Jul

Schizophrenia (SCZ) is a chronic relapsing and remitting disorder with a lifetime prevalence of 4 per 1000 persons.¹Positive symptoms include delusions and hallucinations. Negative symptoms are characterised by deficits in normal behaviour, which are categorised into five domains: blunted affect, alogia, social withdrawal, anhedonia, and avolition. In clinical practice, when monotherapy fails multiple augmentation strategies – such as another antipsychotic, mood-stabilisers, benzodiazepines, lithium, electroconvulsive therapy, and repetitive trans-cranial magnetic stimulation – have been used to improve the clinical state of these patients, but evidence relating to the use of these interventions is lacking.²None of the regulatory bodies has openly endorsed polytherapy with antipsychotics.

The introduction of chlorpromazine in the 1950s revolutionised psychiatry, and the coming of slow-release, slow-acting forms (depot medication) contributed to the closure of asylums and paved the way to community psychiatry. Second-generation antipsychotics ameliorated the situation for a number of psychotic patients, but some remained resistant to all forms of psychopharmacology. In 1958, clozapine was formulated and marketed commercially in 1972. ³ The arrival of clozapine facilitated the rescue of some schizophrenia sufferers for a short time, but the drug disappeared from the scene because of initial untoward incidents. ^4,5 The observation that clozapine has the potential to control the motor symptoms of tardive dyskinesia and to treat the psychotic symptoms of patients already diagnosed with tardive dyskinesia, led to its reintroduction, but with restrictions. ^6,7,8 Clozapine is recommended for use only after a trial of two other antipsychotics. Combining depot antipsychotics with oral drugs of a different class has been the practice ever since the introduction of depot medications, and this practice has come to have general clinical acceptance.

Treatment resistance

Historically, it was observed that a specific group of chlorpromazine users remained symptomatic. They were considered to be refractory to phenothiazines. The availability of clozapine led to a better definition of treatment resistance. ‘Response to treatment’ means a reduction in the severity of symptoms, while ‘remission’ implies an absence of symptoms for a considerable period. ‘Recovery’ signifies absence of the disease for a long period.⁹‘Treatment resistant schizophrenia’ (TRS) is the term used for persistence of psychotic symptoms despite a certain number of adequate treatments. Since the introduction of first-generation antipsychotics, clinicians have been cognizant of TRS and operational definitions have been used such as those developed by Kane et al. ¹⁰ Sometimes, treatment has been based on algorithms such as the Texas Medication Algorithm Project (TMAP).

According to the most common definition of TRS, if patients present with persistent, moderate to severe, positive disorganization or negative symptoms together with poor social and work function over a prolonged period of time after at least 2 adequate trials of neuroleptic drugs, they may meet the criteria of having TRS. ¹¹ A common agreement is that adequate drug treatment requires a duration of 4 to 10 weeks, a dosage equivalent to 1000 mg/d of chlorpromazine, and trials of 2 to 3 different classes of antipsychotic drugs. ¹² The current treatment guidelines recommend 2 or more treatment trials of atypical antipsychotics at adequate dosages. Adequate response to treatment has been defined as at least a 20% reduction in symptoms as measured by rating scales. Typical antipsychotics can also be used for 4 to 6 weeks to screen for TRS.

Resistance to treatment and poor outcome are different from genuine TRS. Resistance to treatment may be defined as a state in which the patient has access to medication, but the effectiveness of the treatment is suboptimal. TRS may be conceptualised as a state in which medication has reached target receptors but does not seem to be effective. Chronicity has often been misconstrued with treatment-resistance. Schizophrenia is a chronic disorder that progresses to various levels of clinical deterioration without sustained remission or full recovery. Poor-outcome SCZ applies to 50% of patients, and TRS comprises a subset of such patients. In these, cognitive impairment, negative symptoms and mood symptoms are independent of positive symptoms, resulting in poor-outcome SCZ.

It is generally accepted that 30% of SCZ sufferers have TRS. Many people with SCZ do not achieve a satisfactory treatment response to their initial antipsychotic drug treatment. They may manifest a poor response to therapy because of intolerance to medication, poor adherence and inappropriate dosing, as well as true resistance of their illness to antipsychotic drug therapy. Assessing treatment resistance is a priority in the management of TRS. ¹³ TRS has to be closely evaluated before a comprehensive management plan is developed (Table 1). From a multidimensional point of view, TRS is dependent on manifold factors, such as longer duration, several episodes, gender, early onset, poor pre-morbid personality, family history, substance misuse, presence of soft neurological signs and a long untreated period.¹⁴ Genes are thought to be involved in the development of TRS; reliable genetic prediction of which patients will be TRS would have serious clinical implications. Structural neuroimaging techniques have revealed that TRS patients do not differ importantly than those responsive SCZ in terms of brain abnormalities.¹⁵

When clozapine fails or rejected

Clozapine may be the preferred drug for TRS – effectively the gold standard – but its side effects put off many patients to the extent that some of them refuse clozapine therapy. It is a unique atypical antipsychotic and there is robust evidence supporting its use in people with TRS. Though clozapine often represents the best hope for recovery, it is associated with severe and enduring adverse reactions that may delay its prescription and increase morbidity and mortality. The major side effects are a) agranulocytosis; b) metabolic side effects; c) myocarditis; d) seizures; e) severe constipation with gastrointestinal complications such as intestinal obstruction, bowel perforation, paralytics ileus and toxic megacolon; and f) sialorrhea. These side effects hinder the popular use of clozapine in TRS. It is a life-saving drug, but without extra care it may itself shorten the life span. Side effects are more common with higher doses. It has been estimated that between 10 and 60% of patients resistant or intolerant with other antipsychotic drugs respond to clozapine.

The side effects mentioned above are inevitably an impediment to its common use. When standard doses (300mg to 5oomg) do not produce the desired effects or patients develop unwanted effects, combining clozapine with other antipsychotics is a common practice for TRS. To mention a few antipsychotics, amisulpride and aripiprazole are atypical antipsychotics ordinarily used in combination with clozapine. The anti-salivatory effect of amisulpride and the alerting effect of aripiprazole are added advantages of such a combination, and these drugs are fairly weight neutral – in contrast to clozapine. Clozapine, representing a second generation of so-called atypical antipsychotic drugs, has shown positive effects in desperate cases of TRS. Furthermore, two epidemiological studies have shown that clozapine has the lowest mortality rate among antipsychotics.

Nevertheless, even supported by the literature as the best-known antipsychotic in terms of efficacy and rates of response, a sizeable number of patients remain resistant to clozapine therapy and continue as symptomatic and dysfunctional. It has been estimated that 40–70% of patients on clozapine may not respond satisfactorily to it.¹⁶ When patients do not respond to clozapine, they are categorised as super-refractory, but the very concept of super-refractory state is debatable. They do not differ from the refractory cases in terms of demographical factors but have high score of positive symptoms. It may be simply explainable that the aetiological mechanism of the illness of such patients may be different from the clozapine responders and that makes them unresponsive to clozapine. There are no operational definitions for super-refractory schizophrenia. According to the schizophrenia algorithm of the International Psychopharmacology Algorithm Project (www.jpap.org), persistence of psychotic symptoms after a trial with adequate doses of clozapine(300-900mg/day) for at least six months is designated as super-refractory cases. ¹⁷

Many predictors of clozapine response have been suggested without any firm ground. These include severe clinical symptoms, higher levels of functioning before the onset of schizophrenia, low levels of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid, reduced metabolism in the prefrontal cortex, reduced volume of the caudate, and the improvement of P50 gating at the 500-ms prepulse interval. ¹⁸ However, none of these factors is consistent or specific as a predictor of clozapine response. More genetic and brain imaging studies are warranted with such patients. In these cases, augmenting strategies are necessary, and some have been in use: typical and atypical antipsychotics, mood stabilizers, antidepressants and electroconvulsive therapy. Some studies have favoured ECT, but no definitive conclusion has been drawn. So also, half of clozapine patients discontinue taking the medication on their own accord. In a retrospectively studied sample of patients who discontinued clozapine, the majority terminated the treatment as a result of their own decision or because of non-compliance with medical procedures such as blood sampling.¹⁹

There are currently no evidence-based pharmacotherapies for the TRS patients who do not respond to clozapine ^20,21 or those who terminate clozapine therapy due to adversative reactions. ²² In the nutshell, clinicians should be prepared to try different alternative treatment options for TRS and super-refractory cases. Thus, combination therapy may become a choice as pre-clozapine therapy or post-clozapine therapy. Clozapine is not a drug that could normally be imposed on patients, but it has to be earned by the patient.

Combination therapy

The range of antipsychotic medications available is wide, with variable effectiveness, and there are also differing profiles for typical and atypical agents, adding to a confusing array of terminologies and dilemmas regarding what the best drug for service users is.²³ Combination therapy involves the addition of a second antipsychotic to the therapy regimen. It is different from adjunctive therapy, in which a second agent is employed to reverse an emergent side effect or to obtain a complementary clinical effect. Augmentation involves the use of a non-antipsychotic along with the antipsychotic already in use. Combination therapy and augmentation therapy are sometimes used interchangeably. In general, ‘combination’ refers to the use of more than one type of disease-specific treatment to treat a particular illness.

A change from one antipsychotic to another in same class seldom produces any additional benefit, whereas switching to an antipsychotic with a different mechanism of action has proved to produce a more impressive response rate. Combination becomes desirable when the drug already in use produces some favourable effect, but that is not sufficient to control the symptoms. It is imperative to distinguish between partial response and no response when considering a change in medication. Past antipsychotic drug response, adverse effect profile differences, concomitant medical disorders and concurrent drug therapy are factors to be considered when choosing between switching and combination or augmentation approaches. A switch is indicated when there is no response to the drug and combination therapy; augmentation is recommended for partial response. Another antipsychotic combination may become necessary as an option for TRS patients who cannot be treated with clozapine for various reasons. It is common practice in such situations to add a second antipsychotic, in combination with the original one.

Clinical team do not have to be disheartened or disillusioned when clozapine therapy fails due to non-response or clozapine intolerance, and also when augmentation and combination therapies do not bring about the desired outcome. Switching back to atypical drugs once again may turn out to be effective in some cases and clozapine is not to be considered as the last resort. A multicentre open label 18-week trial evaluated a switch to olanzapine in 48 clozapine resistant or intolerant patients. ²⁴ Switching to olanzapine 5-25 mg per day resulted in a mean drop in total scores on the Positive and Negative Syndrome Scale (PANNS) and Brief Psychiatric Rating Scale (BPRS) of 17.7 (14.2%) and 9.8 points (20.2%) respectively.

Cautions

Monotherapy is the most desirable form of treatment for SCZ. There is no good objective evidence to support dual antipsychotic therapy except in combination with clozapine. The evidence base supporting such combinations consists mostly of small open-label studies and case series.²⁵ Combination therapy should be considered only when several attempts at monotherapy, including one atypical antipsychotic, fail. It is assumed that two different treatments together may have a different mechanism of action and therapeutic response from that of either drug alone. Studies have been conducted to determine whether treatment with antipsychotic combinations is effective for SCZ and whether such treatment is safe for the same illness. The results of trial studies are based on very low or low-quality results, and research that provides high-quality evidence is needed before firm conclusions may be drawn. The results so far show that there may be some clinical benefit in combination therapy in that more people receiving a combination of antipsychotics showed an improvement in symptoms. For other important outcomes – such as relapse, hospitalisation, adverse events and discontinuing treatment – no clear differences between the two treatment options were observed. Currently, most evidence regarding the use of antipsychotic combinations comes from short-term trials; the assessment of long-term efficacy and safety is limited. There is some very low-quality evidence that a combination of antipsychotics may improve the clinical response.

There are published case reports of serious side effects, such as a higher prevalence of extrapyramidal symptoms (EPS), metabolic side effects, paralytic ileus, grand mal seizures and prolonged QTc in association with a combination of antipsychotics.²⁶Combining three antipsychotics may be extremely dangerous; studies have revealed that such a procedure substantially increases mortality.²⁷A negative case control study exists.²⁸ It should be usual practice to document the rationale for combined antipsychotic use in individual cases in clinical records, along with a clear account of benefits and disadvantages, including side effects.

Newer combinations and augmentation strategies are supported only by case reports and open trial data. Along with advantages, a number of potential concerns regarding antipsychotic combinations have been identified (Table 2) and specific clinical cautions have to be implemented in combination therapy (Table 3). Yet, fixed combinations of drugs are common in medicine and at one time were common in psychiatry. An example is small doses of an antipsychotic in combination with an antidepressant for treating major depression; this lost popularity because of side effects. Also, SNRI-NaSSA combination therapy (e.g. California Rocket Fuel) is prevalently used for treatment-resistant depression.

Olanzapine–amisulpride combination

In spite of the objections put forward against combination therapy, there are isolated case studies favouring the olanzapine–amisulpride combination. Zink et al. (2004) performed a retrospective study, aiming at the systematic evaluation of patients on combined olanzapine and amisulpride. The open study designed as a retrospective chart review of Zink et al. concludes that the olanzapine–amisulpride combination for TRS is encouraging, but requires further evaluation in prospective and randomised studies.²⁹They point out that a reduction of the daily dose of both drugs helped to minimise the side effects of these drugs – such as weight gain and EPS – resulting in better compliance. They did not notice any additional side effects or undesirable drug interactions.

Within the heterogeneous group of atypical antipsychotics, the thienobenzodiazepine derivative olanzapine has a receptor profile that is quite similar to that of clozapine, indicated by having a greater affinity for serotonergic 5-HT_2A receptors than for dopaminergic D₂ receptors. The positive and negative symptoms of schizophrenic psychoses usually respond well to this drug. In contrast to clozapine, olanzapine does not induce major agranulocytosis but may, in a significant number of cases, lead to troublesome side effects including significant weight gain, type ii diabetes, sedation, anticholinergic effects and transient increases in liver enzymes. Assertive weight management from the start of treatment is recommended. Weight should be monitored and also waist circumference measurements made. In addition, blood lipids should be assessed routinely. A suggested schedule for these investigations would be at 3, 6, and 12-month intervals, and biannually thereafter.³⁰The pharmacology of antipsychotics is not the only factor that determines their effect on weight. Olanzapine has also been shown to elevate prolactin significantly in some patients.³¹ As indicated earlier, Olanzapine can succeed in some cases even where clozapine fails.²⁴

Amisulpride is an atypical antipsychotic of the benzamide class. It blocks D2 and D3 receptors (presynaptic in low doses, postsynaptic in higher). Unlike other atypical or typical antipsychotics, it has low affinity for serotonin, α-adrenergic, histaminergic, muscarinic and sigma receptors including D1, D4 and D5 receptors. It can lead to dose-related EPS that are significantly less than those of typical antipsychotics such as haloperidol and comparable to risperidone.³²It is recognised that amisulpride is only sparingly metabolised by liver enzymes, and thus it is not known to participate in many drug interactions.³³ Amisulpride may elevate prolactin, which may cause sexual dysfunction, osteoporosis, amenorrhoea, gynaecomastia or galactorrhoea. It is a weight-neutral compound and may ameliorate negative symptoms.³⁴ Both olanzapine and amisulpiride are not associated with QTc prolongation.

One advantage of the combination of these drugs is that when olanzapine and amisulpride are combined, they may be given at a lower dose, which will spare the patients from the main unwanted side effects of the individual drugs: the over-sedation and weight gain of olanzapine; and the hyperprolactinemia of amisulpride, resulting in sexual side effects of a particularly undesirable extent. Our limited studies have found that this combination was well tolerated by TRS patients and its efficaciousness was similar to that of clozapine, but without any major side effects. Patients have been fully compliant. The combination of these drugs is managed by slowly introducing them one at a time and has been transformative in many cases. More studies of the olanzapine–amisulpride combination are needed in order to report on such outcomes as relapse, remission, social functioning, service utilisation, cost-effectiveness, satisfaction with care, and quality of life.

Table 1. Assessing Treatment Resistance

Table 2. Advantages and disadvantages

Table 3 Physical cautions with combination

Summary

Combination therapies are the second choice when monotherapy fails. Clozapine is the first choice in severe cases of TRS, but there are super-refractory cases of TRS where clozapine fails. At least in isolated cases, the combination of olanzapine and amisulpride (Ami-olan combination) is worth considering for TRS patients who are reluctant to go on to clozapine therapy or in instances when clozapine failed, or patents dropped out. Combination therapies are normally avoided, but clinicians’ helplessness and patients’ despair justifies such measures in hard-to-treat cases of TRS. Only time will tell whether this combination will become an important part of clinical practice in future or will be ruled out as just another dual antipsychotic therapy.

The aetiology of SCZ remains obscure. The symptoms of different psychotic disorders are not clearly demarcated and there are no physiological parameters on which to make a firm diagnosis. In such a situation, the treatment of TRS has to be tailored on an individual basis. Even though it is normally well calculated, it may be somewhat hit and miss. Finding the right combination of antipsychotics or augmenting agents when the clinician is stranded and torn between monotherapy and polypharmacy is a gargantuan task. Clinical judgement along with patient preference must take over when treatment algorithms fall short. Given the data on polytherapy with antipsychotics that is available, it is hard to make any firm recommendation regarding its efficacy and safety of its use. Clinicians should be reminded that they should try monotherapy in adequate dosages before considering combinations.

For the management of TRS, comprehensive treatment strategies that integrate pharmacological, psychological, and psychosocial approaches are highly relevant and for that to happen, TRS should be clearly recognised. NICE offers very little guidance on clozapine resistant cases of SCZ. Combination of antipsychotics is not a panacea or a permanent solution for TRS. More investigation of schizophrenic illness is the only way forward. In comparison with other medical conditions (eg,HIV), research into it is making little progress. As it stands now, deconstructing clozapine’s unique pharmacology may offer ‘light at the end of the tunnel’ for patients who are clozapine intolerant or non-responders.

Background and rationale

Psychiatric trainees in Iraq face many challenges that limit their immediate access to improved training opportunities. These include limited access to classroom teaching, regular clinical supervision meetings and fewer opportunities to attend international conferences and placements. These challenges are more acute in those specialities with the greatest shortage of consultants (for example, forensic and child and adolescent psychiatry).

Furthermore, the fragile security situation in the capital and larger cities and the post-conflict disruption to educational institutions consequent to these difficulties makes it difficult for those in the UK and elsewhere to visit the country and support educators and training on the ground.

Against this background and as a medical educational team in the UK (Oxford University Medical Education Fellows, OUMEF) with an interest in developing training opportunities for peers and colleagues in Iraq, we set up the Oxford Psychiatry in Iraq (OxPIQ) Project, beginning with a project development team that included Medicine Africa, an experienced online distance learning platform.

So what is the role of TEL in the delivery of online distance learning targeted at medical professionals in these circumstances?

Meeting the Challenge – the role of TEL

The concept of Technology-enhanced Learning (TEL), or Web-based learning (WBL), defined as the use of information and communication technologies in teaching and learning ¹, is a relatively new phenomenon. Nevertheless, there is a considerable body of evidence supporting the use of TEL in various clinical and non-clinical settings.

Mccutcheon et al. ² systematically reviewed thirteen studies and found that ten of these studies concluded that online learning is as effective as traditional or classroom teaching, despite the limitations of some of these studies.

In a large meta-analysis, Means and colleagues ³ concluded that students using online teaching performed modestly better compared to students learning similar material using face-to-face teaching. Combining face-to-face and online teaching resulted in larger benefit compared to the use of face to face methods only.

TEL can address the learning limitations in classroom settings due to expanding curriculum coverage and limits on contact time between students and lecturers/trainers alike. It can contribute to better use of such face-to-face classroom contact through the facilitation of the flipped classroom approach. ⁴ In this approach (also called inverted instruction and upside-down teaching), students acquire the basic information of the lesson outside the class (usually using online materials) and then develop their knowledge further in the class by sharing their learning, interacting with other classmates and teacher, and discussing various aspects of the study topic.These advantages have enabled TEL to revolutionise distance learning at many levels – enabling greater access to education by overcoming geographical and time-zone boundaries.

An allied concept within distance TEL is the concept of virtual teams ⁵ where health professionals come together to teach and learn from each other independent of location. Of itself, this offers some advantages. These include the possibility of addressing speciality-specific training gaps through the incorporation of the relevant expertise within the team - and to the creation of what is termed “connectivism”. This term refers to the use of internet technologies to enhance learning through online peer networks ⁶ and the development of communities of practice. ⁷ The latter allows for workplace-based learning with trainees learning from more experienced practitioners and moving towards the same through greater competency acquisition.

In a similar vein, creating networks of professionals may help to establish more longer-lasting relationships of mutual benefit between the UK and Iraqi professionals (e.g. through collaboration on training programmes, conferences, etc.). Also, cross-cultural online learning has been shown to be very useful in improving language skills and cultural awareness of learners and educators. ⁸ With language translation technology, any language difficulties can also be overcome, especially if the educator can observe the learners’ responses to the translated text and offered the opportunity to give further explanations and clarifications when necessary. ⁹ Finally, as well as sharing knowledge and experience within groups, TEL enables opportunities for mentoring and coaching individuals. ¹⁰

For our purposes, these findings and opinions support the use of online learning as a suitable distance learning “add-on” to existing training opportunities in Iraq.

TEL and Learning Theories

Learning theorists suggest that experiential and constructive learning theories are most appropriate to learning in the clinical context. Both are possible with TEL (as well as being facilitative of behaviourist and cognitivist approaches).

For example, the virtual classroom environment can enhance the learning experience of the participants by improving their analytical skills by thinking through case formulation and management plans. ¹¹ Participants in online learning could be assessed and receive the feedback immediately. Ideas can be shared, and there is no passive acquisition or transfer of knowledge as is the case with traditional lectures. These aspects have implications for the design of the educational sessions and are discussed below in the learning methods section.

Challenges of Online Distance Learning

There are many challenges associated with online distance learning. Firstly, there is the potential lack of the required technologies (internet access, laptops or desktop computers), the expenses of subscribing to these online learning templates, the need to have technical support, and similar technical and logistic issues. ¹² These technical problems may impair access to and functioning of the virtual team. The choice of an experienced online platform must, therefore, be considered carefully.

Secondly, there may be ethical issues about the protection of patients’ confidentiality in these sessions, especially when there are different laws of privacy that are applied in the UK and Iraq. This will require knowledge of the relevant professional requirements by the tutor team for example.

Furthermore, the student-teacher relationship has traditionally been underpinned by direct face-to-face contact and being present at the same time and place. ¹¹ Therefore, learners and educators might be less satisfied with online learning. For these reasons, the concept of blended learning (careful integration of online learning with face to face learning experience) has been developed to overcome the limitations of a standalone online or face to face learning and has been found effective and applicable in various settings. ¹³

Thirdly, any distance online learning programme must understand and support existing “local” training provision and arrangements, in the classroom and the workplace. This requires liaison and cooperation with the training providers and institutions on the ground.

For clinical training to be relevant, it needs to reflect the learning needs of trainees in the workplace – in keeping with adult learning principles and cognitive apprenticeship models of learning. ¹⁴ The latter includes the importance of clinical decision-making underscored by the higher levels of Bloom’s (1956) cognitive domain. ¹⁵ To this end, then appropriate learning and assessment methods are needed to enable effecting learning.

In other words, while necessary, TEL may be insufficient in enhancing learning outcomes if allied learning methods are not chosen appropriately. Also, in our view, TEL is not a substitute for bedside teaching.

Table 1 summarises this appraisal of online distance learning (using the online platform provided by MedicineAfrica).

Table 1 Strengths and limitation of using MedicineAfrica (web-based virtual classroom environment)

OxPIQ & Project Development Team

OxPIQ is a partnership between Medicine Africa and psychiatrist members of the Oxford University Medical Education Fellows, with experience of working in Iraq. The Oxford University Medical Education Fellows (http://OUMEF.org) is a group of trainees from across medical and surgical specialities with interest in medical education and training.

Medicine Africa (http://medicineafrica.com) is an innovative clinically targeted online platform developed in collaboration with King’s College London’s Centre for Global Health, within the King’s Somaliland Partnership. Built at low bandwidth, it enables collaboration between medical professionals in the UK and those in remote or fragile states to enhance education in various clinical specialities using online sessions (live courses and mentoring sessions). Please see Appendix 3 for a screenshot of one of the active sessions of OxPIQ.

Following the development of a project team, additional team members were added from the Subcommittee on Iraq of the Royal College of Psychiatrists (http://www.rcpsych.ac.uk/workinpsychiatry/internationalaffairsunit/iraqs...), thus completing the UK dimension.

The next step was to invite representation and support from the Iraqi Board of Psychiatry and the Medical Education Unit in Baghdad. These developments led to the formal launch of OxPIQ Partnership in March 2016. Later on, the many UK and Iraqi doctors joined the Partnership as tutors and learners.

The Virtual Learning Team: Trainees, Specialty Consultants & Tutors

Iraqi psychiatry trainees were then recruited, and their more pressing learning needs to be appraised based on their views and those of the Iraqi Board of Psychiatry supervisors. Learning needs to emerge included the management of older patients with dementia and functional disorders, assessment and management of children and adolescents (with autism and ADHD for example), forensic patients and those with drug and alcohol addiction. The team thus formed was composed of up to ten psychiatry trainees from Iraq and five senior psychiatrists/tutors each, from Iraq and the UK respectively. A schedule of fortnightly seminars was agreed and published on the learning platform. Case-based discussions were used as the main educational activity during these seminars.

Learning Methods and Processes

As noted earlier, the importance of experiential and constructivist learning methods are key to clinical education. Our literature appraisal revealed that they are essential elements of successful TEL in this context too. ^{16, 17} To these must be added learner engagement. ¹⁸

Virtual or online (anonymised) case-based discussions (CBDs) are valid and reliable learning tools. ¹⁶ They are interactive and centred around the students and their learning needs while a facilitator guides the process of learning. Learners are engaged through discussion of actual clinical cases, so preparing learners for real-life experience. ¹⁹ Also, expert facilitation and peer feedback to trainees promotes clinical knowledge and skills’ development. ^{20, 21}

Effective small group teaching is characterised by four main strengths: flexibility, interaction, reflexivity and engagement. ²² Flexibility is when the teacher responds to the needs and learning of the students dynamically and helps them to explore wider pedagogic spaces. A higher degree of interactivity is usually seen in small group teaching compared to a larger group. Teachers are better able to continually engage in self-reflection and listen sensitively to students in a small group and observe the dynamics between the members of the group, leading therefore to better reflexivity. Engagement refers to encouraging the students to develop their academic identity and engage in lively debate about the various aspects of the topic discussed.

We aimed to replicate these characteristics. For example, a small group discussion allowed better interaction with each participant (interactivity); the presence of chat windows enables the facilitator to self-reflect on the process, monitor engagement and respond reflexively using questions and answers to stimulate interest and respond flexibly to individual trainee knowledge gaps. Tutors are encouraged to identify trainees’ learning needs and facilitate interactivity, and timely feedback as these are highly valued by the participants and help to keep them motivated and engaged. ¹⁸

For further reading in this area, we recommend Brindly and colleagues’ ²³ ten strategies to increase students’ motivation towards and engagement with online learning (see table 2).

The focus of the Lesson Plan Design

To these ends, the focus on the lesson design was on using problem-based learning methods (e.g. CBDs) within a small group setting (between 4-12 members) and a format that promoted learner engagement. A sample lesson plan is provided in Appendix 1.

In practical terms, tutorials were held fortnightly in term-time. All participants received an email notification to inform them of the session topic, and the tutor uploaded the slides from the session to the website beforehand. Participants logged-in to the site (http://medicineafrica.com) and interact with the tutor by voice (requiring only simple microphone equipment) and by writing in a chat window.

Evaluation and feedback gathering

The evaluation of the effectiveness of these sessions was reliant originally on trainees’ immediate reaction (table 3, level 1 evaluation, Kirkpatrick ²⁴) using formal feedback tools provided online by MedicineAfrica. This feedback was shared with tutors and the Project Team. Please see Appendix 2 for the template used in collecting feedback after each session.

Subsequently, members of the project team approached trainee representatives, tutors and Iraqi Psychiatry Board leads separately for further feedback and appraisal of learning needs. Furthermore, some months after a tutorial we have asked trainees for evidence of learning across the higher levels of Kirkpatrick’s evaluation model.

Regular feedback from the Iraqi and UK participants has been positive. The sessions have been associated with improved clinical knowledge and skills of the Iraqi Psychiatry Trainees. Requests for certificates of tutorial participation have been agreed upon and provided by the project team addition, so supporting learners’ (and tutors) portfolio development.

Table 3 Kirkpatrick’s (1996) Levels of Training Assessment

Further cooperation

A surprising (and very welcome) outcome of the project was, through the facilitation and support of the Iraqi Board of Psychiatry, the introduction of educational workshops in Baghdad. These workshops were held in Medical City, Baghdad, in May 2017 and April 2018 and were facilitated by tutors (YH & H Al-T) from the OxPIQ Partnership. They covered targeted topics such as old age psychiatry, addiction, organic and forensic psychiatry. Trainees and senior psychiatrists from Iraq attended; their feedback showed how they valued the interactive nature of the teaching and use of CBDs as learning methods, resulting in high levels of engagement.

Conclusions

This paper describes the process of designing, delivering, and the early evaluation of an online distance TEL programme for mental health professionals based in the UK and Iraq.

TEL has had an important role in overcoming the geographical barriers and other challenges to developing training opportunities in Iraq and other developing countries. We are of the view that it could be used more often to connect professionals working in similar circumstances and with other disadvantaged groups, including refugee and asylum seekers. It is a flexible way of providing training to professionals working with those groups in relatively remote and resource-deprived environments.

Greenhalgh ²⁵ suggests that three factors are needed for the success of online educational activity: ease of access, perceived usefulness of the activity to the learning requirements of the students, and the interactivity of the session. In our experience, these are important. Also, we believe that additional consideration should be given to (i) working with an experienced online platform provider; (ii) working with local educational institutions, trainers and learners to identify unmet learning needs and support existing learning opportunities/programmes; and (iii) adopting an iterative approach to feedback and evaluation.

Appendix 1: Example of a Lesson Plan

Appendix 2: Feedback form to be completed by the participants after the session

Appendix 3: MedicineAfrica screenshot during an active session

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

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

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

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

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

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

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

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

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

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

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

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

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

Background

SSRIs (Selective Serotonin Uptake Inhibitors) are very commonly used in Depression and Anxiety. Though considered as safest antidepressants, they have some common side effects which include gastrointestinal side effects, headache and at times sexual dysfunction. Yawning is one of the rare side effects of SSRIs. SSRIs were found to be the commonest cause of not so common drug induced yawning in a meta-analysis^1. Isolated cases of intractable yawning have been reported with citalopram² fluoxetine, citalopram and sertraline³ in the literature .Excessive yawning can cause injury to Temporo-Mandibular Joint (TMJ) ⁴. Paroxetine has also been shown to cause intractable yawning⁵. Yawning possibly helps in thermoregulation and is an unconscious effort by the body to cool the brain ^{6, 7}. It is known that yawning can be contagious. Reading, talking, seeing someone yawn or even thinking about yawning can induce yawning in the subjects⁸. Susceptibility to contagious yawning is different for different individuals depending upon their ability to process information about self⁹.

Case

A 60 year old postman presented with his first episode of depression. He attended the GP who started him on sertraline (an SSRI). He developed serious headaches and did not notice any therapeutic benefit. He was then referred to the psychiatric services for further management. He was assessed, Sertraline was stopped and Cipramil 20mg was introduced. He was reviewed after 2 months and the dose was increased to 40 mg to which he responded partially but relapsed within 4 months. There were no changes in his psycho- social circumstances. Cipramil was stopped and he was started on fluoxetine 20 mg. Once again the response was partial and was overshadowed by midnight insomnia and increased sleepiness in the daytime. Fluoxetine was increased to 40 mg and he was reviewed after 4 months when he reported clear and significant improvement in his depression but complained of “excessive yawning spells” causing him problems at his work place. The psychiatrist was surprised at the number of times he yawned at the Out Patient Clinic review. On further discussion it became clear that this side effect had become highly troublesome. He complained that his jaw was in severe pain. He was unable to do his delivery rounds and was having clear episodes of attention lapses leading to letters being put to wrong addresses. He was transferred to “sorting” the post at sorting counters and was taken off delivery rounds. Even here the intractable yawning continued and he was committing sorting errors. By now it was affecting his colleagues too and they also started yawning (it is known to be contagious).It was affecting his self-confidence and was extremely embarrassing in all social situations to an extent that he started avoiding social interactions. He was drowsy all the time. He was clearly suffering more due to excessive yawning than due to depression. He was unable to perform his employment duties and was signed off sick. At that point the dose of fluoxetine was reduced to 20 mg .After a couple of weeks his yawning reduced significantly but was still disruptive to his routines. He was advised to slowly taper off fluoxetine over next 4 weeks. Unfortunately his depression relapsed and his GP restarted him on Fluoxetine 20 mg. He was reviewed by the psychiatrist after a couple of weeks. Once again he reported return of intractable yawning.

Fluoxetine was stopped once again and he was started on Mirtazapine 15 mg. There was very little response. The dose was increased to 30 mg after around two weeks. This led to him to experience nausea and vomiting. Unfortunately Mirtazapine too had to be stopped.  He was then tried on amitriptyline 50 mg which improved his sleep and symptoms of Depression. He was reviewed in the outpatient clinic after a couple of months .He did not develop any side effects and responded quite well. He then started his job starting from part time to full time within 6 weeks. After 6 months on the same dose of amitriptyline, did not have any symptoms of depression and was finally discharged from the mental health services.

Discussion

SSRI is the first line antidepressants used in the treatment of depression and Anxiety disorders. They are known to have least side effects and safest when it comes to overdosing. Intractable Yawning is quite an unusual and uncommon side effect.  One has to be conscious of the fact that it may cause yawning that can be pathological and can cause severe disruption of patient’s life. It can contribute to poor compliance. It is quite easy to overlook and ignore this side effect as yawning usually seems to represent sleep problems which is also a significant feature of the associated depression itself.

Excessive yawning can cause Jaw/facial pain. It can even cause dislocation of temporo-mandibular-joint. It can cause severe problems with one’s work and self-esteem. The sufferer might be misunderstood for being inattentive, indolent and sluggish. It might affect relationships with spouse/friend/relatives and especially at place of work. It can be misunderstood by doctors and lead to unnecessary tests and investigations. One has to be aware when prescribing SSRIs in patients who are driving or are involved in handling heavy machinery, athletes, airline pilots, surgeons, life guards, air traffic controllers and many other professionals. Due to its contagious nature, it’s not only the patient who is affected but also others around him. Excessive yawning can adversely affect the level of arousal, the level of concentration and work efficiency leading to poor performances in tasks requiring undiverted attention.

Hence excessive or intractable yawning has to be kept in mind while prescribing the so called most safe anti-depressant class of medication, the SSRIs, in this case fluoxetine.

Introduction

Dermatomyositis (DM) is a rare autoimmune process with not yet fully understood aetiology. It is characterised by a combination of striated muscle inflammation and cutaneous changes. The pathogenesis of the cutaneous manifestations of DM is not well understood either. DM occurs in all age groups. Therefore, two clinical subgroups of DM are described: adult and juvenile. The adult form is predominant among female patients with a clinical presentation which includes a Heliotrope rash (Fig. 1), Gottron’s papules (Fig. 2), nail fold telangiectasia and other various cutaneous manifestations in association with inflammatory myopathy.¹ In addition to the previous mentioned symptoms, juvenile patients also commonly suffer from ulcerative skin and recurrent abdominal pain due to vasculitis. An increased occurrence of oncological processes in combination with adult DM has been observed with a slight predominance for the female gender.² These patients carry a higher risk for comorbid cancers. The most common ones include malignant processes of the ovary, lung, pancreas, stomach, urinary bladder and haematopoietic system.³ The significance of these observations is that the development of DM should raise suspicion with regard to a possible parallel oncological process.

Figure 1

Figure 2

Materials and Methods

A retrospective consecutive case series was performed on a group of 12 patients that were hospitalised at the Department of Dermatology, Venereology and Allergology at the Medical University of Gdansk between 1996 and 2013. The diagnostic criteria for DM included: hallmark cutaneous lesions of DM, clinically significant muscle weakness evaluated by electromyography (EMG), indicative laboratory findings - muscle enzymes, muscle biopsy, autoantibodies. All 12 cases had muscle biopsy, serum studies and EMG performed. The retrospective study analysed the age and sex of the patients, course of the disease, accompanying diseases, clinical picture and treatment. The patients with malignancies were analysed by the primary organs of origin, and the period between the diagnosis of DM and that of malignancy (Table 1).

Table 1. Patient characteristics

No. = number (patient), DM = dermatomyositis, F = female, M = male, CK = creatine phosphokinase, ANA = antinuclear antibodies, LDH = lactate dehydrogenase, AST = aspartate transaminase, ALT = alanine transaminase, N = negative, P = positive, USG = ultrasonography, EMG = electromyography, CT = computerised tomography

Limitations

The small sample size is a significant limitation in this retrospective analysis. DM is a rare disease with a prevalence of 1:1000. Increasing sample size, by combining cases from multiple institutions, and implementing control would further strengthen the presented material.

Results

The average age of onset of the disease was 48 years. All 12 subjects were female. Previous medical history included chronic eosinophilic leukaemia, diabetes mellitus type II, hypertension, leiomyomas, hypo- and hyper- thyroid disease, chronic obstructive pulmonary disease, peptic ulcer disease, autoimmune hepatitis and osteopenia. The two most common are diabetes mellitus type II and hypertension. The clinical picture of each case was similar in that all of the patients presented with some form of muscle weakness. In addition, typical features of DM with Gottron’s papules, periorbital oedema, facial oedema and erythema were noted in five patients. Antinuclear Antibodies (ANA) Hep-2 of values >1:160 were identified in nine patients. Additional laboratory markers such as creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST) and alanine transaminase (ALT) were elevated in five patients. Two patients had muscle biopsies performed. The immunohistopathology picture consisted of Immunglobulin G (IgG), fibrinogen, C1q, and C3 deposition around the perimysium and granular deposits of Immunoglobulin M (IgM) in the dermal epidermal junction. Of the 12 patients, four had neoplasms in addition to the diagnosed DM. The primary cancers were originating from the cervix, breast, stomach and ovary. Of these four patients, all had the diagnosis of DM prior to the diagnosis of a malignancy.

Discussion

The diagnosis of DM is made by combining the clinical picture with the results of various laboratory findings: skin and muscle biopsies, EMG, serum enzymes and ANAs.

The clinical picture varies. The typical dermatological presentation consists of a erythematous and oedematous periorbital rash - the Heliotrope rash (Fig. 1). Symmetrical redness and flaking can be observed on the elbows and dorsal sides of the phalanges, especially over the distal metacarpal joints - Gottron’s papules (Fig. 2). Erythematous lesions can also be found on other locations such as the face, upper chest and knees.⁴ The dermatitis heals with atrophy, leaving behind areas that resemble radiation-damaged skin. The striated muscle inflammation most often involves the shoulder and hip area, leading to muscle weakness and atrophy. The intercostal muscles and the diaphragm may be involved causing alarm with regards to respiratory compromise. Dysphagia can be present due to inflammation of the smooth and skeletal muscles of the oesophagus. These inflammatory processes often lead to muscle calcification.⁵ The sum of all these changes clinically is seen most often as weakness, weight loss and subfebrile temperatures. All patients in our study had co-existing muscle and cutaneous symptoms, with variation in severity and localisation. Five patients had the classical picture of shoulder and hip area weakness. The rest of the patients had a more general muscle weakness. Two patients had atypical complaints of hand paraesthesia and extremity pain respectively.

Subtypes of DM exist for the purpose of epidemiological research and sometimes prognosis. They are categorised by the clinical presentation and presence or absence of specific laboratory findings. These subtypes are as follows: Classic DM, Amyopathic DM, Hypo-amyopathic DM and Clinically Amyopathic DM. These subtypes have little impact on routine diagnosis. Common laboratory findings in DM are enzymatic elevation of CK, AST, ALT and LDH; these mainly reflect the muscle involvement. Amyopathic DM lacks both abnormal muscle enzymes and weakness.⁶ Enzymatic elevation may sometimes precede the clinical symptoms of muscle involvement. Hence, an enzymatic raise in a patient with a history of DM, should raise suspicion of recurrence. Positive ANA findings are frequent in DM but not necessary for diagnosis. More myositis-specific antibodies include anti-Mi 2 and anti-Jo 1. A typical histopathological examination shows: myofiber necrosis, perifascicular atrophy, patchy endomysial infiltrate of lymphocytes and occasionally the capillaries may contain membrane attack complexes.⁷

Cutaneous changes and muscular complaints can correspond to: 1. Systemic scleroderma which often has a positive ANA; 2. Trichinosis, in which periorbital swelling and myositis occurs, but there is a prominent eosinophilia and a history of consuming undercooked swine or bear meat; 3. Psoriasis with joint involvement which may give a clinically similar picture to DM. However, the skin changes in psoriasis have a more flaking pattern. In doubtful cases, a skin and muscle biopsy together with an electromyography will set the diagnoses apart. A facial rash may also be observed in systemic lupus erythematosus together with nail fold telangiectasia. They are usually distinguished by a clinical picture with more organ system involvement in systemic lupus and by serological studies. A drug-induced picture of DM exists and is particularly associated with statins and hydroxyurea.⁸

It is estimated that around 25% of DM cases are associated with a neoplastic process that can occur prior, during or after the episode of DM. The risk of developing a malignancy is highest in the first year of DM and remains elevated for years after diagnosis. ^{9, 10, 11} This was the case with patient number 1, 2 and 4 in our study, where the malignant process appeared in the first year following onset of DM. Risk factors seen in DM patients include male gender, advanced age and symptoms of dysphagia.¹² The age range of the four patients in our study with malignancy was between 43 and 66. Symptoms that clinically raised suspicion of a malignant process included weight loss, lack of appetite and dysphagia. All neoplasms were discovered within one year after the diagnosis of DM was made. One patient had a previous history of cervical cancer, six years prior to the onset of DM.

The most common neoplasms seen in patients with DM vary in the world. In Europe the malignancies are located mainly in the ovaries, lungs, and stomach. The cancer types associated with the DM correlate with common cancers seen in the same area. For instance, in Asia, nasopharyngeal carcinoma (which is a rare malignancy in Europe) is a frequent occurrence in DM.^{1, 3} The location of neoplasms seen in our study varied from gastric, breast, ovary and pulmonary. The screening in regards to malignancies in patients with DM is individualised and should be based on risk factors such as previous malignancies, alarming symptoms such as weight loss or dysphagia, or abnormal findings on physical exam. This was the case with patient number 10 in our study who had a previous history of cancer, and patient number 2 who had symptoms of weight loss and decreased appetite. Initial screening was negative for patient number 1 and 2, where the malignancy developed first after the onset of DM. Age-appropriate screening with mammography, faecal-occult blood test and Papanicolaou smear should be considered. Additional investigations with chest films, computerised tomography (CT) scanning of chest, abdomen or pelvis; colonoscopy, cancer antigens; and gynaecological ultrasonography should be done when indicated.

The main objective of treatment in DM is to improve muscle strength and obtain remission, or at least clinical stabilisation. No specific protocol exists with regard to treatment of DM. Treatment is individualised and adapted to the specific condition of the patient. High-dose corticosteroids are the basis of treatment. However, randomised placebo clinical trials failed to show their efficacy. Clinical efficacy of corticosteroid therapy demonstrates itself and hence is the initial treatment of choice. Doses start at around 1 mg/kg/day depending on the corticosteroid of preference. This dosing is maintained for approximately two months until clinical regression is achieved, followed by approximately 10 mg decrease in dose for the coming three months. A maintenance dose of approximately 5-10 mg should be achieved. The exact parameters are patient-specific. In the case of a severe flare of dermatomyositis, 1 g per day for three days of methylprednisolone intravenous pulses can be administered. The systemic effects of long term therapy with corticosteroids have to be kept in mind. Hence, yearly dual-energy X-ray absorptiometry bone scans can be administered to monitor the development of osteopenia.

Further treatment options are offered in situations where the initial disease presentation is severe, involves internal organs, if relapse occurs during steroid dose reduction, and steroid side-effects. It has been proposed that combination therapy is a better method of approach due to lower reported relapse rates and lower need to use high-dose corticosteroids. Methotrexate is second-line therapy when steroids fail alone. Methotrexate is used with a maximum dose of 25 mg per week plus folate supplementation. The limitations of Methotrexate are immunosuppression and pulmonary fibrosis. Methotrexate is considered preferable to Azathioprine because the latter has a longer onset of efficacy. Azathioprine is administered at doses ranging from 1.5 - 3 mg/kg/day and has a side-effect profile is similar to that of other immunosuppressants. Cyclosporin A is a T-cell cytokine moderator that has a similar efficacy profile to Methotrexate. Side-effects include renal impairment, gingival hyperplasia, and hypertrichosis. Dosing of Cyclosporin A ranges from 2 - 3 mg/kg/day.

An expensive but effective and rather low side-effect alternative is intravenous immunoglobulins. The dosage of this medication has not been officially established in the treatment of DM, but options are: 2 g/kg given either in 1 g/kg/day for two days every four weeks; or 0.4 mg/kg/day for five days initially, and then for three days monthly for three to six months. Other alternatives include Mycophenolate Mofetil, Cyclophosphamide, Chlorambucil, Fludarabine, Eculizumab, Rituximab.⁹ Further options might be treatment targeted toward malignancy when associated with DM. This was observed in our patient number 10, where full remission of DM was obtained first after lobectomy and chemotherapy for the mammary carcinoma.

Conclusion

DM mainly affects women and all 12 cases presented in our study were female. One third of our cases had malignancies associated with their course of DM. We conclude that it is reasonable to screen these patients, especially in those with already established cancer risk factor. Age-appropriate screening and beyond is indicated by high risk factors or clinical presentation. High suspicion should be raised in patients with a previous history of oncological treatment since DM can be the first clinical sign of cancer recurrence.

Introduction

What is medical pain? One answer would be a poorly defined concept which suffers the ignominy of poor management.

A quick internet search for the term brings up several hits to clinics offering the services of medical practitioners with pain specialty training. Definitions of ‘medical pain’ however, as opposed to those of its more easily construed post-surgical cousin, are both sparse and elusive in the learned literature. One potential candidate is provided by the International Association for the Study of Pain (IASP), whose professional presence on the web offers both a respectable description of pain syndromes of medical aetiologies as well as a taxonomical guide thereto¹.

With a struggle to even define the concept, is it any wonder that medical patients with pain complaints continue to score reprehensible figures on studies into pain incidence and effective relief? This is far from a new phenomenon, with the British Journal of Anaesthesia (BJA) reporting a staggering 52% of medical inpatients in one study (N=1594) of a UK district general hospital to be in pain on the medical ward, with 20% and 12% of those in pain rating this complaint as severe and unbearable respectively². What is particularly distressing about these statistics is the fact that data collection in the same study occurred over five days; more than ample time for complaints to be reported or recognised and appropriate relief strategies implemented. Barriers clearly exist to the provision of adequate medical pain relief, with practice shown to fall below standards recommended by the Royal College of Anaesthetists.³ A sketchy definition is perhaps one such barrier, but what other challenges exist to management of medical pain?

Predictability & On-Call Skills

In contrast to the anticipated pain following an elective surgical procedure, medical pain is less predictable in onset and consequently more the realm of an on-call physician than a specialist pain management team.  One unambiguous fact when equating specialist pain rounds and the on-call services of a more junior recruit is that the former clearly benefit from greater levels of experience, even allowing for acquisition of specialist training. The latter inevitably rely more heavily on the knowledge base afforded them by theoretical education, which sadly tends to be rather scant in undergraduate medical programmes.

The lack of early teaching of junior staff on the subject represents one barrier to pain management in general, with formal teaching on the subject of medical pain management a particular shortcoming in several international medical curricula. This fact is supported by the findings of a cross-sectional study in one Sydney hospital utilising a multinational population of medical interns and residents⁴, indicating some 56.2% of responders felt education on pain management to be inadequate. Up to 68.8% of responders were willing to receive additional lectures on opiate use to increase their knowledge base in this regard, suggesting a definite dearth of dedicated teaching.

In recognition of similar sentiments, a dedicated junior doctor-targeted postgraduate pain curriculum was suggested in 2011 by the Faculty of Pain Medicine (FPM) of the Australia & New Zealand College of Anaesthetists (ANZCA)⁵. This not only recognises the need for effective pain management skills at an early career stage, but also proposes a core set of competencies and assessments thereof for application to early postgraduate physicians’ skill sets.

A Surgical Predilection?

Skills of junior on-call medics aside, the provision of committed specialist pain services undoubtedly represents one of the major advancements in acute pain patient care. And yet, the needs of medical patients have often been overlooked in favour of acute surgical pain relief, and presumably continue to be so in the face of a lack of convincing evidence to the contrary. One study published in 2008 reporting data from over 220 United Kingdom National Health Service (NHS) hospitals revealed a paltry 16% incidence of routine acute pain service in medical wards⁶. The same study revealed that 82.2% of clinical leads in acute pain services actually recognise this problem of inadequate pain control on medical wards. With this stark admission from front line algologists in mind, why do elderly and general medical patients consistently appear to produce disconcertingly poor results in pain studies?

Perhaps the lack of adequate medical pain services in the light of a frank admission to a predilection for surgical patients reflects inadequate training, staffing or application of resources as a barrier to effective management of medical pain.

Community Confounders

Limitations of secondary care pain services aside, the primary care setting also exhibits a confounding factor for professional provision of medical pain management – the propensity for patients to easily self-medicate their complaints with non-prescription remedies. The immemorial complaint of headache in the community provides a convenient example of the potential for patients to self-manage their pain symptom. In doing so however, they simultaneously skirt the legion of adverse drug reactions, drug interactions and other implications including paradoxical rebound pain which may complicate management later on in the professional setting. Data published following a recent review of literature sources⁷ indicate codeine-based compound analgesics to be the most popular over-the-counter medications dispensed across several international populations. This telling fact may be suggestive of a trend in non-professional pain management which impedes effective management according to professional standards. Assuming a relative deficit of surgical to medical pain patients in the community, this may represent a unique challenge to providers of medical pain services.

Chronicity

One further important consideration to be made in medical pain is its potential for chronicity, with prevalence of leading pain disorders including lower back pain and chronic migraine indicated at 10.2%⁸ and 1-3%⁹ respectively in recent studies. The former in particular has exhibited an explosive trend in prevalence over recent years, with a more than 2.5-fold increase since 1992 in relative prevalence observed in one 2006 American study of households state-wide (N=5357)⁸.

Implicit in the chronicity of pain complaints exist a number of secondary disorders which can prove troublesome for effective engagement of pain management services. The European Journal of Pain quotes a large transnational study of chronic pain patients (N=46,394)¹⁰ as finding 21% of patients to have been diagnosed with depression because of their pain. Interestingly while almost half of subjects were self-administering over-the-counter analgesics and only 2% were being seen by a pain specialist, an astonishing 40% reported inadequate pain relief –an almost anticipated outcome of the ‘do it yourself’ approach to pain management in chronic, refractory cases? This may be less relevant in surgical pain experiences which intuitively represent a more acute event in a more controlled environment, and therefore may be more amenable to effective management than a drawn out pain experience over several years!

Fear of Pain

Chronicity of pain in turn evokes a largely self-explanatory phenomenon known as fear of pain, which can present a potentially sizeable obstacle to management of patients. High levels of fear of pain and also movement as a provocative agent thereof have been described in 38.6% of fibromyalgia syndrome patients (N=233)¹¹, with this heightened fear of a painful experience linked to increased disability, depressed mood and most importantly pain severity. This latter component alludes to one of the more insurmountable barriers to management of chronic medical pain – the impasse resulting from a vicious circle of pain, fear and infinite vice versas.

The fear of pain may in turn be compounded by a fear of narcotic analgesic therapy on both the part of the patient and the prescribing physician, with this being an issue in non-cancer pain as well as malignant disease. The fear of commencing and continuing long term opiates is traditionally said to be particularly prevalent in the primary care setting¹². Fear can arise in view of a number of reasons, including the potential for addiction and major side effects as well as the notion that opiate drugs represent a terminal stage in a disease process. Mention of opiates has been linked to accusations of ‘hidden diagnoses’ on the part of the physician, where patients suspect malignant pathology has been concealed from them by their care provider out of a deep-rooted belief that opiate analgesia is merited solely by cancerous conditions¹³. Whether this signifies an already fragile patient-doctor relationship or a contribution to the deterioration thereof, the connotation for effective management of medical pain remains a significant one. Repeated careful review of patients on long term opiate therapy for chronic non-cancer pain must be emphasised however, with up to 19% of chronic pain patients found to have some form of addictive disorder in a 2001 paper on the subject¹⁴ courtesy of the BJA.

Conclusion

In summary, patients requiring relief of medical pain issues are clearly disadvantaged by the presence of numerous hurdles to effective management of their complaints. The literature base in this regard is conspicuous by its absence, with practices in medical pain management being poorly evidence-based as a result. This represents a major potential target for investigative studies and research into potential trends and best practices. Exploration of effective methods for implementation of improved education for newer staff and also resource allocation for more experienced practitioners would also be of benefit to the standard of care in medical pain.

Introduction

Dilated cardiomyopathy (DCM) is a cardiac muscle disease, characterized by dilatation and impaired contraction of the left ventricle or both ventricles, and leads to progressive heart failure and sudden or heart failure-related death [1]. The life expectancy is limited and varies according to the underlying etiology with a median survival time of about 5 years after diagnosis [2]. Although the pathogenesis of this disease has been extensively studied for decades, it remains ambiguous. Currently, myocarditis, immunological abnormalities, toxic myocardial damage, and persistent cardio-tropic viral infection are all assumed to be causes of DCM [3]. Dilated cardiomyopathy occurring in families, or the familial dilated cardiomyopathy (FDC) may occur in 25% to 35% of DCM cases, implicating a genetic contribution to the etiology [4-7].  More than 30 susceptibility genes have been shown to be associated with an increased risk of developing a DCM. Here we report three strange cases of FDC accompanied by hearing loss and rapid progressive course in brothers from Sichuan Province of China. The presentation of the family was really rare and it is anticipated that more susceptibility genes may be discovered.

Case report

The patient was a boy from Sichuan Province, and had lost his hearing when he was five years old. At the age of eight, the boy presented with cough and acute onset breathlessness. On examination, he had blood pressure (BP) of 90/60mmHg, heart rate (HR) 105/min, raised jugular venous pressure (JVP), crackles over the lung bases and a pansystolic murmur at the apex. A huge cardiomegaly was seen on chest X-ray (CXR), and the cardiothoracic ratio (CT ratio) was 0.721. ECG revealed primary atrioventricular block and left ventricular hypertrophy (LVH). Echocardiography (Echo) showed enlargement of both ventricles of the heart, a decreased left ventricular ejection fraction (LVEF), and severe mitral regurgitation (MR). The patient was treated in line with congestive cardiac failure (CCF). However, he died three months after the acute onset of breathlessness.

Surprisingly, the progression was nearly the same as two of his older brothers. Both of them also lost hearings at the age of five. Then presented with acute onset breathlessness and they were diagnosed with DCM aged seven to eight years. They also died three months later after the acute onset of breathlessness. Because of the terrible experience of his older brothers, the boys’ parents took him to hospital every year to be examined. ECG and Echo images were normal 6 months before the onset of breathlessness. Moreover, the boy had no symptoms 1 month before his presentation.

Discussion

The definition of FDC is clinically based on manifestation with at least two affected members from the same family [5]. The most common mode of inheritance is the autosomal dominant type, while X-linked, autosomal recessive and mitochondrial forms are less common [8, 9]. Although most people affected die in early adulthood, the age of onset, rate of progression, disease complications, as well as overall prognosis and outcome vary within families [5, 10]. Nevertheless, the age of onsets in this family were similar and with a rapid progressive course. All of the sons in the family suffered from DCM as well as hearing loss. The manifestation of the brothers haven’t been reported before. We traced back three generations of this family finding no other affected members.  As all the patients were male, we speculated that the possible mode of inheritance in this family is X-linked. Regrettably, the parents had no daughters and we were not able to investigate the possible association between gender and FDC of this kind. Because of the rapid progressive course, we hypothesize that autoimmune abnormalities might be the pathogenic factors for this disease, but we do not have any solid evidence yet. Fortunately, we were able to get the blood samples from the patient and the relatives. Further studies are needed to explore new susceptibility genes as well as the molecular mechanisms that are involved in the disease.

Introduction

Community acquired urinary tract infection (UTI) due to Escherichia coli is one of the most common form of bacterial infections, affecting people of all ages. Originally ESBL (extended spectrum β-lactamases) producing E. coli was isolated from hospital setting but lately this organism has begun to disseminate in the community.¹

In India community presence of ESBL producing organisms has been well documented. However, various epidemiological factors associated with ESBL producing strains need to be documented. This will allow clinicians to separate patients with community UTI with these factors so that appropriate and timely treatment can be given.² A community UTI when complicated may be a potentially life-threatening condition. In addition, for deciding the empirical treatment for patients with a UTI a thorough knowledge of local epidemiology is required. Therefore, the primary objective of this study was to determine the epidemiological factors associated with ESBL positive community acquired uropathogenic E. coli isolates and to determine their susceptibility to newer oral drugs. Mecillinam is a novel β-lactam antibiotic that is active against many members of family Enterobacteriaceae. It binds to penicillin binding protein (PBP 2), an enzyme critical for the establishment and maintenance of bacillary cell shape. It is given as a prodrug that is hydrolyzed into active agent. It is well tolerated orally in the treatment of acute cystitis.³

Material and Methods

This prospective study was conducted, from Jan 2012- July 2012, in our tertiary care hospital, which caters to medical needs of the community in North India.

Study Group:

The study group included patients diagnosed as having a UTI in outpatient clinic, or the emergency room or patients diagnosed within 48 hrs after of hospitalization. These patients and were labeled as patients having a community UTI. A diagnosis of symptomatic UTI was made when patient had at least one of the following signs or symptoms with no other recognized cause: fever ≥ 38.8˚C, urgency, frequency, dysuria or suprapubic tenderness and a positive urine culture (i.e. ≥10⁵ microorganisms/ml of urine).⁴ Various epidemiological factors for each patient were recorded on individual forms. This included age, presence of diabetes mellitus, renal calculi, pregnancy, history of urinary instrumentation, recurrent UTI (more than 3 UTI episodes in the preceding year) and antibiotics intake (use of β-lactam in the preceding 3 months).²

Patients with a history of previous or recent hospitalization were excluded from study.

Antibiotic susceptibility testing was carried out following Clinical Laboratory Standards Institute (CLSI) guidelines using the Kirby-Bauer disc diffusion method.⁵ The antibiotics, which were tested included Amoxyclav (30/10µg), Norfloxacin (10µg), Ciprofloxacin (5µg), Tetracycline (30µg), Nitrofurantoin (300µg), Trimethoprim-sulfamethoxazole (23.75/1.25µg), Cephalexin (30µg), Cefaclor (30µg), Cefuroxime (30µg), Mecillinam (10µg) (Hi-Media, Mumbai, India).

Detection of ESBL

ESBL detection was done for all isolates according to latest CLSI criteria.⁵

Screening test - According to latest CLSI guidelines, zone diameter of E. coli strain for Ceftazidime <22mm and for Cefotaxime < 21mm is presumptively taken to indicate ESBL production.

Confirmatory test - As per CLSI guidelines, ESBLs were confirmed by placing a disc of Cefotaxime and Ceftazidime at a distance of 20mm from a disc of Cefotaxime /Clavulanic acid (30/10µg) and Ceftazidime/Clavulanic acid (30/10µg) respectively on a lawn culture of test strain (0.5 McFarland inoculum size) on Mueller-Hinton agar. After overnight incubation at 37° C, ESBL production was confirmed if there was a ≥5mm increase in zone diameter for either antimicrobial agent tested in combination with Clavulanic acid versus its zone when tested alone

Control strain - Standard strain of Klebsiella pneumonia ATCC 700603 was used as ESBL positive controland Escherichia coli ATCC 25922 was used as ESBL negative control.

Results

Out of total of 140 strains of E. coli, which were screened for ESBL production, 30 (21.4 %) isolates were found to be positive. High-level resistance was seen for many antimicrobial agents like Cephalexin (92.8%), Cefaclor (90%), Amoxy-clavulanate (88.57%), Cefuroxime (75.7%), Sulfamethoxazole-trimethoprim (72.8%), Norfloxacin (75.71%) and Ciprofloxacin (70%). Sensitivity to Nitrofurantoin was found to be 90%. Only 4.5% of uropathogenic E. coli were resistant to Mecillinam.

Various epidemiological factors seen in ESBL producers include female patients (n =24, 80%), history of antimicrobial intake (n = 17,57 %), elderly age >60 years (n =16 53%), renal calculi (n =15, 50%), history of recurrent UTI (n =11, 37 %), pregnancy (n = 11,37%), diabetes mellitus (n = 7, 23%) and history of urogenital instrumentation (n = 7, 23%).

Discussion

The epidemiology of ESBL positive uropathogenic E. coli is becoming more multifaceted, with increasingly indistinct boundaries between the community and hospital.⁶ In addition, infection with an ESBL producing organisms causing community UTI is associated with treatment failure, delayed clinical response, higher morbidity and mortality. These organisms are multi-resistant to other antimicrobials like Aminoglycosides, Quinolones and Co-trimoxazole. Therefore, empirical therapy with Cephalosporins and Fluoroquinolones often fail in patients with community UTI.⁷

The rate of ESBL producers in our study is lower than that described by other authors. In a similar study Mahesh E et al. reported higher rate (56.2%) of ESBL positivity from E. coli, which were causing UTIs from a community setting.⁸ Additionally Taneja N et al. described a higher rate (36.5%) of ESBL positivity in uropathogens. ^9,10

A high rate of resistance was seen to almost all antimicrobial agents. This is in agreement with other authors like Mahesh et al. and Mandal J et al.^8,11 Mecillinam showed very good results with only 4.5% resistance. Wootton M et al. reported similar high activity of Mecillinam against E. coli(93.5%).³ Auer S et al. reported that Mecillinam can be a good oral treatment options in patients with infections due to ESBL organisms.⁷

A limitation of our study was that being a developing country with limited resources, molecular typing and determination of antimicrobial resistance profiles of the isolates was not done. In our study female patients, elderly, patients with a history of antimicrobial intake, renal calculi and history of recurrent UTI were important factors for infection due to ESBL producers. These findings are similar to risk factors studied by other authors.² In conclusion; this study confirms that ESBL-producing E. coli strains are a notable cause of community onset infections especially in predisposed patients. The widespread and rapid dissemination of ESBL-producing E. coli seems to be an emerging issue worldwide. Further clinical studies are needed to guide clinicians in the management of community onset infections caused by E. coli.

Case Presentation:

We report the case of 36 year old white Caucasian female who used to work as a driving instructor and living with her parents.

She has a diagnosis of congenital adrenal hyperplasia (21 hydroxylase deficiency) and is on long term corticosteroid replacement (prednisolone 4 mg once daily and fludrocortisone

100 mcg once daily) and she is under the care of an endocrinologist.

She was referred for psychiatric evaluation with “anxiety and depressive symptoms” and failure to respond to antidepressant treatment which was prescribed by her General Practitioner.

During the psychiatric assessment, she reported long history of recurrent episodes of elevated mood and depression dating back to her late teens with clear description of distinct periods of mood elevations lasting for few weeks and longer periods of persistent low mood. There was no history of psychotic symptoms and no family history of mental illness.

She was diagnosed with bipolar affective disorder and failed to achieve remission of symptoms on two different antipsychotic medications (quetiapine and olanzapine) and anticonvulsant medication (sodium valproate) before starting lithium carbonate.

The introduction of lithium and gradual titration resulted in significant improvement in her symptoms and mood stability. However, few months later, she reported relapse in her symptoms (mainly reporting features of bipolar depression) despite adequate lithium levels.

She agreed on the introduction of lamotrigine as an adjunctive medication to lithium. The initial dose of lamotrigine was 25 mg daily for two weeks in line with dose recommendation from manufacturer and drug guides.

On the same day of lamotrigine introduction, the patient started to experience visual hallucinations that she never had before (please see patient’s perspective for detailed description of her hallucinations).

With the dose of lamotrigine increased to 50 mg daily after the initial two weeks, she started to report worsening of these abnormal perceptions which developed into more complex visual and auditory hallucinations.   

More importantly, there was no evidence of accompanying manic symptoms or severe depressive symptoms to explain these symptoms and also no alcohol or drug use.

Following a psychiatric review, the dose of lamotrigine was reduced to 25 mg which resulted in immediate reduction in the intensity of the abnormal perceptions. When the lamotrigine was eventually stopped after one week, there was complete cessation of abnormal perceptions.

Lamotrigine was never re-started again and she was maintained on a combination of lithium and quetiapine with good effect.

Investigation:

We used the Naranjo Adverse Drug Reaction Probability Scale (1) to determine the likelihood of whether an adverse drug reaction is related to this specific drug or may be related to other factors. This tool examine factors such as the temporal association of drug administration and event occurrence, alternative causes for the event, drug levels, dose – response relationships and previous patient experience with the medication.

The probability of the adverse drug reaction is concluded from the total score (Definite if the overall score is 9 or greater, Probable for a score of 5-8, Possible for 1-4 and Doubtful if the score is 0).

Questionnaire

1. Are there previous conclusive reports on this reaction? Yes (+1)

2. Did the adverse events appear after the suspected drug was given? Yes (+2)

3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?

Yes (+1)

4. Did the adverse reaction appear when the drug was re-administered? Do not know or not done (0)

5. Are there alternative causes that could have caused the reaction? No  (+2)

6. Did the reaction reappear when a placebo was given? Do not know or not done (0)

7. Was the drug detected in any body fluid in toxic concentrations?

No (0)

8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?

Yes (+1)

9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?

No (0)

10. Was the adverse event confirmed by any objective evidence? Do not know or not done (0)

Scoring 7 (Probable Adverse drug reaction)

Discussion:

Lamotrigine is a phenyltriazine derivative used as an anticonvulsant drug with established mood stabilising properties. In the United Kingdom, it is recommended for use in bipolar affective disorder according to the guidelines from the National Institute of Health and Care Excellence (2) and the British Association for Psychopharmacology (3).

We performed a literature search to find similar case reports. We searched the following databases using the keywords (lamotrigine AND hallucinations): Complementary Medicine (AMED), British Nursing Index BNI), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Excerpta Medica Database (EMBASE), Health Business Elite (HMIC), Medline, PsycINFO and Health Management Information Consortium (HMIC).

The search returned 57 results. Only 8 articles discussed hallucinations and other psychiatric symptoms as side effects associated with lamotrigine and therefore were included in this review.

Psychotic symptoms have been reported with the use of lamotrigine (both as an anticonvulsant or mood stabiliser) but this reaction is mainly seen in patients with history of epilepsy. One study reported 4.8% incidence of psychiatric and behavioural side effects with lamotrigine in 546 patients with epilepsy. (4)

Another study on paediatric patients showed that reversible visual and auditory hallucinations were reported in one patient among 9 patients with epilepsy who received lamotrigine treatment (mean age 5 years). (5) 

Villari et al published a literature review on psychiatric symptoms related to lamotrigine and included case reports documenting full acute psychotic episodes hallucinations and affective switching in patients with and without history of epilepsy.(6)

They found one case report on hallucination with lamotrigine in bipolar patient without epilepsy. In patients with epilepsy, they reported two cases reports and one case series (total number of patients 9) developing psychotic symptoms following lamotrigine and one randomised controlled trial in which four out of 216 patients stopped lamotrigine due to psychotic symptoms (including hallucinations and delusions).

The authors concluded that majority of the case reports concluded that these symptoms were lamotrigine-induced due to the temporal association with lamotrigine treatment and favourable outcome following drug withdrawal. It also appeared that more case reports were from patients with epilepsy, suggesting lower incidence in patients without this condition.

Chistyakova and Amos (7) reported a case of delirium associated with lamotrigine use. The dose of lamotrigine was increased from 200 to 400 mg over two weeks prior to her admission. The patient reported visual and auditory hallucination with confusion. She took an accidental overdose of her medication (200 mg of fluoxetine and 2800 mg of lamotrigine) due to her confusion and medications were stopped.

The authors concluded that delirium may result from lamotrigine toxicity or drug interaction with fluoxetine.

Uher and Jones in 2006 (8) reported a case of a 42-year-old woman with bipolar affective disorder with comorbid alcohol abuse and no history of  neurological illness.

The patient tolerated an initial dose of lamotrigine 50 mg/day but following a dose increase to 100 mg/day, she reported vivid dream-like experiences and subsequently she reported visual hallucinations. These symptoms subsided over a few days when the dose was decreased to 50 mg/day.

The authors suggested a causal association through this dose dependent effect but also pointed out that the concurrent alcohol abuse may have been a contributing factor.

They also highlighted the paucity of case reports documenting this rare adverse reaction and identified two similar case reports in their references (which we were unable to get their full text) and a third paper reporting hallucination in 2 out of 108 patients with epilepsy on a combination of lamotrigine and sodium valproate (9)

Hallucination with lamotrigine when combined with valproic acid was also reported in a case report by Roberts et al (10) in 14 year old girl with epilepsy when it was added to valproic acid and it was suggested that this adverse effect may be due to an interaction between the two medications causing lamotrigine half-life to triple with valproic acid.

Learning points:

• Lamotrigine is an anticonvulsant with an established role in management of bipolar affective disorder, particularly for the treatment and prevention of depressive episodes.
• However, it appears to be associated with variable incidence of psychiatric symptoms which should be known to the prescriber and patient.

• These adverse effects are mainly seen in patients with history of epilepsy but can occur in patients with mental health problem without epilepsy.
• Different mechanisms for inducing these psychiatric symptoms have been suggested, including idiosyncratic reaction, lamotrigine toxicity as a result of concomitant use of another drug that affect lamotrigine metabolism (e.g., valproic acid) and delirium.

• Examples of these psychiatric symptoms including affective switches in depressed patients with bipolar disorder, hallucinations in depressed patients, delirium and psychotic symptoms (mainly hallucinations and delusions) in patients with or without epilepsy.

• Reversible and severe psychiatric disturbances associated with lamotrigine therapy are rarely reported in literature and more research is needed to identify population at risk.
• Patient education about these rare but frightening side effects is essential to improve medication adherence and better outcome of the management of the mental disorder.

Patient perspective:

“The first hallucination I had was one hour roughly after taking lithium and lamotrigine. It was the Pope which appeared as bright light on my wall. He was wearing a white gown and he had gold jewellery. The picture was so clear and very detailed. I’m not religious and this image would not be something I would think of.

Every day on lamotrigine I had black spots moving quickly around the walls. They were in size of about an inch, 20-30 moving around at one time. Like spiders but without legs. I was really scared at first because I hate spiders. It was very unsettling and I changed my whole bed, away from my wall, and had trouble sleeping.

There was another night when I had similar to the black dots, where instead I had smaller black dots like bees moving into the corner of my room. They were all slightly moving as if they were getting their places. There were hundreds of them.

The scariest incident that happened was hearing voices downstairs. I was so sure that people had broken into the house; I went downstairs armed with razors. I was going to cut DNA from the burglars to give to the police as evidence. When I checked the house, there was no one there.

When I was taking lamotrigine with the lithium, it made me very unsettled, more anxious and mentally unstable. I was so tiered for not sleeping and my decisions irrational. It wasn’t a pleasant place to be for me personally.”

Introduction:

There are approximately over 1.6 billion overweight people with a body mass index (BMI) greater than 25 kg/mAnnually, around 2.8 million deaths are attributed to overweight and obesity worldwide⁽¹⁾. Many overweight individuals underestimate their weight and despite acknowledging their overweightness, many are not motivated to losing weight⁽²⁾.Accurate measurement is important as it identifies patients with diagnoses which subsequently impact on their management. Self-reported weight is often used as a means of surveillance but has been shown to bias towards under reporting of body weight and BMI as well as over reporting on height⁽³⁾. Several estimation techniques has been devised to quantify anthropomorphic measurements when actual measurement cannot take place^(4),(5),(6), however, these methods are associated with significant errors for hospitalised patients⁽⁷⁾. There is no published study that questions the validity of visual estimation of obesity in daily clinical setting despite its relevance to the daily practice. We aim to investigate the accuracy of visual estimation compared to actual clinical measurements in the diagnosis of overweight and obesity.

Methods:

This is a case control study. Patients for this study were attending the endocrinology, cardiology and chest pain out-patient clinic in Cork University Hospital, Cork, Ireland. The questionnaire session was carried out at every endocrinology, cardiology and chest pain clinic for 5 consecutive weeks. A total of 100 patients were recruited allowing for a 10% margin of error at 95% confidence level in a sample population of 150 000. Ten doctors of varying grades were chosen randomly to visually score the subjects. Exclusion criteria included patients who were pregnant and who are wheelchair bound. Consent was obtained from patients prior to filling questionnaires. Ethical approval was received from the Clinical Research Ethics Committee of the Cork Teaching Hospitals.

In the waiting room, patients were asked to self- report their weight, height and waist circumference to the best of their estimate. Demographics and cardiovascular risk were obtained from medical charts and presented in Table 1. The questionnaires have a section that specifically tests patients’ awareness of abdominal obesity and patients were asked to choose between obesity and abdominal obesity, relying on their own knowledge of markers of cardiovascular risks. Clinical measurements were taken in the nurses’ assessment room. Weight was measured by using portable SECA scales (Seca 755 Mechanical Column Scale) and was measured to the nearest 0.1kilogram. All patients were measured on the same weighing scale to minimize instrumental bias. Patients were asked to remove their heavy outer garments and shoes and empty their pockets and to stand in the centre of the platform, so that weight is distributed evenly to both feet.

Height was measured by using a height rule attached to a fixed measuring rod (Seca 220 Telescopic Measuring Rod). Patients were asked to remove their shoes and are asked to stand with their back to the height rule. It was ensured that the back of the head, back, buttocks, calves and heels are touching the wall. Patients were asked to remain upright with their feet together. The top of the external auditory meatus is leveled with the inferior margin of the bony orbit. The patients were asked to look straight. Height is recorded to the resolution of the height rule (i.e. nearest millimeter).

Waist circumferences were measured using a myotape. Patients were asked to remove their outer garments and stand with their feet close together. The tape is placed horizontally at a level midway between the lower rib margin and iliac crest around the body. They were then asked to breathe normally and the reading of the measurement was taken at the end of gentle exhaling. This prevents patients from holding their breath. The measuring tape is held firmly, ensuring its horizontal position and loose enough that it allows placement of one finger between the tape and the subject's body. A single operator who has been trained to measure waist circumference as per the WHO guidelines is used repeatedly in order to reduce measurement bias⁽⁸⁾.

The doctors were asked to visually estimate the patients' weight, height, waist circumference and BMI. The estimation is recorded on a separate sheet. All doctors were blinded to the actual clinical measurements. The questionnaires were then collected at the end of the clinic and matched to individual patients. Data entry was performed in Microsoft Excel and exported for statistical analysis on SPSS version 16.

Findings

The study enrolled 100 patients. Demographic and cardiovascular risk details are shown in Table 1. Among these, 42 were obese, 35 were overweight and 23 patients had a normal BMI. The sample has a mean BMI of 29.9kg/m² (95% CI 28.7-31.1) with a mean waist circumference (WC) of 103.2cm (95% CI 100.7-107.2). The average male waist circumference is 105.8 cm while the average female waist circumference is 101.6cm. The mean measured weight was 84.6kg (95% CI 81.0-88.2) and the mean height measurement was 1.68m (95% CI 1.66-1.70).

Table 1: Cardiovascular risk factors

Patient’s perception and doctor’s estimation of anthropomorphic measurements were compared to actual measurements and is displayed in Table 2.

Table 2. Deviation from actual measurement values in both groups

In terms of patients own estimation of height, weight and waist circumference, 49% of patients under estimated their weight by up to 1.5kg, 35% reported accurately to 1.5 kg and 16% over reported weight. 67% of patients estimated height accurately, 18% of patients under-estimated, and 15% over-estimated. When asked to estimate their waist circumference, 68% of patients under estimated by up to 5cm, 30% over estimated and 2 patients estimated accurately to 5cm (Figure 1). We found that 70% of patients regarded obesity as the higher threat to health compared to abdominal obesity. There were no differences in patient’s self reported weight and doctor’s weight estimation (p= 0.236).

Figure 1. Graphical representation of patients estimated weight, height and waist circumference

We then analysed the doctor’s estimation of height, weight, waist circumference and BMI. For the purpose of interpreting the data on BMI, the estimates that is recorded by doctors that matches the patient’s real BMI by clinical measurement is considered accurate. Therefore, for patients who have a normal BMI, 69.5% were correctly estimated as normal and the rest (30.5%) were estimated as overweight. For those patients who are obese, 81% were estimated as obese and by the doctors as a group and the rest (19%) is estimated to be overweight. In patients who are overweight, 63% were correctly estimated as being overweight by doctors, 9% were estimated as being obese and the rest (28%) were mistakenly estimated as having a normal BMI. Accurate BMI estimation by doctors was achieved in 72% patients (Figure 2).

Figure 2. Doctors estimation of BMI compared to actual clinical measurement

Doctors were noted to underestimate the patients’ weight in 53 patients, over estimated in 26, while being accurate in their estimation in 21 patients. Estimation of waist circumference to the nearest 5 cm shows marked under estimation of waist circumference in 71% of patients, over reporting in 3% of patients and 26% accurate estimation. The majority of underestimation of waist circumference happens in the region of 10 to 15cm. For patients who are obese, doctors were able to estimate waist circumference correctly in 58% of obese individuals.

Discussion:

This is the first study demonstrating the relationship of visual estimation of a cardiovascular risk factor and comparing to actual clinical measurements. As obesity and abdominal obesity becomes an increasingly common phenomenon, our perception of the 'normal' body habitus may be distorted⁽⁹⁾.

It is observed that in the bigger hospitals out-patient departments, physicians and nurses are commonly affected by clinical workload and tend to spend a limited amount of time with patients in order to achieve a quicker turnaround time. Cleator et al looked at whether clinically significant obesity is well detected in three different outpatient department and whether they are managed appropriately once diagnosed⁽¹⁰⁾. In all the outpatient departments involving the specialties of rheumatology, cardiology and orthopedics, the actual cases of clinical obesity is higher than what is being diagnosed and the management of obesity was heterogeneous and minimal in terms of intervention. With the ever increasing obese patients attending hospitals, it is understandable that healthcare providers such as physicians, nurses, dietician and physiotherapist resort to relying on visual estimation.

In terms of patient’s own estimation of height, weight and waist circumference, we gained that patients were reasonably good at estimating their own height but tend to under estimate weight. This is probably due to the fact that these patients have not had a recent measurement of weight and their weight estimation is based on previous historical measurement from months to years back, which in the majority of people, is less than their current weight. This also explains why their height estimation is more accurate, as adult heights do not undergo significant changes and are relatively constant.

When attempting to obtain patient’s own estimation of waist circumference, we found that most patients are not at all aware of the method used to measure waist circumference. Some patients even mistaken waist circumference as being their trousers’ waist size. In those who were able to give estimation, a large proportion would under estimate.

The majority of patients think that general obesity is more predictive of cardiovascular outcome compared to abdominal obesity. This lack of awareness is reflective on clinician’s effort in addressing abdominal obesity as an important cardiovascular risk factor to patients during consultations. The lack of proper awareness campaign by healthcare providers along with the evolving markers of cardiovascular risk may further confuse the general public.

Recently, waist circumference, waist to hip ratio along with many serum biomarkers have been noted to correlate to adverse outcomes in obese individuals, independent of BMI. Waist circumference measurement is a relatively new tool compared to the measurement of BMI. This would explain the discrepancy between doctors’ estimation of BMI and waist circumference. Visual estimation is further compromise as many patients would be covered in items of clothing during consultations. In order to obtain a better estimation of waist circumference, the individual have to be observed from many angles, a task that may be impossible in a busy clinic.

Although BMI is a convenient method to quantify obesity, recent studies have shown that waist circumference is a stronger predictor of cardiovascular outcomes^{(11),(12),(13),(14)}.The importance of waist circumference in predicting health risk is thought to be due to the relationship between waist circumference and intra-abdominal fat^{(15),(16),(17),(18),(19),(20)}.We now know that the presence of intra-abdominal visceral fat is associated with a poorer outcome in that patients are prone to develop metabolic syndrome and insulin resistance⁽²¹⁾.We have yet to devise a more accurate measurement on visceral fat and at present limited to using waist circumference measurements.

Although doctors are generally good at BMI estimation, we found that in estimating overweight patients’ BMI, close to 30% were wrongly estimated as having normal BMI. Next to the obese, these groups of patients are likely to have metabolic abnormalities and increased cardiovascular risk. If actual measurement of BMI is not routinely done, we may neglect patients who would benefit from intervention. A simple, short counseling during the outpatient visit with emphasis on weight loss, the need to increase their daily activity levels and the morbidity related to being overweight may be all that is needed to improve the population health in general. Further intervention may include referrals to hospital or community dieticians and prescribed exercise programmes. These intervention tools already exist in the healthcare system and could be accessed readily.

The nature of our study design exposes it to several potential selection and measurement biases. Future studies should include patients of differing ages and socioeconomic background. Additionally, clinicians of differing appointments from various different specialties should be included to obtain a more applicable result. A measure of diagnostic efficacy should also be employed to further assess the value of clinical measurement and therapeutic intervention.

Conclusion:

The appropriateness of visual scoring of markers of obesity by doctors is flawed and limited to the obese individuals. True anthropometric measurements would avoid misdiagnosing overweight individuals as normals. We can conclude that patients’ own estimation of weight is unreliable and that they are unaware of the impact of high abdominal fat deposition on cardiovascular outcome. The latter should be addressed in consultations by both hospital physicians and general practitioners. Further emphasis and education in schools and awareness campaigns should also advocate this emerging cardiovascular risk factor.