PARENTS 2 study: consensus report for parental engagement in the perinatal mortality review process.

OBJECTIVE: The PARENTS 1 study (Parents' Active Role and ENgagement in The review of their Stillbirth/perinatal death) found that parents would endorse the opportunity to give feedback into the perinatal mortality review (PNMR) process. In subsequent focus groups, healthcare professionals were positive about parental engagement, although they considered that there may be significant challenges. The objective of this study was to develop core principles and recommendations for parental engagement in PNMR in the UK. METHODS: A two-round Delphi technique was followed to reach consensus on core principles for parental engagement in the PNMR process; Round 1 included a national consensus workshop and Round 2 an online questionnaire. The consensus meeting was attended by a national panel of stakeholders (clinical and academic experts, parent advocates, managers and commissioners) in stillbirth and neonatal and bereavement care. To develop recommendations for parental engagement, participants discussed four key areas comprising: communication with parents, including receiving feedback; the format of the PNMR meeting; the parental engagement pathway; and challenging aspects of engaging with parents in reviews. Content analysis was conducted to generate recommendations from the meeting for a subsequent anonymous web-based survey. Attendees of the consensus workshop and members of the PARENTS 2 Project Advisory Board were asked to rank recommendations using a 9-point Likert scale from 1 (not important) to 9 (critically important). It had been agreed a priori, in compliance with established Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria, that 'consensus' would be achieved if over 70% of participants scored the principle as 'critical' (score of 7-9) and fewer than 15% scored the principle as 'not important' (score of 1-3). Principles for which consensus was achieved were included in the core recommendations. RESULTS: Of the 29 invited stakeholders, 22 participated in the consensus meeting and 25 (86% response rate) in the subsequent online questionnaire in June 2017. Consensus was agreed on 12 core principles. Of the 25 participants, 96% agreed that a face-to-face explanation of the PNMR process was of critical importance, 72% considered that parents should be offered the opportunity to nominate a suitable advocate, 92% believed that responses to parents' comments should be formally documented, 96% indicated that it was vital for action plans to be translated into lessons learnt and that this process should be monitored, and 100% of stakeholders voted that a plain-English summary should be produced for the parents following the meeting. There was good agreement on a further seven principles. CONCLUSIONS: Key national stakeholders were unanimously supportive of parental engagement in the PNMR process and agreed on core principles to make this process feasible, meaningful and robust. A 6-month pilot of parental engagement in the PNMR process (PARENTS 2 study) in two UK units took place after the consensus on core principles. In collaboration with the National Perinatal Epidemiology Unit, the findings will inform the national standardized PNMR tool. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Parents' and healthcare professionals' experiences of care after stillbirth in low- and middle-income countries: a systematic review and meta-summary.

BACKGROUND: Stillbirth has a profound impact on women, families, and healthcare workers. The burden is highest in low- and middle-income countries (LMICs). There is need for respectful and supportive care for women, partners, and families after bereavement. OBJECTIVE: To perform a qualitative meta-summary of parents' and healthcare professionals' experiences of care after stillbirth in LMICs. SEARCH STRATEGY: Search terms were formulated by identifying all synonyms, thesaurus terms, and variations for stillbirth. Databases searched were AMED, EMBASE, MEDLINE, PsychINFO, BNI, CINAHL. SELECTION CRITERIA: Qualitative, quantitative, and mixed method studies that addressed parents' or healthcare professionals' experience of care after stillbirth in LMICs. DATA COLLECTION AND ANALYSIS: Studies were screened, and data extracted in duplicate. Data were analysed using the Sandelowski meta-summary technique that calculates frequency and intensity effect sizes (FES/IES). MAIN RESULTS: In all, 118 full texts were screened, and 34 studies from 17 countries were included. FES range was 15-68%. Most studies had IES 1.5-4.5. Women experience a broad range of manifestations of grief following stillbirth, which may not be recognised by healthcare workers or in their communities. Lack of recognition exacerbates negative experiences of stigmatisation, blame, devaluation, and loss of social status. Adequately developed health systems, with trained and supported staff, are best equipped to provide the support and information that women want after stillbirth. CONCLUSIONS: Basic interventions could have an immediate impact on the experiences of women and their families after stillbirth. Examples include public education to reduce stigma, promoting the respectful maternity care agenda, and investigating stillbirth appropriately. TWEETABLE ABSTRACT: Reducing stigma, promoting respectful care and investigating stillbirth have a positive impact after stillbirth for women and families in LMICs.

All bereaved parents are entitled to good care after stillbirth: a mixed-methods multicentre study (INSIGHT).

OBJECTIVE: To understand challenges in care after stillbirth and provide tailored solutions. DESIGN: Multi-centre case study. SETTING: Three maternity hospitals. POPULATION: Parents with a stillborn baby, maternity staff. METHODS: Thematic analysis of parent interviews and staff focus groups and service provision investigation. OUTCOMES: 1 Themes; 2 Triangulation matrix; 3 Recommendations. RESULTS: Twenty-one women, 14 partners, and 22 staff participated. Service Provision: Care for parents after stillbirth varies excessively; there are misconceptions; post-mortem does not delay follow-up. PRESENTATION: Women 'do not feel right' before stillbirth; their management is haphazard and should be standardised. DIAGNOSIS: Stillbirth is an emergency for parents but not always for staff; communication can seem cold; well-designed bereavement space is critical. Birth: Staff shift priorities to mother and future, but for parents their baby is still a baby; parents are not comfortable with staff recommending vaginal birth as the norm; there are several reasons why parents ask for a caesarean; better care involves clear communication, normal behaviour, and discussion of coping strategies. Post-mortem: Parents are influenced by discussions with staff. Staff should 'sow seeds', clarify its respectful nature, delineate its purpose, and explain the timescale. FOLLOW-UP: It is not standardised; parents wish to see their multi-professional team. CONCLUSIONS: There is unacceptable variation in care after stillbirth, and insensitive interactions between staff and bereaved parents. Understanding parents' needs, including why they ask for caesarean birth, will facilitate joint decision-making. Every bereaved parent is entitled to good, respectful care. TWEETABLE ABSTRACT: Care too varied & interactions often insensitive after stillbirth; national pathway & training urgently needed PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? Previous studies have shown that improving care after stillbirth is important for families. We investigated the opinions of bereaved parents and maternity staff to find ways to improve care. At three hospitals in 2013, all women who experienced a stillbirth were invited to an interview along with their partners. Thirty-five parents of 21 babies agreed to participate. Twenty-two obstetricians and midwives took part in focus group discussions. What were the main findings? Care was often not as good as it should and could be. Communication with parents was not always as sensitive as they would have liked because staff did not have appropriate training. Some women reported they did not 'feel right' before going to hospital. Once they arrived, there was no standard approach to how care was given. Sometimes there were long delays before the death of the baby was confirmed and action was taken. After it had been confirmed that the baby had died, staff focussed on the mothers' needs, but the parents' priorities were still with their baby. There were several reasons why parents asked for a caesarean birth that staff had not considered. Staff influenced parents' decisions about post-mortem examinations. Parents found it helpful when staff explained the respectful nature and purpose of the examination. After discharge from hospital, there was no consistent plan for how follow-up care would be given. Parents would have liked more information about their next hospital appointment. What are the limitations of the work? The parents interviewed depended on their memories of the details of the care, which happened some time ago. In staff group discussions, junior doctors may not have spoken openly because there were senior doctors present. Further research is necessary to understand and improve care globally. What is the implication for parents? Every bereaved parent is entitled to the best possible care after stillbirth, but some do not get good care. Parents and staff made suggestions that can help to develop processes for how care is given after stillbirth. These suggestions can also inform staff training, so that every single parent is treated respectfully and participates in decision making.

Care in subsequent pregnancies following stillbirth: an international survey of parents.

OBJECTIVE: To assess the frequency of additional care, and parents' perceptions of quality, respectful care, in pregnancies subsequent to stillbirth. DESIGN: Multi-language web-based survey. SETTING: International. POPULATION: A total of 2716 parents, from 40 high- and middle-income countries. METHODS: Data were obtained from a broader survey of parents' experiences following stillbirth. Data were analysed using descriptive statistics and stratified by geographic region. Subgroup analyses explored variation in additional care by gestational age at index stillbirth. MAIN OUTCOME MEASURES: Frequency of additional care, and perceptions of quality, respectful care. RESULTS: The majority (66%) of parents conceived their subsequent pregnancy within 1 year of stillbirth. Additional antenatal care visits and ultrasound scans were provided for 67% and 70% of all parents, respectively, although there was wide variation across geographic regions. Care addressing psychosocial needs was less frequently provided, such as additional visits to a bereavement counsellor (10%) and access to named care provider's phone number (27%). Compared with parents whose stillbirth occurred at ≤ 29 weeks of gestation, parents whose stillbirth occurred at ≥ 30 weeks of gestation were more likely to receive various forms of additional care, particularly the option for early delivery after 37 weeks. Around half (47-63%) of all parents felt that elements of quality, respectful care were consistently applied, such as spending enough time with parents and involving parents in decision-making. CONCLUSIONS: Greater attention is required to providing thoughtful, empathic and collaborative care in all pregnancies following stillbirth. Specific education and training for health professionals is needed. TWEETABLE ABSTRACT: More support for providing quality care in pregnancies after stillbirth is needed. PLAIN LANGUAGE SUMMARY: Study rationale and design More than two million babies are stillborn every year. Most parents will conceive again soon after having a stillborn baby. These parents are more likely to have another stillborn baby in the next pregnancy than parents who have not had a stillborn baby before. The next pregnancy after stillbirth is often an extremely anxious time for parents, as they worry about whether their baby will survive. In this study we asked 2716 parents from 40 countries about the care they received during their first pregnancy after stillbirth. Parents were recruited mainly through the International Stillbirth Alliance and completed on online survey that was available in six languages. Findings Parents often had extra antenatal visits and extra ultrasound scans in the next pregnancy, but they rarely had extra emotional support. Also, many parents felt their care providers did not always listen to them and spend enough time with them, involve them in decisions, and take their concerns seriously. Parents were more likely to receive various forms of extra care in the next pregnancy if their baby had died later in pregnancy compared to earlier in pregnancy. Limitations In this study we only have information from parents who were able and willing to complete an online survey. Most of the parents were involved in charity and support groups and most parents lived in developed countries. We do not know how well the findings relate to other parents. Finally, our study does not include parents who may have tried for another pregnancy but were not able to conceive. Potential impact This study can help to improve care through the development of best practice guidelines for pregnancies following stillbirth. The results suggest that parents need better emotional support in these pregnancies, and more opportunities to participate actively in decisions about care. Extra support should be available no matter how far along in pregnancy the previous stillborn baby died.

Dictyostelium, a microbial model for brain disease.

BACKGROUND: Most neurodegenerative diseases are associated with mitochondrial dysfunction. In humans, mutations in mitochondrial genes result in a range of phenotypic outcomes which do not correlate well with the underlying genetic cause. Other neurodegenerative diseases are caused by mutations that affect the function and trafficking of lysosomes, endosomes and autophagosomes. Many of the complexities of these human diseases can be avoided by studying them in the simple eukaryotic model Dictyostelium discoideum. SCOPE OF REVIEW: This review describes research using Dictyostelium to study cytopathological pathways underlying a variety of neurodegenerative diseases including mitochondrial, lysosomal and vesicle trafficking disorders. MAJOR CONCLUSIONS: Generalised mitochondrial respiratory deficiencies in Dictyostelium produce a consistent pattern of defective phenotypes that are caused by chronic activation of a cellular energy sensor AMPK (AMP-activated protein kinase) and not ATP deficiency per se. Surprisingly, when individual subunits of Complex I are knocked out, both AMPK-dependent and AMPK-independent, subunit-specific phenotypes are observed. Many nonmitochondrial proteins associated with neurological disorders have homologues in Dictyostelium and are associated with the function and trafficking of lysosomes and endosomes. Conversely, some genes associated with neurodegenerative disorders do not have homologues in Dictyostelium and this provides a unique avenue for studying these mutated proteins in the absence of endogeneous protein. GENERAL SIGNIFICANCE: Using the Dictyostelium model we have gained insights into the sublethal cytopathological pathways whose dysregulation contributes to phenotypic outcomes in neurodegenerative disease. This work is beginning to distinguish correlation, cause and effect in the complex network of cross talk between the various organelles involved. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.

Familial searching: a specialist forensic DNA profiling service utilising the National DNA Database to identify unknown offenders via their relatives--the UK experience.

The National DNA Database (NDNAD) of England and Wales was established on April 10th 1995. The NDNAD is governed by a variety of legislative instruments that mean that DNA samples can be taken if an individual is arrested and detained in a police station. The biological samples and the DNA profiles derived from them can be used for purposes related to the prevention and detection of crime, the investigation of an offence and for the conduct of a prosecution. Following the South East Asian Tsunami of December 2004, the legislation was amended to allow the use of the NDNAD to assist in the identification of a deceased person or of a body part where death has occurred from natural causes or from a natural disaster. The UK NDNAD now contains the DNA profiles of approximately 6 million individuals representing 9.6% of the UK population. As the science of DNA profiling advanced, the National DNA Database provided a potential resource for increased intelligence beyond the direct matching for which it was originally created. The familial searching service offered to the police by several UK forensic science providers exploits the size and geographic coverage of the NDNAD and the fact that close relatives of an offender may share a significant proportion of that offender's DNA profile and will often reside in close geographic proximity to him or her. Between 2002 and 2011 Forensic Science Service Ltd. (FSS) provided familial search services to support 188 police investigations, 70 of which are still active cases. This technique, which may be used in serious crime cases or in 'cold case' reviews when there are few or no investigative leads, has led to the identification of 41 perpetrators or suspects. In this paper we discuss the processes, utility, and governance of the familial search service in which the NDNAD is searched for close genetic relatives of an offender who has left DNA evidence at a crime scene, but whose DNA profile is not represented within the NDNAD. We discuss the scientific basis of the familial search approach, other DNA-based methods for eliminating individuals from the candidate lists generated by these NDNAD searches, the value of filtering these lists by age, ethnic appearance and geography and the governance required by the NDNAD Strategy Board when a police force commissions a familial search. We present the FSS data in relation to the utility of the familial searching service and demonstrate the power of the technique by reference to casework examples. We comment on the uptake of familial searching of DNA databases in the USA, the Netherlands, Australia, and New Zealand. Finally, following the adverse ruling by the European Court of Human Rights against the UK in regard to the S & Marper cases and the consequent introduction of the Protection of Freedoms Act (2012), we discuss the impact that changes to regulations concerning the storage of DNA samples will have on the continuing provision of familial searching of the National DNA Database in England and Wales.

Five things physicians and patients should question in hospice and palliative medicine.

Overuse or misuse of tests and treatments exposes patients to potential harm. The American Board of Internal Medicine Foundation's Choosing Wisely® campaign is a multiyear effort to encourage physician leadership in reducing harmful or inappropriate resource utilization. Via the campaign, medical societies are asked to identify five tests or procedures commonly used in their field, the routine use of which in specific clinical scenarios should be questioned by both physicians and patients based on the evidence that the test or procedure is ineffective or even harmful. The American Academy of Hospice and Palliative Medicine (AAHPM) was invited, and it agreed to participate in the campaign. The AAHPM Choosing Wisely Task Force, with input from the AAHPM membership, developed the following five recommendations: 1) Don't recommend percutaneous feeding tubes in patients with advanced dementia; instead, offer oral-assisted feeding; 2) Don't delay palliative care for a patient with serious illness who has physical, psychological, social, or spiritual distress because they are pursuing disease-directed treatment; 3) Don't leave an implantable cardioverter-defibrillator activated when it is inconsistent with the patient/family goals of care; 4) Don't recommend more than a single fraction of palliative radiation for an uncomplicated painful bone metastasis; and 5) Don't use topical lorazepam (Ativan®), diphenhydramine (Benadryl®), and haloperidol (Haldol®) (ABH) gel for nausea. These recommendations and their supporting rationale should be considered by physicians, patients, and their caregivers as they collaborate in choosing those treatments that do the most good and avoid the most harm for those living with serious illness.

Investigating pain in heart failure patients: the pain assessment, incidence, and nature in heart failure (PAIN-HF) study.

BACKGROUND: Patients with advanced heart failure (HF) have high rates of pain and other symptoms that diminish quality of life. We know little about the characteristics and correlates of pain in patients with advanced HF. METHODS AND RESULTS: We identified pain prevalence, location, character, severity, frequency, and correlates in 347 outpatients with advanced HF enrolled from hospices and clinics. We evaluated the correlation of pain with HF-related quality of life, mortality, symptoms and health problems, and current treatments for pain. Pain at any site was reported by 293 patients (84.4%), and 138 (39.5%) reported pain at more than one site. The most common site of pain was the legs below the knees (32.3% of subjects). Pain interfered with activity for 70% of patients. Pain was "severe" or "very severe" for 28.6% of subjects with chest pain, and for 38.9% of those with other sites of pain. The only medication reported to provide pain relief was opioids, prescribed for 34.1% of subjects (P = .001). The strongest predictors of pain were degenerative joint disease (DJD) (odds ratio [OR] 14.95, 95% confidence interval [CI] 3.9-56.0; P < .001), other arthritis (OR 2.8, 95% CI 1.20-6.62; P = .017), shortness of breath (OR 3.27, 95% CI 1.47-7.28; P = .004), and angina pectoris (OR 3.38, 95% CI 1.30-8.81; P = .013). CONCLUSIONS: Pain occurred at multiple sites in patients with advanced HF. Pain correlated with DJD or other arthritis, shortness of breath, and angina. Only opioid analgesics provided relief of pain. Future research should evaluate the etiology of and interventions to manage pain in patients with HF.

Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference.

BACKGROUND: Millions of patients are discharged from intensive care units annually. These intensive care survivors and their families frequently report a wide range of impairments in their health status which may last for months and years after hospital discharge. OBJECTIVES: To report on a 2-day Society of Critical Care Medicine conference aimed at improving the long-term outcomes after critical illness for patients and their families. PARTICIPANTS: Thirty-one invited stakeholders participated in the conference. Stakeholders represented key professional organizations and groups, predominantly from North America, which are involved in the care of intensive care survivors after hospital discharge. DESIGN: Invited experts and Society of Critical Care Medicine members presented a summary of existing data regarding the potential long-term physical, cognitive and mental health problems after intensive care and the results from studies of postintensive care unit interventions to address these problems. Stakeholders provided reactions, perspectives, concerns and strategies aimed at improving care and mitigating these long-term health problems. MEASUREMENTS AND MAIN RESULTS: Three major themes emerged from the conference regarding: (1) raising awareness and education, (2) understanding and addressing barriers to practice, and (3) identifying research gaps and resources. Postintensive care syndrome was agreed upon as the recommended term to describe new or worsening problems in physical, cognitive, or mental health status arising after a critical illness and persisting beyond acute care hospitalization. The term could be applied to either a survivor or family member. CONCLUSIONS: Improving care for intensive care survivors and their families requires collaboration between practitioners and researchers in both the inpatient and outpatient settings. Strategies were developed to address the major themes arising from the conference to improve outcomes for survivors and families.

Epidemiology of hospitalization due to alcohol-related harm: evidence from a Scottish cohort study.

OBJECTIVE: To examine a broad range of risk factors and their association with alcohol-related hospital admissions in a Scottish general population. DESIGN: Observational record-linkage study in Scotland from 1998 to 2008 involving 8305 respondents aged 16-74 years who participated in the 1998 Scottish Health Survey. Outcome was defined as first-time hospital admission with at least one alcohol-related diagnosis. METHODS: Cox proportional hazards modelling was applied to estimate the hazard ratio (HR) of first-time hospitalization with an alcohol-related condition associated with a range of behavioural, social and biological risk factors. FINDINGS: In total, 287 (3.4%) respondents experienced at least one alcohol-related hospitalization during the observation period. Moderate to excessive drinking was the strongest predictor of subsequent admission to hospital with an alcohol-related diagnosis, with clear evidence of a dose - response relationship. Moderate and heavy smoking were also significant predictors of subsequent admission to hospital with an alcohol-related problem. Social factors - such as being in receipt of income-related benefits [HR 1.68, 95% confidence interval (CI) 1.25-2.28]; being retired or economically inactive; and being separated, divorced or widowed (HR 2.34, 95% CI 1.70-3.22) - were also significant predictors of alcohol-related hospitalization. CONCLUSIONS: Moderate and higher levels of weekly alcohol consumption, moderate to heavy smoking, economic circumstances and marital status are the main risk factors for alcohol-related hospitalization in the Scottish population. These findings add to the evidence that population-based strategies are needed to limit alcohol-related morbidity.

Managing cardiac devices near the end of life: a survey of hospice and palliative care providers.

Implantable cardioverter defibrillators (ICDs) and pacemakers may change the character of an individual's eventual death. The objective of this study was to explore hospice and palliative care provider attitudes and experience in managing ICDs and pacemakers for patients near the end of life. A voluntary survey was distributed to session attendees at a national conference. Doctors and nurses surveyed overwhelmingly agreed it is appropriate to disable these devices in a terminally ill patient who does not wish to be resuscitated or prolong life. However, respondents emphasized a less defined burden for pacemakers. Respondents also reported limited involvement in such cases and few institutional protocols. As more terminal patients have these devices, research and education on device management protocols/guidelines and on provider communication skills are critical.

The utility of transoesophageal echocardiography to determine management in suspected embolic stroke.

BACKGROUND: Assessment for source of stroke is a common indication for transoesophageal echocardiography (TOE). Although an abnormality is frequently found, it remains uncertain how frequently the findings alter patient management. Also, the role of transthoracic echocardiography (TTE) prior to or instead of TOE is not well defined. We sought to determine the use of TTE prior to TOE, the outcome of the TOE and its impact on management. METHODS: We retrospectively reviewed the records and echocardiography results of 100 consecutive patients who underwent TOE for any reason at a tertiary hospital. In 35 subjects (35%), the indication was evaluation for source of stroke. Among these, we determined clinical risk factors for stroke, if a TTE was performed prior to their TOE, the results of the TOE and its effect on management. RESULTS: The mean age of the stroke patients was 64.6 years (17-90) and 49% were women. Eighty per cent had at least one risk factor for stroke and 17% had atrial fibrillation. A TTE, performed in 40% prior to the TOE, found an abnormality in 14% (2/14). The TOE showed an abnormality in 71% of patients; 54% had aortic atheroma; 17% PFO; 14% spontaneous echo contrast; 6% left atrial appendage thrombus, 3% left ventricular thrombus and 3% vegetation. In only one patient (3%) the management was altered based on the abnormal TOE findings. CONCLUSION: An abnormality on TOE, although common (71%) and more sensitive than TTE, altered management in only 3% of subjects referred for stroke assessment. Its role requires further consideration.

Extracting coupling and loss coefficients from a ring resonator.

A method is developed for extracting the coupling and loss coefficients of ring resonators from the peak widths, depths, and spacings of the resonances of a single resonator. Although the formulas used do not distinguish which coefficient is coupling and which is loss, it is shown how these coefficients can be disentangled based on how they vary with wavelength or device parameters.

Investigating pain in heart failure patients: rationale and design of the Pain Assessment, Incidence & Nature in Heart Failure (PAIN-HF) study.

BACKGROUND: Heart failure is a major cause of morbidity and mortality and is increasing in prevalence. Treatments for heart failure permit a growing number of persons to live with the illness for many years. The burden of symptoms in persons with advanced heart failure is high. Fatigue, limited exertion, dyspnea, and depression are commonly associated with heart failure, but pain is common as well. METHODS AND RESULTS: Although it is known that underlying comorbidities modify the response to and experience of pain, the interaction between pain and the clinical syndrome of heart failure has not been studied to date. The Pain Assessment, Incidence & Nature in Heart Failure (PAIN-HF) study will evaluate pain in patients with advanced heart failure. Specifically, PAIN-HF will examine the anatomical location of pain, prevalence of pain, its association with aspects of patients' heart failure and comorbid conditions, and its relation to interventions and medications to treat pain. CONCLUSIONS: This study to identify the nature, incidence, and character of pain is an important step in relieving distress and discomfort in persons with heart failure.

Perineural spread of facial squamous cell carcinoma.

A 64 year old man presented with progressive impairment of right sided cranial nerves. Chronic immunosuppression for renal transplantation had resulted in multiple squamous cell carcinomata of the head and neck. Magnetic resonance imaging and subsequent right facial nerve biopsy confirmed perineural spread of a squamous cell carcinoma as the cause of the multiple cranial neuropathies.