A comparison of two neurologic scoring instruments for multiple sclerosis

We examined the degree of association between two neurologic impairment scales, the Extended Disability Status Scale (EDSS) and the Scripps Neurologic Rating Scale (SNRS), with data from a randomized, double-blind, placebo-controlled clinical trial assessing the safety and efficacy of cladribine as treatment for chronic progressive multiple sclerosis (MS). We found that the EDSS and SNRS were not strongly correlated within individual patients, contrary to expectation; moreover, in 9 of the 48 evaluable patients, the directions of their changes from baseline values were not mutually consistent. The scales were differentially sensitive to clinical changes over time, with the EDSS indicating a more abrupt, and the SNRS a more gradual, change in the clinical course of disease. The validity of different impairment scales, and their sensitivity to detect clinical changes, should be formally assessed in future clinical trials using these scales as outcome measures.     

Alzheimer's disease: the benefits of early treatment

The purpose of this review was to summarize research on the clinical benefits of early treatment for Alzheimer's disease via a focused discussion of data on donepezil. Well-controlled clinical trials demonstrate that donepezil is effective in stabilizing or slowing progressive decline in cognition, function, and behavior. Several studies reveal statistically significant and clinically meaningful advantages to initiating treatment early in the course of the disease. Benefits of donepezil treatment include behavioral stabilization and preserved independence, in addition to slowed cognitive decline. Epidemiologic studies and evidence from histopathology underlie a rationale for treating patients who are cognitively impaired but do not have dementia. Clinical trials in such patients indicate that treating patients with mild cognitive impairment (MCI) may delay the onset of Alzheimer's dementia. Substantial evidence favors initiating treatment early in the course of dementia and reinforces the necessity to assess behavior and activities of daily living to accurately evaluate treatment response. Results of early studies of donepezil in MCI are promising and suggest directions for further research.     

Realizing early treatment benefits in dementia

The purpose of this review was to summarize research on the clinical benefits of early treatment for Alzheimer's disease via a focused discussion of data on donepezil. Well‐controlled clinical trials demonstrate that donepezil is effective in stabilizing or slowing progressive decline in cognition, function, and behavior. Several studies reveal statistically significant and clinically meaningful advantages to initiating treatment early in the course of the disease. Benefits of donepezil treatment include behavioral stabilization and preserved independence, in addition to slowed cognitive decline. Epidemiologic studies and evidence from histopathology underlie a rationale for treating patients who are cognitively impaired but do not have dementia. Clinical trials in such patients indicate that treating patients with mild cognitive impairment (MCI) may delay the onset of Alzheimer's dementia. Substantial evidence favors initiating treatment early in the course of dementia and reinforces the necessity to assess behavior and activities of daily living to accurately evaluate treatment response. Results of early studies of donepezil in MCI are promising and suggest directions for further research.     

Azathioprine and methotrexate in multiple sclerosis

Evidence for the effectiveness of immunosuppressive agents in MS is scanty. There are few good quality trials; most have methodological limitations, such as a small sample size and short duration. Moreover, there is no consistency in treatment regimes, patient groups or outcome measures and the clinical benefits remain unclear. Although azathioprine appears to reduce the relapse rate in MS patients, its effect on disability progression has not been demonstrated. Methotrexate may alter the course of disease favourably in patients with progressive MS, but the evidence is again sparse.     

Evolving concepts in the pathogenesis of multiple sclerosis and their therapeutic implications.

Recent evidence suggests that multiple sclerosis (MS) is a continuously active neuropathologic process, even during the subclinical relapsing/remitting phase of the disease. Patients commonly feel well and function without disability for many years, experiencing only occasional relapses and nondisabling symptoms. In time, many evolve into a pattern of continuously progressive neurologic disability termed secondary progressive MS (SP-MS). SP-MS is hypothesized to occur once disease severity has exceeded a threshold. Above that threshold, compensatory mechanisms are inadequate to maintain normal function, and further disease progression is accompanied by progressively worsening disability. Inflammation dominates the early stage of disease. Progressive axonal pathology may underlie clinical disease progression in later stages. These concepts have important implications related to the diagnosis, methods for patient follow-up, type and timing of disease therapy, and the testing of neuroprotective drugs in MS.     

New directions in optic neuritis and multiple sclerosis

Optic neuritis (ON) is the initial presentation in 15% to 20% of cases of multiple sclerosis (MS). Thirty-eight percent to 50% of patients with MS develop ON at some point during the course of their disease. The Optic Neuritis Treatment Trial (ONTT) provided much prospective data about the clinical presentation, clinical course with respect to treatment, and development of MS in patients with ON. The clinical course of MS initially involves episodes of demyelination followed by full recovery; however, later attacks often leave persistent deficits that lead to secondary progression of the disease. The risk of developing progressive neurologic deficits can be reduced by starting therapy with immunomodulating drugs early in the course of the disease. Optical coherence tomography is a noninvasive way to monitor patients with ON to determine if they are undergoing subclinical axonal loss of ganglion cells. Progression of axonal loss on optical coherence tomography may prompt a change in therapy or further imaging.     

Serum uric acid, dehydroepiandrosterone sulphate, and apolipoprotein E genotype in benign vs. progressive multiple sclerosis

The majority of patients with multiple sclerosis (MS) experience gradual progression of disability, either as secondary progressive MS (SPMS) or primary progressive MS (PPMS). A subgroup with relapsing-remitting MS shows a benign course with little or no disease progression and minimal disability decades after the first manifestations, so called benign MS (BMS). In our search to identify factors that are associated with progression of MS, we investigated serum levels of uric acid and dehydroepiandrostenedione sulphate (DHEAS), and apolipoprotein (apo)E genotype in 28 patients with BMS, 33 with SPMS, 21 with PPMS, and 29 healthy individuals. We found no significant changes in uric acid levels and apoE genotype between the four groups. Mean DHEAS levels were lower in MS patients compared with healthy controls (P = 0.049), but there were no significant differences between the clinical subgroups of MS. In patients with SPMS and PPMS there was no correlation between progression rate and serum levels of either uric acid or DHEAS. Our results suggest that serum levels of uric acid and DHEAS, and apoE genotype do not differ between patients with a benign and progressive course of MS.     

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

Multiple sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults. It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops. Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient. Magnetic resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials. Areas of multifocal inflammation are detected with a high sensitivity as new areas of gadolinium enhancement and T2 abnormality, and these may be considered as surrogate markers for clinical relapses. However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing neuroaxonal loss. MR surrogate measures for neuroaxonal loss include atrophy (tissue loss in brain and spinal cord), N-acetyl aspartate, and T1 hypointense lesions. Diffuse abnormality in normal appearing brain tissue may also be monitored using magnetization transfer ratio and other quantitative MR measures. For treatment trials of new agents aimed at preventing disability, measures of neuroaxonal damage should be acquired, especially atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner. Because the MR surrogates for neuroaxonal loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.     

Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis

CONTEXT: Hypointense lesions on T1-weighted spin-echo magnetic resonance images (T1 lesions) represent destructive multiple sclerosis (MS) lesions, consisting of axonal loss and matrix destruction. These lesions are being used as a secondary outcome measure in phase III clinical trials. Clinical determinants of T1 lesions may differ between subgroups of patients with MS and subsequently may have implications for the selection of patients for clinical trials. OBJECTIVE: To determine if clinical characteristics of patients with MS are related to T1 lesion volume. DESIGN: A survey of 138 patients with MS (52 with relapsing-remitting MS, 44 with secondary progressive MS, and 42 with primary progressive MS). SETTING: The Magnetic Resonance Center for Multiple Sclerosis Research, University Hospital "Vrije Universiteit," Amsterdam, the Netherlands. MAIN OUTCOME MEASURES: Type of MS, Expanded Disability Status Scale (EDSS) score, sex, age at first symptoms, and T1 lesion volume. RESULTS: Patients with secondary progressive MS have the highest T1 lesion volume. Patients with relapsing-remitting MS have a lower T1/T2 ratio than patients with secondary progressive MS and patients with primary progressive MS. In patients with relapsing-remitting MS and secondary progressive MS, T1 lesion volume relates to disease duration and EDSS score, while in patients with primary progressive MS sex is important. A trend toward higher T1 lesion volume was shown for male patients with primary progressive MS when compared with female patients with primary progressive MS (1.0 cm(3) vs 0.3 cm(3), P=.03); a trend toward higher T1 lesion volume was found with age at onset in patients with relapsing-remitting MS and in patients with primary progressive MS. CONCLUSIONS: In patients with MS different clinical characteristics associate with T1 lesion volume, suggesting a more destructive type of lesions in certain subgroups. A possible sex difference in (destructive) lesion development on magnetic resonance imaging should be evaluated in more detail, preferably in a cohort.     

Late onset multiple sclerosis

Multiple sclerosis (MS) with clinical onset after 50 years old is unusual and frequently misdiagnosed. Clinical presentation and course seem also to be different that in MS occurring between 20 and 50 years old. The aim of this study was to evaluate the clinical and paraclinical characteristics of late onset MS. We respectively studied MS patients older than 50 years at the onset of the disease. We evaluated demographical data, clinical symptoms, cerebrospinal fluid (CSF), visual evoked potentials (VEPs) and MRI of these patients. We also studied clinical data during the follow-up with the occurrence of new symptoms and the evolution of the disease by the index of progression (EDSS unit per year). In a population of 1 417 MS, 3.4 p.cent had their first symptoms at 50 years old or older and 0.45 p.cent after 59 years old. At the time of the study patients had more frequently a progressive form: 37 p.cent had a primary progressive form and 35 p.cent a secondary progressive MS. None of the patients with onset after 60 years old had relapsing remittent MS. Motor symptoms were the most common neurologic presentation (54 p.cent of patients). Very few patients had a clinical optic nerve involvement during the follow-up. The mean progression index was 1 suggesting a most severe evolution in this subgroup of MS patients. 76 p.cent of patients had oligoclonal banding detected by CSF electrophoresis. The VEPs were abnormal in 81 p. cent of patients tested. 71 p.cent of the brain MRI were consistent with the diagnosis of MS. 60 p.cent of patients had spinal cord MRI abnormal. This study highlights the differences between the late onset MS and earlier onset. As previously reported, our study underlines the high frequency of progressive course, motor function involvement and poor prognosis.     

Cognitive impairment in multiple sclerosis

BACKGROUNd: Cognitive impairment is increasingly being recognized as a common and disabling symptom of multiple sclerosis (MS) that contributes to poor quality of life in affected patients. Despite the high prevalence of cognitive impairment in MS, cognitive function is not assessed routinely in clinical practice or in clinical trials. The perception that cognitive assessments are costly, time-consuming, complicated, and difficult to administer and interpret has contributed, at least in part, to the failure to incorporate cognitive testing into standard clinical evaluation of patients with MS. Detailed studies of cognitive impairment in MS are rare and guidelines for the assessment of cognitive function in MS are lacking.TREATMENT: How to manage cognitive decline in MS also requires further study. Licensed disease-modifying drug (DMD) treatments for MS reduce brain lesion development, and associations between brain lesions and cognitive performance have been reported, providing a rationale for DMD treatment of MS-associated cognitive impairment. There is some evidence for cognitive benefits of DMDs, but as few pivotal DMD trials included cognitive assessments, the effects of these agents on cognition are not fully understood and more studies are needed.CONCLUSIONS: It is only through further studies that it will be possible to identify patients with, or at risk of, cognitive impairment and to provide appropriate therapy to limit the effects of this potentially devastating symptom.     

Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity?

Multiple sclerosis (MS), the most frequent demyelinating disease, is characterized by a variable disease course. The majority of patients starts with relapsing remitting (RR) disease; approximately 50–60% of these patients progress to secondary progressive (SP) disease. Only about 15% of the patients develop a progressive disease course from onset, termed primary progressive multiple sclerosis (PPMS); the underlying pathogenic mechanisms responsible for onset of the disease with either PPMS or relapsing remitting multiple sclerosis (RRMS) are unknown. Patients with PPMS do not show a female predominance and usually have a later onset of disease compared to patients with RRMS. Monozygous twins can be concordant or discordant for disease courses indicating that the disease course is not only genetically determined. Primary progressive multiple sclerosis and secondary progressive multiple sclerosis (SPMS) share many similarities in imaging and pathological findings. Differences observed among the different disease courses are more of a quantitative than qualitative nature suggesting that the different phenotypes are part of a disease spectrum modulated by individual genetic predisposition and environmental influences. In this review, we summarize the knowledge regarding the clinical, epidemiological, imaging, and pathological characteristics of PPMS and compare those characteristics with RRMS and SPMS.     

Clinical outcome measures for research in multiple sclerosis.

The development of new and more sensitive clinical outcome measures for research in multiple sclerosis (MS) has been fueled by the development of effective therapies. As such, active arm comparison studies that require more sensitive clinical outcome measures are now commonplace. The Kurtzke Expanded Disability Status Scale (EDSS), the most widely used measure of neurologic impairment in MS, is particularly designed for classifying patients with respect to disease severity but has been criticized for its noninterval scaling, emphasis on ambulation status, relatively reduced sensitivity in the mid and upper ranges of scores, and absence of adequate cognitive and visual components. In response to perceived difficulties with the EDSS, the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force has developed the Multiple Sclerosis Functional Composite (MSFC). The MSFC includes three components that yield objective and quantitative results: 1) the timed 25-ft walk, 2) the nine-hole peg test, and 3) the 3-second paced auditory serial addition test. This scale has the advantages of continuous scoring with a composite Z score, standardized protocols, and high degrees of reliability and validity. Candidate visual function outcome measures for the MSFC, including the low-contrast Sloan letter chart, are currently under investigation. In addition to measures of neurologic impairment, health-related quality of life (HRQOL) measures have gained increasing importance as clinical trial outcome measures. The MS Quality of Life Inventory, a disease-specific HRQOL measure, has been developed to capture self-reported neurologic dysfunction and the impact of MS upon activities of daily living. MS clinical trials of the future, particularly active-arm comparison studies, will require more sensitive clinical outcome measures such as the MSFC. Measures of visual function and HRQOL should also be incorporated to capture the broad scope of neurologic impairment and disability in MS populations.     

Intravenous immunoglobulin in MS: promise or failure?

There is an established role for intravenous immunoglobulin (IVIG) in the treatment of certain neurologic autoimmune disorders which affect the peripheral nervous system and a variety of immunomodulatory properties of IVIG have been proposed. This prompted an intense research into the efficacy of IVIG in central nervous system autoimmune disorders and until now several well-controlled clinical trials have been performed in different stages and phenotypes of multiple sclerosis (MS). The results were mixed. Speculations that IVIG might be able to reverse fixed neurologic deficits from MS could not be confirmed. Adding IVIG to the conventional treatment of MS relapses with high-dose IVMP also did not provide any additional benefits. Similarly, trials failed to establish a role for IVIG in the treatment of secondary or primary progressive MS. Most consistent beneficial results with a reduction of relapse rates and a slowing of disability have been obtained in relapsing-remitting MS including clinically isolated syndromes although a most recent study did not confirm a reduction of disease activity based on clinical and MRI findings. Trial results also suggest that IVIG might serve to suppress an increased recurrence of relapses immediately after delivery. Consequently, IVIG treatment may be considered as second line option for these indications although there is still uncertainty regarding the actual mechanism(s) of action and optimal dosage of this treatment.     

Immunmodulatorische Stufentherapie der multiplen Sklerose 1. Ergänzung: Dezember 2000

New clinical studies in multiple sclerosis provided data on the treatment of clinical isolated syndromes and secondary progressive forms which may have important implications for the optimal care of MS patients. The MSTKG critically evaluated the available data again and provides evidence-based recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence from MRI for subclinical dissemination of disease. Recent trials indicate that efficacy of therapy with IFN--is more likely with superimposed bouts or other indicators of inflammatory disease activity than without them in secondary progressive MS. If immunoprophylactic treatment is initiated with a provisional diagnosis of MS, confirmation of MS is essential. In long-term treated patients secondary treatment failure should be identified by follow-up examinations and other treatment options discussed.     

A referendum on clinical trial research in multiple sclerosis: the opinion of the participants at the Jekyll Island workshop

Sixty-two experienced multiple sclerosis (MS) investigators attending a research workshop were asked their opinions about clinical trial design, outcome measures, and treatment. Respondents favored repeated clinical observations of neurologic function (eg, Expanded Disability Status Scale or Ambulation Index) over the opinion of a blinded physician and changes on magnetic resonance imaging. There was agreement that stable MS should not be treated with immunosuppressives. Corticosteroids were rated the most effective treatment for recent disease activity. Total lymphoid irradiation and immunosuppressives were judged more potent for the long-term management of progressive disease. No treatment, however, received the support of more than 11% of the respondents for being of "considerable efficacy" in the long-term management of MS. Most favored a placebo-controlled design in future trials. In order to judge the acceptability of current trial design, participants were asked to act as patient surrogates and to indicate whether they would agree to participate in 4 randomized trials for which they would be eligible. The majority consented to participate in the 3 major trials currently under way, and most refused to enroll in the 1 trial that had never been initiated.     

Axonal pathology in multiple sclerosis: relationship to neurologic disability.

In this review, data is summarized supporting the hypothesis that axonal loss is a major pathologic process responsible for irreversible neurologic disability in patients with multiple sclerosis. Pathologic studies implicate inflammatory demyelination as a principal cause of axonal transection and subsequent axonal degeneration. Axonal degeneration caused by chronic demyelination in the absence of active inflammation may also contribute to progressive disability in the later stages of the disease. Studies using magnetic resonance spectroscopy suggest that axonal loss begins at the onset of the disease, and studies using magnetic resonance imaging have documented brain atrophy in the earliest stages of multiple sclerosis. Brain atrophy increases during the relapsing-remitting disease stage without concurrent disability progression. This suggests that compensatory mechanisms maintain neurologic function, despite progressive brain tissue loss during the early stages of the disease. Beyond a threshold, however, further axonal loss leads to continuously progressive neurologic disability. We hypothesize that the rate and extent of axonal loss during relapsing-remitting multiple sclerosis determines when a patient enters the secondary progressive stage of the disease. This view of disease pathogenesis has several important implications. First, surrogate markers of axonal loss are needed to monitor the disease process for patient care and for clinical trials. We propose brain parenchymal fraction, a precise measure of whole-brain atrophy, as an attractive candidate for this purpose. Second, disease-modifying therapy should be used early in multiple sclerosis patients, before extensive axonal loss has occurred. Third, neuroprotective drugs should be tested in combination with anti-inflammatory drugs in multiple sclerosis patients. Finally, studies of the time course of axonal loss, and its mechanisms are critical for effective therapeutic intervention.     

Stem cell challenges in the treatment of neurodegenerative disease

Neurodegenerative diseases result from the gradual and progressive loss of neural cells and lead to nervous system dysfunction. The rapidly advancing stem cell field is providing attractive alternative options for fighting these diseases. Results have provided proof of principle that cell replacement can work in humans with Parkinson's disease (PD). However, three clinical studies of cell transplantation were published that found no net benefit, while patients in two of the studies developed dyskinesias that persisted despite reductions in treatment. Induced pluripotent stem cells (iPSC) have major potential advantages because patient-specific neuroblasts are suitable for transplantation, avoid immune reactions, and can be produced without the use of human ES cells (hESC). Although iPSCs have not been successfully used in clinical trials for PD, patients with amyotrophic lateral sclerosis (ALS) were treated with autologous stem cells and, though they had some degree of decline one year after treatment, they were still improved compared with the preoperative period or without any drug therapy. In addition, neural stem cells (NSCs), via brain-derived neurotrophic factor (BDNF), have been shown to ameliorate complex behavioral deficits associated with widespread Alzheimer's disease (AD) pathology in a transgenic mouse model of AD. So far, the FDA lists 18 clinical trials treating multiple sclerosis (MS), but most are in preliminary stages. This article serves as an overview of recent studies in stem cell and regenerative approaches to the above chronic neurodegenerative disorders. There are still many obstacles to the use of stem cells as a cure for neurodegenerative disease, especially because we still don't fully understand the true mechanisms of these diseases. However, there is hope in the potential of stem cells to help us learn and understand a great deal more about the mechanisms underlying these devastating neurodegenerative diseases.     

Leptomeningeal metastases

LM is an increasingly common neurologic complication of cancer with variable clinical manifestations. Although there are no curative treatments, currently available therapies can preserve neurologic function and potentially improve quality of life. Further research into the mechanisms of leptomeningeal metastasis will elucidate molecular and cellular pathways that may allow identification of potential targets to interrupt this process early or to prevent this complication. Animal models are needed to further define the pathophysiology of LM and to provide an experimental system to test novel treatments [242-245]. There is an urgent need to develop new drug-based or radiation-based treatments for patients with LM. Randomized clinical trials are the appropriate study design to determine the efficacy of new treatments for LM. However, surrogate markers for response must be developed to facilitate the identification of effective regimens. Survival is not the optimal end point for such studies as most patients who develop this complication already have advanced, incurable cancer. Prevention of or delay in neurologic progression is one objective that has been utilized in recent randomized trials in patients with LM, and this end point deserves further attention. Although the development of LM represents a poor prognostic marker in patients with cancer it is important for physicians to recognize the symptoms and signs of the disease and establish the diagnosis as early in the disease course as possible. This may provide an opportunity for effective intervention that can improve quality of life, prevent further neurologic deterioration and, for a subset of patients, improve survival.     

Cortical deficits in multiple sclerosis on the basis of subcortical lesions

Patients suffering from multiple sclerosis have a high frequency of cognitive deficits usually attributable to demyelination and axonal loss in the subcortical white matter. Neurologic abnormalities referable to cortical function are uncommon but have been described. The present study describes three patients with clinically definite MS with deficits in cognitive function referable to cortical location. Two of the patients underwent positron emission tomography and showed profound cortical hypometabolism adjacent to subcortical white matter lesions seen on MRI. This paper points out that neurologic deficits referable to cortical sites may be caused by subcortical white matter lesions and that cognitive dysfunction in patients with MS may progress rapidly in the absence of motoria deficits or other evidence of clinical deterioration. Multiple Sclerosis (2000) 6 50 - 55