Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Modulation of neurotrophic factors in the treatment of dementia, stroke and TBI: Effects of Cerebrolysin.

Neurotrophic factors (NTFs) are involved in the pathophysiology of neurological disorders such as dementia, stroke and traumatic brain injury (TBI), and constitute molecular targets of high interest for the therapy of these pathologies. In this review we provide an overview of current knowledge of the definition, discovery and mode of action of five NTFs, nerve growth factor, insulin-like growth factor 1, brain derived NTF, vascular endothelial growth factor and tumor necrosis factor alpha; as well as on their contribution to brain pathology and potential therapeutic use in dementia, stroke and TBI. Within the concept of NTFs in the treatment of these pathologies, we also review the neuropeptide preparation Cerebrolysin, which has been shown to resemble the activities of NTFs and to modulate the expression level of endogenous NTFs. Cerebrolysin has demonstrated beneficial treatment capabilities in vitro and in clinical studies, which are discussed within the context of the biochemistry of NTFs. The review focuses on the interactions of different NTFs, rather than addressing a single NTF, by outlining their signaling network and by reviewing their effect on clinical outcome in prevalent brain pathologies. The effects of the interactions of these NTFs and Cerebrolysin on neuroplasticity, neurogenesis, angiogenesis and inflammation, and their relevance for the treatment of dementia, stroke and TBI are summarized.

Dietary Supplements in Chemotherapy-Induced Peripheral Neuropathy: A New Hope?

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the main and most prevalent side effects of chemotherapy, significantly affecting the quality of life of patients and the course of chemotherapeutic treatment. Nevertheless, despite its prevalence, the management of the CIPN is considered particularly challenging, with this condition often being perceived as very difficult or even impossible to prevent with currently available agents. Therefore, it is imperative to find better options for patients diagnosed with this condition. While the search for the new agents must continue, another opportunity should be taken into consideration-repurposing of the already known medications. As proposed, acetyl-L-carnitine, vitamins (group B and E), extracts of medical plants, including goshajinkigan, curcumin and others, unsaturated fatty acids, as well as the diet composed of so-called "sirtuin-activating foods", could change the typical way of treatment of CIPN, improve the quality of life of patients and maintain the continuity of chemotherapy. This review summarizes currently available data regarding mentioned above agents and evaluates the rationale behind future research focused on their efficacy in CIPN.

Treatment satisfaction, safety, and tolerability of cladribine tablets in patients with highly active relapsing multiple sclerosis: CLARIFY-MS study 6-month interim analysis.

Background Multiple sclerosis (MS) is a chronic disabling disease that is associated with negative effects on health-related quality of life (HRQoL) due to reduced physical and psychosocial functioning. Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) have been approved for the treatment of adult patients with highly active relapsing multiple sclerosis (RMS). The ongoing CLARIFY-MS study (NCT03369665; EudraCT number: 2017-002632-17) aims to assess the effect of cladribine tablets 3.5 mg/kg on HRQoL of patients with highly active RMS. Objective To report on the design of the CLARIFY-MS study, baseline patient characteristics, and results of a pre-planned interim analysis focusing on treatment satisfaction, safety, and tolerability that includes all data reported till 6 months after start of treatment. Methods The CLARIFY-MS study is a 2-year, open-label, single-arm, prospective, multicenter, phase IV study. Eligible patients with highly active RMS were assigned to receive cladribine tablets 3.5 mg/kg over 2 years. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4; scale range from 0 to 100, higher values indicating higher satisfaction). Safety assessments, including occurrence of treatment-emergent adverse events (TEAEs; any adverse event reported after drug administration), serious adverse events (SAEs), and lymphocyte counts, were summarized descriptively. Results A total of 482 patients from 85 sites in Europe were treated with cladribine tablets. Mean patient age was 37.4 years, 338 (70.1%) were women, median EDSS was 2.5, and 345 (71.6%) were prior users of disease-modifying therapy (DMT). During the first 6 months after the start of treatment, and before reaching the full dose of cladribine tablets, mean TSQM global satisfaction score for the overall population was 70.4 (standard deviation, ± 18.48). The side effects score was 91.9 (± 17.68), convenience scored 86.6 (± 13.57), and effectiveness was 65.8 (± 21.14). A total of 275 patients (57.1%) reported at least one TEAE and 9 patients (1.9%) had a SAE. The majority of observed lymphopenia cases were of grade 1 or 2; 33 (6.8%) of the total study cohort had grade 3 lymphopenia, and no grade 4 lymphopenia was reported. Conclusion Patients reported high treatment satisfaction (TSQM) with cladribine tablets in this pre-planned interim analysis at 6 months. Few serious, and no unexpected, adverse events were reported, and there were no instances of grade 4 lymphopenia over the first 6 months. These preliminary data indicate good tolerability and convenience of administration of cladribine tablets in patients with highly active RMS.

[Orbital pseudotumor - current state of knowledge].

The orbital pseudo-tumor is an orbital inflammatory disease of unknown origin that can affect all the anatomical structures that make up the orbit. The diagnosis is based on the assessment of clinical symptoms, imaging tests and the exclusion of other possible causes. Glucocorticosteroids are used for treatment, but other immunosuppressants as well as biological treatments can be used. The aim of the study is to present, based on the literature review, the current state of knowledge about pathogenesis, symptoms, differential diagnosis, and treatment of the orbital pseudotumor.

Smoking as a risk factor of onset and relapse of Multiple Sclerosis - a review.

INTRODUCTION AND OBJECTIVE: Multiple Sclerosis (MS) is a chronic demyelinating disease caused by damage to myelin in the brain and spinal cord. The cause of the disease is unclear, but it is probably correlated with dysregulation of the immunological system, as well as non-modifiable and modifiable risk factors. Unfortunately, there is no cure for MS. However, the course of the condition has been shown to be modifiable by treatment and various environmental factors. Cigarette smoking is one of the most common addictions around the world, and may be a key modifiable risk factor in MS. Here, we review data available on Pubmed and Scopus from the last 10 years. The following consecutive key words were used in our search: "multiple sclerosis", "smoking", "cigarette", "impact", "progression", and "tobacco". This search yielded 248 initial articles, 43 of which were included in our review. CURRENT STATE OF KNOWLEDGE: In our review, we have examined the impact of smoking on the immunology, course, treatment, relapse, recurrence, quality of life, and changes visualised on MRI among patients with MS in general. We have also explored these patterns in MS subtypes. In general, smoking is reported to have negative effects on MS, including a decrease in quality of life, as well as cognitive and mental state, and an increase in disability, as well as in the frequency of relapses and recurrences. CLINICAL IMPLICATIONS: Smoking has a widespread negative impact on patients with MS. Thus, it is important to educate patients and to help them to give up smoking to improve their health and quality of life. FUTURE DIRECTIONS: Further research about the impact of smoking and nicotine on MS and other neurodegenerative diseases is needed; in particular, research on e-cigarettes.

Cladribine Treatment Improved Homocysteine Metabolism and Increased Total Serum Antioxidant Activity in Secondary Progressive Multiple Sclerosis Patients.

Hyperhomocysteinemia plays a crucial role in the pathogenesis of many diseases of the central nervous system (CNS). The nervous system is particularly sensitive to high homocysteine (Hcy) level mainly due to its prooxidative and cytotoxic effects. Cladribine, a drug recently registered for the treatment of multiple sclerosis (MS), possesses additionally neuroprotective effects which are independent of its peripheral immunosuppressant action. Accumulating evidence suggests that oxidative stress and homocysteine thiolactone-mediated protein homocysteinylation play a causal role in MS. Both of these processes may be attenuated by paraoxonase 1 (PON1). Therefore, in the present study, we aimed to examine whether the beneficial effects of the drug in MS patients with a secondary progressive (SP) clinical course, treated with cladribine subcutaneously (s.c.), may be related to its ability to modify serum PON1 activity, Hcy concentration, and protein homocysteinylation, as well as to correct total antioxidant status. A total of 118 subjects were enrolled into the study: (1) patients with a SP type of MS, SP-MS (n = 40); (2) patients with a relapsing-remitting (RR) type of MS, RR-MS (n = 30); and (3) healthy people (n = 48). Patients with SP-MS were treated with cladribine. The drug was given in SP-SM patients s.c. six times every 6 weeks up to a total mean cumulative dose of 1.8 mg/kg. PON1 activity was assessed spectrophotometrically. The level of Hcy, homocysteine thiolactone (HTL) attached to plasma proteins (N-Hcy-protein), and antibodies against homocysteinylated proteins was assessed with an enzyme immunoassay. The total antioxidant activity of the serum was assessed with the ferric-reducing activity of plasma (FRAP) method. Basically, there was no difference in PON1 activity between untreated SP-MS, RR-MS, and control subjects. Serum Hcy was significantly higher in RR-MS patients (p < 0.001) and in SP-MS patients (p < 0.01) compared to the control group. The N-Hcy protein level was higher in RR-MS patients (p < 0.05) in comparison to the control group. Moreover, the elevated level of antibodies against homocysteinylated proteins was observed in the serum of patients with SP-MS. The total antioxidant capacity of serum was lower in MS patients vs. the control group (p < 0.001). After cladribine treatment, the activity of PON1 did not change in SP-MS patients, whereas cladribine treatment decreased the level of total Hcy (p < 0.05). Treatment with cladribine increased the total serum antioxidant activity in SP-MS patients (p < 0.01). The Expanded Disability Status Scale (EDSS) score did not change in SP-MS patients. Cladribine treatment in the SP-MS group attenuates hyperhomocysteinemia-induced protein homocysteinylation (n.s.). It also stabilises the neurological condition of SP-MS patients. The stabilisation of a neurological condition observed in SP-MS patients after cladribine treatment may be partially related to its ability to reduce elevated Hcy level and to improve serum antioxidant potential.

Successful treatment of anti-NMDA receptor encephalitis with a prompt ovarian tumour removal and prolonged course of plasmapheresis: A case report.

Anti-N-methyl-d-aspartate-receptor (NMDAR) encephalitis is an uncommon autoimmune disorder with a wide spectrum of neuropsychiatric symptoms. There is a great requirement to emphasize the importance of a multidisciplinary team approach in the process of diagnosis and treatment of the potentially fatal condition, including psychiatrists, neurologists, gynaecologists and intensivists. Physicians must be aware that psychiatric and neurological disorders, which are typical features for NMDAR encephalitis in young women with ovarian tumours, may progress into status epilepticus and respiratory insufficiency. This disease can only be successfully treated with prompt surgical intervention and an early implementation of a wide array of immunosuppressive therapies. Optimal timing of initiation of therapeutic plasma exchange, as well as duration of treatment necessary to achieve desirable outcomes in patients with NMDAR remains unknown. The present case report aims to raise awareness about the importance of early implementation of this potentially life-saving therapy and continuing the treatment courses until full subsidence of symptoms.

Predictors of intracranial cerebral artery stenosis in patients before cardiac surgery and its impact on perioperative and long-term stroke risk.

BACKGROUND: The aim of this prospective study was to determine the prevalence of stenosis within intracranial and extracranial arteries in patients before coronary artery bypass surgery (CABG), to evaluate the influence of intracranial artery stenosis on neurological outcome and to identify preoperative risk factors for these patients. METHODS: One hundred and seventy-five patients (71% males, mean age=66.1) scheduled for CABG were enrolled for extracranial Doppler duplex sonography, transcranial color-coded duplex sonography (TCCS) and transcranial Doppler (TCD) examination. RESULTS: Twenty-six patients (14.7%) had extracranial stenosis or occlusion and 13 patients (7.3%) intracranial vascular disease. Six patients (3.5%) had both extra- and intracranial artery disease. The presence of peripheral artery disease and diabetes mellitus was a strong risk factor for extracranial artery stenosis but not for intracranial artery stenosis, which occurred independently also of typical atherosclerotic risk factors like age >70, male sex, hypertension, hyperlipidemia, hyperhomocysteinemia, smoking habit, obesity (BMI>30) and waist to hip ratio >1. Functional neurological outcome of the patients with intracranial arterial disease evaluated 7 days after CABG was the same as the patients without extra- and intracranial stenosis. However, 12-months neurological follow-up revealed significantly more ischemic strokes in patients with intracranial artery stenosis compared to patients without intracranial stenosis (p=0.015). CONCLUSION: The occurrence of intracranial artery stenosis in CABG patients cannot be predicted by well-known atherosclerotic risk factors and seems not to be associated with perioperative stroke.

Disappearance of white matter lesions on MRI and clinical recovery after initiating antiretroviral therapy in a case of HIV infection presenting as spastic paraparesis.

We present a case of a 30-year-old Polish female who presented with increasing for about 2 years spastic paraparesis and urinary incontinence. She denied any risky sexual behaviors, drug abuse, there was no history of surgery or blood transfusions. MRI of the brain showed diffuse, hyperintensive in T2, poorly defined lesions in the white matter. About 3 months later paraparesis increased and control MRI showed progression of previously described lesions. She was then diagnosed with HIV infection. There was a suspicion of progressive multifocal leucoencephalopathy (PML) or vacuolar myelopathy in the course of HIV infection. Antiretroviral treatment was initiated leading, together with rehabilitation, to a progressive improvement of symptoms. Pathological lesions on brain MRI completely disappeared. In conclusion, HIV test should be done in every patient with neurological signs of unknown cause.

Bilateral paramedian thalamic infarction with hypothalamic dysfunction.

Unilateral thalamic lesions cause transient or permanent behavioral, sensory and oculomotor disturbances; bilateral lesions of thalamus result in more severe and longer lasting symptoms. We present an atypical case of bilateral paramedian thalamic infarct with concomitant hypothalamic dysfunction. The only risk factor of ischaemic stroke found in the patient was a short lasting episode of atrial fibrillation. Bilateral paramedian thalamic infarcts may result from occlusion of one paramedian thalamic artery, which arises from the posterior cerebral artery, either with separated or with a common trunk, thus supplying the thalamus bilaterally. Independently of anatomical variants of thalamus blood supply, the most probable cause of infarct in our patient was unilateral or bilateral occlusion of the posterior cerebral artery by cardioembolism, probably in the course of basilar artery occlusion. Hypothalamic dysfunction may accompany thalamic infarcts; thus hypothalamo-pituitary function should be routinely assessed in bithalamic infarcts.

Analysis of ventricular late potentials in signal-averaged ECG of people with epilepsy.

PURPOSE: There has been growing interest in cardiac disturbances in epilepsy patients and their etiologic role in the context of sudden death. Ventricular late potentials (VLPs) recorded on signal-averaged electrocardiography (SAECG) reflects delayed ventricular depolarization and identifies the structural or functional substrate for the ventricular tachycardia in the reentry mechanism. Therefore, abnormal SAECG poses the potential of identifying patients at increased risk of malignant ventricular arrhythmias and sudden cardiac death. The aim of this exploratory study was to screen epilepsy patients who were treated with established doses of antiepileptic drugs (AEDs) on the presence of VLPs. METHODS: Forty-five consecutive patients with the diagnosis of epilepsy and 19 healthy volunteers, aged younger than 46 years, participated in the study. Exclusion criteria included symptoms or signs of diseases other than epilepsy, in particular relating to heart disease or medication influencing the cardiovascular system, as well as seizure reported by patients that occurred <3 days before the ECG examination. The electrocardiogram was recorded according to the standard protocol. The seizure frequency was calculated based on the available data of epileptic events within the preceding 3 months. Disease duration was estimated by determining the time from the first reported seizure to the present. KEY FINDINGS: There were 22 patients (48%) in the epilepsy group and only one patient (5%) in the control group fulfilling the criteria for VLP (p = 0.0005). Subsequently, epilepsy patients were divided into two subgroups according to VLP presence. Patients with VLP had longer disease duration (p = 0.03) compared to those without VLP. Similarly, patients with VLP more frequently had refractory epilepsy (p = 0.03) and had higher monthly seizure frequency (p = 0.02). Analysis of the proportions of generalized seizures (GS) and focal seizures (FS) showed a tendency for higher number of generalized tonic-clonic seizures in the VLP group, but this did not reach statistical significance (p = 0.06). VLP patients tended to be more often on polytherapy (defined as more than one AED per patient) (p = 0.07) as compared to epilepsy patients without VLP. However, if the numbers of AEDs per patients among the subgroups were compared, patients with VLP were treated with more AEDs than patients without VLP (p = 0.01). The study was not sufficiently powered to pinpoint any particular drug or AED combination to influence the appearance of VLP in epileptic patients. In particular, there was no difference in valproate or carbamazepine exposure, considering the percentage of patients exposed or the total daily dose administered. SIGNIFICANCE: Epilepsy patients more frequently display abnormal SAECGs with VLPs as compared to the control population, and their presence correlates with the disease duration, uncontrolled seizures, and polytherapy. Further longitudinal studies are needed in order to stratify the risk of life-threatening ventricular events in epilepsy patients with VLPs.

Presence of L-kynurenine aminotransferase III in retinal ganglion cells and corpora amylacea in the human retina and optic nerve.

BACKGROUND: Corpora amylacea (CAm) are a hallmark of aging and neurodegeneration. The presence of kynurenine aminotransferases I and II (KAT I and II) in CAm in the human retina and optic nerve has been already shown. The present study aimed to examine kynurenine aminotransferase III (KAT III) immunoreactivity in CAm in the human retina and optic nerve. MATERIAL AND METHODS: Polyclonal antibody against KAT III was used on sections of human eyes enucleated due to malignant uveal melanoma. PAS-stained sections of CAm were compared with KAT III stained ones. RESULTS: KAT III immunoreactivity was observed in CAm in the retina, prelaminar, laminar and retrolaminar region of the optic nerve with similar location to PAS-stained sections. The most intense staining was observed in the retrolaminar part of the optic nerve. KAT III immunoreactivity was also present in the cytoplasm of retinal ganglion cells. CONCLUSIONS: Expression of KAT III in CAm in the human retina and optic nerve indicates that this enzyme may be relevant in mechanisms of neurodegeneration leading to CAm formation.

Biventricular versus right ventricular pacing decreases immune activation and augments nitric oxide production in patients with chronic heart failure.

INTRODUCTION: Immune system activation and oxidative stress are involved in the pathogenesis of heart failure (HF). We aimed to test the hypothesis that upgrading from right ventricular pacing (RVp) to biventricular pacing (BiVp) can counteract these phenomena. METHODS: 28 HF patients, with BiVp were switched to RVp for one week, and then returned to BiVp. Immediately prior to, and 48 h after the return to BiVp, left ventricular (LV) systolic function was evaluated by echocardiography, and serum N-terminal pro-brain natriuretic peptide (NTproBNP), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL6), nitric oxide metabolites (NO(x)) and malondialdehyde (MDA) were assayed. RESULTS: LV systolic function significantly improved 48 h after switching from RVp to BiVp: Ao-VTI (p<0.001), SV (p<0.001) and CO (p<0.001), and mitral regurgitation significantly decreased (p=0.003). At the same time, indices of peripheral immune activation decreased: TNF-alpha (p=0.02) and IL6 (p<0.001). MDA decreased (p<0.001), whereas NO(x) increased (p=0.04). NTproBNP and CRP did not change. In addition, in "responders" (i.e. CO increase >10% during BiVp vs. RVp) NTproBNP decreased and NO(x) increased. However, during BiVp, the decreases in TNF-alpha, IL6, and MDA occurred both in responders and in non-responders and were accompanied by a reduction in mitral regurgitation. CONCLUSION: The beneficial effect of BiVp compared to RVp extends beyond improving cardiac haemodynamics and comprises a decrease in immune activation accompanied by an increase in serum NO(x) and decrease in serum MDA.

[Role of matrix metalloproteinases in the pathogenesis of multiple sclerosis]. / Rola metaloproteinaz macierzy zewnatrzkomórkowej w patogenezie stwardnienia rozsianego.

Multiple sclerosis (MS) is an autoimmune disease whose features include a massive lymphocyte recruitment into the central nervous system and segmental demyelinization of the white matter. One of the MS development factors is an increase of matrix metalloproteinases (MMPs) activity with a coincidental decrease of tissue inhibitors of MMPs (TIMPs) activity. Investigations of serum, cerebrospinal fluid and brain tissue of patients showed an increase of MMP-1, -2, -3, -7, -9 and MMP-12 activity. MMPs disrupt the blood-brain barrier (BBB), increase lymphocyte migration into the central nervous system and are involved in degradation of myelin proteins. MMPs induce the appearance of an active form of tumor necrosis factor alpha, a strong proinflammatory cytokine. The drugs used in MS treatment decrease MMPs expression. Multiple actions of MMPs prove their involvement in the pathogenesis and treatment of MS.