Jun

INTRODUCTION

The pituitary gland is a tiny gland located at the base of the brain and is connected to the hypothalamus. Dubbed as the body’s “master gland”, it produces important hormones that control many bodily functions such as those involved in the control of haemodynamics, glucose, fight or flight response, body growth and many more. Any of the pituitary hormones may be affected in pituitary disease, with acute adrenocorticotropic hormone (ACTH) deficiency being the most catastrophic and life-threatening.

Pituitary apoplexy occurs following acute haemorrhage or infarction of the pituitary gland, causing patients to be acutely unwell due to hormonal as well as local compressive effects. These effects cause the usual presentation of pituitary apoplexy such as severe headache, diplopia, visual loss and hypopituitarism.

We report a case of pituitary apoplexy that presented with a 2-week history of loss of peripheral vision and lethargy with stable vital signs.

CASE PRESENTATION

A 49 years of age gentleman complained of loss of peripheral vision in the left eye and lethargy for 2 weeks. The loss of vision was sudden, painless and non-progressive and had caused him considerable difficulties with driving where he would shift into the wrong lane and was honked at. He had no known medical or surgical history of note. Prior to presentation, he had no history of eye pain, eye redness or a history of trauma to the left eye. There were no headaches, neurological deficits or constitutional symptoms.

Clinically, he had bitemporal hemianopia with no other cranial nerve deficits. His Glasgow Coma Scale was 15/15, vital signs were stable and there was no postural change in blood pressure. Examination of other systems was unremarkable. Blood investigations revealed a decreased morning cortisol of 46 nmol/L and a normal thyroid stimulating hormone (TSH) with borderline low free thyroxine. Serum electrolytes, plasma glucose and all other anterior pituitary hormones were within reference range.

A computed tomography (CT) of the brain showed an enlarged pituitary sella with a large well-circumscribed and heterogeneously enhancing mass within. This mass measured 3.5cm x2.7cm x3.5cm (AP xW xCC) and had no calcifications within. It was also compressing onto the optic chiasm.

Two days later, a brain pituitary Magnetic Resonance Imaging (MRI) was done which reported a heterogeneous mass occupying the sella with suprasellar extension measuring 2.7 x2.8 x2.9cm (AP xW xCC) (Figures 1.1 & 1.2). This mass returned mixed solid-cystic intensity with significant enhancement post-contrast administration. There was evidence of layering within the cystic component of this mass. Inferiorly, the right border ended lower than the left (Figures 2.1 & 2.2).

Following consultations with endocrinologists, neurosurgeons and radiologists, a clinical diagnosis of pituitary apoplexy with hypocortisolism and central hypothyroidism was reached. The patient was started on oral hydrocortisone 20mg in the morning and 10mg in the evening; and oral L-thyroxine 100mcg in the morning before he was referred to the neurosurgeon for trans-sphenoidal surgery. While awaiting surgery, no clinical deterioration was reported. An endoscopic trans-sphenoidal surgery successfully took place a week later which revealed an enlarged haemorrhagic pituitary gland (Figure 3.0). The patient was discharged well a week post-surgery.

His histopathology report later confirmed pituitary adenoma where monomorphic tumour cells arranged in nests and trabeculae and some pseudorosettes were seen. The tumour cells exhibited mild pleomorphism with moderate amount of cytoplasm. The stroma was highly vascularised. No necrosis, calcification or mitosis was seen. Immunohistochemistry studies were positive for follicle-stimulating hormone (FSH) and luteinising hormone (LH) and negative for ACTH, growth hormone, prolactin and TSH.

Figure 1.1 and 1.2: MRI brain on coronal view illustrating well-defined and heterogenous suprasellar mass

Figure 2.1 and 2.2: MRI brain on sagittal view illustrating mixed solid-cystic intensity pituitary mass

Figure 3.0: Intraoperative finding showing haemorrhage of the pituitary gland

DISCUSSION

Pituitary apoplexy is a potentially fatal condition caused by haemorrhage or infarction or both. Most cases occur during the fifth decade of life, predominantly in males.¹ In the majority of cases, it is associated with a pre-existing non-functioning macro-adenoma which accounts for 14-54% of pituitary adenomas and has a prevalence of 7-41.3/100,000 population. The standardised incidence rate is 0.65-2.34/100,00.²

The many clinical presentations of pituitary apoplexy result from local compression of adjacent structures or deficiency of pituitary hormones – the former being more common where affected individuals present with headaches, visual disturbances and other symptoms of raised intracranial pressure.³

Subclinical haemorrhages refer to asymptomatic individuals with evidence of pituitary haemorrhage on MRI. In a 2018 retrospective transversal analysis involving 64 patients, 34.38% had subclinical haemorrhage within a non-functional adenoma.⁴ In another retrospective overview by Turgut et al, 186 cases of apoplectic pituitary adenoma presenting with monocular or binocular blindness were published in the last century.⁵ In a case report by Sasaki et al, a 65-year-old gentleman was only diagnosed with pituitary apoplexy following weeks of blood investigations for hyponatraemia and repeat imaging. His only presenting complaints were anorexia, low energy and fever for two weeks.⁶ These studies show that while an early correct diagnosis of pituitary apoplexy is important, it is not necessarily urgent.

On the other end of the spectrum, pituitary apoplexy may also present as a life-threatening situation where patients are unconscious and hemodynamically unstable due to hypopituitarism. In its acutely deficient state, ACTH causes acute adrenal insufficiency hence resulting in hypotension, hypoglycaemia, hyponatraemia and hyperkalaemia. Sometimes, non-specific symptoms precede the symptoms of hypocortisolism. A drop in consciousness level may be due to the tumour’s mass effect transmitting pressure to the brainstem or causing hypothalamic compression.⁷ Espinosa et al reported a 48-year-old gentleman with pituitary apoplexy who presented with the worst headache of his life, requiring urgent neurosurgical intervention which proved to be life-saving.⁸

Complex as it already is, diagnosing pituitary apoplexy may be further complicated when non-specific symptoms can be explained by other causes such as post-general anaesthesia drowsiness, hyponatraemia in a patient on diuretics and headaches in post-partum women receiving spinal anaesthesia.^{9, 10}

While most patients consequently suffer from pituitary insufficiency, the extent, type and duration of therapy differs between patients. Cases of spontaneous recoveries whether a surgical or conservative approach was adopted have also been reported.^{11, 12} However, robust control studies comparing the outcome of surgical with conservative management in patients with pituitary apoplexy have yet to emerge. Nonetheless, studies have proven that visual outcomes significantly improve with surgery.^{13, 14}

Having discussed the varied presentations of pituitary apoplexy, it can be agreed upon that the life-threatening endocrinal condition should be considered in any patient with abrupt neuro-ophthalmic deficits despite the state of clinical stability. This is imperative as prompt medical and surgical management may not only be life-saving, but also significantly improve visual and cranial nerve outcomes.¹⁵

CONCLUSION

Pituitary apoplexy is an endocrinal emergency which requires immediate investigation and treatment. Despite its disastrous pathology, there have been cases where affected patients present with isolated visual disturbances or with no symptoms at all. It is therefore important to have early suspicion of pituitary apoplexy in stable patients with eye complaints as early detection and management are life-saving and significantly improve neuro-ophthalmic outcome.

Introduction

The continuous growth in patient numbers and needs poses several challenges for medical professionals and support staff within the National Health Service (NHS).¹ Health care services are under financial strain in the light of the changing demographic structure of the UK population that requires improved access to health services. Managing patient satisfaction represents another major challenge. Evidence from a recent national survey in the UK shoes that dissatisfaction with the NHS has increased by seven percentage points in 2017, reaching 29 percent, its highest level since 2007.² Staff shortages, long waiting times for surgical operations and access to care, inadequate funding, and slow-paced government reforms are among the reasons for dissatisfaction. For hospitals, long waiting times at the A&E department, and delays for patients in need of critical care represent major concerns.³

Unsatisfactory health care service experiences generate negative outcomes for health service providers in terms of managing patients’ experience of care, and meeting performance targets. As patients are ultimately the receivers of health care provision, understanding their experiences of care is pivotal.⁴ The psychological processes underlying patients’ perceptions and evaluations of service provided by the health care professionals, play a crucial role in patient satisfaction. The cognitive processes of patients and their support network, such as friends and relatives, influence perceptions and attitudes towards health care treatment and service. Research underpinned by knowledge from social psychology can shed light on such cognitive processes and generate insights for effective management of patient satisfaction.

The concept of psychological threat in health care service experiences can be explained through the notion of ‘lock-in situations’⁵ perceived by the patients. For instance, when visiting a hospital or a GP surgery, patients often undertake externally-imposed activities, such as long waiting time for a doctor’s appointment, ease of self-service check-in, lack of acuity in self-care and monitoring, and/or unsatisfactory interactions with support staff – all parts of the service provision. Such situations can be perceived as a threat to the self-determination needs, such as the need for autonomy. Patients who regularly use health care services in the UK associate four main types of threat to health care service experiences, in response to which coping strategies are activated. We discuss these below.

Perceived threats associated with health care services

Patients who use health care services in the UK often report situations they find threatening or questioning their astuteness and sense of control. Interactions with health care staff can make patients feel unintelligent and/or incompetent and restricted in personal control. This is typical of encounters where healthcare support staff are unable to address patients’ queries accurately, and their attempt at resolving the issue is perceived subconsciously as unnecessary and inappropriate by the patients. The above seems to be due to a general lack of trust in the competence of health care personnel, and more conspicuously the perception that they were not willing to act in the interest of patients. Poor health status at the time of accessing health care services might also hinder patients’ willingness to accept advice from health care professionals. Such experiences of threat to self-competence are often associated with negative or even vengeful behavior towards the health service provider, which is the party perceived as threatening. The psychological mechanism behind such behavior is that retaliation alleviates the emotional discomfort caused by threat perceptions⁶.

Threats to personal control are often reported when processes in the health care service provision are perceived as inadequate and lead to, for instance, long waiting times for appointment booking and/or rescheduling. Our qualitative research show that patients perceive the process of booking a doctor’s appointment as ‘a nightmare’, ‘particularly time-consuming’ and ‘complicated’. They perceive a loss of control when seeking to book or reschedule an appointment. When appointments are not scheduled around their commitments, patients perceive that they are not being heard.

Furthermore, health care service experiences are perceived as threatening to the individual’s self-esteem; especially in situations where patients feel ignored by the health care personnel, and their own self-esteem and social identity are being undermined. A key reason is the perceived lack of empathy and concern of health care personnel during interactions with patients.

How patients activate coping strategies

The lock-in situations discussed above can affect satisfaction and well-being, despite patients’ general compliance with requests from health care personnel.⁵ Social psychology research shows that perceived threats, such as those reported in health care service experiences, increase feelings of anxiety, averseness, lack of control, and aggressiveness.⁶ Crucially, in response to threats and consequent negative feelings, patients activate coping strategyas a mechanism of self-defense. We postulate that coping strategies, in turn, influence their behavior, aimed at compensating for the unsatisfactory experience⁷. Such behaviour can be negative, and at times even vindictive towards the health care service provider.

Social psychology research distinguishes between individual’s coping strategies⁸ aimed at addressing the source of the threat (i.e. problem-focused coping), and those focused on re-establishing positive emotions, for instance through the act of venting dissatisfaction caused by the threat (i.e. emotion-focused coping). In health care services, patients often seek to proactively react to threats, thereby engaging in problem-solving. This is especially the case when unsatisfactory health care service experiences are aggravated by a serious illness. Severity of the illness markedly influences patients’ willingness to take actions in response to threats. Crucially, the decision to act seems to benefit patients, as they report feeling ‘back in control of the situation’ – a form of compensatory behaviour⁹. Cerebral activities, such as rational and positive thinking, influence the extent to which patients confront threats. Rational thinkingcan induce patients to take a step back from the experience, reconsider the factors at play, and plan their next actions.

Crucially, in the process of coping with threats imposed by health service experiences, patients often feel overwhelmed. Negative emotions in such threatening circumstances are heightened, and the support from their network of friends and family appears to be fundamental. Intriguingly, for some patients, social media is increasingly seen as a useful source of emotional support, which appears to be gradually replacing conventional forms of verbal, face-to-face support.

Final remarks

We offer an overview on how insights from social science research can be valuable for informing decision-making of health care service providers. This is especially the case in decisions related to staff hiring, training and development, service process improvement and supporting systems design. Lack of empathy and concern from frontline health care staff, outdated service processes and systems represent threats to patients. An implication is that innovative training of frontline staff is necessary for the development of soft skills, which are highly valued by patients. Developing caring and supportive relationships between health care personnel and patients is necessary, as these have considerable bearing on the outcome of healthcare service experiences. Similarly, introducing the practice of simulating patients’ care experience can help to identify threats whilst introducing service improvements and innovations. There is also need for health care service providers to be aware of the fact that patients’ health status at the time of seeking access to and experiencing health services influences their evaluations of the quality of care and of the service experience. It follows that the service provision needs to be adapted to account for patients’ health status and vary according to different patients’ groups. Insights from social science research can inform practice for enhanced provision of health care services. Further survey-based research focusing on the causal links between psychological threat, coping and patient well-being¹⁰ is on hand.

Introduction:

According to DSM V, delirium is defined as disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). This disturbance develops over a short period of time and it represents an acute change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.

The focus of the researchers has shifted from treatment to prevention of the syndrome. There is a need to study risk factors for prevention of delirium¹. Data on delirium in the intensive care unit is scarce in the Indian subcontinent².

A multicenter study indicated risk factors significantly contributing to delirium were related to patient characteristics (smoking, daily use of more than 3 units of alcohol, living alone at home), chronic pathology (pre-existing cognitive impairment), acute illness (use of drains, tubes, catheters, use of psychoactive medication, a preceding period of sedation, coma, mechanical ventilation) and the environment (isolation, absence of visit, absence of visible daylight, transfer from another ward, use of physical restraints)¹. Psychoactive medications can provoke a delirious state. Lorazepam has an independent and dose related temporal association with delirium³.

Each additional day spent in delirium is associated with 20% increased risk of prolonged hospitalisation and 10% increased risk of death⁴.

Hence, the present study was done to assess risk factors and precipitating factors of delirium in a medical intensive care unit of a tertiary care hospital.

Materials and methods:

This is an observational study done over a period of 1 year in a tertiary care medical college hospital located in southern part of India. Ethical committee approval for the study was obtained from the institutional ethical committee.

All patients admitted to medical intensive care unit in our tertiary care hospital, were screened for presence of delirium during the first 72 hours of admission using Richmond Agitation Sedation Scale (RASS) and Confusion Assessment Method for ICU (CAM-ICU). Patients with delirium were classified as delirious and the remaining as non-delirious patients. Comatose patients (RASS score -4 or -5) were excluded from the study.

Patients were initially screened with Richmond Agitation Sedation Scale (RASS). It is a 10-point scale, with 4 levels of agitation (+1 to +4) and 5 levels of sedation (-1 to -5). Level zero indicates calm and alert patient. Patients with RASS score of -4 or -5 (deep sedation and unarousable patients) were excluded from the study. Patients with RASS score of +4 to -3 were then screened for presence of delirium using Confusion Assessment Method for ICU (CAM-ICU). CAM–ICU has 4 criteria:

1) Acute onset and fluctuating course of delirium

2) Inattention

3) Disorganized thinking

4) Altered level of consciousness

The diagnosis of delirium requires the presence of criteria 1 and 2 and of either criterion 3 or 4.

Risk factors for developing delirium were assessed in the study population. Risk factors are those proven factors which may also be present before patient’s admission to intensive care unit, and which predispose the patient to develop delirium. Risk factors were compared between delirious and non-delirious patients. Risk factors which were assessed were history of diabetes and hypertension, history of previous stroke, history of previous cognition impairment, history of previous psychiatric illness, history of previous trauma, history of previous episodes of delirium, history of bowel and bladder disturbances prior to admission (such as constipation and urinary retention respectively), history of alcohol abuse (consumption of more than 2 units of alcohol), history of smoking (more than 10 cigarettes per day), history of consumption of substances other than cigarettes and alcohol (such as cannabis, cocaine etc.), history of uncorrected visual or hearing disturbances before admission, history of usage of barbiturates (such as phenobarbital), benzodiazepines (such as alprazolam, chlordiazepoxide, clobazam, clonazepam) & opioids (such as morphine) before admission, history of usage of sedatives (such as haloperidol, midazolam, fentanyl) and pain killers (such as morphine, tramadol) at the time of admission. Metabolic risk factors which were compared between delirious and non-delirious subjects were uraemia, hyponatremia, hyperbilirubinemia, metabolic and respiratory acidosis.

Precipitating factors weredefined as factors that were the likely causes of delirium in delirious patients. Precipitating factors for delirium which were looked into were exposure to toxins (alcohol/drugs), deranged metabolic parameters, infections and central nervous system causes.

SPSS21 software was used to calculate statistics. Independent t-sample test and the Pearson Chi-square test were used to calculate differences between delirious and non-delirious subjects. Odds ratios (OR) was calculated for all factors using univariate binary logistic regression.

Results:

Total number of patients enrolled in the study was 1582, of which 406 were diagnosed with delirium. Percentage of patients developing delirium within first 72 hours of admission was 25.7%. Hypoactive delirium was present in 52% and hyperactive delirium in 48% of patients. Patients who experienced delirium (57.5 + 17 years) were older compared to their non-delirious (53.3 + 18.1 years) counterparts (p value <0.0001). Among delirious subjects, majority were in the age group of 61-70 years (Figure 1).

Figure 1- Age distribution among delirious patients

38.2% of delirious patients and 39.3% of non-delirious patients were females. 61.8% of delirious patients and 60.7% of non-delirious patients were males.

Alcohol consumption [OR = 6.54 (95% CI 3.76-11.4, p = 0.0001)], previous psychiatric illness [OR = 3.73 (95% CI 1.712-8.159, p = 0.033)], previous cognition impairment [OR = 2.739 (95% CI 1.509-4.972, p = 0.001)], sedatives usage at the time of admission [OR = 2.488 (95% CI; 1.452-4.264), p = 0.001)], visual disturbances [OR = 2.227 (95% CI; 1.328-3.733, p = 0.002)], bowel and bladder disturbances [OR = 1.677 (95% CI 1.044-2.693, p = 0.032)] were significant risk factors contributing to delirium after univariate analysis (Table 1). Metabolic acidosis [OR = 1.996 (95% CI 1.469-2.711, p = 0.0001)] and hyperbilirubinemia [OR = 1.448 (95% CI 1.111-1.886, p = 0.006)] were significant metabolic parameters contributing to delirium after univariate analysis (Table 2).

Precipitating factors (Table 3) for delirium are those factors that were considered the most likely causes of delirium among the delirious patients. Precipitating factors for delirium were classified into toxins, deranged metabolic parameters, infections and central nervous system causes, of which metabolic parameters were most common. Among metabolic parameters, uraemia (25.1%), hepatic encephalopathy (22.7%) and hyponatremia (19.5%) contributed to the majority of cases with delirium.

Table 1 – Univariate analysis of risk factors of delirium

Table 2- Univariate analysis of metabolic parameters

Table 3- Precipitating factors of delirium in the present study

Discussion:

Delirium is classified into hyperactive, hypoactive and mixed type. Hyperactive subtype is present if there is definite evidence in the previous 24 hours of at least two out of the following factors - increased quantity of motor activity, loss of control activity, restlessness, wandering. Hypoactive subtype is present if there is definite evidence in the previous 24 hours of at least two of the following factors - decreased amount of activity, decreased speed of actions, reduced awareness of surroundings, decreased amount of speech, decreased speed of speech, listlessness, reduced alertness, withdrawal. Mixed subtype is present if there is evidence of both hyperactive and hypoactive subtypes in the previous 24 hours⁵. Percentage of patients with hypoactive delirium was high in this study (52%). Hypoactive delirium often carries relatively poor prognosis, occurs more commonly in elderly patients and is frequently overlooked or misdiagnosed as having depression or a form of dementia.

In the present study, delirium was more prevalent in the elderly population. Most of the elderly patients will have multiple risk factors making them more vulnerable to delirium. Delirium is often the only sign of an underlying serious medical illness in an elderly patient and particular attention should be given to identify and correct the underlying illness.

History of alcohol consumption of more than 2 units per day, prior to admission of the patient, was the major risk factor contributing to delirium in this study (OR = 6.54). This was similar to other studies done by Bart¹ et al & Ouimet⁶ et al where consumption of more than 3 units of alcohol (OR 3.23) & 2 units of alcohol (OR 2.03) respectively, was a significant risk factor for delirium. Patients with a previous psychiatric illness were at increased risk for delirium in this study (OR – 3.73). However, other studies explaining its importance in contributing to delirium were not available. Previous cognition impairment was a significant risk factor contributing to delirium (OR = 2.73). The study by Bart¹ et al found that previously diagnosed dementia was an important risk factor (OR = 2.41). Positive correlation with dementia was reported by McNicoll et al⁷ (RR 1.4) and Pisani et al⁸ (OR 6.3). Usage of sedatives (OR = 2.48) at the time of admission was a significant risk factor for developing delirium. Bart¹ et al found that use of psychoactive medication may disturb the neurotransmission in the brain provoking a delirious state and use of benzodiazepines is a risk factor for delirium (OR – 3.34). Pandharipande³ et al found that Lorazepam was an independent risk factor for daily transition to delirium (OR – 1.2). Pisani⁸ et al found that use of benzodiazepines was a significant risk factor for developing delirium with odds ratio of 3.4. Uncorrected visual disturbances were a significant risk factor for developing delirium in this study (OR-2.22). Inouye⁹ et al found that vision impairment (adjusted relative risk – 3.5) was an independent baseline risk factor for delirium. Bowel and bladder disturbances were a significant risk factor contributing to delirium in this study (OR – 1.67). Morley¹⁰ opined that constipation is a frequent, often overlooked precipitating factor for delirium. Tony¹¹ et al was of the opinion that a careful history and physical, including a rectal examination with consideration of disimpaction, may be helpful in assessing and managing delirious patients. Waardenburg¹² concluded that significant urinary retention can precipitate or exacerbate delirium, a disorder referred to as cystocerebral syndrome. Liem and Carter¹³ suggested that increased sympathetic tone and catecholamine surge triggered by the tension on the bladder wall may contribute to delirium. Metabolic acidosis and hyperbilirubinemia were significant metabolic parameters contributing to delirium in this study.Similar findings were reported by Aldemir¹⁴ et al.

Among delirious patients, most common precipitating factors for delirium in this study were uraemia (25.1%), hepatic encephalopathy (22.7%) and hyponatremia (19.5%). Alterations of serum electrolytes, renal function predispose to delirium¹⁵. Hyponatremia causes delirium and the mechanism is not well understood^{16, 17}. Blood urea nitrogen/creatinine ratio greater than 18 is an independent risk factor for delirium in general medical patients⁹.Hepatic failure leads to hyperammonemia, which leads to excessive NMDA (N-methyl-D-aspartate) receptor activation, resulting in dysfunction of glutamate-nitric oxide-cGMP pathway and causing impaired cognitive function in hepatic encephalopathy¹⁸.Excess activation of NMDA receptors results in neuronal degeneration and death¹⁹. In hepatic failure, there may be a shift in regional cerebral blood flow and cerebral metabolic rates from cortex to subcortex resulting in delirium²⁰.

Patients who develop delirium during their stay in hospital have higher 6-month mortality rates, longer hospital stay, increased economic burden and a higher incidence of cognitive impairment at hospital discharge²¹. Limitation of this study was long term follow up of patients who developed delirium was not done.

Conclusion:

Delirium is common in intensive care unit patients and hypoactive delirium is more common. Major risk factor contributing to delirium was alcohol consumption before admission. Most common precipitating factors contributing to delirium were deranged metabolic parameters.

Delirium in ICU patients especially hypoactive delirium is easily missed. Hence, all ICUs should implement both RASS and CAM-ICU for early detection of delirium. Future research needs to be directed at development of scoring systems for detection of delirium, which are easy to use and are accurate.

Schizophrenia sufferers feel like abstract entities with non-animated bodies, often experiencing auditory verbal hallucinations (AVH) due to morbid “objectification” of inner dialogue.¹ From the patient’s perspective, AVHs are a subjective–objective phenomenon. AVH is a non-consensual, dynamic and psychologically charged experience and the voices often echo significant emotions. Derogatory voices are common representations of unconscious self-hatred that cannot stand up to the external world’s logic. Thus, patients need help to incorporate it. Auditory hallucinations may be arising because of an interaction between biological predisposition, perceptual and cognitive factors. According to an integrated model of auditory hallucination (AHs) suggested by Waters et al,² AHs arise from an interaction between abnormal neural activation patterns that generate salient auditory signals and top-down mechanisms that include signal detection errors, executive and inhibition deficits, a tapestry of expectations and memories. Recently, neuro-quantologists have proposed that AVHs may be an objectification of parallel thinking/quantum thinking.³ Parallel thinking is a source for thought insertion. There may be different variables of AVHs. Experiencing AVH has serious impact on the quality of life of the affected individual, and is a significant factor in prevalence of suicides among schizophrenic patients.⁴

Incidence

One in four schizophrenia sufferers experiences persistent AVH .⁵ AVHs are experienced by approximately 53% of schizophrenia sufferers ⁶ and are present in 28% of major affective disorders (Goodwin& Jamison, . ⁷ Evidence indicates that each patient responds differently to the voices, according to his/her evaluation of them (Table 1), which influences the degree of interventions. Specific dimensions of AVHs can give hints to the future likelihood of treatment resistance. Although the percentages differ in various studies, it is assumed that about 30% of patients have command hallucinations and they are seen as the ultimate betrayal of the mind. ⁸ Often, the content of such messages is negative; thus, commanding AVHs are more distressing than commenting ones. Schizophrenia predisposes them to a greater risk of suicides and homicides. Command hallucinations are more prevalent among forensic patients and contribute to their forensic status.

Table1. Patients’ Response to AVH

The multi-factorial polygenic model of schizophrenic disorders has received great support and signifies that genetic factors play a bigger role than environmental factors in familial transmission of these disorders. Relevant studies provide little support for the mechanism of single major locus inheritance. A mechanism involving two, three, or four loci cannot be ruled out even though there is no compelling support for such models.⁹ It has also been proposed that a single gene may be even responsible for hallucinatory experiences ¹⁰ implying that those who have not inherited such a gene may not experience auditory hallucinations, but still could experience other characteristic symptoms of schizophrenia. One may also hypothesise that an individual who has inherited such a “hallucinatory gene” but not all the schizophrenia genes could hear non-clinical voices without having other schizophrenic symptoms. It is also arguable that those who carry such a specific gene are more vulnerable to experience hallucinations when they abuse psychoactive substances and could get misdiagnosed as having schizophrenia, but hallucinations may cease to occur once they abstain from illicit drug abuse.

Measurements for Assessment

AVH is a subjective experience and is hard to measure objectively. Several rating scales are now available for an efficient evaluation of different aspects of voice activities. Some are general and a number of them are specifically designed. Using rating scales facilitates better engagement with patients and helps in reinforcing the message that patients and the distress they experience are carefully considered.

Beliefs About Voice Questions (BAVQ) is an assessment scale useful in measuring the key beliefs about the voices.¹¹ It is typically used in conjunction with the Cognitive Assessment Schedule (CAS).¹² Voice Compliance Scale (VCS) is an observer rated scale aimed exclusively at measuring the frequency of command hallucinations and the level of obedience or confrontation with each recognized command.¹³ Voice Power Differential Scale (VPD) is another measure that can be applied to rate the perceived relative power differential between the voice and voice experience. ¹⁴ On the other hand, Omniscience Scale (OS) is intended to quantify the voice hearer’s beliefs about their voices’ knowledge regarding the bio data. ¹⁵ Another measure presently in use is Risk of Acting on Commands Scale (RACS), designed to assess the level of risk of acting on commands and the amount of associated distress. ¹⁶

The Bonn Scale (BSABS) is used for the assessment of basic symptoms, ¹⁷while the Schizophrenia Proneness Instrument (SPI-A) ¹⁸and the Examination of Anomalous Self Experience (EASE) ¹⁹ are useful aids in identifying minimal changes in subjective experience and for longitudinal monitoring (Table 2). In the extensively used Positive and Negative Syndrome Scale (PANSS), the hallucination item is one of seven in the positive subscale, which also includes delusions, conceptual disorganization, excitement, grandiosity, suspiciousness, and hostility. Given such a great number of scales in use, there is an obvious risk that differential anti-hallucinatory efficacy among antipsychotic drugs may be obscured by means of sum scores for the whole sample in clinical trials.

Table 2. Measurement scales

Treatments

Although many forms of treatments aiming to eliminate AVH or improve quality of life are available, use of medication seems to be the most prevalent. Besides drug treatment, non-invasive physical treatments, such as TMS and different forms of psychological interventions, have recently evolved. Drug therapies are aimed at symptom eradication, whereas psychological therapies tend to foster healing, recovery and personal growth. Rather than being specifically anti-hallucinatory, typically, neuroleptics offer a generalised calming effect and patients are given some “breathing space” to work through their voices. Usage of non-pharmacological tools is needed in the long-term management of refractory cases. Presently, intervention strategies for AVH are based on different models of hallucinations, but regrettably no clear models have been established.

Pharmacotherapy

The current understanding of AVH and the neural mechanisms involved is limited, and knowledge on how CNS drugs, such as antipsychotics, influence the subjective experience and neurophysiology of hallucinations is inadequate. Consequently, using pharmacotherapy in the management of AVH remains very challenging. ²⁰ Despite multiple trials of different combination and adjunctive therapies to an antipsychotic regime, AVH can remain drug resistant. It is also important to note that all antipsychotics are potentially anti-hallucinatory, even though these effects are usually modest. Moreover, given that, even when medications are effective, concordance can be an issue, antipsychotics should be used prudently and weighed up against effectiveness and side effects (Table 3). There are no clear guidelines for the drug treatment of AVH and comparisons of the efficacy of antipsychotics for AVHs are few. Clinical drug trials very rarely focus on single symptom scores, such as hallucinations, and tend to report group mean changes of overall psychopathology, or at best the positive subscale scores.

Evidences show that AVHs persist in spite of treatment in 32% of chronic patients ²¹ and 56% of acutely ill patients.²² Trifluperazine was popular as an anti-hallucinatory drug before the advent of atypical antipsychotic drugs. Clozapine is currently favoured for intractable AVHs and is beneficial in 30–60% of unresponsive patients.

Antipsychotic co-treatment is an option for clozapine augmentation. Olanzapine and risperidone may be alternative drugs in first episode psychosis. However, it is being debated whether clozapine should be used in such cases.

Table 3. Drug Treatment

Clozapine

Use of clozapine is suggested only after two other antipsychotics have been tried. It works better with continued usage and clinicians have to be patient in its upward titration. At six months, improvement in Global Assessment of Functioning score is significantly higher for clozapine in comparison to other antipsychotic drugs.²³ However, when prescribing clozapine, cautions and contraindications must be noted (Table 4).

While higher doses of clozapine may not have more anti-hallucinatory effect, they still carry the risk of inducing the potential side-effects of this highly efficacious drug (Table 5). The most dreaded haematological side-effects are usually manifested within six months. For that reason, during clozapine therapy, patient has to be closely monitored, bearing in mind its limitations in achieving the anti-hallucinatory effects. If higher doses do not have the desired effect, clozapine dose should be titrated downwards to a point of its maximum anti-hallucinatory effect in a particular patient. Such an endeavour can prevent the emergence of serious side-effects, resulting in a complete failure of the therapy. The dose can also be adjusted to a safer level in cases where the psychological interventions are found to be successful. Clozapine can be effective even in lower doses, such as 200 mg/day. Only in the presence of command hallucinations, higher doses should be prescribed to patients whose other positive symptoms are well under control.

Prophylaxis with an antiepileptic drugs, such as lamotrigine or sodium valproate, or similar should be commenced before titrating the dose above 600 mg daily. Close monitoring and active treatment of metabolic dysregulation should be initiated concurrent with clozapine therapy. In clozapine therapy, weighing up safety and superior antipsychotic efficacy and educating the patients on “clozapine lifestyle” is immensely important, as it helps in treating refractory cases of AVH. Thirty percent of patients treated with clozapine may remain unresponsive and clinicians have to lower their expectations to the level of achievement without being cynical. Isolated cases of clozapine-induced joint visual and auditory hallucinations have been reported. ²⁴ In spite of Clozaril treatment having the highest anti-hallucinatory effect, a good percentage of AVH sufferers remain symptomatic and are classed as super-refractory.⁸ According to Gonzales (2006), ²⁵ 50% of patients receiving antipsychotics achieve full remission, while 25% hear voices occasionally and 25% are unresponsive.

Table 4. Cautions & Contraindications of Clozapine

Table 5. Benefits and risks of Clozapine

Benzodiazepines are often abused by voice hearers aiming to reduce their anxiety. Such patients might benefit by the addition of antidepressant, as this could enhance their mental resources to cope with the voices, even though they have no anti-hallucinatory effects per se. Mood stabilisers are sometimes used to augment the efficacy of antipsychotics without any clinical validation. Despite multiple trials of different adjuvant therapies to an antipsychotic regimen, there have been few promising results. Still, in practice, clinicians may get frustrated, as they struggle to provide symptomatic relief to the voice hearers at any cost. Recently allopurinol, an anti-gout agent has been used as an adjunctive therapy and based on three randomized controlled trials, the result has been encouraging. ²⁶

Psychological Interventions

Persistent AVHs alone may not warrant pointless alteration of medication, as non-pharmacological interventions may achieve some control. When clinicians are not cognizant of non-pharmacological therapies, AVH patients that do not respond to antipsychotics alone may be mislabelled as having refractory AVH. In fact, they are only unresponsive to drug treatment, and could potentially respond to an integrated approach. Similarly, patients with treatment-refractory AVH are often over-diagnosed as suffering from hard to treat schizophrenia, even when other positive symptoms have been ameliorated.

There exists a false dichotomy between physical and psychological treatment approaches to AVH. In practice, both treatment modalities have to be modified in a personalised form. After all, psychiatry was originally known as psychological medicine. Presently, even though different forms of non-pharmacological interventions are available for drug-resistant AVH, some have questionable effects. ^27,28,29 (Table 6).

Table 6. Psychological Interventions

CBT therapists predicate that AVHs are a manifestation of the morbid objectification of inner dialogue (thinking in words),and accordingly verbalised thoughts are the raw material for AVHs.Verbal thinking differs from external speech in many respects and has several distinct features. CBT therapists believe that cognitive dysfunctions underlie AVH and they target them with cognitive remediation strategies. Those experiencing voices commonly think that they are caused by a powerful external agency, and are controlling and potentially harmful. Psychological factors, such as meta-cognitive biases, beliefs, and attributions concerning the origins and intent of voices, also play critical modulatory role in shaping the experience of AVH. Teaching patients to recognize the source of the voices alone has yielded beneficial effects.

Specific techniques have been designed to modify the frequency of AVHs and restore a sense of control over them. Earlier methods involved behavioural approaches based upon addressing hypothesized antecedents and reinforcers of voices and explored a variety of specific interventions such as relaxation training, graded exposure to voice triggers, manipulation of environmental possibilities and even aversion therapy. ³⁰ These behavioural techniques were eventually expanded on by the application of cognitive methods. The primary aim of psychological therapy is to change the belief that voices are omnipotent and uncontrollable and to suppress the associated attributes of false identity, wrong intentions, and urges to harm oneself and others. They encourage patients to challenge irrational interpretations and modify maladaptive behaviour, diverting attention from voices with distraction techniques (Table 7).

Reality testing and behavioural experiments are one form of CBT intervention, based on the view that behavioural changes can prompt cognitive changes. Attention switching can also be used to challenge the belief that hallucinations are uncontrollable. Command AVHs are more prevalent among the forensic population and are more distressing than the commenting ones. The risk of the sufferer acting on them is high when voices are perceived as omnipotent and uncontrollable. CBT has been proven beneficial in tackling command hallucinations. Lack of insight and formal thought disorder may not necessarily disqualify CBT for AVH; nonetheless, negative symptoms may pose a barrier to this form of psychological intervention. The current model of CBT for psychosis has been criticized, suggesting that it is simply an extension of general CBT concepts without taking into account the specificities of psychosis. ³¹ Patients with higher intelligence, who have the ability to grasp abstract concepts, might gain greater benefits from CBT. ³²

Table 7. Goals of CBT

Combining psycho-education and supportive psychotherapy has been found to enhance the functioning and self-esteem of voice hearers, providing a therapeutic structure. In the increasingly popular self-help voice-hearing groups, the ethos of recovery is understanding, accepting and integrating the sufferer’s turmoil. Acceptance and non-judgemental support of people with similar experiences has helped many patients cope with the condition. In response, the number of books on AVH, aiming to educate the sufferers and carers, has grown considerably.

Newer Psychological Interventions

Attention Training Technique (ATT) focuses on negating psychological distress through cognitive and meta-cognitive modification. ^33,34 Patients focus on up to five neutral sounds, such as a dripping tap, before switching their attention between different sounds. They then practise listening to all the sounds simultaneously. After a few weeks, they focus on neutral sounds and then on the AVH. Once this process is mastered, they switch attention between voices and other sounds, before being asked to divide their attention among them. This exercise continues for several weeks, whereby the aim is to replace the self-regulatory process with new processing configurations.

Acceptance and commitment therapy (ACT) is aimed at achieving psychological flexibility. It incorporates mindfulness and acceptance, considering AVH as a private experience and asserting that patients experience distress only when they try to deafen the voices. . By reducing struggle with voices and engagement with them, key responses such as arousal, attention and activation of brain areas are hypothesised to be reduced. ³⁵ The ideas behind ACT are consistent with the emphasis on the recovery movement of finding a way to live a valued life despite the ongoing problems. To this effect, unique and effective coping strategies are offered, whereby patients are given the insights that parts of the self are behind the voices. Thus, accepting them means sending a loving message of compassion, acceptance and respect to oneself Two randomised control studies have yielded promising results. ^36,37ACT follows a set manualised structure, rather than relying upon the complex and lengthy process of belief modification: therapy can be much briefer and potentially practiced by a wider range of clinicians and cost effective. ³⁸

There are verbal and non-verbal routes to emotions. As CBT uses the former in voice therapy, it is less effective when patients are negatively involved with the voices. On the other hand, Competitive Memory Training (COMET) uses the non-verbal route. Generally COMET sessions involve four stages.³⁹ A. identification of aspects of negative self-esteem reinforced by the voice; B. retrieval and re-living of memories associated with positive self-esteem; C. positive self-esteem is brought to compete with the content of the voices to weaken associations between voice content and negative self-valuation; and D. learning to disengage from the voices and to accept the voices as psychic phenomenon.

The significant past comes back to the conscious mind in AVH, as life experiences charged with emotion make a compelling impression on the brain. The observation that voices are knowledgeable about patients suggests that auditory hallucinations are linked to memory. In other words, negative experiences from memories evoke emotions, which should be deactivated. Distancing and decentring techniques could help patients to interpret voices as false mental events. As a result, incompatible memories could become tools to modify the power of voices—they are deactivated by new learning. Thus, when voices torment hearers, telling them that they are failures, a competing memory of such success as passing a significant examination is introduced. Posture, facial expression, imagination, self-verbalisation and music are all procedures included in the COMET protocol.⁴⁰

Compassionate mind training (CMT) is used to encourage better resilience to unpleasant commenting voices.CMT involves practicing exercises which promote self-compassion and compassion towards others. It is targeted to activate brain systems involved in social and self-soothing that amend threat systems active when experiencing unfriendly voices. ⁴¹

Mindfulness is paying attention in a particular way – on purpose, in the present moment and non-judgementally. Clinical literature cautions against use of meditation in psychosis, but the effectiveness of mindfulness-based approaches for people with psychosis has been demonstrated in controlled clinical settings. ⁴²and in the community. ⁴³ Abba et al. ⁴⁴ argue that effectiveness of mindfulness is a three-stage process: a. Becoming knowledgeable and developing more awareness of psychotic experiences and observing the thoughts and emotions that follow them. B. Permitting psychosis to come and go without reacting in order to cultivate understanding that distress is produced by the meanings one attaches to thoughts and sensations. C. Becoming autonomous by accepting psychosis and the self by acknowledging that the sensations only form part of the experience, and are not a definition of the self.

Neuroimaging studies are beginning to explain the neural mechanisms of how mindfulness might be working clinically. Structural changes have been observed in the anterior cingulate cortex, which is an area of the brain associated with emotional regulation. ⁴⁵ . There is evidence to suggest that mindfulness practice is correlated to reduced brain activity in the default mode network. ⁴⁶

Limited improvements with mono-therapy have prompted the development of multi-modular approaches. Hallucination-focused Integrative Therapy (HIT) is geared towards integrating CBT with neuroleptics, coping strategies, psycho-education, motivational intervention, rehabilitation and family treatment.⁴⁷ Extant studies indicate that integrated treatment is more effective than TAU (treatment as usual).

The continuum model of psychosis and ordinary mental events has incited the development of normalisation of the voice hearing experience.⁴⁸ Most psychiatric symptoms occur in normal people—just as breathlessness and palpitations occur while exercising—but are potential clinical symptoms. It is the frequency and duration that determine the borderline. According to the cognitive model, an internal mental event receives external attribution. Through normalisation, the external attribution can be reversed.

Although drug treatment may be the most practical way of managing AVH, refractory cases pose formidable challenges and it must be emphasized that psychological treatments are not counterproductive if applied skilfully. Clinicians who espouse the view that psychosis is a medical condition dismiss the usefulness of psychological interventions. The counter argument would be that a patient with a medical condition, such as stroke, benefits from physiotherapy, occupational therapy and psychological approaches.⁴⁹

Repetitive Trans-cranial Magnetic Stimulation

There are several ongoing trials in which the aim is to treat refractory AVH (Table 4). Repetitive transcranial magnetic stimulation (rTMS) is thought to alter neural activity over language cortical areas. Several studies on rTMS have shown improvement in the frequency and severity of AVHs, albeit without offering any strong conclusive evidence for its efficacy .⁵⁰ Moderate rates of AVH attenuation following rTMS have been noted in three meta analyses. Given that remarkable improvements in isolated cases have also been claimed, this suggests that rTMS may be appropriate mode of therapy for some patients.

Available data suggest that .rTMS selectively alters neurobiological factors that determine the frequency of AVH. However, a recent meta-analysis indicated that the effect of rTMS may be short-lived (less than one month).⁵¹ Studies seem to indicate that rTMS may be effective in reducing the frequency of AVHs, with little effect on their other topographical aspects.^50,52 Sham stimulation has also led to improvements in a number of AVH parameters. Compared to bilateral stimulation, rTMS of left tempero-parietal region appears more effective in reducing the AVH frequency . ⁵³ To reduce the distress associated with AVH and help patients to cope with hallucinatory predilection, rTMS could be combined with CBT. The side-effect profile is much cleaner for this biological approach when compared to medications. Still, like any other anti-hallucinatory treatments, neuro-stimulation technique does not guarantee long-term elimination of AVH. Electroconvulsive therapy (ECT) is considered a last resort for treatment resistant psychosis. Although several studies showed clinical improvement, a specific reduction in hallucinations severity has never been demonstrated.

Avatar Therapy

Computer-assisted voice therapy is a budding form of computerised psychological treatment that is currently undergoing trials.²⁸ In this novel therapy, persecutory voices are directly depowered with the aid of a computerised dummy of the alleged persecutor through voice dialogue. Analytically-oriented therapists can even converse with “voices” and such committed clinicians will find computerised voice therapy as another helpful tool. It is hard to ascertain whether the benefits of the avatar therapy were due to the specific technique involved or simply the increased attention and care, and Leff’s team acknowledged the limitations of their work.⁵⁴

Sound Therapy

Another important development in voice therapy is the use of tinnitus control instrument (TCI)—a form of sound therapy—in treating refractory AVH. Similar to AVH, subjective tinnitus is defined as the false perception of sound in the absence of acoustic stimuli. Even though their definitions are similar, the origin and underlying causes of these two conditions differ. Tinnitus is characterised by a simple sound—a monotone—and is non-verbal. In tinnitus, the brain is believed to interpret an internally generated electromagnetic signal as an acoustic sound or sounds.

Kaneko, Oda, and Goto²⁹ reported successful intervention in two cases of refractory AVH with sound therapy, using tinnitus control instrument (TCI) alongside antipsychotic medications. They posited that, in sound therapy, the auditory system is directly helping the limbic nervous system and the neuro-mechanism for AVH is sensitive to sound therapy .⁵⁵ They concluded that low-level auditory stimulation might be hindering the progression of voices and brain might be getting a breathing space to initiate self-healing process.

Future Directions

Hallucinogenic drugs, anti-hallucination medications and neuroimaging studies may lead to a better understanding of AVH. Animal models of hallucinations and pharmacogenetics might help to find more efficacious anti-hallucinatory drugs. AVHs themselves may have a genetic origin.¹⁰ Thus, not all patients that develop schizophrenia would experience AVHs. Such a finding might help shed more light on the genetics-linked mechanism and remedial measures of hallucinations in schizophrenia. Because the biological substrates facilitating drug effects on hallucinations remain largely unidentified, future studies with translational designs should address this important issue to find a more targeted drug treatment of psychosis.⁵⁶

If a derivative of clozapine without the haematological side-effects is formulated in the future, it might be an important milestone in the treatment of refractory AVHs and schizophrenia because clozapine has the most potent anti-hallucinatory effect. Such a novel drug could become the first line of treatment for schizophrenia, as it would address many of schizophrenic symptoms at their onset. This is crucial, as symptoms and habits become stronger and more resistant the more frequently they occur. Fatty acid amide derivatives of clozapine, such as DHA-clozapine, are found to have better pharmacological properties and enhanced safety. However, such claims are awaiting substantiation in clinical trials.⁵⁷ Thus, more attention needs to be directed into this potentially rewarding research arena. It is, however, very likely that, even after a better pharmacological cure is found for AVHs, a few symptoms might linger on for long periods. With this view, efficient non-pharmacological remedies have to be designed to deal with such residual symptoms.

Discussion

Medications help reduce the psychic pain, and protect the dignity of patients, as well as prevent suicides and homicides. From the patient’s perspective, the calming and relaxing effects of pharmacological therapies are a priority for relief from the distress due to AVH. Among the antipsychotics, clozapine has the maximum anti-hallucinatory effect and it is a shame that it cannot be used as a first line treatment choice. Treatment of AVH should be individualistic and clinicians should be prepared to apply several clinical and non-clinical approaches in concert to address them.

More research into the aetiology and mechanism of AVH is warranted in order to find effective treatment strategies. There is no shortage of theories about the mechanism of AVH, but there is no consensus among the investigators. It is unlikely that AVH is a pure neuro-chemical experience or a biological glitch, and this is where the currently available drug treatments fail. The distinction between primary and secondary symptoms was lost with the triumph of biological psychiatry in the last century. Thus, some authors presently claim that AVHs may even be a secondary symptom or a neuroquantological manifestation of an underlying biological disorder. We should not minimise the importance of eliminating symptoms when such symptoms are incapacitating, as in the case of hallucinatory experiences.

The present recovery model that emphasises and supports the patient’s potential for recovery involving hope, supportive relationship, empowerment, social inclusion, coping skills and meaning cannot be achieved without the help of psychological interventions. In this respect, CBT is a useful tool in the rehabilitation of psychotic patients with residual AVH. Jauhar et al.⁵⁸ argued that the effectiveness of CBT in schizophrenia is influenced by failure to consider sources of bias. Consequently, the benefits are more apparent than real, prompting the question of whether CBT has been oversold.⁴⁹ The verdict of Maudsley debate on the issue has been that CBT has not been oversold, but rather has a great impact on symptom reduction and enhancing concordance and insight. Perhaps the most informative trial so far accomplished has been the work on cognitive therapy for command hallucinations, which has proven the benefit of specific model development, and which productively, combined measurement of process and a targeted outcome.⁵⁹

There is ample evidence suggesting that a combination of family and psychological interventions, alongside pharmacotherapy, can be the most effective way of dealing with refractory AVH.⁶⁰ The inner dialogue hypothesis of AVH held by CBT therapists has its opponents.⁶¹ Patients respond to the voices they experience by utilising inner speech. Some observations with corresponding features weaken the inner-dialogue hypothesis. David and Lucas have demonstrated in a single case study that short-term maintenance of phonological representation (inner dialogue) may co-exist with AVHs – they are not synonymous experiences. The cost-effectiveness of psychological interventions is poorly studied, despite being highly relevant for policy decisions in healthcare.

Computerised voice therapy works better with technically minded, highly intelligent patients. In contrast, individuals of low to average intelligence may require a primarily behavioural approach, with limited efforts to understand concepts, such as automatic thinking and schema. Unlike sound therapy through music playing instruments (iPad, iPod, iPhone, etc.), TCI causes no disruption to daily functioning and can be used continuously. Computerised voice therapy and sound therapy warrant standardised case trials. When it comes to treating AVHs, optimizing compliance, reducing the burden of symptoms, and improving control, quality of life and social functioning should be the therapeutic goals.⁶² Neuroquantological views of AVHs⁶³ explain the limitations of pharmacotherapy and the usefulness of psychological interventions.

The Issues

Supporting Professional Activities (SPA) time is a part of each consultant’s new contract. When the new consultant contract evolved in 2003, a suggested breakdown of the week was 7.5 sessions (1 session equates to 4 hours) for direct clinical care (DCC) and 2.5 sessions for SPAs.¹ This was driven by the need for consultants to continue their own professional development (CPD) as well as having the time for input into the development of trainees and medical students.

Examples of CPD work for consultants could include audit for improvement of service or patient care, teaching of patients, medical students or trainees, research, publications, aspects of hospital management and involvement in simulation courses e.g. Advanced Life Support (ALS)/Advanced Paediatric Life Support (APLS).

The General Medical Council (GMC) requires that during annual appraisals, doctors should use supporting information to demonstrate they continue to follow “Good Medical Practice”. This mandates that doctors should ‘take part in educational activities that maintain and further develop’ their competence and performance.¹ With regard to revalidation, the GMC states you will have to demonstrate that you regularly participate in these activities; at Annual Review of Competency Progression (ARCP) it is imperative that accurate records of these CPD activities are presented at the annual job plan review.²

It is clear, therefore, that the provision of allocated time during the working week to complete these aspects of work life are deemed necessary for consultants. The Royal College of Anaesthetists and Association of Anaesthetists of Great Britain and Ireland both support the original view that a consultant should “typically” have 2.5 SPAs in their contract (though this would have to be subject to individual workload). With the demands of service provision it is clear that consultant SPAs are under threat, with around 40% of new consultants offered jobs with fewer SPA sessions than are thought necessary to allow sufficient non-DCC work.³

Since trainees are subject to similar appraisal and development requirements, we wonder if trainees should be allocated SPA time? For progression through training years and to pass the ARCP, it is necessary to provide evidence of trainee development within clinical practice in a similar way to consultants. This can involve a great deal of extra time. Once (notoriously difficult) exams have been passed, each trainee must go through the application process and prove what skills they have assimilated during their training to date. In fact, the ST3 anaesthesia application criteria states that the following are some of the ‘desirable’ criteria that require evidence:

• Relevant academic and research achievements
• Involvement in an audit project, or quality improvement project
• Interest and commitment to the specialty beyond the mandatory curriculum
• Evidence of interest in, and experience of, teaching
• Instructor status in an advanced life support course (ALS, APLS)
• Involvement in management…and understanding of management
• Effective multi-disciplinary team working and leadership
• Effective leadership in and outside medicine
• Achievement outside medicine
• Altruistic behaviour, e.g. voluntary work

The list is extensive and clearly requires a lot of time and input outside of the normal working week. With the expectation that trainees should be prepared to move straight from CT2 to ST3 (assuming their exams are completed), these desirable criteria must be addressed alongside completing other mandatory aspects of training such as, for anaesthesia: an Initial Assessment of Competency (IAC), an Intensive Care Unit (ICU) module, an Initial Assessment of Obstetric Competency (IAOC) and 15 Units of Training. With all these challenges between a core anaesthetic trainee and potential specialist anaesthetic training, there seems little time to complete an adequate number of the desirable criteria; this is a compelling reason to facilitate some time into the trainee contract to help produce more well rounded trainees.

However, therein lies the challenge - anaesthetic training is such a busy programme. Trainees are involved with multiple areas within a hospital such as ICU, theatre work or Obstetric Delivery Suite that they must learn and practice a wide range of skills to demonstrate the proficiency expected of a consultant anaesthetist. With experience of clinical work already at a premium due to European Working Time Directive hours, creating a good teaching environment whilst providing service provision is a hard enough task. It might seem difficult, therefore, to justify taking away yet more clinical time for trainees.

The proposed “7 day National Health Service (NHS)” contract could also pose more difficulties. Current example rotas released by NHS Employers demonstrate an increased likelihood of shift-work for a typical ICU rota.⁴ This shows trainees will be working more weekends and nights than at present, which could reduce the time spent directly with consultants. This would make introducing more non-DCC work difficult to justify as it would likely occur during daylight hours – when training could occur.

How it could be introduced:

Assuming SPA sessions for trainees were implemented, there would also be practical aspects to address. For example, how many SPA sessions to allocate for each level of trainee and how to monitor that this time was spent effectively and efficiently.

Monitoring:

Trainees could propose which aspects to focus on during their SPA sessions, such as management, teaching, quality improvement projects or more time in their sub-specialty interest. The goals could then be set at the initial educational supervisor meeting, much like a Personal Development Plan (PDP), and monitored throughout the year. This would give focus to any SPA time and ensure it is effectively used. If a trainee abuses their time or is not using it appropriately then removal of SPA time could be enforced. This would give the trainees more ability to improve the skills so often considered additional to trainees.

Funding:

In times of NHS austerity, funding would also need addressing. Potentially neither Deanery nor Trust might be willing to pay a doctor for days spent working outside the hospital workload – such as in educational roles or as a college tutor.⁵ A trial in one single deanery could assess the efficacy of such a scheme.

A possible solution would be to remove a few days of study leave allowance, as many trainees do not use their whole entitlement, and re-assign these to SPA time, allowing a trainee more flexibility. Trainees could initially start with fewer SPA sessions when more junior, to allow more clinical time, increasing SPAs to one per week for intermediate or higher trainees who may well be approaching their Certificate of Completion of Training (CCT).

Conclusion:

There are some practical difficulties in establishing trainee SPA sessions and no doubt many feel all contracted time should be spent practicing anaesthesia. However, given the changing way trainees are recruited via a ‘tick-box’ national application system, together with the variety of non-clinical skills expected by consultancy such as an ability to teach, conduct audit work, engage in managerial roles etc., a small change in the training set-up could produce more rounded trainees, benefitting anaesthesia in general and training programmes in the future.

A 38 year male presented to our centre with a two-month  history of jaundice. Past medical & family history was insignificant. Clinical examination revealed a icterus and greenish brown ring in both eyes (Figure 1). Laboratory investigations revealed a mild thrombocytopenia (platelet count-1.2 lakh/mm3) and a prolonged prothrombin time. Liver function tests showed elevated serum levels of alanine aminotransferase & aspartate aminotransferase. Serology for hepatotropic viruses was negative. Serum ceruloplasmin was 9.8 mg/dl (reference range 20-60mg/dl) and 24 hour urinary copper was elevated.

Figure 1

What is the eye finding?

1. Arcus Senilis
2. Pterygium
3. Kayser Fleischer ring
4. Phlycten

Correct Answer:

3. Kayser Fleischer ring

Discussion:

Wilson’s disease is a consequence of defective biliary excretion of copper. This leads to its accumulation in the liver and brain ¹. It is due to mutations of the ATP7B gene on chromosome 13, which codes for a membrane-bound copper transporting ATPase ².

Kayser-Fleischer ring is an outcome of abnormal copper deposition in the membrane in the limbus of cornea. Slit-lamp examination by an experienced observer is required to identify a K-F ring. The colour may range from greenish gold to brown. When well developed, a K-F ring may be readily visible to the naked eye. K-F ring is observed in most individuals with symptomatic Wilson disease and are almost invariably present in those with neurologic manifestations. They are not entirely specific for Wilson’s disease, since they may also be found in patients with chronic cholestatic diseases.

Clinical presentation is variable and patients presenting with chronic hepatitis, cirrhosis & at times acute liver cell failure. The most common presenting neurologic feature is asymmetric tremor. The characteristic tremor is coarse, irregular proximal tremulousness with a “wing beating” appearance.

Typically, the combination of K-F rings and a low serum ceruloplasmin (<0.1 g/L) level is sufficient to establish a diagnosis of Wilson’s disease ³.  However delayed diagnosis in patients with neuropsychiatric presentations is frequent and was in one case as long as 12 years ⁴.Our patient was treated with a none copper diet, oral zinc and d pencillamine. His liver functions became normal over 6 months of treatment and without progression of liver disease.

Arcus Senilis is a grey band of apacity near the sclero-corneal margin, commonly found in the elderly and associated with hypercholesterolemia. Pterygium is a benign wedge shaped fibrovascular growth of conjunctiva that extends onto the cornea. Phylecten is consequence of allergic response of the conjunctive & corneal epithelium usually associated with tuberculosis, staphylococcus protein and moraxella.

Introduction

Phytochemicals, are not regarded as essential nutrients in humans although an increasing number of well-conducted studies are linking higher intake with a lower risk of developing cancer, as well as lower relapse after initial treatment completion ^1,2,3. There is a wide range of dietary phytochemicals, but one of the largest and well-known groups being the polyphenols [Table.1]. The average total dietary intake of polyphenols is reported to be over 1g per day, which is up to ten times higher than that of all other classes of phytochemicals and known dietary antioxidants⁴. The health benefits of phytochemical rich foods or concentrated nutritional supplements are often being highlighted in the medical and popular media and hence they are an increasing topic of conversation between medical practitioners and their patients especially those with cancer who have a particular interest in over the counter self help strategies ^5,6. This article provides an overview of the major classes of phytochemicals with examples of their common food sources. It highlights the international evidence for their anti-cancer mechanisms of action, their clinical benefits, as well as discuss the pros and cons of concentrating them and, into nutritional supplements in an attempt to harness and boost their health benefits. Hopefully this review will provide some useful learning points to aid communication between patients and clinicians [Table. 2].

Classification

There are three major groups of phytochemicals: the polyphenols which can be subcategorized as the flavonoids, phenolic acids and other non-flavonoid polyphenols; the terpenoids, which can be subcategorized as the carotenoids and non-carotenoid terpenoids; and the thiols, which includes the glucosinolates, allylic sulfides and non-sulphur containing indoles (Table. 1). There are other phytochemical group, which although have some properties within these groups, have been classified within a miscellaneous category and examples of these include the betaines, chlorophylls and capsaicin.

Table.1 Classification of phytochemicals with notable food rich sources

Table. 2 learning points

Clinical evidence for cancer prevention.

Although not all, many studies have linked a higher intake of phytochemical-rich foods, such as vegetables, fruit, legumes, nuts, herbs and spices, with a lower incidence of cancer as highlighted in the latest comprehensive review from the World Cancer Research Fund and other systemic reviews^2,3.

More specifically, certain elements of food have been addressed within a number of cohort studies. Carotenoids found in leafy green vegetables and carrots have been linked with a lower risk of breast cancer in a recent meta-analysis demonstrated⁷ and a lower risk of ovarian and pancreatic cancers, especially among smokers in either questionnaire or serum-based studies^{8, 9, 10}. Higher intake of cruciferous vegetables such as cabbage, cauliflower, Brussel sprouts, radishes and broccoli have been associated with a lower prostate cancer risk¹¹, as have foods rich in isoflavones such as pulses and soy products¹², lycopene rich colourful fruits and tomatoes¹³. Foods with abundant levels of flavonoids such as onions, rich in quercetin, have been shown to reduce the incidence of numerous cancers particularly those arising from the lung, especially amoung smokers^{14, 15}. The anthoxanthins, in dark chocolate, have been reported to lower the risk of colon cancer¹⁶ and higher green tea intake lowers the risk of breast, prostate, ovarian and oesophageal cancer, again particularly among smokers and alcoholics^{17, 18}. Finally, coffee consumption has been shown to reduce the risk of non-melanomatous skin cancers and melanoma, even after removing other factors such as ultraviolet radiation exposure, body mass index, age, sex, physical activity, alcohol intake and smoking history^19,20.

Clinical evidence for a benefit after cancer

The benefits of healthy foods do not stop after a diagnosis, especially if combined with other healthy lifestyle habits. For example, breast cancer survivors who regularly consumed more than the government recommended five portions of fruit and vegetables a day, had a third lower breast cancer recurrence risk if combined with regular physical activity²¹. In another study, women with breast cancer who had the highest serum lignan levels, reflecting good intake of legumes, cereals, cruciferous vegetables and soya, were reported to have the lowest risk of death²². Likewise, a lignan and polyphenol rich diet was associated with a lower colorectal cancer relapse rate²³.

The large Shanghai Breast Cancer Survival Study demonstrated that women with the highest intake of the phytoestrogenic polyphenols isoflavones and flavanone found in soya and other beans, had a 29% lower risk of relapse and death²⁴. Similar findings were seen for green tea after breast²⁵ and colorectal cancer²³. Green tea also decreased the abnormal white cell count in 30% of patients with chronic leukaemia and reduced the levels of several markers of proliferation, as well as serum Prostate Specific Antigen (PSA) among men with prostate cancer²⁶. A slowing of PSA progression has similarly been observed in other dietary studies, most notably the randomised trial involving a plant-based diet together with other lifestyle changes²⁷ and a phase II study of pomegranate juice²⁸.

Another cancer influenced by nutrition is skin cancer, as highlighted by a study of individuals who have been treated for basal cell carcinoma or squamous cell carcinoma, and who have a high risk of further lesions due to their on-going solar damage. Those who consumed the highest levels of lutein and zeaxanthin-rich foods, such as leafy green vegetables, had the lowest levels of new cancer formation²⁹.

A number of other studies evaluating the impact of phytochemicals are underway, the largest and probably most comprehensive is the UK’s DietCompLyf prospective trial involving 3159 women treated for breast cancer³⁰.

What are the likely anti-cancer mechanisms of phytochemicals?

The precise biochemical mechanisms through which phytochemicals exert their anti-cancer effects are still being explored, as their actions are wide-ranging and complex but significant advances have been made of late in the understanding the mode of action. The most quoted cancer prevention mechanism is via their antioxidant activity, elicited either through direct free radical absorption or through induction of antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione via a variety of molecular mechanisms^{31, 32}. One of these mechanisms is activation of Nrf2, which switches on genes that code for antioxidant as well as detoxification enzymes^{31, 32}. Phytochemicals, particularly the thiol class such as sulforaphane,have also been shown to inhibit the conver­sion of procarcinogens to their electrophilic, DNA damaging, chemicals^32,33.

A number studies involving known, common carcinogens have highlighted the antioxidant properties of phytochemicals. A good example of their protective effect was an experiment involving the known house-hold carcinogen triclocarban, commonly found in detergents and cleaning agents. Healthy cells exposed to triclocarban tend to mutate into pre-malignant cells, however, the amount and rate of carcinogenesiswas significantly reduced byadding curcumin to the petri dish culture feeds³⁴. In another study, volunteers who ate a diet rich in kaempferol were found, on serum and urine analysis, to have improved SOD activity and higher urinary concentration of these polyphenols³⁵. Rats exposed to cigarette smoke given indole-3-carbinol, a phytochemical rich in cruciferous vegetables, had a lower lung cancer rate than those not given idole-3-carbinol³⁶. Subjects eating a meal of onions, which increased their serum levels of quercetin, demonstrated decreased levels of oxidative metabolites including 8-hydroxydeoxyguanosine (8-OHdG) a marker of DNA damage and repair16^{18, 37}. Quercetin supplementation has also been shown to improving mitochondrial dysfunctions induced by the toxin 3-nitropropionic acid³⁸. A clinical study in Singapore gave Chinese smokers 170g of watercress a day, rich in the indole-3-carbinol, and found a similar effect on urinary markers of DNA damage³⁹. Finally, marinating meat in rosemary and thyme, has been reported to reduced the serum levels of carcinogenic heterocyclic amines (HCA) by 87% compared to subjects who eat the meat unseasoned⁴⁰.

Another key anti-cancer mechanism of phytochemicals appears to be their ability to reduce inflammation. It is now well established that inappropriate inflammation is intimately involved in the cancer process, particularly in the promotion and progression stages of cancer. Inflammation is closely associated with oxidative stress and activation of NF-kappa B family of transcription fac­tors. These factors regulate more than 150 genes involved in mechanisms of cell survival and these target genes are not just pro-inflammatory but also oncogenic. Numerous phytochemicals have been shown to inhibit NF-kappa B signalling, particularly the green tea polyphenol epigallocatechin-3-gallate (EGCG), quercetin, curcumin, caffeic acid and caffeic acid phenethyl ester and the phytochemicals within bilberries^31,41.

More recently, it has been reported mainly from laboratory studies that phytochemicals have an affect on several cancer process through modulation of cellular and signalling events involved in growth, invasion and metastasis³². Pomegranate, for example, rich in the polyphenol ellagic acid, has been shown to directly inhibit cell growth and induce apoptosis in androgen sensitive and aggressive human prostate cancer cells⁴². Pomegranate extract has also been reported to inhibit processes involved in cancer metastasis in a study involving oestrogen sensitive and resistant breast cancer cell lines, showing increased markers of cell adhesion and migration in cancer but not normal cells⁴³. In another study it inhibited a chemokine that attracts breast cancer cells to the bone⁴⁴. Curcumin slows cancer cell growth by blocking the cell cycle, increasing the rate of apoptosis and preventing the invasion and migration of cells^{45, 46, 47, 48}. It has also been found to halt the growth of stem cells that give rise to breast cancer without harming normal breast stem cells⁴⁹. Curcumin has been shown to modulate miRNA expression in breast cancer cells leading to a reduced expression of Bcl-2⁵⁰ and stabilisation of tumour suppressor gene in colorectal cancer cell lines⁵². Green tea, rich in epigallocatechin gallate (EGCG), has demonstrated significant reduction of several factors that promote cancer cell proliferation by inhibiting DNA synthesis, de-differentiation and angiogenesis^{26, 52, 53}. It has also been shown to block ornithine decarboxylase, an enzyme which signals cells to proliferate faster and bypass apoptosis^{50, 54}. Resveratrol has demonstrated epigenetic regulatory properties which influence regulate proliferation, cell survival and apoptosis in prostate cancer by global modulation of gene expression through deacetylation of FOXO transcription factor⁴⁶. Caffeic acid and phenethyl ester, as well as inhibiting NF-κB signaling, also have been shown to inhibit cell motility in vitro and inhibit metastasis of tumour models in vivo⁴⁷. Luteolin, as well as inhibiting tumour growth and metastasis, inhibits epithelial mesenchymal transition which is a basic biological process related to cancer initiation and development⁴⁷.

Finally some polyphenols and other phytochemicals are also able to influence cancer via a hormonal mechanism. Phytoestrogenic compounds, most notably isoflavones and lignans found in soy products, legumes and some cruciferous vegetables, weakly bind to the oestrogen receptor without stimulating proliferation of the cells, yet at the same time blocking the binding of more harmful oestrogens, including those produced endogenously³⁹. This explains why in the previously mentioned Shanghai Breast Cancer Survival Study, women with the highest intake of isoflavones and flavanones-rich foods had a lower risk of death²⁴. In men, phytoestrogenic compounds have been shown to affect 5 alpha reductase lowering endogenous testosterone levels. This may partly explain why men who eat phytoestrogenic foods such as beans and pulses have a lower risk of prostate cancer.

Can concentrating foods into supplements enhance their anti-cancer effect?

If certain foods have anti-cancer effects, then it is not unreasonable to hypothesise that concentrating them into a pill may be a good way to supplement individuals with poor diets or further enhance the benefits in those whoes diets are already adequate. People living with and beyond cancer (PLWBC) are certainly attracted to the potential health benefits of food supplements, as over 65% report regular intake^5,6. There are two main categories of supplements commercially available: the first involves chemicals extracted from food, or made synthetically, such as minerals and vitamins; the second involves purifying and concentrating whole foods:

Vitamins and mineral supplements: The majority of studies, to date, have evaluated extracted chemicals such as vitamins and minerals. Some have shown a benefit. For example, a recent meta-analysis of studies reported that women who took supplements providing an average daily intake of vitamin C over 100mg had a reduced risk of breast cancer relapse⁵⁷. The SU.VI.MAX study randomised French adults to a single daily capsule of ascorbic acid, vitamin E, beta carotene, selenium and zinc, or a placebo, and found no reduction in mortality or cancer-specific mortality overall⁵⁸, although a further analysis in men found a reduction in the risk of prostate cancer. The authors postulated that this difference between the sexes was related to French men having a lower baseline micro-nutrient status⁵⁹. A major trial of selenium and vitamin supplements in a poor region of China, demonstrated reduced risks of oesophageal cancer; at the time this population was known to have widespread micro-nutrient deficiencies⁶⁰.

Unfortunately, most other studies of vitamin, minerals and other extracted nutrients have shown no benefit, or have actually shown an increased risk of cancer. For example, the CARET study found that beta carotene and retinol increased the risk of lung cancer⁶¹. The Health Professionals Follow-up study (HPFS) which followed the lifestyle habits of 51,529 male professionals for over 15 years found that men who took very high doses of zinc (>100mg/day), or took it for long durations were more than twice as likely to develop advanced prostate cancer compared with controls⁶². The randomised SELECT study demonstrated an increased prostate cancer incidence with vitamin E and selenium supplementation⁶³. A further analysis of the HPFS found that of the 4,459 men who had developed prostate cancer, those who took selenium supplementation of ≥ 140 μg/d after diagnosis were associated with a 2.60-fold greater risk of prostate cancer mortality⁶⁴.

The negative effects of vitamin E and beta carotene were once again demonstrated in the ATBC study which found them to increase lung cancer risk, although subsequent analysis showed that men with pre-intervention low plasma levels of beta-carotene had a lower prostate cancer risk following supplementation, and that those with high levels had a higher risk, particularly in smokers⁶⁵. This u-shaped distribution of risk was also observed in the EPIC study where those with folate-deficient diets and those with the highest intake both had a higher risk of cancer⁶⁶. These data have prompted organisation such as the National Cancer Institute to issue statements stating that long term vitamin and mineral supplements should ideally be given to correct a known deficiency⁶⁷, which is rarely routinely detected unless individuals have self funded micro-nutrient analysis (cancernet.co.uk).

Whole food supplements: More recently academic attention has turned towards the evaluation of concentrated whole food supplements, particularly foods rich in polyphenols and other phytochemicals such as herbs, spices, green vegetables, teas and colourful fruits which have appeared to be beneficial in environmental cohort studies. Despite some initial encouragement from smaller evaluations, studies of extracted lycopene or genistein given on their own in more scientifically robust analyses have not demonstrate a benefit for either prostate cancer or benign prostatic hypertophy^{68, 69, 70} neither were there links with the reduction in the risks of breast cancer with regular intake⁵. Of more concern, a randomised study from Memorial Sloan Kettering reported that serum taken from women who had take very high dose soy supplementation (25.8 g twice a day) added to laboratory tumour cells caused them to proliferate faster (Increased K67 expression) and overexpress the tumorigenic growth factor receptor FGFR2⁷¹. This supports the notion that phytoestrogen foods are healthy, but concentrating them into strong supplements is not recommended.

On the other hand, no study of non-phytoestrogenic foods supplements has shown any detrimental effects on cancer outcomes and some have beneficially influenced progression rates. For example, a study carried out at John Hopkins involving pomegranate seed extract, found that men taking the supplements had a reduction in PSA progression rate⁷². A study conducted at the Mayo Clinic found that green tea concentrate decreased the abnormal white cell count in 30% of patients with chronic leukaemia, and a small study from Louisiana University reported that green tea concentrate significantly reduced levels of several cancer-promoting growth factors as well as PSA levels in participants²⁶. In the Vitamins and Lifestyle (VITAL) cohort study, a regular intake of grapeseed extract was shown to be linked with a lower risk of prostate cancer⁷⁰, and another small RCT found that a dietary supplement containing isoflavones, plus other phytochemicals and anti-oxidants delayed PSA progression⁷³. Interestingly one of the most popular supplements, Saw Palmetto, despite an effect in early small studies, showed no benefit for prostate cancer or benign prostatic hypertrophy in the largest randomised evaluation⁷⁴. Likewise, another popular supplement, lycopene, despite similar suggestions from smaller non-randomised trials^{68, 69}, demonstrated no benefits in a more robust evaluation.

So far, the largest trial analysing phytochemical-rich food extracts was the National Cancer Research Network adopted Pomi-T study⁷⁵. This study combined four different food types (pomegranate, green tea, broccoli and turmeric) in order to provide a wide spectrum of synergistically acting nutrients, whilst at the same time avoiding over-consumption of one particular phytochemical. It involved two hundred men, with localised prostate cancer managed with active surveillance or watchful waiting experiencing a PSA relapse, following initial radical interventions.

The results, presented as an oral presentation at the American Society of Clinical Oncology Conference (ASCO), Chicago, showed a statistically significant, 63% reduction in the median PSA progression rate compared to placebo in both men on active surveillance and experiencing a PSA relapse post-treatment. A further analysis of MRI images, demonstrated the cancers size and growth patterns correlated with PSA changes, excluding the possibility that this was just a PSA rather than tumour effect⁷⁵. It was well tolerated, apart from some mild loosening of the bowels in 10% of men, and there was no effect on testosterone levels. At 6 months, significantly more men opted to remain on surveillance rather than proceeding to expensive radiotherapy, surgery or medical castration which can cause unpleasant effects such as depression, hot flushes, weight gain, osteoporosis and erectile dysfunction⁷⁵.

A number of other RCT’s involving whole food phytochemical-rich supplement have demonstrated benefits for some of the distressing symptoms common after cancer treatments, such as fatigue⁷⁶ and urinary infections⁷⁷. There are currently over ten, on-going studies registered with the National Institute of Health. In the UK, the Institute of Preventative Medicine has plans to include the Pomi-T supplement into the next national prostate cancer prevention study. This study will be recruiting men with a higher genetic risk of prostate cancer identified in the national RAPPER study, co-ordinated by the Institute of Cancer Research. Further trials are being designed involving men with prostate cancer already on androgen deprivation therapy and individuals with skin, colorectal and bladder cancer. In the meantime, a trial is passing through the regulatory process to investigate whether the natural anti-inflammatory properties of these ingredients could help joint pains after breast cancer.

Conclusion

There is increasingly convincing evidence to show that plant phytochemicals, particularly polyphenols have significant benefits for humans. Not only do they improve our daily lives by helping our food taste, smell and look appetising, they also reduce our risk of cancer and help people living with and beyond treatments. Living well programmes, slowly being introduced in the UK, are beginning to highlight the importance of phytochemical-rich diets, along side other lifestyle factors, largely being driving by the National Survivorship Initiative and guidelines from influential organisations such as ASCO. Going a step further and concentrating these foods, or extracted elements of these foods, into nutritional supplements gives an opportunity to boost their beneficial anti-cancer effects, but have their pitfalls. Studies of concentrated minerals, vitamins and phytoestrogenic supplements have reported detrimental effects. No study has reported detrimental effects of whole, non-phytoestrogenic food supplements and some have reported significant advantages. Despite these potential benefits and reports that over 60% of patients living with and beyond cancer take nutritional supplements, oncologists have been reluctant to discuss their pros and cons due to a lack of RCTs from academic institutions^{55, 56}. Hopefully this trend will change, particularly following the success of the Pomi-T study⁷⁵ and ongoing studies registered with the National Cancer Institute.

Introduction

Population studies in Norway are showing that taking part of (creative) or receiving (receptive) cultural activities, i.e. arts, is associated with good health and good satisfaction with life among other things,¹. Cultural activities have the potential to affect individuals beneficially: physiologically, biologically and emotionally, and several studies show that cultural activities can stimulate emotions and behaviors that make life easier, ^2–5. Cultural activities can enrich and enhance our memory, stimulate connections among brain networks and enable us to accelerate learning and differentiate feelings of meaning and context,^6,7 Cultural activities have also improved both physical health, social function and vitality among health care staff,⁸.

In an analysis of data from a large longitudinal cohort-study of a working population (called the SLOSH study = Swedish longitudinal occupational survey of health), some interesting associations were revealed between access to cultural activities in the workplace and health. Participants reporting many cultural activities at work had a more favorable improvement of emotional exhaustion during a follow-up period of two years than those whose workplaces did not offer these amenities,⁹. Other studies in which cultural activities have been offered to patients on long-term sick leave confirm that cultural activities have beneficial effects on both self-confidence and pain,^10,11.

In a new approach, an artistic leadership program, called “Shibboleth”, affects not only managers included in the study, but also their employees (who did not participate in the artistic program). This one year art-based program showed statistically significantly more improvement of mental health, covert coping and performance-based self-esteem than the comparison group (who participated in an ordinary leadership program). They also experienced less winter/fall deterioration in the serum concentration of DHEA-S (dehydroepiandrostereone-sulfate), a regenerative/anabolic hormone,¹².

Studies on singers, both amateur and professional singers and choir singers, show positive effects on different biological markers such as oxytocin and testosterone,^13–15. On the basis of results from another Swedish project, ”Prescribed Culture”, which aimed to evaluate the effects of prescribed cultural experiences in the treatment of patients on long term sick leave, it was claimed that cultural experiences have their best effects when used in health promotion and prevention , rather than when the individual is already sick,¹⁶. Multimodal stimulation seems to have particularly strong effects. For instance, concomitant visual and auditory stimulation gives rise to stronger activation of “visual” and “auditory” parts of the brain than separate visual and auditory stimulation,¹⁷.

A mixture of different cultural activities seems to optimize influence on the limbic system since a broader emotional perception is activated,⁷. Cultural activities offered to participants that would not have chosen them spontaneously, could enhance already existing pathways in the brain enabling deeper cognitive behavioral change,^17–20.

Despite this knowledge regarding the potential benefit of cultural activities in different contexts on both individuals and groups there is still a missing accessible practical functioning link between producers of culture and different groups of practitioners within health-care.

Burnout is characterized by emotional exhaustion, detachment from work and decreased effectiveness at work. This can develop in situations with excessive workload and insufficient resources as well as lack of control and support,²¹. If the process of burnout is a reaction to long-term stress, without enough recovery, this can lead to the more severe exhaustion syndrome,²². Symptoms include fatigue, impaired emotional regulation, cognitive problems and sleeping disorders. Most of these patients have an increased sensitivity for stress even after recovery,²². In recent years, Swedish rates of sick leave due to minor psychiatric morbidity , and burnout symptoms, have increased dramatically,^23-24 . Complaints usually include physical, emotional and cognitive exhaustion, which in most cases appear to be related to chronic stress without restitution,^25–28. Today many women in Sweden have stress related symptoms, and some are diagnosed with exhaustion syndrome. If these women are detected at an early stage, the prognosis is good,²².

Alexithymia, (the difficulty to differentiate your own and others feelings), can be a silent but severe problem for persons suffering from this personality trait. Grabe et al.,²⁹ conducted a study in which the questionnaire TAS-20 was used for the assessment of alexithymia. Medical examination was also performed. In this study alexithymia was related to hypertension and arteriosclerotic plaques. Alexithymic personality traits may increase the risk for CVD (cardio vascular disease).

The rationale behind choosing symptoms of exhaustion, SOC and alexithymia as main outcome variables was the intention to examine whether cultural activities in this form can change pattern of thought, feelings and behavior in participants with burnout symptoms. If cultural activities prove effective for this participant group, they could have considerable benefits both financially in terms of reducing sick leave and health care consumption and of reduced individual suffering.

Aim

The aim of the study was to assess to what extent symptoms of exhaustion, sense of coherence, alexithymia and self-rated health among women with burnout symptoms can be beneficially influenced by cultural activities organized in health care centers.

Method

Participants

Four health care centers in Stockholm County hosted the cultural activities. Medical doctors and social workers distributed information about the study to women diagnosed with exhaustion disorder or exhaustion symptoms. Women, native and foreign born, with burnout/exhaustion symptoms (fatigue syndrome or stress-related fatigue) who were curious about new clinical approaches were asked by the doctor to participate in the study and screened for inclusion and exclusion criteria. Participants (women age > 18) with burnout/exhaustion symptoms such as strong fatigue, cognitive problems, and sleep disturbances were enrolled. There was an inclusion criterion with a score above 2 on the KEDS scale. The diagnosis was made by the doctor.

Exclusion criteria: Participants with difficulty in speaking and understanding Swedish, participants with alcohol or drug abuse problems, or/and participants with severe depression or psychiatric borderline. Also excluded were participants with severe somatic diseases (such as serious angina pectoris or participants who had had a stroke). Randomization was done using a 3:1 allocation to intervention or control groups.

The randomization was done using a stratified randomization by center. Randomization was done by the statistician. The group allocations were sent in individual envelopes which were distributed to centers and blinded to the site staff. Envelopes were further drawn in a consecutive order with regard to recruitment of subjects at each of the four health care centers. Thirty-six participants were allocated to the intervention group (nine patients in each group) and twelve participants to the control group. The standard care that each participant received included physiotherapy such as relaxation and physical light training.

All randomized participants gave their written consent to participation in the study. Data were collected over a period of 6 months. The project includes evaluation of six different culture activities. In the selection of the health care centers socio- economic diversity and employment status were considered. We used regularly occurring structured cultural activities in cooperation with culture producers, i.e. actors, musicians, dance teachers. The Regional Research Ethics Committee of Uppsala has approved the study (Dnr. 2012/359).

The culture palette: six different cultural packages

The following cultural activities were included in the study; five of them have previously been presented in the literature with good evidence on other groups of patients. One package (the musical show), which has not been presented previously on groups of patients, was chosen as it represents a combination of different modalities of activities at the same time. The active mechanism of all six cultural activities was to stimulate different modalities of the senses such as the visual, motor, verbal, auditory, emotional and sensational, according to Downing’s levels of perception, ³⁰. All participants were offered six cultural packages:

1. Interactive theater: An experienced actor introduced poetical lyrics and poems and then initiated and participated in discussions with the participants regarding thoughts, emotions, and experiences evoked by the texts.

2. Movie: After showing a movie, a film expert initiated discussions among the participants about experiences and thoughts evoked by the movie.

3. Vocal improvisation and drawing: After participating in a vocal improvisation session with an experienced performance artist and pianist, the participants painted a picture representing emotions, thoughts and pictures evoked during the improvisation

4. Exploring Dance: The participants improvised dance movements under the guidance of a dance movement pedagogue/music teacher. The dance movements were staged according to the situation in the room and with focus on bodily awareness. Afterwards the group discussed their experiences during the dance session.

5. Mindfulness and contemplation: The participants contemplated and practiced mindfulness together with an experienced mindfulness instructor. Attention was on breathing and body awareness. Thoughts, feelings, images and sensations were in focus and experiences were reflected in the group after the contemplation.

6. Musical show: after a musical show including music, song and dance focusing on bodily awareness, the participants discussed thoughts regarding the body with the actor.

Every session in each one of the six different cultural packages lasted for 90 minutes.

Evaluations

Three different standardized scales, and also self-rated health and self-figure drawing, were used.

KEDS - Karolinska Exhaustion Disorder Scale,³¹. Questions about concentration, memory, physical fatigue, endurance, recovery, sleep, hypersensitivity to sensory input, experience requirements and irritation and anger. Higher scores indicate worse disease activity/performance.

SOC - Sense of coherence,³². A key factor in being able to feel well-being and health. This factor has been shown to be crucial to helping individuals mobilize their self-healing systems. Higher scores indicate better performance.

TAS - Toronto Alexithymia Scale,³³. Estimation of ability to recognize and interpret feelings in oneself and others. TAS contains three subscales; the inability to handle emotions due to emotions being poorly recognized (difficulty recognizing), the inability to describe feelings (difficulty describing), and mismatch between coping behavioral emotions (externally oriented thinking). This study used the full scale score, i.e. the summary of the three sub scores. Higher scores indicate worse performance.

Self-rated health (SRH) consists of a single item measure.

Procedures/implementation

The four different health care centers presented each activity on two consecutive occasions. After two weeks of one program, there was a new program on two consecutive occasions etc. Each participant has thus been offered 12 cultural packages during a three-month period, i.e. once a week. During the monitoring period between month 3 and month 6, there was no culture activity offered. The control group was monitored in parallel during the entire period monthly at 0, 3 and 6 months.

The participants evaluated the project individually with questionnaires prior to the sessions, after completion of the intervention at month 3, and at follow-up after 3 months i.e. month 6 (both intervention and control group). In-depth interviews with both participants and producers of culture, i.e. representatives for the various cultural activities and health care staff were conducted during the monitoring period (this data is not presented in this article).

Data analysis

The primary outcome efficacy end point/measure was mean change from baseline to three and six months in the KEDS summary score. The secondary outcome measures were mean change from baseline in the SOC summary score, the TAS summary score and the self-rated health, from baseline to three to six months.

All data were presented using descriptive statistics, i.e. mean and standard deviation for continuous variables and frequency and percentage for categorical variables. For all main outcome variables, data were further analyzed using the Linear Mixed Models, including group (intervention and control) and time (baseline, 3 month and 6 months) as fixed factors. Results were presented as marginal means, the estimated mean value adjusted for the factors included in the analyses model. The difference between intervention and control group with regard to the estimated and adjusted means are defined as the effect size, i.e. the mean difference between the intervention groups for each of the primary and secondary outcomes measures divided by the standard deviation. All tests were two-tailed and p<0.05 was regarded as statistically significant.

IBM SPSS version 22 was used for statistical calculations. In the presentation of the results from the statistical analyses, the measured effect size was used and derived as the absolute difference between active intervention and controls with regard to each of the outcome variables/endpoints used,³⁴.

Results

There were 55 participants screened in this study, however seven participants who met the exclusion criteria of too serious/severe depression was not included into the study. In total, there were 48 participants randomized into the study, age between 41 and 70 years, mean 53.8 (SD= 8.15).

The results showed that for KEDS (exhaustion) there was a statistically significant two-way interaction (P<0.001) with a decreased mean from baseline to three and six month respectively in the intervention group whereas in the control group there was no change. The mean treatment effect size, i.e. the mean difference between groups, in favor of the intervention group was 9.9 (SE=3.0) at 6 months. See table 1 and figure 1a.

There was no difference in mean SOC - Sense of Coherence – scores between the groups. See figure 1b. Further, the results revealed a statistically significantly more pronounced decrease in the intervention group compared to the control group in the alexithymia items of total score, (P=0.007, mean treatment effect size=5.4 (SE=2.2) at 6 months in favor of the intervention group), difficulty describing (P=0.004, 2.4 (0.9)), difficulty identifying (P=0.051, 2.6 (1.3)) but not for external orientation (P=0.334 0.5 (0.8)). See table 1 and figure 1c. There was also a statistically significant difference between the groups with regard to self-rated health (P<0.001) where mean scores increased over time in the intervention group but decreased in the control group. See figure 1d.

Table 1

KEDS (Karolinska Exhaustion Disorder Scale) and TAS (Toronto Alexithymia Scale) and SRH (self-rated health) at baseline, month 3 and month 6.

Figure 1a

Marginal means and 95 % confidence intervals for the KEDS (exhaustion) scale by group and time. Results were based on the linear mixed models analysis adjusted for baseline.

Figure 1b

Marginal means and 95 % confidence intervals for the sense of coherence (SOC) scale by group and time. Results were based on the linear mixed models analysis adjusted for baseline.

Figure 1c

Marginal means and 95 % confidence intervals for the Toronto Alexithymia Scale (TAS) by group and time. Results were based on the linear mixed models analysis adjusted for baseline.

Figure 1d

Marginal means and 95 % confidence intervals for the self-rated health scale (SRH) by group and time. Results were based on the linear mixed models analysis adjusted for baseline.

Discussion

The results show that the different exhaustion factors measured by means of KEDS (Karolinska Exhaustion Disorder Scale) decreased in the intervention group compared to the control group. With regard to the total score of TAS (Toronto Alexithymic Scale) there was a statistically significant decrease in the intervention group compared to the controls, i.e. the participants started to improve their differentiation of feelings and emotions after three months with cultural activities. The same pattern was seen with regard to self-rated health, which improved in the intervention group. However, there was no significant difference between the groups with regard to the development of sense of coherence.

It seems that the different cultural activities have helped the participants become more aware of their feelings and sensations; to describe and to identify feelings. It is not easy to explain the positive results based on one clear paradigm. It is likely a mixture of psychological, neurological and social factors or changes that interact in a complex manner.

Previous studies have discussed the theory of the emotional brain - cultural modalities can “surprise” the cognitive brain unconsciously. LeDoux,²⁰ discusses the upper/slower and the lower/faster pathway in the brain. Emotionally loaded visual and auditory stimuli are transmitted on both types of pathways. Music impulses are for example evoking activities in the emotional brain much more rapidly than in the cognitive brain. However, impulses spread secondarily from the emotional to the cognitive brain. This can trigger the participants awareness of different emotions and may start a process of differentiation, possibly initiating a change of life course. By using different cultural activities, that the participants normally would not try, the differentiation process may be amplified. This suggests that cultural activities can surpass automated thinking and create new "pathways '' with changes in behavior and increased well-being.

In other studies we have observed that a mixture of different cultural activities can increase the amount of stimuli affecting a broader network of emotional correlates, ^14,16,18 . A very interesting long-term decrease in alexithymia, ³⁵ was associated with lowered blood pressure and a decrease in sick leave. By allowing the participants to try new cultural stimuli we may have helped the participants change old habits. A hypothesis is that this may also have contributed to the observed decrease in exhaustion.

Why did we not see any increase in the sense of coherence in the intervention group? It is very difficult to change patterns of thought and behavior although we can argue that the participants in the control group also found a new sense of coherence just by being invited to answer questions about themselves and being focused upon. Many of the participants did not go out spontaneously because of their fear of socializing. Some of them described their situation as black or white, not wanting to change routines that made them feel less safe,³⁶.

Despite the fact that the health care staff did not participate in the culture palette, they were also affected by the cultural activities ³⁶. This may be a mirroring effect, or emotional contagiousness on health care staff, which may also play a role between the participants and their staff. The passive cultural activation phenomenon has previously been presented in the literature,³⁷ and there seem to be possible well-being effects of just watching dance or visiting a theatre, ^6,10 which may explain the positive health care staff response to the culture palette. The results of this study underscore the importance of regarding the health care system as a whole, where patients, health care staff and visiting relatives affect each other. Empathic behaviors contaminate in all directions and we need to be aware of how we project ourselves when working in a caring context.

Modified “culture palettes” and “train the trainer” programs and workshops are now in use in Sweden, inspiring cultural producers to further develop the health care system and a cultural health box - a box with six different books about cultural activities and the research behind this - have been distributed to all health care centers in Sweden, ³⁸.

Developing and adapting cultural programs to fit other kind of groups of participants could cross-fertilize health care thru culture production.

Limitations

This study was limited to women with exhaustion symptoms and therefore further research on implementation of cultural activities within different groups of participants and sexes is needed before we can generalize the results to other groups of participants. Another limitation is that we did not control for outside activities, such as doing walks in nature. In this study we only presented indoor cultural activities.

Conclusion

The cultural activities in this study made exhausted women understand what makes them vital, confirmed, curious, healthy and creative. The study also illustrated that there could be synergistic effects when bringing cultural activities into the health care system³⁶.

When our beautiful mind feels all muddled up

   With a tendency to draw bizarre conclusions;

When the difference between a reality 

   And an imagination becomes all blurred. 

When one hears people, hears things, hears a god,

     That can't be explained. When one sees images, 

Sees aliens, sees prophets, that can't be accounted for. 

       When one smells, tastes, feels things that can't be untangled.

When one worries about other's intentions,

   Their innocent words, their innocent actions; 

When one is preoccupied with a belief 

   That they are not driving their body or their mind.

When one holds an inflated view

    Of being able to communicate with aliens, 

Of possessing powers to heal, 

   Of being a royal, of being able to control the weather.

When the energy of youth is replaced by 

    A lack of motivation, an idleness, an apathy.

When one ignores daily personnel cleanliness, 

   Daily chores, daily social interactions.

When you are in this perplexed state of mind 

    Remember it is an illness called psychosis, 

 Not a curse or black magic or witchcraft.

    Remember, treatment is available, from the experts who care.

A 40 year old patient presented to the hospital outpatient department with one year history of cough, choking sensation following swallowing, hoarseness of voice and loss of weight. History revealed his previous hospital admission 1 year back for management of organophosphorus poisoning during which he was intubated and put on mechanical ventilator for 10 days. Patient developed the symptoms a month after his discharge from the hospital. Cranial nerve examination was within normal limits. What is the possible diagnosis?

1. Gastro-oesophageal reflux disease
2. Tracheo-oesophageal fistula
3. Oesophageal diverticula
4. Oesophageal rupture

Fig 1: Barium swallow illustrating a dilated oesophagus and the TOF with resultant contamination of the trachea and bronchial tree

Fig 2: Oesophagoscopy showing TOF

Correct answer:

2. Tracheo-oesophageal fistula

Discussion:

A tracheo-oesophageal fistula (TOF) is a communication between the trachea and oesophagus which can be congenital or acquired. Congenital and acquired TOFs are associated with multiple complications, including poor nutrition, recurrent pneumonia, acute lung injury, acute respiratory distress syndrome, lung abscess, bronchiectasis from recurrent aspiration, respiratory failure, and death. Acquired TOFs occur secondary to malignant disease, infection, ruptured diverticula, and trauma.^{1, 2} Acquired TOFs are quite rare, and incidence rates have not been well documented. Post intubation TOFs uncommonly occur following prolonged mechanical ventilation with an endotracheal or tracheostomy tube. TOFs caused by endotracheal tube intubation depend on several factors, including prolonged intubation, an irritating or abrasive tube, and pressure exerted by the cuff. Pressures exceeding 30 mm Hg can significantly reduce mucosal capillary circulation and result in tracheal necrosis. Cuff pressure is particularly risky when exerted posteriorly against a rigid nasogastric tube in the oesophagus. Poor nutrition, infection, and steroid use cause tissue alteration, which predisposes patients for the development of TOFs. As a result of laryngeal bypass, spillage of oesophageal contents occurs into the trachea. Saliva, food and gastric juice contaminate the airways. This leads to congestion, infection, pneumonia, bronchial obstruction, atelectasis and respiratory distress. The severity of contamination depends on the width and length of the fistula as well as the posture of the patient. Spontaneous closure of non-malignant TOFs is exceptional.

Patients with acquired TOFs have high mortality and morbidity rates because of critical illnesses and co-morbidities. Acquired TOFs may occur in individuals of any age, and elderly individuals are at increased risk if they become ventilator dependent because of respiratory failure. Acquired TOFs can be diagnosed by instillation of contrast media into the oesophagus (Fig.1) or during direct visualization by flexible oesophagoscopy (Fig.2) or bronchoscopy. A high index of suspicion is needed to diagnose tracheo-oesophageal fistula in a post intubated patient presenting with symptom of cough following deglutition. Since acquired TOFs do not close spontaneously, surgical repair is needed if the patient is stable enough.^{3, 4} Critically ill patients are managed conservatively until stable enough for a major surgical procedure.

Typical oesophageal symptoms of gastro-oesophageal reflux disease include heartburn, regurgitation and dysphagia. The classic presentation of spontaneous oesophageal rupture is chest pain and subcutaneous emphysema after recent vomiting or retching (Mackler’s triad) in a middle-aged man with a history of dietary over-indulgence and over consumption of alcohol. Oesophageal diverticula presents with oropharyngeal dysphagia, usually to both solids and liquids, which is the most common symptom. Retention of food material and secretions in the diverticulum, particularly when it is large, can result in regurgitation of undigested food, halitosis, cough, and even aspiration pneumonia. The patient may note food on the pillow upon waking up in the morning.

Clinical Scenario / Question

A 26-year-old previously healthy male presented with a two day history of pain in his left wrist following trauma inflicted while playing volleyball. It was aggravated by movements around the affected joint. Clinical examination revealed mild tenderness over the left wrist with full range of movements and absence of any swelling. Distal neurovascular status was intact. X-ray of the left hand and wrist was done to rule out an injury to the bones (Fig. 1).

Fig. 1: X-Rays of left hand and wrist

What diagnosis does the X-ray findings indicate?

1. Fracture of left scaphoid bone
2. Osteoblastic metastases
3. Osteopathia striata
4. Tuberous sclerosis
5. Osteopoikilosis

Answer / Discussion

The X-ray in Fig. 1 shows multiple small hyperdense oval and circular lesions scattered in all small bones of the left hand, with preservation of cortical thickness. These findings are suggestive of osteopoikilosis. Similar lesions were also present in the contralateral hand and wrist, as well as the pelvis (Fig. 2), on X-rays done subsequently.

Fig. 2: X-Ray Pelvis showing bone islands

Patient was counselled and reassured about the radiological findings. He was prescribed oral Paracetamol and topical Piroxicam for three days and asked to rest the affected joint. Osteopoikilosis (also called spotted bone) is a benign, possibly autosomal dominant dysplasia of bones, occurring in 1 per 50,000 people.¹ Small bones of hand and feet, long tubular bones and pelvis are most frequently affected. The condition is asymptomatic and is diagnosed incidentally on radiographs taken for other problems. The diagnosis is straightforward, based on the typical radiological appearances of small (up to 10mm) hyperdense opacities distributed symmetrically. No further investigations or any specific treatment are indicated. Patients need to be reassured about the benign nature of radiological findings.

Osteoblastic metastases occur in the older age group, are generally larger in size and do not have such a uniformly symmetric distribution. Osteopathia striata is another rare bone dysplasia, characterized by long hyperdense striations mainly in the metaphyses of long bones and pelvis.² Sclerotic bone lesions in tuberous sclerosis are frequently seen in the axial skeleton especially calvarias and spine, are at times distributed focally and have irregular borders and variable size.³ Subperiosteal new bone formation may be present and other clinical features like epilepsy may also provide a clue. As seen in Fig. 1, there is no break in the continuity of scaphoid bone, thus ruling out a fracture.

A 44-yr-old patient with history of ileal Crohn’s disease was admitted to our Department because of asthenia, subclinical jaundice, painful hepatomegaly, fluid retention and ascites. In 2008 the patient was diagnosed with bladder cancer and was treated by surgical resection of the cancer and intravesical chemotherapy with mitomicyn C. In 2010 he was given azathioprine (AZA) at 2 mg/kg for Crohn’s disease and 3 months later he developed an increase in serum alkaline phosphatase, gamma-glutamyl transpeptidase and transaminases. He was then started on 1.5 mg/kg 6-mercaptopurine (6-MP) once daily. After 9 months he stopped 6-MP because of nausea, vomiting and abnormal liver function tests; 6-MP was therefore discontinued until the normalisation of markers of liver function. Two months later, when the transaminases were within the normal range, he received 6-thioguanine (6-TG) 25 mg a day, that was progressively increased to 80 mg a day. Three months later, the patient was referred to our Department with painful hepatomegaly, ascites and asthenia. Laboratory tests on admission revealed an elevation in AST 198 U/l and ALT 209 U/l. Total bilirubin was 3 mg/dl (direct bilirubin 1.5 mg/dl), LDH 784 U/l, alkaline phosphatase 191 U/l and ammonia 112 umol/l. Virological markers (HBsAg, HBcAb, anti HCV, HBV DNA) were negative. Patient was apyrexial, showed normal blood pressure (130/80 mmHg), tachycardia (110 bpm) and 97% SaO2 on room air. Physical examination revealed right hypochondrial tenderness, abdominal distension and shifting dullness, suggesting the presence of ascites. The rest of the physical examination was unremarkable. An echo-Doppler evaluation revealed thin linear suprahepatic veins and confirmed the presence of ascites. A CT scan of the abdomen showed hepatomegaly with dishomogeneous enhancement after dye injection (mosaic pattern). There was no evidence of any venous thrombosis or splenomegaly (Figure 1A); 6-TG was withdrawn empirically and the patient was started on therapy with albumin 25 g/day and spironolactone 200 mg/day. The average serum Na+ level during diuretic treatment was 134 mEq/l. An abdominal paracentesis of two litres was necessary, due to the progressive increase of ascites.

FIGURE 1A. CT scan of the abdomen on admission: Dishomogeneous enhancement of the liver after dye injection (mosaic pattern) (arrow). Suprahepatic veins are not detectable.

FIGURE 1B. Histological pattern of the liver biopsy specimen: marked centrilobular congestion (arrows) with hepatocyte dropout. There is no evidence of centrolobular veins thrombosis.

A routine laboratory investigation of ascitic fluid showed < 500 leukocytes/µL and < 250 polymorphonuclear leukocytes (PMNs)/µL. The ascitic fluid total protein level was 2.1 g/dl and serum-ascites albumin gradient (SAAG) was > 1.1 g/dL. No neoplastic cells were found. A transjugular liver biopsy was then performed, showing marked centrilobular hemorrhage with hepatocyte necrosis. There was mild ductular reaction, with no evidence of centrilobular vein thrombosis. The histologic diagnosis confirmed veno-occlusive disease (VOD) (Figure 1B). Screening for thrombophilia was also done, showing low levels of serum protein C and protein S. There was no mutation of JAK-2 V617F. The patient was then treated with a hyposodic diet, mild hydric restriction, enoxaparin,spironolactone, lactulose and omeprazole. He was discharged two weeks later, and after 3 months a complete regression of ascites and hepatomegaly occurred, and echography of the liver was unremarkable (Figure 2A and 2B).

FIGURE 2A. Echography of the liver at follow up. No evidence of ascites.

FIGURE 2B. Echography of the liver at follow up. No evidence of ascites. Suprahepatic veins are detectable (arrow)

Discussion

Although VOD was known among complications of 6-TG in childhood, this case-report emphasises the occurrence of VOD in adults with Crohn’s disease, as first described by Kane et al. in 2004¹. The thiopurine drugs were developed more than 50 years ago, and 6-MP was first used as a drug in 1952². Since then, 6-MP and 6-TG have been widely used to treat acute lymphoblastic leukemia in children. VOD mimicking Budd-Chiari like disease was then described as a frequent complication of 6-TG in pediatric patients given the drug for lymphoblastic leukaemia. Later on, in 1976, Griner et al. described the cases of two adult male patients with acute leukaemia developing a fatal Budd-Chiari-like disease while receiving 6-TG³. Since patients were given 6-TG plus cytosine arabinoside, authors were unable to ascribe this complication solely to 6-TG³. VOD exclusively related to 6-TG was first described by Gill et al., who observed a clinically reversible liver VOD developing in a young man with acute lymphocytic leukemia after 10 month administration of 6-TG⁴. Furthermore, sinusoidal obstruction was also reported in a patient with psoriasis treated with 6-TG and other cytotoxic therapy⁵. In 2006, a European 6-TG Working Party established that 6-TG should be considered a rescue drug in stringently defined indications in inflammatory bowel diseases (IBD). The indication for administration of 6-TG should only include its use for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Moreover, 6-TG must be withdrawn in case of overt or histologically proven hepatotoxicity⁶. Although Ansari et al ⁷ found no nodular regenerative hyperplasia (NRH) in the liver of patients given 6-TG, Dubinsky et al.⁸ described NHR as a common finding in 6-TG-treated patients with inflammatory bowel disease in the absence of VOD. By contrast, in our case report we showed histological pattern of VOD and, in accord with Gisbert et al.⁹, would suggest that 6-TG should not be administered out of a clinical trial setting. Given that the proportion of patients with Crohn’s disease achieving an improvement of symptoms during 6-TG treatment is similar to that after methotrexate¹⁰ or infliximab⁶, these drugs should therefore be considered as second line therapy in patients intolerant or resistant to azathioprine and 6-mercaptopurine.

Introduction

Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic disorder associated with the use of neuroleptic agents. NMS is typically characterized by a distinctive clinical syndrome of mental status change, muscle rigidity, fever, and autonomic instability. Atypical cases may present without muscle rigidity and/or hyperthermia. Association of infection in an atypical case can make the diagnosis challenging. We describe a case of NMS in a patient who presented with acute onset of altered mental status complicated with aspiration pneumonia.

Case Report

A 22-year-old female with a history of schizophrenia and seizure disorder presented with acute onset of altered mental status. Her home medications included haloperidol, clonazepam, olanzapine, trazodone, topiramate, benztropine, and trihexyphenadyl. The patient was found unarousable by her mother. She had multiple suicidal attempts in the past (overdosed on acetaminophen, drank cleaning detergent, and cut her wrist). She usually medicated herself without supervision. On examination, the patient was drowsy, afebrile (Temp 36.8^oC/98.3^oF), hypotensive (BP 85/64 mmHg), tachycardic (HR 105 bpm), and tachypnic (24/min). She was noted to be grunting with both inspiratory and expiratory stridor; therefore she was intubated for airway protection. Initial drug screen was negative for all substances of abuse. Acetaminophen and salicylate levels were undetectable. Head CT was unremarkable. Supportive care was provided as the patient was suspected to be overdosed with multiple medications. On the second day of admission the patient developed fever of 38.9^oC/102^oF. Chest xray and chest CT showed bilateral infiltrations (Fig.1), so empirical piperacillin/tazobactam and vancomycin were started for aspiration pneumonia. Sputum culture came back positive for Methicillin-resistant Staphylococcus aureus. However, the patient remained febrile with a temperature of 39.6 ^oC /103.2^oF, despite appropriate antibiotic treatment. We suspected that there might be some other coexisting condition causing high fever. Serum creatine kinase (CK) was checked and found to be 8,105 U/L, up from 106 U/L on admission. We considered the diagnosis of NMS based on alteration of mental status, hyperthermia, autonomic instability, and elevated CK level, with the use of neuroleptic agents, although the patient did not have any muscle rigidity. The patient was started on dantrolene in addition to intravenous fluid and antibiotics. Shortly afterwards temperature and CK level started to trend down (Fig.2,3). Dantrolene was subsequently increased to maximum weight-based dose. Her mental status was gradually improved and returned to baseline. She became afebrile on day 10 of dantrolene treatment and serum CK went back to normal level after 2 weeks. Then bromocriptine was started orally and continued for 2 weeks.

Figure 1A: chest xray  on admission

Figure 1B: chest xray on second day of admission

Figure 1C: chest CT on second day of admission

Figure 2. Temperature trend after starting treatment for NMS

Figure 3. CK trend after starting treatment for NMS

Atypical presentations of NMS can sometimes be difficult to diagnose, as in our patient who presented with altered mental status, fever, and coexisting infection, in the absence of muscle rigidity. We emphasize the importance of a high index of suspicion of NMS in patients using neuroleptic agents.

Discussion

NMS is an idiosyncratic drug reaction to antipsychotic medications and a potentially life threatening condition that occurs in an estimated 0.07% to 2.2% of patients treated with antipsychotics.¹ Patients typically present with fever, rigidity, changes in mental status, and autonomic instability, often attributed to first generation antipsychotics, in particular after the start of medication or an increase in dosage.² Atypical cases of NMS without muscle rigidity and/or hyperthermia have been reported, usually associated with atypical antipsychotic treatment. It has been hypothesized that atypical cases represent early or impending NMS; however pathogenesis remains unclear.³ Risk factors that have been established in case series and case-control studies include agitation, dehydration, acute medical illness, concomitant use of other psychotropic drugs, intramuscular injections and high doses of antipsychotic medications.^4-6

Complications of NMS are often consequences of its symptoms. Pneumonia is the most common complication found in 13% of patient with NMS, likely due to altered mental status combined with difficulty swallowing that lead to aspiration.⁷ Renal failure is the second most common complication (8%), as a result of rhabdomyolysis and myoglobinuria. Other complications have been reported including myocardial infarction, disseminated intravascular coagulation, deep venous thrombosis, pulmonary embolism, hepatic failure, sepsis, and seizure.⁸ Mortality rate of NMS was around 20-30%.^9-10 With early identification and treatment, mortality has significantly reduced to averages 10%.⁶

Withdrawal of the causative agent is the first step in the management of NMS. Supportive therapy, in particular, hydration, fever reduction, and careful monitoring, is the mainstay of management of NMS. In mild cases, supportive treatment alone may be sufficient.⁴ Adding specific therapies, such as dantrolene, bromocriptine, and benzodiazepine to supportive measures has been shown to reduce time to complete recovery, from a mean of 15 days with supportive care alone, to 9 days with dantrolene, and 10 days with bromocriptine.¹ In severe cases, empirical trial of specific pharmacological agents should be started promptly. Electroconvulsive therapy is found to be effective when pharmacotherapy has failed.¹¹

Sometimes NMS is difficult to identify in the presence of critical illnesses which can obscure the manifestation of NMS. As in our case, the patient presented with altered mental status, fever, and autonomic instability which could be simply explained by the presence of pneumonia and sepsis. However, due to lack of clinical response after appropriate antibiotic treatment, other coexisting condition was suspected. It is important to have a high index of suspicion for NMS in the setting of antipsychotic therapy. An absence of muscle rigidity should not exclude a diagnosis of NMS when the rest of the clinical picture points to this diagnosis. Elevated CK level helps support the diagnosis of NMS in patients with atypical presentation. Discontinuation of offending agent and supportive care should initiate promptly, and specific pharmacotherapy should be considered in severe cases. An early diagnosis is the key to successful treatment and patient outcome.

Conclusion

NMS is a rare but potentially life-threatening condition. Atypical presentation makes it more difficult to identify in patients with critical illnesses. Aspirated pneumonia is one of the common complications of NMS and sometimes can obscure signs and symptoms of NMS and delay diagnosis. High index of suspicion for NMS in patients taking antipsychotics is crucial. If not recognized or left untreated, NMD may be fatal.

In rheumatology clinics chronic painful conditions are the norm. Although many pain syndromes are associated with low mood and sometimes clinical depression, the mood disorder often goes unrecognised. Fibromyalgia is one such chronic pain syndrome, 'chronic' arbitrarily defined as lasting longer than six months. It is a common, poorly understood, musculoskeletal disorder which more often affects women between the ages of 25-50 years generally.

In nearly all patients three symptoms predominate, namely, neuropathic pain (nerve injury pain), fatigue and non-restorative sleep disturbance. The chronic neuropathic diffuse pain, described as whole body pain, is felt particularly in deep tissues such as ligaments, joints, and muscles of the axial skeleton in mainly the lower cervical and lumbar spine. The pain is often characterised by an exaggerated and prolonged response to a noxious stimulus (hyperalgesia). Patients may be considered to be malingering because there is no obvious explanation for the symptoms. Anxiety, stress and depression caused by fibromyalgia add insult to injury, with personality and cognitive factors coming into play in addition.¹ Paraesthesiae (abnormal sensory sensations) or dysaesthesiae (painful sensations) of the extremities may also occur. There is no objective muscular weakness or neurological disorder to account for the symptoms, which adds to the diagnostic dilemma. For example, fibromyalgia affecting the supraspinatus muscle of the shoulder would limit initial abduction of the arm because of pain, not because of any muscle weakness. Cognitive function is sometimes described as 'fibrofog' or 'conscious confusion' and may be a primary symptom of fibromyalgia, reflecting impairments in working memory (a form of short-term memory), episodic (memory for events), and semantic memory (memory for words, rules, language).

Nociception refers to the process of information about harmful stimuli conveyed by neuronal activity up to the point of perception in the dorsal horn of the spinal cord where primary afferents synapse.² Evidence is accumulating which shows that atypical sensory processing in the central nervous system (CNS) and dysfunction of skeletal muscle nociception are important in the understanding of fibromyalgia and other chronic pain syndromes^.3The concept of 'central pain sensitization' or 'central sensitivity syndrome' considers fibromyalgia to be a disturbance of nociceptive processing which causes a heightened experience of pain or pain amplification.⁴ Because pain signals are subject to variation in amplitude, the modulation of sensory processing may be the key to understanding the pain response not only in fibromyalgia but also in other conditions, such as irritable bowel syndrome. Descending spinal noradrenergic and serotonergic neurons inhibit the neurotransmitters noradrenaline and serotonin, released from primary afferent neurons and dorsal horn neurons. Therefore, when descending inhibition is decreased, irrelevant nociceptive stimuli are more readily felt. Put another way, in patients with chronic pain syndromes descending inhibition may not be functioning adequately to prevent or mask irrelevant pain stimuli. When appropriate medication is used this normal descending inhibition is enhanced and pain is no longer troublesome.

The release of neurotransmitters (ligands) also requires a mechanism that involves voltage-sensitive calcium and sodium channels. Repetitive action potentials cause the calcium channels to open with the ensuing release of neurotransmitters into the synaptic cleft. The postsynaptic neurons are thus stimulated leading to molecular and structural changes (sprouting) which cause neuropathic pain. Drugs such as Pregabalin and Gabapentin bind to voltage-sensitive calcium channels and reduce calcium influx, which in turn diminishes pain. The concept of central pain sensitization now incorporates affective spectrum disorders and functional somatic syndromes. It seems that the more painful symptoms one has which are difficult to explain, the more likely the patient is suffering from a mood disorder. Dopamine may be involved in the regulation of cognition in the dorsolateral prefrontal cortex and could account for the cognitive deficits.⁵Because cingulate and prefrontal cortices are particularly implicated in pain modulation (inhibition and facilitation of pain), structural changes in these systems could contribute to the chronic pain associated with fibromyalgia.⁶

Many patients with fibromyalgia have an increased sensitivity to sensory stimuli that are not normally or previously painful (allodynia). In other words, minor sensory stimuli that ordinarily would not cause pain in most individuals induce disabling, sometimes severe pain in patients with fibromyalgia^.7 In normal individuals 4 kg/square cm²pressure (approximately the pressure needed to blanch the skin at the top of one’s thumb) causes patients with fibromyalgia to wince with pain or suddenly withdraw when the tender point is palpated. This indicates that pain occurs at a lower pain threshold in fibromyalgia sufferers when this pressure is applied.

The pain of fibromyalgia may be aggravated by emotional stress though the latter is difficult to quantify and evaluate. For instance, corticosteroid hormones are released in high amounts after stress yet fibromyalgia is associated in some patients with a decreased cortisol response to stress. Stress may therefore initiate, inhibit or perpetuate alterations in the corticotrophin-releasing hormone (CRH) neuron, with associated effects on the hypothalamic pituitary axis (HPA) and other neuroendocrine axes.⁸

There are many other possible explanations for fibromyalgia pain. One of the major neurotransmitters involved in nociception is substance P, found in high concentrations in the spinal cord, limbic system, hypothalamus, and nigrostriatal system. It is involved in the transmission of pain impulses from peripheral afferent receptors to the central nervous system. Nerve growth factor (NGF), a cytokine-like mediator may indirectly exert its effect through enhancing glutaminergic transmission and could account for sustained central sensitization in fibromyalgia. ^{9, 10} Another neuropeptide, calcitonin gene-related peptide, a potent vasodilator, present in non-myelinated afferent neurons, may also play a role in pain pathology.⁵

Levels of the neurotransmitter serotonin have been found to be low in some studies in fibromyalgia patients. Although serum levels of serotonin are lower than in some patients with rheumatoid arthritis and healthy controls, the variation is too broad and therefore measurement of serotonin has not proved useful tool in determining a diagnosis of fibromyalgia. ¹¹

Logically, pharmacologic agents used to treat pain in fibromyalgia would act by either increasing levels of inhibitory neurotransmitters or decreasing levels of excitatory neurotransmitter. In the United States of America (USA), Pregabalin was the first drug to be approved by the Food and Drug Administration (FDA) for the treatment of fibromyalgia and has been shown to improve pain, sleep and quality of life. It is ineffective against depression. The main inhibitory mediator in the brain, gamma amino butyric Acid (GABA), is formed from glutamate (excitatory) by the enzyme glutamate decarboxylase (GAD). It is particularly plentiful in the nigrostriatal pathways. About 20% of CNS neurons are GABAergic and it serves as a neurotransmitter at some 30% of all CNS synapses.¹² Pregabalin increases neuronal GABA levels by producing a dose-dependent increase in glutamate decarboxylase activity. In a meta-analysis of 21 clinical trials to estimate treatment differences vs. placebo, statistically significant improvement was observed with Duloxetine, Milnacipran 200 mg/day, Pregabalin 300 or 450 mg/day, and Tramadol plus Paracetamol. The meta-analysis showed a statistically increased risk of discontinuation because of adverse events related to Milnacipran and Pregabalin.¹³

Antidepressants may improve fibromyalgia symptoms by reducing pain, stabilizing mood and improving sleep, though the effect seems to be modest. If abnormal sleep, and hence subsequent tiredness, precedes the development of fibromyalgia the effect of antidepressants may be primarily associated with improved sleep. However, the efficacy of tricyclic antidepressants is difficult to quantify and their limited superiority over placebo lasts no more than a few months. A meta-analysis of ten randomized double-blinded, placebo-controlled studies revealed only poor to moderate evidence for a beneficial effect at low doses of Amitriptyline (25mg daily) over 6-8 weeks. Even when given in higher doses or prescribed for a longer duration, Amitriptyline did not make a great deal of difference. ¹⁴

The efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) is also inconclusive. More promising results have been demonstrated with Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) such as Duloxetine. Both serotonin (5-HT) and noradrenaline (NA) exert analgesic effects via descending pain pathways. Pain is a prominent feature of depression and vice versa and the alleviation of one modifies the other. ^{15, 16} The reduction in pain reduces fatigue and Duloxetine improves mood.

Other drugs used in this condition include Milnacipran and Cyclobenzaprine (a muscle relaxant structurally related to tricyclic antidepressants). Milnacipran and Cyclobenzaprine are not available in the United Kingdom (UK). Tramadol (a serotonin and noradrenaline reuptake inhibitor) is a weak mu-receptor opioid agonist used to control pain but its adverse effects are those of opiates in general, mainly nausea and dependence.

Although other adjunctive non-pharmacological treatments have been advocated the results are disappointing. Assessments of non-drug treatments are generally mediocre. Aerobic exercises benefit some patients, especially when combined with biofeedback, patient education and cognitive therapy. A whole gamut of treatments such as graded exercises, yoga, dietary advice, balneotherapy (heated pool bathing), homeopathy, massage, acupuncture, patient education, group therapy and cognitive behaviour therapy, have been suggested and tried, but few of them demonstrated clear-cut benefits in randomized controlled trials.Support groups may help some patients. ^{17, 18, 19}

Fibromyalgia is now considered to be, in part, a disorder of central pain processing. Central sensitization manifests as pain hypersensitivity, particularly allodynia, and hyperalgesia. It is believed that central sensitization occurs in part through the action of glutamate on the N-methyl-D-aspartate (NMDA) receptor, resulting in an increase in intracellular calcium and kinase activation, leading to hyperalgesia and allodynia.²⁰

Response to standard analgesics is erratic and more promising results have emerged with drugs such as the SNRIs Duloxetine and Milnacipran, the anticonvulsants Gabapentin and Pregabalin, either used alone or in combination, or with other agents such as Amitriptyline. There is only modest evidence to support SSRIs and Tramadol. Treatment needs to be holistic and multidisciplinary, focussing on both physical pain management and psychological dysfunction. The multidisciplinary approach, though difficult to measure, may help by imparting a sense of empathy and support for patients. Overall, most patients with fibromyalgia continue to have chronic pain and fatigue with symptoms persisting for many years, but it is not necessarily a progressive disorder and some patients may show moderate improvement.

INTRODUCTION

The widespread use of office-software in general practice makes the idea of simple, automatic computerised support an attractive one.  Different tools for different diseases have been tested with mixed results, and in 2009 a Cochrane review¹ concluded that “Point of care computer reminders generally achieve small to modest improvements in provider behavior. A minority of interventions showed larger effects, but no specific reminder or contextual features were significantly associated with effect magnitude”.  One year later another review² reached similar conclusion: “Computer reminders produced much smaller improvements than those generally expected from the implementation of computerised order entry and electronic medical record systems”.   Despite this, simple, non-expensive, automatic reminders are frequently part of GPs’ software, even if their real usefulness is seldom tested in real life.

Repeated hospitalisation for heart failure is an important problem for every National Health System; it is estimated that about half of all re-hospitalisation could be avoided³. Adherence to guidelines can reduce re-hospitalisation rate⁴, and pharmacotherapy according to treatment guidelines is associated with lower mortality in the community⁵. In 2004 a software commonly used in Italian primary care implemented a simple reminders’ system to help GPs to improve prescription of drugs recommended for heart failure. We evaluated if this could lead to a decrease in re-hospitalisation rate.

METHODS

In 2003, using Millewin ®, a software commonly used by Italian GPs, we showed that appropriate prescription could increase using a simple pop-up reminders⁶; a year later, using the Italian General Practitioners database ‘Health Search – CSD Patient database (HSD) (www.healthsearch.it), we observed a lower than expected prevalence of codified diagnosis of heart failure and of prescription of both beta-blockers and ACE-Inhibitors/ARBs (data on file). Therefore in 2004 Millewin® embedded a simple reminder system to help heart failure (HF) management. The first reminder aimed to identify patients with HF, but without codified diagnosis: in case of loop diuretic and/or digoxin prescription without codified HF diagnosis a pop-up told the GP that the patients could be affected by HF and invited the physician to verify this hypothesis and eventually to record the diagnosis. The second reminder appeared when a patient with codified HF diagnosis had no beta-blocker and/or ACE-inhibitor/ARB prescription: a pop-up invited the GP to prescribe the missing drug. This reminder system was already activated in the 2004 release of the software, but required voluntary activation in the successive releases. This is a common choice in real life, where positive choices in clinical practice by software-house neither are welcomed nor accepted by GPs. We had no possibility to know who decided to keep using the reminders.

We examined the 2004-2009 HF hospitalisations in Puglia, a Southern Italian Region with a population of over 4000000, and with high HF hospitalisation rate compared with the Italian mean⁷.  We compared the hospitalisations for patients cared for by GPs who used Millewin® in 2004 to those of the patients cared for by GPs who never used Millewin®. Data were provided by the local Health Authority, and were extracted from the administrative database. 

RESULTS

We identified 64591 patients (mean age 76 y, sd 12; 49.9% men) with one or more HF hospitalisation; 17810 had > 2 hospitalisations, and were analysed for the current study.

Figure 1 - Selection process leading to the identification of the patients with > 2 HF hospitalisations

The selection that led to this group is summarised in figure 1. There was no statistically significant difference between patients cared for GPs using or non using Millewin® software as far as age and gender are concerned. The re –hospitalisation rate according to the use or non-use of  Millewin® of patients’ GPs is summarised in table 1.

Table 1: Re-hospitalisation rate of patients cared by Millewin® users and non-users

MW = Millewin®, N.S = Not significant

The mean time before the first re-hospitalisation was 108.5 day +/- 103.3 for Millewin® non-users and 116.4 +/- 107.5 for users (p < 0.05).

DISCUSSION

Even if reasonable and clinically sound, the availability of computerised reminders aimed to help GPs to identify HF patients and to prescribe them with recommended drugs didn’t reduce re-hospitalisation rate. The first possibility to explain this result is that, after the first year, GPs didn’t re-activate the reminders’ system. Unfortunately we couldn’t verify this hypothesis, but it is known that the level of use of such a system may be low in usual care⁸; furthermore providers may agree with less than half of computer generated care suggestions from evidence-based CHF guidelines, most often because the suggestions are felt to be inapplicable to their patients or unlikely to be tolerated⁹.  Epidemiological studies have shown that heart failure with a normal ejection fraction is now a more common cause of hospital admission than systolic heart failure in many parts of the world^10-11. Despite being common, this type of heart failure is often not recognised, and evidence based treatment—apart from diuretics for symptoms—islacking¹². It is therefore possible that increasing ACE-I/ARBs and beta-blockers use in these patients doesn’t influence the prognosis and hospitalisation rate. Unfortunately administrative databases do not permit to distinguish the characteristic of HF. We must also consider that the use of appropriate drugs after HF hospitalisation could spontaneously increase in the last years; a survey in Italian primary care showed that 87% of HF patients used inhibitors of the renin-angiotensin system, and 33% beta-blockers¹³. A further relevant increase in ACE-I/ARBS is therefore unlikely, while a improvement is clearly needed for beta-blockers.   Could more complex and information-providing reminders be more useful? This is unlikely since adding symptom information to computer-generated care suggestions for patients with heart failure did not affect physician treatment decisions or improve patient outcomes¹⁴.  Furthermore, consultation with a cardiologist for starting beta-blocker treatment is judged mandatory by 57% of Italian GPs¹³, thus reducing the potential direct effect of reminders on prescription. Finally we must remember that part of the hospitalisation due to HF worsening can be due to non-cardiac disease, such as pneumonia, anemia, etc; all these cause cannot be affected by improved prescription of cardiovascular drugs.

Albeit simple and inexpensive, computerised reminders aren’t a neutral choice in professional software. Too many pop-ups may be disturbing and may lead to systematic skipping the reminders’ text. This can be a problem, since computerised reminders have proved to be useful for other important primary-care activity, such as preventive interventions¹⁵. In our opinion, at the moment, a computerised reminder-system should be proposed only as a part of a more complex strategy, such as long-term self or group audit and/or pay for performance initiative.

CONCLUSIONS

Availability of computerised automatic reminders aimed to improve detection of heart-failure patients and prescription of recommended drugs doesn’t decrease repeated hospitalisation; these tools should be probably tested in the context of a more complex strategy, such as a long-term audit.

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.

Introduction

Sedation is frequently administered outside of the operating theatre by non-anaesthetic doctors to facilitate minor procedures.  This can be in both primary care including dental surgeries as well as in hospital departments such as radiology, endoscopy and the emergency department.  Clinical practice including medication and monitoring equipment available and the personnel involved, varies not only between hospitals and regions but also between departments.

In the emergency department sedation is often performed in a busy clinical setting by junior doctors.  This enables minor procedures to be carried out with subsequent discharge home reducing admission rates and the requirement for general anaesthesia.  Other advantages include less workload pressure on the anaesthetic team and a significant improvement in the patient experience.  Sedation is not without risk and significant morbidity and mortality is still associated with its use, particularly in the elderly and in combination with other medication^1,2.  Guidelines and protocols do exist to ensure safe practice but often it is only anaesthetic doctors who are aware of them^3-7.  A recent study by Fanning highlighted discrepancies in practice, skills and knowledge of doctors of various specialities and grades who administered sedation⁸.  Anecdotal reports from orthopaedic colleagues suggested the variability in competence of doctors with clear implications for patient safety.  We therefore sought to ascertain the current clinical practice, knowledge and prior training in sedation techniques of specialist registrars in orthopaedic and trauma surgery in our region.

Materials and Methods

A questionnaire based survey of 53 specialist registrars in orthopaedic and trauma surgery in the neighbouring Severn and South Wales regions was carried out.  The questionnaire was modified from that developed by Fanning⁸ and circulated for completion at regional teaching sessions in Swansea and Bristol (Appendix 1).  Each respondent had 15 minutes to complete the questionnaire based on their own experience, practice and knowledge. Respondents were not allowed to confer and full confidentiality was assured.  The questionnaire was split into several sections that ascertained the respondents’ clinical practice including the procedures that sedation was used for, prior training, awareness of protocols and safety issues.  Knowledge of the basic pharmacology of commonly used sedative agents was also tested.  The final section asked respondents whether they had ever encountered any adverse events, the nature of the adverse event and whether assistance was required from the anaesthetic department.      

Results

Orthopaedic specialist registrars (post basic surgical training) who were in higher surgical training completed 53 questionnaires.  Sedation was performed in the emergency department by all respondents for manipulating fractures, reducing dislocated joints and for applying traction.  Twenty-four respondents (45%) had read the sedation protocol for their hospital/emergency department.  Thirteen respondents (25%) completed pre-sedation assessment forms, whilst only eleven (21%) completed the during-procedure monitoring data forms and twelve (23%) filled the after-procedure forms (Figure 1).  Twenty-eight (53%) respondents ensured that either they or an assistant provided the patient with discharge advice.

Figure 1The percentage of respondents who had read the departmental protocol, completed monitoring forms and given advice prior to discharge.

Table 1:  Sedative agents used.

Almost all (98%) respondents administered sedation in the presence of an assistant.  Forty-seven (89%) checked their medication with another healthcare professional.  All fifty-three respondents supplied patients with concurrent oxygen whilst fifty-two ensured that resuscitation equipment was available nearby.  In terms of specific training, forty-seven (89%) registrars had undergone Advanced Life Support training (ALS) but this qualification was only valid (within three years) for thirty-six (68%).  Sixteen registrars (30%) stated they had undergone formal training or teaching regarding sedation (Figure 2).  With regards to monitoring of patients, thirty-six (68%) respondents used pulse oximetry, fourteen (26%) used electrocardiogram (ECG) monitoring and twenty-eight (53%) measured blood pressure. 

Figure 2The proportion of respondents who had received training in administering sedation

Morphine and other opioids were the most commonly used sedative medication (44 responses), followed by midazolam (35 responses), diazepam (31 responses) and propofol (15 responses).  Twelve respondents combined opiates and benzodiazepines, whilst seventeen combined local anaesthesia with sedation (Table 1).  Two-thirds of respondents (35 out of 53, 66%) administered sedation in boluses rather than calculating the correct dose per kilogram.  The pharmacology questions devised by Fanning⁸ tested knowledge of metabolic pathways, duration of action and side effects. Overall, each question was answered correctly by over 50% of respondents (Figure 3).  The mean score was 4.29 out of 7.

Figure 3The percentage of correct answers for each of the seven pharmacology questions.

Eighty percent of surveyed orthopaedic doctors (43 respondents) reported an adverse event after administering sedation.   Twenty-nine respondents had at some stage contacted the anaesthetic department for assistance in managing a patient following sedation (Table 2).

Table 2:  Adverse Events reported.

Discussion

Non-anaesthetic doctors are permitted and often required to administer sedation to perform procedures in settings outside of the operating theatre.  There are various published guidelines that detail the level of care and monitoring that should be provided when sedation is given^3-7.  It has been recommended that the same standards of monitoring apply to procedures under sedation or local anaesthesia as to procedures under general anaesthesia, and are irrespective of the location of the procedure³.

The report by an intercollegiate working party led by the Royal College of Anaesthetists summarised the key aspects of administering sedation based on existing guidelines⁶.  Patients should be first assessed before the procedure by attendant staff, risk factors noted and further examination or investigations performed as necessary.  Drug administration technique should be “one defined by a relevant specialty organisation”⁶ and doses adjusted to individual patient requirements.  Combinations of drugs should be “employed with particular caution” especially sedatives and opioids.  The opioids should be administered first and given time to be maximally effective before any sedative is given.  The patient should be monitored during the procedure by a suitably trained individual recording pulse oximetry, blood pressure and electrocardiography. High flow oxygen should also be available. Doctors administering sedation should be able to control an airway using basic manoeuvres or airway adjuncts.

There is significant morbidity and mortality associated with sedation^1,2.  It is difficult to know the true incidence of cardio-respiratory complications after sedation, as this is often related to the procedure and patient factors.  An audit of 14,000 endoscopic procedures reported a 30-day mortality of 1 in 2000⁹ and there are several anecdotal reports of death following sedation^10,11.

It is apparent that not all doctors are aware of or follow sedation guidelines.  In the study by Fanning⁸, 42% of respondents completed a pre-procedure assessment form and 70% completed monitoring data sheets.  In this study, whilst 45% of respondents had read departmental protocols, only 25% completed a dedicated pre-assessment of the patient and an equally low number recorded monitoring data forms during (21%) and after the procedure (25%).  These low numbers are of potential concern.  Time and resource constraints may play a part, particularly in a busy emergency department.  Also, as junior doctors frequently rotate between hospitals, they may not be aware of departmental policies in each unit.  It is understandably impractical to perform a procedure and concurrently complete a data monitoring form.  This role should be delegated to an assistant.

Knowledge of basic pharmacology amongst respondents seemed reasonable and indeed better scores were achieved than in Fanning’s original paper.  It would appear that a large number of respondents (n=29) have contacted anaesthetic colleagues for help following adverse events.  This may simply reflect an acknowledgement of limited anaesthetic capabilities amongst respondents and a pre-emptive call for assistance rather than an anaesthetic “bail out” after cardio-respiratory compromise.

Whilst the questionnaire used is neither a formal assessment tool of clinical competence nor an accurate log of experience, it serves to highlight the potential limitations of current training.  A clear issue is the low number of respondents who claim to have received formal teaching or training with regards to sedation.  This may be due to the fact that little or no postgraduate training is provided in hospital specialities that require sedation. This is an area that needs to be addressed.  The issues raised by this study are not new.  In fact, a similar survey by Hewitt and Hartley in 1994 had similar findings and suggested that “sedation techniques should be included in induction teaching for A&E and orthopaedic juniors” and that all doctors administering sedation should have the “opportunity of resuscitation refresher courses”¹². 

Conclusion

Sedation is widely administered by non-anaesthetic doctors including orthopaedic surgeons in order to perform basic procedures outside of the operating theatres, mainly in the Accident and Emergency department.  Whilst this study only involves 53 doctors in one speciality across two regions, it does give an insight into the self-reported clinical practice, knowledge and experience of a group of surgical doctors who are often required to administer sedation.  Significantly, the majority of doctors surveyed reported they had not received any formal training.  It is also apparent that departmental guidelines are not always known or followed.  Due to the inherent risks of sedation, it is important that doctors are aware of and follow available guidelines.  It is crucial that adequate training should be given to non-anaesthetic doctors to ensure they have the knowledge and skills to safely administer sedation. Otherwise a medical doctor, perhaps a registrar level from the Accident and Emergency department, should be present for patient assessment and management of airway compromise or any arising complication.