Autologous haematopoietic stem cell transplantation for immune-mediated neurological diseases: what, how, who and why?

In carefully selected patients, autologous haematopoietic stem cell transplantation (HSCT) is a safe, highly effective and cost-saving treatment modality for treatment-resistant, and potentially treatment-naïve, immune-mediated neurological disorders. Although the evidence base has been growing in the last decade, limited understanding has led to confusion, mistrust and increasing use of health tourism. In this article, we discuss what autologous HSCT is, which immune-mediated conditions can be treated with it, how to select patients, what are the expected outcomes and potential adverse effects, and how cost-effective this treatment is.

Alemtuzumab for multiple sclerosis: Long term follow-up in a multi-centre cohort.

BACKGROUND: Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve. OBJECTIVES: To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab. METHODS: Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review. RESULTS: One hundred patients were identified with a mean follow-up of 6.1 years (range 1-13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity. CONCLUSION: Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime.

Ovarioleukodystrophy due to EIF2B5 mutations.

Ovarioleukodystrophy-the co-occurrence of leukodystrophy and premature ovarian failure-is a rare presentation now recognised to be part of the clinical spectrum of vanishing white matter disease. We describe a woman with epilepsy and neuroimaging changes consistent with leukoencephalopathy who presented with non-convulsive status epilepticus after starting hormone replacement therapy in the context of premature ovarian failure. Genetic testing confirmed her to be a compound heterozygote for EIF2B5 mutations; the gene encodes a subunit of eukaryotic translation initiation factor 2B. Mutations in EIF2B1-5 result in vanishing white matter disease. We highlight the importance of ovarian failure as a diagnostic pointer to eukaryotic translation initiation factor 2B (eIF2B)-related ovarioleukodystrophy and present a brief literature review of ovarioleukodystrophy.

Intracranial spread of IgG4-related disease via skull base foramina.

IgG4-related disease (IgG4-RD) is a newly recognised, multiorgan, inflammatory disease, and its full clinical spectrum remains undefined. We present a biopsy-proven case of IgG4-RD presenting with a parapharyngeal mass with intracranial extension and possible involvement of the brain parenchyma. We highlight the importance of considering the diagnosis in those presenting with tumefactive lesions, leptomeningitis or pachymeningitis and emphasise the value of securing a tissue diagnosis so that appropriate long-term treatment can be instigated and complications avoided.

Mitochondrial sirtuins--a new therapeutic target for repair and protection in multiple sclerosis.

Given the significant socioeconomic impact of progressive multiple sclerosis (MS) and the paucity of treatment options, there is an urgent need to develop new and effective therapies for this disabling condition. The relatively recent appreciation that progressive disability is largely driven by neuronal loss has focused considerable research attention on neuroprotective strategies. This has coincided with the emergence of oxidative damage as a prominent effector mechanism of axonal damage in studies of MS pathogenesis, which has opened up a new range of putative targets for neuroprotective therapy in MS. Mitochondrial sirtuins are NAD(+)-dependent protein deacetylases associated with the control of metabolism, aging, and stem cell proliferation and differentiation. Their role in inflammatory demyelinating disease has not been fully characterized, and is the subject of ongoing research. Here, we expound the rationale behind selecting mitochondrial sirtuins as a therapeutic target in demyelinating disease, and report preliminary data that warrant further investigation.

Factors affecting mortality after traumatic brain injury in a resource-poor setting.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of long-term disability and economic loss to society. The aim of this study was to assess the factors affecting mortality after TBI in a resource-poor setting. METHODS: Chart review was performed for randomly selected patients who presented with TBI between 2013 and 2017 at St Mary's Hospital, Lacor, northern Uganda. Data collected included demographic details, time from injury to presentation, and vital signs on arrival. In-hospital management and mortality were recorded. Severe head injury was defined as a Glasgow Coma Scale score below 9. RESULTS: A total of 194 patient charts were reviewed. Median age at time of injury was 27 (i.q.r. 2-68) years. The majority of patients were male (M : F ratio 4·9 : 1). Some 30·9 per cent of patients had severe head injury, and an associated skull fracture was observed in 8·8 per cent. Treatment was mainly conservative in 94·8 per cent of patients; three patients (1·5 per cent) had burr-holes, four (2·1 per cent) had a craniotomy, and three (1·5 per cent) had skull fracture elevation. The mortality rate was 33·0 per cent; 46 (72 per cent) of the 64 patients who died had severe head injury. Of the ten surgically treated patients, seven died, including all three patients who had a burr-hole. In multivariable analysis, factors associated with mortality were mean arterial pressure (P = 0·012), referral status (P = 0·001), respiratory distress (P = 0·040), severe head injury (P = 0·011) and pupil reactivity (P = 0·011). CONCLUSION: TBI in a resource-poor setting remains a major challenge and affects mainly young males. Decisions concerning surgical intervention are compromised by the lack of both CT and intracranial pressure monitoring, with consequent poor outcomes.

ANTECEDENTES: La lesión cerebral traumática (traumatic brain injury, TBI) es un insulto al cerebro causado por una fuerza física externa que produce un estado de conciencia disminuido o alterado, lo que resulta en un deterioro de las capacidades cognitivas o del funcionamiento físico. Es una causa importante de discapacidad a largo plazo y pérdida económica para la sociedad. El objetivo de este estudio fue evaluar los factores que afectan a la mortalidad después de una TBI en un entorno de escasos recursos. MÉTODOS: Se realizó la revisión de historias clínicas de pacientes seleccionados al azar que habían presentado una TBI entre 2013 y 2017 en el Hospital St. Mary's, un hospital privado sin ánimo de lucro ubicado en el distrito de Gulu, Lacor, en el norte de Uganda. Se recogieron datos de las características demográficas, intervalo de tiempo entre la lesión y la atención médica, y signos vitales a la llegada al hospital. Se registró también el manejo hospitalario y la mortalidad. El traumatismo craneal grave se definió como aquel con una escala de coma de Glasgow (Glasgow Coma Scale, GCS) por debajo de 9. RESULTADOS: Se revisaron 194 historias clínicas de pacientes. La mediana de edad en el momento del traumatismo fue de 27 (rango intercuartílico de 2 a 68) años. La mayoría eran varones con una relación varón:mujer de 4,9:1. En el 38,1% de los casos los traumatismos craneales fueron calificados como graves y se observó una fractura de cráneo asociada en el 8,8% de los pacientes. Los tratamientos ofrecidos fueron principalmente conservadores en el 94,9%; tres pacientes (1,6%) precisaron trépanos, en cuatro pacientes (2,1%) se realizó una craneotomía y otros tres pacientes (1,6%) precisaron elevación de una fractura craneal con hundimiento. La mortalidad fue del 33,0%; El 71,9% de ellos tenían un traumatismo craneal grave. Entre los pacientes tratados quirúrgicamente, siete (70%) murieron, incluidos los tres pacientes en los que se realizó un trépano. Los factores asociados con la mortalidad en el análisis multivariable fueron la presión arterial media (P < 0,05), el estado en el traslado (P < 0,05), la dificultad respiratoria (P = 0,040), el traumatismo craneal grave (P = 0,012) y la reactividad pupilar (P = 0,011). CONCLUSIÓN: El TBI en un entorno con pocos cursos continúa siendo un desafío importante, afectando principalmente a varones jóvenes. Las decisiones relativas a la intervención quirúrgica y el momento de su práctica están seriamente comprometidas por la falta de disponibilidad de tomografía computarizada (TAC) y monitorización de la presión intracraneal, lo que conlleva unos pobres resultados.

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.

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.

Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis.

Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was -0.36 overall and -0.15 in those patients completing > or =1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease. We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis.

Neuro-Behçet's disease in Caucasians: a study of 22 patients.

Several analyses of the neurological features of Behçet's disease (BD) have concluded that there are significant racial differences in its clinical expression. Other series, however, failed to elicit such differences. We aimed to describe in this retrospective survey the frequency, nature and relationship to systemic disease of the neurological features in a cohort of BD patients of Caucasian origin. We searched hospital records from nine District General or Regional Centre hospitals in south-west Great Britain and identified 22 individuals of Caucasian ethnic origin with neuro-BD, with a mean of 10 years follow-up per patient - the largest 'western' case series with the longest period of follow-up reported. We found that presentation with neurological features was commoner in our patients (23%) than Middle Eastern series (3-10%). Seizures (27%) were likewise commoner (0-5%), as was optic neuritis (9% compared with 1-2%). Two patients developed movement disorders (chorea and parkinsonism), which have only been rarely reported. Of further clinical significance, we noted that non-neuropsychiatric features: oral ulceration, intraocular inflammation and skin lesions - were virtually always present or exacerbated during neurological complications. Ethnicity--or conceivably environment--may play a significant role in the manifestation of neurological BD.

Sarcoidosis of the nervous system.

Although sarcoidosis is rarely confined to the nervous system, any neurological features that do occur frequently happen early in the course of the disease. The most common neurological presentation is with cranial neuropathies, but seizures, chronic meningitis and the effects of mass lesions are also frequent. The diagnostic process should first confirm nervous system involvement and then provide supportive evidence for the underlying disease; in the absence of any positive tissue biopsy, the most useful diagnostic tests are gadolinium enhanced MRI of the brain and CSF analysis, although both are non-specific. The mainstay of treatment is corticosteroids, but these often have to be combined with other immunosuppressants such as methotrexate, hydroxychloroquine or cyclophosphamide. There is increasing evidence that infliximab is a safe treatment with good steroid sparing capacity.

Neurosarcoidosis: a clinical approach to diagnosis and management.

Sarcoidosis is a rare but important cause of neurological morbidity, and neurological symptoms often herald the diagnosis. Our understanding of neurosarcoidosis has evolved from early descriptions of a uveoparotid fever to include presentations involving every part of the neural axis. The diagnosis should be suspected in patients with sarcoidosis who develop new neurological symptoms, those presenting with syndromes highly suggestive of neurosarcoidosis, or neuro-inflammatory disease where more common causes have been excluded. Investigation should look for evidence of neuro-inflammation, best achieved by contrast-enhanced brain magnetic resonance imaging and cerebrospinal fluid analysis. Evidence of sarcoidosis outside the nervous system should be sought in search of tissue for biopsy. Skin lesions should be identified and biopsies taken. Chest radiography including high-resolution computed tomography is often informative. In difficult cases, fluorodeoxyglucose positron emission tomography and gallium-67 imaging may identify subclinical disease and a target for biopsy. Symptomatic patients should be treated with corticosteroids, and if clinically indicated other immunosuppressants such as hydroxychloroquine, azathioprine, cyclophosphamide or methotrexate should be added. Anti-tumour necrosis factor alpha therapies may be considered in refractory disease but caution should be exercised as there is evidence to suggest they may unmask disease.

Beta-interferon and multiple sclerosis.

Interferon-beta (IFN-beta) is the first therapeutic intervention shown to alter the natural history of multiple sclerosis (MS), a relapsing then progressive inflammatory degenerative disease of the CNS. Since publication of the first randomized placebo-controlled trial of IFN-beta, and subsequent acquisition of US and European product licences for use in relapsing-remitting MS, the hopes and expectations of patients have been elevated greatly only to be dampened as more critical analysis of the trial results, in conjunction with the cost of treatment, led to marked limitations on prescription in several countries. IFN-beta is not a cure. Here we review what is known about the mechanisms of action of IFN-beta in demyelinating disease, and propose a possible model of action of IFN-beta in the treatment of MS.

Erdheim-Chester disease: 25-year history with early CNS involvement.

We report a case of Erdheim-Chester disease (ECD) with a 25-year history following initial presentation with diabetes insipidus and brainstem involvement. The exceptionally long history is particularly notable, given that ECD is a life-threatening disorder and there is a recognised association between central nervous system involvement and poor outcome. The case is a timely reminder of the presenting features of the condition, given the emergence of potential new treatment options.

Adult stem cells--reprogramming neurological repair?

Much excitement has surrounded recent breakthroughs in embryonic stem-cell research. Of lower profile, but no less exciting, are the advances in the field of adult stem-cell research, and their implications for cell therapy. Clinical experience from use of adult haemopoietic stem cells in haematology will facilitate and hasten transition from laboratory to clinic--indeed, clinical trials using adult human stem cells are already in progress in some disease states, including myocardial ischaemia. Here, with particular reference to neurology, we review processes that might underlie apparent changes in adult cell phenotype. We discuss implications these processes might have for the development of new therapeutic strategies using adult stem cells.

Disclosing the diagnosis of multiple sclerosis.

CONTEXT: The question of how best to disclose to patients the diagnosis of serious and/or incurable neurological diseases has been much explored, but that of when has received little rigorous study. The present study investigates this question in relation to multiple sclerosis (MS), a disease marked by its incurability, unpredictability and predilection for young adults. OBJECTIVES: We aimed to ascertain the preferences of Greek MS sufferers concerning when they should ideally be informed they have the disease, and their preferences and reactions regarding disclosure of the diagnosis. Design, setting and patients 1,200 Greek MS patients,members of the MS Society, were asked to complete a questionnaire regarding their experience of and attitudes towards receiving the diagnosis. DESIGN, SETTING AND PATIENTS: 1,200 Greek MS patients,members of the MS Society, were asked to complete a questionnaire regarding their experience of and attitudes towards receiving the diagnosis. RESULTS: 657 patients (55 %) responded. 91% favoured learning the diagnosis immediately, but only 44% had had this experience: 29% had been informed within 1-3 years, and 27% later. Interestingly, however, a significant minority (9 %) suggested a possible preference for delayed delivery of diagnosis and 23.2% stated that concealing the diagnosis would not lead to loss of confidence in their doctor. CONCLUSION: This study-the largest of its kind-provides objective data supporting prompt disclosure of diagnosis as the clearly-expressed preference amongst most patients. Interestingly, however, the results also re-emphasise the importance of a difficult medical art: attempting to judge whether an individual patient is one (of the 91%) preferring immediate disclosure-or of the nearly 1-in-10 (9%) who may not.

Neural progenitor cells from postmortem adult human retina.

BACKGROUND: Given the presence of neural progenitor cells (NPC) in the retina of other species capable of differentiating into multiple neural components, the authors report the presence of NPC in the adult human retina. A resident population of NPC suggests that the retina may constitutively replace neurons, photoreceptors, and glia. METHODS: Adult human postmortem retinal explants and cell suspensions were used to generate cells in tissue culture that display the features of NPC. The phenotype of cells and differentiation into neurons was determined by immunocytochemistry. Dividing cells were labelled with 5-bromo-2-deoxyuridine (BrdU) and neurospheres were generated and passaged. RESULTS: Cells labelled with nestin, neurofilament M (NFM), rhodopsin, or glial fibrillary acidic protein (GFAP) grew out from explant cultures. BrdU labelling of these cells occurred only with basic fibroblast growth factor (FGF-2). Dissociated retina and pars plana generated primary neurospheres. From primary neurospheres, NPC were passaged to generate secondary neurospheres, neurons, photoreceptors, and glia. BrdU labelling identified dividing cells from neurospheres that differentiated to express NFM and rhodopsin. CONCLUSION: The adult human retina contains NPC and may have the potential to replace neurons and photoreceptors. This has implications for the pathogenesis and treatment of retinal disorders and degenerations, including glaucoma, and those disorders associated with retinal scarring.