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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Anxiety in Parkinson’s disease: identification and management 
Anxiety disturbances are recognized as common psychiatric comorbidities in Parkinson’s disease (PD) and contribute to significant impairments in areas of cognitive, functional, motor and social performance. Anxiety in PD results in reduced quality of life, higher levels of care dependency and increased caregiver burden. Surprisingly, there is a paucity of treatment data. In one randomized, controlled study, bromazepam was found to be effective for anxiety in PD. However, usage of benzodiazepines in the PD population is limited by potential risk of confusion and falls. There are no controlled studies of selective serotonin reuptake inhibitors (SSRIs) for anxiety in PD. However, results from uncontrolled studies suggest that SSRIs are effective for anxiety in PD, although in these studies anxiety outcomes were secondary. This review underscores that, given the high prevalence of anxiety disturbances in PD, there is a significant paucity of treatment data for this population. Additional studies are warranted. In the meantime, clinicians should rely on empiric assessments of known risks and putative benefits to guide treatment decisions. Cognitive and behavioral therapies (with or without pharmacotherapy) have demonstrated efficacy and warrant consideration. When feasible, a targeted and individualized multimodal approach utilizing psychotherapeutic interventions along with pharmacologic therapies should be considered.
doi:10.1177/1756285613495723
PMCID: PMC3886380  PMID: 24409202
Anxiety; neurology; Parkinson’s disease; psychiatry
14.  Treatment of complex neurovascular lesions: an interdisciplinary angio suite approach 
Objective:
The objective of this study was to analyse our initial experience using an interdisciplinary angio suite approach to neurosurgical treatment of complex neurovascular lesions and expound technical feasibility and possible applications.
Subjects:
Six out of 451 patients with cranial or spinal neurovascular lesions were surgically treated in the angio suite (biplane angiographic system) during a 28-month observation period. Clinical baseline data, radiological and intraoperative findings as well as clinical and radiological outcome were assessed.
Results:
A ventral spinal perimedullary arteriovenous malformation, a ventral spinal perimedullary fistula, two diffuse frontal dural arteriovenous fistulas, a multifocal temporal arteriovenous malformation and a partially embolized fronto-temporo-basal dural arteriovenous fistula were successfully treated with angiographically confirmed complete occlusion and unimpaired neurological condition of the patients at the 12-month follow up.
Conclusion:
This study demonstrates the feasibility of this approach and points out possible indications, namely ventrally located spinal lesions and diffuse, deep seated cranial lesions.
doi:10.1177/1756285613496861
PMCID: PMC3886381  PMID: 24409203
arteriovenous malformation; dural arteriovenous fistula; intraoperative angiography; neurovascular; surgical treatment
15.  Capsaicinoids in the treatment of neuropathic pain: a review 
The treatment of neuropathic pain is difficult. Oral pharmaceuticals have significant side effects, and treatment efficacy tends to be modest. The use of topical analgesics reduces the potential for systemic side effects and allows direct application of medications to the area of pain. The natural spicy substance, capsaicin, has historically been known for its topical use. Capsaicin, once applied to the skin, causes a brief initial sensitization followed by a prolonged desensitization of the local pain nerves. This occurs through stimulation of the transient receptor potential vanilloid-1 (TRPV1) expressing pain nerve fibers. While low-dose capsaicin has not resulted in good efficacy, the larger dose 8% topical capsaicin has had some of the best data currently available in the treatment of post-herpetic neuralgia (PHN) and other neuropathic conditions. This paper discusses the data currently existing for capsaicin 8% in the treatment of PHN. It further reviews data for the low-dose capsaicin products and the current status in the development of other capsaicinoids, e.g. resiniferotoxin, and high-concentration liquid capsaicin.
doi:10.1177/1756285613501576
PMCID: PMC3886382  PMID: 24409200
capsaicin; capsaicinoids; neuropathic pain; TRPV1
16.  Prophylactic antiepileptic treatment reduces seizure frequency in natalizumab-associated progressive multifocal leukoencephalopathy 
Objective:
Little is known about seizures in natalizumab-associated progressive multifocal leukoencephalopathy (NAT-PML).
Methods:
A review of clinical records of 15 NAT-PML patients with multiple sclerosis (MS) treated at a German university hospital.
Results:
Some 53% (8/15) of our patients developed seizures with often multiple semiologies (seven grand mal, three simple partial motor and two psychomotor seizures). Series of seizures or status epilepticus occurred in seven of these eight. Seizure onset was on average 61 days after onset of NAT-PML and was associated with immune reconstitution inflammatory syndrome (IRIS) in five of eight patients. After having observed severe seizures during NAT-PML in seven of our first nine patients, we started preventive antiepileptic treatment (PAT) with levetiracetam (1000–1750 mg/day). Patient subgroups analyzed for seizures and PAT did not differ in baseline characteristics. Only one of six patients, who received PAT, had a seizure compared with seven of nine patients without PAT (2-tailed Fisher’s exact test, p = 0.04).
Conclusions:
Although the small sample size and retrospective nature of the study are limitations, we propose to treat NAT-PML patients with PAT early after diagnosis, as seizures seem to be common and severe in NAT-PML.
doi:10.1177/1756285613503515
PMCID: PMC3886383  PMID: 24409198
natalizumab; preventive antiepileptic treatment; progressive multifocal leukoence-phalopathy; seizures
17.  The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis 
Daclizumab is a humanized monoclonal antibody of the immunoglobulin G1 (IgG1) isotype that binds to the α-subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor expressed on activated T cells and CD4+CD25+FoxP3+ regulatory T cells. Based on the assumption that it would block the activation and expansion of autoreactive T cells that are central to the immune pathogenesis of multiple sclerosis (MS), daclizumab was tested in several small open-label clinical trials in MS and demonstrated a profound inhibition of inflammatory disease activity. Surprisingly, accompanying mechanistic studies revealed that the most important biological effect of daclizumab was rather a dramatic expansion and activation of immunoregulatory CD56bright natural-killer (NK) cells that correlated with treatment response, while there was no or only minor effect on peripheral T-cell activation and function. These CD56bright NK cells were able to gain access to the central nervous system in MS and kill autologous activated T cells. Additional and relatively large phase IIb clinical trials showed that daclizumab, as add-on or monotherapy in relapsing–remitting (RR) MS, was highly effective in reducing relapse rate, disability progression, and the number and volume of gadolinium-enhancing, T1 and T2 lesions on brain magnetic resonance imaging (MRI), and reproduced the expansion of CD56bright NK cells as a biomarker for daclizumab activity. Daclizumab is generally very well tolerated and has shown a favorable adverse event (AE) profile in transplant recipients. However, several potentially serious and newly emerging AEs (mainly infections, skin reactions, elevated liver function tests and autoimmune phenomena in several body organs) may require strict safety monitoring programs in future clinical practice and place daclizumab together with other new and highly effective MS drugs as a second-line therapy. Ongoing phase III clinical trials in RRMS are expected to provide definite information on the efficacy and safety of daclizumab and to determine its place in the fast-growing armamentarium of MS therapies.
doi:10.1177/1756285613504021
PMCID: PMC3886384  PMID: 24409199
CD25; CD56bright NK cells; clinical trial; daclizumab; IL-2; IL-2 receptor; multiple sclerosis; T cell
18.  The cognitive side of essential tremor: what are the therapeutic implications? 
While essential tremor (ET) has traditionally been categorized as a pure motor disease, cross-sectional and longitudinal studies of cognition in ET have demonstrated that these patients may have cognitive dysfunction. Recent epidemiological studies demonstrate an association between ET (particularly with onset after age 65) and increased risk for cognitive impairment and dementia. Although existing studies have generally conceptualized cognitive changes in ET as consistent with a ‘frontosubcortical’ or ‘corticocerebellar’ profile, results from these same studies suggest that cognitive impairment in ET may in fact be heterogeneous. Furthermore, the underlying mechanisms remain uncertain. Cognitive changes could be a byproduct of the cerebellar dysfunction of ET itself; alternately, they may be a feature of concomitant neurodegenerative diseases that have been associated in several studies with ET, including Alzheimer’s disease, Parkinson’s disease or progressive supranuclear palsy. While the study of cognitive dysfunction in ET has received research attention in recent years, the results of these studies have not been translated into the clinical domain and clinical practice. This review first summarizes the current literature on the potential relationships between ET and cognitive change. We then suggest areas of further clinical evaluation and treatment; these suggestions are directed at physicians caring for ET patients who may demonstrate or complain of cognitive impairment. As we discuss, clinicians should ideally screen ET patients for possible signs or symptoms of cognitive impairment in addition to assessing for psychiatric comorbidity and quality of life. These recommendations are in contrast to most current clinical practice, which does not routinely include such assessment among ET patients. To our knowledge, there have been no pharmacotherapeutic trials to date of any agent for cognitive change associated with ET. We believe that studies for this indication are now called for. Future efforts in this direction will also need to take into account the pathobiology of cognitive changes in ET, which itself is an area that is ripe for future investigations.
doi:10.1177/1756285613489591
PMCID: PMC3825113  PMID: 24228071
clinical; cognition; essential tremor
19.  The role of neuroimaging in the diagnosis of headache disorders 
Headache is a common clinical feature in patients in the emergency room and in general neurology clinics. For physicians not experienced in headache disorders it might be difficult sometimes to decide in which patients neuroimaging is necessary to diagnose an underlying brain pathology and in which patients cerebral imaging is unnecessary. Most patients presenting to the primary-care physician with a nonacute headache and no further neurological signs or symptoms will not be suffering from an underlying serious condition. This review focuses on the main primary headache diseases, including migraine, tension-type headache and cluster headache, as well as frequent secondary headache entities with common clinical presentation and appropriate diagnostic and therapeutic algorithms to help guide the decision on the utilization of neuroimaging in the diagnostic workup.
doi:10.1177/1756285613489765
PMCID: PMC3825114  PMID: 24228072
cluster headache; diagnosis; headache; migraine; neuroimaging; tension-type headache
20.  Notch signalling in adult neurons: a potential target for microtubule stabilization 
Cytoskeletal dysfunction has been proposed during the last decade as one of the main mechanisms involved in the aetiology of several neurodegenerative diseases. Microtubules are basic elements of the cytoskeleton and the dysregulation of microtubule stability has been demonstrated to be causative for axonal transport impairment, synaptic contact degeneration, impaired neuronal function leading finally to neuronal loss. Several pathways are implicated in the microtubule assembly/disassembly process. Emerging evidence is focusing on Notch as a microtubule dynamics regulator. We demonstrated that activation of Notch signalling results in increased microtubule stability and changes in axonal morphology and branching. By contrast, Notch inhibition leads to an increase in cytoskeleton plasticity with intense neurite remodelling. Until now, several microtubule-binding compounds have been tested and the results have provided proof of concept that microtubule-binding agents or compounds with the ability to stabilize microtubules may have therapeutic potential for the treatment of Alzheimer’s disease and other neurodegenerative diseases. In this review, based on its key role in cytoskeletal dynamics modulation, we propose Notch as a new potential target for microtubule stabilization.
doi:10.1177/1756285613490051
PMCID: PMC3825115  PMID: 24228073
cytoskeleton; microtubule stabilization; neurodegeneration; Notch; Spastin; structural plasticity
21.  Kynurenines and other novel therapeutic strategies in the treatment of dementia 
Dementia is a common neuropsychological disorder with an increasing incidence. The most prevalent type of dementia is Alzheimer’s disease. The underlying pathophysiological features of the cognitive decline are neurodegenerative processes, a cerebrovascular dysfunction and immunological alterations. The therapeutic approaches are still limited, although intensive research is being conducted with the aim of finding neuroprotective strategies. The widely accepted cholinesterase inhibitors and glutamate antagonists did not meet expectations of preventing disease progression, and research is therefore currently focusing on novel targets. Nonsteroidal anti-inflammatory drugs, secretase inhibitors and statins are promising drug candidates for the prevention and management of different forms of dementia. The kynurenine pathway has been associated with various neurodegenerative disorders and cerebrovascular diseases. This pathway is also closely related to neuroinflammatory processes and it has been implicated in the pathomechanisms of certain kinds of dementia. Targeting the kynurenine system may be of therapeutic value in the future.
doi:10.1177/1756285613494989
PMCID: PMC3825116  PMID: 24228074
Alzheimer’s disease; dementia; kynurenine; neuroprotective agents
22.  Efficacy and safety of laquinimod in multiple sclerosis: current status 
Laquinimod is a novel immunomodulatory agent, in development as a potential disease-modifying treatment for multiple sclerosis (MS). Structurally related to linomide, its pharmacological predecessor, laquinimod combines anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. In this review we aim to highlight the immunomodulatory and neuroprotective effects of laquinimod, and to describe its effects in animal models of MS. Furthermore, we focus on current results of clinical studies in MS. Randomized, controlled clinical trials in relapsing MS demonstrate a dose–response effect on disease activity, measured by reduced clinical relapse rate, reduced number of brain MRI active lesions, as well as on sustained disability and brain atrophy. Laquinimod has a favourable tolerability and safety profile. A new phase III study, recently completed, will soon provide further details on the therapeutic potential of this drug. Laquinimod is a promising emerging treatment for relapsing–remitting MS that may provide a new therapeutic option in the near future.
doi:10.1177/1756285613499424
PMCID: PMC3825117  PMID: 24228070
laquinimod; multiple sclerosis; oral medication
23.  Magnetic resonance monitoring of lesion evolution in multiple sclerosis 
Disease activity in multiple sclerosis (MS) is strongly linked to the formation of new lesions, which involves a complex sequence of inflammatory, degenerative, and reparative processes. Conventional magnetic resonance imaging (MRI) techniques, such as T2-weighted and gadolinium-enhanced T1-weighted sequences, are highly sensitive in demonstrating the spatial and temporal dissemination of demyelinating plaques in the brain and spinal cord. Hence, these techniques can provide quantitative assessment of disease activity in patients with MS, and they are commonly used in monitoring treatment efficacy in clinical trials and in individual cases. However, the correlation between conventional MRI measures of disease activity and the clinical manifestations of the disease, particularly irreversible disability, is weak. This has been explained by a process of exhaustion of both structural and functional redundancies that increasingly prevents repair and recovery, and by the fact that these imaging techniques do not suffice to explain the entire spectrum of the disease process and lesion development. Nonconventional MRI techniques, such as magnetization transfer imaging, diffusion-weighted imaging, and proton magnetic resonance spectroscopy, which can selectively measure the more destructive aspects of MS pathology and monitor the reparative mechanisms of this disease, are increasingly being used for serial analysis of new lesion formation and provide a better approximation of the pathological substrate of MS plaques. These nonconventional MRI-based measures better assess the serial changes in newly forming lesions and improve our understanding of the relationship between the damaging and reparative mechanisms that occur in MS.
doi:10.1177/1756285613484079
PMCID: PMC3755529  PMID: 23997815
diffusion-weighted imaging; lesion development; magnetic resonance imaging; magnetization transfer imaging; multiple sclerosis; proton magnetic resonance spectroscopy
24.  Therapeutic advances in the management of Pompe disease and other metabolic myopathies 
The world of metabolic myopathies has been dramatically modified by the advent of enzyme replacement therapy (ERT), the first causative treatment for glycogenosis type II (GSDII) or Pompe disease, which has given new impetus to research into that disease and also other pathologies. This article reviews new advances in the treatment of GSDII, the consensus about ERT, and its limitations. In addition, the most recent knowledge regarding the pathophysiology, phenotype, and genotype of the disease is discussed. Pharmacological, immunotherapy, nutritional, and physical/rehabilitative treatments for late-onset Pompe disease and other metabolic myopathies are covered, including treatments for defects in glycogen metabolism, such as glycogenosis type V (McArdle disease), and glycogenosis type III (debrancher enzyme deficiency), and defects in lipid metabolism, such as carnitine palmitoyltransferase II deficiency and electron transferring flavoprotein dehydrogenase deficiency, or riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.
doi:10.1177/1756285613487570
PMCID: PMC3755530  PMID: 23997816
Glycogenosis type II; McArdle disease; RR-MADD; glycogenosis type III; CPT2 deficiency
25.  Targeting ion channels for the treatment of autoimmune neuroinflammation 
Pharmacological targeting of ion channels has long been recognized as an attractive strategy for the treatment of various diseases. Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system with a prominent neurodegenerative component. A multitude of different cell types are involved in the complex pathophysiology of this disorder, including cells of the immune system (e.g. T and B lymphocytes and microglia), the neurovascular unit (e.g. endothelial cells and astrocytes) and the central nervous system (e.g. astrocytes and neurons). The pleiotropic expression and function of ion channels gives rise to the attractive opportunity of targeting different players and pathophysiological aspects of MS by the modulation of ion channel function in a cell-type and context-specific manner. We discuss the emerging knowledge about ion channels in the context of autoimmune neuroinflammation. While some pharmacological targets are at the edge of clinical translation, others have only recently been discovered and are still under investigation. Special focus is given to those candidates that could be attractive novel targets for future therapeutic approaches in neuroimmune autoinflammation.
doi:10.1177/1756285613487782
PMCID: PMC3755531  PMID: 23997817
channelopathy; ion channels; Kv1.3; multiple sclerosis; sodium channels

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