The Effective Management of Idiopathic Intracranial Hypertension Delivered by In-person and Virtual Group Consultations: Results and Reflections from a Phase One Service Delivery.

The increasing incidence of idiopathic intracranial hypertension (IIH) with the obesity epidemic is leading to increased pressures on service capacity. Evidence shows that group consultations (GCs) deliver effective, person-centred healthcare, but the feasibility for IIH is unknown. We set out to develop and test a safe and effective GC service for IIH. Through an interactive approach, we co-designed a bespoke in-person and virtual GC model, where patients are reviewed in a group setting. Improvements were made following each session following patient input and team reflections. Outcomes measured included patient satisfaction, self-perceived health literacy, and successful implementation of the GCs. During the pilot, eight in-person GCs were delivered: once-monthly (Oct-Dec 2019), then twice-monthly (Jan-Feb 2020). Feedback was received from 49/53 patients. 100% felt more satisfied and heard, 100% felt more involved in decision-making, 98% had a better understanding of their condition, 96% felt more able to cope with their condition and keep themselves healthy, 94% rated this as a positive experience, and 90% reported improved access and more time with their clinician compared with existing 1:1 appointments. Since September 2020, in response to the COVID-19 pandemic, we transitioned to weekly virtual GCs, receiving overwhelmingly positive feedback (median scores: patient satisfaction 9.5/10; being listened to by clinician 10/10; involved by clinician in treatment decisions 10/10; clinician explanation of treatment 10/10; and opportunity to discuss condition or treatment 10/10). GCs are safe and effective for IIH, and preferred in our patient cohort. This allowed ongoing high-quality, person-centred care despite challenges from the COVID-19 pandemic.

Immune deficiency: changing spectrum of pathogens.

Current UK national standards recommend routine bacteriology surveillance in severe antibody-deficient patients, but less guidance exists on virology screening and viral infections in these patients. In this retrospective audit, we assessed the proportion of positive virology or bacteriology respiratory and stool samples from patients with severe, partial or no immune deficiency during a 2-year period. Medical notes were reviewed to identify symptomatic viral infections and to describe the course of persistent viral infections. During the 2-year period, 31 of 78 (39·7%) severe immune-deficient patients tested had a positive virology result and 89 of 160 (55.6%) had a positive bacteriology result. The most commonly detected pathogens were rhinovirus (12 patients), norovirus (6), Haemophilus influenzae (24), Pseudomonas spp. (22) and Staphylococcus aureus (21). Ninety-seven per cent of positive viral detection samples were from patients who were symptomatic. Low serum immunoglobulin IgA levels were more prevalent in patients with a positive virology sample compared to the total cohort (P = 0·0078). Three patients had persistent norovirus infection with sequential positive isolates for 9, 30 and 16 months. Virology screening of symptomatic antibody-deficient patients may be useful as a guide to anti-microbial treatment. A proportion of these patients may experience persistent viral infections with significant morbidity.

Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes.

BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature. METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out. RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia. CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.

Penile granulomatosis presenting as pseudoangioedema.

Many conditions may present as angioedema. We report a case of a 46 year-old man presenting with intermittent episodes of penile swelling. Following a series of investigations, he was diagnosed with genital granulomatosis. Ano-genital granulomatosis is a rare chronic inflammatory condition and that can present as diffuse penile, scrotal, vulvar or ano-perineal swelling with non-caseating non-necrotising granulomas on histology.

In pursuit of excellence: an integrated care pathway for C1 inhibitor deficiency.

There are estimated to be approximately 1500 people in the United Kingdom with C1 inhibitor (C1INH) deficiency. At BartsHealth National Health Service (NHS) Trust we manage 133 patients with this condition and we believe that this represents one of the largest cohorts in the United Kingdom. C1INH deficiency may be hereditary or acquired. It is characterized by unpredictable episodic swellings, which may affect any part of the body, but are potentially fatal if they involve the larynx and cause significant morbidity if they involve the viscera. The last few years have seen a revolution in the treatment options that are available for C1 inhibitor deficiency. However, this occurs at a time when there are increased spending restraints in the NHS and the commissioning structure is being overhauled. Integrated care pathways (ICP) are a tool for disseminating best practice, for facilitating clinical audit, enabling multi-disciplinary working and for reducing health-care costs. Here we present an ICP for managing C1 inhibitor deficiency.

Autosomal recessive chronic granulomatous disease presenting with cutaneous dermatoses and ocular infection.

Dermatoses such as eczematous dermatitis and cutaneous infection are recognized presentations of primary immunodeficiency (PID). However, atopic dermatitis affects approximately 10% of infants, and cutaneous infections are not uncommon in children, therefore the challenge for the dermatologist is to distinguish the few patients that have PID from the many that do not. We report on a 6-year-old girl who was ultimately diagnosed with autosomal recessive chronic granulomatous disease (AR-CGD) after presenting to various hospitals with dermatitis, scalp plaques recalcitrant to treatment, and recurrent infections over a 3-year period, and describe some aspects of her diagnosis and management. This report highlights the importance of considering rare disorders such as AR-CGD in the differential diagnosis of recurrent or recalcitrant dermatological infections in children.

IgE-mediated allergy to local anaesthetics: separating fact from perception: a UK perspective.

Local anaesthetic (LA) agents have been routinely used in dentistry, ophthalmology, minor surgery, and obstetrics since the late nineteenth century. Reports relating to adverse reactions and LA allergy have appeared in the published literature for several years. However, the incidence of true, IgE-mediated LA allergy remains uncertain and is presumed to be very low. We critically reviewed the English language literature on suspected LA allergy and its investigation with the aim of estimating the reported prevalence and analysing the role of different tests currently used to identify and confirm LA allergy. Twenty-three case series involving 2978 patients were identified and analysed. Twenty-nine of these patients had true IgE-mediated allergy to LA, thus confirming the reported prevalence of LA allergy in large series to be <1% (0.97%). The protocols used in the investigation of these patients have also been discussed. Evidence from this review confirms the rarity of IgE-mediated allergy to LA and supports an investigation strategy based on using the clinical history to select patients for skin testing and challenge. We believe that such a triage process would alleviate pressures on allergy services without compromising patient safety.

Management of granulomatous common variable immunodeficiency diagnosed in pregnancy: a case report.

Common variable immunodeficiency (CVID) is a rare condition that affects women of childbearing age with important implications in pregnancy. It is characterised by low immunoglobulins (Igs), poor antibody response and a susceptibility to recurrent infections. The cornerstone of management of CVID is Ig replacement. As the transfer of IgG across the placenta in the third trimester of pregnancy is necessary for protection of the infant in the first months of life, failure to recognise this condition and treat it appropriately can have adverse consequences for the neonate, as well as the mother. Here we describe the complex perinatal medical management of a 34-year-old woman who was diagnosed with CVID in the 26th week of pregnancy.

Quantifying the impact of dyskinesias in PD: the PDYS-26: a patient-based outcome measure.

BACKGROUND: Drug-induced dyskinesias are a common and disabling clinical problem in the long-term management of Parkinson disease (PD). Their management and the development of new treatments rely on rigorous and meaningful dyskinesia measurement. Although clinician-based approaches exist, patient-based measures are limited. METHOD: Potential rating scale items concerning daily activities affected by dyskinesias were generated from patients, literature review, and expert opinion. The resulting 42-item questionnaire was administered to 98 patients known to have problematic dyskinesias; 72 patients were invited to complete it twice for test-retest reliability (trt). Rasch analysis guided scale development. Results were cross-validated using traditional psychometric methods by examining scaling assumptions (item means and variances, item-total correlations), reliability (Cronbach alpha, trt), and validity (factor analysis). External validation was performed against standard dyskinesia measures: blinded video rating using modified Goetz and Abnormal Involuntary Movements Scales (AIMS), and Unified PD Rating Scale (UPDRS) questions 32-34. RESULTS: Response rates were high. Fourteen items were removed because of high missing data. The remaining items were Rasch analyzed. Two items were removed because of misfit. The resulting 26 items formed a clinically and statistically conformable set. Traditional psychometric criteria were satisfied and external validation showed good correlation with the UPDRS items and moderate to good correlation with objective dyskinesia measures. CONCLUSION: The 26-item Parkinson Disease Dyskinesia Scale (PDYS-26) satisfied multiple criteria for reliable and valid measurement. Correlations with objective measures suggest that it captures related but not identical constructs. As a patient-derived scale that generates linear measurements, it could complement existing clinician-based dyskinesia measures.

Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study.

BACKGROUND: The seed powder of the leguminous plant, Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for diseases including parkinsonism. We have assessed the clinical effects and levodopa (L-dopa) pharmacokinetics following two different doses of mucuna preparation and compared them with standard L-dopa/carbidopa (LD/CD). METHODS: Eight Parkinson's disease patients with a short duration L-dopa response and on period dyskinesias completed a randomised, controlled, double blind crossover trial. Patients were challenged with single doses of 200/50 mg LD/CD, and 15 and 30 g of mucuna preparation in randomised order at weekly intervals. L-dopa pharmacokinetics were determined, and Unified Parkinson's Disease Rating Scale and tapping speed were obtained at baseline and repeatedly during the 4 h following drug ingestion. Dyskinesias were assessed using modified AIMS and Goetz scales. RESULTS: Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012). No significant differences in dyskinesias or tolerability occurred. CONCLUSIONS: The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD. Assessment of long term efficacy and tolerability in a randomised, controlled study is warranted.

Low dose quetiapine for drug induced dyskinesias in Parkinson's disease: a double blind cross over study.

OBJECTIVE: Drug induced dyskinesias remain a challenging problem in the long term management of Parkinson's disease (PD). We have assessed the effect of quetiapine on dyskinesias in a double blind placebo controlled cross over study. METHODS: Nine patients with PD were enrolled and received 25 mg of quetiapine or placebo at night for two weeks in prerandomised order, with one week of wash out between treatment periods. Assessments were made using on-off diaries, self assessment of dyskinesias, and L-dopa challenges at baseline and after each treatment period. Videotapes were rated blindly by two raters using modified Abnormal Involuntary Movement Scale and Goetz scores. Patients subsequently went on open label quetiapine at 50 mg/day, for a mean duration of 30 days, and completed the same self assessment forms. RESULTS: During the double blind phase, no significant change in dyskinesias was found on either 25 mg of quetiapine or placebo. Duration of off states and Unified PD Rating Scale motor scores also remained unchanged. Moderate tiredness and daytime sleepiness occurred in two patients on quetiapine. One patient dropped out early for unrelated reasons. Eight patients completed the open label phase. On 50 mg/day of quetiapine, a slight reduction in dyskinesias occurred on some scales. Reduction in dyskinesia severity on visual analogue scales was by 50.1%. Off time was not significantly increased. This improvement was not strongly reflected in patients' overall impression of treatment effect. Drowsiness and daytime sleep episodes led to discontinuation in four patients, after completion of the study, and two additional patients stopped treatment after the study because of lack of effect. CONCLUSION: Our study failed to demonstrate an antidyskinetic effect of low dose (25 mg) quetiapine. The absence of an increase in parkinsonism combined with a possible antidyskinetic effect on higher doses warrants further investigation.

A prospective comparison of simultaneous and sequential live-donor renal transplantation.

BACKGROUND: Traditionally, we have performed live- donor renal transplantations sequentially with a cold ischemic time (preservation time) of approximately 3 hr. By performing live-donor renal transplantations simultaneously, cold ischemic times can be reduced to 30 min or less. The purpose of this prospective study was to compare clinical outcomes and biologic markers of kidney function between live-donor renal transplantations performed either simultaneously or sequentially. METHODS: Nine consecutive live-donor renal transplantations were performed in a simultaneous manner by two transplant surgeons. For comparison, 18 consecutive live-donor transplantations were performed sequentially by a single surgeon. Donor and recipient demographic factors, before transplantation, were compared. Posttransplantation comparisons included daily serum creatinine measurements for 5 days, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) for 72 hr postoperatively, nuclear glomerular filtration rate (GFR) at 18 hr postoperatively, creatinine clearance at 96 hr postoperatively, and creatinine clearance at 3 and 6 months posttransplantation. RESULTS: There were no differences in donor and recipient demographic factors preoperatively between the two groups. With simultaneous and sequential recipients, only the cold ischemic times were significantly different (simultaneous: mean=23.6 min; sequential: mean=191.7 min; P<0.01). After transplantation, no differences were detected in the daily fall of serum creatinine, nuclear GFR at 18 hr, or creatinine clearance at 96 hr, 3 months, or 6 months. In both groups, urinary NAG excretion reached a peak at 1 hr postoperatively and then slowly returned to baseline by 72 hr. There was no difference in the amount of NAG excretion between the two groups. CONCLUSIONS: Our study found that there is no difference in tubular injury or postoperative GFR in live-donor kidney transplantations performed simultaneously or sequentially. Our findings indicate that a modest prolongation of the cold ischemic time has no detectable influence on posttransplantation renal function for live-donor transplantations.

Skipping of exon 9 of human CFTR in YAC-transgenic mice.

Exon 9 of the human gene CFTR is skipped in some mRNA transcripts in human tissues. The level of skipping correlates with the number of TG's and T's in the 5' splice acceptor of exon 9. Poorly spliced alleles are associated with mild cystic fibrosis related phenotypes. Here we describe transgenic mice carrying a yeast artificial chromosome (YAC) with the intact human gene CFTR. When the YAC carries 10 TG's and 7 T's at the splice acceptor, there is about 50% skipping of exon 9 in most tissues, whereas 12 TG's and 5 T's give about 90% skipping. The level of skipping is quite uniform over many tissues, except the testis, in which there is a much higher level of correct splicing. These mice confirm that the TG(m)T(n) polymorphism has an effect on splicing and should be valuable for studying this phenomenon.

High dose naltrexone for dyskinesias induced by levodopa.

Ten patients with Parkinson's disease and levodopa induced dyskinesias (LIDs) took part in this randomised, placebo controlled, double blind, crossover trial to assess the efficacy and tolerability of high dose oral naltrexone for LIDs in Parkinson's disease. Patients received naltrexone (5 mg/kg/day) or placebo for 2.5 weeks with 1 week wash out in between. Dyskinesias and motor function were assessed with a levodopa challenge, unified Parkinson's disease rating scale (UPDRS), the unified dyskinesia rating scale (UDRS), and patient diaries. Eight patients completed the trial. There was a small reduction in LIDs measured by patient diaries with naltrexone (20.5 (SD 24.9)%) compared with placebo (-4.1 (SD 22.6)%), p<0.05, although no difference was found by other subjective or objective measures. Naltrexone was well tolerated and caused no significant differences in UPDRS motor scores or off time. This study suggests that short term therapy with high dose naltrexone (250-350 mg/day) has no or minimal effect on reducing LIDs in Parkinson's disease.

Intravenous apomorphine therapy in Parkinson's disease: clinical and pharmacokinetic observations.

Six patients with Parkinson's disease and refractory motor fluctuations, with severe subcutaneous (s.c.) nodule formation as a result of long-term s.c. apomorphine infusions, were switched to intravenous (i.v.) therapy via a long-term in-dwelling venous catheter. Five patients were followed-up for a mean of 7 months (range 0.5-18 months). All patients had plasma apomorphine concentrations measured at baseline during s.c. infusions and three had follow-up measurements when stabilized on i.v. therapy, to test the hypothesis that motor fluctuations in these patients are largely due to impaired absorption of apomorphine. The mean i.v. rate of 9.0 mg/h (range 5-14 mg) and 24-h dose of 256.7 mg (range 90-456 mg) of apomorphine were not significantly reduced compared with the s.c. route (9.24 mg/h and 243.4 mg). However, additional oral anti-parkinsonian medication was reduced by a mean of 59%, and 'off' time was virtually eliminated (mean reduction from 5.4 to 0.5 h per day, P< 0.05). There was also a significant reduction in dyskinesias and markedly improved quality of life. Pharmacokinetic analysis demonstrated more reliable and smoother delivery of apomorphine via the i.v. route, although 'off' periods were not always explained by low plasma apomorphine concentrations. Complication rates were high and included three unforeseen hazardous intravascular thrombotic complications, secondary to apomorphine crystal accumulation, necessitating cardiothoracic surgery. We conclude that i.v. apomorphine therapy holds promise as a more effective way of controlling motor fluctuations than the s.c. route. However, further preclinical research is required before i.v. Britaject apomorphine can be recommended for routine clinical practice. Even when stable plasma apomorphine concentrations were achieved, motor fluctuations could not be totally eradicated, suggesting that postsynaptic receptor changes may also play a role in the refractory 'off' periods in these patients.

Low-dose olanzapine for levodopa induced dyskinesias.

OBJECTIVE: To assess the usefulness of low-dose olanzapine (2.5 to 7. 5 mg/day) for Levodopa-induced-dyskinesias (LID) in patients with PD. METHODS: Ten patients with PD and LID took part in this randomized, placebo-controlled, double blind, crossover trial. Patients received a 2-week course of olanzapine or placebo in each treatment phase with 1-week washout in between. Dyskinesias were assessed at baseline and after each treatment period with an acute dopaminergic challenge and unified PD rating scale (UPDRS) questionnaires. Patients also kept on/off and dyskinesia diaries for the last 3 days prior to each assessment. RESULTS: There was a 41% difference in dyskinesia reduction on olanzapine compared to placebo, as measured by objective dyskinesia rating scales (mean percentage reduction abnormal involuntary movement score: 30% versus -11.2%, p < 0.02). Similar differences were demonstrated by patient diaries (mean reduction: 46% versus -2%, p < 0.02) and UPDRS items 32 and 33. Compared with placebo, treatment with olanzapine resulted in significant increases in 'off' time as measured by patient diaries (30% versus 2%) and reported adverse events (1.7 versus 0.1) including increased parkinsonism (1.1 versus 0.1) and a nonsignificant reported increase in drowsiness. CONCLUSIONS: Low-dose olanzapine is effective in reducing dyskinesias in PD, but even at very low doses can result in unacceptable increases in parkinsonism and 'off' time.