2018

Background

Arrhythmogenic Right Ventricular Dysplasia (ARVD) was first described in a case series of 24 patients back in 1982 ¹, ². Since then, our understanding of its pathophysiology has improved dramatically, with dedicated guidelines and literature being published to help with both diagnosis and management. Prompt diagnosis remains a struggle in majority of developing countries, including Malaysia, where resources and expertise are scarce, and obtaining both cardiac magnetic resonance imaging or endomyocardial biopsies remain a challenge. Furthermore, diagnosis is difficult in most cases as clinical presentation may vary and wide range of clinical mimics exist. We present a unique case of ARVD, diagnosed early through the knowledge of having a deceased sibling, whom had endomyocardial tissue characterization performed in the past confirming the presence of the disease in a first degree relative.

Case Report

A 21-year old gentleman presented to the emergency department following an episode of loss of consciousness, lasting approximately 30 minutes which recovered spontaneously. He denies having any similar episodes in the past. However, he had been suffering from reduced exercise tolerance, with a New York Heart Association (NYHA) Class II, over the past 1 year. He had no known medical illness at the time but smoked 6 cigarettes a day for the past 7 years.

His vital signs were stable on arrival, with a heart rate of 73 beats per minute, regular in rhythm, a blood pressure of 143/84 mmHg, respiratory rate of 19 breaths per minute, temperature of 37 degrees Celcius and oxygen saturation of 98% on room air. Cardio-respiratory examination revealed no murmurs, and normal heart and breath sounds. There were no carotid bruits audible. There was no evidence of any neurological deficits on neurological examination.

Figure 1 – Chest radiography demonstrative cardiomegaly

Figure 2 – Electrocardiogram revealing T-wave inversions in leads V2 to V4 with ventricular ectopic beats

Chest radiography revealed cardiomegaly (Figure 1). Electrocardiogram (ECG) revealed deep T-wave inversions in leads V2 to V4, with ventricular ectopic beats (Figure 2). Due to the suspicious-looking ECG, a serum Troponin-I test was performed, which was elevated at 480 pg/ml. The patient was treated for acute coronary syndrome complicated by cardiac syncope, and was later referred to the medical team for further inpatient management.

However, on further history, it was revealed that the patient had a sibling who had died from an unknown cause, 5 years prior. His younger brother, 14 years of age at the time, was brought in after collapsing whilst playing basketball in a school compound. Unfortunately, he was pronounced dead on arrival to the clinic. A post-mortem was performed due to the unexpected nature of the event. Fortunately, our patient was brought into the same hospital as his sibling, allowing us to trace previous autopsy reports and images, with consent.

Macroscopic examination of the right ventricular cavity revealed epicardial surfaces showing infiltration of excessive fat tissue with nodular fibrosis. The right ventricular cavity appeared dilated and cut sections showed diffuse transmural fibro-fatty replacement of the right ventricular free wall, extending into the endocardium and involving the right ventricular septum (Figure 3a).

Figure 3a – Macroscopic examination of right ventricular cavity, which was dilated and showing signs of transmural fibrofatty infiltration. Figure 3b – Histological evidence of focal lymphocytic infiltration, myocyte hypertrophy and degenerative cytoplasmic changes.

Histology revealed extensive fatty infiltration with interstitial fibrosis, primarily in the epicardium. There was associated myocyte loss with hypertrophy of cardiac muscle cells remaining (Figure 3b). Both macroscopic and microscopic findings were suggestive of ARVD.

After learning of the autopsy results, changes in clinical management took place, with priorities being shifted towards obtaining an echocardiogram, cardiac Magnetic Resonance Imaging (MRI) and Holter recording, as opposed to diagnostic angiography and coronary evaluation. Echocardiography revealed an ejection fraction of 25 to 30%, with evidence of left ventricular dyssynchrony, a tethered posterior mitral valve leaflet with mild eccentric regurgitation, consistent with dilated cardiomyopathy.

Cardiac MRI revealed both left and right ventricular dilatation, end diastolic dimensions being 5.8 cm and 4.4 cm and end-diastolic volume being 153 ml/m² and 149 ml/m² respectively, with evidence of bi-ventricular dyssynchrony. Left ventricular and right ventricular ejection fraction measured 31% and 8% respectively. There was also bilateral atrial dilatation. Gadolinium study revealed late enhancement in areas of the right ventricular wall (Figure 4).

Figure 4 – Four-chamber view of cardiac magnetic resonance imaging revealing evidence of right ventricular enhancement following gadolinium study.

A 24-hours Holter recording revealed up to significant ventricular ectopic burden, many of which were bigeminy and trigeminy in nature. In view of symptoms and the above investigative findings, the patient consented to insertion of an implantable cardiac defibrillator (ICD) 4 weeks later in our centre, and has since recovered well with regular monitoring.

Discussion

ARVD is rare, prevalence ranging between 1 in 2000 to 1 in 5000 (taking into consideration geographical variations) and accounts for 5% of deaths in young adults and 25% of deaths in athletes ³, ⁴. Typical histopathological feature of ARVD is the loss of right ventricular myocardium, replaced heavily by fibro-fatty tissue. Less commonly, left ventricle involvement have been reported ⁵, ⁶. Consequence from such pathological process leads to arrhythmias, heart failure and more importantly sudden cardiac death (SCD), with mortality rate ranging between 4 to 20% and peaking in the fourth decade, equally in both males and females ⁵.

Diagnosis is difficult in most cases as clinical presentation may vary and wide range of clinical mimic exist, including myocarditis, sarcoidosis, Brugada syndrome, idiopathic RV outflow tract VT and congenital heart diseases with right chambers overload amongst others ⁶. A Diagnostic Criteria was developed in 1994, with further modification in 2010 to assist in the diagnosis of ARVD and although the criterion has been shown to be specific, it lacks sensitivity ⁷. Nevertheless, it highlights several key areas, a mix of clinical, radiological, histological and electrophysiological features, that assist in diagnosis ⁴.

Despite not having any further evaluation or investigations performed at the time of presentation, in view of circumstances, our patient’s deceased sibling had supportive histological features. Therefore, our patient met the major criteria of having a first degree relative affected by the disease. More importantly, the suspicious family history had prompted further evaluation for the disease, allowing the medical team to prioritize investigations performed, specifically the Cardiac MRI and Holter evaluation. This led to early risk stratification and decision to implant an ICD for the patient, as he was deemed at high risk of SCD.

Conclusion

This case highlights the importance of good history taking, including a detailed family history of SCD or cardiac-related diseases, especially in young patients presenting with typical cardiac-related symptoms. Early identification and appreciation of risk will subsequently affect the outcomes of such patients affected by ARVD. Furthermore, important diagnosis like ARVD will have implications to relatives and future off-springs, further highlighting the need for detailed evaluation of patients similar to ours described in the above case report.

In a contemporary medical practice caring for complex patients with utmost efficiency, primary care physicians and specialists are expected to work together to organize a seamless transfer from acute to chronic care. The job of the generalist is to sort out and integrate different recommendations from numerous specialists and apply those strategies in the care of the patient long after the index admission. During such interactions with specialists, primary care physicians often realize the impact of differing viewpoints on the overall patient care well beyond the anticipated time frame, whether acute or chronic. To that end, and to better inform such recommendations, this paper proposes the top 10 things primary care physicians wish every specialist knew when addressing problems on the busy hospital ward.

1. Organ-systems work together, not independently

As we see in examples such as the cardio-renal syndrome, hepato-renal syndrome, or hepato-pulmonary syndrome, as the patient gets sicker, the interaction of organ-systems begins to dominate. Indeed, predicting the outcome in comorbid conditions depends not only on understanding the culprit organ, but rather quantifying a complicated interaction of multiple organ-systems. For example, the ADHERE registry algorithm shows the most important predictor for in-hospital death in heart failure patients is not the cardiac function per se, but rather creatinine clearance and BUN^[1]. In other words, the commonly used comments from a specialist asked to evaluate their system of expertise, ‘such and such organ is fine’, might soon become irrelevant and obsolete in the context of multiple complex systems.

Moreover, recent research revealed that genotype, endotype and phenotype are quite different in COPD and asthma^[2]. Therefore, even though a disease may manifest in a single system, the pathophysiological process from which it arose may have been triggered in different organs.

2. Mortality is not the only outcome measure

Specialists seem to treat all-cause mortality as the most important outcome measure in most cases. Or, they choose strategies based on organ specific survival as an alternative, such as MACE (major adverse cardiac events) or creatinine-doubling time^[3]. Life is far more than just being alive. Subsequently, the quality of life (QOL) measures, which capture patient-centred outcomes, provide insight into the effectiveness of interventions but also their meaningfulness to patients, and such measures are gauging previously uncaptured positive aspects of interventions^[4]. The difficulty of defining well-being remains a challenge for researchers and arises from the differences brought about by cultural and societal elements which are context-bound and unique to each community.

3. ADL is one of the most critical prognostic indicators

New biological markers are numerous around here - new renal injury markers, such as NGAL or KIM, to name a few. But a quick, old-fashioned, bedside assessment can easily reveal impairments in Activities of Daily Living (ADL) at each patient visit; and ADLs by Functional Assessment Measures have been consistently shown as strong outcome predictors in acute and chronic illnesses, especially within elderly populations^[5]. In fact, functional measures were deemed to be as important as other objective measures in some prognoses^[6]; for instance, in the BODE score for COPD survival prediction, the ADL measure carries the same weight as the PFT (Pulmonary Function Test). In the management of elderly patients, hospitalization^[7] and initiation of haemodialysis^[8] significantly influence the worsening of ADLs. In the development of a 1-year mortality index after hospital admissions among elderly patients, ADL was of pivotal importance^[9].

Functional impairment is also a strong indicator for readmission: there is a dose-response correlation of severity of impairment and the risk of readmissions^[10]. Intensifying the in-hospital post-ICU physical and nutritional therapy has been shown to improve many aspects of recovery^[11]. In patients with numerous chronic illnesses, the number of comorbidities strongly correlates with the decline of ADL^[12]. Interventions to maintain pre-hospitalization ADL is important in facilitating recovery from hospitalization, and in one study in-hospital mobility programs helped patients to maintain pre-hospitalization ADL while the usual care group experienced significant decline^[13].

4. Effectiveness, not efficacy, matters most in the real-world

“Doctor, I cannot afford the medicine prescribed to me when I was discharged!” This is oft-repeated in offices of generalist physicians. If a patient cannot afford medication and therefore does not take it, the treatment lacks efficacy. In the inpatient setting, efficacy of intervention determines the outcome since patients are most likely to receive the prescribed intervention. This is not the case in the outpatient setting, and the effectiveness of an intervention depends on many other elements, such as the accuracy of diagnosis, patient compliance to the proven intervention, prescription drug coverage, access to care, and finally, efficacy of the intervention^[14].

5. Mental wellness is essential to physical wellness

Health is not limited to the physical body; it also involves mental wellness. In fact, mental and physical health are inseparable. Naturally, serious illnesses affect mood and cognition: therefore, it is important to acknowledge that mental health issues lie squarely within the spectrum of physical disease management. Generalists can help patients with multiple comorbidities manage depressive symptoms through brief psychological interventions; such symptoms related to cognition and mood are expected consequences of any serious illnesses.

Studies have shown that among elderly patients without dementia at baseline, noncritical hospitalization is associated with the development of cognitive dysfunction^[15]. Among elderly patients, the prevalence of cognitive dysfunction is significantly higher in ADHF (acute decompensated heart failure) admissions^[16] or survivors of severe sepsis^[17]. Depression and depressed mood are prevalent in patients suffering serious illnesses^[18]. New models are emerging to integrate psychotherapy in multiple comorbid patients and have been proven to be effective^[19].

6. Pay heed to illness trajectory

“My grandma has never been the same after her hip surgery. Please fix her!”

Primary care physicians often note a decline in the general function and cognition of their patients after index admissions to the hospital. As noted earlier, acute hospital admissions have a strong independent effect on the severity of disability amongst elderly persons^[20]. The multidimensional frailty score, which incorporates ADL and cognitive function, predicts one-year mortality based on a simple scoring system^[21]. Poor functional status attributes to frailty and has led to poor surgical outcomes in the elderly^[22]. The prevalence of functional impairment steadily increases from 28% in the 2 years prior to death to 56% in the last month of life^[23]. Studies demonstrate that gait speed is an important predictor for survival amongst the elderly^{[24] [25]} as well as grip strength^{[26] [27]}.

Furthermore, elderly patients sustain significant impairments long after the index hospitalization^[28]. Amongst elderly patients discharged from the ICU, more than 50% die within a month^[29]. At one-year follow-up, critical ADL capacity, such as taking medications or shopping, was impaired in more than 70% of ICU survivors who remained ventilated for longer than 48 hours^[30]. Delirium sustains a long-lasting effect even after patients are discharged from the hospital, the longer the duration of delirium, the more sustained is the cognitive impairment^[31].

7. Care for the care-givers

There is increasing evidence that caregivers sustain long lasting effects from patient illnesses. Depressive symptoms increase overall for surviving spouses regardless of hospice use^[32]. The RECOVER study^[33] demonstrated that caregivers suffered from high levels of depressive symptoms up to 1 year after a loved one’s ICU admission. In the era of chronic illnesses, it is essential to be mindful of the contributions made by caregivers in disease management. Tools are widely available for the clinician to assess caregiver burden^[34]. This is important because family-support interventions have been shown to improve the quality of communication and decrease the patient’s length of stay in ICU^[35].

8. ‘Exercise and diet’ trumps ‘medicine and surgery’

The COURAGE trial demonstrated that after 7 years, there is no difference between medical management and percutaneous intervention (PCI) in managing coronary disease^[36]. As time progresses after the initial event, the benefits of surgical intervention become less apparent. Similarly, in the long run, intensive statin therapy has not proven to be of greater clinical significance compared to those receiving moderate levels of statin^[37]. As the saying goes, in the long run, “we are what we eat.” Innumerable studies have shown that diet and physical habits have a lasting effect on the health of individuals^[38]. Bariatric surgery has been demonstrating dramatic and long-lasting effects on diabetes control, while the DiRECT study demonstrated that intensive exercise and diet successfully achieved remission in nearly half of the intervention group, compared to only 4% of controls^[39]. Despite the substantial increase in chronic illnesses that are closely tied to our lifestyle and eating habits, physicians of all specialties are poorly trained to provide nutritional counselling to patients^[40].

9. Whose definition of health matters?

If health is defined, as defined by the WHO, is not simply the lack of illness, but “a state of complete physical, mental and social well-being,” it must incorporate many other elements dictated by societal, cultural, moral and philosophical norms and values. Furthermore, the definition of health and the path to attain it should come from the society and community it reflects, since neither healthcare personnel nor the healthcare industry own health. Therefore, the definition should emerge from community interventions and multidisciplinary groups filled with varied stakeholders, rather than from the ivory tower of healthcare researchers. Therefore, medical decision-making processes are rapidly moving away from the paternalistic approach to consensus-based, collegial decisions. Shared decision-making, informed consent, discussions of different treatment options and acquiring second opinions have become standard practice and reflect the empowerment of patients, and communities, to define their own healthcare. Ultimately, as long as patients are competent, they decide their treatment after consulting with physicians, who advocate for the patients’ goals in care and advise them accordingly.

10. Empower healthcare recipients

In the long-term management of chronic illness, participation of the patient is essential. And transparent communication is pivotal for better participation and shared decision-making^[41]. In the new model of health, healthcare providers must play an active role in advocating for patients and promoting well-being while acknowledging that health is a dynamic concept^[42]; these physicians do not simply “coordinate care.” This shift from the physician-centred to the patient-centred approach, in and of itself, will be empowering for patients.

CONCLUSION

Transition of care is one of the most important steps connecting hospital care to primary care. Those problems currently labelled as miscommunication might be more than just a lack of handoff tools or timely messaging; they rather stem from a difference in priorities and varied interpretations of patients’ problems by these two groups of providers. Many questions remain unanswered when facing the future of collaborative healthcare: what kind of doctors are most suited to address the complex interaction of illnesses involving multiple organs? Who can develop a new framework to capture this dynamic and complex interaction of systems, covering many organs in a single patient? Moreover, the next generation of healthcare providers will need to be trained to bear in mind this fundamental concept of patient management. As the twenty-first century progresses, discoveries within medical science will continue to advance the field further away from the current organ-based specialization to pathophysiology-based specialization. This article advances the discussion on the altering role of generalist physicians and the advice of their specialist colleagues, as together they face more and more changes within the practice of medicine.

Introduction

Epidural anaesthesia is one of the favored and effective treatment options for labour pain. It is usually safe and only a handful situations lead to absolute contraindications to this technique such as patient’s refusal, lack of expertise and equipment, severe coagulopathy and infection at the site of puncture (1). However, as with any other technique and procedure, epidural anaesthesia is not flawless. The side effects and complications include hypotension, pruritus, inadequate analgesia, post puncture headache, nerve damage, infection, and epidural haematoma (1,2). Headache is common in one third of the patients after lumbar puncture however, the frequency is less in epidural anaesthesia as the fluid is injected in and not removed in the latter (3). Accidental dural damage and subsequent headache following epidural anaesthesia is uncommon and is an important cause of morbidity which can limit patient severely. Further, in rarest of rare cases Pneumocephalus can develop after epidural anaesthesia which has rarely been reported. We report a patient who developed Pneumocephalus after receiving epidural anaesthesia for labour pain.

Case Report:

A 39 year old female presented to our Emergency Department with severe headache not responsive to analgesics. The headache started developing 10 to 12 hours after she was given an epidural which was attempted three times for labour pain which was four days prior at a nearby medical center . The severity of the headache did not change with lying or the upright position. She had no symptoms of vomiting, no fever and no confusion. Neurological examination and vital signs were unremarkable. The site of the spinal anaesthesia did not reveal any swelling or any signs of infection. An urgent head CT scan was performed which revealed Pneumocephalus denoted by numerous left fronto-parietal extra axial air locules (Figure 1 and Figure 2). MRI spine revealed mild subcutaneous oedema at the site of the needle insertion without any haemorrhage or collection. The patient was admitted and treated conservatively for six days and follow up serial head CT scans showed complete resorption of the Pneumocephalus and the patient’s symptoms resolved completely. The patient was discharged and the follow up was uneventful.

Figure 1: Pneumocephalus seen as locules of air (black color) in the left fronto-parietal region denoted by arrows (Axial section)

Figure 2: Multiple pockets of air seen in the Saggital section marked by arrows demonstrate the Pneumocephalus.

Discussion:

Pneumocephalus is the presence of air in the intracranial cavity. It can be acute ( less than72 hours ) or delayed (more than 72 hours). The most common site is the frontal region (4). Plain skull x-rays can detect Pneumocephalus of about 2 ml, whereas it requires only 0.5 ml of air to be detected by a CT scan (5). Pneumocephalus is most commonly a result of traumatic brain injury, surgical intervention of the brain or infection (5). Trauma accounts for up to 75% percent of the total cases. Chronic infections of ENT especially otitis media also amounts to a number of significant cases. Surgical procedures of brain, spine and ENT like sinus surgery, nasal polypectomy and nasal septum resection accounts for the causes. The incidence after supratentorial craniotomy has been reported to be 100% (6, 7). However, it is very unusual for pneumocephalus to develop post epidural anaeasthesia possibly due to ball valve mechanism in which the air enters the space through the CSF leakage which allows input but not output. Headache post lumbar puncture and epidural anaesthesia is relatively not uncommon but certain situations may demand a more thoughtful approach (3).

In our patient we suspect there was a puncture of the dura during epidural anaesthesia which led to air being trapped and siphoned upwards in an inverted soda bottle fashion. This is supported by the meta-analysis done by Choi et al. which states the incidence of accidental dural puncture in epidural insertion to be 1.5% and among those 52 % will have post puncture headaches (8). In another extensive study performed over ten years, the overall incidence of accidental dural puncture and postdural puncture headache were 0.32% and 0.38%, respectively (9). The authors further stressed that if more than one attempt was required to identify the epidural space, the accidental dural puncture rate increased to 0.91%. In our patient we witnessed the same wherein three attempts were made to identify the epidural space which increased the risk of dural injury and subsequent leaking. Pneumocephalus usually gets absorbed without any clinical manifestations. The conservative treatment involves placing the patient at rest, avoiding Valsalva manoeuver, administering analgesics. With these measures, reabsorption was observed in 85% of cases after 2–3 weeks (5). Use of oxygen mask, nasal catheter, hyperbaric oxygen sessions and good hydration have also been reported. If conservative measures fail to provide the desired results then specific treatment like a epidural blood patch or even surgical closure of the dural gap is indicated (3, 10).

Physicians pursue the interest that during the hospital stay the best patient care needs to be provided; and achieving that in a short time - as a result the patient is expected to recover from illness and return to normal life.

The ability to prevent possible complications that the patients are exposed to, has always generated ambiguity in the current medical practice, since it is assumed, that the relief of the patients once the treatment is established, should always be the same¹. However, it is the awareness and proper care of comorbidities and the baseline condition of the patients that determine the success rate of the treatment, without requiring additional interventions beyond the ones proposed at the beginning of the treatment ^{2, 3}.

This important factor has generated in practitioners the need to be able to monitor the clinical evolution of the patients. Laboratory tests are an important basis of medical diagnosis, and are frequently used to monitor the clinical progress of the hospitalised patient. The patient clinical state sometimes changes suddenly or continuously; requiring the surveillance of the basic variables such as vital signs. Vital signs monitoring activate a warning signal for the immediate reassessment of the patient and reorient the medical decisions at any moment during the hospitalisation, with the goal of avoiding further deterioration or adequately treating any new disease state that the patient may develop ^{3, 4}.

From that point of view and long time ago the medical community has observed the need to generate a code that could be universal and that could be used as an early warning of the patient worsening. As a result of this situation, in different countries around the world, researchers and clinicians have developed scales, scores, algorithms and others tools to identify early patients in risks to be in critical conditions. Those tools are based on the ability of easy data collection and simple clinical interpretations allowing the clinical personnel to make objective and early assessment of the overall clinical state of the patients ⁴.

These scales or scores are not ideal, since there is no perfect scale, and all have statistical weaknesses either in their sensitivity or specificity. The clinical judgment and the physician experience, added to a score from any of these scales, may guide the path to follow according to the particular scenario to treat the patient illness ⁵.

Selecting the ideal scale to be adopted is one of the controversial topics in which a practitioners and institutions can be involved in. Occasionally other services in the hospital such as clinical laboratory and clinical imaging values play an important role in the process of diagnosis of the disease and are counted in the risk scales making easier to have good standard of care. Scientific studies assess the statistical performance of these scales yield controversial results that sometimes distort or endorse these results ⁵. This is why the decision of the ideal scale is based first on the target population that physicians in charge will care of and select the appropriate scale or score that will be applied, to know the implications of the most representative age group of patients that will be attended and to use scales which data acquisition be a simple and quick task to perform⁶.

Based on that, the Royal College of Physicians of the United Kingdom headed by Bryan Williams and collaborators, and many other researchers worldwide have analysed a significant number of scales on the basis that the scale should use systems (track and trigger warning systems protocol) divided into three types. Single parameter systems, multi-parameter systems, total weighted scoring systems and combined systems ⁶.

The researchers came to the conclusion that the performance of these scales was better than those that conserve the third type of system, since not only the parameters are categorized but also those who develop the scale proposed management to be carried out in an easy, orderly scheme and logical within a framework of independent work or in addition to more robust strategies that involve management schemes within a hospital institutions - the so-called (Rapid Response Systems RRS) ⁷.

For Williams et al, the MEWS changed its name after being accepted by the Royal College of Physicians of the United Kingdom as the NEWS scale with its variables defined as (respiratory rate, oxygen saturation, systolic blood pressure, heart rate, consciousness or new confusion and temperature). This score has been recognized and quickly adopted worldwide. The NEWS has an immediate applicability as a parameter of high sensitivity in the detection of clinical deterioration, despite its known low specificity. Thus inviting the attending physician to approach and reassess the state of the patient. The score makes changes in medical decisions according to the new conditions found during the patient’s assessment⁷.

This kind of scales must be endorsed internationally and be easily replicable by all practitioners who wish to adopt them. This allows other physicians to obtain results when implementing actions, reaching better clinical outcomes similar to clinical studies previously published. In the daily practice and clinical application we find different scenarios to use the scales, where the main problem of its application represent extra costs in lab test or clinical images and the time invested by the practitioners and medical personnel ⁷.

For this reason, the scales for clinical assessment should be easy and flexible to be implemented by any person, ideally for any member of the healthcare team to avoid barriers during the process of data acquisition. From this perspective, the scales that are based on easily collected parameters are the most appropriate, but they are often the scales that suffer the rigors of the biases when they are undervalued or overvalued, just the operability can be affected by personnel knowledge and skill.

The interesting thing about this exercise is to see that the people who have the most continuous contact with the patient, such as the nursing staff, physicians with the practice have the ability to use them in their practice and this would make the scales a valuable resource to perform clinical assessments and achieve the goal proposed.

In this new era where the reincorporation of a patient into daily life in a short time is ideal scenario, the medical and nurse staffs and also service providers seek to alleviate the patient's health breakdown. It is here from the hospital point of view where the proper care not only in the quality of care but also in the prevention of complications plays an important role in the applicability of these early detection scales. This is an invitation to success from its inception and to tend to patients being hospitalized for the minimum time required.

Introduction

With the increasing use of ultrasound as a standard examination in the first trimester, more incidental adnexal masses are detected. The reported incidence of adnexal masses in pregnancy varies, depending on the criteria used to define the mass. A literature review by Goh W. et al., found that 1% of all pregnancies are diagnosed with an adnexal mass ¹. A more recent article has suggested adnexal masses are diagnosed in 5% of all pregnancies ². Simple and functional cysts are very common, and they usually resolve after the first trimester ³. Mature teratomas are by far the most common persistent adnexal masses found in pregnancy ⁸. It has been estimated that up to 5% of adnexal masses in pregnancy are malignant ⁴.

Ovarian cysts are typically asymptomatic, but they can cause pain due to pressure on adjacent organs, rupture, bleeding or torsion. The latter case is a significant health condition which mainly requires emergency surgical intervention. During pregnancy, surgical management of ovarian cyst complications is more difficult and more challenging. This is mainly because of other differential diagnosis causing similar symptoms related to pregnancy such as ectopic pregnancy and miscarriage. In case of surgical intervention, the second trimester of pregnancy is supposed to be the safest window for surgery as the risk for drug-induced teratogenicity is smaller than in the first trimester, most functional cysts have disappeared by then and it is technically less difficult than operating during the third trimester ¹³.

Antenatally, ultrasound is considered to be the best first-line imaging to evaluate adnexal masses ⁵. Ovarian mass characterization into benign, malignant or borderline can be challenging in pregnancy. This is mainly due to the effect of high levels of gestational hormones which can cause decidualisation of the cystic or solid parts of the ovaries. Benign masses can mimic malignant masses due to this pregnancy related phenomena ¹². One of the largest data in literature on ovarian mass characterization is published by the International Ovarian Tumor Analysis group (IOTA). All IOTA studies excluded pregnant women when they developed and validated the rules and models to characterize ovarian masses ^14-17. This limits our knowledge and ability to use these models in pregnant women. It is known that tumour markers may be raised in pregnancy and should therefore not routinely been done ⁷. An alternative diagnostic tool is Magnetic Resonance Imaging (MRI) which is considered to be safe in pregnancy and can be helpful if the ultrasound imaging is inconclusive in evaluating whether a mass is benign or malignant ^{6; 10}. The American College of Gynecology and Obstetrics recommends that pregnant patients should be reviewed on a case-to-case basis and stated that there are no known biological effects of MRI on fetuses. However, Gadolinium, which help in characterizing ovarian masses, should be avoided when examining a pregnant patient ¹¹.

The aim of this retrospective study was to look into characteristics, size and subsequent management of cases of adnexal masses in early pregnancy.

Methods

This was a retrospective study of data collected between 12/01/2014 and 14/11/2016 in the Early Pregnancy and Gynaecology Unit (EPAGU) of a tertiary referral centre (Guy’s and St Thomas’ NHS Trust, GSTT) in central London. The Ultrasound reporting system (Astraia Software Gmbh, Version 1.24.10, Munich, Germany, 2016) was searched for data. Cases included were consecutive. The study was approved as a service evaluation audit by the Clinical Governance team at Guy’s and St Thomas’ NHS Trust. The study included women who were diagnosed with an adnexal mass while having a transvaginal ultrasound scan TVS at or before 15 weeks of gestation. Pregnancy was confirmed by a positive pregnancy test and an intrauterine gestation on transvaginal ultrasound scan. Women who had the first gestational TVS after 15 weeks of gestation, pregnancies of unknown location, ectopic or trophoblastic pregnancies and patients who had ovarian stimulation treatment were all excluded.

Repeat ultrasound scan reports were retrieved from the Astraia system. Further procedures, tests and imaging results were retrieved using the Electronic Patient Reporting system at GSTT (EPR application, iSOFT Group plc., USA, 2004), PACS (GE Medical Systems, Wisconsin, USA, 2006), Badgernet (Clevermed, Client version 2.9.1.0, Edinburgh, UK). We have used the subjective impression of the examiner as the index test. If surgery was performed the final outcome to identify benignity or malignancy was considered to be the histological diagnosis if any removed tissue. Cytology was used for a reference test in two cases when ovarian cysts were aspirated only. Borderline tumours were classified as malignant for statistical analysis. Tumours were classified using the criteria recommended by the World Health Organisation (WHO) ^{9; 10}. All ultrasound scan images were available and reviewed by author TEG to confirm the US finding. For statistical analysis, the SPSS software package was used (version 24 for Windows, Chicago, IL, USA). A two tailed student’s t test was used to compare means in ovarian masses diameters and a p value of less than 0.05 was considered statistically significant.

Results

7150 patients underwent transvaginal scans for early pregnancy in that period. In total 48 cases of women with adnexal masses in pregnancy and completed data were analysed. Seven women have been excluded; one woman being postpartum at the time of the finding of a large endometrioma, five pregnancies due to assisted conception and one woman was found to have a corpus luteum cyst (Figure 1).

Figure 1: Study flow chart.

41 women with 46 ovarian cysts could be included in the study. Two women had bilateral ovarian cysts, one had two ipsilateral cysts and one woman had three ipsilateral cysts. The mean age at the time of detection of the ovarian mass was 30 (95%CI:28-32) (Fig.2).

Figure 2: Age distribution in the study group.

The mean gestation at the time of first ultrasound was 7.4 weeks (95%CI:6.6-8.3). The mean diameter of ovarian cysts measured 47.7mm (95%CI:39.9-55.4). In 36 women ultrasound alone was performed to reach diagnosis, one woman had an extra MRI scan, two women had tumour markers on top of the TVUS and in two women an MRI scan and tumour markers were performed after the TVUS. The ovarian cyst(s) was on the right ovary in 16/41 women, on the left in 22/41, bilateral in 2/41 and in one case the side of the cyst was not reported. The most common ultrasound subjective impression was mature teratoma (22/46 cysts), followed by simple cysts (12/46 cysts), haemorrhagic cysts (6/46 cysts), endometriomas (5/46 cysts) and one possible mucinous Borderline tumour. The latter was confirmed later on histology as the stage FIGO 1A intestinal type mucinous Borderline tumour (Fig.3).

Figure 3: Distribution of origin of cysts by histology.

In total 8/41 women (19.5%) underwent surgical intervention; of these eight cases six underwent major surgery under GA and two had a cyst aspiration under local anaesthesia. Seven out of these eight masses were classified as benign on USS and were subsequently confirmed to be benign by histology or cytology. In only one case a complex adnexal mass was found on USS examination at 9 weeks of gestation and the MRI scan reported possible malignancy. Tumour markers in this 23-year-old woman were normal and a laparotomy was performed at 17 weeks of gestation to remove the mass. Histology showed the mass to be a mucinous borderline tumour, FIGO stage IA. In another patient, an oophorectomy had to be performed at the time of the Caesarean section at term for fetal distress as the ovary was found to be necrotic. In this patient an ultrasound at 10 weeks of pregnancy had demonstrated a 6cm diameter haemorrhagic cyst, which had presumably torted during the pregnancy without any symptoms to prompt the patient to refer herself. Histology in this case had shown an infarcted cyst with fibrosis and calcification. In four of the major surgery cases performed under GA uncomplicated laparoscopies were performed to remove the adnexal mass; in one case a laparoscopic salpingoophorectomy was performed as an emergency for a suspected ovarian torsion at 16/40 weeks. In three cases a laparoscopic procedure for cystectomy was performed electively for ongoing pain. In the first case a cyst was diagnosed in early pregnancy subsequently there was a miscarriage and the cyst was removed 4 months after the diagnosis. In the second case a cyst was found in early pregnancy the woman had a termination at 11 weeks of pregnancy and a cystectomy 5 months later. In the third case a laparoscopic cystectomy was performed 8 weeks after the diagnosis, however the woman suffered a miscarriage at 12 weeks of gestation. Histology confirmed dermoid cysts in all four of these cases. The two cyst aspirations performed under local anaesthesia and ultrasound guidance were both symptomatic for torsion, one at nine weeks and one at ten weeks of pregnancy. In both patients the procedure has been successful. 33/41 (80.5%) with no indication for surgical intervention. There was a significant difference in the mean diameter of ovarian cysts in the expectant management group (41.2mm; 95%CI:34.7-47.7) compared with the mean diameter of cysts in the surgically managed group (74.5mm; 95%CI: 49.2-99.8) (Fig.4).

Figure 4: Mean diameter of the ovarian cysts.

In 33/41 patients no surgical intervention was needed during pregnancy. 13/33 patients had no follow up of their ovarian cyst arranged and no further mentioning of the cysts on routine growth and anomaly scans during pregnancy was found. In 20/33 patients at least one routine follow-up scan was performed 1-2 weeks after the diagnosis and in 12 of these 20 patients a second follow-up had taken place at least 1 month after the diagnosis. In one of the 20 patients with recorded follow-up’s an MRI scan had been arranged 2 months after the initial USS finding of a dermoid cyst.

Discussion

The results of our study confirm findings from previous studies: The vast majority of ovarian masses in pregnancy are benign and invasive cancer in pregnancy is rare; The results show a significant relation between size of adnexal mass and probability for surgery; Ultrasound examination of adnexal masses has been proven to be accurate and safe in pregnancy; Managing ovarian cysts in pregnancy can be challenging. Goh et al. have reported similar outcomes, namely that ovarian torsion is still reported as a rare event in pregnancy and that the management of most adnexal masses in pregnancy can be conservatively managed if asymptomatic and if there are no ultrasound findings suspicious for malignancy ⁸. If a surgical intervention is needed for persistent masses with complications such as torsion Goh et al. have found that laparoscopy during 1st and 2nd trimester can be safely performed ¹. In our cohort two out of six women underwent successful major surgery during the 2nd trimester of pregnancy. One had an emergency laparoscopy for a torsion at 16 weeks of pregnancy and the other had a laparotomy at 17 weeks of pregnancy for a mucinous borderline tumour.

However, to our knowledge currently no evident guidelines exist on how to manage and follow-up ovarian masses during pregnancy. The characteristics and presentation of ovarian mass complications in pregnancy can be mimicked by similar symptoms related to pregnancy, such as ectopic pregnancy. In one of our cases a woman with a known ovarian cyst was found to have a necrotic ovary at the time of Caesarean section, despite no signs of torsion at any time during pregnancy. This only highlights how challenging and difficult the assessment of ovarian masses during pregnancy can be. Additional diagnostic examinations such as tumour markers in suspicious ovarian masses have been found difficult to interpret in pregnancy. However, there has been literature suggesting that if a mass is strongly suspicious for malignancy, it is likely that CA-125 will be severely elevated (1000-10 000) ⁷.

The strength of this study is that the data has been collected using the expertise and facilities of a tertiary referral centre in London (GSTT). The limitations of this study include retrospective data collection, small numbers of cases and loss of follow-up. Although, our study shows the benign nature of most ovarian masses in pregnancy and the ability of ultrasound to safely characterize ovarian masses, a prospective study is required to validate our results. As it is difficult to interpret ovarian cancer tumour markers in pregnancy ^7, other models, such as the IOTA Simple Rules^14,16 or the ADNEX model¹⁷ may play a role for further characterisation of ovarian masses. A prospective trial is required to validate these models in pregnancy.

INTRODUCTION

Adult Still’s disease (AOSD) is an inflammatory disorder of unknown etiology characterized by quotidian (daily) fevers, arthritis, and an evanescent rash and multi-organ involvement [1].First described in children by George Still in 1896, subsequently in 1971 Bywaters described 14 patients with similar presentation [2]. The clinical course of adult Still’s disease (AOSD) can be divided into three main patterns: monophasic (or monocyclic), intermittent, and chronic. Patients with monophasic AOSD have a disease course that typically lasts only weeks to months, completely resolving within less than a year in most patients [3]. Systemic features, including fever, rash, serositis, and hepatosplenomegaly, predominate in this group. The patient we diagnosed as AOSD, with monophasic course, went into remission after proper treatment and is symptom free even after stopping the treatment.

CASE REPORT

46 year old Indian male, non-smoker, married, nondiabetic, normotensive admitted at department of internal medicine in our hospital with history of high grade fever, polyarthritis, and skin rash for the last 4 weeks. The fever was high grade, with maximum temperature reaching 39.2°C. The patient also complained of joint pains involving the knee, ankle, wrist and proximal interphalangeal joints. There was no history of oral ulcers, morning stiffness, ocular symptoms, or contact with infected persons. In the hospital, during the febrile period, he developed macular rash mainly on chest and back [Figure 1]. On examination, the patient was sick looking, febrile-39.2°C. Chest on auscultation was normal, cardiovascular examination was unremarkable. Examination of abdomen revealed mild spleenomegaly. Neurological examination was unremarkable. Investigations revealed hemoglobin 12.7g/dl, erythrocyte sedimentation rate (ESR) 120 mm in 1st hour. Total leukocyte count-12.7 x10 9/L. Liver function showed elevated liver enzymes with Aspartate transaminase-125U/L, Alaninie aminotransferase 60 U/L, low albumin 2.3gms/dl. He was worked on lines of pyrexia of unknown origin and his blood, urine and sputum culture showed no growth. Procalcitonin level was less than 0.5ng/ml. Sputum for AFB was negative for three samples; qunatiferon gold test for tuberculosis was negative. IgM CMV, EBV, HIV, hepatitis B and C were negative malarial parasite, Widal and Brucella serology was negative. CT-chest and abdomen were normal, except for mild spleenomegaly. Echocardiogram was normal. ANA, rheumatoid factor was negative. Lactate dehydrogenase (LDH) 978 U/L, His CRP showed a progressive increase from 82mg/L to 284 mg/L, which decreased after starting steroids. His ferritin levels were 40, 000 (normal range 21.8 -274.6 ng/ml), which were reconfirmed by second sample and he had normal transferrin saturation. On the basis of his history, clinical examination and review of his laboratory investigations, diagnosis of AOSD was made. We started him on prednisolone 60 mgs daily along with Diclofenac potassium 50 mg twice daily, to which he responded and become afebrile. He was discharged with a tapering dose of steroids 5mgs weekly. He is doing well and is completely symptom free.

Figure 1: Skin Rash on the back

DISCUSSION

First described in children by George Still in 1896, “Still’s disease” has become the eponymous term for systemic juvenile idiopathic arthritis [4]. In 1971, the term “adult Still’s disease” was used to describe a series of adult patients who had features similar to the children with systemic juvenile idiopathic arthritis and did not fulfill criteria for classic rheumatoid arthritis.

The etiology of adult Still’s disease (ASD) is unknown; both genetic factors and a variety of infectious triggers have been suggested as important, but there has been no proof of an infectious etiology, and the evidence supporting a role for genetic factors has been mixed. It is uncertain whether all patients with AOSD share the same etiopathogenic factors. Proposed pathogens have included numerous viruses; suspected bacterial pathogens include Yersinia enterocolitica and Mycoplasma pneumoniae [5]. As an example of studies of the immunogenetics of ASD, in a series of 62 French patients, human leukocyte antigen (HLA)-B17, -B18, -B35, and -DR2 were associated with AOSD. However, other studies have not confirmed these findings [6].

Adult Still’s disease is very uncommon. Prevalence of AOSD is estimated to be 1.5 cases per 100, 000-1, 000, 000 people, with an equal distribution between the sexes [6]. There is a bimodal age distribution, with one peak between the ages of 15 and 25 and the second between the ages of 36 and 46. The diagnosis of AOSD is possible only by recognizing the striking constellations of clinical and laboratory abnormalities. It is also to be to remember that AOSD is a diagnosis of exclusion. AOSD has been associated with markedly elevated serum ferritin concentrations in as much as 70 percent of patients. Serum ferritin values above 3000 ng/mL in a patient with compatible symptoms should lead to suspicion of AOSD in the absence of a bacterial or viral infection. Abnormally high serum ferritin values were reported in some case reports and it was suggested that high ferritin levels may be a diagnostic marker of Still's disease [7]. Our patient showed almost all features as laid down in Yamaguchi criteria[Table 1] for the diagnosis of AOSD [8] along with a markedly high ferritin levels.

Table 1 : Diagnostic criteria for AOSD (Yamaguchi)⁸

Exclusions: Infections, malignancy, rheumatological diseases. Five criteria with at least two major criteria. ASOD: Adult onset still’s disease. WBC: White blood cell, ANA: Antinuclear antibody, RF: Rheumatoid factor, PMN: Polymorphonuclea

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen or naproxen, help to reduce inflammation [9]. Patients with high-fever spikes, severe joint glucocorticoids, such as prednisone (0.5- 1mg/kg/day)Methotrexate has been used successfully in a small series of people to treat adult Still's disease [10]. Some patients are refractory to these conventional therapies. Tumor necrosis factoralpha (TNF) blockers include infliximab, adalimumab, etanercept, anti-interleukin-1, antiinterleukin-6 agents, and most recently anti CD20-expressing B-cell antibodies are also effective in some cases. Other experimental drugs, including cyclosporine and anakinra, have also been successful in small groups of people [9]. Interleukin 6 inhibitors like tocilzumab showed a good result in patients with AOSD resistant to other immunosuppressive agents such as methotrexate, TNF inhibitors and anakinara [11]. Even with treatment, it's difficult to predict the course of adult Still's disease. Some people might only experience a single episode, while for others adult Still's disease may develop occasional flair up or a chronic condition. About one-third of people with the disorder may fall into each of the above groups.

CONCLUSION

A diagnosis of AOSD should be kept in mind in case of pyrexia of unknown origin particularly in a patient who presents with high-grade intermittent fever, polyarthritis and skin rash of more than two weeks duration. However, the patient should be extensively evaluated to rule out other differentials of AOSD like acute or chronic infections, autoimmune disorders, vasculitis and malignant disorders. Serum ferritin values can be powerful adjuncts in making the diagnosis of AOSD [12], where they are usually higher than other inflammatory diseases. Indeed, extreme elevation of serum ferritin up to 75, 500ng/ mL has been reported in AOSD[12]. Several investigators agree that ferritin levels above l, 000 ng/mL are suggestive of AOSD while levels greater than 4, 000ng/mL are very specific for this diagnosis when accompanied by a compatible clinical picture.

The identification of dark patches on the skin may be the first indication of type 2 diabetes mellitus (DM type 2). DM type 2 is a complex heterogeneous group of metabolic conditions characterised by elevated levels of serum glucose. Causative factors are impairment in both insulin action and insulin secretion. The darkening of the skin is usually evident on the hands and feet, in folds of skin, along the neck, and in the patient’s groin and armpits.¹ The affected skin differs from that which surrounds it, and it feels velvety and also thicker. That skin may have hanging from it the small, soft, skin-coloured growths known as tags, and the area affected may be pruritic. This condition is a nonspecific dermatological disorder termed acanthosis nigricans (AN), which often occurs in patients with high insulin levels. Hud et al. (1992) found that 74% of the obese population exhibits AN.²The association of AN, skin tags, and diabetes mellitus due to insulin resistance – along with obesity in adolescents and young adults – is a well-defined syndrome.^3,4,5

High-insulin levels in the blood may increase the body’s production of skin cells, many of which have increased pigmentation that gives the skin a darkened appearance – dark patches appear on the skin. These are often the outcome of insulin receptors in the skin being triggered, causing mutations of normal tissue that are dark in colour and/or irregular in shape. The condition may be an indication that the blood sugar is persistently high. The term ‘acanthosis nigricans’ was originally proposed by Unna et al. in 1891, but the first descriptions of it were made a year earlier by two researchers working independently of each other: Pollitzer and Janovsk.⁶ Kahn and colleagues tried to clarify the link between AN and insulin resistance in 1976.⁷ Eventually, its presence became established as an indicator of insulin resistance or diabetes mellitus in obese patients.⁸ In 2000, the American Diabetes Association formally accepted AN as such.⁹ It should be borne in mind that AN must not be considered a characteristic feature of DM type 2; it is not a condition that is developed by all those who suffer from the disease.

Figures 1,2,3 - Acanthosis Nigrans

Pathogenesis

Although the pancreas produces insulin in DM type 2, the body cannot make use of it efficiently. The outcome is a build-up of glucose in the bloodstream, which may lead to high levels of blood glucose and insulin. At low concentrations, insulin regulates the metabolism of carbohydrates, lipids, and protein and may promote growth by binding to ‘classic’ insulin receptors. High concentrations of insulin may stimulate keratinocyte and fibroblast proliferation through high-affinity binding to the insulin-like growth factor 1 (IGF-1) receptors.¹⁰ In obese patients elevated IGF-1 levels may contribute to keratinocyte and fibroblast proliferation;¹¹ the binding stimulates the proliferation of keratinocytes and fibroblasts, which leads to AN.

To put this simply, AN is the outcome of a toxic effect of hyperinsulinemia. Excess insulin causes the normal skin cells to reproduce rapidly rate, and it has been demonstrated to cross the dermo-epidermal junction and reach keratinocytes. In those who have dark skin, these new cells have increased melanin. The higher level of melanin results in the creation of a patch of skin that is noticeably darker than the skin surrounding it. The presence of AN is therefore a strong indicator of increased insulin production and, therefore, it is also a predictor for future DM type 2.

When the occurrence of AN is recognised, a prediabetic person has the opportunity to become more alert to their symptoms and to take precautions in the form of diet restrictions and weight loss. This is because overweight people tend to develop resistance to insulin over time. If too much insulin is the cause of AN, it is relatively easy for the patient to counter it by changing to a healthier diet, taking exercise, and controlling their blood sugar. Obesity-associated AN may be a marker for higher insulin needs in obese women with gestational diabetes,¹²andAN has been shown to be a dependable early indicator for metabolic syndrome in paediatric patients.¹³

Autoimmunity?

Unknown autoantibodies other than insulin receptors have been implicated in AN, which may explain the effectiveness of cyclosporine treatment. Kondo and colleagues identified a very rare occurrence – without type B insulin resistance – of generalised AN with Sjögren's syndrome and systemic lupus erythematosus-like features.¹⁴Theirs was the first report of generalised AN involving an area from the mucosa of the larynx to the esophagogastric junction, accompanied by autoimmune disorder (AD) responding to systemic immunosuppressive therapy. AN skin lesions and mucosal papillomatosis were medicated with oral cyclosporine A and were accompanied by lower autoantibody titres. That was an outcome of the development of antibodies to insulin receptors in AD such as systemic lupus erythematosus.¹⁵

Raymond et al. have reported on the association of AN with disordered immunoreactivity.¹⁶ The onset of AN may precede a variety of classic ADs, and different categories of ADs may be present at the same time. If AN is an AD, DM type 2 may also represent a slow and subtle autoimmune process. AN and DM type 2 then become two different expressions of the same disease process, but the former is apparently benign and the latter is ultimately potentially fatal. Autoimmunity is a well-known pathogenic component in DM type 2. The assumption that its pathogenesis encompasses autoimmune aspects is increasingly recognised. That is based on the presence of circulating autoantibodies against β cells, self-reactive T cells, and also on the glucose-lowering efficacy in DM type 2of some immunomodulatory therapies.¹⁷ The autoimmune hypothesis of AN has the potential to modify the direction of DM type 2 research.

The symptoms of ADs are inconstant and this is in divergence to the mechanisms of antigen recognition and effector function that are alike in the response to pathogens. ¹⁸ The symptoms basically depend on the triggering autoantigen and the target tissue. In certain conditions, autoantibodies function as receptor antagonists and in other situations, they function as receptor agonist. Autoantibodies of both types can be made against insulin receptor. When they serve as antagonists as in DM Type 2, the cells of patients are unable to take up glucose, the consequence is hyperglycaemia whereas in patients with agonistic antibodies, cells deplete blood glucose resulting in hypoglycaemia.¹⁸ One wonders whether AN may be an early by-product of such an autoimmune process.

Vitiligo which is the result of depigmentation of the skin is in fact an opposite disorder to AN. Vitiligo is recognised as an AD.¹⁹Thyroid disorders, particularly Hashimoto thyroiditis and Graves’ disease, other endocrinopathies, such as Addison disease, diabetes mellitus, alopecia areata, pernicious anaemia, inflammatory bowel disease, psoriasis, and autoimmune poly-glandular syndrome are all associated with vitiligo. ²⁰ Kakourou et al identify that Hashimoto's thyroiditis is 2.5 times more frequent among children and adolescents with vitiligo than in a healthy age- and sex-matched population and it usually follows the onset of vitiligo. ²¹

As in the case of other ADs, vitiligo susceptibility may involve both target organ-specific genes and immune response genes. ²² The autoimmune theory suggests alteration in humoral and cellular immunity in the destruction of melanocytes of vitiligo. ²³. Vitiligo lesions have an infiltrate of inflammatory cells, particularly cytotoxic and helper T-cells and macrophages;histological evidences further back up an autoimmune aetiology. ²⁴ Like AN, Vitiligo is thus gene linked; immunity derangements may be providing the matrix and genes are the craftsmen in both conditions.

Vitiligo occurs more commonly in DM Type 1. A few recent studies have revealed its increased incidence in DM Type 2. ²⁵ These may be isolated case studies, but offer new insight into the pathogenesis of DM Type 2. There is a logical thread running between the autoimmune assertion of AN and its depigmentation counterpart (vitiligo) which is recognised as an AD. If AN is proven as an AD, the AD hypothesis of DM Type 2 becomes more binding. The autoimmune process of AN warrants further consideration and further study is needed to confirm or falsify the hypothesis of an autoimmune spectrum disorder between AN, vitiligo and DM Type 2.

Even though the common assumption that bacteria flora occupying human body outnumber the body cells has been proven wrong, their revised ratio of 1:1 is still astounding.²⁶ The exact role of the resident microbial colony in human body is unclear. There are less ADs observed among the hunters’ tribal population of Tanzania whose faecal matter contain more varieties of microbes than people in developed countries. ^27,28 This is an observation that need further verification. It is possible that the occupied microbial army may be maintaining the harmony among the human body cells from attacking each other and serving as moderators. Now that anti-autoimmune activity in molecules produced by parasites have been confirmed in haematology lab, these findings may have clinical significance. The aetiology of ADs is multifactorial. Genetic, environmental, hormonal, psychological stress and immunological factors are all considered important in their development. I content that the clue to the mechanism of development of certain ADs and ways of counteracting them may be embedded in the bacterial colony and their interaction with human cells.

International studies

A pilot study by Bhagyanathan and colleagues demonstrated that children with AN have a high incidence of insulin resistance.²⁹ They posit that the detection of insulin resistance in children may present an opportunity to prevent the onset of microvascular changes before the development of DM type 2. Once DM type 2 by hyperglycemia is diagnosed it may be too late for that. Insulin resistance is one of the mechanisms involved in the pathogenesis of DM type 2; therefore, early recognition of insulin resistance is paramount in the prevention or delay of the onset of diabetes. Their study was of 62% of children who had AN alongside high insulin resistance. In children with AN and a high BMI, the incidence of insulin resistance was about 80%. This is evidence that the easily detectable symptoms are of value in the screening of children who are at high risk of developing DM type 2. Bhagyanathan et al. conclude that AN has potential as a screening method because those who have high insulin resistance as well as AN are at high of future DM type 2.

An earlier US study, by Brickman and colleagues, had yielded somewhat similar results.³⁰ This involved 618 youths from different ethnic groups at nine paediatric practices. They were aged from 7 to 17 years. A survey was made of their demographics and their family history with regard to DM type 2, and their weight and height were also measured. AN was scored and digital photographs of their necks were taken. AN was identified in 19%, 23%, and 4% of the African American, Hispanic, and Caucasian youth respectively. It was also found in 62% of those studied who had a BMI greater than the 98th percentile. Using multiple logistic regression, the researchers found that the level of BMI, the presence of maternal gestational diabetes, female gender, and not being Caucasian, were all independently associated with AN. AN was common among the overweight young people and was associated with risk factors for glucose homeostasis abnormality. Brickman et al. concluded that identification of AN offers an opportunity to advise families about the causes and consequences of the condition. ³⁰ That has the potential to motivate those with responsibility for the young people to encourage and effect healthy lifestyle changes that decrease the risk of the development of DM type 2 and cardiovascular disease.

In their research in India, Vijayan et al. determined that BMI, waist circumference and AN are three physical markers for the recognition of insulin resistance in children.³¹ They conducted a cross-sectional school-based study in a semi-rural environment in the state of Kerala, which has become known as the diabetic capital of the country. Their study encompassed 283 children between the ages of 10 to 17. The prevalence of insulin resistance was 35%; this estimate was arrived at by using a homeostasis model assessment of insulin resistance (HOMA-IR). Of the children studied, 30% had a waist circumference above the 75th percentile and 18.7% had a BMI above 85th percentile. AN was diagnosed in 39.6% of the population studied. A significantly high prevalence of insulin resistance was observed among the children with a waist circumference exceeding the 75th percentile, a BMI above the 85th percentile, or a diagnosis of AN. The most sensitive physical marker of insulin resistance was AN (90%) and the most specific was BMI (91%). By combining these parameters their sensitivity may be increased to 94% and their negative predictive value to 96%. Vijayan et al. conclude that these easily recognisable physical markers are an efficient warning of insulin resistance among children.

Acanthosis nigricans in different conditions

AN is not a disease, but a symptom of disease. A high prevalence has been observed recently, and there are a number of varieties. These include benign, obesity associated, syndromic, malignant, acral, unilateral, medication-induced, and mixed AN.^32,33 It has been established that AN may occur in a number of conditions, and a brief discussion of these is appropriate for this paper. Different types of AN are listed in Table 1. It often appears gradually in the prediabetic state, but abruptly in malignancy.

AN may be triggered by a plethora of medications, such as birth control pills, human growth hormones, thyroid medications, and even some bodybuilding supplements. All these medications may cause changes in insulin levels. Medications used to ease the side effects of chemotherapy have also been linked to AN. In most cases, the condition clears up when the medications are discontinued. In rare cases, AN may be caused by gastric cancer (especially gastric adenocarcinoma) or an adrenal gland disorder such as Addison’s disease. Hypothyroidism, Cushing’s disease, and polycystic ovarian disease are also common causes of AN. ^34,35

When AN is present without any identifiable cause in middle-aged and older patients with extensive skin findings, internal malignancy needs to be ruled out. AN has been reported in association with many kinds of cancer, by far the most common being an adenocarcinoma of gastrointestinal origin. In these patients it is a rapid-growing dermatological pigmentation disorder. The skin changes are typically more extensive and severe than those seen in benign AN. Findings may include thickening, unusual roughness and dryness, and/or potentially severe itching (pruritus) and irritation of the skin regions affected. Pigmentary changes may be more pronounced than those observed in benign AN and they are not restricted to areas of hyperkeratosis. Malignant AN is frequently associated with the mucous membranes and with distinctive abnormalities of the oral (mouth) region. For example, reports indicate that the lips and the back and sides of the tongue may have an unusually ‘shaggy’ appearance, sometimes with elevated, wart-like, non-pigmented tissue growths (papillomatous elevations). Malignant AN is also commonly characterised by wart-like thickening around the eyes, unusual ridging or brittleness of the nails, thickening of the skin on the palms of the hands, hair loss, and sometimes other symptoms. Investigators have reported that the development of malignant AN may occur as much as five years before the onset of other symptoms, although the time span before malignancy is typically of shorter duration.

Table 1. Different types of acanthosis nigricans

Genetic links

It is worth noting that certain types of AN may be genetically linked.³⁶ The interaction of genes and the environment is not clearly understood and the different variables of DM type 2 are not established. It is a heterogenous disorder and there is a general consensus that diabetic comorbidities may be the outcome of genetic and environmental susceptibilities.^{37,38,39,40,41} Such factors may have an influence independently or in combination with one another that brings about hyperglycaemic conditions.It would be interesting to explore the possibility of a link between the diabetic genes and the AN gene. DM type 2 may be potentiated by poor quality of insulin or decreased production of insulin, and the distinction between those manifestations is not well recognised. The controversy concerning the relative roles of insulin deficiency and insulin resistance in DM type 2 continues to be unresolved.⁴² Despite the early demonstration that obese people have elevated plasma insulin concentrations, many studies over the years have failed to control satisfactorily for the influence of obesity.⁴³ Another difficulty with the interpretation of plasma insulin concentrations is that sustained hyperglycaemia may have detrimental effects on insulin secretion.⁴⁴ Diabetes mellitus affects every cell of the body, and therefore it affects the beta cells of the pancreas in turn. The spiralling effect of hyperglycaemia adds to the malfunctioning of beta cells, and that results in impaired quantity and quality of insulin. Only a subset of diabetic patients shows AN, and other groups of obese diabetic patients do not develop AN. AN is linked with higher insulin production and obesity, whereas AN may not be present in diabetes with a reduced quantity of insulin. The presence of AN may serve as one of the biological markers to determine subtypes of DM type 2.

The incidence of AN varies in different races, which is evidence that AN may have a genetic contribution – indeed, it has been regarded by some as being strongly influenced by genetic factors. It is thought to be autosomal in nature. AN is common among African-Americans, Hispanics, and American Indians, but it is rare among white people.^45,46 A study from the USA reports the prevalence of AN as 3% among Caucasians, 19% in Hispanics, and 28% in American Indians. ⁴⁷ More recently, studies from Sri Lanka and south India show the prevalence of AN as high as 17.4% and 16.1% respectively in the adult population in general.^48,49

Type 2 diabetes mellitus and schizophrenia

DM type 2 is relatively common among people who have mental health issues. Increased risk for cardiovascular disease and other serious illnesses related to insulin resistance – for example, certain epithelial cell carcinomas, AN, and polycystic ovary syndrome – are long-term concerns associated with the cluster of metabolic abnormalities stemming from insulin resistance. These are often referred to as the metabolic syndrome.⁵⁰ Impaired action of insulin in patients with schizophrenia was reported over fifty-five years ago and later confirmed in Australia.⁵¹ The prevalence of DM type 2 in patients with schizophrenia was found to be higher than it was in the general population, even before antipsychotic medication was in widespread use.

The mechanisms underlying the relationship between schizophrenia and diabetes remain unexplained. The present author has argued in favour of the autoimmune hypothesis of a subset of schizophrenia.^52,53 The proposal is that if AN is an AD, it may be co-existing with DM type 2, or the DM type 2 itself may even be an extension of the same autoimmune process. In other words, there may be a continuum of pathological process between AN and DM type 2. It follows that schizophrenia sufferers may have a predisposition to develop DM type 2; schizophrenia may even be considered as a clinical surrogate of DM type 2.

When AN occurs in a schizophrenic patient, they sometimes develop a delusional misinterpretation of the condition, such as that it is a result of skin cancer or even a manifestation of an external agency. Such situations may result in severe anxiety. Schizophrenia is frequently associated with poor lifestyle choices on the part of the patient, such as a diet high in fat, reduced levels of physical activity, and high rates of smoking-all of these may contribute to the development of a metabolic syndrome and insulin resistance.^54,55 It is worth considering investigation into the early warning signs for DM type 2 – including the AN – before commencing a patient on antipsychotic drugs that lead to a metabolic syndrome.

It is now well recognised that patients treated with clozapine or olanzapine are more often classified as having DM type 2 or impaired glucose tolerance in comparison with patients treated with other second-generation antipsychotics. Clozapine increases the risk of diabetes if there is a history of pre-existing diabetes or a family history of diabetes. According to a US study, the risk is higher if the patient is African-American or of Hispanic origin. Such patients may need close blood sugar monitoring during the initiation of clozapine treatment. I contend that if a patient already has AN, weight-increasing antipsychotics should be avoided. Even though aripiprazole is the most metabolic-sparing agent among the second-generation antipsychotics, Manu et al. report a case of AN in a patient treated with it. That patient did have a family history of DM type 2, which adds to the interest of the case.⁵⁶

Diagnosis and treatment

There is no specific treatment for AN. Treatment is directed towards the specific symptoms that are apparent in each individual. It should be borne in mind that such treatment may require the coordinated efforts of a team of medical professionals. Correcting the underlying disease improves the skin symptoms. Steps that may be taken, depending on what the disease is, include correcting hyperinsulinemia through diet and medication, encouraging the loss of weight in those with obesity-associated AN, removing or treating a tumour, and discontinuing a medication that causes AN. The control of obesity contributes significantly to reversing the whole process, essentially by reducing both insulin resistance and compensatory hyperinsulinemia. However, the pigmentary changes may persist. In drug-induced AN, offending medicines should be stopped. In hereditary AN, lesions tend to enlarge gradually before stabilising and/or regressing on their own.

For those with AN, the recommended treatment may include the use of certain synthetic, vitamin A-like compounds (retinoids). For individuals with malignant AN, disease management requires treatment by oncologists. Reports indicate that AN has improved with therapy used to treat underlying malignancies and has reappeared with tumour recurrences. Other treatment for this disorder is symptomatic and supportive. The treatments considered are used primarily to improve appearance, and include topical retinoids, dermabrasion, and laser therapy. The final outcome of AN varies depending on the cause of the condition. Benign conditions, either on their own or through lifestyle changes and/or treatment, have good outcomes. The prognosis for patients with malignant AN is often poor as the associated cancer is often advanced.

AN may be diagnosed on the basis of thorough clinical evaluation, identification of characteristic physical findings, a complete patient history including medication history, a thorough family history, and various specialised tests.⁵⁷ The age at detection will vary, depending upon the form of AN present and on other factors. For example, benign forms of AN often become evident during childhood or puberty. It is less common for benign AN to be apparent at birth or to develop in adulthood. The latter cases most typically involve AN in association with obesity.

In individuals with skin changes that suggest AN, diagnostic assessment may include various laboratory tests. Examples are the glucose tolerance test and the glycated haemoglobin (HbA1c) test. Additional laboratory studies or other specialised tests may also be utilised in diagnosis in order to help detect or rule out certain other underlying disorders – including a number of endocrine and autoimmune conditions – that may be associated with AN. In addition, in some instances, particularly where the patient presents with signs suggestive of malignant AN, testing may include biopsy and microscopic evaluation of small samples of skin tissue affected.

The onset of malignant AN usually occurs after the patient reaches 40 years of age. Various factors may be indicative of malignant AN in association with an underlying cancer. These include symptom onset in adulthood that is not associated with the use of particular medications, obesity, a positive family history, and certain underlying disorders known to be associated with AN. It is rare for malignant AN to develop during childhood. In such instances, warning signs may include skin changes that progress rapidly and also involvement of the mucous membranes.⁵⁸

AN may be metaphorically linked to the dark pigmentation that appears on the skin of the ripe Sharon fruit. Sharon fruit is the trade name for a variety of persimmon that is grown in Israel. In the fruit the dark patches on the ripe and sugary fruits are the result of condensed tannins. Insulin-resistant AN may be referred to as the Sharon fruit sign in order to emphasise the diagnostic value of the condition. It has been suggested that the official terminology for AN is inappropriate for a significant warning of an increasingly common disease for which early diagnosis is imperative. Because the complex name may have a negative impact on its identification by both clinicians and patients, a less formal term is in use among some of those who are concerned with patient care. It must be borne in mind that AN, otherwise Sharon fruit sign, manifests only in those with the insulin-resistant condition and should not be considered a characteristic feature of DM Type 2. Identification of the Sharon fruit sign may be helpful in the early diagnosis of DM type 2.

Discussion

Diabetes puts an enormous burden on patients, their families, and the health-care system. Detection of the disease at an early state using physical markers and instituting preventive measures will reduce the economic strain on society to a great extent. According to the latest global data from the World Health Organization (2016), an estimated 422 million adults are living with DM type 2 and diabetes prevalence is increasing rapidly.⁵⁹ In 2013 the International Diabetes Federation estimated that 381 million people were living with diabetes.⁶⁰ That number is anticipated to almost double by 2030.⁶¹ About 3.8 million people in the UK have DM type 2, and the charity Diabetes UK has made predictions that it may become as high as 6.2 million by 2035/36.

Most often a diagnosis of DM type 2 is made only when such symptoms as loss of weight, polydipsia, and polyurea have become manifest. By that time the damage to the body may have already come about. Complications arising from diabetes cover the entire area of medical science, so early detection is crucial. Intervention at the prediabetic stage helps to arrest the progress of this condition. AN may herald DM type 2, endocrinopathies, and malignancies. This cutaneous disorder is easily detectable and highly useful in the early detection of the disorders associated with it. Early screening for AN in preadolescent and adolescent people would provide a relatively simple, inexpensive, and non-invasive tool for identifying those young people who have hyperinsulinemia and could benefit from early intervention. That would prevent the development of DM type 2. Young people tend to be reluctant to undergo traditional screening measures and definitive diagnostic tests as they find them invasive and unpleasant.

A sedentary life style and unhealthy dietary habits – as well as the side effects of antipsychotics – make chronically ill psychotic patients more vulnerable to DM type 2 than the general population. Long-standing detained patients in particular are restricted in their mobility and may become more prone to obesity and insulin resistance. It is not clear whether the pathogenesis of psychosis itself has a diabetogenic effect. It is evident that because of the high incidence of DM type 2 among mental health service users, psychiatrists need to become more alert in the diagnosis, management, and prevention of the complications of DM type 2.

Introduction

Within the United Kingdom, all doctors are expected to teach.¹ It is assessed throughout their professional career, during annual appraisals for doctors in training and during consultant revalidation. But how are those just embarking on their medical career expected to develop the necessary teaching skills? As three educators at various stages in our clinical careers, we developed and delivered a small course with the aim of addressing this issue.

The General Medical Council within the United Kingdom, suggest that a basic comprehension of teaching should be gained during the undergraduate and postgraduate training of doctors.² Dandavino et al. further suggest that early development of these teaching skills may have additional benefits for the clinician; such as improving communication and assisting undergraduates to develop their own ability to learn.³ Our local training region, Yorkshire and the Humber Deanery (HEYH), have a mandatory post-graduate training day in teaching skills which focuses on generic and clinical teaching skills. This is delivered towards the end of the first foundation year. It is delivered by doctors who have various roles in medical education. Whilst useful in its content, for many it comes late. Doctors have often already been involved in providing teaching to medical students on placement at this time.

AMC recalls from her first postgraduate (foundation) year. One peer was thrilled to have ‘shaken-off’ a final year medical student who was supposed to accompany them on a shift as a learning experience; stating that they were now able to ‘do some work’. She couldn’t understand the desperation to escape one-to-one teaching. On reflection, it was probable that her colleague found it overwhelming to incorporate the additional responsibility of teaching alongside an already stressful clinical workload. Many share these feelings, with new doctors finding time pressures along with competing clinical demands a challenge to implementing clinical teaching.⁴

We thought that giving our graduates simple tools to understand and overcome these challenges may empower them as teachers. It may also improve their confidence in other areas, such as in their own learning and presentation skills.^5-6 This paper proposes a solution; after creating a short course to be delivered immediately following graduation, to empower new doctors as teachers by providing some basic training in clinical teaching. These doctors are then able to use this training as soon as they begin their foundation training, which is ultimately the beginning of their teaching career.

Methods

Two versions of a half-day course, titled ‘Teach the Medic’ were developed in HEYH which ran in successive years. The original course was designed by a surgical trainee (AMC) and a general practitioner running the undergraduate education curriculum (MS). Initial topics were chosen based on experiences of the authors and colleagues. The optional course (see figure 1), was offered to the cohort of Leeds medical students who were in the transition period between finishing their final examinations and commencing their first post as a doctor.

Figure 1: A representation of the initial course structure. Stations were developed as interactive lectures and delivered to participants by doctors of various training levels.

The initial course received encouraging verbal and written feedback from the participants, which was collected on the day of the course. Further feedback was collected a few months into foundation training, allowing enough time to pass for delegates to use this knowledge. This feedback, whilst encouraging, included that delegates were keen for additional workshop style sessions. Subsequently, a modified half-day course ran the following year, with the recruitment of additional postgraduate teachers (including LES). A further 17 newly qualified doctors from various medical schools completed the course, prior to commencing their HEYH foundation post. This modified course (see figure 2) included scenario based sessions around potentially difficult situations for the clinical teacher, and also explored alternative styles of teaching that could be adopted successfully in the workplace.

Figure 2: A representation of the modified course structure. Building on feedback from the initial course, the three co-authors incorporated new small group scenario based discussions, alongside the interactive lectures.

Results

Initial feedback received from evaluation of the day was positive for both courses. For the second course, initial feedback found that all participants found every session very good (71%) or good (29%) overall. 12/17 (71%) thought that the course should be made compulsory to medical students. We also sent a follow-up survey, distributed six months after the course which generated 14 responses. All respondents felt that the course should be run again. All participants either strongly agreed (n=2, 14%) or agreed (n=12, 86%) that they felt more confident in teaching compared with their peers. Regarding individual sessions, 10 participants (71%) had directly incorporated learning from the ‘Teaching Theory’ session, 12 (86%) from the ‘Teaching for your Learning and Portfolio’ session, 11 (79%) from the ‘Teaching your Peers’ session, and 10 (71%) from the ‘Scenarios’ workshop. All participants stated they would still recommend this course to colleagues. They also reported directly incorporating their learning from the sessions into their teaching practice. The responses gathered from the second course implied that participants felt more confident in teaching when compared to their peers.

Discussion

We feel the course content in ‘Teach the Medic’ complements other courses available later in one’s career, such as the Royal College of Surgeons’ ‘Train the Trainer’ course. We propose this course could be run by a junior doctor who has a strong interest in clinical teaching with involvement of a senior colleague with extensive medical education experience. We felt the course was especially beneficial as participants had continued to find it useful long after its delivery.

To expand this project to include a whole year group as a compulsory course is ambitious. It would require development and the use of more resources, but initial feedback suggested participants will find it extremely useful. Bing-You et al.⁶ agree, having found that undergraduate students would be willing to undertake formal instruction in clinical teaching prior to graduation.

As our short course gains momentum within HEYH, this prospect becomes more achievable. When considering a wider delivered course, one must remember that attendance to ‘Teach the Medic’ was optional; suggesting that those who attended had already identified an interest in teaching. This has the potential to bias our data to some degree. However, we still believe that making the session compulsory would allow skill development and empowerment for those who may not consider themselves aspiring medical educators, but who are still in positions to deliver teaching.

Conclusion

Our evolving teaching skills course suggests that close work with both local medical schools and deaneries is important to allow this course to be incorporated into the training of newly qualified doctors. This may be included as a compulsory part of the final year medical school curriculum, an option for a SSC, or as an integrated part of the new starter induction programme delivered by individual hospitals.