Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM
J Neurol NeuroSurg Psychiatry 2006 Jan;77(1):34-9
University Hospital Eppendorf, Department of Neurology, Martinistrasse 52, D-20246 Hamburg, Germany
Fatigue is a major complaint of Multiple Sclerosis (MS) patients. However, little is known about its pathophysiological mechanisms.
Evidence from Chronic Fatigue Syndrome and studies on sickness behavior suggest that Immune and NeuroEndocrine factors may play a causative role in the development of Fatigue.
We compared whole blood stimulatory capacity for pro- (TNF-, IFN-γ) and Anti-Inflammatory Cytokines (IL-10) as well as Hypothalamo-Pituitary-Adrenal (HPA) Axis function in 15 MS patients with marked Fatigue and 15 patients without Fatigue as determined by the Fatigue Severity Scale (FSS).
Proinflammatory Cytokines were significantly higher (TNF-: 478.9 v 228.2 pg/ml, p = 0.01; IFN-γ: 57.6 v 27.8 pg/ml; p = 0.01) in MS patients with Fatigue.
Furthermore, TNF- values significantly correlated with daytime sleepiness as measured by the Epworth Sleepiness Scale (r = 0.64, p = 0.001).
Controlling for disease activity (as measured by the Cambridge Multiple Sclerosis Basic Score), disease duration, Expanded Disability Status Scale, and Depression further increased the correlation of Cytokine production and Fatigue.
HPA Axis activity was not related to Fatigue but was modestly correlated with Cognitive Impairment.
Our data suggest that Fatigue in MS is at least partially mediated through activation of ProInflammatory Cytokines.
In line with earlier findings, HPA Axis dysfunction seems not to be relevant in MS Fatigue pathogenesis but appears to be linked to Cognitive Impairment.
Our findings suggest that increased levels of inflammatory Cytokines may be involved in MS Fatigue. Investigation of Cytokine profiles may increase the understanding of Fatigue pathogenesis in MS.
Repeat Intrathecal Triamcinolone Acetonide Application Is Beneficial In Progressive MS Patients
Hoffmann V, Kuhn W, Schimrigk S, Islamova S, Hellwig K, Lukas C, Brune N, Pohlau D, Przuntek H, Muller T
Eur J Neurol 2006 Jan;13(1):72-6
Kamillus-Klinik, Department of Neurology, Asbach, Germany
Available ImmunoModulatory and conventional Steroid treatment regimens provide a limited symptomatic benefit for patients with Progressive Multiple Sclerosis (MS).
We performed an open trial on the short-term efficacy of repeated Intrathecal application of the sustained release Steroid TriamCinolone Acetonide (TCA) in 27 Progressive MS patients.
Six TCA administrations, performed every third day, reduced the Expanded Disability Status Scale (EDSS) score [initial: 5.4 +/- 1.3, 3-7.5 (mean +/- SD, range); end: 4.9 +/- 1.1; 2.5-6.5; P < 0.001] and significantly increased the walking distance and speed in particular after the fourth TCA injection.
Concomitantly serially determined CerebroSpinal Fluid (CSF) markers of cell injury, Neuron-specific Enolase, total tau-protein, S-100, and beta-Amyloid did not significantly change within the interval of TCA treatment. No serious side effects appeared.
We conclude that repeat Intrathecal injection of 40 mg TCA provides a substantial benefit in Progressive MS patients with predominant Spinal symptoms and does not alter CSF markers of Neuronal Cell injury.
Abnormalities In Normal Appearing Tissues In Early Primary/Progressive Multiple Sclerosis And Their Relation To Disability: A Tissue Specific Magnetisation Transfer Study
Ramio-Torrenta L, Sastre-Garriga J, Ingle GT, Davies GR, Ameen V, Miller DH, Thompson AJ
J Neurol NeuroSurg Psychiatry 2006 Jan;77(1):40-5
Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
Patients with Primary/Progressive Multiple Sclerosis (PPMS) often develop severe disability despite low levels of abnormality on conventional Magnetic Resonance Imaging (MRI).
This may relate to diffuse pathological processes occurring in Normal Appearing Brain Tissue (NABT) involving both White Matter (NAWM) and Gray Matter (NAGM).
Magnetization Transfer Imaging (MTI) is capable of identifying these processes and may be particularly informative when applied to patients with early PPMS.
To assess the relationship between abnormalities in NABT identified by MTI and disability and other radiological data in patients with early PPMS.
We studied 43 patients within 5 years of disease onset and 43 controls.
The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) were scored.
Magnetization Transfer Ratios (MTR) of NABT, NAWM, and NAGM were calculated and the following MTR parameters were measured: mean, peak height, peak location, and MTR value at the 25th, 50th, and 75th percentiles.
Proton density, T2, T1, and Gadolinium enhancing lesion loads were also calculated.
Differences were found between patients and controls in mean, peak height, and peak location of NAWM and NAGM (p < /=0.001).
Weak to moderate correlations were found between MTR parameters and disability in both NAWM and NAGM. Strong correlations between MTR parameters and lesion loads were found, particularly in NAWM.
MTR abnormalities are seen in NAWM and NAGM in early PPMS and both are associated with disability.
NAWM MTR abnormalities are more closely related to conventional MRI measures than those seen in NAGM.
Multiple Sclerosis In Twins From Continental Italy And Sardinia: A Nationwide Study
Ristori G, Cannoni S, Stazi MA, Vanacore N, Cotichini R, Alfo M, Pugliatti M, Sotgiu S, Solaro C, Bomprezzi R, Di Giovanni S, Figa Talamanca L, Nistico L, Fagnani C, Neale MC, Cascino I, Giorgi G, Battaglia MA, Buttinelli C, Tosi R, Salvetti M
Ann Neurol 2006 Jan;59(1):27-34
Andrea Hospital, University of Rome "La Sapienza", Neurology and Center for Experimental Neurological Therapy, S
Knowledge about the balance between heritable and nonheritable risk in Multiple Sclerosis (MS) is based on twin studies in high-prevalence areas.
In a study that avoided ascertainment limitations and directly compared continental Italy (medium-prevalence) and Sardinia (high-prevalence).
We ascertained 216 pairs from 34,549 patients. This gives a twinning rate of 0.62% among MS patients, significantly less than that of the general population.
In continental Italy, probandwise concordance was 14.5% (95% confidence interval, 5.1-23.8) for monozygotic and 4.0% (95% confidence interval, 0.8-7.1) for dizygotic twins.
Results in Sardinia resemble those in northern populations but in limited numbers.
Monozygotic concordance was 22.2% (95% confidence interval, 0-49.3) probandwise, but no concordant dizygotic pairs were identified.
A questionnaire on 80 items possibly related to disease cause was administered to 70 twin pairs, 135 sporadic patients, and 135 healthy volunteers.
Variables positively (7) or negatively (2) associated with predisposition and concordance in twins largely overlapped and were mainly linked to infection.
If compared with previous studies, our data demonstrate that penetrance in twins appears to correlate with MS prevalence.
They highlight the relevance of nonheritable variables in Mediterranean areas. The apparent underrepresentation of MS among Italian twins draws attention to protective factors, shared by twins, that may influence susceptibility.
Ann Neurol 2005.
Suppression Of Mitoxantrone CardiotToxicity In Multiple Sclerosis Patients By Dexrazoxane
Bernitsas E, Wei W, Mikol DD
Ann Neurol 2006 Jan;59(1):206-9
University of Michigan, Department of Neurology, Ann Arbor, MI
To explore the potential of Dexrazoxane to suppress subclinical CardioToxicity in MS patients receiving Mitoxantrone.
An open-label study was performed to evaluate possible subclinical CardioToxicity in Multiple Sclerosis patients treated quarterly with Mitoxantrone (48mg/m(2) cumulative), with and without concomitant Dexrazoxane, using blinded serial Radionucleide Ventriculography.
No patient experienced symptoms of heart failure. Patients receiving Dexrazoxane, which is Cardioprotective for Anthracyclines, exhibited a significantly lesser decline in Left Ventricular ejection fraction (mean change, -3.80% vs -8.55%, p < 0.001).
These results support a Cardioprotective effect of Dexrazoxane in Mitoxantrone treated Multiple Sclerosis patients.
Ann Neurol 2006;59:206-209.
A Tale Of Two Cannabinoids: The Therapeutic Rationale For Combining TetrahydroCannabinol And Cannabidiol
Russo E, Guy GW
Med Hypotheses 2006;66(2):234-46
GW Pharmaceuticals, Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, UK; University of Washington School of Medicine, Seattle, WA, USA; University of Montana Department of Pharmaceutical Sciences, MT, USA
This study examines the current knowledge of physiological and clinical effects of TetraHydroCannabinol (THC) and Cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations.
Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of Cyclo-Oxygenase (COX) inhibition.
CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing Analgesic, Anti-Emetic, And Anti-Carcinogenic properties in its own right.
In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for Cannabis based extracts in treatment of Spasticity, Central Pain and Lower Urinary Tract symptoms in Multiple Sclerosis.
As well as sleep disturbances, peripheral Neuropathic Pain, Brachial Plexus Avulsion symptoms, Rheumatoid Arthritis and intractable Cancer pain.
Prospects for future application of whole Cannabis extracts in NeuroProtection, drug dependency, and neoplastic disorders are further examined.
The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.
Bone Marrow Transplantation Combined With Gene Therapy To Induce Antigen-Specific Tolerance And Ameliorate EAE
Xu B, Haviernik P, Wolfraim LA, Bunting KD, Scott DW
Mol Ther 2006 Jan;13(1):42-8
University of Maryland, Department of Surgery and Department of MicroBiology and Immunology, Baltimore, MD 21201, USA
Hematopoietic Stem Cell (HSC) transplantation is a potential therapy that can offer Multiple Sclerosis patients a radical, potentially curative treatment.
Using Experimental Autoimmune Encephalomyelitis (EAE) as a model, we previously reported that retrovirally transduced B-Cells expressing Myelin Basic Protein (MBP), MBP Ac1-11, or Myelin Oligodendrocyte Glycoprotein p35-55 induced tolerance and reduced symptoms.
Here, we extend our tolerance approach using Bone Marrow (BM) cells expressing full-length PhosphoLipid Protein (PLP) in a model for Relapsing/Remitting EAE.
Using GFP expression as a marker, we found that up to 50% of cells were positive for transgene expression in peripheral blood after 900 rad irradiation and transduced BM transplantation, and expression was stable in hematopoietic lineages for over 10 weeks.
Upon challenge, T-Cell proliferation in response to PLP p139-151 was reduced and EAE was completely abolished in a pretreatment protocol.
In addition, protection from EAE could be achieved with PLP-transduced BM cells given on day 12 after immunization, a potential therapeutic protocol.
Finally, the protective effect of PLP-expressing BM could also be observed using a nonmyeloablative protocol, albeit with lower efficacy.
Our results suggest that HSC may be useful to achieve long-lasting tolerance to protect mice from EAE and possibly to promote CNS repair in ongoing EAE.