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1.  Towards the implementation of ‘no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model 
Objective:
The introduction of new and potent therapies for the treatment of relapsing remitting multiple sclerosis (MS) has increased the desire for therapeutic success. There is growing doubt that the mere reduction of relapse rate, Expanded Disability Status Scale (EDSS) progression and magnetic resonance imaging (MRI) markers are exclusive and appropriate factors to monitor the new aim of ‘no evidence of disease activity’ (NEDA). However, there is no generally accepted definition so far.
Methods:
To achieve the therapeutic aim of NEDA, a panel of MS experts searched the available literature on clinical and paraclinical outcomes to propose a test battery that is sensitive to detect disease activity in an everyday clinical setting.
Results:
The panel proposed to include, besides relapse rate, disability progression and MRI, neuropsychological outcome measures such as cognitive status, fatigue, depression and quality of life. To standardize the examinations in an economic and schematic way, a multifactorial model [multiple sclerosis decision model (MSDM)] that includes the domains ‘relapse’, ‘disability progression’, ‘MRI’, and ‘neuropsychology’ is proposed. The scheme reflects the complexity of the disease even in the early stages when scales such as the EDSS are not able to distinguish low levels of progression.
Conclusion:
The MSDM aims to support early treatment decisions and uncover timely treatment failure. Prospective investigations are required to prove that such a disease-monitoring concept leads to an early and effective silencing of disease activity.
doi:10.1177/1756285614560733
PMCID: PMC4286940  PMID: 25584069
disease activity; disease monitoring; magnetic resonance imaging; multiple sclerosis; neuropsychology
2.  The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine 
More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT1F receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50–400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient.
doi:10.1177/1756285614562419
PMCID: PMC4286941  PMID: 25584073
migraine; serotonin; receptor; pharmacology; clinical trials
3.  Switch from intravenous to subcutaneous immunoglobulin in CIDP and MMN: improved tolerability and patient satisfaction 
Objectives:
To assess clinical outcomes and patient satisfaction in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or multifocal motor neuropathy (MMN) who were switched from intravenous immunoglobulin (IVIG) to subcutaneous immunoglobulin (SCIG).
Methods:
Eight consecutive patients, four with MMN and four with CIDP, already on long-term, hospital-based IVIG were switched to home-based SCIG. These patients were selected on the basis of their requirement for relatively low treatment doses, problems experienced with IVIG, and their willingness to switch to SCIG.
Results:
After a mean 33 [standard deviation (SD) 19] months receiving SCIG, 7 patients remained neurologically stable and 6 remained on a similar mean weekly immunoglobulin dose relative to their original intravenous dose. A good outcome was reported by 7 of the 8 patients: there were improvements in nausea and headache (n = 4), need to travel to hospital (n = 4), venous access problems (n = 3), immunoglobulin-induced neutropenia (n = 3), treatment wearing-off fluctuations (n = 2), IVIG-induced allergy requiring antihistamine/hydrocortisone (n = 1) and time taken off work (n = 1). The eighth patient required increasing doses of immunoglobulin to maintain strength but still wanted to continue SCIG. Seven patients completed a questionnaire: there was a very high overall satisfaction level with immunoglobulin treatment [mean 96 (SD 5), visual analogue scale (VAS) where 0 = very unsatisfied, 100 = very satisfied]; and very strong preference for subcutaneous over intravenous immunoglobulin (VAS mean 93 [SD 12] where 0 = prefer IVIG, 100 = prefer SCIG).
Conclusions:
In seven of the eight patients, SCIG gave improved tolerability and patient satisfaction with similar efficacy compared with IVIG.
doi:10.1177/1756285614563056
PMCID: PMC4286942  PMID: 25584070
chronic inflammatory demyelinating polyradiculoneuropathy; intravenous immunoglobulins; multifocal motor neuropathy; subcutaneous immunoglobulins
4.  Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use 
Alemtuzumab is a humanized monoclonal antibody therapy that has recently been approved in over 30 countries for patients with active relapsing-remitting multiple sclerosis. It acts by targeting CD52, an antigen primarily expressed on T and B lymphocytes, resulting in their depletion and subsequent repopulation. The alemtuzumab clinical development program used an active comparator, subcutaneous interferon beta-1a, to show that alemtuzumab is a highly efficacious disease-modifying therapy, with benefits on relapses, disability outcomes, and freedom from clinical disease and magnetic resonance imaging activity. The safety profile was consistent across studies and no new safety signals have emerged during follow-up in the extension study. Infusion-associated reactions are common with alemtuzumab, but rarely serious. Infection incidence was elevated with alemtuzumab in clinical studies; most infections were mild or moderate in severity. Autoimmune adverse events occurred in approximately a third of patients, manifesting mainly as thyroid disorders, and less frequently as immune thrombocytopenia or nephropathy. A comprehensive monitoring program lasting at least 4 years after the last alemtuzumab dose allows early detection and effective management of autoimmune adverse events. Further experience with alemtuzumab in the clinic will provide needed long-term data.
doi:10.1177/1756285614563522
PMCID: PMC4286943  PMID: 25584072
alemtuzumab; disease-modifying therapy; efficacy; mechanism of action; multiple sclerosis; safety
5.  Dimethyl fumarate in the treatment of relapsing–remitting multiple sclerosis: an overview 
Multiple sclerosis (MS) shares an immune-mediated origin with psoriasis. Long-term safety and efficacy data generated in Europe from usage of fumaric acid formulations in the latter disease constituted grounds to investigate their effects in MS patients. Dimethyl fumarate (DMF) was found to be the active principle in those formulations and in vitro studies have demonstrated that DMF has immune-modulatory properties exerted through abilities to divert cytokine production toward a Th2 profile, both on lymphocytes and microglial cells. More importantly, DMF was discovered to impact the anti-oxidative stress cell machinery promoting the transcription of genes downstream to the activation of the nuclear factor (erythroid derived 2)-like2 (NRF2). DMF exposure increases the cytosol concentrations of NRF2, which besides immune regulatory effects, has the potential for cytoprotection on glial cells, oligodendrocytes and neurons. Extensive and rigorous clinical trials have assessed the efficacy and safety of DMF at the dose of 240 mg twice and three times a day in relapsing-remitting MS patients during one phase IIb and two phase III trials. Robust, positive results were obtained across a number of clinical and paraclinical parameters. In one study (DEFINE), the relative reductions of the adjusted annualized relapse rate of the low and high dose regimens in comparison with placebo were 53% and 48%, respectively (p < 0.001 for both comparisons). In the other trial (CONFIRM), DMF decreased the annualized relapse rate in comparison with placebo by 44% in the lower and by 51% in higher dosage group (also p < 0.001). The number and size of lesions as detected by magnetic resonance imaging were also significantly decreased in comparison with the patients receiving DMF at every dosage. Multiple post hoc and subgroup analyses corroborated the clinical data, rendering DMF an appealing medication whose potential for impacting the degenerative aspects of MS remains to be explored.
doi:10.1177/1756285614564152
PMCID: PMC4286944  PMID: 25584071
clinical trial results; dimethyl fumarate; DMF mechanism of action; DMF metabolism; MS therapy; safety and efficacy
6.  High noon back pain- severe pseudoradicular pain as a lead symptom of superficial siderosis: a case report 
A superficial siderosis of the central nervous system following a traumatic cervical nerve root avulsion usually leads to gait difficulties and hearing loss, whereas back pain is described only rarely. Here we report on the first case with circadian occurrence of severe back pain as the only symptom of a superficial siderosis. We present a case with the most severe pseudoradicular lumbosacral pain occurring daily at noon for the past 5 weeks. The 48-year-old male white patient did not complain of pain in the morning. A traumatic root avulsion 26 years earlier led to a brachial plexus palsy and Horner’s syndrome in this patient. Superficial hemosiderosis in cranial MRI and examination of the cerebrospinal fluid revealing massive red blood cells as well as xanthochromia and elevated protein levels (742 mg/l) led to the diagnosis of a superficial siderosis. A pseudomeningocele caused by a cervical nerve root avulsion is described as a rare reason for superficial siderosis. Surgery on a pseudomeningocele, diagnosed by MRI, led to an immediate disappearance of complaints in our case. Regular neurological investigation and possibly repeated lumbar puncture to exclude superficial siderosis should be considered in cases with severe back pain and a history of traumatic root avulsion. Modern susceptibility weighted MR imaging (SWI) techniques, sensible to the detection of superficial hemosiderosis, might be helpful in the making of a diagnosis.
doi:10.1177/1756285614548189
PMCID: PMC4218875  PMID: 25371709
back pain; pseudoradicular; root avulsion; superficial siderosis
7.  Evidence for the efficacy of interferon beta-1b in delaying the onset of clinically definite multiple sclerosis in individuals with clinically isolated syndrome 
The BEtaferon®/BEtaseron® in Newly Emerging MS For Initial Treatment (BENEFIT) trial assessed the efficacy of early versus delayed treatment with interferon beta-1b for patients with clinically isolated syndrome (CIS). Patients were randomly assigned to receive either interferon beta-1b 250 μg every other day (early treatment, n = 292) or placebo (delayed treatment, n = 176) for 2 years or until progression to clinically definite multiple sclerosis. Clinical and magnetic resonance imaging (MRI) outcomes were assessed after 2 years (at the end of the placebo-controlled phase) and then again at 3, 5, and 8 years post randomization. MRI assessments were made after 2, 3, and 5 years. The results showed a consistent advantage of early treatment across most clinical and MRI variables, although median Expanded Disability Status Scale scores remained consistently low, with no differences between groups. These findings suggest that early treatment with interferon beta-1b improves long-term outcomes for patients presenting with CIS.
doi:10.1177/1756285614549554
PMCID: PMC4218876  PMID: 25371710
clinically isolated syndrome; early treatment; interferon beta-1b; multiple sclerosis
8.  Patient preferences for disease-modifying drugs in multiple sclerosis therapy: a choice-based conjoint analysis 
Objectives:
With an increasing number of disease-modifying treatments (DMTs) for multiple sclerosis (MS), patient preferences will gain importance in the decision-making process. We assessed patients’ implicit preferences for oral versus parenteral DMTs and identified factors influencing patients’ treatment preference.
Methods:
Patients with relapsing–remitting MS (n = 156) completed a questionnaire assessing treatment preferences, whereby they had to decide between pairs of hypothetical treatment scenarios. Based on this questionnaire a choice-based conjoint analysis was conducted.
Results:
Treatment frequency and route of administration showed a stronger influence on patient preference compared with frequency of mild side effects. The latter attribute was more important for treatment-naïve patients compared with DMT-experienced patients. The higher the Extended Disability Status Scale score, the more likely pills, and the less likely fewer side effects were preferred. Pills were preferred over injections by 93% of patients, when treatment frequency and frequency of side effects were held constant. However, preference switched to injections when pills had to be taken three times daily and injections only once per week. Injections were also preferred when pills were associated with frequent side effects.
Conclusions:
Our results suggest that route of administration and treatment frequency play an important role in the patients’ preference for a given DMT.
doi:10.1177/1756285614555335
PMCID: PMC4218877  PMID: 25371708
choice-based conjoint analysis; multiple sclerosis; oral; parenteral; patient preference; treatment frequency
10.  Extended interval dosing of natalizumab: a two-center, 7-year experience 
Background:
The enthusiasm for natalizumab, a highly efficacious agent in the treatment of multiple sclerosis (MS), has been tempered by the risks of progressive multifocal leukoencephalopathy associated with its use, and strategies to minimize those risks are of great interest. Extended interval dosing (EID) has been proposed as a way to maintain the efficacy of natalizumab while reducing exposure to it. We reviewed a cohort of patients who received natalizumab at 6–8-week intervals instead of the typical infusions every 4 weeks with the goal to assess if patients on EID had an increase in clinical relapses.
Methods:
This is a retrospective review of all patients with MS treated with natalizumab at two MS centers where patients were offered the opportunity to switch to an EID every 6 or 8 weeks.
Results:
A total of 361 patients received natalizumab for 22 ± 13 months (minimum duration 6 months). Of these, 96 patients received EID natalizumab at some point for 20 ± 11 months (minimum duration 6 months). Over the study period, there was no significant difference between the relapse rate in the monthly dosing (13%) and the EID (13%) groups of patients.
Conclusion:
Natalizumab is effective in controlling MS as very few clinical relapses were observed in our dataset. We found that EID did not compromise the treatment effect as measured by relapse rate and no significant breakthrough disease activity was observed. EID is an optional regimen for maintenance natalizumab therapy, but prospective studies are warranted to determine its efficacy.
doi:10.1177/1756285614540224
PMCID: PMC4206618  PMID: 25342976
dosing regimen; multiple sclerosis; natalizumab
11.  Isoniazid in autoimmunity: a trigger for multiple sclerosis? 
Isoniazid (INH) is a prodrug activated by the mycobacterial enzyme KatG, a multifunctional catalase peroxidase. KatG converts INH to reactive antimycobacterial species. For decades, an association between INH and drug-induced lupus erythematosus has been recognized. We present the case of a patient with primary progressive multiple sclerosis whose disease commenced weeks after initiating INH therapy for prevention of tuberculosis. Possible mechanisms by which INH may trigger autoimmunity in humans are discussed.
doi:10.1177/1756285614540361
PMCID: PMC4206619  PMID: 25342979
Isoniazid; Autoimmunity; Multiple Sclerosis
12.  Fumarate treatment in progressive forms of multiple sclerosis: first results of a single-center observational study 
Objectives:
Therapeutic options in progressive forms of multiple sclerosis (MS) are still limited. Dimethyl fumarate (DMF) has immunomodulatory properties but may also exert antioxidative cytoprotective effects. Hence, it may be a therapeutic option for progressive MS. The aim of this observational study was to evaluate safety, adherence and efficacy of fumarates in patients with primary progressive MS (PPMS) or secondary progressive MS.
Methods:
Patients with progressive MS whose condition had failed to respond to standard therapies and had worsened received the fumarate mixture Fumaderm, licensed for psoriasis therapy in Germany, or DMF by pharmaceutical preparation (Bochum ethics approval no. 4797-13). At regular follow-up visits, tolerability and disease course were assessed.
Results:
Twenty-six patients [age 54 ± 7.8 years; female = 13 (50%); PPMS = 12 (46.2%); Expanded Disability Status Scale (EDSS) = 6.0 ± 0.4 (range 3.5–8.0); disease duration = 14.1 ± 8.7 years] were initiated on treatment with Fumaderm (n = 18) or pharmacy-prepared DMF (n=8). During a mean follow-up period of 13.2 ± 7.5 months (range 6–30) only five patients (19.2%) reported minor complaints. In 15 patients (57.7%) EDSS remained stable. In five cases (19.2%) there was even a decrease in EDSS while in six patients (23.1%) there was an increase in EDSS of more than 0.5 points, reflecting deterioration. Laboratory values were controlled for lymphopenia, renal and hepatic values, without any safety problems. We observed no significant differences between the two pharmaceutical forms.
Conclusion:
Our pilot data indicate that fumarate therapy appears to be safe and well tolerated by patients with progressive MS. In more than 75% of cases no further disease progression was evident. However, controlled studies are warranted to evaluate the detailed therapeutic potential of fumarates and their long-term effects in progressive MS.
doi:10.1177/1756285614544466
PMCID: PMC4206620  PMID: 25342977
antioxidative; cytoprotective; fumarate; neurodegeneration; progressive multiple sclerosis
13.  Teriflunomide in the treatment of multiple sclerosis: current evidence and future prospects 
A number of novel oral agents are now approved for use in relapsing multiple sclerosis (MS). Among these agents, teriflunomide has shown promise with respect to clinical efficacy and safety in relapsing MS patients. In this review we aim to clarify the role of teriflunomide in the context of current and emerging MS treatment options by summarizing relevant points on the use of teriflunomide in MS, with a discussion of teriflunomide’s pharmacologic properties, pivotal clinical trials, and safety and tolerability.
doi:10.1177/1756285614546855
PMCID: PMC4206621  PMID: 25342978
clinical trials; multiple sclerosis; review; teriflunomide
14.  A review of the use of magnetic resonance imaging in Parkinson’s disease 
To date, the most frequently used Parkinson’s disease (PD) biomarkers are the brain imaging measures of dopaminergic dysfunction using positron emission tomography and single photon emission computed tomography. However, major advances have occurred in the development of magnetic resonance imaging (MRI) biomarkers for PD in the past decade. Although conventional structural imaging remains normal in PD, advanced techniques have shown changes in the substantia nigra and the cortex. The most well-developed MRI markers in PD include diffusion imaging and iron load using T2/T2* relaxometry techniques. Other quantitative biomarkers such as susceptibility-weighted imaging for iron load, magnetization transfer and ultra-high-field MRI have shown great potential. More sophisticated techniques such as tractography and resting state functional connectivity give access to anatomical and functional connectivity changes in the brain, respectively. Brain perfusion can be assessed using non-contrast-agent techniques such as arterial spin labelling and spectroscopy gives access to metabolites concentrations. However, to date these techniques are not yet fully validated and standardized quantitative metrics for PD are still lacking. This review presents an overview of new structural, perfusion, metabolic and anatomo-functional connectivity biomarkers, their use in PD and their potential applications to improve the clinical diagnosis of Parkinsonian syndromes and the quality of clinical trials.
doi:10.1177/1756285613511507
PMCID: PMC4082302  PMID: 25002908
diffusion tensor imaging; magnetization transfer; relaxometry; resting state fMRI
15.  Defining a role for laquinimod in multiple sclerosis 
Multiple sclerosis (MS), an inflammatory disease affecting the central nervous system, is considered to exhibit an important neurodegenerative component as well. Laquinimod is an orally administered quinoline-3-carboxamide under development for the treatment of MS. In vitro and animal studies have revealed various mechanisms by which laquinimod may exert its effects on the immune and nervous systems. These include effects on the innate immune system that promote the differentiation of anti-inflammatory/regulatory T cells, the activation of microglia cells, an increase in the expression of brain-derived neurotrophic factor, as well as the prevention of inflammation-induced excitotoxicity. Two phase III studies revealed the clinical benefits of laquinimod in patients with relapsing–remitting MS and exhibited a benign safety profile for this drug. Ongoing clinical trials will help to define the optimal dose and indication for laquinimod in MS. This article reviews current experimental and clinical evidence on the role of laquinimod in patients with this disabling disease.
doi:10.1177/1756285614529615
PMCID: PMC4082303  PMID: 25002907
laquinimod; multiple sclerosis; neuroprotection; relapsing–remitting multiple sclerosis
16.  Experience in the use of clobazam in the treatment of Lennox–Gastaut syndrome 
Clobazam is a 1,5-benzodiazepine used successfully worldwide since the 1970s as an anxiolytic and antiepileptic drug. Since its recent Food and Drug Administration (FDA) approval in the United States in 2011 as adjunctive treatment for Lennox–Gastaut syndrome, it has continued to show sustained efficacy and a better safety and tolerability profile compared with other benzodiazepines. The two randomized, controlled studies that led to the US FDA approval, as well as the follow-up multicenter, open-label study of clobazam, showed ≥50% seizure reduction for more than 50% of Lennox–Gastaut syndrome patients, while none of the other FDA-approved treatments for LGS have demonstrated efficacy rates better than 50%. Clobazam appears to have a safe profile and sustained effectiveness over the first 3 years of use in LGS and other epilepsy syndromes with intractable seizures, which makes it a viable long-term treatment option.
doi:10.1177/1756285614521314
PMCID: PMC3994921  PMID: 24790647
benzodiazepine; clobazam; drop seizures; Lennox–Gastaut syndrome; open-label trial; pediatric epilepsy
17.  Para-dichlorobenzene toxicity – a review of potential neurotoxic manifestations 
Background:
Para-dichlorobenzene (PDCB) is an active ingredient of mothballs, deodorizers and fumigants. Due to the easy availability of this chemical, there is a considerable risk for accidental or intentional toxic exposure. Recently, multiple cases of PDCB toxicity due to mothball ingestion were reported. PDCB toxicity can affect multiple organ systems including liver, kidneys, skin, lung and the central nervous system (CNS). CNS toxicity often results in leukoencephalopathy and heterogeneous neurological manifestations.
Objectives:
The objective of this study was to illustrate the clinical presentation, imaging findings, diagnosis and management of PDCB toxicity.
Methods:
We carried out a literature review of the pharmacological and toxicological properties of PDCB.
Conclusions:
PDCB and other aromatic hydrocarbons are capable of CNS tissue damage and in promoting functional neurological decline. While very little is currently known about prevalence of PDCB addiction, it cannot be ruled out that its illicit use among young people is under-recognized. The number of cases of PDCB toxicity might also rise due to the increasing industrial and domestic use of this chemical.
doi:10.1177/1756285614521889
PMCID: PMC3994922  PMID: 24790648
Paradichlorobenzene; mothballs; neurotoxicity; aromatic hydrocarbons; leukoencephalopathy; demyelination
18.  Dabigatran etexilate for secondary stroke prevention: the first year experience from a multicenter short-term registry 
Background:
There are growing concerns for the side effects of dabigatran etexilate (dabigatran), including higher incidence of dyspepsia and gastrointestinal bleeding. We conducted a multicenter early implementation study to prospectively evaluate the safety, efficacy and adherence to dabigatran for secondary stroke prevention.
Methods:
Consecutive atrial fibrillation (AF) patients with ischemic stroke (IS) or transient ischemic attack (TIA) received dabigatran for secondary stroke prevention during their hospital stay according to American Heart Association recommendations at five tertiary care stroke centers. The study population was prospectively followed and outcomes were documented. The primary and secondary safety outcomes were major hemorrhage and all other bleeding events respectively defined according to RE-LY trial methodology.
Results:
A total of 78 AF patients (mean age 71 ± 9years; 54% men; 81% IS, 19% TIA; median CHADS2 (Congestive heart failure, Hypertension, diabetes mellitus, age >75 years, prior stroke or TIA); range 2–5) score 4 were treated with dabigatran [(110mg bid (74%); 150mg bid (26%)]. During a mean follow-up period of 7 ± 5 months (range 1–18) we documented no cases of IS, TIA, intracranial hemorrhage, systemic embolism or myocardial infarction in AF patients treated with dabigatran. There were two (2.6%) major bleeding events (lower gastrointestinal bleeding) and two (2.6%) minor bleedings [hematuria (n = 1) and rectal bleeding (n = 1)]. Dabigatran was discontinued in 26% of the study population with high cost being the most common reason for discontinuation (50%).
Discussion:
Our pilot data indicate that dabigatran appears to be safe for secondary stroke prevention during the first year of implementation of this therapy. However, high cost may limit the long-term treatment of AF patients with dabigatran, leading to early discontinuation.
doi:10.1177/1756285614528064
PMCID: PMC3994923  PMID: 24790645
atrial fibrillation; dabigatran etexilate; secondary prevention; stroke; transient ischemic attack
19.  Sphenopalatine ganglion stimulation for the treatment of cluster headache 
Cluster headache is a severe, debilitating disorder with pain that ranks among the most severe known to humans. Patients with cluster headaches have few therapeutic options and further, 10–20% develop drug-resistant attacks. The often brief duration of cluster attacks makes abortive therapy a challenge, and preventive medications are almost always provided to patients, but the side effects of these preventive medications can be significant. The sphenopalatine ganglion (SPG) is believed to play a role in headache pain and cranial autonomic symptoms associated with cluster headache, which is a result of activation of the trigeminal-autonomic reflex. For over 100 years, the SPG has been a clinical target to treat primary headache disorders using pharmacologic and nonpharmacologic methods. Radiofrequency lesioning and nerve-resection therapies, while initially beneficial, are irreversible procedures, and the use of neurostimulation provides one method of interfacing with the neural pathways without causing permanent damage to neural tissue. SPG neurostimulation is both reversible and adjustable, and has recently been tested in both proof-of-concept work and in a randomized, sham-controlled trial for the treatment of cluster headache.
A randomized, sham-controlled study of 32 patients was performed to evaluate further the use of SPG stimulation for the acute treatment of chronic cluster headache. Of the 32 patients, 28 completed the randomized experimental period. Overall, 68% of patients experienced an acute response, a frequency response, or both. In this study the majority of adverse events were related to the implantation procedure, which typically resolved or remained mild in nature at 3 months following the implant procedure. This and other studies highlight the promise of using SPG stimulation to treat the pain-associated cluster headache. SPG stimulation could be a safe and effective option for chronic cluster headache.
doi:10.1177/1756285613510961
PMCID: PMC3994920  PMID: 24790646
cluster headache; neurostimulation; sphenopalatine ganglion
20.  Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case–control studies 
Objectives:
Chronic cerebrospinal venous insufficiency (CCSVI) has recently been implicated in the pathogenesis of multiple sclerosis (MS). This comprehensive meta-analysis of case–control studies investigates the association of CCSVI with MS.
Methods:
Through Medline, EMBASE and Cochrane database searches, case–control ultrasound studies comparing CCSVI frequency among patients with MS and healthy controls were identified.
Results:
We identified 19 eligible studies including 1250 patients with MS and 899 healthy controls. The pooled analysis showed that CCSVI was associated with MS [odds ratio (OR) 8.35; 95% confidence interval (CI) 3.44–20.31; p < 0.001) with considerable heterogeneity across studies (I2 = 80.1%). This association was substantially attenuated in sensitivity analyses excluding studies that were carried out by the group that originally described CCSVI, included investigators who had also been involved in publications advocating endovascular procedures for CCSVI treatment, or were conducted in Italy. Our most conservative sensitivity analysis combining different exclusion criteria yielded no association of CCSVI with MS (OR 1.35; 95% CI 0.62–2.93; p = 0.453) without any heterogeneity (I2 = 0%).
Conclusion:
There is considerable heterogeneity across different case–control studies evaluating the association of CCSVI and MS. The greatest factor contributing to this heterogeneity appears to be the involvement of investigators in other publications supporting endovascular procedures as a novel MS treatment.
doi:10.1177/1756285613499425
PMCID: PMC3932766  PMID: 24587827
chronic cerebrospinal venous insufficiency; meta-analysis; multiple sclerosis; ultrasound
21.  Specific aspects of modern life for people with multiple sclerosis: considerations for the practitioner 
Multiple sclerosis (MS) is a chronic, debilitating, neurodegenerative disease that has a high impact on patients’ quality of life. Individuals are often diagnosed in early adulthood and are faced with the difficulty of managing their lifestyle within the context of this chronic illness. Here we review factors that influence the disease course and the challenges that might be encountered when managing patients with MS.
The majority of diagnosed patients are women of childbearing age, making pregnancy-related issues a key concern. MS typically stabilizes during pregnancy and evidence suggests that the disease has no impact on the risk of complications or outcomes. However, the effect of disease-modifying therapies on outcomes is less clear, and discontinuation of treatment prior to pregnancy or when breastfeeding is recommended. Awareness of genetic risk factors is important for patients planning a family, as several genes increase the risk of MS.
Further aspects that require consideration include infections, vaccinations, environmental factors, surgery and the emergence of osteoporosis. Vaccinations are generally not a risk factor for MS and may be beneficial in terms of protection against infection and reducing the number of relapses. Environmental factors such as vitamin D deficiency, low exposure to sunlight, smoking and Epstein−Barr virus infection can all negatively influence the disease course. Furthermore, osteoporosis is generally higher in patients with MS than the general population, and the risk is increased by the environmental and genetic factors associated with the disease; bone mineral density should be assessed and smoking cessation and correction of serum vitamin D levels are recommended. Finally, as patients with MS are typically young, they are at low risk of surgery-related complications, although they should be carefully monitored postoperatively. Awareness of, and planning around, these factors may minimize the impact of the disease on patients’ lifestyle.
doi:10.1177/1756285613501575
PMCID: PMC3932767  PMID: 24587828
disease-modifying therapies; Epstein−Barr virus infections; genetic risk factors; multiple sclerosis; osteoporosis; pregnancy; vaccination; vitamin D
22.  Tolcapone addition improves Parkinson’s disease associated nonmotor symptoms 
Background:
Addition of catechol-O-methyltransferase inhibitors to a conventional levodopa/dopadecarboxylase inhibitor regimen improves motor symptoms in patients with Parkinson’s disease. Optimizing dopamine substitution is also beneficial for nonmotor features.
Objectives:
To investigate the efficacy of supplemental tolcapone intake on nonmotor symptoms.
Design/methods:
A total of 125 levodopa-treated patients additionally took tolcapone in this observational trial. Initially and following 4 weeks of tolcapone intake, the neurologist scored with Unified Parkinson’s Disease Rating Scale parts I, II, IV, the nonmotor symptoms scale for Parkinson’s disease and recorded the off time. The patients rated themselves with the EuroQuol, its visual analogue scale and the nonmotor screening questionnaire. Caregivers reported the daily duration of care giving.
Results:
All scores improved except for Unified Parkinson’s Disease Rating Scale part IV and domains 4, 5 and 8 of the nonmotor symptoms scale for Parkinson’s disease.
Conclusion:
This trial demonstrates that tolcapone addition may improve nonmotor features.
doi:10.1177/1756285613512392
PMCID: PMC3932768  PMID: 24587824
nonmotor symptoms; Parkinson’s disease; tolcapone
23.  4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review 
This systematic review summarizes the existing evidence on the effect of 4-aminopyridine (4-AP) as a symptomatic treatment of decreased walking capacity in patients with multiple sclerosis (MS) when administered as an immediate release compound and a slow release compound. It summarizes existing evidence on the basic mechanisms of 4-AP from experimental studies and evidence on the clinical use of the compound. A systematic literature search was conducted of the following databases: PubMed and EMBASE. Thirty-five studies were included in the review divided into 16 experimental studies, two clinical studies with paraclinical endpoints and 17 clinical studies with clinical endpoints. Animal studies show that 4-AP can improve impulse conduction through demyelinated lesions. In patients with MS this translates into improved walking speed and muscle strength of the lower extremities in a subset of patients at a level that is often of clinical relevance. Phase III trials demonstrate approximately 25% increase in walking speed in roughly 40% and improved muscle strength in the lower extremities. Furthermore, 4-AP might have an effect on other domains such as cognition, upper extremity function and bowel and bladder, but this warrants further investigation. Side effects are mainly mild to moderate, consisting primarily of paraesthesia, dizziness, nausea/vomiting, falls/balance disorders, insomnia, urinary tract infections and asthenia. Side effects are worse when administered intravenously and when administered as an immediate release compound. Serious adverse events are rarely seen in the marketed clinical dosages.
In conclusion, 4-AP is easy and safe to use. Slow release 4-AP shows more robust clinical effects and a more beneficial side-effect profile than immediate release 4-AP.
doi:10.1177/1756285613512712
PMCID: PMC3932769  PMID: 24587826
4-aminopyridine; experimental studies; fampridine slow release; multiple sclerosis; translational medical research; treatment outcome
24.  Mechanisms of action of ACTH in the management of relapsing forms of multiple sclerosis 
Acute and subacute inflammation, the mechanisms by which demyelination and axonal loss occur in multiple sclerosis (MS), result from the migration of activated immune cells into the central nervous system parenchyma. The triggering antigen is unknown, but the process involves deregulated immune response of T and B lymphocytes, macrophages, and mediators with expansion of autoreactive T cells creating a shift in the balance of pro- and anti-inflammatory cytokines favoring inflammation. Ongoing disease activity and exacerbations early in the course of relapsing–remitting MS may prevent full remission and propagate future progressive disability. A key strategy of immune therapy is timely initiation of treatment to achieve remission, followed by maintenance of remission. In this context, treatment with high-dose methylprednisolone (MP) is currently recommended to induce a faster recovery from a clinical exacerbation that results from an acute inflammatory attack. Adrenocorticotropic hormone (ACTH or corticotropin) gel is an alternative for patients who do not respond to or do not tolerate corticosteroids. ACTH is a universal agonist in the melanocortin (MC) system and, as such, among other functions, stimulates the adrenal cortex to produce cortisol. MCs are a family of peptides that includes ACTH and other MC peptides. This system has five classes of receptors, all of which show a strong affinity for ACTH, suggesting a more complex and dynamic mechanism than only inducing endogenous corticosteroid production. ACTH and MCs regulate processes relevant to MS, including anti-inflammatory and immunomodulatory functions involving lymphocytes, macrophages, the sympathetic nervous system involved in inflammatory processes, and reduction of pro-inflammatory cytokines. The clinical implications of the mechanistic differences between corticosteroid and ACTH gel treatment remain to be elucidated. Recent data show that patients experiencing an acute exacerbation, who previously had suboptimal response to or were unable to tolerate MP treatment, showed positive clinical outcomes with fewer adverse events with ACTH gel.
doi:10.1177/1756285613518599
PMCID: PMC3932770  PMID: 24587825
ACTH; adrenal cortex hormones; melanocortins; multiple sclerosis/immunology; multiple sclerosis/therapy
25.  Targeting heat shock proteins to modulate α-synuclein toxicity 
Parkinson’s disease is a slowly progressive neurodegenerative disorder typically characterized by the loss of dopaminergic neurons within the substantia nigra pars compacta, and the intraneuronal deposition of insoluble protein aggregates chiefly comprised of α-synuclein. Patients experience debilitating symptoms including bradykinesia, rigidity and postural instability. No curative treatment currently exists and therapeutic strategies are restricted to symptomatic treatment only. Over the past decade a class of molecular chaperones called the heat shock proteins has emerged as a potentially promising therapeutic target. Heat shock proteins aid in the folding and refolding of proteins, and target denatured proteins to degradation systems. By targeting heat shock proteins through various means including overexpression and pharmacological enhancement, researchers have shown that α-synuclein aggregation and its associated cytotoxicity can be therapeutically modulated in an array of cell and animal models. This review highlights the relevant progress in this field and discusses the relevance of heat shock proteins as therapeutic modulators of α-synuclein toxicity to the rapidly evolving understanding of Parkinson’s disease pathogenesis.
doi:10.1177/1756285613493469
PMCID: PMC3886379  PMID: 24409201
α-synuclein; heat shock protein; molecular chaperones; parkinsonism

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