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Background: Persons with severe Multiple Sclerosis (PwsMS) face complex needs and daily limitations that make it challenging to receive optimal care. The implementation and coordination of health care, social services, and support in financial affairs can be particularly time consuming and burdensome for both PwsMS and caregivers. Care and case management (CCM) helps ensure optimal individual care as well as care at a higher-level. The goal of the current qualitative study was to determine the experiences of PwsMS, caregivers and health care specialists (HCSs) with the CCM., Methods: In the current qualitative sub study, as part of a larger trial, in-depth semi-structured interviews with PwsMS, caregivers and HCSs who had been in contact with the CCM were conducted between 02/2022 and 01/2023. Data was transcribed, pseudonymized, tested for saturation and analyzed using structuring content analysis according to Kuckartz. Sociodemographic and interview characteristics were analyzed descriptively., Results: Thirteen PwsMS, 12 caregivers and 10 HCSs completed interviews. Main categories of CCM functions were derived deductively: (1) gatekeeper function, (2) broker function, (3) advocacy function, (4) outlook on CCM in standard care. Subcategories were then derived inductively from the interview material. 852 segments were coded. Participants appreciated the CCM as a continuous and objective contact person, a person of trust (92 codes), a competent source of information and advice (on MS) (68 codes) and comprehensive cross-insurance support (128 codes), relieving and supporting PwsMS, their caregivers and HCSs (67 codes)., Conclusions: Through the cross-sectoral continuous support in health-related, social, financial and everyday bureaucratic matters, the CCM provides comprehensive and overriding support and relief for PwsMS, caregivers and HCSs. This intervention bears the potential to be fine-tuned and applied to similar complex patient groups., Trial Registration: The study was approved by the Ethics Committee of the University of Cologne (#20-1436), registered at the German Register for Clinical Studies (DRKS00022771) and in accordance with the Declaration of Helsinki., (© 2024. The Author(s).)

Purpose/objectives: Care and case management (CCM) aims to provide optimal care for patients and their caregivers on an individual and superordinate level of health care providers and authorities. To facilitate a clear and systematic CCM process as part of a clinical study intervention, a semistructured manual is the prerequisite., Primary Practice Settings: The ongoing COCOS-MS (Communication, Coordination and Security for People with Multiple Sclerosis) study is a randomized controlled Phase II clinical intervention study. The CCM manual is being tested on the intervention group consisting of severely affected individuals with multiple sclerosis (MS; Expanded Disability Status Scale [EDSS] >5) and their caregivers receiving CCM for 12 months in addition to standard care. The intervention comprises monthly personal visits and weekly telephone calls during which the CCM manual is applied., Findings/conclusions: The CCM manual has been developed on the basis of previous literature and well-established questionnaires following theoretical aspects and prior scientific work covering individual domains of life of people with MS. Within the COCOS-MS study, its feasibility is being tested meticulously. It allows for a standardized assessment while being tailored to the individual. At the end of the intervention period, it will be analyzed statistically and qualitatively. Consequently, conclusions can be drawn as to whether the CCM manual is feasible or has to be adapted for use in standard care after analyzation., Implications for Case Management Practice: The CCM manual serves as a tool for the continuous, long-term, cross-sectoral care for patients suffering from severe MS and their caregivers. The manual provides guidance in adequately addressing patients' complex symptoms, problems, and needs, as well as assessing existing resources both at the individual patient level and at a superordinate level., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Introduction: Patients with multiple sclerosis (MS) have complex needs that range from organising one's everyday life to measures of disease-specific therapy monitoring to palliative care. Patients with MS are likely to depend on multiple healthcare providers and various authorities, which are often difficult to coordinate. Thus, they will probably benefit from comprehensive cross-sectoral coordination of services provided by care and case management (CCM). Though studies have shown that case management improves quality of life (QoL), functional status and reduces service use, such benefits have not yet been investigated in severely affected patients with MS. In this explorative phase ll clinical trial, we evaluated a CCM with long-term, cross-sectoral and outreaching services and, in addition, considered the unit of care (patients and caregivers)., Methods and Analysis: Eighty patients with MS and their caregivers will be randomly assigned to either the control (standard care) or the intervention group (standard care plus CCM (for 12 months)). Regular data assessments will be done at baseline and then at 3-month intervals. As primary outcome, we will evaluate patients' QoL. Secondary outcomes are patients' treatment-related risk perception, palliative care needs, anxiety/depression, use of healthcare services, caregivers' burden and QoL, meeting patients' and caregivers' needs, and evaluating the CCM intervention. We will also evaluate CCM through individual interviews and focus groups. The sample size calculation is based on a standardised effect of 0.5, and one baseline and four follow-up assessments (with correlation 0.5). Linear mixed models for repeated measures will be applied to analyse changes in quantitative outcomes over time. Multiple imputation approaches are taken to assess the robustness of the results. The explorative approach (phase ll clinical trial) with embedded qualitative research will allow for the development of a final design for a confirmative phase lll trial., Ethics and Dissemination: The trial will be conducted under the Declaration of Helsinki and has been approved by the Ethics Commission of Cologne University's Faculty of Medicine. Trial results will be published in an open-access scientific journal and presented at conferences., Trial Registration Number: German Register for Clinical Studies (DRKS) (DRKS00022771)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. Methods: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients-Intervention-Comparator-Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20 m without resting (Expanded Disability Status Scale score >6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. Results: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient's wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. Conclusions: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs.

Background: Palliative and Hospice Care (PHC) focuses on improving quality of life for anyone who has a serious illness. Multiple Sclerosis (MS) patients have significant PHC needs, yet PHC still mostly attends to cancer patients. The implemented and evaluated nationwide PHC-MS hotline (Strupp et al., 2017) appeared to provide a useful service to patients., Objectives: Prospective follow-up study to evaluate the impact of the hotline and analyse challenges and possible barriers to integrating PHC services., Methods: Information on implementing PHC services was gathered through follow-up hotline consultations utilising a standardised documentary sheet. Data was analysed descriptively and several individual cases are presented., Results: Of 303 calls to the hotline (54.5% female, mean age 51 years, 87.7% chronic progressive MS, mean duration of illness 17 years, median EDSS 8), for 84 (27.7%) PHC services were indicated. Of these 84 patients, 32 agreed to follow-up calls which were conducted at least once. For 6 (19%) patients, PHC service integration was successful. For 5 (16%) PHC was refused. For 5 (16%) PHC did not fit current patient needs, and for 7 (22%) PHC has not yet been contacted by patients (or caregivers). For a further 9 (28%) follow-ups revealed that no more consultation was possible (e.g., caller lost to follow-up)., Conclusion: The PHC approach and its services as well as legislation are still highly focused on cancer care, although patients with long-term neurological conditions would likely benefit greatly from them., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: Patient and public involvement in clinical practice guideline development is recommended to increase guideline trustworthiness and relevance. The aim was to engage multiple sclerosis (MS) patients and caregivers in the definition of the key questions to be answered in the European Academy of Neurology guideline on palliative care of people with severe MS., Methods: A mixed methods approach was used: an international online survey launched by the national MS societies of eight countries, after pilot testing/debriefing on 20 MS patients and 18 caregivers, focus group meetings of Italian and German MS patients and caregivers., Results: Of 1199 participants, 951 (79%) completed the whole online survey and 934 from seven countries were analysed: 751 (80%) were MS patients (74% women, mean age 46.1) and 183 (20%) were caregivers (36% spouses/partners, 72% women, mean age 47.4). Participants agreed/strongly agreed on inclusion of the nine pre-specified topics (from 89% for 'advance care planning' to 98% for 'multidisciplinary rehabilitation'), and <5% replied 'I prefer not to answer' to any topic. There were 569 free comments: 182 (32%) on the pre-specified topics, 227 (40%) on additional topics (16 guideline-pertinent) and 160 (28%) on outcomes. Five focus group meetings (three of MS patients, two of caregivers, and overall 35 participants) corroborated the survey findings. In addition, they allowed an explanation of the guideline production process and the exploration of patient-important outcomes and of taxing issues., Conclusions: Multiple sclerosis patient and caregiver involvement was resource and time intensive, but rewarding. It was the key for the formulation of the 10 guideline questions and for the identification of patient-important outcomes., (© 2018 EAN.)

Background and Purpose: Palliative and hospice care (PHC) still mainly focuses on patients with cancer. In order to connect patients severely affected by multiple sclerosis (MS) and caregivers to PHC, a nationwide hotline was implemented to facilitate access to PHC., Methods: The hotline was designed in cooperation with the German Multiple Sclerosis Society. Self-disclosed information given by callers was documented using case-report forms supplemented by personal notes. Data were analysed descriptively., Results: A total of 222 calls were documented in 27 months. The patients' mean age was 51.12 years (range 27-84 years) and mean illness duration was 18 years (range 1 month to 50 years). Inquiries included information on PHC (28.8%) and access to PHC (due to previous refusal of PHC, 5.4%), general care for MS (36.1%), adequate housing (9.0%) and emotional support in crisis (4.5%). A total of 31.1% of callers reported 'typical' palliative symptoms (e.g. pain, 88.4%), 50.5% reported symptoms evolving from MS and 35.6% reported psychosocial problems. For 67 callers (30.2%), PHC services were recommended as indicated., Conclusions: The hotline provided insight into the needs and problems of patients severely affected by MS and their caregivers, some of which may be met by PHC. Future follow-up calls will demonstrate if the hotline helped to improve access to PHC beyond providing information. Overall, the hotline seemed to be easily accessible for patients severely affected by MS whose mobility is limited., (© 2017 EAN.)

Background and Purpose: The European Association of Palliative Care Taskforce, in collaboration with the Scientific Panel on Palliative Care in Neurology of the European Federation of Neurological Societies (now the European Academy of Neurology), aimed to undertake a review of the literature to establish an evidence-based consensus for palliative and end of life care for patients with progressive neurological disease, and their families., Methods: A search of the literature yielded 942 articles on this area. These were reviewed by two investigators to determine the main areas and the subsections. A draft list of papers supporting the evidence for each area was circulated to the other authors in an iterative process leading to the agreed recommendations., Results: Overall there is limited evidence to support the recommendations but there is increasing evidence that palliative care and a multidisciplinary approach to care do lead to improved symptoms (Level B) and quality of life of patients and their families (Level C). The main areas in which consensus was found and recommendations could be made are in the early integration of palliative care (Level C), involvement of the wider multidisciplinary team (Level B), communication with patients and families including advance care planning (Level C), symptom management (Level B), end of life care (Level C), carer support and training (Level C), and education for all professionals involved in the care of these patients and families (Good Practice Point)., Conclusions: The care of patients with progressive neurological disease and their families continues to improve and develop. There is a pressing need for increased collaboration between neurology and palliative care., (© 2015 EAN.)

Patients severely affected by multiple sclerosis (MS) have a large range of unmet needs. Although initially counterintuitive, specialized palliative care (PC) may be beneficial for these patients and their relatives. PC has advanced greatly in recent years, yet it is still predominantly tumour patients who profit from this. For MS, a first randomized phase II trial has already demonstrated significant benefits for patients and their caregivers when PC was included in their care. However, there are barriers: neurologists not convinced about PC, or PC not taking on MS patients. Studies have shown that misunderstandings and a lack of information among healthcare professionals about the roles and services of PC for MS are still prevalent. This topical review will give an overview of the unmet needs of patients as well as the possible benefits and barriers of PC for MS, and will describe models of services on how to "open locked doors"., (© The Author(s), 2015.)

Objective: Multiple sclerosis (MS) patients' caregivers are sometimes considered as "hidden patients." How much more this might be true for caregivers of severely affected MS patients has so far been scarcely studied. Palliative care also addressing relatives' needs might therefore be very relevant for these caregivers. However, we do not yet know which unmet needs they have and how these could be met. Our aim was to gain an insight into the subjectively unmet needs of caregivers of severely affected MS patients in Germany., Method: The study employed a qualitative cross-sectional approach for assessing unmet needs. Twelve caregivers of severely affected MS patients were recruited using a convenience sampling approach. Face-to-face interviews were conducted, audiotaped, and transcribed verbatim, followed by qualitative content analysis., Results: Unmet needs were sorted into the following categories: "relationship to physician," "individual support by the healthcare system," "relationship to the individual severely affected by MS," "end-of-life issues," "self-care," and "higher awareness of MS." Caregivers tended to group the unmet needs of their care recipients with their own and rarely focused on their own wishes and restrictions., Significance of Results: A close patient-caregiver dyad makes it difficult to differentiate unmet caregiver needs. However, the palliative care approach might help caregivers of severely affected MS patients by answering questions on disease progress and end-of-life issues, as well as by offering respite care, support for self-care, and help in preserving one's identity, and also anticipating the time to come after the death.

Objective: Research findings suggest that patients severely affected by multiple sclerosis benefit from palliative care. Our objectives were to (1) implement a pilot palliative care counseling hotline for severely affected multiple sclerosis patients and their caregivers in order to connect them to palliative care, and (2) evaluate its preliminary feasibility through a pilot study., Method: The hotline was designed in cooperation with the local state association of the German Multiple Sclerosis Society and based on a review of the literature. The initial study setting for the hotline was the broader region of the cities Cologne and Bonn in Germany. The hotline was introduced through a magazine published by the German Multiple Sclerosis Society and leaflets sent to local healthcare providers. Calls were conducted using a semistructured interview guide and documented by a standardized case report form. Measures to assess feasibility were both quantitative (e.g., number of calls) and qualitative (e.g., criteria for eligibility for palliative care)., Results: During its pilot year, the hotline received 18 calls. Some 15 callers were included in the analysis, and 10 of these 15 were deemed eligible for palliative care due to such criteria as medical characteristics, care or nursing conditions, caregiver strain, and concerns regarding death and dying. Access to palliative care services could be provided for all 10 callers., Significance of Results: Based on our pilot feasibility study, the hotline seems to be a valuable service for patients severely affected by multiple sclerosis (MS) and their caregivers in order to gain information about and access to palliative care. It will be extended on a nationwide scale through a grant of the German Multiple Sclerosis Society. Awareness of the hotline needs to be enhanced in order to attract and support a significant number of new callers.

Objective: People feeling severely affected by multiple sclerosis (MS) comprise a heterogeneous group, and this heterogeneity leads to very distinct needs and makes planning for needs difficult. To provide optimal care, it is important to identify specific needs in specific subgroups. Our objective was to identify the specific palliative care (PC) needs of patients who felt severely affected by the disease by analyzing their feeling (1) more or (2) less severely affected and their possible differences in expressed care needs., Method: A self-report questionnaire with 25 needs categories including 7 categories pertaining to care was applied to patients who felt severely affected by MS. An additional single question identified patients feeling more (≥7, median-split) and less (<7) severely affected. Differences were analyzed by chi-squared and Mann-Whitney U tests. The sample (N = 573) was composed of respondents who replied to an invitation by the German Multiple Sclerosis Society to participate in a survey on unmet needs of severely affected patients., Results: Of 573 patients (median age 51), 358 (62.48%) felt more severely affected. Compared to patients feeling less severely affected, they found the stress on their next of kin to be higher (p < 0.001), were in greater need of home visitation (p < 0.001), did not have permanent neurologists (p = 0.016), and felt that they visited them too rarely (p < 0.0001). They also needed more emotional support from their nursing care service (p = 0.006)., Significance of Results: A self-rating scale can identify two groups of patients with different care needs. These data may help shaping patient-centered support structures. Palliative care, with its multidisciplinary approach, might be one further option to meet the specific needs of patients and their relatives.

Background: Patients severely affected by multiple sclerosis (MS) present with complex symptoms and needs requiring an interdisciplinary care approach., Objective: Analysis of when and why specialized palliative care integration would be beneficial via examining health care professionals' attitudes., Design: A two-round online Delphi study and expert workshop were undertaken and analyzed descriptively., Setting/subjects: Following an extensive online search, 164 professionals with expertise in treating and caring for severely affected patients with MS were contacted. Professionals included neurologists, urologists, general practitioners, MS nurses, speech therapists, physiotherapists, psychologists, and palliative care physicians. Forty-six consented to participate: 33 of 46 (71.4%) and 15 of 33 (45.5%) experts responded in the first and second round, respectively., Results: Consensus was reached among all respondents (100%) defining the term "severely affected": 78.8% and 86.7%, respectively, thought that specialized palliative care should begin once the disease has progressed (Expanded Disability Status Scale [EDSS]>6 and nursing care required). When the need exists for communication about disease progression (93.3%), psychological support (93.3%), relatives support (93.3%), and pain medication (86.7%) specialized palliative care should be consulted. Specialized palliative homecare was rated (93.3%) "very important." The workshop documented the paucity of home visits and specialized MS care in nursing homes., Conclusions: Our results clearly identified specific areas in which palliative care will likely prove to be a valuable asset in the treatment course of MS. This information should serve clinicians, indicating when to consider palliative care services and help further reduce or eliminate uncertainty about how palliative care can be integrated in the course of MS.

Background: The needs of patients feeling severely affected by multiple sclerosis (MS) have rarely been investigated. However this is essential information to know before care can be improved, including adding palliative care (PC) services where helpful. Since it remains unclear at what point specialized palliative care should begin for this patient group, this study focuses on needs in general., Objective: The objective was to explore the subjectively unmet needs of patients feeling severely affected by MS., Methods: The study used a qualitative cross-sectional approach for needs assessment. Fifteen patients self-reporting feeling severely affected by MS were recruited and interviewed using a combination of purposive and convenience sampling (five were accompanied by a caregiver relative). Interviews were recorded and transcribed verbatim, followed by qualitative content analysis., Results: Unmet needs were identified in the main categories "support of family and friends," "health care services," "managing everyday life," and "maintaining biographical continuity." Patients expressed the desire for more support from their families and to be viewed as distinct individuals. They see a substantial deficit in the physician-patient relationship and in the coordination of services. A decrease in expressed unmet needs was found for patients more severely affected and less socially integrated., Conclusions: To address the unmet needs of severely affected MS patients, health care services need to be improved and linked with existing PC services. Special attention is required to form supporting professional-patient relationships. Multiprofessional services should be accessible for patients, while integrating relatives. All services should have an individual approach to provide needs-tailored support.

Objective: Investigate multiple sclerosis patients' desire to communicate with their physicians about their disease progression and end-of-life issues., Methods: Persons meeting the inclusion criteria of feeling severely affected by MS were invited via the German MS society to complete a needs questionnaire. Replies to questions on physician empathy and wishes about communication regarding disease progression and death and dying were quantitatively analyzed. Endpoints (point 1+2/4+5) of 5-point-likert scales are summarized under results., Results: 573 of 867 questionnaires meeting our criteria were analyzed. In response to a general question 64% (n = 358) indicated a wish for disease progression and death and dying to be addressed by their doctor. A majority (76%, n = 427) considered it important that progression of their disease be discussed, while 44% (n = 246) regard addressing death and dying as unimportant. No objective disease criteria could be identified to explain the wish for communicating end-of-life issues. Doctors who were retrospectively viewed as avoiding raising critical aspects of the illness were perceived as less empathetic (p < 0.001)., Conclusion: People with MS have a desire to talk about progression of their disease with their doctors., Practice Implications: Physicians should be empathetic in raising critical aspects of the patients' illness individually., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Research has only started recently to specifically concentrate on the group of patients severely affected by multiple sclerosis (MS)., Aim: The aim of this study was to assess the perception on patients' unmet needs by healthcare professionals., Methods: Focus groups and expert interviews were recorded, transcribed verbatim and analysed by qualitative content analysis., Results: Unmet needs were identified in four main categories ('support from family/friends'; 'healthcare services'; 'managing everyday life'; 'maintaining biographical continuity'). Whereas physicians assessed most unmet needs in the category 'healthcare services', nurses and social workers focussed on unmet needs in the categories 'support from family/friends' and 'maintaining biographical continuity'. Although the study focused on unmet needs of patients, professionals also voiced their unmet needs when caring for these patients. The group of professionals identified more subcategories than patients and included unmet needs of relatives., Conclusion: Adding professionals' perspective to that of patients is essential to gain a holistic view on patients' unmet needs and to further optimize their care. The perspective of palliative care might contribute to meet unmet needs of severely affected MS patients.

Background: 80-100% of patients with multiple sclerosis (MS) display a polyspecific, intrathecal humoral immune response against a broad panel of viral agents including antibodies to measles, rubella and varicella zoster virus as its three most abundant components (called MRZ reaction [MRZR]). However, a positive MRZR reaction can also be found in some patients with CNS vasculitis, another rare autoimmune condition, raising the question whether this marker is really of high specificity for MS as previously claimed or whether it just represents a non-specific marker of CNS autoimmunity. Besides MS and CNS vasculitis, paraneoplastic neurological disorders (PND) represent the best recognized models of CNS autoimmunity., Objective: To investigate MRZR for the first time in patients with PND., Patients and Methods: Forty-two patients with MS and 34 with PND were compared in this study. The intrathecal synthesis of antibodies against measles, rubella, and varicella zoster virus was detected by calculation of the respective antibody indices (AI)., Results: A positive MRZ reaction as defined by a combination of at least two positive AIs was present in 37/42 patients with MS, but in none of the patients with PND (p < 0.0001). Median AI values differed significantly between groups (p < 0.0005)., Conclusions: Our results confirm that MRZR is not a general marker of CNS autoimmunity. Taking into account the very rarity of CNS vasculitis as well the lack of MRZR positivity in infectious inflammatory CNS conditions as previously demonstrated, MRZR might indeed be a promising marker of MS. Further investigations on MRZR in more rare autoimmune conditions, which were not available for analysis in this study, are now warranted to refine further the specificity of this parameter.

Background: A polyspecific, intrathecal humoral immune response against neurotropic viruses such as measles, rubella and varicella zoster virus (MRZ reaction, MRZR) is present in 80-100% of patients with multiple sclerosis (MS), but has not to date been evaluated in patients with neuromyelitis optica (NMO)., Aims: To evaluate whether MRZR distinguishes NMO and MS., Methods: 20 patients with NMO and 42 with MS were included. The intrathecal synthesis of antibodies against measles, rubella and varicella zoster virus was detected by calculation of the respective antibody indices (AI)., Results: A positive MRZ reaction, as defined by a combination of at least two positive AIs, was found in 37/42 MS, but in only 1/20 NMO patients (p<0.0001). Median AI values differed significantly between the groups (p<0.0005)., Conclusions: The polyspecific antiviral humoral immune response characteristic for MS is widely missing in NMO, irrespective of the NMO-IgG status of the patients. Our findings further strengthen the case for NMO being pathologically distinct from MS.

Measuring quality of life (QOL) has made essential contributions for the management of patients with multiple sclerosis (MS). QOL measures may be used for helping to assess the complex changes which patients with MS have to go through during the disease trajectory, and they may be used for pharmacoeconomic research. The large number of tests available includes generic ones such as Short Form SF-36 and Sickness Impact Profile, health-related ones such as MSQOL-54, FAMS, or HAQUAMS, and patient generated measures such as the Patient Generated Index and SEIQOL-DW. Depression, cognitive impairment, and fatigue are important factors influencing QOL. Since the different tests measure quite different facets of QOL, this review intends to help the reader select a tool suited to the aim and specific question. It is hoped that QOL measures may help to better understand patients, to become a more helpful medical partner, to assist patients to develop perspectives for their future, and to decide about therapies or even palliative interventions.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. The etiology of MS is not yet fully understood. Besides of genetic predisposition and environmental factors autoimmune mechanisms seem to play a major role in the pathogenesis of MS. Therapy of MS therefore comprises mainly immunomodulatory and immuno-suppressive therapeutic concepts. Interferon beta (Avonex, Rebif, Betaferon/Betaseron) and Glatirameracetate (Copaxone) offer effective therapeutic options for the long-term treatment of relapsing-remitting MS. With Mitoxantron (Ralenova) being recently approved by the EMEA for the treatment of secondary-progressive and progressive-relapsing MS an effective therapeutic option is now available also for this group of patients. The standard treatment for acute MS continues to be the intravenous administration of high-dose methylprednisolone. Several promising new agents (Antegren, Statins) are currently under clinical examination and could expand the spectrum of available therapeutic strategies soon. Recent and ongoing trials as well as upcoming studies on MS therapy are summarized in this review.

We compared the sensitivity of single and triple dose Gd-DTPA magnetic resonance imaging (MRI) in detecting enhancing lesions in the spinal cord of 13 patients with multiple sclerosis (MS). We detected two enhancing lesions in two of 13 (15%) patients when the single dose of Gd-DTPA was used and 12 lesions in five of 13 (38%) patients when the triple dose of Gd-DTPA was used. These results suggest that: (1) the use of triple dose increases the sensitivity of spinal cord MRI when studying relapsing-remitting or secondary progressive MS patients, (2) triple dose Gd-DTPA enhanced of the spinal cord MRI might be useful in monitoring disease activity in patients with MS.

Introduction: We performed this study to define the sensitivity of delayed gadolinium-enhanced magnetic resonance imaging (MRI) in detecting active lesions in the brains of patients with multiple sclerosis (MS)., Material and Methods: T1-weighted images were obtained in 27 patients with relapsing-remitting or secondary progressive MS before, 5-7 min and 20-30 min after the injection of 0.1 mmol/kg gadolinium-DTPA., Results: One-hundred-and-three enhancing lesions were found on the early and 110 on the delayed scans (increase=6.4%). Six patients had 8 additional lesions in the delayed scans, while 1 patient had 1 more lesion on the early scan. Two of the 12 (17%) patients with no enhancing lesions on the early scans had 2 enhancing lesions on the delayed scans. The average increase of enhancing lesion detection with delayed scanning was 14.5% for those patients who already had enhancing lesions on the early post-contrast scans. A significant increase of the enhancing lesion volume was found with delayed scanning (P=0.004)., Conclusion: These data indicate that it is possible to increase MRI sensitivity in detecting MS active lesions by delaying the scanning after gadolinium injection.

Purpose: To compare the sensitivity of conventional spin-echo, fast spin-echo, fast fluid-attenuated inversion recovery (FLAIR), and turbo gradient spin-echo MR sequences in the detection of multiple sclerosis lesions., Methods: Conventional spin-echo, fast spin-echo, fast FLAIR, and turbo gradient spin-echo sequences were performed on a 1.0-T MR imager in seven patients with clinically definite multiple sclerosis. The images in each sequence were evaluated by two raters and consensus was reached by agreement., Results: In comparing conventional spin-echo with fast spin-echo sequences, five lesions were seen only by conventional spin-echo and 63 were seen only by fast spin-echo; in comparing conventional spin-echo with fast FLAIR sequences, 18 lesions were seen only by conventional spin-echo and 109 only by fast FLAIR; in comparing conventional spin-echo with turbo gradient spin-echo sequences, 51 lesions were seen only by conventional spin-echo and seven only by turbo gradient spin-echo; in comparing fast spin-echo with fast FLAIR sequences, 45 lesions were seen only by fast spin-echo and 52 only by fast FLAIR., Conclusion: Fast spin-echo and fast FLAIR sequences improve the sensitivity of MR imaging in the detection of multiple sclerosis lesions with reduced acquisition time as compared with conventional spin-echo sequences. These sequences should therefore be considered for serial studies in patients with multiple sclerosis. The sensitivity of turbo gradient spin-echo was inferior to the other sequences, but its reduced acquisition time could make this technique the ideal choice for patients who cannot tolerate longer examination times.

Fast fluid-attenuated inversion recovery (fast-FLAIR), fast spin echo (FSE), and turbo-gradient spin echo (TGSE), new pulse sequences for magnetic resonance imaging (MRI), are able to display multiple sclerosis (MS) lesions more conspicuously (fast-FLAIR) and with shorter imaging times (FSE, TGSE) than is conventional spin-echo MRI. In this study, we scanned 7 MS patients, using fast-FLAIR (18 axial brain slices), FSE (27 slices), and TGSE (9 slices) sequences in the same session, to compare the brain MRI lesion loads detected by these different sequences and the intraobserver reproducibility of these measurements. On the subset of slices (n = 9) covered by all three measurements, the mean lesion load was 7.577 mm3 on fast-FLAIR, 5.248 mm3 on FSE, and 3.080 mm3 on TGSE (p = 0.006) sequences. The mean intraobserver coefficients of variation were 2.92% for fast-FLAIR, 2.86% for FSE, and 4.31% for TGSE (not significant). These findings demonstrate that both fast-FLAIR and FSE sequences may be potentially useful for serial MRI studies for monitoring clinical trials, while TGSE might be useful for speeding diagnostic MRI in MS patients. Longitudinal, clinically correlated studies using these new MRI sequences are needed to confirm these preliminary data.

Objectives: To compare the sensitivity of fast spin echo (FSE) and of fast fluid attenuated inversion recovery (fast FLAIR) in detecting spinal cord lesions in multiple sclerosis., Methods: With a 1.5 Tesla machine and a multicoil receiver array, FSE images (with two different pixel sizes) and fast FLAIR images of the spinal cord were obtained from 13 patients with multiple sclerosis., Results: Twenty three lesions (10 cervical, 12 thoracic, and one lumbar) were found in seven patients (54%) using FSE with the larger pixel size. Seventeen lesions (seven cervical and 10 thoracic) were detected in the same seven patients using FSE with smaller pixel size. Nine lesions (five cervical and four thoracic) were found using fast FLAIR in six patients (46%). All the lesions found using fast FLAIR were detected using the other two techniques and all the lesions detected by FSE with smaller pixel size were detected using FSE and greater pixel size., Conclusion: Fast FLAIR sequences detect substantially fewer cord lesions in patients with multiple sclerosis.

In this study, we performed a post-contrast magnetization-prepared rapid acquisition gradient echo (MP RAGE) sequence with subsequent reconstruction of axial slices with 5-, 3-, and 1-mm thickness in 26 patients with multiple sclerosis (MS) to investigate the disease activity going on below the resolution of conventional scans. One hundred three enhancing lesions were detected using MP RAGE reconstructed with 1-mm-thick slices, 93 using MP RAGE reconstructed with 3-mm-thick slices and 82 using MP RAGE reconstructed with 5-mm-thick slices. The detection rate using 1-mm MP RAGE was 25.6% higher compared with 5-mm MP RAGE and 12% higher compared with 3-mm MP RAGE. Using 1-mm MP RAGE, we detected five enhancing lesions in 2 of the 12 patients (16.6%) who showed no enhancing lesions on the 5-mm MP RAGE and one enhancing lesion in 1 of the 10 patients (10%) who showed no enhancing lesions on the 3-mm MP RAGE. The increased sensitivity of 1-mm MP RAGE over the other two reconstruction slice thicknesses was due to improved detection of small lesions, located mainly in cortical/subcortical areas. These data indicate that the size of enhancing lesions in MS is highly variable, and that a significant proportion of disease activity goes undetected when performing conventional scans.

In this study, we compared a fast fluid-attenuated inversion recovery (fast-FLAIR) sequence to conventional spin-echo (CSE) in the evaluation of brain MRI lesion loads of seven patients with clinically definite multiple sclerosis. Interleaved CSE (3000/20, 5 mm contiguous axial slices) and fast-FLAIR (9000/150/2200, 5 mm contiguous axial slices) sequences were performed on a 1.0 T machine. Lesions were counted consensually by two observers and then segmented independently by two other observers using a local thresholding technique, with subsequent manual editing in the case of poorly defined lesions. Four hundred and two lesions were detected in at least one of the two sequences: 128 were seen only on fast-FLAIR, 17 only on CSE. Forty-one lesions were larger on fast-FLAIR, while no lesion was considered larger on CSE. The numbers of periventricular (P = 0.05), cortical/subcortical (P = 0.02) and discrete (P = 0.05) lesions detected using fast-FLAIR were higher than those detected using CSE. The median lesion load was 7185 mm3 on CSE and 8418 mm3 on the fast-FLAIR, the average being 18% (range = 11.6-29%) higher on the fast-FLAIR images. Lesion contrast ratio was higher for lesions on the fast-FLAIR than on the CSE sequence (P < 0.0001). The percentages of poorly defined lesions which needed manual editing after the local thresholding technique was applied and the total time needed for the measurements were lower (P < 0.001) when fast-FLAIR images were used compared with CSE. This resulted in a reduced inter-rater coefficient of variation in measuring lesion volumes. Our data indicate that fast-FLAIR sequences are more sensitive than CSE in detecting multiple sclerosis lesion burden and that fast-FLAIR is a promising technique for natural history studies and clinical trials in multiple sclerosis.

The possibility of antagonizing tumor necrosis factor-alpha (TNF-alpha) in vivo with antibodies or soluble TNF receptor has focused much interest on the role of this cytokine in the natural course of MS. We studied nine patients prospectively and serially for one year (14 time points, 131 observations). TNF-alpha and the 55 kDa soluble TNF receptor were measured every 4 weeks in the serum and at defined time points in the CSF. Each value was correlated to clinical symptoms and to MRI measurements obtained on the same day. All patients with relapsing-remitting disease showed periodic increases of TNF concentrations. Overall, the association between serum TNF-alpha levels and bursts of Gd-DTPA enhancement on cranial MRI was not sufficiently tight to reach statistical significance. However, serum TNF levels > 50 pg/ml and measurable CSF levels were always associated with Gd-DTPA enhancing MRI lesions. Isolated high serum TNF peaks were noted during episodes of infection, hay fever or psychic stress. After treatment with glucocorticoids, TNF levels were suppressed for several months, whereas new Gd-DTPA enhancing lesions continued to appear. The concentrations of the soluble 55 kDa TNF receptor did not show marked fluctuations. These results are consistent with an active role of TNF-alpha in MS during periods of disease activity and provide further support for the clinical evaluation of anti-TNF therapies.

We studied whether a triple dose of gadolinium-DTPA alone or in combination with delayed scanning increases the sensitivity of brain MRI for detecting enhancing lesions in patients with MS. We obtained T1-weighted brain MRI scans in two sessions for 22 patients with clinically definite MS. In the first session, we obtained one scan 5 to 7 minutes after the injection of 0.1 mmol/kg gadolinium-DTPA (standard dose). In the second session, 6 to 24 hours later, we obtained one scan before the two scans 5 to 7 minutes (for all patients) and one hour (for 11 patients) after the injection of 0.3 mmol/kg gadolinium-DTPA (triple dose). We detected 83 enhancing lesions in 14 patients when the standard dose of gadolinium-DTPA was used. The numbers of enhancing lesions increased to 138 (average increase 66%; p = 0.001) and the numbers of patients with such lesions to 18 (increase 28%) when we used the triple dose of gadolinium-DTPA. In addition, the total area per patient occupied by such lesions was greater (p < 0.0001) and lesion signal intensity higher (p = 0.0001) on the triple-dose scans than the standard-dose scans. There was an increase in the number of large enhancing lesions (p = 0.03) in the scans obtained 1 hour after the injection of the triple dose of gadolinium-DTPA. These data indicate that in patients with MS, a triple dose of gadolinium-DTPA can reveal many more enhancing lesions, which also appear larger. This suggests that the pathologic nature of "active" lesions in MS is heterogeneous, which might have impact on planning clinical trials.

Autoimmune T cells play a key role as regulators and effectors of autoimmune disease. In multiple sclerosis (MS), activated T cells specific for myelin components or other locally expressed autoantigens enter the CNS and recognize their antigen(s) on local antigen-presenting cells. After local stimulation, the T cells produce a plethora of cytokines and inflammatory mediators that have profound effects on the local cellular environment, induce and recruit additional inflammatory cells, and contribute to myelin damage. An increasingly detailed knowledge of these processes will greatly facilitate the development of new immunotherapies. This article focuses on the role of T cells in MS. We provide a brief overview of the principles of T-cell immunology, discuss the experimental techniques available for studying T cells, address the role of T cells in the pathogenesis of MS, and highlight modern concepts for immunotherapy.

To characterize the role of B lymphocytes in the pathogenesis of Multiple Sclerosis (MS), we have isolated mononuclear cells from cerebrospinal fluid (CSF) and stimulated them with a polyclonal B-cell mitogen (pokeweed mitogen). This study has been done with MS patients selected for the occurrence of an acute attack in the course of the disease and with patients hospitalized for other neurological diseases. Five of the 11 MS patients had B lymphocytes producing in vitro antibodies (Abs) directed against purified human myelin basic protein (hMBP), as revealed by Western blot analysis. None of the 20 patients with other neurological diseases showed such a reactivity. The produced Abs recognized only 1 or 2 hMBP peptides without dominance for a certain peptide. This result emphasizes the presence of B cells producing Abs against MBP in CSF of MS patients and shows the interest of studying mononuclear cells of CSF as a good marker of the pathogenesis.