Osterberg A, Boivie J, Thuomas K
Eur J Pain 2005 Oct;9(5):531-42
University Hospital, Department of NeuroScience and Locomotion, Division of Neurology, Linkoping, Sweden
Pain is more common in Multiple Sclerosis (MS) than has previously been recognized. In the present study we have investigated the occurrence of Central Pain (CP) in MS and defined its characteristics.
Questionnaires were sent to all 429 patients with Definite MS in the patient register at our Neurology department. All admitting to pain were interviewed and offered an extended interview and examination.
Three hundred and sixty four patients responded (86%), of whom 57.5% reported Pain during the course of their disease (21% Nociceptive, 2% Peripheral Neuropathic and 1% related to Spasticity).
One hundred patients (27.5%) had CP, including 18 patients (4.9%) with Trigeminal Neuralgia. The Non-Trigeminal CP was, in 87%, located in the lower and in 31% in the upper extremities. It was mostly BiLateral (76%) and constant, with 88% experiencing daily Pain.
Only 2% had Paroxysmal attacks. Aching, burning, pricking were the commonest qualities. The Pain was intense with small to moderate spontaneous variation.
In 5.5% of all patients (20% of the patients with CP), Pain was a presenting symptom, alone or in combination with other symptoms.
The most common Neurological symptoms/signs besides CP were Sensory abnormalities (98%, dominated by abnormal sensibility to painful stimulus and temperature).
Trigeminal Neuralgia in MS started later in life and after longer disease duration than Non-Trigeminal Pain.
Both types of CP existed either chronically or as a feature of relapse. Central Pain is thus an important symptom in MS (around 30%) and causes much suffering.
Interferon As A Treatment For Uveitis Associated With Multiple Sclerosis
Becker MD, Heiligenhaus A, Hudde T, Storch-Hagenlocher B, Wildemann B, Barisani-Asenbauer T, Thimm C, Stubiger N, Trieschmann M, Fiehn C
Br J Ophthalmol 2005 Oct;89(10):1254-7
University of Heidelberg, Interdisciplinary Uveitis Center, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany
In addition to Optic Neuritis (ON), Multiple Sclerosis (MS) may also involve the eye with a typically BiLateral intermediate Uveitis.
The aim of this pilot study was to evaluate the efficacy of type I Interferons (IFN-ß) for the treatment of MS associated Uveitis.
In this non-randomised, retrospective observational case series 13 patients (eight female, five male) with proved MS and associated Uveitis from five Uveitis centers who were treated with Interferon-ß-1a were included.
Visual Acuity (VA), cell count in the aqueous Humour and Vitreous, as well as the presence of Cystoid Macula Oedema (CMO) were observed.
All except one patient had a BiLateral form of intermediate Uveitis (total of 24 eyes).
Seven patients had documented CMO before IFN treatment (n = 13 eyes). Median duration of treatment was 24.6 months (range 7.9-78.7).
VA improved in 17 eyes (comparing VA before therapy and at last follow up); while 10 eyes (36%) improved >/=3 Snellen lines. Aqueous cell count improved by 1.2 (SD 1.1) grades in all eyes.
Vitreous cell count improved by 1.7 (1.4) in all eyes. Only two patients still had minimal CMO on last follow up angiographically. CMO resolved after or during IFN treatment in nine eyes.
IFN has been shown to have beneficial effects in patients with MS and/or ON.
As shown in the models of Experimental Allergic Encephalomyelitis (EAE) and Uveitis, the Neurological and Ophthalmological manifestations seem to share similar pathogenic mechanisms.
Treatment of MS associated Uveitis with IFN-ßappears to have beneficial effects on VA, IntraOcular inflammation activity, and the presence of CMO.
Vallittu AM, Peltoniemi J, Elovaara I, Kuusisto H, Farkkila M, Multanen J, Eralinna JP
Acta Neurol Scand 2005 Oct;112(4):234-7
University of Turku, Department of Virology, Turku, Finland
Glatiramer Acetate (GA) is routinely used in Multiple Sclerosis (MS) patients who cannot tolerate or fail to respond to Interferon-beta (IFN-ß).
The aim of this study was to assess the efficacy and tolerability of GA in these patients.
Fifteen Relapsing/Remitting MS patients who had discontinued IFN-ß therapy due to side effects were included in this open, 1-year prospective study.
Neurologic examinations and laboratory assessments were performed every 3 months. The induction of MxA protein production was also evaluated.
Eleven of fifteen patients (73%) tolerated GA well whereas four patients (27%) discontinued treatment due to side effects.
The relapse rate reduced from 1.86 per year to 0.91 per year. Neither laboratory abnormalities nor MxA protein induction was found.
GA can be considered as a good treatment alternative to IFN-ß-intolerant MS patients.
However, some patients were not able to use available Immunomodulative treatments, which emphasizes the need for new therapeutic options. The lack of MxA protein induction confirms the different mechanisms of action of GA and IFN-ß.
Marta CB, Oliver AR, Sweet RA, Pfeiffer SE, Ruddle NH
Proc Natl Acad Sci USA 2005 Sep 27;102(39):13992-7
University of Connecticut Medical School, Department of NeuroScience, Farmington, CT 06030-3401
AntiBodies to Myelin components are routinely detected in Multiple Sclerosis patients. However, their presence in some control subjects has made it difficult to determine their contribution to disease pathogenesis.
Immunization of C57BL/6 mice with either rat or human Myelin Oligodendrocyte Glycoprotein (MOG) leads to Experimental Autoimmune Encephalomyelitis (EAE) and comparable Titers of Anti-MOG AntiBodies as detected by ELISA. However, only immunization with human (but not rat) MOG results in a B-Cell-dependent EAE.
In this study, we demonstrate that these pathogenic and nonpathogenic Anti-MOG AntiBodies have a consistent array of differences in their recognition of antigenic determinants and biological effects.
Specifically, substituting Proline at position 42 with Serine in human MOG (as in rat MOG) eliminates the B-Cell requirement for EAE.
All MOG proteins analyzed induced high Titers of Anti-MOG (tested by ELISA), but only AntiSera from mice immunized with unmodified human MOG were Encephalitogenic in primed B-Cell-deficient mice.
Nonpathogenic IgGs bound recombinant mouse MOG and deglycosylated MOG in Myelin (tested by Western blot), but only pathogenic IgGs bound glycosylated MOG.
Only purified IgG to human MOG bound to live rodent Oligodendrocytes in culture and, after cross-linking, induced repartitioning of MOG into lipid rafts, followed by dramatic changes in cell morphology.
The data provide a strong link between in vivo and in vitro observations regarding DeMyelinating Disease, further indicate a biochemical mechanism for Anti-MOG-induced DeMyelination, and suggest in vitro tools for determining Autoimmune AntiBody pathogenicity in Multiple Sclerosis patients.
Defective ATM-p53-Mediated Apoptotic Pathway In Multiple Sclerosis
Deng X, Ljunggren-Rose A, Maas K, Sriram S
Ann Neurol 2005 Oct;58(4):577-84
Vanderbilt University Medical Center, Department of Neurology, Nashville, TN
Defective elimination of AutoReactive Cells is thought to play a role in the development of AutoImmune Diseases including Multiple Sclerosis (MS).
We examined the activation of the ATM-CHK2-p53 pathway in MS patients after subjecting their Peripheral Blood Mononuclear Cells to gamma-irradiation.
We found that peripheral blood mononuclear cells from a subset of MS patients show resistance to cell death induced by irradiation.
This defect is due to impaired constitutive expression and activation of ATM (Ataxia Telangiectasia Mutated), resulting in impaired stabilization of p53.
We predict that these fundamental defects likely alter the regulation of the Immune population of cells in MS and may contribute to the development or progression of the disease.
Ann Neurol 2005;58:577-584.
Increased Disability And MRI Lesions After Discontinuation Of IFN-ß-1a In Secondary/Progressive MS
Wu X, Dastidar P, Kuusisto H, Ukkonen M, Huhtala H, Elovaara I
Acta Neurol Scand 2005 Oct;112(4):242-7
University of Tampere, NeuroImmunology Unit, Medical School, Tampere, Finland
To examine Neurological and Magnetic Resonance Imaging (MRI) changes following discontinuation of Interferon-ß-1a (IFN-ß-1a) treatment in Secondary/Progressive Multiple Sclerosis (SPMS).
The study involved 21 SPMS patients who received subcutaneous (s.c.) IFN-ß-1a 44 microg three times weekly (t.i.w.) for 12 months and were thereafter followed up without treatment for a further 12 months.
The number of relapses, Disability on the Expanded Disability Status Scale (EDSS) and MRI were recorded at baseline, at 12 months of IFN-ß-1a 44 microg t.i.w. and 1 year after discontinuation of treatment.
During the 12-month treatment EDSS score and volumes of Brain T2- and T1-weighted lesions remained without significant progression, but at 12 months after treatment discontinuation both EDSS score and the volumes of Cerebral lesions increased significantly.
CerebroSpinal Fluid fraction increased significantly both during the treatment and during follow-up.
Discontinuation of IFN-ß-1a 44 microg t.i.w. in SPMS may be associated with an increase in Neurological Disability and Brain lesions on MRI.
Prospective Assessment Of Changing From Placebo To IFN-ß-1a In Relapsing MS: The PRISMS Study
Oger J, Francis G, Chang P; On behalf of the PRISMS Study Group
J Neurol Sci 2005 Oct 15;237(1-2):45-52
University of British Columbia, Division of Neurology, Department of Medicine, Room S159, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5
The efficacy of Interferon-ß (IFN-ß) has been shown in several placebo-controlled, parallel-group studies in Relapsing/Remitting Multiple Sclerosis (RRMS).
PRISMS, the largest such study to date, clearly demonstrated the efficacy of IFN-ß-1a on all outcome measures over 2 years during the placebo-controlled, parallel-group phase.
However, this study's placebo-crossover design also provided us with a unique opportunity to conduct a prospective within-group assessment, eliminating the impact of inter-patient variability.
At the start of year 3, patients receiving placebo during years 1-2 were re-randomized in a dose-blinded fashion to receive IFN-ß-1a, 22 or 44 mcg subcutaneously three times weekly, during years 3 and 4.
Clinic visits occurred 3-6 monthly and T2 MRI scans were obtained after 1 and 2 years on therapy.
Comparison of the mean relapse count per patient over 2 years (the primary outcome measure) during time on placebo (years 1 and 2) with that during active treatment (years 3 and 4) revealed a decrease from 2.6 to 1.2 in both dose groups (54% relative reduction; p< 0.001).
Disability progression, T2 MRI lesion activity and accumulation of T2 lesion burden were also significantly improved with therapy (p< 0.01). No new safety issues were noted.
These data provide further support for IFN-ß-1a's efficacy in RRMS. The ability to detect significant treatment effects with reduced patient numbers in this type of before/after analysis, may be due to the reduction in inter-patient variability.