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.

Axonal motor protein KIF5A and associated cargo deficits in multiple sclerosis lesional and normal-appearing white matter.

AIMS: Understanding the causes of axonal pathology remains a key goal in the pursuit of new therapies to target disease progression in multiple sclerosis (MS). Anterograde axonal transport of many proteins vital for axonal viability is mediated by the motor protein KIF5A, which has been linked to several neurological diseases. This study aimed to investigate the expression of KIF5A protein and its associated cargoes: amyloid precursor protein (APP) and neurofilament (NF) in post mortem MS and control white matter (WM) and to determine if KIF5A expression is influenced by the presence of MS risk single nucleotide polymorphisms (SNPs) identified in the region of the KIF5A gene. METHODS: Using immunoblotting assays we analysed the expression of KIF5A, APP and NF phospho-isoforms in 23 MS cases and 12 controls. RESULTS: We found a significant reduction in KIF5A and associated cargoes in MS WM and an inverse correlation between KIF5A and APP/NF protein levels. Furthermore, homozygous carriers of MS risk gene SNPs show significantly lower levels of KIF5A protein compared to MS patients with no copies of the risk SNPs. CONCLUSIONS: We conclude that reduced expression of axonal motor KIF5A may have important implications in determining axonal transport deficits and ongoing neurodegeneration in MS.

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.

Reduced axonal motor protein expression in non-lesional grey matter in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a neurological disease characterised by central nervous system inflammation, demyelination, axonal degeneration and neuronal injury. Preventing neuronal and axon damage is of paramount importance in attempts to prevent disease progression. Intact axonal transport mechanisms are crucial to axonal integrity and evidence suggests these mechanisms are disrupted in MS. Anterograde axonal transport is mediated to a large extent through the kinesin superfamily proteins. Recently, certain kinesin superfamily proteins (KIF5A, KIF1B and KIF21B) were implicated in MS pathology. OBJECTIVES: To investigate the expression of KIF5A, KIF21B and KIF1B in MS and control post-mortem grey matter. METHODS: Using both quantitative real-time polymerase chain reaction (PCR) and Immunodot-blots assays, we analysed the expression of kinesin superfamily proteins in 27 MS cases and 13 control cases not linked to neurological disease. RESULTS: We have shown significant reductions in KIF5A, KIF21B and KIF1B messenger ribonucleic acid (mRNA) expression and also KIF5A protein expression in MS grey matter, as compared to control grey matter. CONCLUSION: We have shown significant reductions in mRNA and protein levels of axonal motor proteins in the grey matter of MS cases, which may have important implications for the pathogenesis of neuronal/axonal injury in the disease.

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.

Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells.

AIMS: we explored whether cellular fusion and heterokaryon formation between human and rodent cells in the cerebellum of mice occurs after intravenous injection of human bone marrow-derived mesenchymal stem cells (MSCs). The influence of central nervous system inflammation on this process was also assessed. In addition, we examined whether tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, factors associated with inflammation, increase cellular fusion between human MSCs and rodent cerebellar neurons in vitro. METHODS AND RESULTS: human MSCs were intravenously injected into mice with experimental autoimmune encephalomyelitis (EAE) and control mice. After 22 days, mouse Purkinje cells expressing human Golgi Zone were found within the Purkinje cell layer of the cerebellum, indicating that fusion and heterokaryon formation had occurred. The numbers of heterokaryons in the cerebellum were markedly increased in mice with EAE compared with control mice. Rodent cerebellar neuronal cells labelled with enhanced green fluorescent proteinin vitro were co-cultured with human bone marrow-derived MSCs in the presence of TNF-alpha and/or IFN-gamma to determine their influence on fusion events. We found that fusion between MSCs and cerebellar neurons did occur in vitro and that the frequency of cellular fusion increased in the presence of TNF-alpha and/or IFN-gamma. CONCLUSIONS: we believe that this is the first paper to define fusion and heterokaryon formation between human MSCs and rodent cerebellar neurons in vivo. We have also demonstrated that fusion between these cell populations occurs in vitro. These findings indicate that MSCs may be potential therapeutic agents for cerebellar diseases, and other neuroinflammatory and neurodegenerative disorders.

The relationship between relapse, impairment and disability in multiple sclerosis.

OBJECTIVE: To describe the spatial relationship between relapse and disability in multiple sclerosis (MS). METHODS: 141 relapse onset MS patients were studied. For each patient an examination was performed and a relapse history obtained. Multivariate logistic regression examined whether there was an association between localizing clinical signs and a history of relevant relapse in order to explore the spatial relationship between relapse and subsequent disability. RESULTS: The presence of impaired vision or sensation was independently associated with a history of one or more anatomically related relapses. The presence of weakness or cerebellar ataxia in a limb was not associated with a single relevant relapse but was associated with multiple relevant relapses. A history of multiple episodes of weakness or ataxia in the same limb was uncommon. CONCLUSIONS: Our data suggest that motor pathways are relatively resistant to chronic impairment from acute relapse, whereas afferent pathways are more susceptible. This, in combination with prominent usage of the Expanded Disability Status Scale, which is dependent on mobility and motor function at higher scores, may explain the paradox between natural history studies that suggest relapses are irrelevant to long-term disability and shorter studies at lower disability levels suggesting relapses are responsible for disability accumulation.

KIF5A and the contribution of susceptibility genotypes as a predictive biomarker for multiple sclerosis.

There is increasing interest in the development of multiple sclerosis (MS) biomarkers that reflect central nervous system tissue injury to determine prognosis. We aimed to assess the prognostic value of kinesin superfamily motor protein KIF5A in MS by measuring levels of KIF5A in cerebrospinal fluid (CSF) combined with analysis of single nucleotide polymorphisms (SNPs; rs12368653 and rs703842) located within a MS susceptibility gene locus at chromosome 12q13-14 region. Enzyme-linked immunosorbent assay was used to measure KIF5A in CSF obtained from two independent biobanks comprising non-inflammatory neurological disease controls (NINDC), clinically isolated syndrome (CIS) and MS cases. CSF KIF5A expression was significantly elevated in progressive MS cases compared with NINDCs, CIS and relapsing-remitting MS (RRMS). In addition, levels of KIF5A positively correlated with change in MS disease severity scores (EDSS, MSSS and ARMSSS), in RRMS patients who had documented disease progression at 2-year clinical follow-up. Copies of adenine risk alleles (AG/AA; rs12368653 and rs703842) corresponded with a higher proportion of individuals in relapse at the time of lumbar puncture (LP), higher use of disease-modifying therapies post LP and shorter MS duration. Our study suggests that CSF KIF5A has potential as a predictive biomarker in MS and further studies into the potential prognostic value of analysing MS susceptibility SNPs should be considered.

EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs.

OBJECTIVES: To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations. METHODS: The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design. RESULTS: Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence > 5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1-5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fivefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fluid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fluid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD. CONCLUSIONS: Neuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.

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.

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 (good practice point) [corrected],stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point).

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.