The NeuroPsychiatry Of Multiple Sclerosis: A Review Of Recent Developments
Ghaffar O, Feinstein A
Curr Opin Psychiatry 2007 May;20(3):278-85
NeuroPsychiatry Division, Department of Psychiatry, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, Canada
Purpose Of Review
The aim of this review is to summarize the current literature on the NeuroPsychiatry of Multiple Sclerosis (MS).
Data from community samples have supported earlier findings from tertiary referral centres of high rates of Depression in MS patients.
NeuroImaging offers important clues as to the pathogenesis of Depression, but PsychoSocial factors cannot be ignored and emerge as equally important predictors.
Cognitive-behavioural therapy is an effective treatment, rivalling standard dosing of Sertraline in patients with Depression.
An allied disorder - Pseudobulbar Affect - occurs in up to 10% of MS patients and responds well to a combination of Dextromethorphan and Quinidine. Cognitive Dysfunction affects approximately 40% of MS patients.
Markers of Cerebral Atrophy have emerged as more important correlates of impaired Cognition than lesion volume.
Moreover, functional MRI studies have demonstrated the Brain's ability to compensate, in part, for damage. Should the disease burden be too severe, however, compensatory mechanisms fail and Cognitive deficits increase accordingly.
NeuroPsychiatric abnormalities are common in MS patients. No aspect of mentation is spared. Advances in NeuroImaging are increasing our understanding of the pathogenesis of these disorders.
Translating these findings into improved methods of treatment for patients presents researchers with pressing challenges.
The Copaxone Study Group
Schwid SR, Goodman AD, Weinstein A, McDermott MP, Johnson KP
J Neurol Sci 2007 Apr 15;255(1-2):57-63
University of Rochester, Department of Neurology, Rochester, NY, USA
Although Cognitive Impairment is common in patients with Multiple Sclerosis (MS), its value as a clinical trial endpoint remains uncertain.
For example, in the randomized, blinded, pivotal trial of Glatiramer Acetate (GA) in patients with Relapsing MS, improvements occurred in NeuroPsychological test scores during 2 years of treatment regardless of whether patients received GA or placebo, likely due to practice effects.
To assess long-term changes in NeuroPsychological status following 10 years of prospective evaluation in a typical ImmunoTherapy trial cohort.
Participants in the ongoing open-label GA extension study repeated the Brief Repeatable Battery of NeuroPsychological Tests an average of 10.6+/-0.4 years after their initial baseline evaluation.
Mean scores on tests of memory and semantic retrieval were not significantly changed over 10 years of follow-up, but tests of Attention showed declines for the group as a whole.
Using a threshold of a 0.5 SD decline to define significant worsening, individual tests showed declines in 27-49% of participants and a composite score showed worsening in 19%.
Controlling for age, gender, and education level, Cognitive tests tended to worsen more in participants with better baseline Cognitive test scores and higher EDSS scores.
Changes in Cognitive test scores during the first 2 years of observation were predictive of 10-year changes.
Most patients with Relapsing MS had stable Cognitive performance during 10 years of prospective evaluation, some of which may be related to a therapeutic effect of GA.
Because Cognitive changes occur slowly on average, they may not be responsive enough to serve as useful endpoints in studies of course-modifying therapies in Relapsing MS.
Kos D, Kerckhofs E, Nagels G, D'hooghe MB, Ilsbroukx S
NeuroRehabil Neural Repair 2007 Apr 4
Vrije Universiteit Brussel, Department of Rehabilitation Research, Brussels, Belgium
Fatigue is one of the most common and most disabling symptoms of Multiple Sclerosis (MS). Although numerous studies have tried to reveal it, no definite pathogenesis factor behind this Fatigue has been identified.
Fatigue may be directly related to the disease mechanisms (primary Fatigue) or may be secondary to non-disease-specific factors. Primary Fatigue may be the result of Inflammation, DeMyelination, or Axonal Loss.
A suggested functional Cortical reorganization may result in a higher energy demand in certain Brain areas, culminating in an increase of Fatigue perception.
Higher levels of some Immune markers were found in patients with MS-related Fatigue, whereas other studies rejected this hypothesis.
There may be a disturbance in the NeuroEndocrine System related to Fatigue, but it is not clear whether this is either the result of the interaction with Immune activation or the trigger of this process.
Fatigue may be secondary to sleep problems, which are frequently present in MS and in their turn result from Urinary problems, Spasms, Pain, or Anxiety. Pharmacologic treatment of MS (symptoms) may also provoke Fatigue.
The evidence for reduced activity as a cause of secondary Fatigue in MS is inconsistent. Psychological functioning may at least play a role in the persistence of Fatigue.
Research did not reach consensus about the association of Fatigue with clinical or demographic variables, such as age, gender, disability, type of MS, education level, and disease duration.
In conclusion, it is more likely to explain Fatigue from a multifactor perspective than to ascribe it to one mechanism.
The current evidence on the pathogenesis of primary and secondary Fatigue in MS is limited by inconsistency in defining specific aspects of the concept Fatigue.
By the lack of appropriate assessment tools, and by the use of heterogeneous samples. Future research should overcome these limitations and also include longitudinal designs.
Jasperse B, Jakobs C, Eikelenboom MJ, Dijkstra CD, Uitdehaag BM, Barkhof F, Polman CH, Teunissen CE
J Neurol 2007 May;254(5):631-7
VU University Medical Center, Dept. of Neurology, de Boelelaan 1117, PO box 7057, 1007, MB, Amsterdam, The Netherlands
Axonal degeneration is considered to play a major role in the development of clinical disability in Multiple Sclerosis (MS).
N-AcetylAspartic Acid (NAA) is a Neuron-specific marker constantly identified in MR-Spectroscopy studies of the normal and MS Brain.
To our knowledge there are no studies available that evaluated NAA in CerebroSpinal Fluid (CSF) as a possible marker for disease severity.
To evaluate CSF concentrations of NAA in MS in relation to disease phenotype, clinical measures of disability and MRI markers of disease burden.
NAA concentrations were determined in CSF of 46 patients with MS (26 Relapsing/Remitting (RRMS), 12 Secondary/Progressive (SPMS) and 8 Primary/Progressive (PP/MS)).
Prior to Lumbar Puncture, MS-patients underwent MRI and clinical examination, including the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC).
Additionally, CSF concentrations of NAA were determined in 12 patients with Other Neurological Diseases (OND).
Median CSF NAA concentration was 0.74 (IQR: 0.59-0.94) in RRMS , 0.54 (IQR: 0.35-0.73) in SPMS and 0.83 mumol/l (IQR: 0.56-1.03) in PPMS patients.
SPMS patients had a significantly lower NAA concentration than RRMS patients.
NAA concentrations correlated with EDSS (r = -0.37, p = 0.016), MSFC (r = 0.41, p = 0.010), normalized Brain Volume (r = 0.49, p = 0.001), T2 lesion load (r = -0.35, p = 0.021) and Black Hole lesion load (r = -0.47, p = 0.002).
No differences were observed between OND (median: 0.57 IQR: 0.28-0.73) and MS patients.
CSF NAA concentration in MS patients is related to clinical performance and MRI measures of disease burden and may therefore be an important Neuron specific marker of disease severity and possibly progression.
Progression In Multiple Sclerosis: Further Evidence Of An Age Dependent Process
Koch M, Mostert J, Heersema D, De Keyser J
J Neurol Sci 2007 Apr 15;255(1-2):35-41
University of Groningen, University Medical Centre Groningen, Department of Neurology, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
The Relapsing/Remitting phase and the Progressive phase of Multiple Sclerosis (MS) seem to be the result of distinct pathophysiological processes.
Previous research on the natural history of MS was largely focussed on relapses and disability scores. In this study we evaluated 438 patients with Secondary or Primary/Progressive MS.
The influence of gender, initial disease course, onset manifestation and age at disease onset on age at progression and time to progression were evaluated with Kaplan-Meier survival analysis and Cox multivariate regression models.
The analysis of these data showed that the initial disease course (SPMS or PPMS) had no influence on the age at progression.
Gender had no influence on age at progression in PPMS and SPMS patients nor on time to progression in SPMS patients.
PPMS patients with Visual or BrainStem/Cerebellar onset had a significantly younger age at progression.
SPMS patients with Motor onset had a significantly higher age at progression and longer time to progression.
Time to progression was significantly shorter in SPMS patients with higher age at disease onset.
Our data give further support to the notion that progression in MS is an age dependent process independent of relapses.
Interferon-beta Therapy Reduces CD4+ And CD8+ T-Cell Reactivity In Multiple Sclerosis
Zafranskaya M, Oschmann P, Engel R, Weishaupt A, van Noort JM, Jomaa H, Eberl M
Immunology 2007 May;121(1):29-39
Justus-Liebig-Universitat Giessenx, Biochemisches Institut, Infektiologie, and Universitatsklinikum Giessen und Marburg, Institut fur Klinishe Chemie und Pathobiochemie, Giessen, Germany
Therapy with Interferon-beta (IFN-ß) has well-established clinical effects in Multiple Sclerosis (MS), albeit the ImmunoModulatory mechanisms are not fully understood.
We assessed the prevalence and functional capacity of CD4+ and CD8+ T-Cells in healthy donors, and in untreated and IFN-ß-treated MS patients, in response to Myelin Oligodendrocyte Glycoprotein (MOG).
The proportion of CD45RO+ Memory T-Cells was higher in MS patients than in healthy donors, but returned to normal values upon therapy with IFN-ß.
While CD45RO+ CD4+ T-Cells from all three groups responded to MOG in vitro, untreated patients showed augmented proliferative responses compared to healthy individuals and IFN-ß treatment reduced this elevated reactivity back to the values observed in healthy donors.
Similarly, the response of CD45RO+ CD8+ T-Cells to MOG was strongest in untreated patients and decreased to normal values upon ImmunoTherapy.
Overall, the frequency of peripheral CD45RO+ Memory T-Cells ex vivo correlated with the strength of the cellular in vitro response to MOG in untreated patients but not in healthy donors or IFN-ß-treated patients.
Compared with healthy individuals, responding CD4+ and CD8+ cells were skewed towards a Type 1 Cytokine phenotype in untreated patients, but towards a Type 2 phenotype under IFN-ß therapy.
Our data suggest that the beneficial effect of IFN-ß in MS might be the result of the suppression or depletion of AutoReactive, Pro-Inflammatory Memory T-Cells in the periphery.
Assessment of T-cell subsets and their reactivity to MOG may represent an important diagnostic tool for monitoring successful ImmunoTherapy in MS.
Kappos L, Bates D, Hartung HP, Havrdova E, Miller D, Polman CH, Ravnborg M, Hauser SL, Rudick RA, Weiner HL, O'connor PW, King J, Radue EW, Yousry T, Major EO, Clifford DB
Lancet Neurol 2007 May;6(5):431-41
University Hospital, Basel, Switzerland
Natalizumab is a new treatment option for patients with active Relapsing/Remitting Multiple Sclerosis.
In phase III studies, Natalizumab was highly effective and well tolerated; however, three cases of Progressive Multifocal Leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months).
In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with Natalizumab.
On the basis of these reviews, we make recommendations for appropriate selection of candidates for Natalizumab and pretreatment assessments.
In addition, a three-step diagnostic and management algorithm was developed to monitor Natalizumab-treated patients with Multiple Sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments.
Maintaining clinical vigilance allows for early suspension of Natalizumab in potential cases of PML, thereby increasing the opportunity for Immune reconstitution, which may improve prognosis if PML is confirmed