Neil Scolding

EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases

Despite high‐dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune‐mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence‐based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain‐Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short‐term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second‐line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third‐line therapy in relapsing–remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post‐partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (level A), stiff‐person syndrome (level A), some acute‐demyelinating diseases and childhood refractory epilepsy (good practice point).

Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro.

Bone marrow-derived mesenchymal stem cells (MSCs) are of therapeutic interest in a variety of neurological diseases. In this study, we wished to determine whether human MSCs secrete factors which protect cultured rodent cortical neurons from death by trophic factor withdrawal or nitric oxide (NO) exposure. Medium conditioned by MSCs attenuated neuronal death under these conditions, a process which was dependent on intact PI(3)kinase/Akt pathway signaling. Trophic withdrawal and NO exposure in cultured cortical neurons led to reduction in Akt signaling pathways, whereas NO administration activated p38 MAPkinase in neuronal cultures. Addition of MSC-conditioned medium significantly activated the PI3kinase/Akt pathway and in neurons exposed to NO, MSC-conditioned medium reduced p38 signaling. We show that MSCs secrete brain-derived neurotrophic factor (BDNF) and addition of anti-BDNF neutralising antibodies to MSC-conditioned medium attenuated its neuroprotective effect. Exposure of neurons to BDNF increased activation of Akt pathways and protected neurons from trophic factor withdrawal. These observations determine the mechanisms of neuroprotection offered by MSC-derived factors and suggest an important role for BDNF in neuronal protection.

The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group

Current therapies for multiple sclerosis effectively reduce inflammation, but do little in terms of repair to the damaged central nervous system. Cell-based therapies may provide a new strategy for bolstering regeneration and repair through neuro-axonal protection or remyelination. Mesenchymal stem cells modulate pathological responses in experimental autoimmune encephalitis, alleviating disease, but also stimulate repair of the central nervous system through the release of soluble factors. Autologous and allogeneic mesenchymal stem cells have been safely administered to individuals with hemato-oncological diseases and in a limited number of patients with multiple sclerosis. It is therefore reasonable to move mesenchymal stem cells transplantation into properly controlled human studies to explore their potential as a treatment for multiple sclerosis. Since it is likely that the first such studies will probably involve only small numbers of patients in a few centers, we formed an international panel comprising multiple sclerosis neurology and stem cell experts, as well as immunologists. The aims were to derive a consensus on the utilization of mesenchymal stem cells for the treatment of multiple sclerosis, along with protocols for the culture of the cells and the treatment of patients. This article reviews the consensus derived from our group on the rationale for mesenchymal stem cell transplantation, the methodology for generating mesenchymal stem cells and the first treatment protocol for multiple sclerosis patients.

Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort

Objective: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). Methods: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7–107.3). Results: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12–18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02–17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50–6.19) were predictive of AID expression. Conclusions: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. Classification of evidence: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.

Neurosarcoidosis: a study of 30 new cases

Methods: The frequency, nature, relationship to systemic features, value of investigation findings and outcomes for a cohort of patients with neurosarcoidosis (NS) were studied by performing a retrospective survey of case records from nine District General or Regional Centre hospitals in south-west England and south Wales over a 12-year period (1990–2002). Thirty patients (29 Caucasians) were included—16 (53%) males and 14 (47%) females, including 13 with histological confirmation of CNS disease, making this one of the largest series of biopsy-confirmed NS; the remaining cases had “Probable” NS according to the Zajicek criteria. The male preponderance is of interest particularly considering the female predominance of systemic sarcoidosis. Results: The indicative prevalence of NS in this geographical area was estimated at one per 100 000, given an approximate population of 3 million. The most frequent features were headaches, visual failure, ataxia and vomiting. Cranial neuropathy occurred in 80% of patients, and as a presenting feature in 50%—though facial nerve involvement was seen in only 23%, and in none of those with definite disease. Unsurprisingly, no diagnostic clinical patterns emerged overall when only definite cases were analysed, but within our definite group of patients, meningeal and/or parenchymal lesion enhancement was observed in all but one case, while distinction from multiple sclerosis might also be aided by the observation that in all NS cerebrospinal fluid (CSF) samples with positive oligoclonal bands (27%), banding was accompanied by elevations of CSF protein. Conclusion: From a prognostic perspective, the reported association of seizures in NS with a poor long-term outcome was not supported, while the suggestion that myelopathy also predicts an adverse prognosis was confirmed.

CNS lupus A study of 41 patients

Background: CNS lupus is a serious but potentially treatable illness, which, though long recognized, may still present very difficult diagnostic challenges. We believed that further detailed study of patients with neuropsychiatric lupus would yield clinical information of practical value in improving both recognition and management of this difficult illness. Methods: A retrospective case analysis of 41 patients with CNS systemic lupus erythematosus (CNS-SLE) was performed largely in the southwest of England and South Wales, covering the period 1990 to 2002. Results: We found that primary neurologic presentation of SLE was not rare (10/41 patients), and there was an unexpected emergence of movement disorders (particularly parkinsonism and myoclonus) early in the disease course (4/10 patients). These showed a good response to immunosuppressants, but not to standard dopaminergic therapy. Typically, the erythrocyte sedimentation rate (ESR) or plasma viscosity was elevated during neurologic episodes while C-reactive protein levels were normal, and lupus-related serum antibody tests usually supportive. But, significantly, neither a normal ESR nor negative serology excluded CNS lupus. MR brain imaging is more commonly abnormal in patients with focal neurologic deficits and normal or shows wholly nonspecific change with more diffuse manifestations (cognitive decline, epilepsy). Abnormal CSF correlated significantly with poorer outcome. At the end of the period of study, 54% had no more than minor functional disability, the remainder having a severe or fatal outcome. Conclusions: Our observations, particularly the emergence of non-choreic movement disorders, the blood, serum, and imaging findings, and the prognostic importance of CSF abnormalities, should help improve both the recognition of CNS systemic lupus erythematosus, perhaps particularly in elderly individuals, and its management.

Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection and with sparse CNS infiltration

Multiple sclerosis is a currently incurable inflammatory demyelinating syndrome. Recent reports suggest that bone marrow derived mesenchymal stem cells may have therapeutic potential in experimental models of demyelinating disease, but various alternative mechanisms, ranging from systemic immune effects to local cell replacement, have been proposed. Here we used intraperitoneal delivery of human mesenchymal stem cells to help test (a) whether human cells can indeed suppress disease, and (b) whether CNS infiltration is required for any beneficial effect. We found pronounced amelioration of clinical disease but profoundly little CNS infiltration. Our findings therefore help confirm the therapeutic potential of mesenchymal stem cells, show that this does indeed extend to human cells, and are consistent with a peripheral or systemic immune effect of human MSCs in this model.

Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis.

Recent studies have revealed extensive cortical demyelination in patients with progressive multiple sclerosis (MS). Demyelination in gray matter lesions is associated with activation of microglia. Macrophages and microglia are known to express myeloperoxidase (MPO) and generate reactive oxygen species during myelin phagocytosis in the white matter. In the present study we examined the extent of microglial activation in the cerebral cortex and the relationship of microglial activation and MPO activity to cortical demyelination. Twenty‐one cases of neuropathologically confirmed multiple sclerosis, with 34 cortical lesions, were used to assess microglial activation. HLA‐DR immunolabeling of activated microglia was significantly higher in demyelinated MS cortex than control cortex and, within the MS cohort, was significantly greater within cortical lesions than in matched non‐demyelinated areas of cortex. In homogenates of MS cortex, cortical demyelination was associated with significantly elevated MPO activity. Immunohistochemistry revealed MPO in CD68‐positive microglia within cortical plaques, particularly toward the edge of the plaques, but not in microglia in adjacent non‐demyelinated cortex. Cortical demyelination in MS is associated with increased activity of MPO, which is expressed by a CD68‐positive subset of activated microglia, suggesting that microglial production of reactive oxygen species is likely to be involved in cortical demyelination.

Contribution of relapses to disability in multiple sclerosis.

The impact of relapses on long-term disability in multiple sclerosis remains unclear; however some evidence suggests that relapses play an important role in determining subsequent prognosis. We report on outcome, prognostic factors for recovery and the contribution of relapses to the accumulation of fixed disability in a large series of patients with documented relapses. Two hundred and seventynine relapses in 182 patients were assessed before, during and after relapse by expanded disability status scale and data analysed to assess degree of recovery. Factors affecting outcome were considered including sex, age and site of relapse.Mean EDSS prior to relapse was 3.73, during relapse 5.18 and post relapse 4.23. Mean interval to post relapse assessment was 127 days post relapse. Mean residual change in EDSS score (pre to post relapse) was 0.50 points. Overall 49.4 % of patients had a residual increase in disability post relapse of at least 0.5 EDSS points and 32.7 % had an increase of at least 1 point. No significant difference was observed in mean residual EDSS for sex, site of relapse or age at relapse or in the proportion of patients with a residual increase in disability of ≥ 1 EDSS point post relapse. 14.4 % of patients had no increase in EDSS score during relapse compared to pre relapse.These results suggest that acute relapses are commonly associated with an objective worsening of disability in the majority of patients with MS and that recovery is incomplete in approximately half and not influenced by gender, age or site of lesion. Therapies which reduce relapse frequency and/or severity might therefore be expected to slow or prevent worsening of disability if initiated prior to the onset of more permanent damage.The impact of relapses on long-term disability in multiple sclerosis remains unclear; however some evidence suggests that relapses play an important role in determining subsequent prognosis. We report on outcome, prognostic factors for recovery and the contribution of relapses to the accumulation of fixed disability in a large series of patients with documented relapses. Two hundred and seventynine relapses in 182 patients were assessed before, during and after relapse by expanded disability status scale and data analysed to assess degree of recovery. Factors affecting outcome were considered including sex, age and site of relapse. Mean EDSS prior to relapse was 3.73, during relapse 5.18 and post relapse 4.23. Mean interval to post relapse assessment was 127 days post relapse. Mean residual change in EDSS score (pre to post relapse) was 0.50 points. Overall 49.4 % of patients had a residual increase in disability post relapse of at least 0.5 EDSS points and 32.7 % had an increase of at least 1 point. No significant difference was observed in mean residual EDSS for sex, site of relapse or age at relapse or in the proportion of patients with a residual increase in disability of ≥ 1 EDSS point post relapse. 14.4 % of patients had no increase in EDSS score during relapse compared to pre relapse. These results suggest that acute relapses are commonly associated with an objective worsening of disability in the majority of patients with MS and that recovery is incomplete in approximately half and not influenced by gender, age or site of lesion. Therapies which reduce relapse frequency and/or severity might therefore be expected to slow or prevent worsening of disability if initiated prior to the onset of more permanent damage.

CSF oligoclonal band status informs prognosis in multiple sclerosis: a case control study of 100 patients

Objective: Oligoclonal band (OCB) negative multiple sclerosis (MS) is well recognised but uncommon, studied in only a few usually small case series. These reached differing conclusions on whether its clinical features or course differ from OCB positive disease. The study hypothesis was that a definitive study would not only be of clinical and prognostic value but also potentially offer information about the possible role of CSF oligoclonal immunoglobulins in MS disease processes. Methods: A collaborative cohort of well documented patients in southwest England and south Wales was used to identify and analyse a large group of patients with OCB negative MS and make comparisons with age and sex matched OCB positive controls. Results: An approximate minimum 3% of patients with MS were OCB negative. They were significantly more likely to exhibit neurological or systemic clinical features atypical of MS (headaches, neuropsychiatric features and skin changes). Non-specific MRI, blood and (other) CSF abnormalities were also more common, emphasising the need for continued diagnostic vigilance, although the incautious application of McDonald diagnostic criteria in OCB negative cases renders categorisation as “definite” MS more likely. Studying the uniformly assessed Cardiff group (69 patients), we found the prognosis for neurological disability was significantly better for OCB negative cases. The age adjusted hazard ratio for OCB negative and OCB positive subjects to reach Disability Scale Status (DSS) 4 and DSS 6 was, respectively, 0.60 (95% CI 0.39 to 0.93; p = 0.02) and 0.51 (95% CI 0.27 to 0.94; p = 0.03). Conclusion: There are clear clinical differences between OCB negative and OCB positive MS, in particular a better prognosis for disability. This is consistent with a secondary but nonetheless contributory role in disease process for intrathecally synthesised immunoglobulins.