No

Introduction

Hyperthyroidism is one of the most frequently encountered conditions in clinical endocrinology.¹ The modes of treatment available are antithyroid drugs, surgery and radioiodine (RAI) and although each of these is highly successful in controlling or curing hyperthyroidism none leads to permanent euthyroidism on a consistent basis. ² Although over the last three decades RAI therapy has replaced surgery as the leading form of definitive treatment ^{3, 4, 5} there is no universally accepted dose or regime for its use. Previous attempts to individualise the dose of RAI to reduce the rate of post-RAI hyper- or hypothyroidism have been unsuccessful ^{6, 7}. Fixed dose RAI administration has therefore become the most commonly used regime although the actual dose of RAI used varies considerably and ranges between 185MBq to 600MBq ^{8, 9}. For the last two decades we have used a fixed RAI dose of 550MBq for all patients. Others have used this regime with a high success rate ¹⁰ and a prospective head to head comparison with the calculated dose method found the fixed dose regimen to be superior for curing Graves’ hyperthyroidism ¹¹.

Conflicting results have been produced in several studies that have attempted to predict outcome following RAI therapy by correlating cure rate with various pre-treatment factors including age, gender, aetiology of hyperthyroidism, goitre size, use of antithyroid drugs, free thyroxine levels at diagnosis and thyroid antibody status. Various forms of calculated or low fixed dose RAI therapy have been used in these studies but no study used a high fixed dose of 550MBq. In this study we have evaluated the overall success rate of high fixed dose RAI therapy and attempted to identify simple clinical predictors of failure to respond the initial RAI dose. 

Patients and Methods

The study is a retrospective analysis of 584 consecutive patients referred to the Shropshire endocrinology service (Princess Royal Hospital and Royal Shrewsbury Hospital) over a 14 year period for the treatment of hyperthyroidism. These patients received RAI therapy at Royal Shrewsbury Hospital, which is the only centre providing facilities for RAI administration in the county of Shropshire and also draws referral from adjoining trusts in Powys, North Wales. Information for this study was obtained from the thyroid database which is maintained on all patients who have received RAI since 1985 at the above hospitals.

RAI was administered both as a primary (53%) and as secondary (47%) treatment. A majority of patients with moderate to severe hyperthyroidism were rendered euthyroid by antithyroid drugs (ATD). Ninety percent (518/584) patients were pre-treated to euthyroidism by antithyroid drugs (carbimazole in 95% and propylthiouracil in 5%) before RAI therapy. Carbimazole was withdrawn one week and propylthiouracil 4 weeks prior to RAI therapy. A standard RAI dose of 550MBq was administered to all patients without a prior uptake study. Thyroid function was measured at 6 weeks and at 3, 6 and 12 months following RAI therapy. ATD drugs were not recommenced routinely following RAI therapy and were reserved for patients who were persistently and significantly hyperthyroid following RAI administration. Patients who developed clinical and biochemical hypothyroidism after the initial 6-8 weeks were commenced on thyroxine. Patients with high free thyroxine level (FT4) and a suppressed thyroid stimulating hormone (TSH) level and those on antithyroid medication were defined as being hyperthyroid, those with low FT4 or on thyroxine as hypothyroid and those with normal FT4 and a normal or low TSH as euthyroid. At the end of one year if a patient remained hyperthyroid, another RAI dose of 550MBq was administered. The patient was considered to have been “cured” if euthyroidism or hypothyroidism was achieved during the first year following RAI therapy and “not cured” if patient remained persistent hyperthyroidism at the end of this period.

 Information recorded on the database included age, gender, aetiology, indication (primary or secondary), dose of RAI, number of RAI doses, name and duration of antithyroid drugs used, if any, and FT4 and TSH levels at diagnosis, at the time of RAI therapy and at 6 weeks, 3, 6 and 12 months after RAI therapy. Diagnosis of Graves’ disease was based on the presence of Graves’ ophthalmopathy or a combination of a diffuse goitre and a significant titre of thyroid peroxidase antibodies or if radionuclide scan showed diffuse uptake. Toxic nodular disease was diagnosed on the grounds of a nodular goitre and a focal increase in radionuclide uptake. Patients who could not be classified to either of the groups on clinical grounds and where a radionuclide scan could not be performed for a variety of reasons, were categorised as “unclassified” on aetiological grounds.

Statistical analysis

Continuous random variables were compared using t-tests and association of categorical variables by using chi-squared tests. The effect on outcome (cure of hyperthyroidism) of all variables was assessed by using logistic regression analysis and a step-wise routine was applied to choose the best set of predictors. All analyses were carried out by using NCSS2000.

Results

Data on 584 patients was included with a mean age of 56 years (range 20-90) and a female preponderance (82%). Assessment of the aetiology of hyperthyroidism was made by the above-mentioned criteria. In 110(15%) patients precise aetiological diagnosis could not be made. 344/474 (72%) patients had hyperthyroidism secondary to Graves’ disease and 134/474(28%) had toxic nodular disease. 518 patients received pre-RAI antithyroid medications. Mean free thyroxine level at time of diagnosis was 45.4pmol/L in 259 patients in whom this information was available.  Data for thyroid status at 3, 6, and 12 months post-radioiodine were available in 97, 94 and 100% patients respectively (see Table 1).

Table 1: Thyroid status at 3, 6 and 12 months

FT4 values were entered onto the database more recently and this result was available in 259 patients. The group of patients where FT4 data was available was comparable to the group where this information was not available in all respects apart from age (mean age (SD) 54 (±15) vs 58 (±14) years respectively, p<0.02). Similarly, the group of patients in whom the aetiology could not be ascertained was not different from the group where the aetiology could be identified in any respect apart from the age (mean age (SD) 60 (±13) vs 55 (±15) respectively).

Table 2 – Forward Stepwise (Wald) logistic regression analysis to identify factors independently associated with failure to respond to first dose of RAI

* Regression analysis carried out with free T4 as a continuous variable and separately as a categorical variable at a cut off of 45pmol/l

One year following RAI treatment, 543(93%) patients were either euthyroid (162;28%) or hypothyroid (383;65%) and considered “cured”; 39(7%) patients remained hyperthyroid and required further doses of RAI, with 34(6%) patients requiring two doses and 5(1%)  patients three doses. At 3 months, 484 out of 571 (85%) patients, and at 6 months, 490 out of 549 (89%) patients were “cured” (table 2). On univariate analysis no correlation could be established between the failure to respond to the first dose RAI and age, gender, aetiology or use of antithyroid medication (p = ns for all) although the rate of hypothyroidism was significantly higher at the end of one year in patients with Graves’ disease as compared to those with toxic nodular disease (77.1% vs. 50.3%, p<0.01). These results were not affected by limiting the analyses to any of the following groups: only those patients in whom the aetiological diagnosis could be made (n=478), only those patients in whom FT4 value was available (n=259) or only those patients where both FT4 was available and aetiology could be ascertained (n=209). On univariate analysis FT4 at diagnosis was associated with the outcome when it was used as a continuous variable (p<0.05) or as a categorical variable with the cut off set at mean FT4 value of 45pmol/L (p=0.01) and high values were associated with failure to respond to the first dose of RAI (mean ± SD, 57.28±20.1 v 44.58±16.1 pmol/L, p<0.05). On multivariate analysis with all variables, FT4 was found to be independently associated with outcome and again this association was seen when FT4 was used as a continuous variable (p=0.01) as well as a categorical variable (p=0.02). On using step-wise selection routine only FT4 could be chosen as a predictor when criterion for selection was set at p=0.05 and a value of over 45pmol/L predicted failure to respond to the first dose of RAI.

Discussion

The use of a standard fixed-dose RAI therapy is gaining increasing popularity and several studies have now shown that formal estimation of the required dose based on the thyroid size and iodine kinetics does not lead to a higher cure rate ^6,7,10,11 or a lowerhypothyroidism rate ⁷. For several years we have used 550MBq dose for all patients of hyperthyroidism. The overall success rate with this regime was 93% and only 7% of patients required a repeat RAI dose. These figures are comparable to those from most other centres, which have used a similar dose of RAI ¹⁰. In addition to achieving a high cure rate, hyperthyroidism was controlled rapidly with 85% of the patients becoming either euthyroid or hypothyroid within 3 months of treatment. Early onset of hypothyroidism (>70% at 12 months) facilitated institution of thyroxine replacement therapy during the first year during which the patients were being closely followed.

The use of a relatively higher dose of RAI leads to more stringent restrictions to the normal life of patients and these have to be followed for a longer period of time than is the case with the use of a lower dose. Majority of patients accept these restrictions at the prospect of a cure of hyperthyroidism. However, even at this dose, 7% of patients required repeat dosing which in turn led to another restrictive period for these patients. In view of this it is useful to be able to predict failure of the first dose in an individual patient. This would enable us to warn these patients about the higher possibility of requiring repeat dosing, further period of post-RAI restrictions and target them for a closer follow up. To allow us to make this prediction we correlated simple clinical pre-treatment variables to the need for repeat dosing. We found that there was no statistically significant correlation between age, gender, aetiology and the use of anti-thyroid medication prior to RAI and the outcome following RAI therapy although a high free thyroxine level at diagnosis predicted a failure of the first dose to achieve a cure of hyperthyroidism. There are several conflicting reports in the literature on the correlation between these factors and the response to RAI therapy. Most of the studies have failed to show a significant association between the age of the patient and the outcome irrespective of whether the age was used as a continuous or a categorised variable ^12-15 although in a study where a standard 150 gray RAI was used age >50 was found to be associated with a higher failure rate ¹⁶. In one study, male gender was associated with a lower cure rate following a single dose of RAI in patients with Graves’ disease ¹² although others have failed to confirm this association ^13,14. Use of antithyroid drugs prior to RAI has been shown to independently reduce the success rate of RAI ^{17, 18} while other studies have shown such an association with the use of propylthiouracil but not with carbimazole ^{19, 20}. Literature on the association between the aetiology of hyperthyroidism and the outcome is even more confusing. Patients with toxic nodular disease have been considered to be more radio-resistant as compared to patients with Graves’ disease ²¹ although opposite results have also been noted ²². In other studies no correlation could be established on multivariate analysis between the aetiology and outcome following RAI ^{14, 18}. Our study is the only one which analyses the influence of these factors on the outcome following the use of a standard 550MBq RAI dose and the above studies which have attempted to identify clinical predictors of outcome have either used various forms of the calculated dose regime or a lower fixed-dose RAI regime. We feel that this is the reason for the inconsistencies in the results and when a 550MBq dose RAI is used only FT4 value at diagnosis could predict the failure of RAI therapy to achieve cure. This dose of RAI appears to override the variations in the response induced by the remaining pre-treatment variables studied.

Studies using smaller doses or calculated doses of RAI have shown the outcome to be inversely associated with the thyroid size ^{14, 16} although this could not be ascertained in our study due to the lack of consistent documentation of the size ofgoitre in the clinical notes. In addition there are several possible confounding factors. Firstly the overall cure rate could have been influenced by the long period of time over which patients have been included (15 years) and the resulting changes in the criteria and threshold for the use of RAI. However if we divide the figures into 3 time periods of 5 years each, the findings remain consistent during each of these periods. Secondly, in over 50% of our patients, RAI was administered as a primary measure and it could be argued that a larger number of patients with milder hyperthyroidism may have been included in our cohort as compared to the patients at other centres where RAI is mainly reserved for patients who fail to respond to ATD. However there was no significant difference in the cure rate between those patients who received RAI as a primary measure and those in whom RAI was administered as a secondary treatment (94% v 93%). Thirdly in 15% of patients the aetiology could not be ascertained by using our well-defined criteria, mainly because of the practical difficulty of performing radionuclide scans in some of the patients where the diagnosis could not be made clinically. We do not feel that our results on the association between the aetiology and the cure rate were affected, as the patients with undefined aetiology were comparable to the remaining patients in all respects apart from age and had similar outcomes. Lastly the information on the FT4 value at diagnosis was available in only 259 patients. To exclude a selection bias this group was compared to the group of patients where this information was not available. Again the only difference between the two groups was the age distribution. In both instances this difference was not large (though statistically significant) and we do not feel it affected the outcome, especially as age does not appear to influence the outcome following RAI therapy. We could not assess the impact of post-RAI use of antithyroid drugs as these were not routinely restarted following RAI therapy at our centre.

In conclusion, high fixed dose RAI therapy is a very effective treatment for patients with hyperthyroidism and has a high success rate. Failure to respond to this dose cannot be predicted by most of the pre-treatment variables apart from the severity of the hyperthyroidism as judged by the FT4 value at diagnosis. Patients who present with severe hyperthyroidism should be warned regarding the higher possibility of requiring further doses of radioiodine even when treated with a dose of 550MBq.

Pre-eclampsia is a multisystem disorder of pregnancy that forms an integral part of the spectrum known as hypertensive diseases of pregnancy. The National High Blood Pressure Education Program (NHBPEP) Working Group¹classifies hypertensive diseases in pregnancy into 4 groups:

1)     Gestational hypertension 

·       New onset hypertension in pregnancy presenting after 20 weeks

·       No proteinuria

·       BP returns to normal less than 12 weeks postpartum

·       Final diagnosis made only postpartum                                                                                                                                                            

2)     Chronic hypertension

·       BP >140/90 mm Hg before pregnancy or diagnosed before 20 weeks gestation not attributable to gestational trophoblastic disease
or

·       Hypertension first diagnosed after 20 weeks gestation but persistent after 12 weeks postpartum.

3)     Pre-eclampsia/eclampsia

·       BP > 140/90 mm Hg after 20 weeks gestation in a women with previously normal blood pressure

·       Proteinuria (>0.3 gm urine protein in 24 hr). 

·       Eclampsia is defined as seizures that cannot be attributed to other causes in a woman with pre-eclampsia

4)     Superimposed pre-eclampsia (on chronic hypertension)

·       New onset proteinuria (>300 mg/24 hr) in a woman with hypertension but no proteinuria before 20 weeks gestation

·       A sudden increase in proteinuria or blood pressure, or platelet count less than 100,000 in women with hypertension and proteinuria before 20 weeks gestation

Epidemiology

Pregnancy induced hypertension complicates about 10% of pregnancies, but there is a widespread geographic variation in its incidence.The incidence is higher in developing countries. The highest reported rate of pre-eclampsia is 7.1% (deliveries) from Zimbabwe², while the incidence is as low as 0.81% (deliveries) in Colombia³. In UK, the incidence of severe pre-eclampsia is 5/1000 maternities⁴, while the incidence of eclampsia is 4.9/10,000 maternities⁵. The incidence of severe pre-eclampsia in European countries ranges from 2/1000 (deliveries) in Norway to 6.4/1000 (deliveries) in Belgium and Hungary⁶.

The 8^th Confidential Enquiry into maternal and child heath⁷ revealed pre-eclampsia and eclampsia as the second leading cause of direct maternal death, thereby contributing to a maternal death rate of 0.83 / 100,000 maternities.

Worldwide studies show that mortality from pre-eclampsia can be as high as 0.4%, while that in eclampsia varies from 6.1% in developing countries to 1.8% in UK ^{5, 8-9}.

Estimates of maternal mortality from the developing countries (in Asia, Africa, Latin America and the Caribbean) suggest that 10-15% of maternal deaths are associated with hypertension in pregnancy, while eclampsia is associated with 10% maternal mortality¹⁰.

Severe pre-eclampsia is also associated with significant maternal morbidity, including eclamptic seizures, intracerebral haemorrhage, pulmonary oedema due to capillary leak or heart failure, acute renal failure, liver dysfunction, and coagulation abnormalities.

Fetal complications include abruptio placentae, intrauterine growth restriction, premature delivery, and intrauterine fetal death. The incidence of stillbirths and neonatal deaths in mothers who suffered eclampsia was 22.2/1000 and 34.1/1000, respectively, in the UK with a higher incidence in developing countries⁵.

More than half a million women die each year from pregnancy related causes across the globe. The Millennium Development Goals have placed maternal health as a basic human right, one that is integral to the core of the fight against poverty and inequality. The high incidence of pre-eclampsia and its complications makes its prevention and effective management important. The following article attempts to outline the pathophysiology and management of pre-eclampsia.

Aetiology & Risk factors

Pre-eclampsia is commonly referred as the “disease of theories” making its prevention and management an ongoing challenge worldwide. Although the aetiology is still largely unknown, there are a few hypotheses regarding the pathophysiology and prediction of pre-eclampsia.

It has been postulated that pre-eclampsia may be autoimmune in nature. Seminal-vesicle-derived transforming growth factor 1 (TGF-1) initiates a post mating inflammatory reaction, which is a type 2 immune response towards paternal antigens resulting in maternal-fetal (paternal) immune maladaptation¹¹. This idea originates from epidemiological studies demonstrating the protective effect of long-term sperm exposure and is supported by the fact that frequency of pre-eclampsia is higher in nulliparous women or multiparous women with a new partner, teenagers, women who conceive after donor insemination or oocyte donation, and women with autoimmune conditions.

Another potential mechanism responsible for pathogenesis of pre-eclampsia is placental hypoperfusion which in turn releases various factors that trigger endothelial activation / dysfunction. Nitric oxide, disordered endothelin metabolism, thromboxane/prostaglandin imbalance, cellular fibronectin, inflammatory cytokines (TNF-α, IL-6, IL-1α, and IL-1β) and otherfactors such as lipid peroxides and reactive oxygen intermediateshave all been implicated in mediating the endothelial cell injury¹². This is well-supported by the fact that pre-eclampsia commonly occurs in pre-existing metabolic (diabetes, hypercholesterolemia), renal, vascular disorders (hypertension) and connective tissue disorders that result in poor placental circulation. In cases of multiple gestation or increased placental mass, it is not surprising for the placenta to become underperfused.

However, majority of the pre-eclamptic women do not suffer from any underlying medical conditions. In these women, lack of placental cytotrophoblastic invasion of uterine spiral arterioles and arrest of arteriolar remodelling results from failure of pseudo-vascularisation of the invasive cytotrophoblasts¹³. Deregulation of angiogenesis-related gene products such as vascular endothelial growth factor (VEGF), angiopoietin and ephrin family proteins, placental growth factor (PlGF) and their receptors have been implicated in this process¹⁴.Shallow placentation leads to reduced placental perfusion and subsequent ischaemia. 

Obese (BMI ≥30 Kg/m2) women are at higher risk for pre-eclampsia compared to lean women (odds ratio = 3.3). The exact mechanism is not completely understood but possible explanations are: increased stress due to the hyperdynamic circulation associated with obesity; dyslipidaemia or increased cytokine-mediated oxidative stress; and direct haemodynamic effects of hyperinsulinaemia¹⁵ (increased sympathetic activity and increased tubular sodium resorption).

 On the other hand, smoking actually decreases a woman’s risk of pre-eclampsia. Inhibition of thromboxane A₂production by nicotine might explain the decreased risk. However, the adverse effects of smoking on pregnancy significantly outweigh any beneficial effects¹⁶.

Epidemiological and clinical risk factors for pre-eclampsia are classified as maternal, paternal, and/or pregnancy-specific^{2, 17} (Table 1, below).

Table 1: Pre-eclampsia Risk Factors

What exactly happens in Pre-eclampsia?

The triad of physiological derangements in pre-eclampsia include
1. Vasospasm
2. Plasma volume contraction
3. Local or disseminated intravascular coagulation.

Although the cause of pre-eclampsia is unknown, we have already discussed that the placenta is largely implicated. The sequence of events starts with vasospasm caused by increased production or sensitivity to vasoconstrictors (angiotensin II, serotonin and endothelin) and/or decreased production or sensitivity to vasodilators (prostacyclin and nitric oxide). This is followed by plasma volume contraction, increased capillary permeability and, in severe cases, low plasma oncotic pressures. Redistribution of fluid occurs from the intravascular to interstitial fluid spaces causing peripheral tissue oedema. Along with this, intravascular coagulation may occur due to platelet activation, thrombocytopenia and, often, reduced production of anti-thrombin III.

The net effect is organ hypoperfusion. Commonly affected systems are kidney (manifested by reduced GFR, proteinuria, hyperuricaemia and occasionally oliguria), liver (manifested by elevated transaminases with or without epigastric and right upper quadrant pain), and the brain (manifested by headaches, transient visual disturbances due to occipital lobe ischaemia and rarely convulsions, i.e. eclampsia). This leads to increased maternal morbidity.

 Placental insufficiency resulting from uterine hypoperfusion is characterised by intrauterine fetal growth retardation and less commonly placental abruption or fetal death. Preterm delivery, low birth weight, respiratory distress syndrome, and admission to the neonatal intensive care lead to increased perinatal morbidity.

In spite of major advances in understanding the pathophysiology of the disease in recent years, interventions to prevent hypertensive disorders in pregnancy have had disappointing results, hence early detection, continued surveillance and timely intervention still remains the key towards decreasing the inherent maternal and fetal morbidity and mortality associated with severe pre-eclampsia and eclampsia.

Prevention of pre-eclampsia

Till date there is no well-established measure for prevention of pre-eclampsia in the general population. Calcium is clearly of benefit amongst high risk women in communities where low dietary calcium intake is prevalent. A Cochrane systematic review in 2010 concludes that calcium supplementation approximately halves the risk of pre-eclampsia, reduces the risk of preterm birth and the rare occurrence of the composite outcome 'death or serious morbidity¹⁸.

Low dose aspirin (antiplatelet agent) therapyefficiently reduces the development of pre-eclampsia in women with abnormal uterine artery Doppler studies. If started in early gestation (< 16 weeks), it also causes a significant reduction in the incidence of severe pre-eclampsia, gestational hypertension and IUGR¹⁹.

Some studies have suggested that prophylactic use of antioxidants (vitamin C, E) may be beneficial as well but this is not routinely recommended²⁰ in practice.

Evidence is also lacking to support lifestyle preventative interventions for pre-eclampsia, such as rest, exercise and reduced dietary salt intake.

The pre-eclampsia community guideline (PRECOG)

This has been developed for screening and detection of onset of pre-eclampsia in the community²¹. It includes:

• Initial risk assessment at community booking using pre-determined criteria, to identify factors that predispose women to pre-eclampsia in a given pregnancy. Following this, women are offered referral before 20 weeks gestation for specialist input to their antenatal care plan if they have been identified as high risk: this may be for clarification of risk, necessary investigations, advice on early intervention or pharmacological treatment.
• Systematic community assessment for onset of pre-eclampsia from 20 weeks gestation. The frequency of assessment is determined by the likelihood of developing pre-eclampsia. Women with no risk factors for pre-eclampsia are offered assessments at weeks 16, 28, 34, 36, 38, 40, and 41 weeks.Women with one risk factor for developing pre-eclampsia (excluding previous pre-eclampsia, multiple pregnancy and underlying medical conditions like hypertension, renal disease, diabetes, antiphospholipid syndrome)  are reviewed in the community at least once every three weeks before 32 weeks, and then at least once every two weeks, until delivery.  At every visit, recommendation is to look for presence of any signs or symptoms like new hypertension, new proteinuria, headache/visual disturbance, or both, epigastric pain/vomiting, or both, reduced fetal movements, small for gestational age infant. In the presence of two such, they are referred for early specialist input, individual assessment, and discussion of obstetric risk.
• Recommendations have been made within the scope of this guideline for improving accuracy inblood pressure measurement, increasing reliability of proteinuria test with dipstick and community assessment of fetal growth and well being which provide the parameters for referral. Referral is made forstep-up assessment in hospital day unit within 24/48 hoursor admission in accordance with set criteria. All pregnant women are also made aware that pre-eclampsia may develop between antenatal assessments, and they could self-refer at any time.
• It is recognised that all women benefit from a continuity of care in the community and need midwifery or GP care as part of their individual antenatal care plan, whatever be their obstetric risk.

Management of Pre-eclampsia

Antenatal Care

These patients should be under consultant led care with multidisciplinary input from the anaesthetic and neonatal teams as necessary.

Women with risk factors for developing pre-eclampsia may be considered for uterine artery doppler velocimetry at 20-24 weeks to look for increased impedance to flow (resistance index >95^th centile or early diastolic notch), which is predictive of developing pre-eclampsia or IUGR in late gestation, however the specificity and sensitivity varies widely between different studies^22-25.

At diagnosis of pre-eclampsia, the best practice is to offer initial hospital admission for assessment and formulation of follow-up care. Assessment of proteinuria should be done by automated reagent strip reading device. Visual assessment of the dipstick is not recommended nowadays because of high error rates^26-28. If the automated reagent strip reading of urine yields a result of 1+ or more, this should be followed up with a spot urinary protein:creatinine ratio or a 24 hour urine collection to quantify the proteinuria. Significant proteinuria is diagnosed if the urinary protein:creatinine ratio is more than 30mg/mmol or the validated 24 hr urine sample has more than 300 mg of protein. Baseline blood investigations should include full blood count, liver function (bilirubin and transaminases), electrolytes and kidney function tests. Antihypertensive medications may need to be commenced with the aim of maintaining the systolic blood pressure below 150 mm Hg, and the diastolic pressure between 80 - 100 mm Hg. Labetalol is the first line treatment. However, in patients in whom labetalol cannot be used (e.g. in patients with bronchial asthma), alternatives include nifedipine (contraindicated before 20 weeks of gestation), methyldopa, atenolol and metoprolol. 4-6 hourly blood pressure, daily assessment of proteinuria, along with haematological and biochemical monitoring are also carried out. Inpatient management is required till the blood pressure stabilises.

Following discharge blood pressure can be checked in the community or in antenatal day assessment 2-3 times a week depending on clinical circumstances. Quantification of urinary protein is not necessary after the initial assessment, however, blood tests for full blood count, liver and kidney functions need to be repeated at least twice weekly (thrice weekly if the hypertension is moderate or severe). There is often a rise in serum uric acid level, which has been associated with poor maternal and fetal outcome^{29, 30}. However, there is no evidence to use serum uric acid levels for clinical management.

Fetal monitoring:

Ultrasound assessment of fetal growth and amniotic fluid volume along with umbilical artery doppler velocimetry needs to be done at initial diagnosis of pre-eclampsia to exclude IUGR and then every 2 weeks if the pregnancy is managed conservatively and the results remain normal CTG monitoring is commonly done at diagnosis, along with the ultrasound assessment. If normal, further CTG should be performed weekly unless otherwise clinically indicated.

Delivery

In pre-eclampsia with mild or moderate hypertension, women may be delivered between 34 and 37 weeks of gestation, depending on maternal and fetal condition, presence of risk factors and availability of neonatal intensive care facilities. If severe pre-eclampsia develops, refractory to treatment or fetal wellbeing delivery may need to be done earlier.

Pre-eclampsia is considered to be severe in case of

1)       Severe hypertension with proteinuria or

2)       Mild / moderate hypertension and proteinuria with one or more of the following signs / symptoms:

Ø  Severe headache , not responding to medications

Ø  Visual disturbance (blurring or flashing of light)

Ø  Severe pain in upper abdomen or vomiting

Ø  Papillo-oedema

Ø  Signs of clonus (³ 3 beats)

Ø  Liver tenderness

Ø  HELLP syndrome

Ø  Decrease in platelet count to less than 100 x 109 per litre

Ø  Abnormal liver enzymes (ALT or ASTrising to above 70 iu/litre).

HELLP syndrome

HELLP Syndrome (haemolysis, elevated liver enzyme, low platelets) is a form of severe pre-eclampsia that is associated with high maternal and perinatal morbidity and mortality and may be present without hypertension or, in some occasions, without proteinuria.

A diagnosis of HELLP syndrome is made after confirmation of haemolysis, either by blood film microscopy showing fragmented red cells or increased serum LDH level. An AST or ALT level of above 70 iu/l is significant while a level more than 150 iu/l is associated with increased morbidity to the mother, though neither of them are independent risk factors for increased maternal morbidity ³¹.  A low platelet count (less than 100 x 10 ^{6 /}ml) supports the diagnosis. 

There is some evidence to suggest that the severity of pre-eclampsia differs according to the time of onset. More severe form occurs with the onset of pre-eclampsia prior to 34 weeks of gestation. This form is associated with abnormal uterine artery blood flow, IUGR and adverse maternal and fetal outcomes^32-33.

There may be some difference in the pathophysiology of these two disease types. The early onset disease may be associated with placental abnormalities, while the late onset one is more linked to maternal constitutional factors such as increased BMI³⁴. 

In severe pre-eclampsia, delivery is appropriate anytime beyond 34 weeks of gestation following corticosteroid administration to achieve fetal lung maturity. Delivery before 34 weeks is only indicated in maternal/fetal compromise or hypertension refractory to treatment^35-37. Prolonging pregnancy at early gestation may improve the perinatal outcome but has to be carefully balanced against maternal wellbeing. If conservative management is planned, ultrasound assessment of fetal growth, amniotic fluid volume and umbilical artery doppler flow should be done at admission, and thereafter, every two weeks. In case of normal ultrasound findings, weekly CTG monitoring should suffice, unless clinically indicated otherwise (for e.g. reduced fetal movement, vaginal loss, abdominal pain or deterioration of maternal condition).

Eclampsia

Generalised tonic-clonic seizures, with or without raised blood pressure and proteinuria, occurring during or after pregnancy with no other identifiable cause is classified as eclampsia. The cause is usually multi-factorial including cerebral vasoconstriction, ischaemia, vasogenic oedema, or other pathology. Although it is more likely to occur in women with severe rather than mild pre-eclampsia, there is no convincing test for predicting the onset of eclampsia. Convulsions may occur antepartum (38-53%), intrapartum (18-36%), or postpartum (11-44%)³⁸. Women with a history of previous eclampsia are at increased risk of eclampsia (1-2%) and pre-eclampsia (22-35%) in subsequent pregnancies³⁹.

Intrapartum Care

During labour, hourly blood pressure monitoring in women with mild or moderate hypertension, and continuously in severe hypertension is ideal. Antenatal hypertensive treatment should be continued, with the aim of maintaining the systolic blood pressure below 150 mm Hg, and the diastolic pressure between 80-100 mmHg. If oral medications fail to control the blood pressure, then intravenous anti-hypertensives are indicated to prevent the known risk of vascular damage due to uncontrolled hypertension.

Hydralazine, a peripheral arteriolar vasodilator, has been widely used as the first-line treatment for acute hypertension in pregnancy, in the past.It is administered as bolus doses (5-10 mg) intravenously, every 20 minutes to a maximum dose of 30 mg, with careful monitoring of blood pressure. The side effects include headache, nausea, and vomiting. Importantly, hydralazine may result in maternal hypotension, which may subsequently cause fetal distress. Preloading with 500 ml of crystalloid fluid before or with the first dose of intravenous hydralazine may avoid this⁴⁰. Labetalol is another antihypertensive that can be given intravenously, either as bolus doses or as an infusion to manage severe hypertension. It is commonly used as the first line drug in many centers in UK. However, it is not suitable for patients with bronchial asthma. Nifedipine may also be used orally to control blood pressure (sublingual administration is not recommended).However, it can interact with magnesium sulphate to produce profound muscle weakness, maternal hypotension and fetal distress^41-43. Recent evidence suggests labetalol and nifedipine as better alternatives than hydralazine⁴⁰. In all cases, the blood pressure should be monitored closely, along with fetal monitoring, as sudden decrease in maternal blood pressure will reduce the utero-placental blood flow, resulting in fetal distress.

Magnesium sulphate isthe agent of choice for treatment of eclampsia. It is also used in women with severe pre-eclampsia for prophylaxis of eclampsia andis usually commenced once delivery decision is made or in immediate postpartum period.  In women with less severe disease the decision will depend on individual case assessment. Evidence shows that magnesium sulphate more than halves the risk of eclamptic seizures⁴⁴.It has also been shown to reduce maternal morbidity related to pneumonia, mechanical ventilation and intensive care⁴⁵.However, there is little evidence to suggest that it decreases the risk of stillbirth or neonatal death.Magnesium sulphate is usually continued for 24 hours following delivery or 24 hours after the last seizure, whichever is the later, unless there is a clinical reason to do otherwise. This is based on the findings of the Collaborative Eclampsia Trial, 1995. However, recent evidence suggests that magnesium infusion may be stopped earlier (12 hours postpartum), especially when used in conjunction with other clinical parameters^{46, 47}. Regular assessment of the urine output, deep tendon reflexes, respiratory rate, oxygen saturation and serum concentration is done as long as magnesium sulphate is continued to avoid toxicity. Features of magnesium toxicity include suppression/loss of patellar reflexes, drowsiness and respiratory depression. Intravenous calcium gluconate is used for reversal of magnesium toxicity.

Fluid restriction is the usual practice, unless there is associated maternal haemorrhage, to reduce the chance of fluid overload and pulmonary oedema. As per NICE guidelines, total fluids should be limited to 80 ml/hour in women with severe pre-eclampsia. Strict intake-output chart should be maintained. The regime of fluid restriction should continue until postpartum diuresis commences.

The mode of delivery should be individualised taking into account the gestation, presentation, cervical favourability for induction of labour and well-being of the fetus. Vaginal delivery is generally preferable but in case of extreme prematurity or fetal compromise, caesarean section is more likely.

Haematological and biochemical monitoring needs to be continued in labour and is dictated by the patient condition and need for analgesia/anaesthesia. For those on magnesium sulphate, bloods must be repeated every 6 hours.

Anaesthetic management

The anaesthetic management in pre-eclamptic patients is important, and should start with a detailed pre-anaesthetic assessment. Appropriate history and physical examination are important. Pre-eclamptic patients are at increased risk of oedema of the pharyngolarynx and assessment of airway is vital^48-49. Clinical assessment of the cardiopulmonary and fluid status is required, along with laboratory investigations including renal biochemistry and coagulation status.An appropriate understanding of the obstetric interventions such as antihypertensive medications, and magnesium sulphate infusion is required.

Anaesthetic management should include appropriate monitoring, and should include NIBP, pulse oximetry and urine output. Invasive blood pressure monitoring (arterial line) is indicated in patients with poorly controlled blood pressure, or when NIBP is difficult to obtain (e.g. in the obese patients).

Pulmonary oedema is a rare but serious complication of severe pre-eclampsia, which can lead to increased maternal mortality (10%) and perinatal mortality as high as 50%⁵⁰. Central venous pressure monitoring is indicated in patients with pulmonary oedema, poor urine output or when difficulty in fluid management is anticipated in the peripartum period. Pulmonary arterial catheters are rarely needed. Non-invasive monitoring of cardiac output may be required in patients with difficult fluid management or coexisting cardiac problems.

The safety of regional anaesthesia in pre-eclamptic patients is now well established⁵¹. Lumbar epidural may be used for labour analgesia in women with pre-eclampsia if the mothers opt for it. Early epidural should be considered as it helps to diminish the hypertensive responses to pain. Platelet count >75x10⁹/L in the absence of other coagulation abnormalities is not associated with increased likelihood of regional anaesthetic complications in the setting of pre-eclampsia⁵². The presence of a functioning epidural catheter allows the epidural block to be titrated for LSCS if indicated. If central neuraxial block is contraindicated, then intravenous opioids may be used for labour analgesia^53-54. Few studies have mentioned the successful use of remifentanil PCA in these patients⁵⁵.Regional blockade is currently the preferred mode of anaesthesia for caesarean section. It has long been argued that while titrated epidural blocks are safe, single shot spinal or CSE techniques may produce profound hypotension. However, multiple studies have demonstrated the safety of spinal and CSE in pre-eclamptic patients for LSCS with no adverse effects on mother or fetus^56-58. In fact the incidence of hypotension in pre-eclamptic patients following regional anaesthesia is less than that in healthy patients, and is successfully managed by intravenous boluses of ephedrine or phenylephrine^59-60.Doses of local anaesthetics in regional anaesthesia remain the same in pre-eclamptic patients as in normal healthy parturients.

Though regional anaesthesia is preferred for LSCS, a general anaesthesia may still be needed if regional anaesthesia is contraindicated (e.g. coagulopathy as in HELLP syndrome), and in emergency situations where the baby has to be delivered as early as possible. General anaesthesia increases the risk of hypertension during induction and emergence, loss of airway due to pharyngolaryngeal oedema, aspiration and transient neonatal depression. Extreme care is to be undertaken to obtund the hypertensive response during induction-intubation, as this has been a significant past cause of maternal mortality⁶¹. Several agents (alfentanil, fentanyl, remifentanil, magnesium sulphate, intravenous lignocaine and esmolol) have been suggested for induction, and clinicians should use familiar ones. All opioids rapidly cross the placenta and increase the risk of neonatal depression, and appropriate facilities for neonatal resuscitation must be available. Remifentanil has the advantage as it is rapidly metabolised by the neonate, and any respiratory depression is usually brief^{62- 63}.Maintenance of anaesthesia is done by inhalational anaesthetic agents. Isoflurane is considered to be a good choice, because of its vasodilating properties. Vigilance is also required during emergence from anaesthesia, to prevent hypertension, as well as aspiration.

Anaesthetists must also be aware of the potential drug interactions of agents commonly used in pre-eclampsia. Magnesium sulphate and calcium channel blockers may potentiate the action of muscle relaxants and appropriate monitoring is vital.

Post delivery analgesia

This is maintained by simple analgesics like paracetamol. Non-steroidal anti-inflammatory agents have been used; however, caution must be exercised due to their effect on cyclo-oxygenase pathway, especially those with renal insufficiency and coagulopathy. A few case reports of significant increase in blood pressure in postpartum women have been reported following their use⁶⁴. Patient controlled analgesia with opioids has been used widely, and is considered to be a safe option.

Use of oxytocic agents

Syntocinon is the drug of choice. Ergometrine should be avoided because of its propensity to cause hypertension. Synthetic prostaglandins such as Carboprost (15 methyl PGF ₂ alpha) may be given with caution after considering the risk-benefit ratio, especially because it can aggravate hypertension.

Use of thromboprophylaxis

This should be considered in all patients with pre-eclampsia.

Most of the existing guidance focuses on management of blood pressure and its associated problems in the antenatal and intrapartum period but the postpartum phase can often be poorly looked after ⁶⁵. Regular blood pressure monitoring at an interval of 4-6 hours should be done as an inpatient initially and blood platelet count, transaminases and creatinine should be measured to note any changing trends. The aim is to maintain blood pressure <160/110mmHg, thereby preventing cerebral injury from occurring. In order to achieve this, beta-blockers, calcium-channel blockers and ACE inhibitors can be used in a stepwise manner. Use of methyldopa is usually avoided as it has the potential to cause depression and psychosis in postpartum period. Women are discharged to the community care if they are asymptomatic, blood pressure, with or without treatment, is 149/99 mmHg or lower and blood test results are stable or improving. Blood pressure isthen checked daily/alternate days in the community till 2 weeks postpartum. Antihypertensives should continue till blood pressure falls below 130/80 mm of Hg and the dose adjustments need to be made by the GP. If blood pressure becomes uncontrolled, then women would require urgent referral to the hospital.

In most cases, the hypertension and/or proteinuria resolve within six weeks postpartum. Any women whohad pre-eclampsia complicating their pregnancy, needs to have blood pressure and urine protein checked at 6-8 week postnatal visit at the GP surgery. If still requiring antihypertensive treatment at that stage or persistent proteinuria further assessment is warranted to find out cause for raised blood pressure if any and also identify and advise on risk factors for cardiovascular disease and lifestyle changes.

For all these women preconception counselling should be offered for subsequent pregnancies especially if risk factors are identified so that potentially preventative strategies can be initiated.

Table 2  outlines briefly the management strategies for mothers with chronic hypertension and gestational hypertension. However, a detailed discussion is outside the scope of this article.

Introduction

First described in 1971 by Spillane et al.1, painful legs and moving toes (PLMT) is a syndrome consisting of pain in lower legs with involuntary movements of the toes or feet. Pain varies from moderate discomfort to diffuse and deep and usually precedes movements by days to years. The movements themselves are often irregular and range from flexion/extension, abduction/adduction to clawing/straightening and fanning/ circular movements of the toes.1,2 This syndrome may affect one leg or spread to involve both legs.3

PMLT incidence and prevalence remain largely unknown since it is still a relatively rare disorder worldwide. Age of onset is between the second and seventh decades of life. It has been postulated that lesions of the peripheral or central nervous system after nerve or tissue damage might lead to impulse generation that subsequently causes the symptoms seen in PLMT.4 We report a case of PMLT that presented to our Neurology Movement Disorder Clinic along with a discussion on the pathophysiology, differential diagnosis and clinical management of this rare debilitating condition.

Case report

63 year old, morbidly obese (BMI 41.7) Caucasian male patient with past medical history of stroke 10 years ago, on long term anticoagulation, hypertension, type II controlled diabetes mellitus, asbestos exposure, bilateral hip and knee osteoarthritis, left total knee replacement 2 years ago, and non-traumatic ruptured Achilles tendon; presented with complaints of involuntary movements in both legs over the last 8-10 years. He had unprovoked flexion and extension of the toes along with feet movement at all times with no diurnal variation. He admitted to having a constant severe pain described as 'twisting a rubber band' with 10/10 intensity that radiated up to his calf accompanied by numbness and dorsal swelling of both feet for many months. He claimed to have partial relief whilst walking but had difficulty walking without a cane as he ‘“could not balance with constantly moving [his] feet”’. Tylenol 500mg as required and amitriptyline 20mg at night prescribed by his primary care physician provided no relief.

He also has a history of snoring, daytime fatigue, and non-restorative sleep with frequent nocturnal awakenings due to bilateral feet pain. He recalled having a stroke with transient confusion and focal hand weakness along with visual problems about 10 years previously. All laboratory and radiological investigations were negative and he recovered fully. He had previously served with the US armed forces and had been exposed to ‘Agent Orange’ in Vietnam.

He had no medical allergies and his current medications include amitriptyline 25mg at night, hydrochlorothiazide 25mg once daily, lisinopril 10mg once daily, loradatine 10mg once daily, metoprolol tartrate 20mg twice daily, simvastatin 20mg once daily, vitamin B complex one tablet once daily and warfarin once daily. He denied any history of alcohol, tobacco, or recreational drug abuse in the past. His mother had a history of hypertension and chronic low back pain; no members of his family had any neurological or movement disorders.

Physical examination revealed an alert, awake, and well oriented male with bilateral lower extremity varicose veins. He was observed to have semi-rhythmic flexion-extension and occasionally abduction movements of the phalanges, especially in the great toes. There was a profound decrease in vibration sense below both knees and it was almost absent on both feet, decreased reflexes in both feet, and absent proprioception in the phalangeal joints. He was also observed to have decreased pinprick and monofilament sensation in both legs below the knee. Bilateral ankle reflexes were diminished with negative Babinski sign. Both lower extremity dorsalis pedis and posterior tibial pulsations were palpable. He did not have any cerebellar signs. He did have pitting oedema up to his shins in both lower extremities, extending from his feet to upper one third of the legs. There were no abnormalities noted on the bilateral lower extremity EMG and there was no electrodiagnostic evidence of large-fiber neuropathy.

He was diagnosed with painful legs and moving toes syndrome and started on a trial of gabapentin 300mg at night. He was advised to increase it to 1200mg and to continue taking his amitriptyline 25mg at night. Scheduled MRI of the brain could not be done due to his morbid obesity. He was arranged follow up in three months in the clinic.

Methods

A review of published literature on PLMT was done using MEDLINE and PubMed databases. Searches were conducted to find articles from 1971 – 2010. Medical subject headings used to search the databases included PLMT with subheadings of Movement disorder, Electromyography, and Polysomnography as well as keyword search using ‘PLMT’. Single author reviewed titles and abstracts of potentially relevant articles.

Review of current literature

We reviewed approximately 19 PLMT articles that have been published to date with a total of 72 patients: 30.5% males, 69.5% females (median age 55 & 64 years,

respectively). Clinical presentations in the majority of the cases were burning pain in lower extremities and involuntary movements of the toes. The most common predisposing conditions were neuropathy and radiculopathy (see Table 1).

Table 1 - Painful Legs & Moving Toes Syndrome ~ Review of Literature (1971- 2010)

Total Number of articles reviewed = 19
Total Number of Cases: Male = 22 (Median Age = 55 years); Female = 50 (Median Age = 64 years)
Author/Article References in chronological order (Top to below): 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 16, 17, 23, 24, 25, 29, 31, 32, 33

In 1981 Schott GD et al reported that in 3 PLMT patients the EMG revealed evidence of denervation in the affected muscles. Montagna et al of the University of Bologna, Italy reported 3 cases of PLMT that exhibited evidence of peripheral neuropathy on EMG. Polysomnography (PSG) studies on these patients showed reduced movements during sleep with increase in slow wave or rapid eye movement sleep.5 This suggested the movements could have arisen centrally.

Guimaraes et al of the Universidade Nova Lisboa, Portugal reported one patient with a history of Hashimoto’s disease whose lower extremity EMG showed spontaneous arrhythmic bursts of the affected muscles during wakefulness which disappeared during sleep6. Both suggested the movements could have arisen centrally.

Alvarez et al of the Mayo Clinic described 14 cases of PLMT in 2008 in which burning pain often preceded the movements. PSG studies confirmed these movements would also persist in light stages of sleep which pointed to a central origin.7 Eisa et al of Yale University School of Medicine, Connecticut described 2 cases of PLMT in which one patient had a past history of lumbosacral root injury and the other systemic lupus erythematosus with peripheral neuropathy on EMG.8 Interestingly, in the latter patient her pain occurred years after the onset of involuntary toe movements.8

Discussion

Spinal cord and cauda equina diseases, neuropathies, radiculopathies, drugs and other systemic diseases are the main cause of this syndrome although many cases are still idiopathic. The most common predisposing conditions were neuropathy (i.e. polyneuropathy from alcoholism, hypertrophic mononeuritis, or tarsal tunnel syndrome) and radiculopathy.7 Other etiologies include nerve root lesions, peripheral nerve trauma, spinal ganglia lesions, cauda equina lesion, Wilson’s disease, herpes zoster myelitis, HIV, neuroleptics, and chemotherapeutic agents.9-19

The involuntary movements appeared bilaterally in the toes in our patient, which suggests that central reorganization (especially in the spinal level) is the cause of PLMT. EMG and nerve conduction studies have proven helpful in demonstrating spontaneous arrhythmic bursts of affected muscles and underlying neuropathy in some patients. Although the exact mechanism remains elusive, it has been proposed that impulses generated in lesioned peripheral nerve, posterior nerve root/ganglion, or afferent fibers pass into the spinal cord - some to higher areas to cause pain, while others into the local interneuron and motor neurons to generate involuntary movements of the toes.5

In patients with clinical or electrophysiological evidence of peripheral nerve or root problem, these lesions can initiate or even alter afferent input to the spinal cord and cause subsequent central and efferent motor reorganization, which may explain the limited

success these patients had with nerve blocks or lumbar sympathetic blockade.2 Similarly, some have suggested that even though the radiation of pain following local trauma seemed to resemble causalgia,20 there was a lack of hyperpathia and changes in the soft tissue, bones, and blood vessels as well as a poor response to sympathetic blockade, thus making clinical features of PLMT inconsistent with known radicular disorders.3

Interestingly, some believed that the central nervous system played an essential role in PLMT via a central oscillator.21 It has also been proposed that hyper-excitability of the damaged peripheral nerves could cause symptoms of PLMT by way of the sympathetic nervous system. More specifically, the sympathetic nervous system could potentially serve as a bridge between injured afferent fibers and sympathetic nerve fibers,22 allowing abnormal afferent impulse to travel to efferent fibers and ultimately leading to continuous pain with involuntary movements. This was evident in the fact that lumbar sympathetic ganglion blockade provided moderate symptomatic relief for some patients even though it was short-lived.4 Interestingly, one of the explanations put forth was the possibility of spinal/supraspinal reorganization,23 which coincided with the hypothesis of central reorganization mentioned above.

Clinical Management

Numerous treatments including antiepileptics, benzodiazepines, antispasmodic agents, and antidepressants have been tried with little success.1,2,24,25 However, temporary success was observed with local anesthetic nerve blocks, epidural blocks, sympathectomy/sympathetic blockade, neurectomies, botulinum toxin type A injection, transcutaneous electrical nerve stimulation, vibratory stimulation, and epidural spinal cord stimulation.1,2,15,26,27 Analgesics, steroids, anti-inflammatory agents, vitamin B12 injections, propranolol, quinine sulphate, and local anesthetics only offered temporary relief as well.3 GABAergic agents such as gabapentin and pregabalin were the most effective in attenuating the pain and the movements, possibly via both central and peripheral mechanisms.7,24,25 It has been reported that gabapentin as high as 600mg three times daily could control symptoms of PLMT long-term.25

Treatment of PLMT has also been attempted with botulinum toxin A at the level of lumbosacral roots and peripheral nerves with moderate relief of symptoms, although toe movements did return after a few months.8 It was suggested that botulinum toxin A might have acted via reduction of muscle spindle discharge leading to decreased central sensitization, as well as antisympathetic, antiglutamergic, or anti-inflammatory effects.28

Differential Diagnosis

The syndrome of PLMT exhibits certain features similar to the restless leg syndrome (RLS). In RLS the sensation in the legs could be burning, creeping, or tingling coupled with an urge to move them, especially early in the night. Movements such as walking or stretching relieve the symptoms whereas rest makes them worse. However, in PLMT pain is severe, constant, unrelated to the sleep-wake cycle, and is not relieved by

movements or walking.23 In addition, its involuntary movements of the toes or feet also differ from the myoclonic jerks of RLS.

In conditions such as thalamic syndrome and limb pain with myoclonus, patients may experience pain and involuntary movements as well but they often occur simultaneously as opposed to in PLMT where pain often precedes the movements.17 In disorders such as Parkinson’s disease and dystonia, sustained involuntary movements in the feet can be present and pain can be an associated feature. But the movements are typically sustained muscle contractions, which are different from the typical movements associated with PLMT.

Prognosis

PLMT is a newly discovered syndrome and since there has not been a systematic study following these patients long-term, it is currently quite difficult to predict the outcome of this syndrome and its effect on lifespan, though there has yet been a report of a patient actually dying from this syndrome. However, it is known that PLMT is a debilitating condition that greatly reduces patients’ quality of life.

Conclusion

Since Spillane et al first described it in 1971, there have been more reported cases of PLMT and its variants over the years. Though much progress has been made in elucidating its etiology, its exact mechanism still remains a mystery. Similarly, even though EMG and nerve conduction studies have proven helpful in demonstrating spontaneous arrhythmic bursts of affected muscles and underlying neuropathy in some patients, diagnosis of PLMT remains largely on history and clinical presentation.

Physicians should be aware of this rare debilitating condition. It is important to consider PLMT in a patient with painful legs and/or restless leg syndrome without any significant history of neurological disease or trauma. Treatments such as different combinations of medications and invasive techniques are complex and generally lead to a poor outcome.

Introduction

William Osler has said that "A desire to take medicine is perhaps the great feature which distinguishes man from animals" This desire, however may play havoc when a person starts taking medicines on their own (i.e. self-medicating), forgetting that all drugs are toxic and their justifiable use in therapy is based on a calculable risk ¹.

Self-medication (SM) can be defined as obtaining and consuming drugs without the advice of a physician². There is a lot of public and professional concern about the irrational use of drugs in SM. In developing countries like India, easy availability of a wide range of drugs coupled with inadequate health services result in increased proportions of drugs used as SM compared to prescribed drugs². Although, over-the-counter (OTC) drugs are meant for SM and are of proved efficacy and safety, their improper use due to lack of knowledge of their side effects and interactions could have serious implications, especially in extremes of ages (children and old age) and special physiological conditions like pregnancy and lactation ³, ⁴. There is always a risk of interaction between active ingredients of hidden preparations of OTC drugs and prescription medicines, as well as increased risk of worsening of existing disease pathology ⁵ . As very few studies have been published in our community regarding usage of self medication we conducted this cross-sectional study in the coastal region of Pudhucherry, South India, t assess the prevalence and pattern of SM use.

Materials and methods:

The present study was a cross-sectional survey conducted in coastal region of pudhucherry, south India. For this study we recruited 200 patients randomly from both urban and rural communities (100 each) for a period of six months during 2009. Patients who were = 18 years of age and who were able to read and write the local language (Tamil) or English were included in the study after informed consent explaining the purpose of the study. Participants with intellectual, psychiatric and emotional disturbances that could affect the reliability of their responses were excluded from the study. To collect data regarding SM usage a structured questionnaire was prepared, after an extensive literature review.. The structured questionnaire contained 25 items in the form of closed and open ended questions. Initially the tool was validated by a panel of experts in the field of public health for the appropriateness of each item and assessment of content validity (0.91) and re-test reliability coefficient (0.89). Approval to conduct the study was granted by the Institute ethics committee prior to data collection. Each participant underwent a face to face interview to collect data followed by an informal educational counseling about potential adverse effects of consuming common SM. Data collected was analyzed using SPSS for windows statistical software version 14 (SPSS Inc., Chicago, Il, USA). Data was presented using descriptive statistics (i.e. numbers, percentage) and inferential statistics (i.e. Chi-square). A probability value of < 0.05 was considered to be significant.

Results

Basic demographic details:

The majority of the participants were female (56%). Most of the participants (60%) were between 26-45 years of age. There were an equal number of participants from the rural and urban community. Among the total 200 participants 70% were literate.

Findings related to usage of SM:

Overall, out of 200 participants, 71 % of them reported that they have used SM in the past. The frequency of SM use varied among the subjects with a minimum of at least one time to maximum of 5 times and above See Figure 1. When the participants were asked about the reasons for SM use, the majority of them - 41.5% - stated lack of time to visit a doctor as the main reason followed by minor illness and quick relief. See Table 1.   The major source through which the participants learned to use SM were as follows, directly from pharmacist (57.3%), prescription of previous illness (21.5%), friends (12.5%), television (5.5%) and books (3%).See Table 2. The main indications for SM use were fever (36%), headache (35%), then cough/cold/sore throat (20%). See Table 3 for detailed data.

Figure 1: Frequency of self medication Use

Table 1: Reasons for Self Medication Use

Table 2: Sources of Self Medication Use

Table 3: Indications for Self Medication Use

While calculating chi-square to find out the association between usage of SM and selected demographic variables we found an association between residence (i.e. rural or urban) and gender; urban people were more likely to use SM than rural people (urban, 60/100 vs. rural 82/100, p value = .006). In relation to gender females were more likely to use SM in comparison to males (female, 78/112 vs. 43/88, p value= .002). Other variables were not significantly associated with SM use. Finally, when the subjects were asked about the side effects of their used self medications 93.5% of them said that they are not aware of the side effects and only the remaining 6.5% of them said they are aware of the side effects.

Discussion 

The current study examined the prevalence and pattern of SM use in a coastal region of South India. The study findings revealed 71% of the people reporting SM use in the past,  this prevalence rate in our study is consistent with previous finding³,⁶,⁷,⁸,⁹,¹⁰,¹¹ The figure of participants who use SM is very high, which requires immediate attention. The frequency of self medication use in our study ranged from a minimum of one time to a maximum of 5 times and above, this finding was in line with the findings of a study by Nalini (2010)¹².

Participants cited multiple reasons for use of SM like lack of time , quick relief from illness and ease and convenience, a similar reasons were cited  in an another Indian study¹³. In the current study participants reported SM use in a variety of conditions like headache, stomach ache, cough and fever, this these finding are comparable with those of Sontakke et al (2011) ¹⁴. The reason for SM use may be mufti-factorial, in our study an association was found between gender and residence, i.e. female and rural people reporting more  SM use, this finding was similar to two previous studies¹⁵,¹⁶ To establish the reasons why requires further research. One potential limitation of this study is the limited sample size, which we tried to overcome by adopting a random sampling method so as to generalize findings.

Conclusion

Factors influencing SM include patient satisfaction with the healthcare provider, cost of the drugs, educational level, socioeconomic factors, age and gender ¹⁷. Interactions between prescribed drugs and the drugs taken for SM is an important risk factor of which healthcare providers must be aware of.^17,2

Easy availability of wide range of drugs without a prescription is the major factor responsible for irrational use of drugs in SM as, thus resulting in impending health problems (antimicrobial resistance, increased load of mortality and morbidity) and economic loss. The need for promoting appropriate use of drugs in the health care system is not only for financial reasons, with which policy makers and manager are usually most concerned, but also for health and medical care of patients and the community. There is need for authorities to strengthen existing laws regarding OTC drugs to ensure their rational sale and use. Also, specific pharmacovigilance is needed and the patient, pharmacist and physician must be encouraged to report any adverse events. Periodic studies on the knowledge, attitude about and practice of SM may give insight into the changing pattern of drug use in societies.

Chronic obstructive pulmonary disease (COPD) is a debilitating condition resulting in significant morbidity and mortality. It is the fifth leading cause of death in the UK ¹, estimated to be the third by 2020 ².

Definition:

1. COPD is a preventable and treatable disease with some extra-pulmonary effects that may contribute to the severity in individual patients Its pulmonary component is characterised by airflow limitation that is progressive and not fully reversible. There is an abnormal inflammatory response of the lung to noxious gases and particles, most commonly cigarette smoke ³.
2. Airflow obstruction is defined as post-bronchodilator FEV₁/FVC ratio (where FEV₁ is the forced expiratory volume in one second and FVC is the forced vital capacity) of less than 0.7 If FEV₁ is ≥ 80% predicted, a diagnosis of COPD should only be made in the presence of respiratory symptoms ⁴.

Incidence/ Prevalence:

Within the UK it is estimated that 3 million people are affected with COPD ⁴. However, only 900,000 are diagnosed ^-4An estimated two million people who have COPD remain undiagnosed ⁴.

Causes:

90% of cases are smoking related ⁴, particularly those with >20 pack year smoking histories ⁵. Environmental and occupational factors can also play a role, including exposure to biomass fuels such as: coal, straw, animal dung, wood and crop residue which are used to cook in some countries and heat poorly ventilated homes COPD occurs in 10-20% of smokers, suggesting there is an element of genetic susceptibility ^{2-3, 5}.

Diagnosis:

To make a diagnosis of COPD an obstructive deficit must be demonstrated on spirometry in patients over the age of 35 years with risk factors (mainly smoking) and signs and symptoms of the disease ⁴.

Signs and Symptoms:

1. Progressive dyspnoea on exertion
2. Chronic cough
3. Chronic sputum production
4. Wheeze
5. Frequency of exacerbations – particularly during winter months ⁴
6. Functional status – bearing in mind gradual progression of disability, effort intolerance and fatigue.
7. Features suggestive of Cor pulmonale ⁵:
   1. Peripheral oedema
   2. Elevated jugular venous pressure
   3. Hepatomegaly
   4. Right ventricular heave
   5. Tricuspid regurgitation

Investigations/ Tests to consider:

1. Post-bronchodilator Spirometry – essential in confirming the diagnosis of COPD.
   1. Demonstrating an obstructive picture.
   2. FEV₁ is used to assess the progression and severity of COPD, but correlates poorly with the degree of dyspnoea ^3-6. (Table 1)

2. Pulmonary functions tests – Markers suggesting the presence of emphysema include:
   1. Reduced TLCO and KCO due to a reduced surface area for gaseous exchange ⁵.
   2. Raised Total lung capacity, residual volume and functional residual capacity due to air trapping ⁵.

3. Chest radiograph – Is not required for the diagnosis, but is recommended to exclude other conditions such as interstitial lung disease, pleural effusions or pneumothorax. It may demonstrate features of the condition, such as ^{3, 5}:
   1. Hyperinflated lung fields
   2. Flattened diaphragms
   3. Bullous changes, particularly at the apices

4. BODE index prognostic indicator – This is grading system shown to be better than FEV₁ at predicting the risk of hospitalisation and death in patients with COPD. Patients are scored between 0 and 10, with higher scores having an increased risk of death. It encompasses ^{3, 5-7}: (Table 2)
   1. BMI
   2. Airflow Obstruction – taking into account the FEV₁
   3. Dyspnoea – in accordance with the Medical Research Council (MRC) scale ^5.
   4. Exercise capacity – measured by the distance walked in 6 minutes. (Table 3)

Table 1. Severity of airflow obstruction ⁴

Table 2. BODE Index ^{3, 5-8}

Table 3. Medical research council (MRC) Dyspnoea scale ^{5, 8}

Differential Diagnosis:

1. Asthma – the most important differential diagnosis to consider.
   1. This is steroid and bronchodilator responsive
   2. Indicative of reversible airway obstruction.
   3. It is not associated with smoking.
   4. Patients with asthma may exhibit ^{3, 9}: chronic non-productive cough, variability in breathlessness, diurnal /day-to-day variation, nocturnal wheeze and dyspnoea
   5. However both conditions may coexist creating diagnostic uncertainty.

2. Alpha₁ antitrypsin deficiency is an autosomal dominant condition associated with an increased risk of developing emphysema at an early age ^{3, 5, 9}.
   1. It can occur in non-smokers
   2. Can be asymptomatic and thus under-diagnosed with an estimated 1 in 2000-5000 individuals being affected ⁵.
   3. The disease is worse in smokers
   4. COPD can develop in patients < 35years of age
   5. It is associated with liver cirrhosis.
   6. All patients with COPD should be screened.
   7. Emphasis should be made to avoid smoking, including passive smoking.

3. Other conditions to consider include:
   1. Bronchiectasis
   2. Interstitial lung disease
   3. Cardiac failure.

Treatment:

Goals of management include:

1. Early and accurate diagnosis
2. Improve symptoms and quality of life
3. Reduce the number of exacerbations
4. Improve mortality

Non-pharmacological management:

1. Smoking cessation – an accurate smoking history should be obtained, including the number of pack years smoked. All current smokers with COPD should be encouraged to stop at every opportunity, and offered smoking cessation advice. Advising the patient alone will help a certain proportion to stop, whilst referral to smoking cessation services has been shown to further increase in quit rates. There are a range of nicotine and other pharmacological therapies available such as Bupropion (Zyban^®) and Varenicline (Champix^®) ^{3-4, 7, 8}.
2. Vaccinations – A once off Pneumococcal and annual Influenza vaccine should be offered.
3. Pulmonary rehabilitation – Should be offered to patients who have had a recent exacerbation requiring hospitalisation and those that have an MRC score of ≥ 3, but are still able to mobilise and thus have the potential for further rehabilitation. It is not suitable for those patients that are immobile or limited in their mobility due to symptoms of unstable angina or a recent cardiac event. Benefits are seen in terms of reduced hospital admission, improved quality of life and exercise tolerance Commitment to the programme should be relayed to the patient, and each programme should be tailored to their individual needs. This usually includes ^3-5:
   1. Disease education – which can improve the ability to manage their illness.
   2. Exercise – tailored programmes to prevent de-conditioning and improve functional exercise capacity, dyspnoea and quality of life ⁴. This includes strength and endurance training of upper limbs and respiratory muscles Benefits may be seen even after 6 months.
   3. Physiotherapy – to teach active cycle breathing techniques or to use positive expiratory pressure masks in patients with excessive sputum production.
   4. Nutritional support – in the form of supplementation or dietician advice in patients with a suboptimal BMI. A low BMI is associated with increased mortality as it is associated with poor exercise capacity, reduced diaphragmatic mass and impaired pulmonary status. Alternatively, weight loss is recommended in patients who are in the obese range.
   5. Psychological – Assessment for support at home, introduction of patients to day centres, assessing for features of depression and anxiety, and aiding in the obtainment of a car disability badges may require referral to occupational therapy and social services.

4. Travel advice – Patients who are planning air travel and have FEV₁ <50%, Sa0₂ < 93%, or are on long term oxygen therapy (LTOT) should undergo formal assessment ^-4Patients with bullous disease should be informed that they are at increased risk of pneumothorax during high altitude flights ⁴.

Pharmacological management:

1. Bronchodilators – Provide long term benefit in reducing dyspnoea. This is not reflected in improvements in FEV₁ as it may not show reversibility ⁴.
   1. Start with an inhaled SABA (short-acting beta₂-agonist) or a SAMA (short-acting muscarinic antagonist) on an as required basis for symptomatic relief. If symptoms remain despite regular SABA therapy (i.e. four times a day), then treatment will need to be stepped up.
   2. If symptoms persist or if the patient is having recurrent exacerbations add in a LABA (long-acting beta₂ agonist) or a LAMA (long acting muscarinic antagonist).
   3. If symptoms continue, add in a LAMA if already on a LABA (or vice versa).
   4. If FEV1 <50% add in an inhaled corticosteroid (ICS). This can be offered as a combination inhaler.

Inhaled therapy should offer sufficient bronchodilator response. A spacer can be used for those with poor technique. Nebulisers are reserved for patients who demonstrate respiratory distress despite maximal inhaled therapy, and for those that show an improvement in symptoms or exertional capacity ⁴.

Diagram 1: Summary of step-by-step management ⁴

2. Corticosteroids – A short course of oral steroids may be used during exacerbations. A maintenance course however is not recommended Any patients on long term steroids should be weaned off.
3. Mucolytic agents – May be considered in patients with a chronic cough who have difficulty expectorating. They should only be continued if symptomatic benefit is evident, otherwise they can be stopped. There is no evidence to show that they reduce the exacerbation frequency.
4. Theophylline – Should only be offered in people that are unable to use inhaled therapy or after trials of SA and LA bronchodilators ⁴. The same generic brand should be prescribed as individual brands will have different efficacy. It is usually used as an adjunct to beta₂-agonists and muscarinic antagonists. Interactions with macrolides and fluroquinolones and other drugs are also common, and as such the theophylline dose should be reduced if interactions are known. Caution should be taken in prescribing theophylline in the polypharmacy patient ^{3, 5}. Little evidence has been shown to support theophylline usage in COPD (compared to asthma), however it is used for its anti-inflammatory effects As such levels are only performed if toxicity is suspected and should not be adjusted if in the sub-therapeutic range.
5. Oxygen therapy – Patients should be assessed for long-term oxygen therapy (LTOT) if they exhibit ⁴:
   1. Severe airflow obstruction
   2. Features of Cor pulmonale
   3. Hypoxaemia (Sa0₂ ≤ 90%)
   4. Cyanosis
   5. Polycythaemia

Patients with stable COPD who are receiving maximum medical therapy are assessed by measuring arterial blood gases taken on two separate occasions at least 3 weeks apart. To meet the criteria patients must have ⁴:

1. A Pa0₂ < 7.3 kPa when stable, or
2. A Pa0₂ >7.3 but < 8.0 kPa when stable and:
   1. Pulmonary hypertension or
   2. Peripheral oedema or
   3. Secondary polycythaemia or
   4. Nocturnal hypoxaemia

LTOT should be used for a minimum of 15L per day, including during sleep ^3-4.

Patients who continue to smoke should be made aware of the serious risk of facial injuries due to the highly flammable nature of oxygen.

When to refer:

Referrals for specialist advice or specialist investigations may be appropriate at any stage of the disease.

Other possible reasons for referral ⁴

Follow-up:

Patients with stable mild-moderate COPD should be reviewed by their general practitioner at least once a year and those with severe COPD twice yearly.

At each visit ⁴:

1. An opportunity should be taken to ask about their current smoking status and the desire to stop.
2. Assessment of adequate control of symptom: dyspnoea, exercise tolerance and the estimated number of exacerbations per year.
3. Assessment of inhaler technique.
4. To assess the effects/side effects of each drug treatment.
5. The need for pulmonary rehabilitation.

For those patients with very severe airflow obstruction (FEV₁ < 30%), the above still remains, in addition to the assessment of ⁴:

1. Features of Cor pulmonale
2. Nutritional status
3. The need for LTOT
4. Signs of depression
5. The need for occupational therapy and social services input
6. Referral to specialist and their services
7. Measurements of:
   1. FEV₁ and FVC
   2. BMI
   3. MRC dyspnoea scale
   4. Sa0₂ via pulse oximetry

Those patients requiring long term non-invasive ventilation will be reviewed by a specialist on a regular basis.

Patient Information:

§ www.patient.co.uk/health/Chronic-Obstructive-Pulmonary-Disease.htm
§ www.lunguk.org/you-and-your-lungs/conditions-and-diseases/copd
§ http://smokefree.nhs.uk/ways-to-quit

Interest in cross-species transplantation has recently been rekindled¹. This is due to many developments including the shortage of donor organs, advances in transplant medicine, investment in biotechnology research, and the non-availability of more ethically suitable alternatives to human organs. Increasing success rates in allotransplantations (organs from different member of the same species) has increased the demand on donor organs^{1, 2}. Other types of transplantation include autotransplants (a person’s own organs or tissues are used for transplantation) and isotransplants (organs from one person are transplanted into another genetically identical person, like an identical twin). These options are limited in terms of body parts used and numbers.

Good facts inform good ethics. It is therefore obligatory to look into the current research knowledge about xenotransplants (organs from one species to another, for example animal to human) in more detail. The advocates of xenotransplantation argue that it could provide organs “relatively quickly” and hence save more lives.  If animal organs were easily available for transplantation most eligible recipients would receive the transplantation much earlier on in their illness. It is argued that this may decrease distress and suffering. Whilst xenotransplantation may theoretically increase the survival time, it is unclear, however, whether the negative impact on recipients’ quality of life due to long-term immunosuppressant therapy and the risk of zoonotic infections would in fact worsen the overall long-term outcome³. Recent research suggests that xenotransplantation may be associated with the transmission of pig microorganisms including viruses, bacteria, fungi, and parasites. Because of the recipient’s likely immunosuppressed state, infection and pathologic consequences may be more pronounced. Transmission of most microorganisms with the exception of the porcine endogenous retroviruses may be prevented by screening the donor pig and qualified pathogen-free breeding. However, porcine endogenous retroviruses represent a special risk as they are present in the genome of all pigs and infect human cells in vitro. Until now, no porcine endogenous retrovirus transmission was observed in experimental and clinical xenotransplantations as well as in numerous infection experiments⁴. Nevertheless, strategies need to be developed to prevent their transmission to humans. It is equally possible that many eligible recipients may be denied having a trial of xenotransplantation by doctors who believe that there is an unfavourable risk-benefit ratio. The limited long-term data on outcomes of xenotransplants thus renders ethical analysis difficult.

There is some evidence to suggest that the recipients of animal organ donation may develop a different self image with possible consequences for their identity^5,6.  This happens with human organs at times, but may be a more significant problem with animal organs, as the recipient knows that they have been given a non-human organ. Loss of identity jeopardises the core principle of autonomy, which underpins all medical treatment.

The risk of zoonosis to the recipient and to the wider society cannot be accurately estimated⁷. Hence there is a requirement for vigilant post-operative monitoring⁵ with a possibility of engaging article5 and 8 of the European Convention of Human Rights (for England and Wales: Human Rights Act 1998)^†. Article 12 may also be engaged as the recipients may be restricted from having physical relationships, carrying out their routine day to day activities and socialisation. This is because the prevention of possible risk to the wider public from zoonosis may require the recipient to be put under restrictions with regard to their engagement with others. This may include restrictions to go out, which can result into de facto temporary detentions at home. Hence consenting to xeno-transplantation would be “binding and contractual” over a long period of time. The subject may not have the right to withdraw. This is entering into a de facto contract with potential restrictions or even deprivation of human rights. This would restrict the ability to give informed consent even for a well informed patient, as it is difficult to be fully appreciative of future restrictions of one’s liberty.

Autonomous decision making and thus informed consent may also be put at risk by other factors surrounding xenotransplantation. The decision to embark on xenotransplantation may be primarily driven by an instinctual wish to survive due to a lack of other viable alternatives. Patients in these circumstances may have little or no consideration to medium and long-term effects on themselves and society. However, it is the consideration of such long-term consequences that make a truly autonomous decision, and differentiate it from a decision that is purely based on immediate instinct. Whilst the wish to survive is legitimate it is difficult to make decisions free of the pressure to survive when there is a lack of alternatives.

It also brings up an even more important question: Can any person ever consent to a future restriction or deprivation of their liberty or other human rights? Even if there were an option to define acceptable future restrictions it would be likely that patients could still challenge the legality of any such agreements. They could quite reasonably argue that they have agreed to the restrictions under duress because of a lack of viable alternatives to their xeno-transplants.

Xenotransplantation touches questions of utilitarianism (greatest good for the greatest numbers) and public protection². Utilitarianism takes into account the reasonable interests of society in good outcomes, fairness in the distribution of resources, and the prevention of harm to others. The Nuffield council on bio-ethics embraces a utilitarian approach. However, there are limits to the utilitarian argument for xenotransplants. Even if they were widely available, the treatment would be immensely expensive. Production of a pathogen free donor organ would involve rearing animals in strictly controlled environments, subjecting them to rigorous standards of examination and surveillance. The additional costs of developing a sustainable work force to provide transplantation and post-transplant surveillance of the patient and the community would be high.  The insurance providers may not cover expenses of a xenotransplant. Public health care providers may decline to provide this treatment as it may not be recommended by expert groups as cost effective. Xenotransplantation may commence in the developing world where the regulations are lax and the poor can be more easily exploited⁸. Patients who would potentially benefit from xenotransplantation may not be able to afford it due to its cost with serious implications for fairness.

Xenotransplantation also raises other ethical questions in relation to the wider community.  We have seen that consent of an individual to a xenotransplant has significant bearing on the protection of society⁷. Should the members of a community therefore be consulted if there were any xeno-transplantation experiments in their region? The risk is primarily due to the risk of zoonotic infections, the need for surveillance, and possible quarantine of contacts^7,9.  In addition, if health authorities were to fund expensive experimental interventions like xenotransplantation, other routine treatments of greater potential benefits to society may be jeopardised. Society may also have views about particular animals being used as donor animals¹⁰.  For example religions like Islam and Judaism may feel that pigs are ‘ritually unclean’. They may therefore not approve of certain animals to be used for donation, and more worryingly may fail to socially accept recipients with such ‘unclean’ transplants¹¹.

From a deontological perspective (this judges the morality of an action based on the action's adherence to a ruleor principle) some authors assert that animals have rights similar to those considered appropriate for humans^12,13. The protection of animals has legal status in many countries. Consequentialists may view the suffering and death of an animal as acceptable for the betterment of a human patient, as they would judge the morality of an action primarily by its end result. They would argue that potential benefits and improvement in human welfare arising from xenotransplantation may justify the loss of animal life. However, this will never satisfy the animal rights lobby; especially as whilst minimising the risk of acquired infections, the animals have to forgo greater suffering in the form of isolation, monitoring and investigations. Furthermore, genetic modification can have both immediate and long-term negative effects on animals.

In summary, xenotransplantation has significant ethical consequences. On an individual level, there are the questions of pressure to consent that may negate autonomy and the validity of that consent as well as the difficulties that arise when patients are asked to consent to future restrictions of their human rights. On a societal level there are questions of cost and benefit analysis as well as risks from zoonotic infections. In addition, questions of animal rights need to be addressed before any programs are likely to go ahead.

^†Appendix of articles of the Human Rights Act.

• Article 8 of the Human Rights Act 1998 (The right to respect for private and family life, home and correspondence)
• Article 5 (The right to liberty).
• Article 12 (The right to marry and found a family)

Introduction

The use of convulsive therapy for psychiatric conditions evolved after its first use by Meduna using camphor in 1934, and by 1938, Cerletti and Bini had documented the use of electricity to induce convulsions and therapeutic benefit. The technique has been extensively modified by the addition of muscle relaxants and general anaesthesia. Electroconvulsive Therapy is now an important and effective treatment option for certain severe neuropsychiatric disorders.

Most developments and changes in the practice of ECT have been driven to reduce the adverse effects and not by the need to make it more efficacious. The aim is to induce a generalised tonic-clonic seizure with a sufficient dose to maximise efficacy but not too high to reduce cognitive side effects. The newer brief-pulse, constant-current, square-wave machines are more efficient in inducing seizure than the older sine-wave, constant-voltage machines.

Between January and March 2002, there were nearly 12800 ECT administrations in England to 2300 individuals ¹. The National Institute of Clinical Excellence currently recommends that ECT is only used to achieve rapid and short term improvement of severe symptoms after an adequate trial of other treatment options have proved inefficient and/or when the condition is life threatening as in people with severe depression, catatonia or prolonged/severe manic episode². The newer guidelines on depression suggest that ECT be considered as a treatment option in moderate depression when it has failed to respond to multiple treatments¹⁵. It has been noted from the observation of the users experiences that the cognitive impairment often outweighed their perception of any benefit after ECT treatment.

It has been recognised that the induction of a generalised tonic-clonic seizure is necessary to achieve a therapeutic response and a number of studies demonstrate superiority of ECT over Sham ECT. It is also noted that administration of an electrical stimulus that fails to induce a seizure and immediate termination of a seizure after induction does not result in clinical improvement. Stimulus which just about produces a generalised tonic-clonic seizure may not ensure therapeutic potency, but the degree to which the stimulus intensity exceeds the Seizure Threshold is an important determinant of the therapeutic effectiveness. Unfortunately, this also corresponds to the cognitive side effects³.

Seizure Threshold

Seizure Threshold is empherically defined as the minimal electrical dose that induces generalised tonic clonic seizure activity. Boylan et alfound that greater that 40% of individuals had an initial seizure threshold of less than 50mC with unilateral electrode placement⁴ and Scott and Dykes and Sakheim concluded that for bilateral ECT, this was around 7%^5,9.

Standard fixed doses continue to be used in UK, and this can result in a dose which is several times the seizure threshold, contributing to acute and long term cognitive side effects without any additional benefits of clinical efficacy. It is also associated with a greater risk of missed or partial seizures that have no therapeutic effect.

There is a great deal of variability between seizure thresholds in different individuals. Many factors influence it and Box 1 summarises them. Seizure threshold is generally higher in older men than younger women. Electrolyte imbalances, particularly, hyponatremia and hypocalcaemia can lower the seizure threshold. It is important for the clinician to consider these before starting the course of ECT.

Initiation of a course of Electroconvulsive Therapy treatment should routinely involve the estimation of the seizure threshold by gradual dose titration (Stimulus dosing) and then treatment by using the supra threshold doses. Once seizure threshold is determined a dose of 1.5 to 2 times the seizure threshold for bilateral ECT and at least 2.5 to 3 times the seizure threshold for unilateral ECT may provide the best balance of clinical efficacy and cognitive side effects³. This is supposed to be a better practice compared to the fixed dose method used to initiate the ECT treatment.⁶

Missed Seizure

An adequate electrical dose will manifest as generalised tonic, followed by clonic activity of skeletal muscle, accompanied by a typical seizure pattern on EEG. The absence of both is deemed a missed seizure⁷.Pippard’s audit of ECT practice showed that in nearly 22% of ECT treatments, there was either no seizure or a brief seizure.

The causes of Missed Seizures are summarised in Box 2. Missed seizures may be due to faulty technique leading to insufficient stimulus intensity, excess impedance or premature stimulus termination. Individual patient factors such as electrolyte imbalances, particularly dehydration and hypercarbia can lead to missed seizures. A common reason for raised seizure threshold is the administration of high dose of anaesthetic induction agent ⁵. Propofol, the most commonly used agent for ECT increases seizure threshold and also decreases the seizure duration. Use of alternatives like Methohexital, Etomidate or Ketamine may be successful as they either have minimal or no effect on seizure threshold and may increase the seizure duration.

During the course of treatment seizure threshold usually rises and this may lead to missed seizures. In addition to delaying the improvement, missed seizures cause more irritability and restlessness¹⁰. By measuring the seizure duration during the course of ECT missed seizure could be anticipated and appropriate steps can be taken. Some of the effects of a missed seizure are listed in Box 3.

A missed seizure should prompt monitoring and correction of electrolyte imbalance if any. Seizure activity during the ECT procedure is affected by medication as well. Administration of seizure threshold increasing drugs should be reviewed and where possible stopped or reduced. If the treatment is for depression, consider using tricyclic drugs which lower the seizure threshold and augment ECT.

The maximum dose deliverable by the ECT machines is restricted in some countries and this may be inadequate due to very high seizure threshold in a few individuals. The US Food and Drug Administration restrict the maximum output of ECT machines to 576 millicoulombs compared to the Royal College of Psychiatrists which has recommendeda maximum output charge of 1200millicoulombs⁸. While higher electric doses may be able to induce generalised seizure activity, the cognitive side effects are also increased¹¹. Therefore attempts must be made to decrease the seizure threshold to minimise these side effects.

Seizure Threshold Lowering Techniques

The aim of ECT treatment is to induce a generalised seizure activity; failure to do so makes the treatment session ineffective and of no therapeutic benefit. If a patient does not have generalised tonic-clonic seizure after a stimulus it is important to wait for at least 20 seconds after a non-seizure and at least 45 seconds after a partial/focal seizure prior to restimulating. Using appropriate techniques to avoid like low stimulus intensity, inappropriate application of electrodes, premature stimulus termination, etc are important⁶.

Charter and Simpson established the use of hyperventilation immediately before the application of the electrical stimulus and it has been shown to enhance seizure duration¹². Sleep deprivation safely reduces the seizure threshold and also increases the seizure duration¹³. Caffeine prolongs the seizure duration, but has no effect on the seizure threshold¹⁴.

Conclusions

ECT remains the most maligned and misunderstood of psychiatric treatments. Whilst it has no doubt, successfully saved many lives and provided relief from the abyss of depression, proving its efficacy, the thrust of recent developments have been towards minimising the side effects. Adequate training and supervision of trainee psychiatrists will be essential to raise the standards of ECT administration techniques and skills.

Being aware of the significance of seizure threshold and ways to lower it, as an alternative to electric dose increase may address to some extent, the concerns about cognitive difficulties.

“The more we care for the happiness of others, the greater our own sense of well being becomes.”  The Medicine of Altruism: Dalai Lama

Introduction

The fundamental mission of any medical school is to select those individuals who possess the qualities and personality traits best suited to becoming a good doctor. The first part of this article takes a critical look at how United Kingdom (UK) medical schools select doctors, which can vary considerably, and asks whether it can be improved. The qualities needed to be a good doctor are discussed and asks whether work experience illustrates at least some of these personal qualities and should therefore be an essential prerequisite for applying to medical school. Such experience helps the student to make an informed career choice and exploring it at interview can reflect student motivation to study medicine. My experience in Ghana gave me the opportunity to find out at first hand if I had what it takes to become a doctor. The trip was totally inspirational. It made me realise that medicine is much more than being master of all sciences. In Ghana I saw many of the qualities one needs to be a doctor, how this contrasts with the current selection criteria in the UK, and made me wonder whether the UK system offers our society the best practice available.

Critique of UK medical school selection           

Applying to medical school has become increasingly competitive. Selection into medical schools is not an exact science but one assumes that best available evidence is being used. The present system almost certainly turns away students who would make good doctors and accepts some who are mediocre or poor or even drop out of medicine altogether. The selection criteria for entry into medicine have to be accurate. However, no system is fool proof and the number of drop-outs in UK training stands at 6.8 – 12%.^1,2,3 I believe that better selection criteria would reduce the drop-out rate and save personal distress among those who made an unwise choice. This makes economic sense. There is widespread agreement that we should select medical students on wider criteria than scores of academic success,^{4, 5} though in practice many medical schools have valued academic scores at the expense of other considerations.^{6, 7} A Levels alone should not be sufficient to gain a place at medical school. True communication calls for some shared life experiences and empathy with others. I believe that students who are totally absorbed in their studies to the exclusion of almost everything else are less likely to make good doctors. In one study, a ten-year follow-up after entry into medical school showed no correlation between academic score at entry and drop-out rate, but significant correlation between low interview scores and later drop-out.⁸ Reasons for drop-out were a variety of personal reasons including lack of motivation for study or for medicine. In a medical school that carefully evaluates applicants, empathy and motivation to be doctors were found to be particularly important in predicting both clinical and academic success.⁹

Another major study, looking at the dropping out from medical schools in the UK over a ten year period (1990-2000), ¹⁰ showed that drop-out rates increased during this period and concluded that the probability of dropping out of medical school is 20% lower for students with a parent who is a doctor. The authors comment that this may be the result of greater commitment or better preparation and insight before starting the course. Ethnic background of students was recorded only between 1998-2000. The study found that Indian females were around 1.9% less likely to drop out compared with white females, whereas Indian males were no different from white males. Other ethnic groups were less likely to drop-out by around 0.8%.  A concerning fact in this paper was the degree to which drop-out rates varied between different medical schools. No study to date has been done to find the reasons for these differences. Surely potential applicants need to be aware of these results. The differences could be accounted for by variable selection processes among the medical schools.¹¹ Some medical schools shortlist for interview only on predicted academic performance or the number of A* GCSEs or decide by the UK Clinical Aptitude Test (UKCAT) / BioMedical Admissions Test (BMAT) scores. Some use information presented in the candidate’s personal statement and referee’s report while others ignore this because of concern over bias. In some cases candidates fill in a supplementary questionnaire. Interviews vary in terms of length, panel composition, structure, content, and scoring methods. Some schools do not interview.

The commonest reasons cited in many papers for dropping out of medical school were because it is not for them, they found it boring, they did not like patients, the work environment was not what they want to spend their time on, or they did not like responsibility.¹² Essentially they had realised too late that Medicine was not for them. They had failed to find out what they were letting themselves in for before applying and the medical school had failed to pick this up. There is a strong argument for pooling resources so that applicants get one good assessment instead of four poor ones.                  

A levels, used for medical selection, do not indicate any personality attributes of the candidate and are affected by socio-economic bias. The UKCAT was introduced to level the playing fields. This test doesn’t examine acquired knowledge and candidates can’t be coached to pass, so in theory it should provide a fairer assessment of aptitude than A level grades. It was also thought that the various components of the UKCAT, namely verbal reasoning, quantitative reasoning, abstract reasoning, and decision making, could help to pick the students who have the personality attributes to make good doctors. Unfortunately, a recent paper suggests that the UKCAT does not provide any more assessment of aptitude than A levels.¹³ However, an inherent favourable bias towards students from well-off backgrounds or from grammar and independent schools was also found. Moreover the test does not compensate for talented candidates whose education has been affected by attending a poor school. Another paper looked at the predictive validity of the UKCAT.¹⁴ This showed that UKCAT scores did not predict Year 1 performance at two medical schools. Although early prediction is not the primary aim of the UKCAT, there is some cause for concern that the test failed to show even the small-to-moderate predictive power demonstrated by similar admission tools.   

There is no doubt that potential doctors must have enough intellectual capacity to do the job but they must also possess other important traits (Table 1):

What patients rate highly among the qualities of a good doctor are high levels of empathy and interpersonal skills.¹⁵ Personality traits such as conscientiousness have been positively associated with pre-clinical performance.¹⁶ 

The criteria being used more and more by admission tutors include the candidate’s insight into medicine including as evidenced from work experience.¹⁷Surprisingly, very little has been written on work experience and the value placed on it varies considerably between medical schools. Many would regard this experience as a prerequisite for entry into medical school. It enables a student to experience at first hand what he/she is letting him/herself in for. Some find the experience fascinating and challenging while others may find it is not for them. Work experience should not be seen as a hurdle to climb, but part of the decision-making process in determining whether medicine really is for you. I fear that another contributing factor to the increase in drop-out rates from medical schools is the increasing difficulty in obtaining work experience. Gone are the days when students could join theatre staff and watch an exciting operation or shadow doctors in Accident and Emergency (A&E). Useful work experience is so important and it is becoming harder and harder to get, but is still possible. Therefore considerable desire, commitment and motivation by the student are required to obtain it. The work does not need to be medically related, but work experience in any care setting is essential. These placements can be used to illustrate at least some of the personal qualities that are sought after in a good doctor including: appreciation of the communication skills required of a doctor; a thorough awareness of the realities of medicine and the National Health Service (NHS); an understanding of teamwork; an ability to balance commitments; and observation of the caring and compassionate nature of the doctors. Furthermore, as demonstrated in general practice,¹⁸ personal experiences can have a highly positive influence on an individual’s attitude to a particular speciality. Encouraging school students to experience general practice would therefore not only increase their awareness of the life to which they are about to commit, but could aid recruitment to general practice as a speciality.

My Ghana Experience

I decided that, as part of my work experience, I would go to Ghana with a charity organisation (Motec UK Life). The reason was not to impress medical admissions tutors, but to discover if I had what it takes to become a doctor. I realised how comfortably we live in our small bubble, with little appreciation of what goes on in the rest of the world. Ghana is a third world country, which not only has great poverty and malnutrition but also has many deadly diseases such as Acquired Immunodeficiency Syndrome (AIDS)/Human Immunodeficiency Virus (HIV), malaria, hepatitis, typhoid and sickle cell disease. My trip was demanding as I was stripped of my luxuries and removed from my comfort zone, but it helped me to understand the real values in life through helping the most needy and vulnerable people. I felt the suffering and the pain they went through, day in and day out, but knew that making even the slightest difference to their lives motivated me and enabled me to persevere through my time there.

One of the hospitals we stayedwas Nkawkaw, which was in the middle of a shantytown with houses made of metal sheets. Yet, despite the presence of great poverty and disease, I did not find a single person who was not extremely kind and welcoming and always smiling. It made me think of the contrasting situation back home in the UK where people were relatively well off, and yet so unhappy. I spoke to as many people as possible, not realising that I was developing my people- and communication-skills. I played football with the children and made them smile. I was able to visit the AIDS/HIV clinic and gained a first-hand account of how this devastating disease was controlled and dealt with in a third-world country. The pain, grief and suffering were immense and difficult to comprehend unless one was actually there witnessing it. AIDS here hurts everyone, but children are always the most vulnerable. The children were born with HIV from their mothers, or infected through breast milk, or in the past infected by unsafe medical treatments. They were often orphaned and destitute, having to build their own homes, grow their own food, and care for younger brothers and sisters. That is the cruel reality.

Equally heartbreaking was seeing so many people in the HIV clinic who could

not afford the anti-retroviral drug that would improve the quality and duration of life. This feeling of helplessness motivated me even further to pursue a career in medicine in order to help people at their most vulnerable. On this trip I was greatly impressed by the dedication, commitment and professionalism shown by the doctors in difficult situations. I saw doctors working with little supervision and little equipment, and yet they seemed confident, well organised, and adapted themselves well to the conditions. Their enthusiasm and compassion never waned despite working long hours.

I saw many types of operation being performed including joint replacements, hernia repairs and caesarean sections. On one particular day, I observed the team performing many knee and hip joint replacements. The deformities of the joints were much more severe than seen in the UK. I enjoyed and appreciated the skills of the orthopaedic surgeons in carrying out these operations, which were being done under spinal anaesthesia, and so I was able to talk to the patients and comfort them. Throughout the day, after seeing many operations, I did not flinch or feel queasy at the sight, and this further encouraged me to believe that I could handle a career in medicine. On watching the caesarean sections, the excitement of bringing new life into the world was overwhelming. Seeing another baby being born with severe hydrocephalus marred this. No treatment facilities for this condition were available for hundreds of miles and the baby was too ill to be transferred such a large distance. I witnessed the doctors conveying the heartbreaking news to the family with compassion. It became clear to me that there are negative aspects to this career. There is a great deal of emotion and stress to cope with in such circumstances but I believe that, given training, I would be mentally stronger to take control of these situations.

I was always allowed to follow the doctors on their ward rounds, and was encouraged to ask questions and make comments, so that I often felt that I was being treated as a medical student, which was strange in some ways but also very gratifying. On this trip I was involved in teaching and in helping to set up a workshop, which lasted for a whole day for doctors from all over Ghana. This involved lectures as well as demonstrating the latest surgical and theatre equipment. I was impressed by the teamwork and organisation shown by the group. The communication skills of the group had to be of the highest quality in order to get the message across. I found that teaching about the devastating effects of HIV, in a local school in Ghana, was particularly challenging as some of the students before me were sufferers and so I found it difficult to look them in the eye, knowing that although they were being taught the safety precautions, many did not have much of a future. This reinforced my feeling of helplessness but, although this situation was heartbreaking, I remained enthusiastic for the children, to keep their morale high in order to prepare them for their inevitable future.

Conclusion    

My trip was totally inspirational. It made me realise that medicine is much more than being a master of all sciences. In Ghana I observed in doctors the real passion and drive needed for medicine as well as many other essential qualities I believed doctors needed. This contrasts with the current selection criteria in the UK; sadly we are missing out on too many good doctors because of our obsession with grades rather than looking for real qualities that are going to make a difference to our patients.I discovered that seeing the immense suffering, and the close bond of doctors and patients in an entirely different social and economic context, helped me to evaluate and shape my own emotions and personal values. My motivation in wanting to become a doctor has increased tremendously since this trip. My trip to Ghana also inspired me to create a medical journal in my school as a fund-raising initiative. I brought together a group of fellow students to write articles about common teenage problems (teenage drinking, anorexia, obsessive compulsive disorder (OCD), stress, smoking, sexually transmitted diseases (STDs)) as well as articles on euthanasia and assisted suicide, stem cell research and the NHS. I wrote about my personal experiences in Ghana in addition to editing and publishing the school journal. All the funds raised from the school medical journal will be going to the HIV victims in Ghana.

Introduction

Lactic acidosis is an important cause of metabolic acidosis in hospitalised patients. This usually occurs either due to over production or under utilisation of lactate¹ . Most cases of lactic acidosis are due to marked tissue hypoperfusion or hypoxia in systemic shock.

Asymptomatic lactic acidosis has been reported previously during acute severe asthma and attributed to fatiguing respiratory muscles, hypoxaemia and liver ischaemia. It has also been linked to β2 agonist therapy in asthma, although lactic acidosis causing increasing dyspnoea in the asthmatic patient has only been recorded rarely.

Case presentation

We present a case of lactic acidosis in a patient with acute severe asthma who did not have any overt signs of sepsis or tissue hypoperfusion.

Mr IL was a 49 years old male who was known to have moderate asthma. He had multiple previous admissions to hospital with exacerbation of asthma but had never required an intensive care admission and had never been intubated. His other comorbidities included atrial fibrillation, ischaemic heart disease and depression.

His usual medications included salbutamol, budesonide and salmeterol inhalers, aspirin, atorvastatin and digoxin. He was a mechanic by trade with no obvious occupational sensitisation. He had no pets at home. He was a smoker with a 20 pack year history. Recent lung function tests showed an FEV1/FVC of 0.68 with a post bronchodilator FEV1 of 4.17 L (95% predicted).

He was admitted with a 1 week history of worsening shortness of breath, dry cough and wheeze. His baseline blood tests including full blood count, C reactive protein, liver and renal function were normal. Chest radiograph was unremarkable. Arterial blood gas showed no evidence of hypoxia or acidosis.He was treated as acute severe asthma with back to back nebulisers, intravenous hydrocortisone and magnesium sulphate resulting in gradual improvement in bronchospasm and peak expiratory flow rate.

Despite optimal treatment, his breathing started to deteriorate. Arterial blood gas at this time showed lactic acidosis with normal oxygenation (Table 1). There was no clinical or biochemical evidence of haemodynamic compromise or sepsis. A presumptive diagnosis of lactic acidosis secondary to salbutamol was made. The nebulisers were withheld and he has transferred to high dependency unit for closer monitoring. The acidosis completely resolved in the following 12 hours on stopping salbutamol and the patient made an uneventful recovery.

Table 1: Serial Arterial Blood Gases (On admission, 4 hours later and on stopping salbutamol)

* Salbutamol witheld

Discussion

Lactate is a product of anaerobic glucose metabolism and is generated from pyruvate. Normal plasma lactate concentration is 0.5-2 meq/L. Most cases of lactic acidosis are due to marked tissue hypoperfusion or hypoxia in systemic shock² .

Lactic acidosis can occur in acute severe asthma due to inadequate oxygen delivery to the respiratory muscles to meet an elevated oxygen demand³ or due to fatiguing respiratory muscles⁴ . A less recognised cause of lactic acidosis is treatment with salbutamol. The mechanism of this complication is poorly understood.

Salbutamol is the most commonly used short acting βagonist. Stimulation of β adrenergic receptors leads to a variety of metabolic effects including increase in glycogenolysis, gluconeogenesis and lipolysis⁵ thus contributing to lactic acidosis.

Table 2 shows an assortment of previously published case reports and case series of lactic acidosis in the context of acute asthma.

Table 2: Details of etiology and consequences of lactic acidosis in previously published case reports 

Conclusion

In this case, the patient developed lactic acidosis secondary to treatment with salbutamol nebulisers. The acidosis resolved spontaneously without any specific treatment.

Lactic acidosis secondary to β agonist administration may be a common scenario which can be easily misinterpreted and confuse the clinical picture. Acidosis itself results in hyperventilation which could be mistaken for failure to treat the  response. This may in turn lead to inappropriate intensification of treatment.

INTRODUCTION:

Hypertension is common but, with early detection and treatment, it is rare to see malignant hypertension. We report a patient who presented with signs suggestive of thrombotic thrombocytopenic purpura and severe hypertension, which resolved with the treatment of hypertension.

CASE REPORT:

A 34 year old African American male presented to the emergency department (ED) having experienced nausea, vomiting and diarrhoea for two days.  He denied haematochezia, meleana or sick contacts at home.  He complained of blurred vision without photophobia, headache and mild chest discomfort.  His past medical history was unremarkable.  The patient did not have any significant family history. Smoking history was significant for a pack of cigarettes daily for seven years.  He reported occasional alcohol intake, and denied use of recreational drugs.  On presentation, this patient’s blood pressure was 201/151 mmHg, with a mean of 168 mmHg.  Pulse 103 beats per minute, respirations 20 per minute and temperature 98.4F.  Physical examination was otherwise unremarkable, including absence of focal neurological deficits.

Blood tests showed: Haemoglobin 12.6 g/dl, White cell count 13.9 g/dl, Platelets 67000, Sodium 136, Potassium 3.4, BUN 24, Creatinine 2.56 and LDH 556. Chest x-ray showed cardiomegaly.  A non-contrast computed tomography scan of the brain did not show any sign of stroke (haemorrhage).  Urinalysis was positive for proteins 4+, a large amount of blood, 0-2 white blood cells/high power field (HPF) and 0-2 red blood cells/HPF.

Figure 1

The patient’s initial treatment whilst in the ER consisted of a Labetalol drip.  His mean arterial pressure decreased to approximately 115 mmHg during the first hour, and his chest pain and headache improved with the control of elevated mean arterial pressure.  Furthermore, over the next 24 - 48 hours, the patient’s blood pressure was brought down to 138/86 mmHg and his blurred vision improved significantly.  Subsequently, intravenous medications were switched to an oral regimen.  Blood peripheral smear from the day of admission was significant for the schistocytes (Figure 1) suggesting ongoing haemolysis.  Renal ultrasound was unremarkable.  His cardiac ultrasound revealed an enlarged left ventricle, however no valvular abnormality was seen.  Serum calcium and thyroid stimulating hormone levels were normal, as were urine catecholamines and vanillylmandelic acid level.  On two week follow up in the outpatient clinic, the patient’s platelet count and creatinine had returned back to baseline and peripheral smear did not reveal any schistocytes as the blood pressure came under better control. [Table 1]

Table 1

DISCUSSION:

Malignant hypertension is a medical emergency with an incidence of 1% in hypertensive patients¹and is more common in the African American population².  Depending on the clinical presentation, it must be differentiated from thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), glomerulonephritis and vasculitis.

Suspicion for TTP was initially high in this patient because of haemolysis, thrombocytopaenia, central nervous system (CNS) manifestations and renal insufficiency.  However, TTP did not explain the presence of elevated blood pressure^3,4nor the improvement in symptoms and signs with the management of this, which clearly supports our diagnosis.  Rapidly progressive glomerulonephritis did not explain the CNS symptoms, and a normal prothrombin time and activated partial thromboplastin time ruled against disseminated intravascular coagulation⁵.  The patient did not have a history of preceding diarrhoea⁶, which could possibly direct towards haemolytic uraemic syndrome (HUS)⁴.  There was no history of prosthetic valves, nor clinical evidence of vasculitis. The patient’s symptoms of severe hypertension, haemolysis, thrombocytopaenia and renal failure were consistent with malignant hypertension, and treating the hypertension⁷gradually resolved the thrombocytopaenia, haemolysis and renal failure⁸. 

CONCLUSION:

This case report highlights that malignant hypertension is a medical emergency which can present with features resembling a wide variety of diseases, including TTP and HUS.  Using appropriate management to control the elevation in blood pressure can help reveal the underlying diagnosis.

Introduction

Malaria is a major worldwide scourge, infecting and killing several million individuals each year¹. Malaria is common in mostly tropical and subtropical areas such as The Americas, Asia and Africa^{2, 3}.

The NADPH oxidase complex is responsible for the reduction of  oxygen in cells, yielding a superoxide anion (O₂^˚-) that is subsequently converted into other ROS; including hydrogen peroxide (H₂O₂) and the hydroxyl radical (OH˚)⁴.

The Sequence analysis showed that the NCF1 wild type gene is 15,236 bp long, contains 11 exons and has an intron/exon structure identical to the highly homologous pseudogene⁵. The pseudogene which is highly homologous to the wild type gene is located on the same region of the chromosome, which is 7q11.23 of chromosome 7⁶. Comparative sequence analysis between the wild type gene and pseudogene demonstrates greater than 98% homology but the pseudogene has a GT deletion (ΔGT) at the start of exon 2⁷. The genomic pattern of wild type NCF1 gene and its pseudogene may influence the production of reactive oxygen species (ROS) in parasitic and bacterial infections and also in autoimmune diseases.

During malarial infection, the ROS production can contribute to rapid parasite clearance in mild malaria⁸ but in severe malaria the high capacity production of ROS was associated with anaemia. This means that ROS has a possible role in both parasite clearance and anaemia during P.falciparum infection⁹.  Genetic variation in components of the leukocyte NADPH oxidase may, therefore, influence disease susceptibility to, and disease duration of parasitic infection and autoimmune disease¹⁰.

Study Design

Inclusion and exclusion criteria

Patients who had fever with malarial parasites detected microscopically from blood smears and had no evidence of other illnesses were selected. Patients were excluded if they developed other illnesses within three days of admission or if there was any other present infection.

Relatives of patients in the hospital and in the laboratory and members of the community without malaria or any other febrile illness were included after clinical evaluation. These formed the control group of healthy individuals.

Patients and healthy individuals

To determine the association of NCF1 gene in malaria, the blood samples were collected from malarial patients and healthy individuals in storage tubes coated with EDTA. Malaria was diagnosed on the basis of clinical observation and positive smear test containing various types of plasmodium.

Materials and Methods

The restriction fragment length polymorphism (RFLP) method was performed to determine the prevalence of NCF1 gene GT deletion (ΔGT) among patients with malaria and among healthy individuals in a Pakistani population. In order to determine whether there was an association between NCF1 gene GT deletion (ΔGT) at the start of exon 2 with susceptibility to malaria, 88 malarial patients and 100 healthy individuals were genotyped for the GT deletion by restriction enzyme analysis.

Genetic Analysis

Genomic DNA of patients and of the healthy control subjects was extracted from venous blood samples using the nucleospin blood extraction kit (NucleoSpin^® Blood, Germany) according to the manufacturer’s protocol. The NCF1 gene was analyzed by the restriction fragment length polymorphism (RFLP) method. The exon 2 was amplified using both forward and reverse primer as shown in Table 1. The reaction mixture (50 μl) for PCR was prepared in 0.2 ml tubes (Axygen^®, California, USA) by adding the following: 1.2 μl of sample DNA (50 ng /μl), 5 μl (10X)  from the PCR buffer (Fermentas, Burlington, Canada), 4 μl of 25mM magnesium chloride (MgCl₂) (MBI Fermentas, Burlington, Canada), 3 μl of 2 mM deoxyribonucleotide triphosphates (dNTPs) mixture (MBI Fermentas, Burlington, Canada), 2.6μl of each forward primer (10 pm/μl), 2.6 μl of the reverse primers (10 pm/μl) and 1.2μl Taq DNA polymerase (MBI Fermentas, Burlington, Canada) in 30.40 μl nuclease free water with cycling conditions 95 °C for 5 min, followed by 35 cycles at 95 °C for 1 min, 60.6 °C for 1 min, 72 °C for 1 min and finally a 10 min extension at 72 °C.

The amplified products were then treated with the restriction enzyme BsrGI (Geobacillus stearothermophilus GR75) (Fermentas life science). For a 20 μl mixture we took 10 μl of PCR product, 2 μl 10X buffer tango, 1 μl BsrGI enzyme and 7 μl of nuclease free water to make the mixture volume up to 20 μl and checked the result on 2% agarose gel.

Table 1: sequence of primers and product size

Table 3: Total number of Patients and healthy individuals enlisted with respective mean age.

A chi-square test was performed to test the null hypothesis regarding whether there was an association between gender and the number of subjects in the control group and patient groups. No statistically significant association was found, c² (1, N = 188) = 0.559, p = 0.4545”. Similarly, a chi-square test was performed to test whether there was any association between the gender and ages of subjects in the control group and in the patient group. Again no statistically significant association was found, c² (1, N = 188) = 0.299, p = 0.5848”.

PCR amplification of exon 2 of NCF1 gene

The exon 2 was amplified by polymerase chain reaction to obtain 358 base pair long regions in the case of the wild type gene and 356 base pair long regions in the case of the pseudogene. The products were treated with a restriction enzyme, Geobacillus stearothermophilus, GR75 (BsrGI) which digests only the wild type gene (GTGT), which meant two bands of  265 bp and 93 bp were obtained respectively. Whereas with the pseudogene (ΔGT)   there was no digestion and the original band of 356 bp was obtained. When the individuals had both the wild type gene (GTGT) and the pseudogene (ΔGT)three bands of 265 bp, 93 bp and 356 bp were obtained, two of the wild type gene and one of the pseudogene respectively, which is shown in figure 1.  

Figure 1: Agarose gel (2%) showing genotypes of eight patients with malaria. The GT deletions (ΔGT) were checked using the RFLP method, using the restriction enzyme BsrGI. The lane L contains 50 base pair markers, while lane 1 contains a negative sample and 3 and 7 contain amplified wild type gene (GTGT) products. Lane 2, 5 and 6 contain amplified wild type gene and pseudogene (ΔGT) products and lane 4, 8 and 9 contain amplified pseudogene products respectively. The result shows that the 2^nd, 5^th and 6^th patients have both the wild type gene and pseudogene (GT/GTGT). The 3^rd and 7^th patients have the wild type gene (GTGT) and THE 4^th, 8^th and 9^th patients have the pseudogene (ΔGT).

Genotypic Frequencies of wild type gene and pseudogene in Malaria Patients

It was found that in the Pakistani population, the frequency of the wild type gene in malarial patients (37.5%) was no higher than in healthy individuals (45%) with P = 0.30427. The combination of wild type gene and pseudogene(GTGT/ ΔGT) was equally prevalent in malarial patients (39.8%) as it was in healthy individuals (40%) with P = 0.99999,while the pseudogene (ΔGT) was also slightly different among healthy individuals (15%) as compared to malarial patients (22.7%) with P = 0.19263 which is shown in table 4. There was no significant association found because the P values was greater than 0.05.

Table 4: Show the association of NCF1 gene with malaria

Robert Moots is Professor of Rheumatology at the University of Liverpool and Director for Research and Development at the University Hospital, Aintree. He is also a Consultant Rheumatologist at the hospital.

He graduated from St Mary’s Hospital, London University in 1985 and also worked at Harvard Medical School. He became a Consultant Rheumatologist at University Hospital Aintree in 1997 and the youngest full-time professor of Rheumatology and Head of Department in 2003.

Professor Moots has published extensively in rheumatology, winning the prestigious Michael Mason prize for rheumatology research. He advises the UK Department of Health and NICE. His research interests are inflammatory rheumatic diseases, in particular innate cellular immunity in rheumatoid arthritis, immunotherapy, new therapeutic targets and clinical trials.

How long have you been working in your speciality?

I’ve been working as a consultant in rheumatology since1997, when I returned to the UK from the USA. Of course I was a trainee in rheumatology for a few years before then.

Which aspect of your work do you find most satisfying?

Its hard to single out any one thing. The great fun of being Professor is that no two days are the same. My job varies so much from looking after patients, to teaching, running research and also communicating and sharing research findings with other clinicians and scientists throughout the world – giving me the opportunity to visit countries, where I would not normally have visited.

What achievements are you most proud of in your medical career?

Clinically, I often deal with rare rheumatic diseases, or situations where normal treatments have failed and other doctors have said there is “no more that can be done”. Each patient that I see in this situation, who then goes on to recover and have a normal happy life, gives me a great satisfaction. Academically, building up a successful research team of talented individuals in Liverpool, the first academic rheumatology unit in that city, has been a great privilege.

Which part of your job do you enjoy the least?

Trying to balance the demands of patient care with the many other calls on my time can be rather wearing. But nothing is worse than the ever expanding administration tasks and bureaucracy!

What are your views about the current status of medical training in your country and what do you think needs to change?

When I visit other countries to lecture, I always try to see how medicine runs there. I attend clinics and hospitals, see patients and learn how practice compares to the UK. I am pleased to note that the standard in the UK remains amongst the highest of all countries.

How would you encourage more medical students into entering your speciality?

Its hard to image why students and doctors could consider any specialty other than Rheumatology! Rheumatology provides the opportunity to see patients of all ages, develop a close rapport with patients as the diseases tend to be chronic and prevalent, perform cutting edge research to understand pathophysiological process underlying the diseases and access drugs that can make a revolution to lives with great outcomes.

What qualities do you think a good trainee should possess?

Be keen to learn, open, honest and bright. I also like trainees to challenge accepted wisdom – a considered critical approach is needed to move things forward and to keep us on our toes.

What is the most important advice you could offer to a new trainee?

Don’t accept non-evidence based dogma. Don’t learn bad habits. Be critical and try to improve things. Try to spend some time away from your unit and ideally out of your country – seeing how medicine works in other environments to get life and work in a better perspective.

What qualities do you think a good trainer should possess?

Good trainers should be excellent clinicians, inspirational leaders and listeners with patience. If you know someone like this, you should really treasure them!

Do you think doctors are over-regulated compared with other professions?

No – but I fear that we are getting there in the UK.

Is there any aspect of current health policies in your country that are de-professionalising doctors? If yes what shouldbe done to counter this trend?

With a recent change in government in the UK and major changes to the Health Service planned, it’s a little too early to tell. We have to be vigilant though.

Which scientific paper/publication has influenced you the most?

For much of my working life, I was focused on the T cell as the major driver for diseases such as rheumatoid arthritis. The paper that changed that was: Edwards SW, Hallett MB. Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunol Today.1997 Jul;18(7):320-4. This crucial paper from Steve Edwards, the world leader in neutrophil biology opened my eyes to a whole new field of work. I didn’t know at the time that I would eventually have the privilege of working with Steve.

What single area of medical research in your specialty should be given priority?

That’s an easy one – it should be whatever my group are working on at the time.(I just wish that were the case!)

What is the most challenging area in your specialty that needs further development?

Many rheumatic diseases such as rheumatoid arthritis can be treated extremely successfully (with patients enjoying a full remission) if they can access the right drugs at the right time. There is still much variability in time to diagnosis and in provision of appropriate medications – the challenge is to ensure that best practice can be rolled out more effectively.

Which changes would substantially improve the quality of healthcare in your country?

There needs to be a greater understanding of the importance of rheumatic diseases in the UK. These conditions are prevalent, may cause significant morbidity (and indeed mortality), cost the nation considerably in reduced productivity and in disability payments – yet many of these conditions can be treated most effectively.

Do you think doctors can make a valuable contribution to healthcare management?  If so how?

Its crucial that doctors are fully engaged in management. We are in the best position to be advocates for our patients but cannot do this effectively without understanding the health care system and take the lead in ensuring this works for the best.

How has the political environment affected your work?

The consequences of the recent change in Government in the UK are likely to be considerable for the National Health Service. This will involve major changes to the work of staff at all levels. It is too early to know the full extent of this – but we all wait with trepidation

What are your interests outside of work?

With so much to do, its hard to find the time for much else apart from relaxing with my family. I travel a lot and especially enjoy taking my children with me. My 10 year old has heard me lecture so much that I suspect she can give my talk for me (and do it better). She has also taken to asking questions at the end of my lecture, which always scares the chairperson of the meeting!

If you were not a doctor, what would you do?

I’m not sure that I would be fit for anything else!

Definition

Gastro-oesophageal reflux (GOR) is the passage of gastric contents into the oesophagus.  In most infants with GOR the outcome is benign & self-limiting. ⁽¹⁾

Incidence/Prevalence

Peak incidence of GOR is around 4 months of age, and it resolves spontaneously by 1-2 years of age in most patients. ⁽²⁾

Regurgitation (possetting or spitting up) is the most common presentation in infants with GOR.  Regurgitation of at least one episode a day is seen in:

• 50% of infants 0-3 months
• 67% of infants at 4 months
• 5% at 10 to 12 months of age ⁽³⁾

It is important to note that in infants (younger than 1 year of age) who are otherwise well and symptomatic, regurgitation may be considered entirely normal. ⁽⁴⁾

Causes/Risks

GOR occurs due to the transient, inappropriate relaxation of the lower oesophageal sphincter, which allows the stomach contents to pass into the oesophagus.

GOR can be physiological or pathological:

• Physiological GOR – when the infant has normal weight gain and experiences no complications and is generally well.
• Pathological GOR – also known as gastro-oesophageal reflux disease (GORD) is when reflux is associated with other symptoms like failure to thrive or weight loss, feeding or sleeping problems, chronic respiratory disorders, oesophagitis, haematemesis etc ⁽³⁾

Several anatomical and physiological conditions make infants (younger than 1 year of age) more prone to GORD than older children and adults:

• Short, narrow oesophagus
• Delayed gastric emptying
• Shorter, lower oesophageal sphincter that is slightly above, rather than below, the diaphragm
• Liquid diet and high calorie requirements, putting a strain on gastric capacity
• Larger ratio of gastric volume to oesophageal volume⁽⁴⁾

Most children have no specific risk factors for GORD.  Children with the following conditions are at increased risk for developing GORD and for progressing to severe GORD:

• Severe neurological impairment
• Prematurity
• Cystic fibrosis
• Gastro-oesophageal abnormalities (even after surgical repair), e.g. Oesophageal atresia, diaphragmatic hernia, pyloric stenosis
• Bronchopulmonary dysplasia (preterm infants with lung disease)
• Hiatus hernia
• Oesophageal sphincter disorders
• Raised intra-abdominal pressure⁽⁵⁾

Symptoms

GORD in infants and children can present with a variety of symptoms many of which can be relatively non-specific.  Equally, other pathologies may lead to the development of reflux.  Those in the early years tend to be based on observations by parents, while older, more vocal children express symptoms more akin to adult presentations. 

As such, the history/symptoms will be broadly divided into those expected for infants (<1yr), young children (1-5yrs) and older children (>5yrs).

Infants^(6-10)

1. Excessive possetting/regurgitation
   1. Possetting is a normal phenomenon in infants
   2. Frequent episodes, together with vomiting may indicate underlying GORD
   3. Projectile vomiting may indicate an obstructive pathology
2. Difficult/rapid cessation of feeds
   1. There may be difficulty initiating feeds and latching
   2. Early cessation may be precipitated with the onset of reflux
3. Failure to thrive
   1. No weight loss can be expected
   2. Weight loss crossing centiles on the growth chart must be addressed urgently
4. Sleep disturbance
   1. Particularly after an evening feed
   2. This is often associated with irritability and inconsolable crying
5. Irritability and inconsolable crying
   1. One of the commonest presentations to the GP
   2. This may occur during feeds or shortly afterwards
6. Apnoeic episodes
   1. A witnessed pausing in respiratory effort
   2. Occurring at night, it can mimic obstructive sleep apnoea
   3. This may indicate a more serious underlying pathology and requires urgent assessment
   4. It is likely to be more prevalent in this age group

Young Children^(6-10)

1. Regurgitation/vomiting
   1. Beating/rubbing the chest may be an early sign of this pathology
   2. Reflux symptoms can be typical of those in adults
2. Failure to thrive
3. Refusing food
   1. Similar to the infant, however, the younger child can be more vocal in their refusal
4. Abdominal/chest pain
   1. With increasing age, children may demonstrate gastric irritation with abdominal pain
   2. Acid reflux producing oesophagitis may present as chest discomfort
   3. Both are similar to symptoms adults experience
5. Irritability
6. Persistent/nocturnal cough/wheezing
   1. There may be a dry, non productive cough
   2. Secondary to pharyngeal irritation
   3. There may be no co-morbidities or underlying pathologies
   4. Symptoms can be mistaken for asthma by parents

Older Children ⁽⁹⁾

1. Dyspepsia/vomiting
   1. These symptoms in older children are thought to have a similar reliability in diagnosis as in adults
2. Dysphagia/odynophagia
   1. As children become more articulate they may be able to describe these symptoms in relation to meals
   2. Particularly with chronic GORD and the development of a Barrett’s Oesophagus
3. Abdominal/chest pains
4. Persistent/nocturnal coughing/wheezing

Other Symptoms

Symptoms which can be identified but which maybe considered less life-threatening include:

1. Dental erosions
2. Hiccups
3. Halitosis

Those deserving urgent investigation and intervention include:

1. Forceful/Bilious vomiting
2. Suggesting a possible obstructive pathology
3. This requires urgent surgical referral
4. Force of vomiting may not always indicate the severity of the problem
5. Upper gastrointestinal bleeding/hematemesis
6. This may be a consequence of increased pressure from vomiting
7. Similar to a Mallory-Weiss pathology
8. An urgent review by local Paediatric Gastroenterologists is warranted
9. Profuse diarrhoea or constipation
10. Failure to thrive/weight loss
11. Lethargy
12. Apnoeic episodes

Physical Signs

As with the previous section, physical signs will be considered for each age range as above: infants (<1yr), young children (1-5yrs) and older children (>5yrs).

Infants⁽⁹⁾

1. Irritability when lying flat
   1. Particularly following feeds
   2. Especially when supine
2. Weight loss
   1. Regular monitoring with repeat measurements
   2. A single weight cannot imply loss
   3. This is usually a late sign
3. Arching of the back
   1. Secondary to oesophageal irritation
   2. Can be associated with increased tone and crying
4. Dehydration
   1. Loss of fluid through vomiting
   2. Look for
5. Dry mouth
6. Sunken fontanelle
7. Prolonged capillary refill time
8. Reduced skin turgor
9. Reduced urine output
10. Crying without tears
11. Apnoeas
    1. Periods of reduced respiratory effort
    2. Noted by parents as pauses in breathing

Young Children ⁽⁹⁾

1. Weight loss
2. Dehydration
3. Anaemia
   1. Associated with chronic symptoms and gradual loss of iron
   2. Look for Pallor/pale conjunctivae, Glossitis, Angular stomatits, Pica
4. Dysphagia/choking with food
   1. Particularly with prolonged GOR and development of stricturing
5. Difficulty in breathing/wheezing/lower respiratory tract infection (LRTI)
   1. Similar to asthma on examination
   2. Signs of LRTI on auscultation
   3. Possibly stridor

Older Children ⁽⁹⁾

1. Weight loss
2. Dehydration
3. Anaemia
4. Dysphagia/Choking with food
5. Difficulty in breathing/Wheezing/LRTI
6. Persistent sinusitis

Signs requiring urgent intervention include ⁽⁹⁾:

1. Hematochezia
   1. Unaltered blood in stool
   2. Stools take on a red appearance
2. Onset of vomiting after 6 months of life
3. Fever
   1. Uncommon with GOR
   2. Indicating an infective pathology
4. Hepatosplenomegaly
   1. An underlying condition other than GOR is likely
   2. Important pathologies must not be missed
5. Bulging fontanelle
   1. Indicating increased intracranial pressure and an alternative pathology underlying the reflux
6. Macro/microcephaly
   1. Suggestive of hydrocephalus or a congenital malformation
7. Seizures
   1. Related to a number of other problems
   2. Metabolic pathologies should figure highly in any differential diagnosis
8. Abdominal distension with reduced bowel sounds
   1. Tinkling bowel sounds and an pain may suggest bowel obstruction

Differential diagnoses

Common differential diagnoses have been noted in Table 1, however, this is by no means a definitive list of conditions or presentations.  It should be taken as an indication to the diverse presentations that can mimic or precipitate GOR (adapted from ⁽⁹⁾ and ⁽¹⁰⁾).

Table 1

Investigations and management of infants (<1 yr old)

Complicated cases of GORD (not gaining weight/faltering growth or non-GI symptoms e.g. cough), should be referred to a Paediatrician while investigating for causes and instituting simple management.

Simple investigations to do in primary care:

1. Abdominal examination for hernias/pyloric stenosis (test feed)
2. Urine dip to rule out UTI
3. Blood tests for electrolyte abnormalities, coeliac screen (if weaned)

Referral to a Paediatrician will result in imaging investigations such as Abdominal x-ray and upper GI contrast study to rule out malrotation/hiatus hernia/achalasia in older children, sometimes GORD can be seen on contrast studies.   The Paediatrician may go on to arrange a pH/impedance study, upper GI endoscopy or allergy testing.

Management

1. Calculate feed requirements, parents may be over feeding, e.g. approximate fluid requirement 100-120ml/kg/day every 3-6hrs (depending on age and whether weaned on to solids)
2. In thriving infants there is no evidence that pharmacological therapy will make a significant difference to symptoms.
3. Therefore the mainstay of management is reassurance. Simple pharmacological intervention can be tried with feed thickener (in formula fed babies) or Alginates e.g. Gaviscon (can be mixed with water for breast fed babies)
4. If there are continued concerns refer to Paediatrician for on going investigations and management.
5. Recent evidence shows that some infants may have cow’s milk protein intolerance ⁽⁹⁾.  Therefore for breast fed babies the mother could try cutting out dairy from her diet (important to have supervision from dietician re: nutritional requirements while breast feeding).  Formula fed babies can have a 2 week trial of hydrolysed/amino acid based formula e.g. Progestimil, Nutramigen, Neocate.  
6. Reviews from ESPGHAN ⁽⁹⁾ and DTB ⁽¹¹⁾ recommend H2RA (H2 receptor antagonists eg. Ranitidine) may help, though there is little evidence – these could be commenced while waiting for an appointment with the Paediatrician.
7. (Currently there is no role for Domperidone.  The next medication a Paediatrician may try is Omeprazole ± omission of cow’s milk protein) ⁽¹¹⁾

Investigation and management of older children (>18mths)

As before, complicated cases of GORD (not gaining weight/faltering growth or non-GI symptoms e.g. cough), should be referred to a Paediatrician while investigating for causes and instituting simple management.

Investigations

1. Urine dip, if there are symptoms of vomiting
2. Stool H. Pyloti antigen test
3. Bloods tests inc. inflammatory markers, H. Pylori antigen, celiac screen

Management

1. If main symptom heartburn with no evidence of H. Pylori:
2. Reassurance and lifestyle changes (weight loss, dietary changes, timing of meals), up to 4 week trial of PPI (Proton pump inhibitor e.g. lansoprazole, omeprazole).
3. If symptoms improve then continue PPI for up to 6 months, then wean off over 4 weeks (evidence that if stopped suddenly patients may get rebound symptoms) ⁽¹⁰⁾.
4. If PPI doesn’t help or symptoms recur after stopping the PPI, then refer to a Paediatrician.
5. The Paediatrician may investigate with more blood tests e.g. Autoimmune screen, allergy testing, imaging, pH/impedance study, endoscopy.

Chronic pain, arbitrarily defined as that lasting longer than six months, is a clinical, social, and economic problem. It is often accompanied by feelings of low mood and despondency.

Whether chronic pain induces clinical depression or depression initiates psychosomatic pain (through physiological mechanisms) is difficult to prove. The burden of illness increases when patients suffer from both. Financial hardship and medical costs affect the quality of life which leads to difficulties in coping and further decreased functioning, making the treatment of both conditions more complicated. Therefore, better recognition, assessment, and treatment of comorbid pain and depression should, at least in theory, lead to better outcomes.

Pain is broadly categorized into three groups: nociceptive (any painful stimulus), neuropathic (for example, diabetes), and psychogenic. Nociceptive pain occurs with direct noxious stimuli. Neuropathic pain is a result of disease or injury to the nervous system or spinal cord. Psychogenic pain has no discernible physical origin. Although the precise physiological mechanisms are not entirely understood, there are two basic categories of sensory neurones. The first type is myelinated and fast conducting; the second is unmyelinated and slow conducting.

Acute pain which follows damage to tissue (an ankle sprain, for example) is usually correlated with hyperalgesia (an increase in the pain elicited by a noxious stimulus and felt as a sharp, burning sensation) and allodynia (‘other’ pain evoked by a normally innocuous stimulus) and serves to protect the injury from further trauma while allowing the damage to be repaired.

Depression is often a chronic disorder and though its symptoms may be alleviated by appropriate medication and other therapies, physical complaints tend to be more intractable. For example, fibromyalgia (FM), a syndrome characterized by widespread muscle pain and generalized tender points, is often associated with major depressive disorder.¹ However, although the vast majority of patients with fibromyalgia do not meet criteria for a psychiatric disorder, psychological symptoms are common. In a randomized controlled trial of primary care patients with musculoskeletal problems and depression, antidepressant medication followed by a self-management pain programme led to improvement in both.² The tricyclic antidepressant amitriptyline was traditionally used usually in small doses, to treat pain, with moderate success. In addition to its own intrinsic analgesic effect amitriptyline appears to enhance the effects of opioid analgesia. Other antidepressants are now in vogue; for example, duloxetine, a serotonin (5-HT)/noradrenaline (NA) reuptake inhibitor, is sometimes used for diabetic neuropathic pain.

Of the numerous neurotransmitters at least two, namely 5-HT and NA, may prove to be one common link between depression and pain. Both serotoninergic and noradrenergic pathways ascend from subcortical areas (brainstem, hypothalamus and thalamus) to the whole neocortex and mediate emotional and physiological responses.³ Their pathways descend the spinal cord and suppress nociceptive inputs. Serotoninergic cell bodies located in the raphe nucleus in the brainstem, and noradrenergic neurones located in the locus coeruleus (also in the brainstem) send projections to various parts of the brain involved in the control of mood, appetite, sexual activity, attention and concentration. Theoretically at least, a dysfunction at the level of the serotoninergic and noradrenergic neurons could affect both ascending and descending pathways resulting in the psychological and physically painful symptoms of depression. Neurotransmitters may open or close the ‘gate’ on perception of painful stimuli. Therefore adrenergic and serotoninergic pathways from the brainstem to the spinal cord will inhibit incoming painful stimuli. This is perhaps an oversimplification as some sensory fibres enter via the ventral spinal roots.

The hypothalamic pituitary axis (HPA) is probably also involved. The hypothalamus, which synthesises and secretes neurohormones, has a wide range of physiological functions including regulation of thirst and hunger, sexual behaviour, defence reactions such as fear and rage, and circadian rhythm: disturbances of all these functions are frequently seen in depressed or anxious patients. The HPA is also affected in patients with physical stress as well as major depression, as shown by increased levels of adrenocorticotropic hormone and cortisol in the plasma. Stimulation of the lateral areas of the hypothalamus produces a diffuse sympathetic discharge possibly because some areas of the hypothalamus control adrenaline and NA secretion. Prolonged stress associated with pain leads to depletion of central 5-HT and malfunction of other associated receptors.⁴

The hypothalamus and limbic system (whose boundaries are difficult to define) with its associated structures – the amygdala, hippocampus and septal nuclei, are involved in the mental and affective aspects of emotions. The amygdala, a cluster of nuclei in the medial temporal lobe, may have a role in the reciprocal relationship between pain and depression. The amygdala controls not only emotional behaviour but also memory. However, mixed results have been reported regarding the level of activity of the amygdala in response to pain.

Nociceptor afferents terminate within distinct regions of the dorsal horn and within the spinal cord, synapses are sites of considerable modification, hence the term ‘gate’ for the dorsal horn cells. The neurotransmitter for slow pain is believed to be substance P, and glutamate is the putative transmitter secreted by primary afferent fibres subserving fast pain.⁵

5-HT and NA neurotransmitter systems influence neuroplasticity in the brain. Most currently available antidepressants act through reuptake inhibition of either or both. Therefore, it would seem feasible to prescribe dual-action antidepressants when pain symptoms are associated with depression. However depressed patients with pain comorbidity are less likely to take antidepressant medications compared to those with depression alone. Also, individuals who develop pain or depression are at risk for developing the other, thus escalating the clinical management. Furthermore, when pain is refractory to treatment, it is associated with more depressive symptoms and worse depression outcomes, and vice versa. Depressive symptoms are very common in physically ill patients. Unfortunately, depression is often overlooked in pain patients because pain symptoms take priority or worse still, comorbid depression is not considered.

It is difficult to state with certainty whether or not unexplained pain is ‘psychological’. Such an assumption might be perceived as demeaning and patronizing to patients and the suggestion of providing cognitive therapy misinterpreted as him/her overplaying their reaction to pain or that the pain is ‘psychological’. Others do not like being labelled ‘psychiatric’, and are therefore reluctant to take antidepressants even when a physiological explanation is given. Pain perception involves physical and emotional factors and its primary function is to protect the organism from harm. It follows therefore, that pain thresholds and pain tolerance vary from individual to individual, and especially among patients with depression.

Antidepressants are frequently used in the treatment of depression and generalized anxiety disorders. Their use extends beyond these areas, however, and it is now accepted that antidepressants are efficacious in treating chronic pain syndromes in addition to their effects on psychological features such as low mood, inordinate guilt, or feelings of worthlessness. Because physical symptoms are often the main complaint in many depressed patients and pain is common as a presenting symptom, clinicians need to know about the dual use of antidepressants for both. Future antidepressants may involve neurotransmitters, other than 5-HT and NA, which could include dopaminergic pathways, opioid (antagonists of morphine-type drugs) receptors and the pentapeptides (enkephalins) which bind to these receptors.

Introduction

Case presentation

A 52 year-old Caucasian male with a history of chronic obstructive airway disease (COPD) presented to the emergency department complaining of progressive shortness of breath. Two days prior, the patient had presented to the ED with similar complaints that resolved with aerosol treatments and the patient was discharged on a metered dose inhaler (MDI).  The patient had been prescribed MDI’s (metered dose inhalers) previously for management of his COPD, but due to financial constraints he had been unable to fill his prescription for the past month. Emergency medical services (EMS) suspected COPD exacerbation and administered 40 mg prednisone IV and two albuterol-ipratropriumnebulisertreatments en route to the hospital, which improved the patient’s breathing symptoms.                                             

Upon arrival to the hospital, his blood pressure was 129/90, respirations 28, pulse 127, and he had an oxygen saturation of 100% on 7L/min. Physical examination revealed increased work of breathing, and wheezes in all lung fields with prolonged expiratory phase. The cardiovascular exam was normal except for tachycardia.  A Routine electrocardiogram (ECG) revealed sinus tachycardia and T wave inversions in anterior leads. Chest x-ray showed old scarring in the left lower lobe. Routine cardiac enzymes showed mild elevation with a serum troponin level of 0.68ng/ml (normal range 0.0ng/ml-0.05ng/ml). The second set of troponin peaked at 1.66 ng/ml (normal 0.0ng/ml-0.05ng/ml). In view of the elevated cardiac enzymes atransthoracicechocardiogram was performed which demonstrated multiple wall motion abnormalities and reduced left ventricular ejection fraction of 25%. Coronary angiography demonstrated normal coronary arteries. Left ventriculography revealed hypokinetc mid-anterior and apical segment with a hypercontractile base with reduced ejection fraction (EF) of around 25% (normal range EF 55-65%)  (Figure 1)

Figure 1. Left ventriculography demonstrating the classic appearance of Takotsubo cardiomyopathy

In light of the systolic dysfunction not in proportion with the degree of coronary artery stenosis and the multiple areas of wall motion abnormalities seen on echocardiogram, the diagnosis of Takotsubo cardiomyopathy (TCMP) was made. The diagnosis was further supported by the presence of ECG changes, troponin elevation, and the added social stresses of being unemployed. Over the course of his stay in hospital, the patient’s breathing improved with oral prednisone, inhaled tiotropium, and fluticasone/salmeterol. The patient was also treated with an angiotension converting enzyme inhibitor (ACE inhibitor), aspirin, statin, and beta-blockers. There were no adverse coronary events during the course of his hospital stay and the patient was discharged after four days. A Follow up echocardiogram after 4 weeks showed normal left ventricular systolic function.

DISCUSSION

Takotsubo cardiomyopathy (TCMP), also called stress-induced cardiomyopathy, apical ballooning syndrome, or broken heart syndrome, is a transient systolic dysfunction of the ventricles in the absence of significant coronary artery disease. Once thought to be a rare syndrome, TCMP is increasingly being identified in clinical practice, however, the prevalence and incidence are not known. It is estimated that 0.7-2.5% of patients who present with acute coronary syndrome are found to have TCMP¹ .The majority of these patients are postmenopausal females, with a mean age of 62-75 years. They may present with chest pain and have a recent history of an emotional stress or severe medical illness. ¹

The clinical manifestations of TCMP can mimic those of an acute myocardial infarction. Although, chest pain is a common presenting symptom, patients may also have complaints ofdyspnoeaand arrhythmias. In our casedyspnoeawas the predominant symptom and was easily confused with COPD exacerbation. Recently a few cases of concomitant stress cardiomyopathy with obstructive airway disease have been documented in literature. ^2-4 While the pathophysiology of the coexistence of these two disorders is not fully understood, it is thought that both stress induced cardiac dysfunction due to exaggerated sympathetic activation and use of sympathomimetic bronchodilators instigates the myocardial stunning in such patients.  Furthermore, an emotional stressor, such as death of a family member, or a physiological stressor, such as an acute medical illness, is thought to be a trigger for cardiomyopathy. ⁵ It is believed that the syndrome is not a result of anischemia, but there is some evidence to suggest thatoestrogenlevels may have a role in modulating the sympatho-adrenal outflow in TCMP. In mice models, chronic oestrogen supplementation seemed to have protective effects from exaggerated sympathetic outflow from the heart and brain⁶ . Postmenopausal women with low levels ofoestrogenmay be more vulnerable to the exaggerated catecholamine release in responses to stressors. ⁷  

The characteristic finding in TCMP is a transient mid-ventricular or apical ballooning due to a hypokinetic portion seen on echocardiogram or on a left ventriculography. Systolic dysfunction is usually transient, inconsistent to the perfusion area of a single coronary artery, and usually resolves within 4-6 weeks. ⁸ Additional findings include ECG changes with ST segment deviations in precordial leads being the most common. Cardiac enzymes have been noted to have moderate elevations.^9.

As data regarding the treatment of TCMP is limited, medical management mainly consists of symptomatic therapy with aspirin, ACE inhibitors, beta-blockers, and diuretics, also used in acute coronary syndrome.¹⁰   Patients who present acutely are treated as acute coronary syndrome and often receive emergency coronary angiography. However, less invasive imaging techniques, such as echocardiograms, should first be examined carefully.  Due to the transient nature of the syndrome, the duration of treatment is unknown with some studies suggesting that there is no benefit with chronic treatment. ¹¹   The prognosis is fairly good, with in hospital mortality rates being reported to range from 0-8%, and recovery of left ventricular function in the majority of patients. ^{9, 12} 

TCMP is difficult to distinguish from acute coronary syndrome on first presentation. Our patient had significant social stress. She presented with severedyspnoeaand was treated for COPD exacerbation. Elevation of cardiac enzymes and ECG changes lead to further evaluation and diagnosis of stress cardiomyopathy. This atypical presentation of TCMP showcases the importance ofutilisingthe routine noninvasive imaging and laboratory values to guide the diagnosis. Furthermore physicians need to maintain a high clinical suspicion for this syndrome.

Eating disorders are defined as those disorders in which there is excessive concern with the control of body weight and shape, accompanied by grossly inadequate, irregular or chaotic food intake. It is widely accepted that eating disorders occur in young adults and adolescents, however, a number of reports have described series of young patients with eating disorders aged from eight years upwards.^1,2The range of disorders in children includes selective eating, food avoidance emotional disorder, functional dysphagia and pervasive refusal syndrome.  

ANOREXIA NERVOSA.

The DSM IV diagnostic criteria for anorexia nervosa are as follows:

1. Refusal to maintain body weight at or above a minimally normal weight for age and height (e.g weight loss leading to maintenance of body weight less than 85% of expected; or failure to make weight gain during growth period).
2. Intense fear of gaining weight or becoming fat, even though underweight.
3. Disturbance in the way one’s body weight and shape is experienced, undue influence of body weight or shape on self evaluation, or denial of the seriousness of current low body weight.
4. Absence of at least three consecutive menstrual cycles

Subtypes:

Restricting Type: During the current episode of anorexia nervosa, the person has not regularly indulged in binge eating or purging behaviour.

Binge-Eating/Purging Type: During the current episode of anorexia nervosa, the person has regularly indulged in binge eating or purging behaviour.³                       

The above criteria are intended primarily for use with older patients and do not adequately address the problems of anorexia nervosa in children. For example, criterion D in DSM IV applies only to post-menarcheal females and states that there should be an “absence of at least three consecutive menstrual cycles”. This is clearly inapplicable in this age group, where the majority are premenarcheal. Equally unhelpful is the statement that weight should be maintained at less than 85% of that expected, for expected weight can only be calculated on the basis of height and age. Yet growth may also be impaired because of poor nutrition, so further adjustments have to be made. For these reasons, the Eating Disorders Team at Great Ormond Street Hospital for Sick Children in London, U.K, developed a more practical diagnostic criterion for early onset anorexia nervosa.⁴The current criteria is as follows:

Great Ormond Street diagnostic criteria for early-onset Anorexia Nervosa:

1. Determined weight loss (e.g. food avoidance, self-induced vomiting, excessive exercising and abuse of laxatives).
2. Abnormal cognitions regarding weight and/or shape.
3. Morbid preoccupation with weight and/or shape.⁵

Weight loss: Since children should be growing, static weight may be regarded as equivalent to weight loss in adults. Weight loss is a real cause for concern in children, since they have lower total body-fat deposits and therefore do not have much fat to lose. One measurement for weight loss uses the Tanner-Whitehouse Standards⁶ where 100% represents the desired weight for a child’s sex, age and height, and 80% or less is classed as ‘wasting’.

Food avoidance: Children with anorexia nervosa give a variety of reasons for refusing food, the most common of which appears to be a fear of becoming obese. Other reasons include feelings of nausea or fullness, abdominal pain, appetite loss and difficulty swallowing. ⁷

Self-induced vomiting: Fosson et al (1987) reported that at least 40% of the 48 children included in their study of early-onset anorexia nervosa were known to be vomiting at presentation.

Excessive exercising: This is not uncommon in children with anorexia nervosa. Daily exercise workouts may be a feature in these children’s lives. Sometimes exercise may be carried out in secret in the privacy of the bedroom or bathroom.

Laxative abuse: This is not as common as in adult populations partly because children have less access or opportunity to obtain laxatives, but nevertheless, it still occurs.

Abnormal cognitions regarding weight and/or shape: The main beliefs are centred around body image and its distortion, although it must be acknowledged that body image is difficult to assess reliably. Many children with anorexia nervosa will report that they consider themselves fat even when severely underweight, which is similar to the clinical observation seen in adult patients with the same condition.

Preoccupation with weight: Children with anorexia nervosa tend to be preoccupied by their own body weight and are often experts at calorie counting. This preoccupation is closely related to fear of fatness.

Physical Aspects

The majority of physical changes in anorexia nervosa are predominantly related to the effects of starvation and dehydration. This includes slow pulse rate, low blood pressure and poor circulation leading to cold hands and feet. Often there is excess fine hair especially on the back, known as ‘lanugo’. Teeth may be pitted, eroded and decayed from gastric acid during vomiting.

A wide range of biochemical changes have been described in anorexia nervosa, although there is little information specifically relating to children. These include low haemoglobin and white cell count, low levels of potassium and chloride, raised liver enzymes such as alanine transaminase and alkaline phosphatase, and low levels of plasma zinc and serum iron.

A number of endocrine changes appear in anorexia nervosa and evidence suggests that this is due to the secondary effects of starvation. Changes include increased cortisol, growth hormone and cholecystokinin, and decreased luteinizing hormone, follicle stimulating hormone, oestrogen, triodothyronine and thyroid stimulating hormone.

BULIMIA NERVOSA

The DSM IV diagnostic criteria for bulimia nervosa is as follows ⁸ :    

1. Recurrent episodes of binge eating e.g, eating large amounts of food in two hours, and a sense of lack of control during the episode.
2. Regular use of methods of weight control:
3. vomiting
4. laxatives
5. diuretics
6. fasting or strict diet
7. vigorous exercise.
8. Minimum average of two binges a week in three months.
9. Self-evaluation is influenced by body weight or shape.
10. The disturbance does not occur exclusively during episodes of anorexia nervosa.

Sub-types:

Purging Type: During the current episode of bulimia nervosa, the person regularly engages in self-induced vomiting or laxative misuse, diuretics or enemas.

Non-purging Type: During the current episode of bulimia nervosa, the person has used other inappropriate compensating behaviours such as fasting or excessive exercise, but not regularly used purging behaviour. ²

Self-induced vomiting can lead to complications such as fluid and electrolyte disturbance and gastro-intestinal bleeding. Other physical complications include dental erosions, enlargement of the salivary glands, and muscle weakness.

OTHER EATING DISORDERS IN CHILDREN

Food Avoidance Emotional Disorder

This term was first introduced by Higgs et al (1989)⁹, to describe a group of underweight children presenting with inadequate food intake and emotional disturbance who did not meet the criteria for anorexia nervosa.

The operational definition we use has evolved from Higgs and colleagues original description together with clinical experience and is as follows:

1. Food avoidance not accounted for by primary affective disorder.
2. Weight loss.
3. Mood disturbance not meeting criteria for primary affective disorder.
4. No abnormal cognitions regarding weight or shape.
5. No morbid preoccupation regarding weight or shape.
6. No organic brain disease or psychosis.

Selective Eating

Selective eaters are a group of children who present with very restricted eating habits in terms of the range of foods they will accept. Characteristics include:

1. Have eaten a narrow range of foods for at least 2 years.
2. Unwillingness to try new foods.
3. No abnormal cognitions regarding weight or shape.
4. No fear of choking or vomiting.
5. Weight may be low, normal or high.

Pervasive Refusal Syndrome

This term was first described by Lask et al (1991).¹⁰ The main features are:

1. Profound refusal to eat, drink, walk, talk or self-care.
2. Determined resistance to efforts to help.

Initially these children present with features fairly typical of anorexia nervosa, but the food avoidance is gradually followed by a more generalised avoidance with a marked fear response.

Functional Dysphagia

Children with this condition generally present with complaints of difficulty or pain on swallowing. Features include:

1. Food avoidance.
2. Fear of swallowing, choking or vomiting.
3. No abnormal cognitions regarding weight or shape.
4. No morbid preoccupation regarding weight or shape.
5. No organic brain disease or psychosis.

For more information on the above eating disorders in children see Lask & Bryant-Waugh (1999).⁵

INCIDENCE AND PREVALENCE

For a number of reasons, the incidence and prevalence of childhood-onset anorexia are not known. There have been no epidemiological studies which have focussed specifically on this age group and the strict diagnostic criteria used in wider epidemiological studies may lead to a substantial underestimate of the true incidence. ² However studies in adolescent populations estimate the prevalence to be in the order of 0.1-0.2% ^{11, 12} and it is likely to be even lower in children. Although debatable, an increase in actual referral rate of anorexia nervosa in children has been reported.² Gender distribution: Five to ten percent of cases of anorexia nervosa in the adolescent and young adult population occur in males.¹³ However, in children, studies have reported that between 19 and 30% of children with anorexia nervosa have been boys.^7,9,14,15

At present, there is little epidemiological information on the other eating disorders in children.

MANAGEMENT AND INTERVENTIONS¹⁶

Initial assessment

Comprehensive assessment should include physical, psychological and social components. Those with low to moderate risk should be managed as an outpatient. Those who are severely emaciated, with serious risk of self harm, with severe deterioration or with poor response to treatment are deemed high risk and should be considered for inpatient treatment or urgent referral to specialist services.

Anorexia nervosa – outpatient care

Psychological interventions

Psychological interventions are the key element in the management of anorexia.

The delivery of psychological interventions should be accompanied by regular monitoring of a patient’s physical state including weight and specific indicators of increased medical risk.

• When delivering psychological treatment consider, in conjunction with the patient:

– Cognitive analytical therapy (CAT)

– Cognitive behaviour therapy (CBT)

– Interpersonal psychotherapy (IPT)

– Focal psychodynamic therapy

– Family interventions focused explicitly on eating disorders

• Focus of treatment should be on weight gain, healthy eating, and reducing other symptoms related to eating disorders.

• Dietary counselling should not be provided as the sole treatment for anorexia nervosa.

Medication

Pharmacological interventions have a very limited evidence base for the treatment of anorexia nervosa.

• Medication is not effective as sole or primary treatment; caution should be exercised in its use for comorbid conditions such as depression or obsessive–compulsive disorder, as these may resolve with weight gain alone

• Avoid using drugs that affect the heart such as antipsychotics, tricyclic antidepressants, some antibiotics and some antihistamines.

Anorexia nervosa – inpatient care

•Body Mass Index (BMI) is a measure of weight in relation to height. Normal BMI range is 18.5-24.9. BMI below 17 is a concern and GPs should consider referral to specialist services. However, BMI below 15 is serious and inpatient care should be considered.

• Consider inpatient treatment for patients with high or moderate physical risk, who have not improved with appropriate outpatient treatment or have significant risk of suicide or severe self-harm.

• Admit to setting that can provide the skilled implementation of refeeding with careful physical monitoring (particularly in the first few days of refeeding) and in combination with psychosocial interventions

• Consider increased risk of self-harm and suicide at times of transition for patients with anorexia nervosa, especially that of the binge–purging sub-type.

Psychological treatment

• Psychological treatment is a key element of an inpatient stay, but evidence for what kind of treatment or approach to treatment is effective, is limited.

• A structured symptom-focused treatment regimen with the expectation of weight gain should be provided, with careful monitoring of the physical status during refeeding.

• Provide psychological treatment with a focus on both eating behaviour and attitudes to weight and shape, and wider psychosocial issues with the expectation of weight gain

• Do not use rigid behaviour modification programmes.

Feeding against the will of the patient

• Feeding against the will of the patient should be an intervention of last resort in care and should only be done in the context of the Mental Health Act 1983 or Children Act 1989.

Post-hospitalisation treatment in adults

• Following discharge, extend the duration of psychological treatment over that normally provided to those who have not been hospitalised, typically for at least 12 months.

• Offer outpatient psychological treatment that focuses on both eating behaviour and attitudes to weight and shape, and on wider psychosocial issues, with regular monitoring of both physical and psychological risk.

Anorexia nervosa –physical management

Anorexia nervosa carries considerable risk of serious physical morbidity. Awareness of the risk, careful monitoring and, where appropriate, close liaison with an experienced physician, are important in the management of the physical complications of anorexia nervosa.

Managing weight gain

• Aim for an average weekly weight gain of 0.5–1 kg in inpatient settings and 0.5 kg in outpatient settings. This requires about 3500 to 7000 extra calories a week

• Provide regular physical monitoring and consider multivitamin/multimineral supplementation in oral form for both inpatients and outpatients.

• Total parenteral nutrition should not be used unless there is significant gastrointestinal dysfunction.

Managing risk

• Inform patients and their carers if the risk to their physical health is high

• Involve a physician or paediatrician with expertise in the treatment of medically at-risk patients for all individuals who are at risk medically.

• Consider more intensive prenatal care for pregnant women to ensure adequate prenatal nutrition and fetal development.

• Oestrogen administration should not be used to treat bone-density problems in children and adolescents as this may lead to premature fusion of the epiphyses.

• Healthcare professionals should advise people with eating disorders and osteoporosis or related bone disorders to refrain from physical activity that significantly increases the likelihood of falls.

Additional considerations for children and adolescents

The involvement of families and other carers is particularly important.

The right to confidentiality of children and adolescents with eating disorders should be respected.

Family members, including siblings, should normally be included in the treatment of children and adolescents with eating disorders. Interventions may include sharing of information, advice on behavioural management and facilitating communication.

Anorexia nervosa

• Family interventions that directly address the eating disorders should be offered to children and adolescents with anorexia nervosa.

• Offer children and adolescents individual appointments with a health professional separate from those with their family members or carers.

• For children and adolescents, once a healthy weight is reached, ensure increased energy and necessary nutrients are available in the diet to support growth and development.

• Involve carers of children and adolescents in any dietary education or meal planning.

Inpatient care of children and adolescents with anorexia nervosa

• Inpatient care of children and adolescents should be within age-appropriate facilities (with the potential for separate children and adolescent services), which have the capacity to provide appropriate educational and related activities. They should also balance the need for treatment and urgent weight restoration with the educational and social needs of the young person.

• Consider using the Mental Health Act 1983 or the right of those with parental responsibility to override the young person’s refusal to receive treatment that is deemed essential.

• Seek legal advice and consider proceedings under the Children Act 1989 if the patient and those with parental responsibility refuse treatment where treatment is deemed essential.

Bulimia nervosa

Following the initial assessment consider:

• As a possible first step, an evidence-based self-help programme – direct encouragement and support to patients undertaking such a programme may improve outcomes. This may be sufficient treatment for a limited subset of patients.

Psychological treatment should form the key element of treatment, so consider:

• For adolescents: Cognitive behavioural therapy for bulimia nervosa (CBT-BN) adapted as needed to suit their age, circumstances and level of development.

• Where there has been no response to CBT or it has been declined: other psychological treatments,particularly interpersonalpsychotherapy (IPT). (Note: patients should be informed that IPT takes 8–12 months to achieve results comparable with CBT-BN).

Medication may have a role

• Consider a trial of an antidepressant drug as an alternative or additional first step to using an evidence-based self-help programme.

• In terms of tolerability and reduction of symptoms, SSRIs (specifically fluoxetine) are the drug of first choice for the treatment of bulimia nervosa.

• The effective dose of fluoxetine may be higher than for depression.

• Beneficial effects will be rapidly apparent and are likely to reduce the frequency of binge eating and purging, but the long-term effects are unknown.

• No drugs, other than antidepressants, are recommended for the treatment of bulimia nervosa.

Physical management

• Assess fluid and electrolyte balance where vomiting is frequent or there is frequent use of laxatives.

• If electrolyte balance is disturbed, consider behavioural management as the first option

• If supplementation is required, use oral rather than intravenous preparations.

Bulimia nervosa – inpatient or day care

• Consider inpatient treatment for patients with risk of suicide or severe self-harm.

• Admit patients to a setting with experience of managing this disorder.

PROGNOSIS ¹⁷

If untreated, anorexia nervosa carries high mortality rates of

10-15%. If treated, one third have full recovery, one third partial recovery and one third have chronic problems. Poor prognostic factors for anorexia nervosa include: chronic illness, late age of onset, bulimic features such as vomiting and purging, anxiety when eating with others, excessive weight loss, poor childhood social adjustment, poor parental relationships and male sex.

Prognosis for Bulimia nervosa is generally good, unless there are significant issues of low self esteem or evidence of severe personality disorder.

USEFUL RESOURCES

Dr James Moon is a Senior Lecturer and Consultant Cardiologist at UCL and the Heart Hospital.  He set up and runs the cardiac MRI department dividing his time between clinical practice and research. 

He is part of a team of 5 research fellows in the new Heart Hospital Imaging department. He is interested in understanding the structure and function of the heart, particularly the heart muscle, and in detecting abnormalities of the heart to better target treatment.

How long have you been working in your speciality?

12 years (3 as consultant)

Which aspect of your work do you find most satisfying?

The creative aspects of research - joining the dots on information that does not fit and constructing a coherent body of work.

What achievements are you most proud of in your medical career?

Changing statin prescribing in England – as a registrar, I did not having access to cardiac MRI for 2 years and I worked relentlessly at all levels of the healthcare system –including up to Commons Health Select Committee - on this with the result that £1billion was saved or diverted to treat more individuals with statins – the UK now has the highest uptake of statins for primary prevention in the world.

Developing new ways of detecting different types of disease with MRI or CT scanners – in its latest iteration, we may be onto a technique that can measure a fundamental process common to most diseases and organs – not just the heart, and with CT as well as MRI: the volume of cells, fibrosis and their ratio.

Which part of your job do you enjoy the least?

New bureaucracy which we did without just a few years ago..

What are your views about the current status of medical training in your country and what do you think needs to change?

I worry about a tickbox ‘learning portfolio’ culture which dumbs down initiative and personal responsibility leaving a misplaced sense of entitlement.

How would you encourage more medical students into entering your speciality?

I’ve not seen the need to – cardiology is a fantastic, over-subscribed specialty with something for everyone so its pretty competitive.  

What qualities do you think a good trainee should possess?

The same as those of a doctor.  I have never seen this trainee:consultant divide; there is a continuum of learning and responsibility development.

What is the most important advice you could offer to a new trainee?

My advice is about learning rather than being a trainee. Medicine does not have that many raw facts to learn. What it does have is interconnected systems. Rarely consciously try and learn information – rather, try and link everything you have ever learned together, preventing isolated islands of knowledge. It takes longer to create the story, but you will never forget it and it’s far more rewarding. If you encounter something new - a tricky JVP waveform, an ECG repolarisation abnormality or some esoteric MRCP clinical sign, invoke your know of the physical world and apply it to explain the new phenomena – write the essay, deconvolute the phenomena and build it back up, perhaps with subtle changes to see where that gets you. You have spent decades  learning about the Krebb’s cycle, anatomy, electron transport, fractals, Newtonian dynamics, Brownian motion, fluid dynamics, conservation of energy, entropy, cell structure, evolutionary biology, statistics etc etc – use them.

What qualities do you think a good trainer should possess?

I am not sure I know, but generating enthusiasm in people, and then rewarding and promoting it - that’s a good starting point.

Do you think doctors are over-regulated compared with other professions?

No.

Is there any aspect of current health policies in your country that are de-professionalising doctors? If yes what shouldbe done to counter this trend?

It’s the effects on individuals that concern me.  I fully understand the need for process, protocol teamwork and hierarchy, but these remove individual responsibility

Which scientific paper/publication has influenced you the most?

The non-medical maths/science/philosophy books and magazines I read at school and university. I particularly remember Martin Gardner recreational maths books.  Recently I have used fractals and the concepts behind trapdoor ciphers in my understanding of cardiology.

What single area of medical research in your speciality should be given priority?

Prioritize individual researchers/teams rather than topics to create progress through their enthusiasm and own perceptions of priorities.

What is the most challenging area in your speciality that needs further development?

Managing our increasing technical capability which comes with ever reducing incremental benefit.

Which changes would substantially improve the quality of healthcare in your country?

I would overhaul the way society pays for and develops drugs. I would focus on increasing drug company reward for the risk associated with genuine innovation whilst reducing reward for expensive ‘me too’ drugs with no added value.  My group estimated that about 10% of the NHS drug budget could immediately be reallocated improving societal value for money in prescribing, paying for all those much needed NICE decision cancer type drugs and concurrently turbocharging rather empty pharmaceutical drug development pipelines.

Do you think doctors can make a valuable contribution to healthcare management?  If so how?

Absolutely. If you have transparently good and altruistic ideas, are selfless about who gets he credit for them, and sufficiently driven to achieve results, the NHS is a wonderful place - its like a demagnetized iron – apply a sufficiently persuasive external field, and the domains line up, generating far more force and direction than expected. 

How has the political environment affected your work?

The UK has been great for my field –new techniques are adopted early and the international bane of my field - cardiology-radiology turf wars are less acrimonious here as socialized medicine does not reimburse on a pay per procedure basis..

What are your interests outside of work?    

My young family, recreational science, cooking.

If you were not a doctor, what would you do?

Who knows.  Perhaps an economist or maybe evolutionary biologist.