxicity results in a non‐length‐dependent sensory neuronopathy. Deficiencies occur in the context of malnutrition, malabsorption, increased nutrient loss (such as with dialysis), autoimmune conditions such as pernicious anemia, and with certain drugs that inhibit nutrient absorption. When promptly identified, therapeutic nutrient supplementation may result in stabilization or improvement of these neuropathies. This article is protected by copyright. All rights reserved.
Zielsetzung der Studie war es, Ablagerungen des phosphorylierten Alpha-Synucleins in der Haut von Patienten mit Morbus Parkinson und atypischen Parkinson-Syndromen zu untersuchen und deren Auswirkungen auf das periphere Nervensystem zu erforschen. Dazu wurden Hautbiopsien von 92 Patienten mit Morbus Parkinson, 12 Patienten mit MSA und 13 Patienten mit einer Tauopathie sowie 83 gesunden Kontrollpersonen immunhisto-chemisch gefärbt und unter dem Mikroskop untersucht. Mit einer Sensitivität von 52 % für den Morbus Parkinson und 67 % für die MSA bei hoher Spezifität stellt der Nachweis von Phospho-Alpha-Synuclein in den kleinen Nervenfasern der Haut einen geeigneten Biomarker dar. Während die Ablagerungen des phosphorylierten Alpha-Synucleins bei Patienten mit Morbus Parkinson eher in autonomen Strukturen nachweisbar waren, fanden sie sich bei Patienten mit MSA eher in sub- und intraepidermal gelegenen Nervenfasern. Phospho-Alpha-Synuclein konnte in allen untersuchten Nervenfasersubtypen nachgewiesen werden, also in CGRP-, SP-, TH- und VIP-positiven Fasern. Bei den in der vorliegenden Studie untersuchten Parkinson-Patienten waren keine Veränderungen in der sensiblen Neurographie des Nervus suralis erkennbar. Die intraepidermale Nervenfaserdichte sowie die Innervation der Schweißdrüsen waren jedoch teilweise vermindert und auch in der QST zeigten sich Auffälligkeiten. Ein Zusammenhang zu dem Vorhandensein von Phospho-Alpha-Synuclein-Ablagerungen konnte jedoch nur für die Innervation der Musculi arrectores pilorum hergestellt werden. Bei der Untersuchung der pathophysiologischen Hintergründe, durch die Phospho-Alpha-Synuclein-Ablagerungen zu Nervenfaserschädigungen führen, konnten die Hinweise auf eine Beteiligung von axonalen Transportproteinen, Mikrotubuli oder Mitochondrien nicht erhärtet werden.
Background:
Polyneuropathy (pnp) is recognized as a clinical feature of Parkinson's disease (PD). Whether pnp is a result of the alpha-synucleinopathy or related to treatment is debated. Previous studies support underlying disturbances in the methionine cycle mediated by L-dopa.
Objective:
Describe possible relationships between methionine cycle metabolism and the development of pnp in L-dopa treated PD. Furthermore, we aim to investigate possible genetic risk factors by genotyping specific SNPs in enzymes involved in the abovementioned pathways.
Methods:
In a cross-sectional study design, L-dopa treated PD patients (n = 33) and controls (n = 16) were evaluated with biochemical and genetic analyses. Subjects were assessed clinically and with regards to signs of pnp using established clinical neuropathy rating scales.
Results:
16/33 patients fulfilled a study diagnosis of pnp compared to 0 age-matched controls. Levels of homocysteine (Hcy) were significantly higher in patients with pnp (n = 16) compared to controls. A significant correlation between neuropathy scores and Hcy was seen in the whole patient group (n = 33). A significant difference in the genotype distribution of the COMT A158G polymorphism was demonstrated, favoring the low activity genotype in patients with pnp compared to both controls and patients without pnp.
Conclusions:
Pnp is a prevalent condition in L-dopa treated PD and an association may exist with elevated levels of Hcy, possibly reflecting an underlying impaired cellular methylation capacity. Furthermore, an association may exist between the low activity COMT genotype and pnp. These preliminary findings and the suggested pathophysiological mechanisms should be confirmed in future large-scale studies.
Introduction:
Peripheral neuropathy related to levodopa/carbidopa intestinal gel (LCIG) therapy for advanced Parkinson disease (PD) is under investigation and is debated in the literature. The purpose of the study was to detect whether small nerve fibers are damaged during LCIG infusion.
Methods:
Five advanced PD patients were enrolled prior to starting LCIG infusion. Six PD patients on oral levodopa (LD) treatment and 6 PD patients naïve to LD were also enrolled. Clinical examination, the Quantitative Sensory Testing battery testing, nerve conduction studies, and intraepidermal nerve fiber density examinations were collected at baseline and at 3, 6, and 12 months after LCIG infusion was started in the study cohort.
Results:
After 3, 6, and 12 months, severe skin denervation and increased thermal thresholds were observed in the LCIG group.
Conclusions:
Significant damage to small nerve fibers was detected in PD patients soon after LCIG infusion had started, suggesting careful monitoring of small fiber impairment during LCIG is needed. Muscle Nerve, 2016.
Background:
Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) can effectively manage motor and non-motor complications in advanced Parkinson's disease (PD). Healthcare costs, quality of life (QoL), effectiveness, and tolerability were assessed in routine care treatment with LCIG.
Methods:
The seventy-seven patients enrolled in this prospective, open-label, 3-year study in routine medical care were LCIG-naïve (N = 37), or had previous LCIG treatment for <2 (N = 22), or ≥2 (N = 18) years. Healthcare costs were collected monthly. PD symptoms and QoL were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQoL 5-Dimension Visual Analog Scale (EQ-5D VAS); LCIG dose, safety, and tolerability were monitored.
Results:
Mean monthly costs per patient (€8226 ± 5952) were similar across cohorts, remained steady during 3-year follow-up, and increased with PD severity and QoL impairment. In LCIG-naïve patients, significant improvements compared to baseline were observed on the UPDRS total score and PDQ-39 summary index score through 18 months (n = 24; UPDRS, p = 0.033; PDQ-39, p = 0.049). Symptom control was maintained during 3-year follow-up in LCIG-experienced cohorts. Small changes in mean daily LCIG dose were observed. Adverse events were common and generally related to the device, procedure, levodopa, or laboratory evaluations.
Conclusions:
Costs in LCIG-treated patients were stable over 3 years. LCIG treatment led to significant improvements in motor function and QoL over 18 months in LCIG-naïve patients and no worsening was observed in LCIG-experienced patients over 3 years despite natural PD progression over time. The long-term safety was consistent with the established LCIG profile.
Introduction:
Intermittent oral delivery of levodopa is a major contributing factor for motor complications in Parkinson's disease (PD). Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) into the jejunum using a portable pump via percutaneous endoscopic gastrostomy (PEG) improves motor complications and quality of life (QoL).
Objectives:
To record long-term effectiveness of advanced PD patients undergoing LCIG infusion in routine care, by Unified Parkinson's Disease Rating Scale (UPDRS), Non-Motor Symptoms Scale (NMSS), PDQ-8 and EQ-5D questionnaires.
Methods:
Overall, 375 patients from 75 movement disorder centers in 18 countries were enrolled in this prospective non-interventional study. The 12-month interim outcomes of the first 172 included patients are presented here.
Results:
There were reductions of mean daily "Off" time from baseline (BL) (7.1 ± 3.5 h) and "On" time with dyskinesias (5.2 ± 4.5 h) at month 12 (M12) of -4.7 ± 3.4 and -1.7 ± 5.0 h respectively (p < 0.0001; p = 0.0228). UPDRS II and III "On" scores decreased from BL to M12 (p = 0.0107 and p = 0.0128). Total NMSS and PDQ-8 scores improved at M12 (p = 0.0014 and p = 0.0100). Mean LCIG dose administered through PEG at first visit (day after implantation) was 1304 ± 618 mg/day and remained stable through M12. Continuous LCIG infusion tolerability and adverse drug reactions were consistent with the known safety profile of previous studies.
Conclusions:
This observational, routine-care study supports long-term safety and efficacy of LCIG infusion in advanced PD including motor, non-motor and QoL improvements.
Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak- Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.
Patients with Parkinson's disease (PD) treated with oral levodopa have a higher prevalence of chronic, prevalently sensory, usually mild axonal polyneuropathy (PNP). Several studies showed a positive association among PNP, cumulative levodopa dosage, low serum B12 and high-homocysteine and methylmalonic acid level. Anecdotal severe acute or subacute PNPs thought to be Guillain-Barré syndrome have been reported in patients receiving continuous intraduodenal infusion of levodopa/carbidopa intestinal gel (LCIG). We report an additional acute case and by a systematic literature search we also reviewed the clinical and laboratory features of 13 other acute and 21 subacute PNP cases occurring during LCIG treatment. In series with at least nine patients, the mean frequency of acute and subacute PNP is 13.6% and the mortality rate at 6 months in acute cases is 14%. The great majority of PNP cases displayed axonal sensory-motor and reduced vitamin B12 levels, and alterations of metabolites of 1-carbon pathway were found in most patients. We discuss the possible role of high-levodopa dosage, vitamin B12, B6 and folate deficiency and accumulation of homocysteine and methylmalonic acid in the pathogenesis to conclude that there is enough, although circumstantial, evidence that alterations of 1-carbon pathway are implicated also in acute and subacute PNP during LCIG usage. There is no solid proof for a dysimmune pathogenesis and in our opinion acute, subacute and chronic PNP, either after oral levodopa or LCIG, represent a continuum. Finally, we propose recommendations for prevention and management of PNP occurring during LCIG treatment.
Continuous infusion of intraduodenal levodopa/carbidopa is an effective treatment that improves the motor complications and the quality of life of patients in the advanced stages of Parkinson's disease. However, it is not free of complications. These may present in the post-operative period following surgery (gastrostomy) or in the long-term during the follow-up period and can be related with the medication (levodopa/carbidopa), the stoma, the gastrostomy or the device (pump, enteral tube, parts of the FREKA system). The aim of this review is to report on the management of the complications that can be observed in patients with advanced Parkinson's disease treated with continuous infusion of intraduodenal levodopa/carbidopa.
A new peripheral neuropathy activities measure, the Overall Neuropathy Limitations Scale (ONLS), was derived by modifying the Overall Disability Sum Score (ODSS) slightly. Its inter-rater reliability was found to be high and its correlation with the ODSS (r = 0.97), 36-item Short Form Questionnaire Physical Component Summary Score, and participation and impairment measures was significant. Acceptable responsiveness (standardised response mean 0.76) was shown by the ONLS. The results obtained from the questionnaire agreed closely with those obtained from observation of the tasks on the ONLS, but were not equivalent. The simplicity of the ODSS is shared by the ONLS, but the ONLS has better content validity and less ceiling effect, which may make it more useful for clinical practice and research.
Dr. Kimura has built upon his extensive experience teaching electromyography (EMG) around the world and has transferred his knowledge to this resource, which is intended for clinicians who perform electrodiagnostic procedures as an extension of their clinical examination. It covers noninvasive electrodiagnostic methods, particularly electromyography (EMG). This resource provides a comprehensive review of most peripheral nerve and muscle diseases, including specific techniques and locations for performing each test.
Background:
This interim 12-month analysis is a part of an open-label, observational, prospective study on health outcomes and cost impact of levodopa/carbidopa intestinal gel (LCIG, Duodopa) in Parkinson disease (PD). The specific aim was to investigate clinical and health-related quality of life (HRQoL) effects in routine care.
Methods:
Unified PD rating scale (UPDRS) was the primary efficacy measurement. PD QoL questionnaire 39 (PDQ-39) assessed HRQoL. Subjects were assessed at baseline, ≥3 months after surgery, and then every 3 months.
Results:
Twenty-seven treatment-naïve subjects when started with LCIG showed a decrease in UPDRS score that was statistically significant throughout the year: UPDRS total score (mean ± SD), baseline = 52.1 ± 16.1, N = 27, month 0 (first visit; at least 3 months after permanent LCIG) = 43.1 ± 16.7, N = 27, P = 0.003; month 12 = 42.5 ± 22.6, n = 25, P = 0.017. PDQ-39 results also showed a tendency for improvement: PDQ-39 (mean ± SD), baseline = 33.6 ± 10.8, N = 27, month 0 = 27.1 ± 11.8, N = 27, P = 0.001; 12 months = 28.8 ± 12.8, n = 23, P = 0.126.
Conclusions:
LCIG provides functional improvement beginning at first visit that is sustained for 12 months.
To ascertain the prevalence and determinants of neuropathy in patients with Parkinson disease (PD), in particular, the roles of vitamin B12 and levodopa exposure.
We performed a cross-sectional study of 37 patients with PD and 37 age- and gender-matched controls, using a sensitive and validated neuropathy scale. The prevalence of neuropathy was determined and compared between groups. We then ascertained the role of vitamin B12 by a separate case-control analysis (1) comparing numbers of patients in whom the neuropathy was directly attributable to vitamin B12 deficiency and (2) comparing serum vitamin B12 levels in patients with PD with neuropathy with a second control group consisting of age- and gender-matched consecutive patients with neuropathy without PD. We also determined correlations between cumulative levodopa exposure, PD duration, neuropathy status and score, and vitamin B12 status and levels in all patients with PD and, specifically, in those with neuropathy.
Fourteen of 37 (37.8%) patients with PD and 3 of 37 (8.1%) control subjects had neuropathy (p = 0.005), corresponding to an odds ratio (95% confidence interval) for neuropathy, of 6.9 (1.78-26.73). Vitamin B12 deficiency was a significantly more common cause of neuropathy (p = 0.024) and vitamin B12 levels were significantly lower (p = 0.002) in patients with PD with neuropathy than in age- and gender-matched consecutive control subjects with neuropathy without PD. Cumulative levodopa exposure correlated with PD duration (p = 0.001) and vitamin B12 levels (p = 0.044), in patients with PD with neuropathy.
Neuropathy is more prevalent in patients with PD than in control subjects. This may be predominantly due to vitamin B12 deficiency, which could relate to cumulative levodopa exposure in susceptible individuals. Vitamin B12 monitoring and supplementation, as well as serial clinical assessment for neuropathy, may be advisable in patients with PD.
Levodopa/Carbidopa intestinal gel infusion (LCIG) for Parkinson's disease is under debate to provoke polyneuropathy (PNP). In our cohort of 20 thus treated patients, two developed debilitating axonal PNP with deficient pyridoxin and folate levels, and marginal cobalamin. Homocysteine was highly elevated. The neuropathies responded to vitamin replacement. We assume that LCIG can provoke PNP most likely of malnutritional origin. To avoid this side effect, the assessment of predisposing factors before treatment as well as neurophysiological and laboratory screenings appear necessary.
This article reviews literature on three emergencies in Parkinson's disease (PD): Akinetic crisis, severe dyskinesias or life-threatening dyskinesias, and polyneuropathy during duodenal L-Dopa gel infusion treatment. Akinetic crisis is also known as Parkinsonian hyperpyrexia, Neuroleptic-like malignant syndrome, Acute akinesia, and Malignant syndrome in parkinsonism. It appears in 0.3% of PD patients/year, and is characterized in the most severe cases by total akinesia with dysphagia, hyperthermia, dysautonomia, increment of muscle enzymes and alterations of mental status, but it may also appear in less severe forms ("forme frusta"). At difference with the continuum of motor hypokinesias observed in PD it is characterized by transient (in cases with favorable outcome) unresponsiveness to rescue drugs. Life-supporting measures are mandatory in patients affected by this emergency. Severe dyskinesia, or life-threatening dyskinesia, is due to increased dopaminergic stimulation (either by the patient or by the prescriber): when it appears the level of dopaminomimetic stimulation should be reduced. Polyneuropathy during duodenal L-Dopa gel infusion is a recently described complication, attributed to the onset of Guillain-Barré syndromes. However, hemapheresis was not effective in some reported cases, and recent evidence suggests that Vitamin B12 deficiency or direct high-dose chronic L-Dopa toxicity might play a role in its origin.
We describe two patients who developed subacute axonal peripheral neuropathy under duodopa treatment. Comprehensive diagnostic workup including muscle and sural nerve biopsy revealed that the most probable cause of subacute axonal peripheral neuropathy was cobalamin and vitamin B6 deficiency in both the patients.
Peripheral neuropathy (PN) is thought to be coincidental in patients with idiopathic Parkinson disease (IPD). We sought to examine the prevalence of PN in a population of IPD patients and a potential relationship to levodopa use and fasting methylmalonic acid (MMA) levels.
In a prospective cohort study, IPD patients randomly selected from a comprehensive database were compared to control subjects regarding the presence and severity of PN using clinical and electrophysiological measures. IPD severity was determined using the Unified Parkinson's Disease Rating Scale (UPDRS). We determined the relation of levodopa use with serum levels of cobalamin, MMA, and homocysteine (Hcy). We also explored the association between presence and severity of PN and age, duration of IPD, cumulative levodopa dosing, cobalamin, MMA, and Hcy levels.
Fifty-eight randomly selected IPD patients were compared to 58 age- and sex-matched controls. PN was present in 55% of IPD patients and 9% of controls. Patients with IPD had greater prevalence of PN and fasting MMA/Hcy levels than controls. IPD patients with PN were older and exhibited higher UPDRS scores, fasting MMA/Hcy levels, and cumulative levodopa exposure. PN severity in IPD subjects positively correlated with both levodopa exposure and MMA levels.
IPD patients have a higher prevalence of PN than controls. Although causality is not established, levodopa exposure is associated with MMA elevation and sensorimotor neuropathy in IPD patients. Cobalamin replacement concurrent with levodopa therapy should be considered to protect against development of PN in IPD patients.
In studies of Guillain-Barré syndrome, functional deficit is usually assessed according to a functional scale consisting of several categories. The level of interobserver agreement in this scoring method is not known; furthermore, this method seems to be insensitive when applied to bedridden and artificially ventilated patients. We have developed an additional score (MRC-sumscore), reflecting muscle strength in general. Both scoring methods, tested in Guillain-Barré patients, have an almost perfect interobserver agreement. For the functional score kappa = 0.85, and for the MRC-sumscore r2 = 0.96. The MRC-sumscore is easily assessed and more sensitive than the functional score when patients are bedridden or artificially ventilated.
To perform a psychometric evaluation of the inflammatory neuropathy cause and treatment (INCAT) sensory sumscore (ISS) in sensory-motor immune-mediated polyneuropathies. This new sensory scale was evaluated to strive for uniformity in assessing sensory deficit in these disorders.
The ISS comprises vibration and pinprick sense plus a two-point discrimination value and ranges from 0 (normal sensation) to 20 (maximum sensory deficit). Before its clinical use, a panel of expert neurologists concluded that the ISS has face and content validity. The construct validity of the ISS was investigated by correlation and regression studies with additional scales (Nine-Hole Peg Test, 10-Meter Walking Test, a disability sumscore). All scales were applied in 113 patients with a stable neurologic condition (83 patients who experienced Guillain-Barre syndrome [GBS] in the past, 22 with chronic inflammatory demyelinating polyneuropathy [CIDP], 8 patients with a monoclonal gammopathy associated polyneuropathy), and 10 patients with recently diagnosed GBS or CIDP with changing clinical conditions. Reliability of the ISS was evaluated in the stable patients. Its responsiveness was investigated in the patients examined longitudinally.
A moderate to good validity was obtained for the ISS (stable group: r = 0.38 to 0.56, p < or = 0.006; longitudinal group: R = 0.60 to 0.82, p < or = 0.007, except for the association with the 10-Meter Walking Test [p = 0.08]). Acceptable internal consistency, and inter- and intraobserver reliability were demonstrated for the ISS (alpha = 0.68 to 0.87; R = 0.85 to 0.89, p < 0.0001). Standardized response mean scores for the ISS were high (> or =0.8), indicating good responsiveness.
All psychometric requirements are provided for the the inflammatory neuropathy cause and treatment sensory sumscore. The use of this scale is therefore suggested for bedside evaluation of sensory deficit in the individual patient with a sensory-motor immune-mediated polyneuropathy as well as in clinical trials.
We assessed prospectively clinical and quality of life changes in 9 patients with Parkinson's disease (PD; H&Y > or = 3) with severe motor fluctuations and dyskinesia who started continuous daily levodopa duodenal infusion through percutaneous endoscopic gastrostomy. Seven patients completed the follow-up period. Duration of "off" periods and time with disabling dyskinesia shortened significantly in all patients (P < 0.01). Total daily dose of levodopa infused did not differ from baseline equivalents. There were significant improvements in UPDRS-II (activities of daily living) and -IV (motor complications) in the "on" condition (P < 0.02), and in four PDQ-39 domains (mobility, activities of daily living, stigma, bodily discomfort; P < 0.05). Two patients withdrew for adverse events. Our results demonstrate that a satisfactory therapeutic window can be achieved and maintained for several months in advanced PD patients.
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Levodopa, methylmalonic acid, and neuropathy in idiopathic Parkinson disease
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Duodenal levodopa infusion for advanced Parkinson's disease: 12-month treatment outcome
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Reversible encephalopathy and axonal neuropathy in Parkinson's disease during duodopa therapy
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Subacute axonal neuropathy in Parkinson's disease with cobalamin and vitamin B6 deficiency under duodopa therapy
- Pp Urban
- I Wellach
- S Faiss
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