Permanent non-progressive cinnarizine and flunarizine-induced parkinsonism: An under-recognized tardive syndrome in the elderly?

Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.

Generalized Rhythmic Delta Activity Frontally Predominant Differentiates Dementia with Lewy Bodies From Alzheimer's Disease and Parkinson's Disease Dementia: A Conventional Electroencephalography Visual Analysis.

Introduction. An easily accessible and inexpensive neurophysiological technique such as conventional electroencephalography may provide an accurate and generally applicable biomarker capable of differentiating dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and Parkinson's disease-associated dementia (PDD). Method. We carried out a retrospective visual analysis of resting-state electroencephalography (EEG) recording of 22 patients with a clinical diagnosis of 19 probable and 3 possible DLB, 22 patients with probable AD and 21 with PDD, matched for age, duration, and severity of cognitive impairment. Results. By using the grand total EEG scoring method, the total score and generalized rhythmic delta activity frontally predominant (GRDAfp) alone or, even better, coupled with a slowing of frequency of background activity (FBA) and its reduced reactivity differentiated DLB from AD at an individual level with an high accuracy similar to that obtained with quantitative EEG (qEEG). GRDAfp alone could also differentiate DLB from PDD with a similar level of diagnostic accuracy. AD differed from PDD only for a slowing of FBA. The duration and severity of cognitive impairment did not differ between DLB patients with and without GRDAfp, indicating that this abnormal EEG pattern should not be regarded as a disease progression marker. Conclusions. The findings of this investigation revalorize the role of conventional EEG in the diagnostic workup of degenerative dementias suggesting the potential inclusion of GRDAfp alone or better coupled with the slowing of FBA and its reduced reactivity, in the list of supportive diagnostic biomarkers of DLB.

Non-length-dependent somatosensory small fiber pathology presenting with restless legs syndrome in pre-motor Parkinson's disease. Evidence from skin biopsy in four patients.

BACKGROUND: The determinants of restless legs syndrome (RLS) occurring in co-morbid association with Parkinson's disease (PD) are currently unknown. METHODS: We performed a skin biopsy in proximal and distal sites of lower limbs in four PD patients, in which RLS had emerged in the pre-motor phase. RESULTS: A reduced somato-sensory intraepidermal nerve fiber (IENF) density mainly in the proximal sites, indicative of non-length-dependent small fiber pathology (SFP), was found in all patients, in absence of electroneurographic signs of large fiber neuropathy. DISCUSSION: The lack of known secondary causes of SFP is consistent with a process intrinsic to PD and, likewise, the absence of known disease conditions associated to RLS, would support the view of a link between the latter disorder and the distal axonopathy. The non-length-dependent pattern of SFP suggest an involvement of the somato-sensory dorsal root ganglia small neurons, consistent with a somato-sensory neuronopathy, which characterizes the RLS in these patients. CONCLUSION: If these findings will be confirmed in a larger cohort of patients, the RLS co-morbid with PD should be regarded as an heterogeneous condition, since the one emerging in the pre-motor phase might represent a prodromal feature of the neurodegenerative disease as an epiphenomenon of somato-sensory SFP. In contrast, for the RLS developing in clinically manifest PD, a possible association with the impairment of the DAergic diencephalo-spinal pathway and the induction by chronic DAergic treatment has been hypothesized.

A prospective study of the cumulative incidence and course of restless legs syndrome in de novo patients with Parkinson's disease during chronic dopaminergic therapy.

The authors report the cumulative incidence of Restless Legs Syndrome (RLS) over a 3 years follow-up period in 92 de novo Parkinson's disease patients under chronic dopaminergic therapy and the clinical course of the sensory-motor disorder over 12 months as from its onset. The overall cumulative incidence of RLS was found by 15.3%, i.e. 14 incident cases, and by 11.9%, i.e. 11 incident cases, after the exclusion of possible "secondary" forms of the disorder. These figures are higher than those reported in general population in Germany (Study of Health in Pomerania), confirming our previous findings of incidence rate of the disorder. At the end of the 3 years follow-up period the prevalence of "current" RLS was significantly higher than that previously found in drug naïve Parkinson's disease patients and in controls, supporting the view that RLS emerging in the course of chronic dopaminergic therapy is the main determinant of the co-morbid association with Parkinson's disease. During the 12 months period of observation the RLS showed a frequency of occurrence of 6.08 episodes per month on average and a remittent clinical course was prevailing in the 11 incident cases, with a significant frequency decrease in the second as compared to the first 6 months, i.e. 3.26 versus 8.9 episodes per month, and none of the patients developed augmentation in the same period. It is hypothesized that the remittent course could be due to long-term adaptation (downregulation) of the hypersensitive post-synaptic dopamine receptors in the spinal cord to a continuous dopaminergic stimulation, possibly coupled with compensatory up-regulation of pre-synaptic dopamine re-uptake mechanism, in the patients in which the hypothalamic A11 area, site of origin of the dopamine-mediated diencephalo-spinal pathway, is involved in the neurodegenerative process.

A long-term prospective follow-up study of incident RLS in the course of chronic DAergic therapy in newly diagnosed untreated patients with Parkinson's disease.

It is currently controversial if and in which terms Parkinson's disease (PD) and restless legs syndrome (RLS) are linked in co-morbid association. In a cohort of 106 de novo PD patients (67 male and 39 female, aged 42-83 years), 15 of them developed RLS, which was prospectively assessed at 6-month intervals from the starting of dopamine(DA)ergic therapy. The incidence rate of total RLS was 47 per 1,000 case/person per year and 37 per 1,000 case/person per year after the exclusion of possible "secondary" forms of the disorder (n = 3). These figures are higher than those reported in an incidence study conducted in German general population (Study of Health in Pomerania), in which the method of ascertainment of RLS similar to ours has been used. An incidence rate of total RLS significantly higher than that reported in the above-mentioned study was found in the age ranges 55-64 years and in the age range 45-74 years standardized to European general population 2013  (70 and 53 per 1,000 case/person per year, respectively, p < 0.01). Ten out of 12 patients (83.3 %) developed RLS within 24 months from the starting of DAergic medication (median latency 7.5 months). These findings support the view that sustained DAergic therapy could represent the critical factor inducing an increased incidence of RLS in patients with PD and that the latter disease should be regarded as the condition predisposing to the occurrence of the former and not viceversa as previously hypothesized. The mechanism underlying the increased incidence of RLS remains unclear and deserves further investigation.

A study of the prevalence of restless legs syndrome in previously untreated Parkinson's disease patients: absence of co-morbid association.

OBJECTIVE: The co-morbidity between Parkinson's disease (PD) and restless legs syndrome (RLS) is currently controversial, mainly because in most of the studies so far conducted, the patients were already on therapy with dopamine(DA)ergic drugs. This study has been carried out to assess the prevalence of RLS in de novo PD patients previously unexposed to DAergic drugs. METHODS: One hundred nine cognitively unimpaired outpatients with PD (70M/39F), mean age 66.89 years±9.37 SD were included in the study. The mean duration of PD was 15.81 months±11.24 SD, and the median Hoehn and Yahr (H&Y) stage was 2 (range 1.5-3). All patients underwent interview to assess the occurrence of overall life-time and current "primary" form of RLS according to the criteria of the International RLS Study Group (IRLSSG). One hundred sixteen age and sex matched subjects (74M/42F, mean age 66.52.years±8.65 SD) free from a history of neurological diseases, were taken as controls and likewise interviewed. "Secondary" forms of RLS in both patients and controls were subsequently excluded. RESULTS: No significant difference was found (chi-square test) in the frequency of overall life-time and of current "primary" RLS between PD patients and controls (6 out of 109 versus 5 out of 116 and 3 out of 109 versus 3 out of 116, respectively). CONCLUSIONS: This survey does not support the concept of a co-morbid association between the two conditions and confirm indirectly the findings of previous studies reporting the onset of RLS after diagnosis of PD has been made in the great majority of patients and so likely on ongoing DAergic treatment. Therefore, we speculate that RLS occurring in these patients could be related to DAergic therapy for PD.

A case-control study of Parkinson's disease and tobacco use: gene-tobacco interactions.

A case-control study of genetic, environmental, and occupational risk factors for Parkinson's disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age-matched and gender-matched controls. Participants completed an interviewer-administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene-tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1-1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation.

Absence of co-morbidity of Parkinson disease and restless legs syndrome: a case-control study in patients attending a movement disorders clinic.

We have carried out a case-control survey of the prevalence of restless legs syndrome (RLS) in 118 Parkinson's disease out-patients with different stage of disease severity by using the International restless legs syndrome Study Group clinical criteria. This study failed to demonstrate a significantly augmented prevalence of either primary and secondary restless legs syndrome pooled together or primary restless legs syndrome alone among Parkinson's disease patients as compared to age and gender matched controls. The results of our survey do not confirm a significant co-morbid occurrence of the two disorders. However, an unavoidable limitation of this and all previous studies is that most of the patients examined were already treated with dopaminomimetic drugs, which could have abolished a mild unrecognized RLS anteceding the diagnosis of Parkinson's disease or possibly masked the subsequent emergence of the sensory-motor disorder following the onset of Parkinson's disease.

Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy.

As the occurrence of restless legs syndrome (RLS) in diabetes is controversial, the aim of this study was to assess the prevalence of RLS in a cohort of patients with diabetic neuropathy and to analyze the features of the associated neuropathy. We investigated the occurrence of RLS diagnosed in accordance with the criteria of the International Restless Legs Syndrome Study Group in a cohort of patients with polyneuropathy and mononeuropathy multiplex associated with diabetes mellitus (DM), or impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) in a retrospective study. RLS was present in 33/99 patients with neuropathy associated with DM/IGT/IFG (84 with distal polyneuropathy and 15 with multiple mononeuropathy). Comparing patients with or without RLS, small fiber sensory neuropathy was more common in the RLS patients (15/33 vs. 15/66), as were symptoms of burning feet (10/33 vs. 6/66). In several patients, RLS was responsive to neuropathic pain medications. The frequent occurrence of RLS in association with thermal dysesthesias may reflect the involvement of small sensory fibers in the form of hyperexcitable C fibers or A-delta fiber deafferentation. We suggest that RLS may be triggered by abnormal sensory inputs from small fibers, especially involved in neuropathy associated with DM/IGT/IFG. Our data show that RLS is a relevant feature of diabetic neuropathy, as a frequent and potentially treatable manifestation of small fiber involvement in the course of DM and IGT/IFG.