2015

Introduction

The NHS is supplied with approximately 300 000 NG tubes per year¹. There are approximately 800-1000 incidents reported to the NPSA every year related to the insertion and use of NG tubes. Difficulties are often encountered with their insertion, especially in the setting of general anaesthesia. Whilst stridor and injury related to the use of NG tubes has been previously reported^2,3, it has been related to prolonged siting. We describe a case acute stridor occurring in the recovery room due to direct trauma of the airway upon NG tube insertion.

Case report

A 61-year-old male presented with clinical symptoms of bowel obstruction. His medical history included atrial fibrillation (AF) treated with flecainide, and a 30-pack year smoking history. He was previously independent with a World Health Organisation performance status of 0. After CT confirmation of bowel obstruction, he was scheduled for an emergency laparotomy. A predicted P-Possum 30 day mortality was calculated at over 10%. He required no organ support pre-operatively, although his AF was poorly controlled. He had a low thoracic epidural sited awake, followed by induction of general anaesthesia with a rapid sequence induction. An arterial line, a central venous line, and an NG tube were inserted once anaesthetised. The NG tube was documented as difficult to site, and there were several attempts at a blind insertion via the oral and nasal route, before successfully inserting under direct vision using a laryngoscope.

The operative finding was that of an unresectable caecal tumour, and a defunctioning loop colostomy was formed. The total duration was 150 minutes. Following peripheral nerve stimulation and administration of 2mg/kg Sugammadex, he was woken, extubated and escorted to recovery.

Within minutes of being in the recovery area, he was acutely stridulous. Emergency assistance was called, and after assessment he was given nebulized adrenaline (1mg diluted in 4mls 0.9% saline), and 200mg of intravenous hydrocortisone. The nasogastric tube was removed, and his breathing was then supported with CPAP via a Mapleson C circuit and 100% oxygen. Direct examination of his airway, and indirect nasendoscopy with a Storz fibre-optic scope were performed. Significant bruising of his soft palate was seen, in addition to bruising and oedema of the soft tissues around the arytenoid cartilages with a small haematoma within the valleculae [Figure 1]. After approximately twenty minutes his stridor settled.

He was transferred to a level 2 high dependency unit later that day. He did not suffer from any further airway compromise, and his symptoms completely resolved.

Discussion

The insertion of an NG tube, whilst often deemed low risk, may result in life threatening consequences⁴. There even exists a “NG tube syndrome” ⁵, the pathophysiological mechanism of which is thought to be paresis of the posterior cricoarytenoid muscles secondary to ulceration and infection over the posterior lamina of the cricoid. There is no doubt that insertion of an NG tube in the anaesthetised patient can prove to be difficult, with a failure rate of up to 50% on first pass⁶, with repeated attempts at insertion being required. However, this case highlights the need for a controlled and ordered approach to managing the difficulties that can be encountered. Medical training incorporates NG insertion as a basic skill within the curriculum, but this affords new anaesthetic trainees little help with the anaesthetised and intubated patient.

There are several techniques described to insert NG tubes in anaesthetised, intubated patients⁷. There is evidence to suggest that modified techniques such as a reverse Sellick’s manoeuvre or neck flexion with lateral pressure are better than blind insertion in the neutral position. In the right hands, insertion under direct vision can overcome most difficulties, but is again not without risk.

We feel it is important to remember that NG insertion can cause patient harm, and potentially lead to life threatening consequences. Whatever the approach or technique that is chosen, having a logical and ordered approach is paramount. Using suitable alternative methods for insertion, or abandoning the procedure, as opposed to blindly continuing to repeat the same unsuccessful method must be key for success, as would be the case for approaching any clinical encounter.

Published with the written consent of the patient.

Introduction

Bednar tumour, first described by Bednar in 1957, is a pigmented variant of dermatofibrosarcoma protuberans (DFSP).It is a rare entity, constituting1 to 5% of all DFSPs, which in turn, represent 0.1% of skin malignancies. It differs from DFSP by the presence of dendritic cells containing melanin, interspersed between the fusiform cells characteristic of DFSP. The most frequent location is in the trunk followed by upper and lower extremities and the head and neck region. We report a case of Bednar tumour occurring on the shoulder of a 29-year-old male.

Case report

A 29 year old male patient presented with a slow-growing swelling on his left shoulder for the past two years. Physical examination revealed a large, nodular, subcutaneous mass measuring 8x7 cm in left suprascapular region. Clinical impression was of soft tissue tumour and total resection with 3-cm margins was performed. Grossly, tumour measured 9x4.5 cm, with grey white to grey black cut surface (Figure 1a, 1b). Microscopy showed spindled cells arranged in a tight storiform pattern admixed with scattered heavily pigmented cells (Figure 2). On immunohistochemistry, tumour cells were positive for vimentin and CD34 (Figure 3a, 3b) and negative for S100, SMA and desmin. Pigmented cells were found positive for S100 and HMB 45 (Figure 4a, 4b) and negative for other markers. Thus, a final diagnosis of Bednar tumour was rendered.

Figure 1 - Gross appearance of the tumour with cut surface grey white to grey black

Figure 2 - Spindle cells in storiform pattern admixed with scattered heavily pigmented cells

Figure 3 - Tumour cells were positive for vimentin (3a) and CD34 (3b)

Figure 4 - Pigmented cells showed positivity for S100 (4a) and HMB 45 (4b)

Discussion

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive soft tissue neoplasm with intermediate malignant potential, regarded as a low grade sarcoma by the WHO classification of tumours of the skin.^1,2,3

It was first described by Darier and Ferrand as a distinct cutaneous disease entity called progressive and recurring dermatofibroma in 1924. The term dermatofibrosarcoma protuberans was officially coined in 1925 by Hoffman.⁴

Histopathologically, DFSP is characterised by irregular, short, intersecting fascicles of tumour cells arranged in a characteristic storiform pattern. Cells have spindle-shaped nuclei which are embedded fairly uniformly in a collagenous stroma. There are several histological variants of DFSP. These include Bednar tumour, fibrosarcomatous, fibrosarcomatous with myoid/myofibroblastic change, myxoid, granular cell, palisaded, giant cell fibroblastoma, combined and indeterminate.⁵

Pigmented DFSP (Bednar tumour), first designated as storiform neurofibroma by Bednar, is a clinically and morphologicallydistinct variant of DFSP, constituting 5%-10% of all cases of DFSP.^1,5 Clinical presentation is in the form of erythematous blue or brown coloured plaque lesions, with a smooth or irregular surface, often adhering to the deep tissue. The tumour may be exophytic, nodular or multilobulated and is generally firm in consistency.² The lesions present as a slow growth, over a period of months or years. They have been described in all ethnic groups, with preponderance in blacks. They occur in third and fourth decades of life, however they may also occur in infancy and show a slight male predominance.^1,5

The histogenesis of Bednar tumour is controversial. Some authors regard these tumours as being of neuroectodermal origin because of the presence of dendritic melanocytes and cells suggestive of Schwannian differentiation; while others believe attribute the origin to various kinds of local traumas, such as previous burns, vaccination scars, insect bites or vaccination such as BCG.^3,6

Histopathologically, Bednar tumour is characterised by scattered melanosome-containing dendritic cells within an otherwise typical DFSP. The number of melanin-containing cells varies from case to case. Abundant pigmented dendritic cells can cause black discoloration of the tumor, whereas scant pigmented cells can be only identified microscopically.^3,5 They grow invasively into the dermis and may reach the subcutaneous strata, fascia and musculature, in a manner similar to that of dermatofibrosarcoma protuberans. Occasionally, Bednar tumour may undergo fibrosarcomatous transformation with rare examples of pulmonary metastasis.⁵ Wang et al have reported a case of Bednar tumour with prominent meningothelial- like whorls.⁷

Immunohistochemically, most of the tumour cells stain positively with CD 34 and vimentin, and are negative for neuron-specific enolase, HMB-45 and protein S-100. However, cells containing melanin are positive for the usual melanocytic markers such as S-100 protein.⁵ On electron microscopy, three populations of cells have been identified, most of the cells being represented by fibroblasts. The second population exhibits fine elongations, enclosed in basal membrane while the third population consists of dendritic cells containing melanosomes and premelanosomes.^3,5

The differential diagnoses include pigmented (melanotic) neurofibroma, psammomatous melanotic schwannoma, and desmoplastic (neurotrophic) melanoma. Pigmented neurofibroma can be differentiated from Bednar tumour by more extensive storiform growth and strong positivity for CD34 in latter. Psammamatous melanotic schwannoma is circumscribed, heavily pigmented with psammoma bodies, tumour cells being S- 100 positive and CD34 negative. Desmoplastic melanoma shows junctional activity and neurotropism.

Treatment consists of complete excision of the tumour with maximum preservation of normal tissue to maintain function and for optimal cosmesis. Moh’s Micrographic Surgery (MMS) or staged wide excision “Slow Moh’s “(with formal histopathological sectioning and delayed reconstruction for complete circumferential peripheral and deep margin assessment) has become the standard surgical treatment for DFSP.^6,8

Bednar tumour presents a diagnostic challenge to the clinician because of resemblance to other commonly occurring pigmented lesions. Histopathological and immunohistochemical examination are necessary to arrive at the correct diagnosis.

Introduction

Claimants in medical negligence cases are increasingly making use of negligent failure to warn of risk in claims for compensation following medical mishaps when an inherent risk in a medical procedure has manifested itself resulting in injury. In order to succeed the claimant must establish firstly that the failure to warn was negligent and secondly that the negligence has caused a loss. This paper focuses on causation in failure to inform cases but briefly considers the shift in judicial attitudes to the requirement to give warnings in order to explain how the duty to inform and the available remedies have diverged.

Members of the medical profession commonly believe that to find a negligent failure to inform has caused a loss to the claimant a court must be satisfied that the patient would not have consented to the treatment had they been told of the risk. This was probably true until 2004 when the House of Lords came to a surprising decision which has since received a mixed reception.

The Changing nature of the requirement to give warnings

In the early days of medical litigation whether non-disclosure amounted to negligence was left to the standards of the medical profession. A medical professional was under a duty to at least equal the standards of a reasonably skilled and competent doctor; this would be assumed if s/he had acted in accordance with a body of professional opinion. This is referred to as the Bolam test.[i] There was disquiet amongst academic lawyers that doctors were being allowed to set their own standards and over time the courts have been wrestling back control.[ii]^,[iii] Following the Recent Supreme Court ruling in Montgomery[iv] there is now no doubt that patient autonomy is paramount and the need to inform will now be judged by reference to a reasonable person in the patient’s position.

In Montgomery the claimant, a diabetic, alleged she had been given negligent advice during her pregnancy.  In particular she was not warned of risk of shoulder dystocia, the inability of the baby’s shoulders to pass through the pelvis, assessed at 9-10% for diabetic mothers and not informed of the possibility of delivery by elective caesarean section. The Consultant responsible for her care gave evidence (at paragraph 13) that she would not routinely advise diabetic mothers of this risk because if mentioned, “most women will actually say, ‘I’d rather have a caesarean section.’” The Supreme Court in finding (at paragraph 87) for the claimant held, “The doctor is therefore under a duty to take reasonable care to ensure  that  the  patient  is  aware  of  any  material  risks  involved  in  any recommended  treatment,  and  of  any  reasonable  alternative  or  variant treatments.  The  test  of  materiality  is  whether,  in  the  circumstances  of  the particular case, a reasonable person in the patient’s position would be likely to  attach significance to the risk, or the doctor is or should reasonably be aware that the particular patient would be likely to attach significance to it.” Although expressed as, “a duty to take reasonable care,” the medical professional is expected to, “ensure,” that the patient has the requisite knowledge. The test in failure to inform cases now focuses, not on the actions of the medical professional but, on the patient’s knowledge of the risks.

Chester v Afshar[v]

On 21^st November 1994 Mr Afshar carried out a microdiscectomy at three disc levels on Miss Chester. There was no complication during the operation and the surgeon was satisfied that his objectives had been met. When Miss Chester regained consciousness she reported motor and sensory impairment below the level of L2. A laminectomy shortly after midnight the next day found no cause and the surgeon’s only explanation was cauda equine contusion during the retraction of the L3 root and cauda equine dura during the L2/L3 disc removal. During the legal proceedings Miss Chester brought against Mr Afshar it was found that the operation carried an unavoidable 1-2% risk of cauda equine syndrome (CES) and that the surgeon had not warned the patient about this risk. It was further found that, had the warning been given, Miss Chester would have sought a second (and possibly third) opinion meaning that the operation would not have taken place on 21^st November.

The surgeon and the patient did not agree what was said about the risks of the operation before consent was obtained but the issue was decided in favour of the patient: the surgeon had failed to give a proper warning about the risk of CES. In order to succeed in her claim Miss Chester needed to establish that this failure had caused her loss but her lawyers did not argue that she would have refused consent if she had been informed. They took a different approach; the 1-2% risk of CES is not patient specific and is realised at random. If warned of the risk Miss Chester would have sought a second opinion meaning that the operation would have happened at a later date and possibly with a different surgeon. This subsequent operation would have carried the same 1-2% risk of CES. The High Court of Australia had previously accepted (in a different case) that the claimant can satisfy the burden by showing that, if informed, s/he would have chosen a different surgeon with a lower risk of adverse outcome but there was no evidence in this case that by choosing another surgeon Miss Chester could have reduced the risk.[vi]

At the time Mr Afshar failed to advise Miss Chester of the risks two paths should have been open to her. She could choose to have the operation with the defendant on 21^st November which resulted in CES or to seek a second opinion and undergo the operation at a later date giving her a 98-99% (a better than balance of probabilities) chance of avoiding CES. Thus the failure to inform did not increase the 2% risk of CES but the court found, as a matter of fact, that it did cause the CES. Although the physical harm that Miss Chester had suffered (because of the inevitable risk) did not fall within the scope of the doctor’s duty to inform (to allow the patient to minimise risk) a majority of the House of Lords felt that the surgeon should be held liable because otherwise the patient would be left without a remedy for the violation of her right to make autonomous decisions about treatment.

There are two leaps in Chester the first is the notion that negligence causes a loss if it induces the claimant to follow a path with an associated risk that is realised when they could have followed another path with exactly the same risk. The second is that violating a patient’s right to make autonomous decisions should, as a matter of policy, make the surgeon liable for personal injury which happens after the patient is deprived of their right to make a decision about treatment. The next two paragraphs will consider these leaps in turn.

Equally risky paths: The first leap

In Wright[vii] the patient had developed a streptococcus pyogenes infection that had seeded into her proximal femur resulting in osteomyelitis. Her admission to hospital was delayed for two days by the defendant clinic’s negligent handling of her first presentation. On admission to hospital the patient had the additional misfortune to receive woefully inadequate treatment resulting in septic arthritis and permanently restricted mobility. The patient took the questionable decision to sue the clinic but not the hospital. One of the patient’s arguments against the clinic was that had she been admitted to hospital without the two day delay she would have been treated by different staff who would, almost certainly, not have been negligent. The claimant argued that, as in Chester, although the clinic’s negligence did not increase the random risk of receiving negligent hospital care it had, as a matter of fact, caused the negligent care. Lord Justice Elias rejected this suggestion precisely because the delay had not increased the risk that the hospital would provide the patient with inadequate treatment. However, the other members of the Court of Appeal found for the patient but for another reason; given two extra days the hospital would probably have realised their mistakes and been able to correct them before any permanent harm resulted.

Violated autonomy and personal injury: The second leap

There have been attempts to expand the scope of the majority reasoning in Chester. In Meiklejohn[viii] the patient was treated for suspected non-severe acquired apastic anaemia with Anti Lymphocyte Globulin and Prednisolone the latter causing an avascular necrosis. At an initial consultation a blood sample was taken from the patient for “research purposes” but possibly to exclude dyskeratosis congenital, the condition from which he was actually suffering. The patient argued he had not given informed written consent to the taking of a blood sample for research purposes and that had he been told about the uncertainty in the diagnosis he would have delayed treatment pending the result of the blood test or asked to have been treated with Oxymetholone instead. He further argued these violations of his autonomy required that he be given a remedy for the injury which had actually occurred through a reasonable misdiagnosis of his rare condition. Lady Justice Rafferty sitting in the Court of Appeal dismissed this argument stating at paragraph 34 that, “Reference to [Chester] does not advance the case for the Claimant since I cannot identify within it any decision of principle.”

Conclusion

Courts deciding failure to warn cases have shifted the emphasis from the reasonable practices of the medical profession to the autonomy of the patient; from the duty of the medical professional to the rights of the patient. Medical professionals are now required to give enough information to allow a reasonably prudent patient to make an informed decision about their own treatment. While this change has been taking place there has been no corresponding revision of the remedies available when a patient’s autonomy is infringed. If autonomous decision making is to be properly protected a remedy should be vested in every patient who has had their autonomy infringed whether or not that patient has suffered physical injury; autonomy infringements should be actionable per se (without proof of loss) and result in the award of a modest solatium (a small payment representing the loss of the right to make an informed decision about treatment.) Under the present arrangements the wrong that the patient complains of (infringement of autonomy) is not what they are seeking damages for (personal injury.)

In a small way, the court in Chester has sought to close this gap between the patient’s right and the remedy available by extending the existing law and widened the circumstances in which damages can be recovered by a patient following an infringement of autonomy. Medical professionals who fail to warn patients of small risks may be held liable if disclosing the risk might cause the patient to delay treatment while further deliberations take place. Paradoxically it could conceivably be argued that medical professionals who fail to disclose significant risks (greater than 50%) should escape liability because the loss was more likely than not to happen anyway!

Both Chester extensions to the law have been tested independently in Wright and Meiklejohn and rejected but this does not mean that it has been overruled. The two subsequent cases were heard by the Court of Appeal which cannot overrule the House of Lords (now the Supreme Court.) Both cases were distinguished meaning that the court was satisfied that they were not factually the same as Chester. Clearly Wright is not concerned with rights to autonomy and Meiklejohn is a failure to warn of uncertainties in diagnosis or failure to obtain written informed consent to research rather than risks inherent in treatment. If the facts of Chester were to come before the Courts again the decision would have to be the same; a surgeon could not necessarily escape liability by proving that, informed of the risk, the patient would have consented to the operation.

Summary points

• Patients have a right to be informed of material risks inherent in medical treatment
• An injured patient does not necessarily need to prove they would not have consented to the operation if the risks had been disclosed
• A legal claim against a health care professional may be successful if the patient would have delayed the operation to a later date
• This extension of the law has critics but the situation is unlikely to change in the near future

Introduction

A clearer understanding of the aetio-pathogenesis of schizophrenia would ultimately lead to effective treatment strategies and provide the impetus for elucidation. The autoimmune hypothesis promulgates that it is the auto-antibodies that are responsible for schizophrenia and, according to the viral hypothesis, it may be the body’s abnormal response to a slow viral infection or the undefeated viral antigens causing the schizophrenia pathology. The autoimmune and viral hypotheses are interlinked, as autoimmune disorders can be triggered by microbial infection. Viral aetiology is less convincing than the autoimmune model, but from a treatment perspective, the former is more promising than the latter. To gain a detailed understanding of aetiological models of a subset of schizophrenia, herein the author has reported on a review of the literature relating to the immunity- and viral-based aetiological models of schizophrenia. Genetic vulnerability has been highlighted in the schizophrenia literature alongside environmental factors. The veracity and contestability of the immunity- and viral-based aetiological hypothesis of schizophrenia merits further investigation.

Schizophrenic Syndromes

A prerequisite for incorporating autoimmune and viral aetiology into a scientific discussion would be acceptance of the heterogeneous hypothesis of schizophrenias; they may be a cluster of entities with different aetiologies and the end-stage of different disease processes. ¹ Autoimmune or viral aetiology may account for one subgroup.

Schizophrenia has diverse signs and symptoms, and a long history of controversy. Nosologists designate it as polythetic, whereas most other mental illnesses are monothetic, seemingly affecting only one brain system. ² In the second half of the twentieth century, the psychosocial model gave way to evidence that it is a brain disorder. Schizophrenia has a long history of controversies and there has been much contention over the aetiology, psychopathology, nomenclature, and diagnostic criteria. Schizophrenia is currently seen as a neurodevelopmental encephalopathy, in which the cognitive deficits are produced due to the errors during the normal development of the brain ³ or a neuro-degenerative disorder and the cognitive deficits are derived from a degenerative process that goes on unalterably. Modern neuroimaging techniques and an intensification of studies of necropsy tissue have been responsible for this shift. Researchers seem to agree that a neurodevelopmental or degenerative assault precedes the symptoms by several decades.

The aetiology of the cognitive deficits is unidentified and several potential factors, genetic and epigenetic, are envisaged. Environmental factors—including infectious agents and disturbance in utero through malnutrition—account for a few cases. Autoimmunity and viral theories would fit in with the neuro-developmental and neurodegenerative hypotheses. Proponents of viral aetiology view viruses as acting alongside susceptible genes to initiate a trajectory that manifests as psychotic symptoms.

Lessons from Autoimmunity

Disorders of an autoimmune nature are known to occur with increasing frequency in patients with another autoimmune disease. This is somewhat like the coexistence of multiple psychosomatic disorders in a person; as per Halliday’s psychosomatic formula, association of other psychosomatic afflictions justifies the diagnosis of a new psychosomatic condition. ⁴ It is well recognised that the central nervous system (CNS) may be directly affected by autoimmune processes, as in the case of multiple sclerosis (MS) and autoimmune limbic encephalitis. A physical autoimmune disease, such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome are also associated with psychiatric morbidity. Paediatric autoimmune neuropsychiatry disorder is a post-infection (group A Beta-haemolytic streptococcal infection) autoimmune disorder characterised by abrupt onset of obsessive compulsive disorder (OCD) and Tourette’s syndrome, brought about by molecular mimicry. ⁵ Nicholson et al observed that 20% of OCD patients were positive for anti-basal antibodies, considered to be part of a post-streptococcal autoimmune reaction. ⁶

Autoimmunity is a misdirected response occurring when the immune system attacks the body; it is the loss of tolerance to self-antigens. Immunological tolerance to one’s own tissue is probably normally acquired during foetal life, helping to prevent the occurrence of the autoimmune process (see Table1). Some clones of cells that can produce auto-antibodies (forbidden clones) are thought to be produced throughout life, and are suppressed by large amounts of self-antigens or antigen-specific T cells. Auto-antibodies are produced for a wide variety of antigens; some are organ-specific and others are non-organ-specific. Some microorganisms or drugs may trigger changes in individuals who are genetically vulnerable to autoimmunity.

Table 1- Mechanisms preventing and causing autoimmunity

A human disease may be considered of autoimmune origin on the basis of knowledge from molecular biology and hybridoma technology, ⁷ along with the Witebsky postulations. It is established by the presence of auto-antibodies and T cells that react with host antigens. Approximately 25% of patients with an autoimmune disease (AD) tend to build up additional auto-antibodies. Strausburg et al (1996) explained several hypotheses for the virally-triggered autoimmune mechanism (see Table 2). ⁸ Allergy is the consequence of a strong response to a harmless substance, but ADs are caused when the destructive potential of the immune system is misdirected to oneself. ADs share common effect or mechanisms with hypersensitivity reactions and can be classified into three main types corresponding to the type ii, type iii, and type IV categories of hypersensitivity reactions (see Table 3)

Table 2 - Virally triggered autoimmune mechanisms

Table 3 - Classification of Autoimmune disorders

Shared Aetiology

ADs are characterised by shared threads in terms of their propensity to co-exist in a patient or direct relatives. Two major autoimmune clusters have been recognised via, thyrogastric—mostly organ-specific—diseases and lupus-associated—mainly multi systems—diseases. ⁹ Some ADs are distributed within either cluster and there are also overlaps within each cluster. These patterns of concurrence depend predominantly on genetic determinants.

Poly-autoimmunity is the term proposed for the association of multiple autoimmune disorders in a single patient and such co-occurrences indicate a common origin of the disease. ¹⁰ Adriana et al, by grouping diverse ADs in the same patient, demonstrated that they are true associations as part of autoimmune tautology rather than chance findings.

Co-Occurrence of ADs

Theories for autoimmune aspects of schizophrenia raise the concept of early infection by microorganisms with antigens so analogous to CNS tissue that resulting antibodies act against the brain.Some data suggest that an autoimmune process precedes schizophrenia, non-affective psychosis, and bipolar disorder, ¹¹ but do not establish whether this is affected by viral attack, as viral footprints may be hard to detect, especially in the target organ, once the autoimmune process has begun. Psychosis is reported in 25% of SLE cases.

A Danish study revealed that schizophrenia is associated with a large range of ADs. ¹² The researchers found that a history of any AD in the patient is allied with a 45% increase in the incidence of schizophrenia. Specifically, nine ADs have a higher prevalence rate among patients and 12 ADs have a higher prevalence rate among their parents than among comparison groups. In comparison with the control group, Thyrotoxicosis, Celiac disease, Acquired haemolytic anaemia, interstitial cystitis, and Sjogren’s syndrome had a higher prevalence rate among schizophrenia sufferers and their family members.

Three of the Ads—namely, celiac disease, thyrotoxicosis, and acquired haemolytic anaemia—have been previously associated with schizophrenia. Celiac disease involves an immune reaction to wheat gluten. This could be due to increased permeability of the intestine, raising the level of antigen exposure, resulting in increased risk of an autoimmune response to brain components or it may be that gluten proteins are broken down into psychoactive peptides. Eaton et al opined that the association of schizophrenia and ADs could be due to common genetic causes, perhaps related to the HLA or other genes, and some cases of schizophrenia may be consequential to the production of autoantibodies that disrupt the brain function.

Researchers for a Taiwan study identified a greater variety of ADs in schizophrenic patients than anticipated and recommended further research. ¹³ Chen et al. found that 15 ADs are significantly associated with the schizophrenia group. Their studies also confirmed an earlier observation of a negative relationship between schizophrenia and rheumatoid arthritis (RA). It has been observed in a small sample study that mothers of schizophrenia patients have a lower risk for RA.¹⁴

Rheumatoid Connection

The negative correlation between schizophrenia and RA is puzzling. ¹⁵ Such dissociation was interpreted as the effect of antipsychotic medication. Similarly, the metabolic changes associated with one disease may inhibit another.¹⁶ Genes predisposing a person to have one disorder may have a protective influence against another and, in that way, the negative rheumatoid connection with schizophrenia is consistent with an autoimmune model.

RA has a genetic predisposition partly mediated by major histocompatibility complex (MHC) alleles and triggered by infection. Similarly, schizophrenia has genetic and environmental associations and has been cautiously connected with MHC genes other than those perhaps involved in RA. In addition to gene products accountable for antigen presentation, the MHC gene complex holds a multitude of genes-controlling aspects of immune response. Hypothetically, depending on the set of genes an individual has inherited at the MHC complex, a viral assault will lead the immune system to an immune cascade toward the development of RA, or along a genetically-predetermined path with a network of cytokines and immune mediators and directed against CNS components, resulting in schizophrenia. ¹⁷

The negative rheumatoid connection may be attributable to two mutually-exclusive alleles of the same gene. Such associations may lead to novel treatment strategies; sickle cell anaemia patients are thought to be less affected by malaria. Of note, the combined research of Karolinska Institute in Sweden and John Hopkins’s University School of Medicine in the United States have recently discovered the genes and the specific deoxyribonucleic acid (DNA) sequences that regulate them plot together to the progress of RA; rheumatology may be inching close to an early detection method and effective treatments. Such a development could hopefully happen in the schizophrenia research.

Commonalities

Even though ADs superficially seem different, the vast majority of them share several similarities. Like ADs, schizophrenia, as such, is neither infectious nor congenital. Schizophrenia and ADs have well-established genetic propensities, and a combination of genes, rather than a single gene, is thought to be responsible for their manifestations. Both schizophrenia and ADs can be triggered by environmental toxins and they have a remitting and relapsing course. Worsening of symptoms is observed when patients are exposed to stress and both conditions have a peak increase in late adolescence or early adulthood. These similarities argue in favour of an autoimmune aetiological model of schizophrenia. ¹⁸

Apparently, there is an interesting epidemiological dissimilarity between ADs and schizophrenia. The incidence of ADs is on the increase in developed countries, whereas schizophrenia has a consistent incidence of 1% globally. According to the hygiene hypothesis of ADs, the widespread practice of hygiene, vaccination, and antibiotic therapy in rich countries have disabled children’s immune systems to deal with proper infections and are more geared to charge with one’s own tissues in highly-destructive ways. ¹⁹ The incidence between the sexes was thought to be almost similar in the case of schizophrenia, but a recent study shows that for every three males with schizophrenia, there are two females with the disease. ²⁰ ADs are slightly higher among the female population.

Immune Modulation of Clozapine

Antipsychotics may have an immunosuppressant effect; plasma levels of IL-6, soluble IL-6R and transferrin-receptor (TfR) were significantly lower after antipsychotic drug treatment. Activation of cell-mediated immunity may occur in schizophrenia; neuroleptic agents may modulate this through suppression of IL-6 or IL-6R-related mechanisms. ²¹ The antipsychotic effect may involve a counter-effect on the brain-mediated immune system.

Clozapine, the gold standard for refractory schizophrenia, is a dibenzodiazepine and lowers D2 receptor occupancy and is also a 5-hydroxytryptamine antagonist. Studies indicate that among the atypical antipsychotics, clozapine seems to have an immunosuppressant effect along with neuro-modulatory effect. It has been suggested that clozapine may diminish antibody synthesis in hematopoietic cells and also argued that a possible immunosuppressive action may contribute to its superior antipsychotic efficacy. ²² The long-term immunosuppressive effects of antipsychotics may inhibit putative autoimmune responses against neurological sites and could, thus, act synergistically with the direct antagonistic action on brain receptors for the evident improvement of psychotic symptoms. ²³ It is also conjectured that the increase of soluble IL-2 receptor levels in Clozapine-treated patients indicates an immunosuppressant mechanism. ²⁴

Haloperidol may also be a neuro-immune-modulating drug. A study of in-vitro effects of clozapine and haloperidol on cytokine production by human whole blood suggested that both drugs, at concentrations within their therapeutic range, may exert immunosuppressive effects through an enhanced production of IL-1 receptor antagonists. ²⁵

It is well recognised that unlike other antipsychotics, clozapine works better over time, as immune modulation may take longer than neuro modulation. In addition to the neuro modulation, antipsychotics may be working on the principles of immune modulation, as well. If a derivative of clozapine, without its haematological and metabolic side effects is discovered, such a drug would become the first line of choice among the antipsychotics, and that could be a significant event in schizophrenia research. The immunosuppressant effects of clozapine seem to have public health awareness that patients on clozapine are advised to have the winter flue jab. Elderly patients on antipsychotic medications are more prone to get pulmonary infections, indicating that such drugs have a delicate immunosuppressant property.

Autoimmune-Neuropsychiatric Disorder?

If schizophrenia is an AD, a higher rate of other ADs may be expected among schizophrenics. Most studies confirm that it is tied to irregularities affecting multiple levels of the immune axis.There are multiple interlinked causative factors in the aetiology of schizophrenia. There are suggestions that the neuro-behavioural changes follow an abnormal response to microbial invasion, but that does not necessarily lead to an autoimmune process. The literature deciphering the role of viruses in neurotransmitter abnormalities linking neurodevelopment assaults and the neuropsychological manifestations of schizophrenia is unhelpful. For those who adhere to the autoimmune model of schizophrenia, the simplest suggestion would be that the pathogenesis of the subset of schizophrenia studied may be caused by antibodies in the plasma and CSF that react with brain proteins, resulting in a neuro-autoimmune process.

Lessons from Viral Infections

The concept that certain psychiatric disorders are the neuro-behavioural sequel of the body’s immune response to viral infections was prevalent in the early part of the 20^th century. That was an outcome of research conducted into rabies in the late 1880s, which revealed the affinity of viruses for the nervous system. Research into tertiary syphilis also provided evidence of an infectious aetiology for specific psychiatric disorders. Investigation of the encephalitis lethargica pandemic (1919 - 1928) contributed to recognition of viral causation on account of similarities apparent between the psychotic symptoms associated with encephalitis lethargica and the clinical presentation of schizophrenia. ²⁶

Post-influenza depression, depression following mononucleosis, and hallucination associated with herpes encephalitis are well recognised. Menninger, who studied post-influenza psychosis, promulgated the first acceptable viral hypothesis for schizophrenia. ²⁷ In the mid-twentieth century, psychodynamic studies began to encompass the origins of schizophrenia and viral aetiology lost its novelty. Dementias associated with Acquired Immune Deficiency Syndrome (AIDS) have reawakened interest in the correlation between virology and psychiatric disorders, and different authors have revisited these hypotheses in the last three decades. ^28-36

The immune response to influenza and other viruses involves cell-mediated immunity and cytokine activity, which tend to turn tryptophan into kynurenic instead of serotonin. The outcome of this deviation is mood disturbance. It is the body’s immune response that blocks the conversion of tryptophan into serotonin, thereby resulting in post-influenza depression. It is arguable that there may be other psychiatric disorders consequential to a slow immune response of the body to viral infections. The possibility of viral oncogenesis was originally ridiculed, but now there is some evidence to support the view that viruses are responsible, at some stage, for approximately 20% of human malignant diseases. ³¹

In theory, a virus could induce schizophrenic symptoms or depression by stimulating antibodies that cross-react with brain tissue, without necessarily gaining entry into the brain. At different developmental stages, the immune response may become less efficient and viral agents may become potentiated, leading to neuropsychiatric conditions. The supposedly inflammation-mediated brain diseases occur at different stages—for instance, schizophrenia in late adolescence or early adulthood, and Alzheimer’s typically at an advanced age. It is well established that the human immunodeficiency virus (HIV) may lead to a form of AIDS dementia, and other common viruses that infiltrate the neurons may cause other types of dementia. HIV/AIDS and Borna Disease Virus (BDV) in animals help to bring the infection-based model of schizophrenia to the realm of scientific imagination

Viruses can influence the human genome. After becoming effective, viral sequences are integrated into the genome of brain cells. These sequences are not thought to be inheritable, but may cause mutations that interfere with brain functions and contribute to the development of psychiatric disorders. ³⁷ It may be arguable that the combination of the body’s sustained immune response and the constant release of antigens of a hypothetical slow virus (schizovirus) may account for the neuro-behavioural alterations. In the following paragraphs, the author discusses how viral pathogens and other potential contributors could interact and lead to schizophrenic psychopathology.

Immune Responses

Neuro-developmental theories of schizophrenia fit the hypothesis that viral insult occurs early in sufferers, not proximally to a psychotic episode. The interaction between host and virus is affected by coordinated activity of the immune system and the brain. There is evidence that schizophrenia is accompanied by mutations in the immune system. Innate immunity is the first defence against microbes; infection results in invasion by live microorganisms and their toxic products, stimulating an inflammatory response. Neuronal functions are disrupted by pathogens and the brain’s inflammatory responses. Non-cytolytic viruses may affect neurones without causing cyto-architectural alteration, but disturbing neurotransmitter production and weakening hormones involved in neurodevelopment. ³⁸ In schizophrenia, immune infiltration is absent, as are vital inclusion bodies and minimal gliosis. There is subtle disruption of neuronal function and brain development, but no significant loss of neuronal cells. Thus, the schizophrenia subset may have a viral aetiological origin, bringing about anomalous, specific immune responses, an autoimmune basis, or both. What triggers the autoimmune process is uncertain, but microbial triggers are a strong possibility.

Immune dysfunctions including lymphocytic abnormalities, protein abnormalities, auto-antibodies, and cytokines have been suggested in seriously-ill patients ³⁹. One study showed significantly higher plasma levels of interleukin-6 (IL-6) in schizophrenics, and soluble IL-6R and soluble IL-2R were significantly high in mania. ⁴⁰ A few early investigators claimed to have microscopically visualised virus-like particles in the cerebrospinal fluid (CSF) of patients or in chicken embryos inoculated with CSF. Studies of viral antibodies, viral antigens, viral genomes, the cytopathic effect of specimens on cell cultures, and animal transmission experiments are other avenues for exploring the viral infection hypothesis.

The subset of schizophrenics in question may have a highly-sensitive surveillance system, but a less-discerning immune mechanism than the general population. It could be the over-reaction of the immune system to the microbial adversary that may eventually lead to the schizophrenia pathogenesis. The fault may lie in the surveillance system, as well as in the body’s anomalous response to the microbial invasion. ¹⁷ In general, innate and acquired immune mechanisms interact and cooperate, but any derangement can lead to deviant immune responses that may result in neuropsychiatric abnormalities.

From an evolutionary perspective, innate immunity is less evolved and the mammalian brain is endowed with a complex immune response system, implying that the neurobehavioral aberrations of schizophrenia could be more linked with deviant and vigorous specific immune responses. ¹⁷ It is possible that the proposed subset of schizophrenia may have either an autoimmune basis or a viral aetiological origin, bringing about anomalous, specific immune responses, or both. It has been argued that a gene family involved in the specific immune system and autoimmunity is involved in schizophrenia. ⁴¹ The genome-wide association studies (GWAS) have been disappointing in schizophrenia, whereas the major histocompatability complex (MHC) region continues to be the best replicated.

Epidemiological Findings

Epidemiological studies offer useful supporting evidence for viral aetiology (see Table 4). Epidemiological studies characterised by certain broad patterns of incidence and distribution of schizophrenia offer evidence to suspend the scepticism of the viral causal hypothesis. In a study of adults at risk of exposure in utero to the 1957 influenza A2 epidemic in Helsinki, those at risk during the second trimester had significantly more hospitalisations for schizophrenia than those potentially exposed during the other trimesters or immediate years. ⁴² Researchers for nine subsequent epidemiological studies scrutinised the risk of schizophrenia after possible intrauterine exposure to influenza in Europe and the USA; these identified a small majority claiming to find an association.⁴³ Falsifying the influenza link with the origin of schizophrenia does not altogether make the viral aetiology null and void. There could still be an unknown virus (schizo-virus) as the causative agent. The Hepatitis C virus came to medical attention only 15 years ago. At least these epidemiological studies illustrated that viruses can help set the stage for schizophrenia as a long-term sequel

Table 4 - Suggested Evidences for Viral aetiology

A worldwide average of 1% prevalence of “core schizophrenia” is generally accepted, ⁴⁴ even though such a concept of universal distribution and gender equality has opposition. ⁴⁵ However, there is evidence to assume that there may not be gross variations in this global prevalence. Cross-culturally stable rates, despite decreased fecundity in affected individuals, support an external biological aetiology. These point toward biologically-interlinked and multifactorial causation including an evolutionary genetic factor, as a single biological factor would be insufficient. The preservation of susceptibility genes for schizophrenia in the human gene pool is an evolutionary enigma; gene carriers or first-degree relatives may have some compensatory evolutionary advantage. ⁴⁶ In a multifactorial aetiological model of schizophrenia, infectious theories are contestable. ¹⁷

Such a consistent prevalence, if true, could also be argued in favour of a biologically-inter-linked and multi-factorial causation of schizophrenia, as it is obvious that a single biological factor would be insufficient to maintain a delicate and consistent global prevalence of a disease. Many viruses are relatively constantly distributed, while genetic diseases present distinct geographical clustering due to inbreeding. One may hypothesise that where viral loading is high, genetic input may be less and vice versa. The consistent global incidence points toward universal microbes, a readily-available environmental factor, or, more specifically, a “schizovirus.” The interaction of vulnerable host genes with a virus could yield epidemiology like that of schizophrenia.

Birth patterns rank highly among epidemiological observations in schizophrenia. ⁴⁷ Many more schizophrenics are born in winter and spring than in summer and fall. ⁴⁸ Infectious aetiology is a plausible explanation, as many viruses show a surge in the same months and viral aetiology is a more convincing explanation of the consistency in question. While gene coding for particular proteins is inherited, environmental and developmental factors are undoubtedly implicated in modulating genes’ expression.

Exposure to prenatal infections and other obstetric complications are neuro-developmental assaults that increase vulnerability to schizophrenia. ^49-52 In obstetrics, infection in the mother generates antibodies transmitted to the foetus, producing auto-antibodies that upset neural development and increase the schizophrenia risk. ⁵³

Schizo-Virus or any Microbe?

It is not certain whether it is body’s abnormal response to any virus and other microbes or a specific unknown virus that results in “schizophrenic reactions.” It is even unclear that the unbeatable antigens of this hypothetical virus alone are capable of inducing the neuro-behavioural changes associated with schizophrenia. The hepatitis C virus came to medical attention only 15 years ago. The rotavirus was isolated in 1973 and the HIV virus was isolated in 1983. Non-detection of a pathogen does not exclude its role in the pathogenesis. If a specific virus is responsible for schizophrenia, it should have been with human society for a very long time, as the illness has been reported from the beginning of recorded human history. Some people may have a genetic vulnerability to the hypothetical schizovirus; inheritability would lie in contracting the specific virus. Poliomyelitis has a concordant rate of 36% among monozygotic twins; the rest are attributed to environmental factors. The majority of children exposed to the polio virus may not develop poliomyelitis and a genetic propensity may be required for the viral manifestation. It is even reported that 10% of the world population rarely catch influenza, in spite of its yearly mutation.

Cardiac disease due to endocarditis (caused by an autoimmune process affecting many parts of the body), a sequel to acute rheumatic fever, is an analogy to demonstrate how, theoretically, a microbial infection may lead to impaired neurodevelopment and psychiatric disorders in a different scenario. Endocarditis is triggered by a reaction to streptococcal bacteria, not a bacterial infection. It may begin a chronic process, leading to valvular cardiac disease. Generally, rheumatic heart diseases are diagnosed 10 - 20 years following rheumatic fever. Similarly, schizophrenia could be an autoimmune complication of a subtle microbial infection; finding and countering the antigenic triggers of ADs may lead to an effective cure.

HIV/AIDS

Patients with HIV are at risk for developing psychiatric symptoms and disorders similar to those seen in the general population, as well as those that are direct effects of HIV. HIV is a neurotropic and lymphotropic virus that causes immune suppression and allows the entry of opportunistic pathogens with an affinity for the CNS. There is some evidence that HIV may trigger a psychotic episode and contribute to first-onset schizophrenia. ⁵⁴ Serious CNS complications occur late in the course of HIV infection, when the immunity function has diminished considerably. The viral load is closely associated with the degree of cognitive impairment. HIV-associated dementia (AIDS dementia complex) is defined as acquired cognitive abnormality in two or more domains and is associated with functional impairment and acquired motor or behavioural abnormality in the absence of other aetiology. It is estimated that 30% to 60% of patients experience some CNS complications during the course of their illness and 90% reveal neuropathological abnormalities at autopsy.

Pearce argued that HIV-related encephalitis could engender a scenario for a viral aetiology of schizophrenia. ¹⁷ HIV produces symptoms after being latent for several years. HIV was not identified as the aetiological agent of AIDS until the conditions for viral replication in lymphoid cell lines were identified. Prior to the evolution of PCR serology techniques, it was debatable whether the virus was in circulation at all. This indicates that the absence of a demonstrable virus does not mean the absence of a subtle virus-induced disease process. No virus, as such, is currently detectable in the schizophrenia disease process. Even in the absence of opportunistic infections, HIV infection of the brain causes severe neuro-behavioural syndromes, such as AIDS dementia, without infecting neurons, but by complex interaction with host molecules and non-neuronal cells. All these suggest that a rare or unknown infectious agent is involved; it would not be identified unless it was specifically tested for.

The finding that the neurophysiological and psychological stress of HIV infection can aggravate an underlying psychotic illness implies that viruses, without being a direct causative agent in psychotic episodes, can unmask pre-existing psychiatric vulnerabilities, acting on the brain physiology through unknown pathways. A curious aspect of HIV-related psychosis is that it responds to anti-psychotic treatment and to anti-retroviral drugs. Several anti-psychotic drugs have been shown to have antiviral properties, both in vitro ⁵⁵ and in vivo. ⁵⁶ The deduction is that a virus could initiate events resulting in psychosis, and anti-psychotic drugs can interrupt that sequence. All these features of HIV infections are consistent with the idea that a virus can cause neurobehavioral abnormalities after several years.

Borna Disease Virus

It has been recognised that Borna disease virus (BDV) could cause neuropsychiatric complications including neurological, behavioural, and mood alterations in animals. ⁵⁷ A ribonucleic acid (RNA) virus from the family Bornaviridae, it is a neurotropic virus with an affinity to a variety of hosts, particularly hoofed animals, and can cause persistent infection of the CNS. Such an infection may be either latent or chronic and slow, but BDV presents with the latent type, characterised by a lack of viral particles. It may resemble the alleged pathogens in non-affective psychosis. The severity of clinical symptoms depends on the immune response of the host.BDV can directly influence the CNS through the binding of viral proteins with neurotransmitter receptors and indirectly through immune response and inflammatory reactions.

Depending on the host’s age and the integrity of the immune response, an infection may be asymptomatic or involve a broad spectrum of behavioural disorders. The severity of clinical symptoms depends on the immune response of the host.^{58, 59} Unusual features of BDV biology include nuclear localisation of replication and transcription, varied strategies for the regulation of gene expression, and interaction with signalling pathways, resulting in subtle neuropathology.⁶⁰ BDV can directly influence the CNS through the binding of viral proteins with neurotransmitter receptors and indirectly through immune response and inflammatory reactions. The issue of human BVD infection has been recently questioned by American researchers who reported an absence of association of psychiatric illness with antibodies to BDV or with nucleic acids in serially-collected serum and white blood cell samples from 396 participants. ⁶¹ However, BDV in animals helps to bring the infection-based model of schizophrenia to the realm of the scientific imagination.

Neurotransmitters

It is an overstatement to say that schizophrenia is a neurotransmitter disease, although it is well established that it incorporates a derangement of dopamine activity. Some viruses have been shown to alter dopamine metabolism. ⁶² The literature deciphering the role of viruses in bringing about neurotransmitter abnormalities linking neurodevelopment assaults and the neuropsychological manifestations of schizophrenia is unhelpful. ⁶³ It has been reported that in rodents, BDV could crash neurotransmitter systems, including dopamine, neuropeptides, and glutamate. ⁶⁴ How viruses alter neurotransmitters is a central issue. Communication between the immune system and the brain is crucial to defend against viral infection; this is mediated through neurotransmitters. Viruses are bound to tamper with the intrinsic communication system as part of their cellular offensive. Some viruses have been shown to alter dopamine metabolism. ⁶⁵

Genetics

The undisputed genetic factor in schizophrenia may be posited to discount the viral hypothesis. However, genetic factors do not exclude environmental contributions. Monozygotic twins have a concordance rate of only 48%. Brief reactive psychosis due to acute sequels to viral infection, though regarded as unrelated to schizophrenia, may still be schizophrenic reactions and they do not progress to schizophrenia only because the sufferers are not genetically predisposed to schizophrenia. Genetic predilection may be attributable to genes that determine idiosyncratic differences in immune responsiveness to common viral pathogens.

Susceptibility and immune response to infectious agents are known to be subject of genetic control and may involve multiple interacting susceptibility genes. ⁶⁶ The genetic component of schizophrenia may engross multiple interacting susceptibility genes. These together or singularly may moderate the virus, and the virus and gene product may act at different points. Many cases would have a genetic foundation and it may be extremely rare to develop schizophrenia independently of a genetic anomaly. A small subset of patients may have a purely genetic form. Research should also be directed at identifying risk genes and why they assert themselves and cause the disease. Any future research which sheds more light on some people are affected more readily than others would bring researchers closer to more effective treatments and early intervention (see Table 5).

Table 5 - Future Directions

Summary

There are multiple interlinked causative factors in schizophrenia and viral infection may be only a trigger. Viral infections may be the cause of vigorous immune responses or triggering an autoimmune process that lead to neuro-behavioural aberrations and a subset of schizophrenia would emerge as viro-immuno-neuropsychiatric disorder or autoimmuno-neuro-psychiatric disorder. If such a subset of schizophrenia contains an autoimmune component, either triggered by infectious agents or due to unidentified intrinsic factors, the disease process would be determined by genetic vulnerability. There is not sufficient evidence established to identify viruses as being implicated in the aetiology of schizophrenia, but researchers have reason to anticipate further laboratory studies, as newer, more sensitive laboratory technologies are evolving. A viral or autoimmune model of schizophrenia may illuminate its pathogenesis, but not necessarily the diversity of psychiatric symptomatology. In the last few decades, schizophrenia research has been focussed on neurotransmitter derangements and neuro-developmental anomalies. The cause of a tsunami is not in the sea water, but due to the tectonic shifts under the sea bed; the aetiology of schizophrenia may be similarly due to immune alterations.

Pellagra psychosis due to niacin deficiency was hidden under the schizophrenia umbrella. ⁶⁷ There may be other psychotic disorders grouped under schizophrenia, and they may have a pure biological aetiology—chemical or infectious—but with genetic vulnerability. No one can be sure whether it is the toxic chemical of the pathogens or the immune response of the host, or both, that may lead to the psychopathology. Searching for this hypothetical virus is a challenging task, but if researchers found it, the benefits would be enormous. A viral aetiology of certain types of schizophrenia, if demonstrable, could affect radical changes in treatment and management. In fact, the hypothesis of viral aetiology is more promising than any other biological hypothesis, as it gives a message of potential drug cure. In this contest, it is interesting to note that the antigenic similarity between components of the streptococcus and cardiac tissue resulted in rheumatic heart diseases, but with the advent of penicillin, this disease has virtually disappeared. Only time will determine the validity and therapeutic prospects of the viral and autoimmune aetiology of schizophrenia.

Davison opined that as evidence accumulates about the autoimmune basis of at least a subset of psychiatric disorders, clinicians should keep abreast of immune-neuropsychiatric research. ⁶⁸ Psychiatry must constantly expand to meet the growing needs with the emergence of novel ideas in other medical specialities and it is high time to introduce a new terminology—“Psycho-immunovirology”—to study the viral aetiological mechanisms involved in psychiatric disorders like schizophrenia. Neuro-virology and psycho-immuno-virology could develop as an interdisciplinary field which represents a melding of virology, psychiatry, the neurosciences and immunology.

Angiogenesis is an integral process in biological programmes of embryonic development, tissue damage and regeneration, tumour growth and progression and pathogenesis of inflammatory and autoimmune diseases. MS (multiple sclerosis) is a demyelinating disease of the CNS (central nervous system). Angiogenesis has been a consistent feature of demyelinating plaques of MS^1-3. Many inducers of angiogenesis are expressed in these plaques. They are also closely associated with the animal model of MS viz. EAE (experimental autoimmune encephalomyelitis)⁴ (Table 1). This has led to the suggestion that inhibition of angiogenesis by suppressing these effectors or inhibiting the elements of angiogenic signalling pathways might provide a viable way to target therapy to manage MS.

Table 1. Angiogenic mediators of MS

[Note: Inhibitory effects of thalidomides were described by Sherbet⁴; D’Amato et al.⁶; Kenyon et al.⁷; Lu et al.⁸]

Multiple sclerosis is an autoimmune inflammatory condition and so immunomodulators have been used in treatment. It is recognised that aberrant activation of the immune system and the associated network of its regulation are important events in the pathogenesis of the disease. This is the rationale for using immunomodulatory agents in disease control. Among immunomodulators of note are Fingolimod which prevents infiltration of auto-destructive lymphocytes into the CSF, Teriflunomide which reduces lymphocyte infiltration of the CNS, axonal loss and inflammatory demyelination, and dimethyl fumarate, which modulates the immune system by many mechanisms. Furthermore, much attention has been devoted to the immunomodulatory properties of MSCs (mesenchymal stem cells) ^4,5. Thalidomides are also capable of modulating the function of key element of the immune system related to the pathogenesis of MS, but this brief article is intended to emphasise the potential of thalidomide and its analogues as potent inhibitors of angiogenesis and the latent possibility of their use as a therapeutic agent in the control of MS.

Thalidomide was introduced over four decades ago to treat respiratory infections and to combat morning sickness in pregnant women. It was withdrawn when it was found to be highly teratogenic. The teratogenic effects are a result of the binding of thalidomide to cereblon, a protein found in both embryonic and adult tissues. Cereblon is required for normal morphogenesis. It is inactivated by binding to thalidomide and this leads to teratogenesis⁹. Thalidomide possesses immunomodulatory, anti-inflammatory, anti-angiogenesis and cell proliferation inhibitory properties and this has suggested its use in the treatment of cancer⁵. Analogues of thalidomide, viz. lenalidomide and pomalidomide, have been synthesised and these possess reduced toxicity and greater efficacy^{10, 11}. Recently, many studies have elucidated the signalling pathways which thalidomides inhibit and thereby suppress cell proliferation, promote apoptosis and inhibit angiogenesis. These have led to the suggestion of combining the modulators of these signalling pathways to synergise with thalidomides to deliver the suppressor effects with enhanced efficacy and at lower concentrations thus reducing the side effects⁵ (Figure 1).

Most of the work on the efficacy of thalidomide and the analogues has been carried out in preclinical models. Quite understandably, in the clinical setting very little effort is seen to check whether thalidomide or the analogues provide any beneficial effects in MS or neuro-inflammation. Clinically orientated investigations so far relate mainly to multiple myeloma and some other forms of haematological malignancies but not solid tumours⁵. Any perceived beneficial effects are probably outweighed by the side effects. We need to expend more effort and design and develop new analogues with reduced toxicity. In this context one should emphasise that pre-clinical exploration of the potential synergy between the thalidomides and the acknowledged modulators of the signalling pathways would be worthwhile. This might enable the delivery of benefits more effectively and at lower dosages. It is needless to say that safety of drug administration is of paramount importance.

Poetry is a way of expressing the subjective experiences that spill over the rational mind and it permits spontaneous overflow of subjective feelings. The ability to express oneself through poetry, and share that experience, is one of the unique human experiences that distinguish us from lower biological forms. The strife and struggle of modern men have made them miserable wretches on the face of this beautiful cosmos, and the technological revolution has taken the poetic sense from them; a time old coping mechanism. Those not capable of expressing their own sorrows and joys of everyday life in poetic words could find a surrogate writer in The Gushing Fountain.

In his collection of poetry, Dr Latoo (who is currently working as a Consultant Psychiatrist in United Kingdom) has catered poems for every mood and occasion: love, parting and sorrow, inspiration, rapture, memory, nature, solitude, and contemplation. Some of them are deeply personal and the author is trying to unearth a time capsule he had left in his native country of Kashmir. Dr Latoo appears to be searching for inner truths and making a self exploratory pilgrimage in his collection of poetry. Poetry has the power to describe and dramatize one’s own life, and Dr Latoo has done it well. The themes generally move from childhood to old age, love to grief, sorrow to joyfulness, aggressive nationalism to corrupted politicians, and depression to psychosis. There are pearls of mystical wisdom embedded in the poetry:

“Be choreographed by a great master for our sustenance
Rather than just be a part of random unplanned accident?”

There are wise statements in “Divine Justice”:

“Anything like fatalism shall be a contradiction
Of the Divine justice, free will and Lord’s will.”

All poetries have some hidden messages, and the book as a whole stands for immense moral values. “Woman” stands for women’s rights and dignity. The thoughts about the forgotten orphans are heart touching. “Behold a Man - Judging others” points towards the fallacy of judging other people without correcting oneself. Mental health professionals are particularly prone to this error because they are often professionally bound to assess their clients; we are only supposed to assess others and not judge others. We should not even judge ourselves, but only do self-assessment - God is the only Judge. The author writes about very ordinary humble human beings like the barber, Rupa, Ayesha, Ahmed, Puja etc. “Marriage” highlights the sanctity of wedlock. These poetries reflect the world view of the author. “Hold fast to thy dreams” may be inspired by Langston Hughes (1902 - 1967) and reminded me of my father who liked the verses of Hughes on dreams. “A raven who wants to be a dove” refers to people who pretend to be what they are not - wearing borrowed garments.

There are also poems about the author’s travelling experiences. A century ago, if a poet wrote about airport, he would have been frowned upon by the peer group, but in the 21^st century it is appropriate to write such poetry. “Noisy airport and my mind” illustrates the hustle and bustle of contemporary life and gives the book a modern flavour. “By the Dal Lake” is nostalgic and the author is trying to recapture and share his lost Kashmiri literary Empire with the readers. Born in Kashmir, there is no surprise that the author renders beautiful nature in his poems. One wonders, if William Wordsworth were born in Kashmir, what would have been the content of his writings. Dr Latoo’s dual identity is evident when he writes about Kashmir and London.

In these days of global union through mere technology, poetry may have a serious role in the “international soul-union.” The days of regional poetry are over. Poets like Dr Latoo may be able to contribute to the formation of a healthier global village; poetry penetrates beyond the psychic realm into the spiritual dimension. There is a mission of peace and love in the Gushing Fountain, and the author is not enforcing any strong convictions on the readers. There is a poet-philosopher in the author of the Gushing Fountain.

The author has used rhyming and free verse styles of poetry. Metaphors and similes are appropriately embedded in various situations:

“A smile on our face blooms the gardens of her innocent soul
A tear in our eyes arises from the blood of her bruised heart.” (From the poem, “Mother”)

Lyrical poetries are ravishingly harmonious and there are no repetitions. The thoughts are clear and there is an exotic element in all the poetry. On the whole, all the poems are cerebral and riveting. The works are relevant to the present century and can be appreciated by scholar and casual readers alike. Every poem is an experience to be savoured and memorised. Let these pieces of poetry echo and reverberate not only in the conflict-ridden valleys of Kashmir, but all around the world until they find rest in the minds of the waiting millions.

Psychiatry is going through an identity crisis because the newer medications are not as effective as expected to be and clinicians are turning to different forms of psychotherapy. Poetry/lyric therapy could be another form of psychotherapy that needs attention in the field of soft psychiatry. Dr Latoo’s book could be an inspiration and encouragement in this line of treatment. Hypnotherapists readily recognize that words are like loaded bullets and are highly potent. To an extent, poetry therapy involves the principles of both hetero- and self- hypnotherapy. Primitive and modern religions take advantage of the potentials of different forms of poetry in religious rituals for healing and promoting health.

A study of the mechanism of poetry writing is helpful in developing better conceptual models of creativity and deeper understanding of mental process. Sudden flashes of creative insight and other intuitive leaps, which arise from states of mind through intermediate steps that remain hidden beneath consciousness, and such ultrafast processing involving a concealed intermediate step, is consistent with quantum computations. A poet who enjoys superior mental health is capable of swinging from the unconscious quantum logic to the classical logic of consensus consciousness with an ultrafast speed. In psychotic states, “the quantum gates” do not shut swiftly as in normal mental states and the sufferers get trapped in the quantum logic. The usefulness of poetry therapy in psychotic patients, who get stuck in the quantum logic of the unconscious mind back to the classical logic of ordinary consciousness, needs further analytical studies. The primary aetiology of psychotic disorders may be biological, but secondary symptoms are quantum-linked and the new generation of psychotherapists have to learn the quantum meta-languages to communicate with psychotic and depressed patients. Poetry is such a source of quantum meta-language.

Poetry therapy promotes abstract thinking and develops imaginative powers. It is also a means of relieving and revealing innermost sentiments; it helps to ventilate overpowering emotions and hidden tensions. It is a form of self-expression and aids to build greater self-esteem; useful in strengthening interpersonal skills and communication skills. It would be valuable in repairing the assault of psychosis on the personalities of the sufferers. Quoting from my own memory lane, I became interested in poetry therapy when I comprehended the core problem of a patient who wrote:

“Moon, you shine at the centre of the sky,
Catching attention from all over the world,
Don’t you know that I am lonely?”

Poetry is of the heart and imagination whereas science is about reason and logic and may be grounded on contradictory principles. If science is about objectivity, poetry is essentially about subjectivity and to blend those human experiences harmoniously is a hard task; Dr Latoo has successfully achieved this goal. A man of science, when he writes poetry, has to liberate himself from the shackles of rationalism so that he can be a wholly free human: to be a poet one has to be a natural human being. To quote from Jean-Jacques Rousseau: “Man is born free and everywhere he is in chains.” Let us hope that the Gushing Fountain will have a part two and even more!

All sciences end as poetry!

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.

Case Report

A 41-year-old woman with a 6-year history of mild psoriasis presented with a rash under her breasts. The differential diagnosis included flexural psoriasis, an allergy to the nickel in her under wired bra, and intertriginous dermatitis (moisture-associated skin damage). She was prescribed Trimovate cream (GlaxoSmith Kline) and developed a florid weeping eczema within 48 hours of application (Figure 1). The eczema settled with the withdrawal of Trimovate and application of Betnovate RD cream (GlaxoSmith Kline). The history was very suggestive of a contact dermatitis to Trimovate cream.

Figure 1 showing eczema

She was referred to the Dermatology department and was patch tested to the European standard, medicament and steroid batteries. She had a number of positives including cetearyl alcohol, sodium metabisulphite, and clobetasone butyrate. These are all components of Trimovate.  She was given advice sheets on all her allergens and on avoiding them she has had no recurrence of eczema.

Discussion

Contact dermatitis is a type IV allergy and usually appears within 2 to 3 days after contact with an external allergen. This case is likely to be an example of concomitant sensitisation, where one sensitivity facilitates the acquisition of another sensitivity to a chemically unrelated ingredient within a product.Whilst there has been a previous case report of concomitant sensitivity to sodium metabisulphite and clobetasone butyrate in a patient using Trimovate cream,¹ this is the first report of a patient reacting to three of the ingredients found in Trimovate - sodium metabisulphite, clobetasone butyrate, and cetearyl alcohol. Allergy to clobetasone butyrate is rare, with only 5 previously reported cases.^{1, 2, 3} Allergy to sodium metabisulphite is not uncommon, producing a positive reaction in approximately 4% of patients who are patch tested.^{4, 5} Allergy to cetearyl alcohol is also rare, with one study estimating the incidence of positive reactions to be 0.8% among 3062 patients that were patch tested.⁶

Detection of the allergen, or allergens, is important, as avoidance results in resolution of the eczema. Our patient highlights the fact that it is insufficient to simply advise a patient to avoid the topical medicament that has caused a reaction. Ideally, patients with a topical medicament allergy should be patch tested to identify which components the patient is allergic to, so that they can be avoided in all products. In this case, in addition to Trimovate, there are a number of other products that our patient will now avoid. This is of particular significance in view of her history of psoriasis, for which she has used moisturizers and topical steroid preparations in the past, and will likely need again in the future. Clobetasone butyrate is often used in facial and flexural psoriasis. Cetearyl alcohol is a particularly important allergen to identify, as it is found in many products including a number of commonly used moisturizers such as Diprobase (MSD), Cetraben (Genus) and Epaderm (Mölnlycke) cream, and most steroid creams although not steroid ointments. Our patient was therefore advised to use only steroid ointments and has had no recurrence of the contact dermatitis. To conclude, GPs should consider sending their patients with contact dermatitis for patch testing, as the identification of all allergens is valuable to management.  

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

Figure 1

What is the eye finding?

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

Correct Answer:

3. Kayser Fleischer ring

Discussion:

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

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

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

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

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

Introduction

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

Classification

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

Table.1 Classification of phytochemicals with notable food rich sources

Table. 2 learning points

Clinical evidence for cancer prevention.

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

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

Clinical evidence for a benefit after cancer

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

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

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

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

What are the likely anti-cancer mechanisms of phytochemicals?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Conclusion

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

Introduction

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

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

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

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

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

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

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

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

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

Aim

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

Method

Participants

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

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

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

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

The culture palette: six different cultural packages

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

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

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

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

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

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

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

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

Evaluations

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

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

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

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

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

Procedures/implementation

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

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

Data analysis

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

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

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

Results

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

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

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

Table 1

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

Figure 1a

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

Figure 1b

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

Figure 1c

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

Figure 1d

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

Discussion

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

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

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

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

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

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

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

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

Limitations

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

Conclusion

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

Introduction:

Dengue made its debut as early as 1780, when Benjamin Rush described the condition as “break bone fever”. This hitherto unfamiliar infection has now grown to demand the attention of all public health care providers. It is a mosquito borne, fast emerging, viral infection manifesting in four serotypes ^(1). Approximately 2.5 billion people, living mainly in urban areas of tropical and subtropical regions, are estimated to be at risk of acquiring dengue infection ⁽²⁾. While dengue is endemic in more than 100 countries, most cases are reported from Southeast Asia and the western Pacific regions. Around 50 million cases and 24,000 deaths are estimated to occur in these 100 endemic countries. This includes hospitalisation of nearly half a million cases of dengue haemorrhagic fever (DHF), of which 90% are children. Treated (DHF)/dengue shock syndrome (DSS) is associated with a 1% mortality rate while mortality rate among untreated cases escalates to 20%^(3,4).

India is one of the seven identified countries in the Southeast Asia region regularly reporting incidence of DF/DHF outbreaks. The first confirmed report of dengue infection in India dates back to 1940s, and since then more and more new states have been reporting the disease which mostly strikes in epidemic proportions often inflicting heavy morbidity and mortality, in both urban and rural environments^.(5)

The various manifestations of dengue may not have a distinct line of demarcation: apart from the classic features, reports of rare presentations have recently become more frequent ^(6,7). During recent outbreaks in India, the clinical manifestations which were shown by the patients were slightly different from those in previous years^(8).. There have been many reports of difficulties in the use of the previous classification, which were summarised in a systematic literature review ⁽⁹⁾. Difficulties in applying the criteria for dengue haemorrhagic fever in the clinical situation, together with the increase in clinically severe dengue cases which did not fulfil the strict criteria, led to the request for the classification to be reconsidered .Hence, WHO revised the dengue case classification into dengue (with or without warning signs), and severe dengue ⁽¹⁰⁾.The present study was done to analyse the clinical features, complications, cost incurred and outcome of cases admitted to a tertiary care teaching hospital in Bangalore.

Methodology:

A record based descriptive study was conducted in paediatric patients admitted with signs and symptoms suggestive of dengue fever to KIMS hospital Bangalore, during the period between January 2012 to December 2012. SD BioLine kit was used for testing with NS1 antigen\ IgM\ IgG. The medical records were perused for collecting data about these cases using a pre-designed proforma. Data was analysed for the clinical presentations, outcome and direct cost incurred in respect to hospital charges and laboratory investigations.

Results:

Out of 1230 cases admitted with clinical signs and symptoms suggestive of dengue syndrome 757 (61.5%) cases were found to be NS1 antigen\ IgM\ IgG positive for dengue. Among the 757 positive cases, males were 499 (65.9%) and females 258 (34.1%). The majority of the cases were in the school going age group and this consisted of 310 cases (41%) and adolescent children which accounted for 249 cases (33%), the median age being 8 years of age. The least number of cases were seen in infants which accounted for 45 cases (6%).

Table 1. Sex distribution

The majority, 88.5% of cases presented as dengue fever without warning signs, 6.34% with dengue fever with warning signs and 5.15% with severe dengue. Of the cases with warning signs 92.3% of cases had fever, 42.5% cases had vomiting and 38.2% cases had abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority (87%) presented with petechiae followed by haematemesis (9%) and epistaxis (4%). Rashes were seen in 4% and arthralgia in 13% of cases. Pleural effusion was seen in 21% of cases and ascites was seen in 16% of cases. Complications in the form of acute respiratory distress syndrome (ARDS) was seen in 12.06% cases, 6% cases showed neurological manifestations in the form of encephalopathy and 1.3% cases had renal failure.

Table 2. Severity of dengue

Table 3. Presenting complaints

Fig 1 presenting complaints.

Haemoglobin level of > 12gm% was found in 73.4% cases, 9-12gm% in 23.4%, 6-9gm% in 2.1% and <6 gm% in 1.1% of cases. Platelet count of < 20,000 was found in 21.5% of cases, 20-50 thousand in 39.5% , 50,000 to 1.5 lakh in 36% of cases and >1.5 lakh was found in 3% of cases. Majority (65.5%) of cases were NS1 Ag positive alone or with IgM/ IgG/ or both positive.

Remaining were positive for either of the antibodies.13.7% cases werepositive for all the three i.e. Ag, IgM,& IgG. The mortality rate was found to be 8.6%

Figure 2: outcome

Cost incurred which includes direct cost (transporting patient to the hospital, diagnostic testing and laboratory investigations, medications, hospitalisation, food) was found to been average of Rs.12,611=00. The indirect cost loss of wages of patient &attendants) was found to be an average of Rs.3, 109=00. The hidden cost (out of pocket expenses) was found to be an average of Rs.50=00. The cost of treatment of other co-morbid conditions was found to be an average of Rs.2, 275=00. The total cost of treating dengue syndrome was 18,045=00

Discussion:

In the present study it was found that males were commonly affected and the most common age group was between 5 to 15 yrs of age. Similar results were reported in a study by Faridi et al, 76% of all cases of DHF /DSS were aged 6 years or more^[11].

In the present study, the most common presenting symptoms was fever followed by vomiting and abdominal pain which is similar to study done by Kumar A et al showed fever in 99.2% followed by myalgia (64.6%), vomiting (47.6%), headache (47.6%) and abdominal pain (37.5%) ⁽¹²⁾.

In the present study, the most common bleeding manifestation was haematemesis and epistaxis. In a study by Ratageri et al, common bleeding manifestations were gastrointestinal bleeding (22%) and petechiae (18%) ^[13]. The gastrointestinal tract was reported as the commonest site of bleeding (61%) in a study by Ahmed et al ^[14].

In the present study majority of cases had platelet count between 20,000 to 50,000/mm3.In a study by Kamath et al, platelet counts less than 50,000/mm were noted in 62.3% ^[15]. In our study complicated cases showed ARDS and neurological manifestations in the form of encephalopathy. Almost all the cases which expired were found to have ARDS. Dengue associated ARDS is associated with a high mortality ^[16]. Dengue infection is found to cause neurological manifestation ranging from non-specific symptoms to encephalitis and rarely Guillain-Barre Syndrome ^[17]. In our study the mortality rate was found to be 8.6% , in the study by Anju et al overall mortality seen was 6% ^[18], compared to 3% by Ahmed et al ^[14].

Conclusion:

The seropositivity for dengue was 61.5% with NS1 antigen\ IgM\ IgG. Males were commonly affected and most vulnerable age group was found to be 5-15 year olds. The median age was 8 years. 88.5% of cases presented as dengue fever without warning signs, the remaining being dengue with warning signs and severe dengue. Fever was the most common symptom seen followed by vomiting and abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority presented with petechiae followed by haematemesis. The mortality rate was 8.6%. Acute Respiratory Distress Syndrom (ARDS) and multiple organ dysfunction syndrome (MODS) was found to be the most dreadful complications with high rates of mortality .

In this study it was found that cost incurred which includes direct cost (transporting patient to the hospital, diagnostic testing and lab investigations, medications, hospitalisation, food) was found to bean average of Rs. 12,611=00. Thus dengue syndrome also causes significant economic burden on the patients.

In the recent few years, the world has seen varied clinical presentation of the dengue fever in different epidemics, even in the same regions and even with the period of time. Where some known features are still manifesting, few atypical features are noted from several parts of the world. A continuous seroepidemiological surveillance and timely interventions are needed to indentify the cases, so that its complications, outbreak and mortality can be minimised.

Moreover community awareness, early diagnosis and management and vector control measures need to be strengthened, especially during peri-monsoon period, in order to curb the increasing number of dengue cases.

INTRODUCTION

Anaesthetic management of a patient with a tracheal tumour is challenging, as the airway is shared with the surgeon and patency must be maintained despite airway manipulation.

Several anaesthetic techniques have been used in patients requiring tracheal resection and reconstruction. Cardiopulmonary bypass standby after femoral artery and vein cannulation and then intravenous/inhalational induction while oxygenating the patient has been considered to be a reasonable approach. Intratracheal tumours are challenging to anaesthetists because of the difficulty in establishment of a patent airway before commencement of surgery. The principal anaesthetic consideration is ventilation and oxygenation in the face of an open airway.

CASE REPORT

A 56 year old male with no other co-morbidities presented to the Thoracic Oncology department with a history of progressive dyspnoea and orthopnoea.On examination he was found to have dyspnoea at rest and could not complete full sentences while talking. Change of position made no difference to his symptoms.

Routine blood investigations which included full blood count, renal and liver functions, coagulation profile, ECG and 2DEcho were within normal limits. PFT showed a typical intrathoracic obstructive picture.

His chest X-ray showed bilateral hyperinflated lungs suggesting airtrapping. CT of the chest showed an intratracheal growth about 4 cm above the carina almost completely obstructing the lumen. An awake flexible bronschoscopy confirmed the CT scan findings. A 2.7mm flexible bronschocope was passed with difficulty beyond the tumour to visualise the carina. Excision of the intratracheal tumour was planned with possible resection and anastomosis of the involved tracheal segment. A careful perioperative plan was  discussed and decided in agreement with the thoracic surgeons, anaesthetist, cardiovascular surgeons and the rest of the team members.

Flexible and rigid bronchoscope, a Sanders venturi, an additional anaesthesia machine and various sizes of reinforced and normal endotracheal tubes and tracheostomy tubes were kept ready.

Preoperatively the patient had incentive spirometry and bronchodilator nebulisation and intravenous steroids. An awake epidural at T9-10 level and radial artery cannulation were done under local anaesthesia without any problems. Two 16 gauge peripheral IV lines were sited under local anaesthesia.

After adequate preoxygenation anaesthesia was induced with IV propofol along with oxygen and sevoflurane with BIS monitoring.  As mask ventilation proved to be easy the patient was paralysed with suxamethonium. There was no difficulty in ventilation after muscle paralysis. An 8.5 number COETT portex tube was placed in  the trachea with the cuff just beyond the cords to avoid possible trauma to the tumour. Since there was preoperative evidence of airtrapping, ventilator settings were set to an I:E ration of 1:3 with a tidal volume of 550ml, respiratory rate of 12-14 per minute and PEEP of 4. At these ventilator settings the airway pressures were reaching up to 22 cm of  H20 and ETCO2 reaching a maximum of 40mmHg. Anaesthesia was maintained with oxygen: air with sevoflurane and atarcurium for muscle paralysis.

Flexible bronchoscopy was done to confirm the position of the endotracheal tube, which showed that the ETT was adequately above the tumour.

A laryngeal drop procedure was done in the supine position with neck extension to facilitate mobilisation of the trachea for resection anastomosis. After the laryngeal drop procedure a right thoracotomy was done in the left lateral position. At this point of the procedure, the patient was ventilated with low tidal volumes of 300 and respiratory rate of 16-20 to keep the ETCO2 at around 40.The right lung was surgically retracted and the trachea  was exposed up to the carina. A repeat bronchoscopy was done through the ETT to help identify the upper and lower extent of the tumour. The trachea was then opened below the tumour, after which a 6.5 reinforced tube was introduced through the left bronchus to aid ventilation of the left lung. This ETT was withdrawn intermittently to help visualisation and aid surgical excision of the tumour and  sleeve resection of the trachea. The left lung was ventilated till partial closure of the trachea. The left-sided tube was then removed. Ventilation resumed through the orotracheal tube with intermittent occlusion of the defect with gauze by the surgeon.  The orotracheal tube was adjusted under vision before closure of the trachea to position it above the anastomotic site. The trachea was sutured and the thoracotomy incision closed without any adverse event. The neck was kept in a flexed position to avoid tension on the tracheal anastomotic area.

The patient was then extubated in the immediate postoperative period without any problems and the recovery was uneventful.

DISCUSSION

Anaesthetic management of a patient with a tracheal tumor is challenging, as the airway is shared with the surgeon, and patency must be maintained despite airway manipulation^{1, 2}. Several anaesthetic techniques have been used in patients requiring tracheal resection and reconstruction ^3–5.

Primary tracheal masses are very rare and mostly malignant, occurring in 0.2 in 1,00,000 persons per year ⁶ and among these squamous cell carcinomas form the main bulk. Cardiopulmonary bypass standby after femoral artery and vein cannulation and then intravenous/inhalational induction while oxygenating the patient with the oxygen inhalation has been considered to be a reasonable approach ⁷. Byrne JG et al (2004) advocated planned use of CPB to facilitate complete resection of thoracic malignancies after careful patient selection ⁸.

These patients are often mistaken to have asthma and require treatment with inhaled corticosteroids and beta agonists ⁹. They are generally treated for many years for asthma or COPD, unless a CT scan or endoscopic procedure is done for the symptoms ¹⁰. Intratracheal masses usually start getting symptomatic when 75% or more of the tracheal lumen is obstructed. Tracheal lesions present at lower level can have more complicated management of airway, anaesthesia and surgery for successful and safe removal of the mass. ¹⁰

Intratracheal tumours are challenging to anaesthetists because of the difficulty in establishment of a patent airway before commencement of surgery. The principal anaesthetic consideration is ventilation and oxygenation in the face of an open airway. Ventilation can be managed in many ways, including manual jet ventilation, high frequency jet ventilation, distal tracheal intubation, tracheostomy, spontaneous ventilation and CPB.¹¹

Knowledge of various techniques available for management of such cases is vital. In order to have a successful and safe outcome it is extremely important to have good communication between the anaesthetic, surgical and intensive care team.

The challenge in managing such cases lies in establishing and maintaining a patent airway and also preventing seepage of blood and tumour particles distally into the tracheobronchial tree during the surgery.

There is a possibility of total airway obstruction during ventilation attempts using positive pressure because airway obstruction has a fixed and dynamic component. Dislodgement of the tumour, possibly from trauma following intubation causing total obstruction, should also be considered.

Thus an intratracheal tumour was successfully removed without any complications and by avoiding CPB. This case report also highlights the importance of proper planning and good communication between team members to ensure a successful and safe outcome.

Introduction

Increasing number of term deliveries undergo induction of labour (IOL). This figure is as high as 1 in 4 in developed countries, making it one of the most common procedures a woman may experience in pregnancy. ¹ IOL may be achieved with pharmacological, mechanical or surgical methods. ^{1, 2} Mechanical methods were the first methods used to ripen the cervix and induce labour. The National Institute of Clinical Excellence (NICE) does not recommend the routine use of mechanical methods for IOL as only heterogeneous small studies were available at their time of publication more than half a decade ago. ² However, since then there is increasing evidence of safety and efficacy of mechanical IOL. Subsequent publications including those from World Health Organization (WHO) and Cochrane Database of Systematic Reviews support the use of balloon catheter for IOL. ^{1, 3} It is therefore important to revisit the role of mechanical methods of IOL.

The Cochrane Database of Systematic Reviews concluded that mechanical methods of induction of labour have a lower risk of uterine hyperstimulation with similar caesarean section rates and delivery within 24 hours as prostaglandins. Furthermore, mechanical methods reduce the risk of caesarean section when compared with oxytocin induction of labour. ³ This review is consistent with another earlier systematic review. ⁴

Both Pfizer’s Prostin (PGE) and Cook Medical’s Cervical Ripening Balloon (CRB) are licensed for IOL. While the use of Prostin is a standard care in Singapore, the CRB has not been used routinely. We therefore propose a study to evaluate the use of CRB for IOL in Singapore.

Methods

A prospective cohort randomised controlled study was conducted in a tertiary referral maternity unit in Singapore. Pregnant women aged 21 – 40 years old with a singleton pregnancy with no major fetal anomaly who were suitable for vaginal delivery and scheduled for a planned IOL at 37⁺⁰ to 41⁺⁶ weeks gestation were invited for the study. Cases were excluded if at the start of the planned IOL, they were in spontaneous labour, had a cervical dilatation of ³3 cm, had confirmed rupture of membrane, had abnormal cardiotocogram (CTG), had a scarred uterus such as previous caesarean section, had malpresentation in labour, or if caesarean section delivery was indicated. Women who were unable to give or had withdrawn their consent to participate in the trial were also excluded for the study.

All suitable pregnant women receiving team care who require elective IOL were identified in antenatal clinic, antenatal or labour wards by the attending doctor or clinical research coordinator (CRC). Following routine counselling for IOL by the attending doctor, the woman will be offered participation in the study and a member of the research team will counsel and obtain informed consent from her. The woman will be made to understand that participation in the study is voluntary, does not affect her medical care and consent for participation can be withdrawn at any stage of the study. Women who were uncertain in their participation were offered the opportunity to participate during her follow-up or on the day of IOL after further consideration. Patient information leaflet on IOL as well as information of the study were made available to the participants.

On the day of the IOL, the participants were reviewed for the appropriateness of the IOL and participation in the study. A presentation scan, vaginal examination for cervical dilatation and CTG were performed. If they were suitable, they were randomly allocated PGE or CRB IOL in labour ward. Randomization was achieved with third party sealed envelope allocation. A total of 75 envelopes containing a folded paper with the words “Cervical Ripening Balloon” and another 75 identical envelopes containing a folded paper with the word “Prostin” were prepared and shuffled after sealing. These randomized envelopes were then labelled sequentially with their randomization allocation number from 1 to 150. The participants who underwent randomization were allocated to the next randomization allocation numbered envelop which contain either allocation for CRB or PGE IOL.

Participants undergoing CRB IOL will have the CRB inserted after cleaning the vulva and vagina with Cetrimide solution. The uterine and vaginal balloons of the CRB will be gradually inflated with normal saline, initially 40 ml and 20 ml respectively, and a further 20 ml each hour later until each balloon is 80 ml. CTG monitoring was undertaken before and after each inflation for at least 20 minutes. If the participant was not in labour after complete inflation of the balloons, she would be transferred to the antenatal wards for rest before removing the CRB 12 hours after insertion in labour ward when possible.

Participants undergoing PGE IOL will have 3 mg Prostin tablet inserted in the posterior fornix after cleaning the vulva with Cetrimide solution. CTG monitoring was also undertaken for at least 40 minutes after PGE insertion. If the participant was not in labour, she would be transferred to the antenatal wards. If there was no response to the first PGE, a repeat dose was given after 6 hours in labour ward when possible.

Participants will undergo artificial rupture of membrane (ARM) and/or oxytocin infusion augmentation of labour as necessary. If the participant was not in labour or ARM was not possible after removing the CRB or 2 cycles of PGE, the participant would have been considered having a failed IOL and will leave the study protocol with her subsequent management determined by the specialist attending to her. This would typically involve insertion of a third or first PGE in the PGE or CRB arm respectively.

Upon delivery of the pregnancy, a member of the research team will interview the participant and obtain demographics, labour and delivery outcomes data from the clinical notes. Pain and maternal satisfaction scores and comments were also recorded by interviewing the participants in the post-natal period; these findings will however be discussed separately.

The data was collected on a pro forma and entered into an excel spreadsheet. The data was then analysed using IBM SPSS Statistics version 19.

This study was approved by the SingHealth centralised institutional review board with the reference number of 2013/553/D.

Results

A total of 138 women were approached to join the study but 40 (29.0%) women declined. There was no significant difference in maternal age (27.8 ± 5.4 vs 28.7 ± 5.2 years; p = 0.373), ethnicity, proportion of primigravidae (62.5% vs 53.1%; p = 0.349), weight (61.2 ± 15.4 vs 64.4 ± 13.8 kg; p = 0.228), BMI (24.8 ± 5.8 vs 25.3 ± 5.0 kg/m²; p = 0.646) and primary indication for IOL between women who declined and accepted enrolment to the study respectively.

The remaining 98 women were enrolled for the study. Eight-seven women were randomized after excluding 6 women in spontaneous labour, 1 woman with non-cephalic fetal presentation, and 1 woman had confirmed ruptured of membrane on admission for their IOL, as well as 3 other cases in which the women presented for IOL without the availability of the research team (figure 1).

Figure 1. Flow diagram of recruitment, randomisation and completion status

In the CRB arm, one woman withdrew from the study after 8 hours 55 minutes as she felt the discomfort was too unbearable. Another woman was excluded when she was found to have spontaneous version to breech in labour. One woman randomized to PGE did not receive it as she went into spontaneous labour prior to IOL. Another woman in the PGE arm was subsequently found to be only 36⁺³ weeks and was therefore excluded from analysis (figure 1). The remaining 83 cases were analysed and their characteristics are shown in table 1.

The induction to vaginal delivery time, as well as, vaginal delivery rate were similar in both arms of the study (table 2). Compared to PGE arm, participants undergoing CRB IOL were faster in achieving cervical dilatation ≥4 cm (14.4 ± 5.7 vs 23.5 ± 16.6 hr; p = 0.001) and requesting epidural (16.4 ± 5.4 vs 23.2 ± 15.8 hr; p = 0.040), as well as more likely to require oxytocin infusion for augmentation (77.4% vs 50.0%; p = 0.020). Uterine hyperstimulation defined as >5 contractions every 10 minutes was only found in PGE arm. Cervical dilatation from 0 – 2 cm to ≥4 cm was achieved without regular contractions in 2 (6.9%) cases in the CRB arm and 1 (2.4%) case in the PGE arm. The mean frequency of uterine contractions at cervical dilatation ≥4 cm was 2.5 ± 1.4 in 10 minutes for CRB arm compared to 3.8 ± 1.4 in 10 minutes for PGE arm (p <0.001). No case of uterine rupture was observed.

There was 1 (3.2%) case for failed CRB IOL where both uterine and cervical balloons were found in the vagina suggesting that either placement of the uterine balloon was not optimal or it was expelled after placement. The woman went on to have Prostin and delivered vaginally. In the 9 (17.3%) cases in the PGE group that did not respond after 2 cycles, all went on to have the third Prostin successfully except for 2 women who required Caesarean section for persistent failed IOL.

The birth outcomes of both arms of the study were also similar with no case of stillbirth (table 3). There were 2 case of neonatal intensive care unit admission in the PGE arm for continuous positive airway pressure therapy; both were discharged from NICU within 24 hours.

Table 1. Characteristics of participants undergoing cervical ripening balloon (CRB) and Prostin (PGE) induction of labour.

¹ Values are mean ± SD, p calculated with Student t-test; ² Values are percentage (n), p calculated with Pearson chi-square test; ³ Values are percentage (n), p calculated with Fisher’s exact test.

Table 2. Labour outcomes of participants undergoing cervical ripening balloon (CRB) and Prostin (PGE) induction of labour.

¹ Values are mean ± SD, p calculated with Student t-test; ² Values are percentage (n), p calculated with Pearson chi-square test; ³ Values are percentage (n), p calculated with Fisher exact test.

Table 3. Birth outcomes of participants undergoing cervical ripening balloon (CRB) and Prostin (PGE) induction of labour.

¹ Values are mean ± SD, p calculated with Student t-test; ² Values are percentage (n), p calculated with Pearson chi-square test; ³ Values are percentage (n), p calculated with Fisher exact test.

Discussion

To the best of our knowledge, this is the first randomized controlled study to assess the use of CRB for IOL in Singapore. Our study concur with the published literature that both CRB and PGE have similar rate of vaginal deliveries and rate of deliveries within 24 hours. Both methods are effective and safe with PGE having a higher risk of uterine hyperstimulation and need for Caesarean section for failed IOL.

Pharmacological induction of labour using PGE is the most established form of IOL. However, it is important to be able to offer alternative methods to women particularly in cases of hypersensitivity or allergy to PGE. PGE can cause bronchospasm complicating asthma, a medical condition which affects 4 – 12% of pregnant women. ^{5, 6} Similarly, caution should be exercised in the use of PGE in women with other common medical conditions such as hypertension and epilepsy.

In addition, women may not respond to PGE for IOL, or the PGE may only result in uterine tightenings which do not lead to cervical dilatation. In these situations the CRB may be considered as an adjunct for IOL to avoid Caesarean section of ‘failed IOL’.

The risk of uterine hyperstimulation and the need for a repeat dose in 6 to 8 hours for PGE typically require the women to be admitted for IOL. The use of CRB does not require planned intervention until 12 hours later. This potentially allows an outpatient IOL if further studies support its safety in this aspect.

The application of PGE is relatively straightforward and is already performed by both doctors and midwives. The insertion of CRB may however be considered too invasive for midwives thus limiting the type and hence availability of staff to commence IOL. We have explored the learning curve in the insertion of CRB and will discuss this separately.

Conclusion

Both CRB and PGE are effective methods for IOL at term. Each method has its own benefits and limitations. The availability of both methods in an obstetric unit will allow the clinician to choose the most appropriate form of IOL, provide a complementary method of IOL, as well as offer women choice in their IOL.

Introduction

Oesophageal cancer (OC) is the eighth most common cancer affecting an estimated 481,000 people worldwide with a rapidly rising incidence. Due to the poor prognosis of patients with these cancers it is the sixth leading cause of cancer related mortality with 406,000 deaths.^1,2 Although the overall 5-year survival has increased from 4% in the 1970s³ to currently ranging between 15 to 20%⁴, it remains a challenge to treat as clinical presentation is often late and diagnosis is made at advanced stages. Incidence and mortality rates for OCs are two fold higher in males compared to females, however this ratio rises to up to 5-10:1 for oesophageal adenocarcinomas. Cohort studies have shown that the incidence of OC increases with age; the average of onset is between 65 to 70 years. ¹⁴ This article seeks to discuss the epidemiology, diagnosis and staging, prevention and current trends in the management of OC.

Methods

We searched PubMed/MEDLINE, EMBASE and Cochrane Library and Central Register of Controlled Trials (CENTRAL) databases up to November 2014. Our search strategy used a combination of MeSH, textwords, and appropriate words variants of “oesophagus”, “cancer”, “epidemiology”, “adenocarcinoma”, or “squamous cell carcinoma”, and “staging”, “transhiatal oesophagectomy”, “transthoracic oesophagectomy”, “chemotherapy”, “radiotherapy”. This was supplemented with selected systematic reviews, evidence based guidelines and consensus statements.

Epidemiology

There have been major changes in the epidemiology of OC over the last thirty years. The two key histological types of OC are adenocarcinoma and squamous cell carcinoma (SCC) and they differ significantly in their fundamental patterns of incidence and aetiological factors. Oesophageal SCC comprises the majority of cases worldwide and represents 90% of all OCs in most Eastern countries. However the incidence of adenocarcinoma has risen rapidly over the last three decades and it is now the predominant histological type in Western Europe, USA and Australia, particularly amongst white males.^{5, 6} There are other rare histological types, which include lymphoma, leiomyosarcoma, melanoma, rhabdomyosarcoma and small cell carcinoma.⁷ OC accounts for almost 3% of all cancers in the UK and is the ninth most common malignancy in the UK. There were 8,173 new cases in 2008; incidence rates have increased over the last thirty years in the UK and are now one of the highest in Europe.⁸ Incidence rates of OC differ markedly by geographical locations and between ethnic groups; overall, rates are twice as high in less developed regions compared with more-developed regions and the highest rates occur in Asia. In this region, especially in Iran, Turkey, Kazakhstan and China, a very high incidence of oesophageal SCC exists with greater than 100 cases per 100,000 population annually. A similar trend is also seen in South Africa.^9-12 In contrast, the rate of rise in incidence of oesophageal adenocarcinoma in more-developed countries has exceeded that of oesophageal SCC, which has remained the same or decreased. Oesophageal adenocarcinoma now comprises approximately 50% of all OCs in these countries. ¹³

Who gets oesophageal cancer?

The aetiology of OC is multifactorial, with interactions between environmental risk exposures and genetic factors. These can be divided between the two different histological types of OC.

Pathology of oesophageal tumours

Oesophageal tumours are classified as epithelial and non epithelial. Epithelial tumours include papilloma, intraepithelial neoplasia, carcinoma and carcinoid tumours. Non epithelial tumours include leiomyoma, lipoma and gastrointestinal stromal tumours (Table 1).

Table 1: WHO histological classification of oesophageal tumours

Oesophageal adenocarcinoma

Established risk factors for oesophageal adenocarcinoma (Fig. 1) include gastro-oesophageal reflux disease, Barrett’s oesophagus, obesity, male sex, tobacco smoking and a low intake of fruit and vegetables.^{15, 16} There is evidence to suggest that previous infection with Helicobacter Pylori and the use of non-steroidal anti-inflammatory drugs may decrease the risk of OC. ¹⁷

Fig. 1: Adenocarcinoma of the oesophagus (from Lewin et al. Gastrointestinal pathology and its clinical implications)

Barrett’s oesophagus (Fig. 2) occurs when there is metaplastic change in the lining of the oesophagus from normal stratified squamous mucosa to single layered columnar glandular mucosa with variable degrees of goblet cell differentiation.¹⁸ This transition usually occurs in the context of chronic gastro-oesophageal reflux disease, which causes exposure of the epithelium to refluxate. Gastro-oesophageal reflux disease is a major contributory factor and 5% of people with reflux disease develop Barrett’s oesophagus. The estimated prevalence of Barrett’s oesophagus is just under 2% amongst adults in the West and the annual incidence is approximately 0.1%. However, there is evidence to suggest that the rate of diagnosis is increasing by 2% annually.¹⁹ There has been a rise in the incidence of gastro-oesophageal reflux disease, which may be explained by a number of factors. The rise in the prevalence of obesity, specifically central and intra-abdominal obesity has been found to have a link with oesophageal adenocarcinoma. This can be explained by the fact that an increase in adiposity will cause a rise in intra-abdominal pressure thereby increasing reflux that may be asymptomatic. However, studies also suggest that obesity is a strong independent risk factor for oesophageal adenocarcinoma regardless of gastro-oesophageal reflux symptoms implying an underlying link. ^{20, 21} Another factor that may contribute to the rise in reflux disease is the increased use of drugs that relax the lower oesophageal sphincter. There is evidence to suggest that individuals with previous H. Pylori infections are less likely to develop oesophageal adenocarcinoma.²² This might be explained by the gastric atrophy that results from this infection, which will reduce the acidity and quantity of gastric secretions and thus decreasing the chances of gastro-oesophageal reflux. However, the prevalence of H. Pylori infections is decreasing in the Western population, which may contribute to the rising incidence of oesophageal adenocarcinoma. Gastro-oesophageal junction (GOJ) adenocarcinoma was classified by Siewert and Stein into three types. Type I arises from 1 to 5 cm proximal to the GOJ (tumours of the distal oesophagus), type II arises from 1 cm proximal to 2 cm distal to the GOJ (true cardiacarcinoma), and type III arises from 2 to 5 cm distal to the GOJ (subcardial gastric carcinoma). ⁶¹

Fig. 2: Barrett’s oesophagus (adapted from WHO classification of oesophageal tumours)

Oesophageal squamous cell carcinoma

The major risk factors for the development of oesophageal SCC (Fig. 3,4) are tobacco use and alcohol consumption; particularly a combination of both.^{23, 24} Nitrosamine exposure in tobacco smoking and the alcohol metabolite aldehyde, which is a known carcinogen, are probably the underlying reasons for these two risk factors. The high incidence of oesophageal SCC in Northern China, Iran and areas of Southern Africa may be related to a diet rich in nitrosamines and deficient in trace elements and vitamins A & C.

Other risk factors for oesophageal SCC in the Western world include low socioeconomic status, poor oral hygiene, achalasia, history of thoracic radiation, caustic injury, hereditary tylosis and Plummer-Vinson Syndrome.²⁵

Fig. 3: Squamous cell carcinoma of the oesophagus

Fig. 4: Microscopic picture of squamous cell carcinoma (adapted from WHO classification of oesophageal tumours)

How does oesophageal cancer present clinically?

Patients presenting with symptoms of OC almost invariably have advanced disease. The most common presenting symptom is progressive dysphagia with 74% of patients reporting difficulty swallowing.²⁶ This is graded according to the following: ²⁷

• Grade 1: Able to swallow most foods
• Grade 2: Able to swallow soft foods only
• Grade 3: Able to swallow liquids only
• Grade 4: Unable to swallow anything

17% of patients will also report pain on swallowing food and liquids (odynophagia). ²⁶ Typically, patients with oesophageal adenocarcinoma will be white males with a background of gastro-oesophageal reflux disease who have developed dysphagia. On the other hand, patients with oesophageal SCC will present with dysphagia, associated with weight loss and a history of smoking and increased alcohol intake may exist.

Other less common symptoms include dyspnoea, cough, hoarseness, acute haemorrhage and pain which may be retrosternal, back or right upper abdominal. These will usually represent the existence of metastatic disease.

Physical examination is often normal; positive clinical findings may include cachexia, lymphadenopathy and hepatomegaly in the presence of metastases.

How is oesophageal cancer diagnosed?

It is essential to have a low threshold if cancers are to be detected at an early, treatable stage. National Institute for Health and Clinical Excellence (NICE) guidelines state that a patient presenting with symptoms suggestive of upper gastrointestinal cancer should be referred to a team specialising in the management of these cancers. Specifically; patients of any age presenting with dyspepsia in association with alarm symptoms should be urgently referred for endoscopy or to a specialist. The classical ‘alarm’ symptoms associated with OC includes dysphagia, vomiting, anorexia, weight loss and symptoms associated with gastro-intestinal blood loss. Patients aged 55 or more with persistent, recent onset, and unexplained dyspepsia should be referred urgently for an endoscopy.

Diagnosis is usually made by oesophago-gastro-duodenoscopy where multiple biopsy samples must be taken from any mucosal abnormality to exclude early tumours. Suspicious lesions including oesophageal strictures may require repeated biopsies if initial results are negative.

Once diagnosis is made patients should be urgently referred to an Upper Gastro-intestinal team at a specialist centre for investigations to stage disease and further management.

Staging oesophageal cancers

It is essential to accurately stage disease to exclude patients with widespread metastatic disease for whom surgery will not be curative and to identify subgroups of patients who will require neo-adjuvant therapies. Whilst it is difficult to completely eliminate the possibility of ‘open and shut’ cases where tumours are found to be inoperable at the time of surgery; it is important to develop a staging strategy with investigations and procedures that help to minimise this risk. The TNM (Tumour, Node, Metastasis) staging system is used to classify the depth of tumour invasion into or through the oesophageal wall, the status of regional lymph nodes and metastases to distant sites. The TNM7 categories are shown in Tables 2 and the current stage groupings is shown in Table 3. ²⁸

Table 2: TNM7 staging system

Table 3: Stage classification for oesophageal cancer in the 2010 TNM7 staging system

Initial staging assessment includes Computed Tomography (CT) (Fig. 5) of the thorax, abdomen and pelvis and its major role will be in evaluating the T stage to detect local tumour invasion into adjacent structures and determining the presence or absence of metastatic disease. However CT will not be able to determine the depth of tumour invasion. Endoscopic ultrasound (EUS) (Fig. 6) is the main modality used to stage the primary tumour and primarily aids in distinguishing T1 lesions from T2-4 lesions. This method has an accuracy ranging from between 73% to 89% in tumour staging.²⁹ Accurately distinguishing tumour stage will affect treatment as T1 lesions may be treated with endoscopic therapy or with oesophagectomy whereas T2-4 lesions may require neo-adjuvant chemo-radiotherapy prior to surgery. EUS is also used for evaluation of regional lymph nodes however although sensitivity is approximately 80%, the specificity is lower at approximately 70%. ³⁰ It is best to perform a EUS-guided lymph node biopsy for confirmation of involvement.

Fig. 5: CT scan shows irregular wall thickening of the esophagus and enlarged metastatic lymph node.

Fig. 6: Endoscopic ultrasound (EUS) of oesophagus showing T3 tumour

FDG-PET (¹⁸F-fluoroudeoxyglucose PET) (Fig. 7) is a key modality for the detection of distant metastatic disease in OC.^{31, 32} PET may reveal previously occult distant metastases in nodal and non-nodal sites with a sensitivity of 67% and high specificity of 97%. ³³ It can also reveal metastases to bone, which may not be detected using conventional methods. An investigation has shown PET to be the only modality that predicted intended curative resection and it may also be used to prevent unnecessary surgical explorations.³⁴ The use of PET has been shown in a study to change the management of patients from curative to palliative due to detection of previously unknown metastases.³⁵ It has also been used in a prospective study to assess response early after neo-adjuvant chemotherapy to determine the need for urgent surgery or further chemotherapy. The usage of CT and PET in combination has become increasingly available and is useful in selective cases.³⁶

Fig. 7: FDG PET/CT image demonstrating increased uptake at the distal oesophagus and coeliac lymph node in oesophageal cancer case

Minimally invasive surgery is also used as a method to stage OC in many specialist centres.³⁷ A staging laparoscopy can visualise the primary tumour, identify metastases such as hepatic and regional nodal and can accurately detect intraperitoneal dissemination of disease, which may not have been appreciated on other radiological staging investigations. Samples of peritoneal ascites or washings for cytology can also be obtained at this stage if present.

Endoscopic mucosal resection (EMR) can provide accurate histological staging for high grade dysplasia and intramucosal carcinomas. ³⁸ In many cases EMR alone can be a therapeutic intervention depending on the depth of invasion on the specimen.

Treatment

The management of OCs requires a multi-disciplinary team approach involving surgeons, oncologists, radiologists, pathologists, specialist nurses, dietitians and specialists from other specialties if required. Patients considered for surgery or chemo-radiotherapy will require a fitness assessment. In addition to pulmonary function tests, ECG and echocardiogram, cardio-pulmonary exercise testing (CPEX/CPET) is now being increasingly used to assess fitness for major surgery.

OCs can be managed with surgery, chemotherapy or radiotherapy, a combination of the three or palliation in many cases. Disease that is locally advanced without signs of distant metastases is treated with an intention to cure and this will involve a multimodal approach. Metastatic, disseminated and recurrent disease will be treated with palliative intent with chemotherapy to increase survival or measures such as radiotherapy or stent placement for symptomatic relief.

Surgical

Surgical resection can be part of a multimodal approach or alone and is the main option for curative treatment. There are a number of surgical procedures that can be used however it is important to ensure removal of macroscopic and microscopic tumour in association with dissection of lymph nodes with either method as these are vital prognostic factors following surgery.

Open oesophagectomy (OO):

Options for resection include trans-hiatal oesophagectomy and transthoracic approaches and the choice of approach will depend on the location of the tumour, access to lymph nodes and surgeon preference. An Ivor Lewis oesophagectomy (also known as Lewis-Tanner oesophagectomy) involves abdominal mobilization of the stomach and right thoracic approach for resection of the oesophagus. The three-stage modified McKeown oesophagectomy involves a laparotomy, right thoracotomy and neck anastomosis. A resection margin 8-10 cm proximally and 7 cm distally is recommended to achieve an R0 resection (recommendation class IIB, level of evidence C). The next step is to construct a conduit for the anastomosis and this can be achieved by using a gastric tube, large or small bowel. A gastric tube is preferred due to the following factors; ease of use, tension free and longest term conduit survival (recommendation class IIA, level of evidence C). The anastomosis can be performed in the chest or the neck. This relies on multiple factors such as ease of the anastomosis, tension on the repair, ability to diagnose and treat complications and the oncological status. Circular staplers or hand sewn technique usually used with no significant differences in the outcomes. A drainage procedure such as pyloroplasty is recommended to avoid delayed gastric emptying (recommendation class I, level of evidence B). ⁶²

Radical oesophagectomy using either approach has a perioperative mortality of 5-10% and morbidity of 30-40%. ³⁹ Lymph node dissection plays an important role owing to the extensive submucosal lymphatic drainage of the oesophagus. This has meant that nearly 80% of patients undergoing surgery have positive lymph nodes and prognostically this is of importance.^{40, 41} However, there has been controversy with regards to the extent of lymph node dissection required. For optimal staging 10 lymph nodes for T1 and 20-30 lymph nodes for T2 and T3 tumours should be harvested. ⁶² In order to perform a curative resection for carcinoma of the middle and lower third of the oesophagus it is recommended to dissect the abdominal and mediastinal lymph nodes. Three-field lymphadenectomy in the abdomen, chest and neck, is performed in Japan for oesophageal SCC.⁴² Proponents of radical lymphadenectomy argue that it does allow optimal staging, improves loco-regional disease free survival improving the quality of life for these patients.

Minimally invasive oesophagectomy (MIO):

Minimally invasive approaches, which involve laparoscopic mobilisation of the stomach, thoracoscopic mobilisation of the oesophagus and hybrid or robotic approaches, are increasing in many specialist centres. Benefits of this approach include shorter recovery times, decreased post-operative pain and reduced cardiopulmonary complications without jeopardising the oncological outcomes. Luketich et al. reported a mortality rate of 1.7%, leak 5% and empyema 6% following MIO. ⁶³Several randomised controlled trials (RCTs) and comparative studies were conducted to investigate the efficacy and outcomes of MIO. A study by Li et al was conducted on 407 patients underwent MIO and OO found that the overall incidence of complications was lower in the MIO patients. The incidence of pulmonary complications was 20.7% in contrast to 39.7% in the OO group. However, there was no difference in the overall survival among the groups. Another comparative retrospective study by Mu et al. didn’t reveal any difference in the morbidity, anastomotic leak rate, pulmonary complications and length of stay between the approaches and the authors concluded that both techniques are equivalent. ^{63, 64}

Neo-adjuvant chemotherapy

This aims to improve operability; achieving this by shrinking the tumour prior to surgery, down-staging the disease as well as treating occult metastatic disease. Response to treatment can be assessed prior to surgery with repeat radiological investigations. It is now common for patients in the UK with locally advanced disease to undergo neo-adjuvant chemotherapy followed by resection. This is based on the results of a multi-centre study conducted by the Medical Research Council (OEO2), which showed a 9% improvement in two-year survival in patients given 2 cycles of Cisplatin and 5-Fluorouracil chemotherapy compared to those who were not. Five-year survival with surgery alone was 17%, compared with 23% with neoadjuvant chemotherapy.⁴³ The MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial randomized patients to chemotherapy with surgery or to surgery alone and it was found that patients in the chemotherapy group (who received Epirubicin, Cisplatin and infused 5-Fluorouracil, ‘ECF’) had a significant improvement in progression-free survival and a 13% increase in 5-year survival.⁴⁵

In a meta-analysis of neoadjuvant chemotherapy, there was an overall all-cause absolute survival benefit of 7% at 2 years with the addition of chemotherapy. When analysed by subtype, chemotherapy had no significant effect on mortality for patients with squamous cell carcinoma; however, there was a significant survival benefit for patients with oesophageal adenocarcinoma (HR 0.78; p=0.014). ⁴⁷

As a result of this evidence, neoadjuvant chemotherapy is a standard of care for patients with operable mid and lower oesophageal and GOJ adenocarcinoma. The ongoing MRC OEO5 trial is evaluating optimal neoadjuvant chemotherapy regimens: 4 cycles of chemotherapy with ‘ECX’ (Epirubicin, Cisplatin and Capecitabine) compared to two cycles Cisplatin and 5-Fluorouracil, as in OEO2.⁴⁴

Patients who are deemed suitable for surgical management of mid or distal oesophageal (including GOJ) adenocarcinomas are referred to the GI oncology team to assess fitness for chemotherapy. Many of the criteria assessed are similar to those in the pre-operative assessment, particularly performance status and medical comorbidities. Significant history of renal disease or cardiovascular disease, especially ischaemic heart disease would be a relative contraindication to systemic chemotherapy. Toxicities from chemotherapy are wide-ranging and include gastrointestinal upset, hair loss, skin rash, neurotoxicity, renal toxicity, bone marrow suppression (with risk of neutropaenic sepsis, thrombocytopaenia, and anaemia), cardiovascular toxicity, and chemotherapy-related fatigue. In the MAGIC trial, three cycles of epirubicin, cisplatin and capecitabine (ECX) chemotherapy were given both before and after surgery, and approximately one quarter of patients had CTCAE grade 3 or 4 neutropaenia. ⁴⁵

The REAL 2 trial ⁴⁸ was a 2x2 factorial non-inferiority comparison of cisplatin versus oxaliplatin and 5-fluorouracil (5-FU) versus oral capectiabine in patients with oesophageal, gastro-oesophageal junction and gastric tumours. Treatment was given as triplet chemotherapy: epirubicin plus platinum agent (cisplatin or oxaliplatin) plus 5-FU or capecitabine. The trial results showed that oxaliplatin was at least as effective as cisplatin, and oral capectibine was at least as effective as intravenous 5-fluorouracil. There was less grade 3 and 4 neutropaenia with oxaliplatin versus cisplatin, but this was offset by an increase in neuropathy and diarrhoea. As a result of this trial, EOX chemotherapy can be used as an alternative to ECX in both the neoadjuvant and metastatic settings (Table 4).

Table 4: Efficacies of major combination chemotherapy drugs

Neo-adjuvant chemo-radiotherapy

In contrast to the UK, patients in the USA commonly receive neo-adjuvant chemo-radiotherapy (CRT) for locally advanced oesophageal carcinoma. There is evidence that preoperative CRT is superior to surgery alone. A meta-analysis of ten randomised controlled trials showed a hazard ratio for all-cause mortality of 0.81 (95% CI 0.70 to 0.93; p=0.002). This corresponded to a 13% absolute survival benefit at 2 years.⁴⁷ In the subgroup analysis of the Dutch CRT trial (which used paclitaxel and carboplatin combination chemotherapy), the beneficial effect was more pronounced in patients with squamous cell carcinoma (HR 0.34; 95% CI 0.17 to 0.65) compared to adenocarcinoma (HR 0.82; 95% CI 0.58 to 1.16).⁴⁹

There has been no direct head-to-head comparison of neoadjuvant chemotherapy and neoadjuvant CRT in the context of a phase III randomised control trial. Concerns regarding the added morbidity of CRT have meant that chemotherapy alone is the standard neoadjuvant treatment of choice in the UK. However, the role of neoadjuvant CRT is currently being reassessed in the Neo-SCOPE trial.

Definitive chemo-radiotherapy (CRT)

According to current UK consensus guidelines, CRT is the definitive treatment of choice for localised squamous cell carcinoma of the proximal oesophagus. ⁵⁰ Localised squamous cell carcinoma of the middle or lower oesophagus may be treated with CRT alone, or CRT plus surgery. ⁵⁰

In a pivotal study, US Intergroup RTOG-8501 randomised 121 patients with squamous cell carcinoma or adenocarcinoma to receive CRT (cisplatin and 5-Fluorouracil with 50 Gray in 25 fractions), or radiotherapy alone (64 Gray in 32 fractions). This trial ⁴⁶, together with a subsequent systematic review ⁵⁵, demonstrated a survival superiority of CRT over radiotherapy alone (1-year mortality odds ratio 0.61; 95% CI 0.31 to 0.89; p<0.001). This was at the expense of increased toxicity.

This and similar studies ^56-57 have demonstrated a remarkably consistent median survival of 14-18 months and 2 year overall survival of 30-40% with CRT.

CRT practice in the UK is somewhat varied, but within the authors’ multidisciplinary team Cisplatin and 5-Fluorouracil chemotherapy is given in weeks 1 and 5 of a five-and-a-half week course of radiotherapy. The radiation dose used is 50.4 Gray in 28 daily fractions, treating Mondays to Fridays. An alternative radiation dose-fractionation which is supported by the Royal College of Radiologists guidelines is 50 Gray in 25 daily fractions. ⁵⁸

There are few trials directly comparing surgery alone with CRT. A study of 80 patients with squamous cell carcinoma randomised to surgery or CRT failed to show superiority of either strategy in terms of early disease free survival or overall survival. ⁵¹ Adding surgery to CRT can improve local control rates compared with CRT alone, but combined-modality therapy has not been shown to improve survival. It predictably also leads to significantly more treatment-related morbidity.⁵²

The French FFCD 9102 trial recruited 444 patients with potentially resectable OC (90% squamous cell carcinoma) to receive induction CRT. Those patients who showed evidence of response to CRT were then randomised to further CRT or surgery. Median overall survival was 19.3 months in the CRT alone arm, and 17.7 months in those randomised to surgery. The trial met its endpoint of non-inferiority for 2 year overall survival. Again, toxicity was shown to be significantly higher in patients who received both CRT and surgery.⁵³

Although definitive CRT is a current recommended standard of care for localised squamous cell carcinoma of the oesophagus, there is insufficient evidence to to support either a surgical or non-surgical approach ⁵⁰. Surgery should be considered in patients who have histologically-confirmed residual disease at the end of CRT.

For patients deemed unsuitable for surgery with localised adenocarcinoma of the oesophagus, CRT is a valid option for treatment. An American case series of 25 patients with a median age of 77 years showed that CRT using two cycles of mitomycin-C and 5-fluorouracil in combination with radiation (dose 50.4Gy in 28 daily fractions) was effective and tolerable. 68% of these patients had no evidence of residual disease on post-treatment endoscopy. This small series of patients had a two year overall survival of 64%, with a median overall survival of 35 months.⁵⁴

Salvage surgery after definitive CRT

Local recurrence occurs within the first year in 10-30% of patients treated with definitive CRT.⁵⁰ Salvage curative oesophagectomy may be considered within a multidisciplinary team setting. Repeat staging investigations including a CT-PET and EUS are required before a final decision for salvage surgery is made. Survival benefit is limited, and such surgery is associated with an increased in-hospital mortality rate and increased morbidity.⁵⁹ Informing patients of the potential high risks and poor outcomes is an integral part of the decision-making process for salvage surgery.

Palliation

The majority of patients diagnosed with OC are never treated with curative intent as a result of advanced disease or their physical fitness and comorbidities not allowing for radical treatment. It also includes patients who have developed recurrent or metastatic disease following resection. For this group of patients, there are a number of palliative treatments available for relief of symptoms, prolonging and maximising their quality of life. Once again, a multidisciplinary, holistic approach is required to provide the best treatment.

Treatments to provide symptomatic relief such as dysphagia can include intraluminal brachytherapy, endoscopic stenting using self-expanding metal stents or repeated endoscopic dilatations. Dysphagia can also be palliated by chemotherapy or external beam radiotherapy. Laser-thermal Nd-YAG endoluminal tumour destruction and photodynamic therapy can also be administered however this requires a number of treatments and may be more suitable for short exophytic tumours. It is essential to manage pain and nutrition and feeding options through a gastrostomy, jejunostomy or even intravenously can be provided to ensure adequate nutritional status. In addition to providing symptomatic relief it is important to also ensure that these patients receive social and psychological support by identifying and addressing the needs of the patients as well as their carers.

Palliative radiotherapy can be offered to patients with symptomatic primary oesophageal tumours in the context of metastatic or inoperable disease. Palliative dose and fractionation options are varied, but include 27 Gray in 6 fractions treating twice a week for 3 weeks; 30 Gray in 10 fractions treating daily for 2 weeks; 20 Gray in 5 fractions treating daily for 1 week.⁵⁸ The aim of such radiation treatment is to palliate dysphagia. This effect is not immediate, and therefore patients with significant dysphagia are better served initially by endoscopic stenting.

Chemotherapy has been shown to be effective in improving symptoms and overall survival. Patients with good performance status are offered combination chemotherapy. This can be with EOX, as per the MAGIC trial, ⁴⁵or with Cisplatin and 5-Fluorouracil, with or without the addition of Epirubicin (CF or ECF). 5-Fluorouracil can be substituted for oral Capecitabine (i.e. CX or ECX) without any adverse effects on outcomes.⁴⁵

When choosing palliative systemic chemotherapy for patients with incurable OC, the primary aim should be about maximising quality of life. Improvements in outcome with more intensive chemotherapy regimens, such as docetaxel, cisplatin and 5-Fluorouracil, have been shown to be offset by significantly more toxicity.⁶⁰ As a result, Docetaxel containing regimens are not approved in the UK for this indication.⁵⁰

Conclusions

The incidence of oesophageal carcinoma is increasing and despite advances in management and treatment the overall prognosis remains poor. It is essential to recognize and diagnose early, to have a clear pathway for subsequent investigations to ensure accurate staging. This will allow appropriate therapy to be administered to ensure the best possible outcomes are achieved. Treatment of OC is still a challenge however recent advances in surgery, endoscopic treatments and new therapeutic agents will hopefully improve prognosis.

Introduction

For decades the genus Acinetobacter has undergone several taxonomical modifications. Large number of non-fastidious, aerobic, Gram-negative bacteria (GNB) are included in this genus. In the last few years these organisms are genetically modifying into highly resistant forms resulting in untreatable nosocomial infections¹ and health care associated infections.² Acinetobacter is also a major cause of invasive type infections in children resulting in untreatable urinary tract infections (UTIs), skin infections and septicemia.³ One identified cause of the resistance mechanism in carbapenem resistant Acinetobacter spp. is the production of the MBL enzyme.⁴ It has been revealed through various published studies that Acinetobacter displays a specific type of mechanism of resistance against different antimicrobials. Some of them, for example β-lactam, are inhibited by enzymatic degradation, while quinolones are rendered ineffective due to a genetic mutation preventing the binding of an antibiotic to a distinct binding site. The same is true with aminoglycosides in which the resistant strains are noticed to acquire a gene involved in enzymatic modification.¹

Although polymixin resistance in Acinetobacter spp. was reported the specific cause of resistance was unknown until 2008. In 2013, one study detected the presence of hetero-and adaptive resistance due to mutation in specific gene for the first time.^1,21 Hence the aim of this current study was to evaluate the trend of sensitivity/resistance pattern of Acinetobacter spp. against broad spectrum antibiotics.

Method and Materials

The objective of the study was to evaluate the sensitivity of Acinetobacter spp. to 08 broad spectrum antibiotics. The Kirby Bauer Disc Diffusion method was used following the standard procedures as laid down by CLSI 2013.⁶ A total of 52 isolates were collected from Feb 2014-March 2014 from patients admitted to tertiary care hospitals in Karachi. The isolates were identified by routine lab procedures.

Antimicrobial agents and medium: Standard (Oxoid) discs of Amikacin (30 µg), Cefoperazone (75 µg), Ceftriaxone (30 µg), Ciprofloxacin (5 µg), Colistin (10µg), Fosfomycin (50 µg), imipenem (10 µg), Polymixin B (300units), Mueller Hinton Agar (Oxoid UK) and Mueller Hinton broth (Oxoid UK) were used.

0.5 McFarlan Standard: The inoculum was grown at 37⁰C for 2-6 hrs. Turbidity Standard of 0.5 McFarland was achieved by incubating broth culture.

Inoculation of test plates:The plates were inoculated with the culture of Acinetobacter spp. by the help of sterile cotton swabs. The excess fluid was removed after the cotton swab was dipped into inoculum suspension. When the inoculum were dried the antibiotic discs were placed with sterile forceps onto the agar surface.¹⁵

Incubation of test plates: The isolates after application of antibiotic discs plates were incubated for 24 hours and results were interpreted according to CLSI standards ^5,6. Interpretative standards for used antibiotics and Zone diameter of inhibition are shown in Table 2⁵.

Control strain: Escherichia coli ATCC 25922was used as a control strain to maintain accuracy and precision of procedures.

Results

It is reported that out of all the samples 61.5% were obtained from male patients. Infections caused by Acinetobacter spp. had a high prevalence among both the genders among the age group 51-75 yrs. The most frequent site of isolate collection was tracheal aspirate (55.76%) among both genders and the second highest percentage of isolate was obtained from sputum (19.23%) as shown in Table 1. The Colistin and Polymixin B were found equally effective against Acinetobacter spp. by inhibiting 98% of isolates each and 19.23% isolates showed sensitivity against Amikacin. The isolate showed the highest degree of resistance against Imipenem (98%), followed by Cefoperazone (94.23%) and Ceftrioxone (92.3). Surprisingly 32.69% of isolates exhibited intermediate sensitivity (IS) against Fosfomycin as indicated in Table 3 and Figure 1.

Table 1: Age and gender specific distribution of Acinetobacter spp. among patients

Table 2: Zone diameter interpretive standards for Acinetobacter spp. CLSI standards table of antibiotics for Acinetobacter spp.

*Since the interpretive standards for Colistin, Fosfomycin and Polymixin B against Acinetobacter spp. is not established in CLSI 2013 mannual zone diameter interpretative standards for Enterobacter spp. and E. coli were used.²⁰

Figure 1: Susceptibility pattern of Acinetobacter spp. against broad spectrum antibiotics

Table 3: Total % efficacy of different antibiotics among Acinetobacter spp. isolated (N= 52)

Discussion

Our present study shows that the Acinetobacter spp. were highly resistant to Cefoperazone (94.23%). This finding is further substantiated by research that observed Cefoperazone to be only effective when used in combination.^7,8

We also observed that only 19% isolates were sensitive to Amikacin, which contradicts the findings of Liu et al 2013 ³ who observed 100% efficacy. However, they also discovered that 82% were inhibited by Imipenem while Fluoroquinolone was also found to be effective against 70% of all isolated organisms and Cefoperazone as least effective.

Organisms isolated from sputum showed a high degree of resistance to most of antibiotics, Zheng W and Yuan S also observed such results⁹.Nwadike et al 2014¹⁰ found a high prevalence of resistant Acinetobacter spp. isolates against Ciprofloxacin (100%) and Amikacin (50%).¹⁰

Polymixin inhibited 98% of isolates, which is similar to figures found by Haeili et al 2013¹ who observed 95.5% susceptibility to Polymixin B. The second most effective antibiotic was Colistin - Trottier et al 2007¹² also observed 100% susceptibility of A. baumanni to Colistin. Similarly, Vakilietal 2014¹³ found a low rate (i.e, 11.6%) of Colistin resistance.

Colistin has emerged as a viable choice for treatment of multidrug resistant Acinetobacter strains. In several studies,^13,14 where 98% of isolates were resistant to Imipenem these results support the work of Khajuria et al 2014¹⁶ who also reported reduced efficacy. Our findings are in contradiction to the study by of Tripathi et al 2014¹⁷ who reported that Imipenem was a highly effective drug in comparison to other broad spectrum antibiotics.Fosfomycin surprisingly exhibited unusual results in our study; 32% of Acinetobacter spp. were IS while 65% were resistant. However, previous studies showed that Fosfomycin were proved to be good option to treat infections caused by Acinetobacter spp.¹⁸ Zhang et al 2013¹⁹ reported that Fosfomycin used alone was highly ineffective in treatment of Penicillin Drug Resistant-Acinetobacter baumannii (PDR-Ab).Another study revealed that Acinetobacter spp. has developed adaptive resistance against Polymixin.²¹

Acinetobacter spp. are emerging as a resistant bacteria and a common cause of nosocomial and hospital acquired infections. There is a serious need to take necessary measures by hospital administration in maintaining environmental and personnel cleanliness according to current Good Manufacturing Practices. Pharmacists should educate patients about the drawbacks of self-medication and not completing medication courses, which is resulting in development of resistant bacterial pathogens.