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Guillain-Barre syndrome (GBS) is a heterogeneous disorder causing muscle weakness, sensory change, dysautonomia and often involving cranial neuropathies. An immune response to recent infection or to triggers such as vaccines, is thought to be responsible. Immunological cross-reaction with the peripheral nerve causes subsequent demyelinating or axonal damage. GBS is a continuous spectrum of disease rather than discrete phenotypes. Recognised GBS variants in order of frequency are: (1) classical; (2) Miller Fisher syndrome; (3) pharyngeal-cervical-brachial; (4) bifacial weakness with paraesthesia of limbs (BFP); and (5) paraparetic.1 At the time of publication, no reports of BFP variant GBS post COVID-19 vaccination have been described. We report five remarkably similar cases of BFP post-Vaxzevria. All of them presented to Wessex hospitals: Queen Alexandra Hospital, Portsmouth; Southampton General Hospital; Poole Hospital; and St Mary’s Hospital, Isle of Wight, within a 3-month period. A 66-year-old man developed interscapular back and leg pain, particularly severe at night, 1 week after his first dose of Vaxzevria. He had paraesthesia of both hands and feet and was unsteady. Ten days later, he developed bilateral facial weakness with numbness of the tongue and mouth. Examination revealed marked bilateral lower motor neuron (LMN) facial weakness. Tone, power and reflexes were normal in the limbs except absent right ankle jerk. Light touch and pinprick sensation was reduced symmetrically in both lower limbs to the knee and vibration to the ankles. His gait was ataxic. A 43-year-old man …

BACKGROUND: Wilson's disease, first described by Samuel Wilson in 1912, is an autosomal recessive metabolic disorder resulting from mutations in the ATP7B gene. The disease develops as a consequence of copper accumulating in affected tissues. There is no gold standard for the diagnosis of Wilson's disease, which is often delayed due to the non‐specific clinical features and the need for a combination of clinical and laboratory tests for diagnosis. This delay may in turn affect clinical outcome and has implications for other family members in terms of diagnosis. The Leipzig criteria were established to help standardise diagnosis and management. However, it should be emphasised that these criteria date from 2003, and many of these have not been formally evaluated; this review examines the evidence behind biochemical testing for Wilson's disease. OBJECTIVES: To determine the diagnostic accuracy of three biochemical tests at specified cut‐off levels for Wilson's disease. The index tests covered by this Cochrane Review are caeruloplasmin, 24‐hour urinary copper and hepatic copper content. These tests were evaluated in those with suspected Wilson's disease and appropriate controls (either healthy or those with chronic liver disease other than Wilson's). In the absence of a gold standard for diagnosing Wilson's disease, we have used the Leipzig criteria as a clinical reference standard. To investigate whether index tests should be performed in all individuals who have been recommended for testing for Wilson's disease, or whether these tests should be limited to subgroups of individuals. SEARCH METHODS: We identified studies by extensive searching of, e.g. the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, the Web of Science and clinical trial registries (29 May 2019). Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Inborn Errors of Metabolism Register: 29 May 2019. SELECTION CRITERIA: We included prospective and retrospective cohort studies that assessed the diagnostic accuracy of an index test using the Leipzig criteria as a clinical reference standard for the diagnosis of Wilson's disease. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and extracted data and assessed the methodological quality of each included study using the QUADAS‐2 tool. We had planned to undertake meta‐analyses of the sensitivity, specificity at relevant cut‐offs for each of the biochemical tests for Wilson's, however, due to differences in the methods used for each biochemical index test, it was not possible to combine the results in meta‐analyses and hence these are described narratively. MAIN RESULTS: Eight studies, involving 5699 participants (which included 1009 diagnosed with Wilson's disease) were eligible for inclusion in the review. Three studies involved children only, one adults only and the four remaining studies involved both children and adults. Two evaluated participants with hepatic signs and six with a combination of hepatic and neurological signs and symptoms of Wilson's disease, as well as pre‐symptomatic individuals. The studies were of variable methodological quality; with high risk if bias for participant selection and the reference standard used being of greatest methodological concern. Key differences between studies include differences in assay methodology, different cut‐off values for diagnostic thresholds, different age and ethnicity groups. Concerns around study design imply that diagnostic accuracy figures may not transfer to populations outside of the relevant study. Index test: caeruloplasmin Five studies evaluated various thresholds of caeruloplasmin (4281 participants, of which 541 had WD). For caeruloplasmin a cut‐off of 0.2 g/L as in the Leipzig criteria achieved a sensitivity of 77.1% to 99%, with variable specificity of 55.9% to 82.8%. Using the cut‐off of 0.1 g/L of the Leipzig criteria seemed to lower the sensitivity overall, 65% to 78.9%, while increasing the specificity to 96.6% to 100%. Index test: hepatic copper Four studies evaluated various thresholds of hepatic copper (1150 participants, of which 367 had WD). The hepatic copper cut‐off of 4 μmol/g used in the Leipzig criteria achieved a sensitivity of 65.7% to 94.4%, with a variable specificity of 52.2% to 98.6%. Index test: 24‐hour urinary copper Three studies evaluated various thresholds of 24‐hour urinary copper (268 participants, of which 101 had WD). For 24‐hour urinary copper, a cut‐off of 0.64 to 1.6 μmol/24 hours used in the Leipzig criteria achieved a variable sensitivity of 50.0% to 80.0%, with a specificity of 75.6% to 98.3%. AUTHORS' CONCLUSIONS: The cut‐offs used for caeruloplasmin, 24‐hour urinary copper and hepatic copper for diagnosing Wilson's disease are method‐dependent and require validation in the population in which such index tests are going to be used. Binary cut‐offs and use of single‐test strategies to rule Wilson's disease in or out is not supported by the evidence in this review. There is insufficient evidence to inform testing in specific subgroups, defined by age, ethnicity or clinical subgroups.

OBJECTIVES: Alemtuzumab is a newly licensed treatment of active relapsing-remitting multiple sclerosis (RRMS) in Europe, which in phase II and III studies demonstrated superior efficacy over β-interferon in reducing disability progression over 2-3 years. In this observational cohort study, we sought to describe our longer-term experience of the efficacy and safety of alemtuzumab in active RRMS. METHODS: Clinical and laboratory data including serial Expanded Disability Status Scale (EDSS) assessments, from all 87 patients treated with alemtuzumab on investigator-led studies in Cambridge, UK, from 1999 to 2012, were collected. The occurrence of adverse events including secondary autoimmunity, malignancy and death, and pregnancy outcomes was recorded. Baseline variables including age, disease duration and relapse rate were compared in univariate and logistic regression analyses between groups with different disability outcomes. RESULTS: Over a median 7-year follow-up (range 33-144 months), most patients (52%) required just two cycles of alemtuzumab. In the remaining patients, relapses triggered re-treatment to a total of three cycles (36%), four cycles (8%) or five cycles (1%). Using a 6-month sustained accumulation of disability definition, 59/87 (67.8%) of patients had an improved or unchanged disability compared with baseline. By an area under the curve analysis, 52/87 (59.8%) patients had an overall improvement or stabilisation of disability. Higher baseline relapse rate was associated with worse long-term disability outcomes, with trends for longer disease duration and older age at first treatment. Secondary autoimmunity was the most frequent adverse event occurring in 41/86 (47.7%) patients, most commonly involving the thyroid gland. CONCLUSIONS: Alemtuzumab is associated with disease stabilisation in the majority of patients with highly active RRMS over an average seven-year follow-up. No new safety concerns arose over this extended follow-up.

Background Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing–remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991–1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9 /l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

Objective: To test the hypothesis that accelerated peripheral blood mononuclear cell recovery after alemtuzumab treatment of multiple sclerosis is associated with recurrent disease activity and to investigate the claim that CD4 counts greater than 388.5 × 10 6 cells/mL at 12 months can be used to identify patients who may benefit from further treatment. Methods: A total of 108 patients were followed for a median of 99 months post alemtuzumab. Patients were classified as active or nonactive after each cycle of treatment based on clinical relapse, increasing disability, or new T2/enhancing MRI lesions. These outcomes were correlated with CD4, CD8, CD19, CD56+ NK, and monocyte counts. Results: Of 108 patients, 56 (52%) relapsed at some point during follow-up. Mean annualized relapse rate after alemtuzumab was 0.17 vs 1.67 prior to treatment (equating to a 90% reduction). Of 108 patients, 28 (26%) met the criteria for sustained accumulation of disability. Median time to the lower limit of normal for CD19, CD8, and CD4 was 3, 19.5, and 32 months, respectively. There was no significant difference in the recovery of any cell population between patients with and without disease activity or accumulation of disability after treatment. Conclusion: This study does not support the use of cell counts as biomarkers for identifying patients at greater risk of active disease following treatment with alemtuzumab.

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28(-)CD57(+)), highly proliferative (Ki67(+)), oligoclonal, memory-like CD4 and CD8 T cells (CCR7(-)CD45RA(-) or CCR7(-)CD45RA(+)) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.

Objective: To determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab. Methods: In this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumab treatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9–11 months after treatment. Results were compared with well-defined historical controls. Results: Serum antibodies against common viruses remained detectable after treatment, and vaccine responses were normal to T-cell–dependent recall antigens (tetanus, diphtheria, and polio), a T-cell–dependent novel antigen (meningococcus C), and T-cell–independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment. Conclusion: In this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab. Classification of evidence: This pilot study provides Class III evidence that patients with relapsing-remitting multiple sclerosis appear immunocompetent after treatment with alemtuzumab.

In vitro, two different classes of antibodies are recognized according to the assay used to identify them: binding antibodies (BAbs) and neutralizing antibodies (NAbs). There is emerging agreement that NAbs are correlated with reduced therapeutic efficacy of IFNβ. None of the pivotal trials in relapsing-remitting multiple sclerosis (MS) showed an effect of NAbs on disease progression. Among the therapeutic monoclonal antibodies natalizumab, alemtuzumab, and daclizumab are humanized monoclonal antibodies, whereas rituximab is a mouse-human chimeric antibody. NAbs are associated with reduction of the therapeutic effect of IFNβ, and patients with persistent high titers of NAbs should be switched to an alternative therapy. Patients with low or intermediate titers should have their IFN bioactivity measured with an in vivo mRNA MxA induction test. Patients with repeated abrogation of the mRNA MxA response to IFN injections should be switched to another therapy.

BackgroundAlemtuzumab is recently licensed for use in active relapsing-remitting multiple sclerosis (RRMS) in Europe and the USA. This observational cohort study investigated the long term safety of alemtuzumab in RRMS.MethodsClinical data was collected from a cohort of 87 patients who participated in open label studies of alemtuzumab in Cambridge, UK from 1999 to 2012. Pregnancy outcomes and the occurrence of moderate to severe infections were recorded.ResultsOver a median 7-year follow-up (range 33–144 months), no serious infections occurred that required hospitalisation. There were 11 cases of varicella zoster virus reactivation and one case of primary varicella zoster virus infection. In this cohort 15 babies were born to 12 women treated with alemtuzumab. The median interval from their most recent alemtuzumab treatment to birth was 26 months (range 13–86 months). All of the babies were healthy and delivered without complications. One woman had experienced a miscarriage at 8 weeks gestation but went on to have two successful pregnancies.ConclusionsDuring prolonged follow-up of this cohort of patients treated with alemtuzumab no serious infections occurred. No increased risk of miscarriage or foetal abnormality was seen in the small number of pregnancies studied.