Adam Stępień

Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFα, and INFγ concentrations are elevated in patients with atypical and idiopathic parkinsonism

We investigated serum levels of interleukin (IL)-2, IL-10, IL-6, IL-4, TNFalpha, INFgamma in 7 patients with atypical parkinsonism (AP), 31 idiopathic PD (iPD) patients, 17 idiopathic PD with cardiovascular risk factor (iPD-CVRF) patients, and 20 age-matched controls (healthy, non-parkinsonian patients). Cytokine concentrations were measured using the Becton Dickinson (BD) human Th1/Th2 Cytokine kit II with a flow cytometry system. The concentrations of IL-2, IL-10, IL-4, IL-6, TNFalpha, and INFgamma were detectable in the serum from all groups, including the control. Increased serum IL-2, IL-10, IL-4, IL-6, TNFalpha, and INFgamma concentrations were found in all groups of parkinsonian patients, as compared to the control group. The highest elevations of serum IL-2, IL-4, IL-6, TNFalpha, and INFgamma concentrations were observed in AP patients, as compared to the iPD and iPD-CVRF groups. However, the serum IL-6 concentration was higher in the iPD-CVRF group than in the iPD group. The IL-10 level was significantly higher in all groups of PD patients relative to the control group, but was the lowest in the serum from the AP patients. Moreover, the serum levels of lipid peroxidation products were enhanced 2.1- and 1.5-fold in AP and both iPD groups, respectively. These results argue in favor of the involvement of immunological events in the process of neurodegeneration in AP and PD.

Diagnosis and management of neuropathic pain: review of literature and recommendations of the Polish Association for the study of pain and the Polish Neurological Society - part one.

Neuropathic pain may be caused by a variety of lesions or diseases of both the peripheral and central nervous system. The most common and best known syndromes of peripheral neuropathic pain are painful diabetic neuropathy, trigeminal and post-herpetic neuralgia, persistent post-operative and post-traumatic pain, complex regional pain syndrome, cancer-related neuropathic pain, HIV-related neuropathic pain and pain after amputation. The less common central pain comprises primarily central post-stroke pain, pain after spinal cord injury, central pain in Parkinson disease or in other neurodegenerative diseases, pain in syringomyelia and in multiple sclerosis. A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on various types of neuropathic pain, with special focus on the available international guidelines, and has formulated recommendations on their diagnosis and treatment, in accordance with the principles of evidence-based medicine (EBM). High quality studies on the efficacy of various medicines and medical procedures in many neuropathic pain syndromes are scarce, which makes the recommendations less robust.

Involvement of multiple protein kinases in cPLA2 phosphorylation, arachidonic acid release, and cell death in in vivo and in vitro models of 1‐methyl‐4‐phenylpyridinium‐induced parkinsonism – the possible key role of PKG

The study was aimed at investigating in vivo and in vitro the involvement of the cGMP/cGMP‐dependent protein kinase (PKG) signaling pathway in MPP+‐induced cytosolic phospholipase A2 (cPLA2) activation of dopaminergic neurons. MPP+ activated neuronal nitric oxide synthase (NOS)/soluble guanylyl cyclase/cGMP pathway in mouse midbrain and striatum, and in pheochromocytoma cell line 12 cells, and caused an upward shift in [Ca2+]i level in the latter. The activation was accompanied by increases in total and phosphorylated cPLA2, and increased arachidonic acid release. Effects of selective inhibitors [2‐oxo‐1,1,1‐trifluoro‐6,9‐12,15‐heneicosatetraene (AACOCF3), (E)‐6‐(bromomethylene)tetrahydro‐3‐(1‐naphthalenyl)2h‐pyran‐2‐one (BEL)] indicated the main impact of cPLA2 on arachidonic acid release in pheochromocytoma cell line 12 cells. Treatment of the cells with the protein kinase inhibitors GF102610x, UO126, and KT5823, and with the nitric oxide synthase (NOS) inhibitor NNLA revealed the involvement of protein kinase C (PKC) and extracellular signal‐regulated kinases 1 and 2 (ERK 1/2), with the possible key role of PKG, in cPLA2 phosphorylation at Ser505. Inhibitors of cPLA2 and PKG increased viability and reduced MPP+‐induced apoptosis of the cells. Our results indicate that the neuronal NOS/cGMP/PKG pathway stimulates cPLA2 phosphorylation at Ser505 by activating PKC and ERK1/2, and suggest that up‐regulation of this pathway in experimental models of Parkinson’s disease may mediate dopaminergic neuron degeneration and death through activation of cPLA2.

Pergolide mesylate, a dopaminergic receptor agonist, applied with L-DOPA enhances serum antioxidant enzyme activity in Parkinson disease.

The aim of this study was to compare patients with Parkinson disease (PD) patients treated with pergolide mesylate (PM), a dopaminergic receptor agonist, together with l-DOPA and those these treated with l-DOPA alone on the concentration of free radicals (FR), glutathione, and the activity of superoxide dismutase (SOD) and catalase in the serum. The study was carried out using 16 age-matched control subjects, 16 PD patients treated with l-DOPA at a dose of 1 to 1.5 g daily, and 16 PD patients treated with l-DOPA 1 to 1.5 g daily with PM 0.75 to 1.25 mg daily. The mean duration of treatment of PD was 6 years (range, 2–8 years) with l-DOPA, and 2 years with PM + l-DOPA or l-DOPA alone. Although there was no significant difference in lipid peroxidation products among the 3 groups, patients treated with l-DOPA showed high levels of FR as determined by dichlorofluorescein. Although catalase and SOD activities were elevated in both groups of PD patients, additional treatment with PM further enhanced catalase activity compared with those treated with l-DOPA alone. Interestingly, patients treated with PM + l-DOPA showed a significantly increased level of glutathione compared with those treated with l-DOPA alone. Collectively, these data suggest that PM + l-DOPA is a more efficient therapy in maintaining an antioxidative defense in PD patients compared with treatment with l-DOPA alone.

Effects of interferon β-1a and interferon β-1b monotherapies on selected serum cytokines and nitrite levels in patients with relapsing-remitting multiple sclerosis: a 3-year longitudinal study.

Objective: Interferon (IFN)β treatment is a mainstay of relapsing-remitting multiple sclerosis (RRMS) immunotherapy. Its efficacy is supposedly a consequence of impaired trafficking of inflammatory cells into the central nervous system and modification of the proinflammatory/antiinflammatory cytokine balance. However, the effects of long-term monotherapy using various IFNβ preparations on cytokine profiles and the relevance of these effects for the therapy outcome have not yet been elucidated. Methods: Changes were compared in serum levels of TNFα, IFNγ, interleukin (IL)-6, IL-10 and nitrite between RRMS patients given 3-year treatment with intramuscular IFNβ-1a (30 μg once a week) or subcutaneous IFNβ-1b (250 μg every other day). Only the data from patients who completed the 3-year study (n = 20 and n = 18, respectively) were analyzed. Results: Three-year IFNβ-1a or IFNβ-1b monotherapy reduced serum nitrite levels by 77 and 71%, respectively, lowered multiple sclerosis relapse annual rate by 70 and 71%, respectively, and significantly and similarly lowered Expanded Disability Status Scale scores in both study groups (by 0.9 on average). The two monotherapies showed little if any effect on cytokine levels and cytokine level ratios after the first year, but exerted diverging effects on these indices later on; the only exception was the IFNγ/IL-6 ratio that showed a monotonous rise in both study groups over the entire study period. Conclusion: During long-term IFNβ monotherapy, the levels of the studied cytokines show no relevance to the course of RRMS and neurological status of patients, whereas there seems to be a link between these clinical indices and the activity of nitric oxide-mediated pathways.

Clinical Application of Autologous Adipose Stem Cells in Patients with Multiple Sclerosis: Preliminary Results

The clinical outcome of autologous adipose stem cell (ASC) treatment of patients with multiple sclerosis (MS) was investigated following one year of observation. Methods. The clinical and MRI outcomes of 16 ASC-treated patients with RRMS and SPMS are reported after a one-year follow-up period. Results. At 18 months of follow-up, some patients showed “enticing” improvements on some exploratory efficacy measures, although a significant benefit was not observed for any measure across the entire group. Neither the progression of disability nor relapses were observed in any cases. In four patients, we found new gadolinium+ (Gd+) lesions on MRI. Our results indicate that ASC therapy is safe and does not produce any substantial side effects. Disease progression-free survival (PFS) of 18 months was seen in all patients with RRMS and SPMS. In these patients, EDSS scores did not progress above baseline scores. Gd-enhancing lesions were observed in two cases with RRMS, but these patients did not exhibit changes in EDSS score. Conclusion. Intrathecal treatment with ASCs is an attractive form of therapy for patients with MS but should be reserved for cases with aggressive disease progression, for cases that are still in the inflammatory phase, and for the malignant form.

Risk of vascular events in different manifestations of cerebral small vessel disease: A 2-year follow-up study with a control group

Background and purpose Natural course of cerebral small vessel disease (CSVD) has not yet been thoroughly studied. The aim of the single center study was to establish risk of vascular events or death in different manifestations of CSVD. Methods 150 consecutive, functionally independent patients with marked MRI features of CSVD and with recent lacunar stroke (n = 52, LS), deep hemorrhagic stroke (n = 20, HS), vascular parkinsonism (n = 28, VaP), vascular dementia (n = 50, VaD) and 55 controls (CG) with high atherothrombotic risk free of cerebrovascular events were prospectively recruited and followed for 24 months. Results Mean age and sex distribution were similar in CSVD and CG but patients with CSVD were less likely to have CAD (19% vs 40%, p = 0.02) and tended to have higher prevalence of diabetes (54% vs 37%, p = 0.11). The risk of vascular events or death was increased in any patients with moderate to severe white matter lesions at baseline MRI (HR 2.0; 95% CI 0.85–7.2), in CSVD (4.56; 95% CI 1.3–14.9) vs CG, regardless of its clinical manifestation: LS or HS (HR 4.70; 95% CI 1.3–16.2) and VaD or VaP (HR 4.59; 95% CI 1.3–15.7). Adjustment for confounders did not change the results substantially. Conclusions Patients with symptomatic CSVD regardless of the clinical (acute or chronic) manifestation had more than fourfold the risk of vascular events or death in 24 months of observation compared with controls with high atherothrombotic risk free of cerebrovascular events.

Significance of Haemodynamic and Haemostatic Factors in the Course of Different Manifestations of Cerebral Small Vessel Disease: The SHEF-CSVD Study-Study Rationale and Protocol.

Rationale. This paper describes the rationale and design of the SHEF-CSVD Study, which aims to determine the long-term clinical and radiological course of cerebral small vessel disease (CSVD) and to evaluate haemostatic and haemodynamic prognostic factors of the condition. Design. This single-centre, prospective, non-interventional cohort study will follow 150 consecutive patients with different clinical manifestations of CSVD (lacunar ischaemic stroke, vascular dementia, vascular parkinsonism or spontaneous deep, intracerebral haemorrhage) and 50 age- and sex-matched controls over a period of 24 months. The clinical and radiological course will be evaluated basing on a detailed neurological, neuropsychological and MRI examinations. Haemodynamic (cerebral vasoreactivity, 24 h blood pressure control) and haemostatic factors (markers of endothelial and platelet dysfunction, brachial artery flow-mediated dilatation test) will be determined. Discussion. The scheduled study will specifically address the issue of haemodynamic and haemostatic prognostic factors and their course over time in various clinical manifestations of CSVD. The findings may aid the development of prophylactic strategies and individualised treatment plans, which are critical during the early stages of the disease.

Degenerative pontine lesions in patients with familial narcolepsy

BACKGROUND AND PURPOSE Narcolepsy is characterized by chronic excessive daytime sleepiness with episodic sleep attacks. There are several associated symptoms of narcolepsy: cataplexy (bilateral muscle weakness without loss of consciousness provoked by an emotional trigger, e.g. laughter), sleep paralysis and hypnagogic-hypnopompic hallucinations. Most cases are sporadic; familial narcolepsy contributes to only 1-5% of all cases. While most cases of narcolepsy are idiopathic and are not associated with clinical or radiographic evidence of brain pathology, symptomatic or secondary narcolepsy may occur occasionally in association with lesions caused by tumours, demyelination or strokes of the diencephalon, midbrain, and pons. There are some examples of non-specific brainstem lesions found in magnetic resonance imaging (MRI) in patients with idiopathic narcolepsy. MATERIAL AND METHODS The authors present eleven patients from a five-generation family with many members who suffer from episodic excessive daytime sleepiness. Narcolepsy was diagnosed in 9 patients. Sleepiness was frequently associated with cataplexy, hypnagogic-hypnopompic hallucinations and sleep paralysis. Improvement in their clinical state was observed during the treatment with modafinil. All probands had MRI of the brain, routine blood tests, EEG, polysomnography, examination of the level of hypocretin in cerebrospinal fluid and evaluation by means of Epworth and Stanford Sleepiness Scales. RESULTS In 9 patients with narcolepsy, decreased thickness of the substantia nigra was found and in six of them degenerative lesions in the pontine substantia nigra were also noticed. CONCLUSIONS The significance of these changes remains unclear. No data have been published until now concerning the presence of any brain lesions in patients with familial narcolepsy.

Importance rating of risk factors of ischemic stroke in patients over 85 years old in the polish population

INTRODUCTION The European population is aging and the number of elderly patients suffering from ischemic brain stroke increases. A better knowledge of the correlation between the risk factors and the course of the disease in old people may be useful for planning medical care and prophylactic strategies. AIM This prospective study aimed to perform a demographic and clinical analysis of the etiology of ischemic stroke, survival rate and severity of post-stroke disability in patients who developed ischemic stroke at the age of over 85 years in the Polish population. METHOD The study group consisted of 159 patients over 85 years old with ischemic stroke. The prevalence of risk factors such as sex, hypertension, hyperlipidemia, atrial fibrillation, heart failure and diabetes was evaluated. The outcome was assessed using the Barthel scale and the National Institutes of Health Stroke Scale. RESULTS The most common risk factors of ischemic stroke were hypertension and atrial fibrillation. Patients with atrial fibrillation had a more severe course of ischemic stroke. CONCLUSION The course of brain stroke in the Polish population is more severe in patients over 85 years old than in younger ones. The key risk factor in this group is atrial fibrillation.