Therapeutic Advances in Neurological Disorders recent issues

Benefit of repetitive intrathecal triamcinolone acetonide therapy in predominantly spinal multiple sclerosis: prediction by upper spinal cord atrophy

Thu, 05 Nov 2009 08:25:12 PST

Intrathecal injection of triamcinolone acetonide (TCA) has been shown to provide substantial benefit in a subset of progressive multiple sclerosis (MS) patients with predominant spinal symptoms. We examined whether atrophy of the upper spinal cord (USC) as measured by MRI can serve as a predictive marker for response to repetitive intrathecal TCA application. Repetitive administration of 40 mg TCA was performed in 31 chronic progressive MS patients up to six times within 3 weeks. Expanded Disability Status Scale (EDSS) and maximum walking distance (WD) were assessed before and after the treatment cycle. Cervical 3D T1-weighted images were acquired on a 1.5T scanner at baseline. Mean cross-sectional area of the USC was determined using a semi-automated volumetry method. Results were compared with a group of 29 healthy controls to group patients into those with and without atrophy. Results show a negative correlation between the degree of USC atrophy and treatment benefit. A higher treatment benefit in patients with little USC atrophy but short initial maximum WD was observed. Absence of USC atrophy as measured on MRI is a predictive marker for intrathecal TCA therapy outcome in progressive MS. Patients with initial poor walking abilities, but only little or no atrophy, benefited most from TCA therapy.

Review: Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms

Awad, A., Stuve, O. — Thu, 05 Nov 2009 08:25:12 PST

For patients with relapsing-remitting multiple sclerosis (RRMS), there are currently six approved medications that have been shown to alter the natural course of the disease. The approved medications include three beta interferon formulations, glatiramer acetate, natalizumab and mitoxantrone. Treating aggressive forms of RRMS and progressive disease forms of MS still presents a great challenge to neurologists. Intense immunosuppression has long been thought to be the only feasible therapeutic option. In patients with progressive forms of MS, lymphoid tissues have been detected in the central nervous system (CNS) that may play a critical role in perpetuating local inflammation. Agents that are currently approved for patients with MS have no or very limited bioavailability in the brain and spinal cord. In contrast, cyclophosphamide (CYC), an alkylating agent, penetrates the blood-brain barrier and CNS parenchyma well. However, while CYC has been used in clinical trials and off-label in clinical practice in patients with MS for over three decades, data on its efficacy in very heterogeneous groups of study patients have been conflicting. New myeloablative treatment paradigms with CYC may provide a therapeutic option in patients that do not respond to other agents. In this article we review the scientific rationale that led to the initial clinical trials with CYC. We will also outline the safety, tolerability and efficacy of CYC and provide neurologists with guidelines for its use in patients with MS and other inflammatory disorders of the CNS, including neuromyelitis optica (NMO). Finally, an outlook into relatively novel treatment approaches is provided.

Review: Identifying patient subtypes in multiple sclerosis and tailoring immunotherapy: challenges for the future

De Jager, P. L. — Thu, 05 Nov 2009 08:25:12 PST

The accelerating pace of technological and analytical development in the fields of genetic and phenotypic profiling has ushered in an era of great promise for multiple sclerosis (MS) research. As we continue to identify modest but meaningful associations to MS susceptibility, disease course, treatment response, and other clinical or paraclinical phenotypes, we must begin to (1) embark on the challenging set of studies that will integrate disparate observations into clinical algorithms, and (2) validate their clinical utility. Genetic data are receiving much of the attention today, but they are unlikely to be sufficient to offer a personalized approach to disease management in MS. Rather, the genetic architecture of the disease, once uncovered, will offer a fixed platform upon which more dynamic molecular profiles can be assembled to deconstruct the structure of the patient population that we label with a diagnosis of MS. The tools and methods to gain insight into the heterogeneity of MS patients are available today; we must now realize their potential in enhancing the care of MS patients.

Review: Deep brain stimulation in Parkinson's disease

Groiss, S.J., Wojtecki, L., Sudmeyer, M., Schnitzler, A. — Thu, 05 Nov 2009 08:25:12 PST

During the last 15 years deep brain stimulation (DBS) has been established as a highly-effective therapy for advanced Parkinson’s disease (PD). Patient selection, stereotactic implantation, postoperative stimulator programming and patient care requires a multi-disciplinary team including movement disorders specialists in neurology and functional neurosurgery. To treat medically refractory levodopa-induced motor complications or resistant tremor the preferred target for high-frequency DBS is the subthalamic nucleus (STN). STN-DBS results in significant reduction of dyskinesias and dopaminergic medication, improvement of all cardinal motor symptoms with sustained long-term benefits, and significant improvement of quality of life when compared with best medical treatment. These benefits have to be weighed against potential surgery-related adverse events, device-related complications, and stimulus-induced side effects. The mean disease duration before initiating DBS in PD is currently about 13 years. It is presently investigated whether the optimal timing for implantation may be at an earlier disease-stage to prevent psychosocial decline and to maintain quality of life for a longer period of time.

Review: Improving symptom control in early Parkinson's disease

Isaacson, S. H., Hauser, R. A. — Thu, 05 Nov 2009 08:25:12 PST

Motor symptoms in Parkinson’s disease (PD) are caused by a severe loss of pigmented dopamine-producing nigro-striatal neurons. Symptomatic therapies provide benefit for motor features by restoring dopamine receptor stimulation. Studies have demonstrated that delaying the introduction of dopaminergic medical therapy is associated with a rapid decline in quality of life. Nonmotor symptoms, such as depression, are common in early PD and also affect quality of life. Therefore, dopaminergic therapy should typically be initiated at, or shortly following, diagnosis. Monamine oxidase-B inhibitors provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-term outcomes, making them an important first-line treatment option. Dopamine agonists (DAs) provide moderate symptomatic benefit but are associated with more side effects than levodopa. However, they delay the development of motor complications by delaying the need for levodopa. Levodopa (LD) is the most efficacious medication, but its chronic use is associated with the development of motor complications that can be difficult to resolve. Younger patients are more likely to develop levodopa-induced motor complications and they are therefore often treated with a DA before levodopa is added. For older patients, levodopa provides good motor benefit with a relatively low-risk of motor complications. Using levodopa with a dopa-decarboxylase inhibitor lessens adverse effects, and further adding a catechol-O-methyl transferase inhibitor can improve symptom control.

Review: Pathophysiology and treatment of bacterial meningitis

Hoffman, O., Weber, J. R. — Thu, 05 Nov 2009 08:25:12 PST

Bacterial meningitis is a medical emergency requiring immediate diagnosis and immediate treatment. Streptococcus pneumoniae and Neisseria meningitidis are the most common and most aggressive pathogens of meningitis. Emerging antibiotic resistance is an upcoming challenge. Clinical and experimental studies have established a more detailed understanding of the mechanisms resulting in brain damage, sequelae and neuropsychological deficits. We summarize the current pathophysiological concept of acute bacterial meningitis and present current treatment strategies.

Acknowledgements

Tue, 24 Nov 2009 02:56:22 PST

Long-term daclizumab therapy in relapsing-remitting multiple sclerosis

Rojas, M. A., Carlson, N. G., Miller, T. L., Rose, J. W. — Tue, 01 Sep 2009 09:18:17 PDT

We performed a retrospective review of side effects and clinical outcomes in relapsing-remitting (RR) multiple sclerosis (MS) patients receiving long-term treatment with daclizumab. Twelve patients with RR MS were initially treated with daclizumab at 1 mg/kg IV, again 14 days later and then monthly treatments (average duration 42.1 months). Daclizumab dose (0.85 mg/kg to 1.5 mg/kg) was adjusted based on clinical response. Daclizumab was generally well tolerated. There was a significant reduction in relapse rate and improvement in Expanded Disability Status Scores (EDSSs) (p < 0.0001). Long-term treatment with daclizumab in RR MS patients has apparent benefit that will require formal confirmation.

Implementation of computer-based language therapy in aphasia

Archibald, L. M.D., Orange, J. B., Jamieson, D. J. — Tue, 01 Sep 2009 09:18:18 PDT

A first step in evaluating the use of computers in language therapy for individuals with aphasia is to establish the treatment as active in small groups prior to large-scale clinical trials. The present study evaluated a comprehensive computer-based language therapy program in a group of eight individuals with chronic in aphasia varying broadly in age, time post onset and aphasia type. Results revealed an overall therapeutic benefit in auditory comprehension, as well as positive trends in functional communication. Findings suggest that comprehensive therapy programs may be beneficial for many individuals with aphasia, and computer-based therapy may be one feasible avenue of providing this intervention.

Review: A review of the use of zonisamide in Parkinson's disease

Bermejo, P. E., Anciones, B. — Tue, 01 Sep 2009 09:18:18 PDT

Although zonisamide was previously only used to treat epilepsy, recently more applications have been forthcoming. Due to a good side effect profile, a lower frequency of interactions and a more comfortable posology, there are several studies regarding its uses in other pathologies such as migraine, neuropathic pain, essential tremor and various psychiatric diseases. A multicentered, randomized, double-blind, placebo-controlled study conducted in Japan suggested that zonisamide, as an add-on treatment, has efficacy in treating motor symptoms in patients with Parkinson’s disease. In addition, other studies support the utility of zonisamide in other symptoms of this disease. The therapeutic doses of zonisamide for the treatment of Parkinson’s disease are considerably lower than those for the treatment of epilepsy. This antiepileptic drug has been used in Japan for more than 15 years and so it is expected that it will be safe and well tolerated in patients with Parkinson’s disease. However, the pharmacological mechanisms of the antiparkinsonian actions of zonisamide remain unclear and more basic investigation is warranted. The aim of this paper is to review the structure, mechanisms of action, pharmacokinetics and antiparkinsonian action of zonisamide.

Review: Evidence-based drug treatment in amyotrophic lateral sclerosis and upcoming clinical trials

Ludolph, A. C., Jesse, S. — Tue, 01 Sep 2009 09:18:18 PDT

Amyotrophic lateral sclerosis/motor neuron disease is a severe neurodegenerative disease characterized by upper and lower motor neuron degeneration for which there is no truly effective treatment. Several therapies have shown promise in preclinical models of motor neuron disease; however, most of them failed in human studies, so that the noticeable progress in understanding the cellular mechanisms of motor neuron degeneration has not been matched with the development of therapeutic strategies to prevent disease progression or to extend survival longer than achieved by riluzole. We review treatment development in motor neuron disease and discuss the strengths and limitations of past as well as upcoming clinical trials.

Review: Menstrual migraine: therapeutic approaches

MacGregor, E. A. — Tue, 01 Sep 2009 09:18:18 PDT

The development of diagnostic criteria has enabled greater recognition of menstrual migraine as a highly prevalent and disabling condition meriting specific treatment. Although few therapeutic trials have yet been undertaken in accordance with the criteria, the results of those published to date confirm the efficacy of acute migraine drugs for symptomatic treatment. If this approach is insufficient, the predictability of attacks provides the opportunity for perimenstrual prophylaxis. Continuous contraceptive strategies provide an additional option for management, although clinical trial data are limited. Future approaches to treatment could explore the genomic and nongenomic actions of sex steroids.

Review: Depression in epilepsy: mechanisms and therapeutic approach

Mula, M., Schmitz, B. — Tue, 01 Sep 2009 09:18:18 PDT

In patients with epilepsy, mood disorders represent a frequent psychiatric comorbidity but they often remain unrecognized and untreated. However, comorbid depression may have a major impact on the quality of life of patients with epilepsy, sometimes even more than the seizures. Among the potential neurobiological and psychosocial determinants, epilepsy-related variables (age at onset of seizures, temporal lobe epilepsy and frequency of seizures) and the antiepileptic drug treatment have been associated with depression. Nonetheless, data on treatment strategies are still limited with a lack of controlled trials on the use of antidepressant drugs. Moreover, the issue of psychotropic drug treatment of depression in epilepsy is interlinked with that of worsening seizures. This paper is aimed at discussing all these subjects in the light of current literature on the neurobiology of depression in epilepsy.

Monoclonal antibodies in multiple sclerosis treatment: current and future steps

Helliwell, C. L., Coles, A. J. — Mon, 29 Jun 2009 07:52:14 PDT

The 39-item Parkinson's Disease Questionnaire (PDQ-39): is it a unidimensional construct?

Hagell, P., Nilsson, M. H. — Mon, 29 Jun 2009 07:52:14 PDT

The 39-item Parkinson's Disease Questionnaire, and particularly its summary index (PDQ-39SI) is a widely used patient-reported clinical trial endpoint. A basic assumption when summing items into a total score is that they represent a common variable. We therefore assessed the unidimensionality of the PDQ-39SI using Rasch and confirmatory factor analysis. Both analyses showed model misfit. Adjustment for differential item functioning and disordered response category thresholds did not improve model fit, and residual analyses showed deviation from unidimensionality. These data indicate multidimensionality and challenge the interpretation and validity of PDQ-39SI scores. Clinicians and investigators should use and interpret the PDQ-39SI with caution.

Review: Diagnosis and management of essential tremor and dystonic tremor

Gironell, A., Kulisevsky, J. — Mon, 29 Jun 2009 07:52:14 PDT

Essential tremor (ET) is the most common adult movement disorder. Traditionally considered as a benign disease, it can cause an important physical and psychosocial disability. Drug treatment for ET remains poor and often unsatisfactory. Current therapeutic strategies for ET are reviewed according to the level of discomfort caused by tremor. For mild tremor, nonpharmacological strategies consist of alcohol and acute pharmacological therapy; for moderate tremor, pharmacological therapies (propranolol, gabapentin, primidone, topiramate, alprazolam and other drugs); and for severe tremor, the role of functional surgery is emphasised (thalamic deep brain stimulation, thalamotomy). The more specific treatment of head tremor with the use of botulinum toxin is also discussed. Several points are discussed to guide the immediate research into this disease in the near future. Dystonic tremor is a common symptom in dystonia. Diagnostic criteria for dystonic tremor and differential diagnosis with psychogenic tremor and ET are described. Treatment of dystonic tremor matches the treatment of dystonia. In cases of symptomatic dystonic tremor similar to ET, therapeutic strategies would be the same as for ET.

Review: Current treatment of vestibular, ocular motor disorders and nystagmus

Strupp, M., Brandt, T. — Mon, 29 Jun 2009 07:52:14 PDT

Vertigo and dizziness are among the most common complaints with a lifetime prevalence of about 30%. The various forms of vestibular disorders can be treated with pharmacological therapy, physical therapy, psychotherapeutic measures or, rarely, surgery. In this review, the current pharmacological treatment options for peripheral and central vestibular, cerebellar and ocular motor disorders will be described. They are as follows for peripheral vestibular disorders. In vestibular neuritis recovery of the peripheral vestibular function can be improved by treatment with oral corticosteroids. In Menie`re's disease a recent study showed long-term high-dose treatment with betahistine has a significant effect on the frequency of the attacks. The use of aminopyridines introduced a new therapeutic principle in the treatment of downbeat and upbeat nystagmus and episodic ataxia type 2 (EA 2). These potassium channel blockers presumably increase the activity and excitability of cerebellar Purkinje cells, thereby augmenting the inhibitory influence of these cells on vestibular and cerebellar nuclei. A few studies showed that baclofen improves periodic alternating nystagmus, and gabapentin and memantine, pendular nystagmus. However, many other eye movement disorders such as ocular flutter opsoclonus, central positioning, or see-saw nystagmus are still difficult to treat. Although progress has been made in the treatment of vestibular neuritis, downbeat and upbeat nystagmus, as well as EA 2, state-of-the-art trials must still be performed on many vestibular and ocular motor disorders, namely Menie`re's disease, bilateral vestibular failure, vestibular paroxysmia, vestibular migraine, and many forms of central eye movement disorders.

Review: Blood pressure and dementia -- a comprehensive review

Kennelly, S. P., Lawlor, B. A., Kenny, R. A. — Mon, 29 Jun 2009 07:52:14 PDT

Alzheimer's disease (AD) and vascular dementia (VaD) are important causes of cognitive decline in the elderly. As a result of an ageing population worldwide, the incidence of dementia is expected to rise exponentially over the coming decades. Vascular risk factors are implicated in the pathogenesis of both AD and VaD. Hypertension in midlife is particularly associated with an increased risk of developing dementia. One might hope the treatment of high blood pressure in midlife would reduce the risk of developing dementia, as it does the risk of stroke. Divergent results have been reported in studies examining this effect, with the evidence suggesting that certain antihypertensives confer benefits beyond others. This implies that certain drugs may have neuroprotective properties separate to their blood pressure lowering capabilities. Recent trials have added to our understanding of these relationships.

Review: Pathogenesis and treatment of immune-mediated neuropathies

Lehmann, H. C., Meyer zu Horste, G., Kieseier, B. C., Hartung, H.-P. — Mon, 29 Jun 2009 07:52:14 PDT

Immune-mediated neuropathies represent a heterogeneous spectrum of peripheral nerve disorders that can be classified according to time course, predominant involvement of motor/sensory fibers, distribution of deficits and paraclinical parameters such as electrophysiology and serum antibodies. In the last few years, significant advances have been achieved in elucidating underlying pathomechanisms, which made it possible to identify potential therapeutic targets. In this review, we discuss the latest development in pathogenesis and treatment of immune-mediated neuropathies.

Fixed-dose sumatriptan/naproxen sodium compared with each monotherapy utilizing the novel composite endpoint of sustained pain-free/no adverse events

Landy, S., White, J., Lener, S. E., McDonald, S. A. — Thu, 30 Apr 2009 03:02:25 PDT

A novel composite endpoint, sustained pain-free/no adverse events, was recently proposed as a more rigorous means of capturing in a single measure the attributes of migraine pharmacotherapy that patients consider most important: rapid and sustained pain-free response with no side-effects. Using pooled data from two replicate randomized, double-blind, parallel-group, placebo-controlled studies, this post hoc analysis compared the fixed-dose combination tablet sumatriptan/naproxen sodium (n = 726) with sumatriptan monotherapy (n = 723), naproxen sodium monotherapy (n = 720), and placebo (n = 742) with respect to sustained pain-free/no adverse events and closely related composite measures. Sustained pain-free/no adverse events was defined as having both a sustained pain-free response from 2 through 24 hours post-dose with no use of rescue medication and having no adverse events within up to 5 days after dosing with study medication. The percentage of patients with sustained pain-free/no adverse events was 16% with sumatriptan/naproxen sodium compared with 11%, 9% and 7% for sumatriptan, naproxen sodium and placebo, respectively (p50.01 sumatriptan/naproxen sodium versus each other treatment). Sumatriptan/naproxen sodium was also significantly more effective than sumatriptan, naproxen sodium, and placebo for other composite endpoints including the percentages of patients with (1) sustained pain-free/no adverse events within 1 day; (2) sustained pain-free/no drug-related adverse events within up to 5 days; (3) sustained pain-free/no drug-related adverse events within 1 day; (4) sustained pain relief/no adverse events within up to 5 days; and (5) sustained pain relief/no adverse events within 1 day. The results demonstrate the superiority of sumatriptan/naproxen sodium to sumatriptan monotherapy, naproxen sodium monotherapy and placebo with respect to the rigorous and clinically relevant endpoint of sustained pain-free/no adverse events and reinforce the usefulness of utilizing this new composite endpoint.

Progress in enzyme replacement therapy in glycogen storage disease type II

Thu, 30 Apr 2009 03:02:25 PDT

Glycogen storage disease type II (GSDII) is an autosomal recessive lysosomal disorder caused by mutations in the gene encoding alpha-glucosidase (GAA). The disease can be clinically classified into three types: a severe infantile form, a juvenile and an adult-onset form. Cases with juvenile or adult onset GSDII mimic limb-girdle muscular dystrophy or polymyositis and are often characterized by respiratory involvement. GSDII patients are diagnosed by biochemical assay and by molecular characterization of the GAA gene. Ascertaining a natural history of patients with heterogeneous late-onset GSDII is useful for evaluating their progressive functional disability. A significant decline is observed over the years in skeletal and respiratory muscle function. Enzyme replacement therapy (ERT) has provided encouraging results in the infantile form. It is not yet known if ERT is effective in late-onset GSDII. We examined a series of 11 patients before and after ERT evaluating muscle strength by MRC, timed and graded functional tests, 6-minute walk test (6MWT), respiratory function by spirometric parameters and quality of life. We observed a partial improvement during a prolonged follow-up from 3 to 18 months. The use of different clinical parameters in the proposed protocol seems crucial to determine the efficacy of ERT, since not all late-onset patients respond similarly to ERT.

Review: Drug and nondrug treatment in tension-type headache

Bendtsen, L. — Thu, 30 Apr 2009 03:02:25 PDT

Tension-type headache (TTH) is a common primary headache with tremendous socioeconomic impact. Establishment of an accurate diagnosis is important before initiation of any treatment. Nondrug management is crucial. Information, reassurance and identification of trigger factors may be rewarding. Psychological treatments with scientific evidence for efficacy include relaxation training, EMG biofeedback and cognitive-behavioural therapy. Physical therapy and acupuncture are widely used, but the scientific evidence for efficacy is sparse. Simple analgesics are the mainstays for treatment of episodic TTH. Combination analgesics, triptans, muscle relaxants and opioids should not be used, and it is crucial to avoid frequent and excessive use of simple analgesics to prevent the development of medication-overuse headache. The tricyclic antidepressant amitriptyline is drug of first choice for the prophylactic treatment of chronic TTH. The efficacy is modest and treatment is often hampered by side effects. Thus, treatment of frequent TTH is often difficult and multidisciplinary treatment strategies can be useful. The development of specific nonpharmacological and pharmacological managements for TTH with higher efficacy and fewer side effects is urgently needed. Future studies should also examine the relative efficacy of the various treatment modalities; for example, psychological, physical and pharmacological treatments, and clarify how treatment programs should be optimized to best suit the individual patient.

Review: Therapy for Alzheimer's disease: how effective are current treatments?

Lanctot, K. L., Rajaram, R. D., Herrmann, N. — Thu, 30 Apr 2009 03:02:25 PDT

Available symptomatic therapies for the treatment of Alzheimer's disease (AD) have been based on known neurotransmitter dysfunctions associated with the illness. The second-generation cholinesterase inhibitors and the N-methyl D-aspartate receptor antagonist memantine have been widely prescribed and studied. Meta-analyses of these therapies were reviewed, focusing on effectiveness and tolerability. Although many of the meta-analyses demonstrate statistically significant improvements, some question if these benefits are sufficient to justify their current widespread and protracted use. This has spurred the development of new disease-modifying therapies that aim to have a greater impact on this debilitating illness.

Review: Comparing drug treatments in epilepsy

Chadwick, D., Shukralla, A., Marson, T. — Thu, 30 Apr 2009 03:02:25 PDT

The great majority of randomised controlled trials (RCTs) that compare antiepileptic drugs are industry sponsored and have the objective of obtaining a monotherapy license for a drug. Such trials do not inform everyday clinical practice as they tend to be too short and to depart from clinical practice by restricting clinicians in their choice of actions. The data that exists provides evidence that drugs with actions on voltage-gated sodium channels provide best seizure control for localised onset seizures and epilepsy syndromes, while valproate provides best seizure control for generalised epilepsy and unclassified syndromes. Drugs do, however, vary in their tolerability over the short term and in their risk for rare serious idiosyncratic adverse events, chronic toxicity and teratogenicity; issues that cannot be examined within the scope of RCTs.