No

Introduction

Bed bugs belong to the family Cimicidae and there are two species involved in the modern resurgence; the Common bed bug, Cimex lectularius and the Tropical bed bug, Cimex hemipterus. They are wingless insects with an oval-flat shape that allows them to hide in narrow cracks and crevices. The adults are dark brown, 4-5mm long, becoming to around 10mm when fully blood-engorged. There are five smaller juvenile stages (nymphs) that are similar in appearance, although lighter in colour. All nymphs require a blood meal to moult to the next stage, and both adults also bloodfeed for nutrition, and egg development in the case of the female. Bed bugs are solely haematophagous ectoparasites. After feeding they return to a harbourage and do not remain on the host. The main hosts are humans, but pets, bats, and birds may act as secondary hosts.

Epidemiology

In the past, bed bugs were particularly an affliction of the poor. However, in the early part of the modern resurgence it was the tourist areas and the hospitality sector that were initially impacted.^1-3 Today, bed bugs have conquered quite diverse locations, ranging from hospitals, hotels and homes, to trains, cruise ships, and even airplanes. Most commonly, bed bugs travel in comfort as stowaways in luggage, although they can be transferred via furnishing and other belongings, as well by spreading to adjoining properties. Unfortunately, exact figures on the occurrence of bed bugs are unknown, as there are no mandatory reporting requirements. Additionally, due to the stigma associated with bed bugs, many infestations are simply not reported.

During the day, the largely nocturnal bed bugs will crawl deep into crevices of bed frames and mattresses (Fig.1), or behind wallpaper, and floor moldings. Here they tend to lay their eggs, often several hundred during the female lifetime. Live bed bugs, shed nymphal skins, and dark excrement spots indicate an active infestation. At night they are attracted by carbon dioxide, heat and other host odours to a victim, from which they may take a blood meal every 3-5 days. The adult bugs can survive long periods of starvation, up to five months at 22^oC or even longer at cooler temperatures. When a host is found, they insert their mouthparts into the skin, blood feeding for 5-10 minutes. When bed bugs are in large numbers, often lines of bites occur on the unfortunate victim and this sign is almost a sure indication of the presence of the insect. The bites tend to occur along the arms and legs, down the back and across the shoulders.^4,5

There has been long speculation whether bed bugs can transmit diseases, and in fact more than 40 different pathogens have been implicated. This has included Hepatitis B and C viruses, Human Immunodeficiency Virus (HIV), and Coxiella burnetii (Q fever). Recently, research has indicated that bed bugs are capable of transmitting the agent of Chagas Disease, Trypanosoma cruzi,in the laboratory. However, to date there is not one piece of evidence that bed bugs have transmitted any pathogen to humans.^4,6

Clinical Features

During the act of feeding, saliva is injected which contains a variety of anticoagulants as well as other proteins whose function has yet to be determined. Contrary to popular belief, there is no evidence that bed bugs inject an anaesthetic. One protein, Nitrophorin, is involved in the transport of nitric oxide into the wound. This results in local vasodilation that increases blood supply to the feeding insect. The same protein can also induce a sensitivity to the bite.⁶

The diagnosis of Cimicosis is via the clinical appearance of the bite reaction and confirmation of an actual bed bug infestation (Table 1).^3,5 The most commonly affected body parts are those that are left uncovered during sleep (Fig. 2,3,4), notably the arms, shoulders and legs. In young children, the face and even the eyelids can be bitten. Rarely, however, armpits are bitten, which are often preferred by other insects and ticks (Table 2).

Figure 1: Typical appearance of bed bugs

Figure 2: Bites on the back, note the lines of bites common in moderate to large infestations

Figure 3: Bed bug bites on the arm, typical formation

Figure 4: Bed bug bites on the torso and arm

Figure 5: Bullae due to bed bug bites

Figure 6: Bed bugs, their droppings and eggs underneath a mattress

The degree of the bite reaction often depends on the level of prior exposure. With low level sensitization, individuals may develop a 1-2 cm wheal, with a small central haemorrhagic point. This haemorrhagic point can be recognized easily by diascopy. In contrast, a highly sensitized person will react immediately and may develop a wheal up to 15cm across (6 inches). If many bed bugs are present, an urticarial rash may develop as a result of the large number of bites and subsequent trauma to the area from scratching. On rare occasions, vesicles and bullae (Fig. 5) may form on the arms and legs. In the course of Cimicosis, papules that are extremely itchy may develop and can persist for several days to weeks. Due to the strong pruritus eczematous lesions, bacterial infections may occur, although this is extremely rare. There are case reports of systemic reactions such as anaphylaxis and asthma, although these are uncommon.

Through repeated exposure, some individuals may develop a tolerance to the bites. The clinical symptoms are then largely inapparent with small punctures at the bite site. Small blood spots are then the only clues that an infestation may be present.

Differential Diagnosis

Since reactions to stings and bites of various arthropods are non-specific, bed bug bites are commonly misdiagnosed. Single bites, notably that of other insects such as mosquitoes, fleas and biting midges may appear very similar morphologically (Table 2).

Consideration of where the bites are on the body can assist in the differential diagnosis. For bed bugs, lines of bites are very common in moderate to large infestations and this clinical picture is virtually unique amongst blood sucking arthropods. For the most part, the identification of the actual pest is required to confirm the diagnosis. Histologically, bed bug bites resemble perivascular eosinophilic infiltrates through the superficial and deep dermis, with minimal spongiosis.

Other possible diagnostic confounders can be various allergic reactions and other medical conditions such as urticaria, chickenpox, prurigo subacuta, and erythema multiforme.^7,8 These do not show a central haemorrhagic point in the lesion which allows a correct diagnosis. However, in young children the diagnosis can sometimes be difficult. 

Treatment

The treatment of Cimicosis is symptomatic. Local lesions can be treated with antipruritics e.g. Polidocanol 2-4% in Lotio alba (aqueous lotion) and topical antiseptic. Spirit of menthol may also be helpful. Local treatment with antihistamines is controversial. In severe reactions topical glucocorticoids such as Betamethasone may be required. In severe itching, the use of oral antihistamines is recommended. With infected bites, antibiotic therapy may be required. Uncomplicated bed bug bites tend to stop itching within 1-2 weeks, although temporary scarring from the bite may remain for several months.

Management

Treatment of patients with bed bug bites ultimately comes down to removing the source of the irritant, namely the eradication of the active infestation. Bed bugs have a typical pungent odor. This can be used to detect bed bugs through specially trained sniffer dogs that can rapidly locate the insects.⁹ Due to insecticide resistance, bed bugs are very difficult to control with traditional insecticides alone, and non-chemical means of eradication must be employed to reduce the overall insect biomass. Bed bug control should be undertaken by professionals trained in bed bug management, and the process may take some weeks to achieve.

Prevention

When travelling (1) always inspect the bed and surrounds for bed bugs hiding beneath the mattress and/or in seams of the bedding. Also, look for blood stains or small black dots (Figure 6, Table 1). (2) If present, request another room. (3) Always keep your luggage on the desktop or the luggage rack. A good preventative is to seal luggage in plastic or garbage bags during travelling, even when in transit. (4) When returning home, all clothing should be washed in at temperatures exceeding 60°C or frozen for one week with delicate fabrics. If there is no choice, then repellents containing N, N-Diethyl-meta-toluamide (DEET) should reduce the biting rate, but will not completely prevent all bed bug bites.^10,11

Bed bugs can enter homes via an array of additional ways, particularly from objects bought second hand at flea markets or thrift stores, for example wooden frames, vintage clothes, furniture and the like. These should be heat-treated for a minimum of 10-20 minutes to kill bugs and their eggs.

Introduction

Striae distensae, or stretch marks, are linear scars in the dermis which arise from rapid stretching of the skin over weakened connective tissue. It is a common skin condition that rarely causes any significant medical problems but is often a significant source of distress to those affected. Striae distensae were described as a clinical entity hundreds of years ago, and the first histological descriptions appeared in the medical literature in 1889.¹ With a high incidence and unsatisfactory treatments, stretch marks remain an important target of research for an optimum consensus of treatment. These appear initially as red, and later, as white lines on the skin, representing scars of the dermis, and are characterized by linear bundles of collagen lying parallel to the surface of the skin, as well as eventual loss of collagen and elastin. The estimated prevalence of striae distensae range from 50 to 80%.^2,3 The anatomical sites affected vary, with areas commonly affected including the abdomen, breasts, thighs and buttocks.⁴ The three maturation stages of striae include the acute stage (striae rubra) characterized by raised, erythematous striae, the sub-acute stage characterized by purpuric striae, and the chronic stage (striae alba), characterized by white or hypo-pigmented, atrophied striae.⁵ Although stretch marks are only harmful in extreme cases, even mild stretch marks can cause distress to the bearer⁶ (Table 1).

Table 1: Histological comparisons between striae rubrae and striae albae

Aetiology

Striae may result from a number of causes, including, but not limited to, rapid changes in weight, adolescent growth spurts, corticosteroid use or Cushing Syndrome, and generally appear on the buttocks, thighs, knees, calves, or lumbosacral area.⁷ In addition, approximately 90% of all pregnant women develop stretch marks either on their breasts and/or abdomen by the third trimester.⁸ Genetic predisposition is also presumed, since striae distensae have been reported in monozygotic twins.^9,10 There is decreased expression of collagen and fibronectin genes in affected tissue.¹¹ The role of genetic factors is further emphasised by the fact that they are common in inherited defects of connective tissue, as in Marfan’s syndrome.^12,13 Obesity and rapid increase or decrease in weight have been shown to be associated with the development of SD.¹⁴ Young male weight lifters develop striae on their shoulders.¹⁵ Striae distensae also occurs in cachetic states, such as tuberculosis, typhoid and after intense slimming diets.¹⁶ Rare etiologies include human immunodeficiency virus positive patients receiving the protease inhibitor indinavir and chronic liver disease.^13,15 A case of idiopathic striae was also reported.¹⁷

Rosenthal¹⁸ proposed four aetiological mechanisms of striae formation: insufficient development of tegument, including elastic properties deficiency; rapid stretching of the skin; endocrinal changes; and other causes, possibly toxic.

Pathogenesis

The pathogenesis of striae is unknown but probably relates to changes in the components of extracellular matrix, including fibrillin, elastin and collagen.¹⁹ There has been emphasis on the effects of skin stretching in the pathogenesis of striae because the lesions are perpendicular to the direction of skin tension.²⁰ A possible role of glucocorticoids in the pathogenesis of striae has been suggested because of an increase in the levels of steroid hormones and other metabolites found in patients exhibiting striae.²¹ There are studies suggesting the role of fibroblasts in the pathogenesis of striae. Compared to normal fibroblasts, expression of fibronectin and both type I and type III procollagen were found to be significantly reduced in fibroblasts from striae, suggesting that there exists a fundamental aberration of fibroblast metabolism in striae distensae.²²

Pathological aspects

The earliest pathological changes are subclinical to be detected by electron microscopy only. These changes include mast cell degranulation and the presence of activated macrophages in association with mid-dermal elastolysis.²³ When the lesions become become clinically visible, collagen bundles start showing structural alterations, fibroblasts become prominent, and mast cells are absent.²³ On light microscopic examination, Inflammatory changes are conspicuous in the early stage, with dermal oedema and perivascular lymphocytic cuffing.²⁴ In later stages, there is epidermal atrophy, loss of rete ridges and other appendages including hair follicles are absent.²⁵

Evaluation of striae distensae

Approaches to evaluating SD severity visually include the Davey ²⁶ and Atwal scores,²⁷ although these have not been validated specifically for SD. An objective evaluation of SD may be carried out using skin topography, imaging devices including three-dimensional (3D) cameras, reflectance confocal microscopy and epiluminescence colorimetry.^28,29,30

Table 2: Visual scoring systems for the assessment of striae distensae

Management

Striae distensae (striae alba) is a very challenging cosmetic problem for dermatologists to treat. Various modalities of treatment have been tried. Although therapeutic strategies are numerous, there is no treatment which consistently improves the appearance of striae and is safe for all skin types.³¹ Weight loss by diet alone or a combination of diet and exercise do not change the degree of striae distensae.³²

Topical treatments

Topical tretinoin (0.1%) ameliorates striae and the improvement may persist for almost a year after discontinuation of therapy.³³ More recently, tretinoin has been shown to improve the clinical appearance of stretch marks during the active stage (striae rubra), although with not much effect during the mature stage (striae alba).³⁴ Some of the studies have proven the inefficacy of the vitamin A derivative in the treatment of SD, but most of the patients included in these early studies presented with old lesions that had evolved into whitish atrophic scars.³⁵ A study comparing topical 20% glycolic acid and 0.05% tretinoin versus 20% glycolic acid and 10% L-ascorbic acid, found that both regimens improved the appearance of striae alba.³⁶

Hydrant Creams: 1) Trofolastin (a cream containing Centella asiatica extract, vitamin E, and collagen-elastin hydrolysates). The exact mechanism of action was identified as the stimulation of fibroblastic activity ³⁷ and an antagonistic effect against glucocorticoids.³⁸ 2) Verum (a cream containing vitamin E, panthenol, hyaluronic acid, elastin and menthol). The results suggest that the product may show the benefit of massage alone.³⁹ 3) Alphastria (a cream composed of hyaluronic acid, allantoin, vitamin A, vitamin E, and dexpanthenol). Only one study was conducted, which concluded that the product markedly lowered the incidence of stretch mark development after pregnancy.⁴⁰

Glycolic acid (GA): The exact mechanism of action of GA in the management of striae distensae is still unknown because, although GA is reported to stimulate collagen production by fibroblasts and to increase their proliferation in vivo and in vitro, which may be useful for the treatment of stretch marks.^41,42 A study comparing topical 20% glycolic acid and 0.05% tretinoin versus 20% glycolic acid and 10% L-ascorbic acid, found that both regimens improved the appearance of striae alba.⁴³

Trichloroacetic acid (TCA; 10–35%): It has been used for many years as a treatment option for striae distensae and is repeated at monthly intervals with reported improvement in texture and color of marks.⁴⁴

Other topical products: Several oils have been used in the prevention of SD. A non-randomized, comparative study investigated the effect of almond oil in the prevention of SD in which they noted significant differences in the frequency of SD between the groups (almond oil and massage 20%, almond oil alone 38.8%, control 41.2%).⁴⁵

Overall, there is limited evidence for the efficacy of topical therapy for the treatment of SD.

Microdermabrasion

Microdermabrasion may improve many skin problems including acne scars, skin texture irregularities, mottled pigmentation and fine wrinkles. Karimipour et al reported that microdermabrasion induces epidermal signal transduction pathways associated with remodelling of the dermal matrix.⁴⁶ However, studies documenting the efficacy of rnicrodermabrasion in treatment of striae are lacking. Published in 1999, a book on microdermasion written by a French dermatologist, Francois Mahuzier, and translated to English, has a chapter "Microdermabrasion of stretch marks^”.⁴⁷ The author states that 10-20 sessions of microdermabrasion at an interval of not less than 1 month, each session resulting in bleeding points, provide satisfactory results. The author concludes that, "microdermabrasion is the only effective treatment of stretch marks today."

Lasers

Lasers have recently become a popular therapeutic alternative to ameliorate and improve the appearance of stretch marks. Most commonly used lasers used include pulsed-dye laser (PDL), short- pulse carbon dioxide and erbium-substituted yttrium aluminium garnet (YAG), neodymium- doped YAG (Nd:YAG), diode, and Fraxel.

Pulsed dye laser: The dilated blood vessels render the striae rubrae a good candidate for PDL.⁴⁸ The 585- nm pulsed dye laser has a moderate beneficial effect in the treatment of striae rubra.⁴⁹ To evaluate the effectiveness of the 585-nm flashlamp-pumped pulse dye laser in treating cutaneous striae, 39 striae were treated with four treatment protocols.⁵⁰ Subjectively, striae appeared to return toward the appearance of normal skin with all protocols. Objectively, shadow profilometry revealed that all treatment protocols reduced skin shadowing in striae. Laser treatment of SD should be avoided or used with great caution in darker skin types (IV–VI), because of the possibility of pigmentary alterations after treatment.⁵¹

Excimer laser: Studies have shown temporary repigmentation and improvement of leukoderma in SD with excimer laser, although it failed to show any improvement in skin atrophy.^52,53 To evaluate the true efficacy of the 308-nm excimer laser for darkening striae alba, 10 subjects were treated using the excimer laser on the white lines of striae, while the normal skin near to and between the lines was covered with zinc oxide cream. The results of this study showed the weakly positive effect of the 308-nm excimer laser in the repigmentation of striae alba.⁵⁴

Copper Bromide laser: copper-bromide laser (577-511 nm) has been used for stretch marks. A clinical study was conducted in 15 Italian women with stretch marks, treated with the CuBr laser (577-511 nm) and followed-up for 2 years.⁵⁵ The results of the study concluded that the copper-bromide laser was effective in decreasing the size of the SD and there were some pathogenic considerations that justified the use of this laser.

1,450-nm Diode Laser: The non-ablative 1,450-nm diode laser has been shown to improve atrophic scars and may be expected to improve striae. To evaluate the efficacy of the 1,450-nm diode laser in the treatment of striae rubra and striae alba in Asian patients with skin types 4-6, striae on one half of the body in 11 patients were treated with the 1,450-nm diode laser with cryogen cooling spray with the other half serving as a control.⁵⁶ None of the patients showed any noticeable improvement in the striae on the treated side compared to baseline and to the control areas. The study concluded that the non-ablative 1,450-nm diode laser is not useful in the treatment of striae in patients with skin types 4, 5, and 6.

1,064-nm Nd:YAG Laser: A study was aimed to verify the efficacy of this laser in the treatment of immature striae in which 20 patients with striae rubra were treated using the 1,064-nm long-pulsed Nd:YAG laser.⁵⁷ A higher number of patients (55%) considered the results excellent when compared to the same assessment made by the doctor (40%).

Intense Pulsed Light: In order to assess the efficacy of IPL in the treatment of striae distensae, a prospective study was carried out in 15 women, all of them having late stage striae distensae of the abdomen.⁵⁸ All the study subjects showed clinical and microscopical improvement after IPL. It seems to be a promising method of treatment for this common problem with minimal side-effects, a wide safety margin and no downtime.

Fractional Photothermolysis: To determine the efficacy of fractional photothermolysis in striae distensae, 22 women with striae distensae were treated with two sessions each of fractional photothermolysis at a pulse energy of 30 mJ, a density level of 6, and eight passes at intervals of 4 weeks and response to treatment was assessed by comparing pre- and post-treatment clinical photography and skin biopsy samples.⁵⁹ Six of the 22 patients (27%) showed good to excellent clinical improvement from baseline, whereas the other 16 (63%) showed various degrees of improvement. This study concluded that Fractional photothermolysis may be effective in treating striae distensae, without significant side effects.

Ablative 10,600-nm carbon dioxide fractitional laser: Ablative 10,600-nm carbon dioxide fractional laser systems (CO₂ FS) have been used successfully for the treatment of various types of scars. To assess the therapeutic efficacy of CO₂ FS for the treatment of striae distensae, 27 women with striae distensae were treated in a single session with a CO₂ FS and clinical improvement was assessed by comparing pre- and post-treatment clinical photographs and participant satisfaction rates.⁶⁰ The evaluation of clinical results 3 months after treatment showed that two of the 27 participants (7.4%) had grade clinical 4 improvement, 14 (51.9%) had grade 3 improvement, nine (33.3%) had grade 2 improvement, and two (7.4%) had grade 1 improvement. None of the participants showed worsening of their striae distensae.To assess and compare the efficacy and safety of nonablative fractional photothermolysis and ablative CO(2) fractional laser resurfacing in the treatment of striae distensae, 24 ethnic South Korean patients with varying degrees of atrophic striae alba in the abdomen were enrolled in a randomized blind split study and were treated with 1,550 nm fractional Er:Glass laser and ablative fractional CO(2) laser resurfacing.⁶¹ These results of the study support the use of nonablative fractional laser and ablative CO(2) fractional laser as effective and safe treatment modalities for striae distensae of Asian skin with neither treatment showing any greater clinical improvement than the other treatment.

UVB/UVA1 Combined Therapy: Besides lasers, light sources emitting ultraviolet B (UVB) irradiation have been shown to repigment striae distensae. A study was conducted on 9 patients with mature striae alba who received 10 treatment sessions, and biopsies were taken at the baseline and end of the study.⁶² At the end of the study, all patients reported some form of hyperpigmentation that was transient and did not affect any surrounding tissues. No changes were seen on biopsy to indicate an effective remodelling collagen effect of the device, although it needs further assessment. Another study was conducted to analyse the histologic and ultrastuctural changes seen after UVB laser- or light source-induced repigmentation of striae distensae in which analyses of biopsied skin after treatment with both the UVB laser and light source showed increased melanin content, hypertrophy of melanocytes, and an increase in the number of melanocytes in all patients.⁶³

Radiofrequency devices: RF devices are based on the principle of heat generation that occurs in response to poor electrical conductance according to Ohm’s law (heat generation is directly correlated with tissue resistance). The heat that is generated is sufficient to cause thermal damage to the surrounding connective tissue,⁶⁴ which is responsible for the partial denaturation of pre-existing elastic fibers and collagen bundles.⁶⁵ Initial collagen denaturation within thermally modified deep tissue is thought to represent the mechanism for immediate tissue contraction; subsequent neocollagenesis further tightens the dermal tissue and reduces striae.⁶⁶ The efficacy and safety of combination therapy with fractionated microneedle radiofrequency (RF) and fractional carbon dioxide (CO2) laser in the treatment of striae distensae has been evaluated revealing that this combination therapy is a safe treatment protocol with a positive therapeutic effect on striae distensae.⁶⁷ A recent study evaluating the effectiveness of a RF device in combination with PDL subjected 37 Asian patients with darker skin tone with SD to a baseline treatment with a RF device and PDL.⁶⁸ All histological evaluations demonstrated an increase in the amount of collagen fibers, and six of the nine specimens showed an increase in the number of elastic fibers.TriPollar RF device appears to be a promising alternative for the treatment of striae distensae in skin phototypes IV-V.⁶⁹

Needling therapy:

To evaluate the effectiveness and safety of a disk microneedle therapy system (DTS) in the treatment of striae distensae, 16 Korean volunteers with striae distensae alba or rubra were enrolled which received three treatments using a DTS at 4-week intervals.⁷⁰ Marked to excellent improvement was noted in seven (43.8%) patients, with minimal to moderate improvement in the remaining nine. This study revealed that Disk microneedle therapy system (DTS) can be effectively and safely used in the treatment of striae distensae without any significant side effects. Another study assessed and compared the efficacy and safety of needling therapy versus CO2 fractional laser in treatment of striae and the results supported the use of microneedle therapy over CO2 lasers for striae treatment.⁷¹

Platelet-rich plasma:

Platelet-rich plasma has these wound-healing properties, affecting endothelial cells, erythrocytes, and collagen,⁷² which potentially aids in the healing of the localized chronic inflammation believed to be a factor in the aetiology of striae distensae. Platelet-rich plasma is well tolerated by the patients and is a safe and cost effective treatment option for striae distensae.

Platelet-rich plasma alone is more effective than microdermabrasion alone in the treatment of striae distensae, but it is better to use the combination of both for more and rapid efficacy.⁷³

The plasma fractional radiofrequency and transepidermal delivery of platelet-rich plasma using ultrasound has also been found to be useful in the treatment of striae distensae.⁷⁴

Since thermal damage from intradermal RF has characteristics similar to those of many wounds, combination treatment with intradermal RF and autologous PRP would eventuate in enhanced localized collagen neogenesis and redistribution. In one of the studies, three sessions of intradermal RF were used combined with autologous PRP administered once every four weeks.⁷⁵ All of the participants showed satisfactory changes and no patient was reported to show no improvement.

Transepidermal retinoic acid:

Transepidermal retinoic acid delivery using ablative fractional radiofrequency associated with acoustic pressure ultrasound has also been used for the treatment of stretch marks.⁷⁶

Conclusion

Striae distensae are an extremely common, therapeutically challenging form of dermal scarring. Adequate scientific knowledge and the evidence behind both preventative and therapeutic agents are vital in order to understand striae and to offer patients the best therapeutic options. The treatment of this cosmetically distressing condition has been disappointing and there is no widely accepted surgical procedure for improving the appearance of stretch marks. Laser therapy has been advocated as a treatment for striae distensae.

INTRODUCTION

Hepatitis viruses are the most widespread cause of hepatitis and some cancer lymphomas in humans¹.Hepatitis is a serious disease of the liver and described as a lifelong infection with swelling and inflammation (presence of inflammatory cells) in the liver, that if progresses, may lead to cirrhosis (scarring) of the liver, liver cancer, liver failure, and death. Hepatitis B (HBV) and Hepatitis C (HCV) are one of the viral types of hepatitis that leads to jaundice (a yellow discolouration of skin, mucous membrane and conjunctiva of the eye), anorexia (poor appetite), fatigue and diarrhoea and presumably it remains undiagnosed and leads to chronic carrier state but most infected individuals remain asymptomatic^1-3. The hepatitis B virus is a DNA virus belonging to the Hepadnaviridae family of viruses and hepatitis C virus is a small, single stranded, RNA virus with a diameter of about 50 nm, belonging to Flaviviridae family of virus. Hepatitis B surface antigen (HBsAg) is present in the serum of those infected with hepatitis B, consisting of the surface coat lipoprotein of the hepatitis B virus. Anti-HCV antibody, a substance that the body makes to combat HCV ⁴. Hepatitis B virus is transmitted through blood and blood products, semen, vaginal fluids, and other body fluids. Hepatitis C virus is a blood borne or parenterally transmitted infection. Vehicles and routes of parenteral transmission include; contaminated blood and blood products, multi-transfusions (thalassemic and haemophilic patients), needle sharing, contaminated instruments (e.g. in haemodialysis, reuse of contaminated medical devices, tattooing devices, acupuncture needles, razors) and occupational and nosocomial exposure^5-8. It stands to reason that an occupational risk for transmission of hepatitis virus in the health care setting, where unknown carriers of hepatitis infections are undergoing different procedures, in which there is a chance of contact of percutaneous blood, including transmission from infected patients to staff, from patient to patient, and from infected providers to patients⁹. There is a lack of routine serological screening prior to surgery, which is one of the factors responsible for increased disease transmission. The major risk factors include; re-use of contaminated syringes, surgical instruments and improperly screened blood products². Without meticulous attention towards infection control and disinfection and sterilization procedures, the risk for transmission of blood borne pathogens in the health care setting is magnified.

The aim of our current study was to estimate the incidence of Hepatitis B and Hepatitis C among patients going through eye surgery at department of ophthalmology Liaquat University of Medical and Health Sciences Jamshoro at Hyderabad. This is one of the largest tertiary care centres in Sindh. This institution is a great referral centre for whole interior Sindh province.

MATERIAL AND METHODS

Study design and patients

This prospective observational study was carried out at Liaquat University Eye Hospital, Hyderabad, from June 2014 to February 2016. A total of 2200 patients undergoing eye surgery, who were unaware of hepatitis B & C infection were included in this study. No re­striction was placed based on age and gender to ensure maximum participation.

Blood samples

The blood samples of all these patients were collected in the Hospital laboratory, Scientific Ophthalmic Diagnosis & Research Lab. Each patient was serologically screened, by using immuno-chromatography (ICT method) for qualitative detection of antigen for Hepatitis B and Hepatitis C virus antibodies, to find the carrier status of patients before surgery.

The blood was collected by a qualified technician / phlebotomist of our hospital laboratory under supervision of a consultant pathologist. Samples were allowed to coagulate at room temperature for 30 minutes, and then centrifuged at 3000 revolutions per minute (RPM) for 10 minutes. The serum samples were separated and kept frozen at -20°C for chemical and immunoassays. The HBV screening was based on the detection of antigen and detection of viral specific antibodies HCV in the sera using enzyme immunoassays. The test only shows whether a person has ever been infected by HBV or HCV, and not whether the virus is still present. According to the manufacturers’ literature, the relative sensitivity and specificity of HCV and HBV testing kits was 96.8% and 99% respectively.

Those patients with test results were found positive on screening test, were further confirmed by testing ELISA (Enzyme-Linked Immunosorbent Assay) method (4th generation ELISA) and were given advised for further testing on Polymerase Chain Reaction (PCR) for qualitative or quantitative detection of DNA/RNA (the viral gene).

All the data was entered in SPSS version 16 and the prevalence and percentage of all variables was measured.

RESULTS

A total number of 2200 patients were operated during the study, 1255 (57.04%) patients were male and 945 (42.95%) were female

Of these 2200 patients, 338 (15.36%) were serologically positive for hepatitis B virus & hepatitis C virus. Out of the 338 HBV or HCV positive patients, 56 patients (2.54%) were positive for hepatitis B surface antigen (HBsAg) and 282 patients (12.81%) were positive for hepatitis C antibody (HCVAb). (Figure 1&2). The majority of them were female, and 226 (66.86%) were in their 4^th and 5^th decade of life in both sexes (Figure 3).

Figure 1- A: Serologically positive for hepatitis C antibodies, B: Serologically negative for hepatitis C antibodies

Figure 2 - A: Serologically negative for hepatitis B antigen, B: Serologically positive for hepatitis B antigen

Figure 3: Incidence of Hepatitis B & C in different age group

DISCUSSION

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the principal causes of liver diseases, with different frequency rates and various types all over the world. The World Health Organization (WHO) estimates that there are near 4 million people with chronic HBV infection and 170 million people with chronic HCV infection worldwide. Mortality rate of Hepatitis B is estimated to result in 563,000 deaths and hepatitis C in 366,000 deaths annually ^{1, 6, 10-12}. The occurrence of hepatitis varies from country to country. The epidemiological estimates by WHO show that there is low prevalence of hepatitis C (<1%) in Australia, Canada and Northern Europe, and almost 1% in countries of medium endemism, such as the USA and most of Europe. The frequency is at its peak (>2%) in many countries of Africa, Latin America, Central and South-East Asia ⁵. As far as the Pakistani population is concerned, the incidence of hepatitis B and C is escalating. Previous studies reveal that the Pakistani population affected by HBV 10% and HCV is 5-10% ³. At times it will also vary among different regions of the same country, and is continuing to rising in certain parts, especially in the rural areas, the percentage of infected individuals is significantly higher ². The total incidence of Hepatitis B and Hepatitis C in our study was found to be 15.36%. This was almost comparison to Naeem et al found to be 12.99% ² and in our previous study reported incidence of anti HCV was 29.60% ⁷. W Ul Huda et al reported 17.33% incidence of HCV infection among their operated patients⁵, whereas a study conducted by Khurrum et al reported 6% incidence of anti HCV antibodies in health care workers in a local hospital¹³. The prevalence of Hepatitis B and Hepatitis C in preoperative cataract patients was found to be higher in males (59.18%) than females (40.82%), and Ahmed et al also showed that the total prevalence of Hepatitis B and Hepatitis C in males was very high compared to females among preoperative cataract patients¹⁴, which is controversial to our result. A study conducted in 2010 on different eye camps in Pakistan showed that 108 out of 437 patients were infected with Hepatitis B and Hepatitis C with a higher prevalence of the diseases in females with 60.18% (65/ 108) than in males with 39.81% (43/108) ¹⁵. Concerning demographic variables, the increase in the risk for HCV seropositive incidences increased with the age i.e. 7.1% at the age of 20 to 30 years whereas 21.4% at the age of 40 to 50 years. In our study, the higher prevalence of hepatitis B & C were in the age range of 30 – 60 years, which is comparable to the study of Talpur et al, in which 65% positive patients were above the age of 40 years¹⁶.

This study shows that the prevalence of these hepatitis causing viral pathogens are quite high. Doctors and paramedical staff in surgical and medical practice are at high risk of acquiring blood borne diseases from the patients on whom they operate.

CONCLUSION

The aim of the present study was to assess the prevalence of HBV and HCV infection among preoperative patients. The incidence of these hepatitis causing viruses are higher in our population. Therefore, it is a mandatory task to screen every patient for hepatitis B and C before any surgical procedure. The surgeons and health care professionals should protect themselves by using protective masks, eye protection glasses, and double gloves before handling infected cases. The used infected material, needles and other waste material should be destroyed properly using Biosafety protocols.

INTRODUCTION

Like doctors in other specialties, general medical practitioners (GPs) are exposed daily to human suffering which most of society try to avoid.¹ The World Health Organisation (WHO) predicts that by 2030 depression will be ‘the leading cause of disease burden globally.’ And that 1 in 4 individuals seeking health care are ‘troubled by mental or behavioural disorders, not often correctly diagnosed and/or treated.’^{2, 3} Doctors suffer from stress, anxiety and depression (as well as vascular disease, cirrhosis of the liver and road traffic accidents) more than the general population.^4-10 Help for doctors is inadequate and doctors are reluctant to seek help.^{1, 4, 11} Where improvement is suggested, it is usually as counselling and general support.¹¹ Instead of ‘more of the same’, we suggest a radically different approach: Adaptation Practice, which Clive Sherlock pioneered and has taught since 1975. It is pragmatic and safe. This study tests its acceptability to a group of working doctors.

Doctors bear the responsibility for fellow human beings’ health, well-being and, often, for their very survival. Added to this, GPs are under increasing pressure from more patients who want more cures and from health service managers who demand clinical excellence and more administration and more managerial skills of them. GPs’ stress is related to increasing workloads, changes to meet requirements of external bodies, insufficient time to do the job justice, paperwork, long hours, dealing with problem patients, budget restraints, eroding of clinical autonomy, and interpersonal problems.^{6, 10, 12} The recent rise in the GMC’s Fitness to Practice complaints related to patients’ expectations of doctors is yet another stress making them feel threatened.¹³

Job satisfaction for GPs is at its lowest level since a major survey started ten years ago, while levels of stress are at their highest. In 2015 there had been a year on year increase in the number of GPs reporting a slight to strong likelihood of their leaving ‘direct patient care’ within five years, with 53% of those under 50 and 87% of those over 50.⁶

By nature and vocation, GPs want to help but too much pressure is unbearable and takes its toll. They work, not with numbers, data or profits, but with human suffering, which, inevitably, is an emotional burden because of compassion and because it makes them aware of their own vulnerabilities and mortality. ^{3, 14} When combined with heavy workloads and low morale, doctors themselves inevitably suffer emotionally and psychologically.^{7, 10, 14} At the same time they and others feel they should be invincible.^{1, 15-17} What professional help is available for them is inadequate.^{3, 4, 18, 19} Existing support services in the UK are underfunded and sporadic.⁴ Some are outsourced to counselling services, and some of these are by telephone. Doctors do not like to be counselled and are reluctant to use these services.^{4, 15, 17}

Doctors themselves are the mainstay for diagnosis and treatment of mental illnesses but are not adequately trained.^{3, 20} Mental illness is not well understood and conventional treatments are insufficient and often harmful. ^{15, 20-23} Consequently, doctors do not have the wherewithal to deal with the emotional and psychological problems they face every day in their patients and often in themselves, their colleagues and their families.^{4, 12, 18}

There is significant prejudice, stigmatisation and intolerance of mental ill health within the medical profession due to lack of understanding and fear.^{3, 4, 9, 15, 17, 20, 21, 22, 24} This not only affects how doctors treat their patients, it also exacerbates their own difficulties when they suffer with emotional and psychological problems themselves, and dissuades them from self-disclosure and from seeking professional help.^{3, 4, 8, 10, 18, 20, 25, 26} To succumb to stress, anxiety and depression is seen as being weak and inadequate as a person and in particular as a doctor. ^{3, 4, 15} Doctors think they should know the answers and should be able to cope.^{1, 4}

However, doctors are willing to learn work-related skills as this present study set out to show.¹¹ Adaptation Practice is training; not treatment or therapy. The course in this study was presented as a postgraduate programme for doctors to learn how to cope with stress, anxiety and depression.

METHOD

Recruitment

We asked by letter all 314 GPs registered in one UK urban and semi-rural Health Authority Area if they would be interested in a course of twelve fortnightly seminars to learn the basics of Adaptation Practice: a programme of self-discipline to cope with stress, anxiety and depression. Included, was the Hospital Anxiety and Depression Scale (HADS). Those who responded and whose HADS scores were ≥ 8 (the threshold for anxiety and depression) were invited to the course.

Stress, anxiety and depression

Anxiety and depression were assessed by the HADS and stress by a simple stress scale (SSS – see Table 1) one month before training started, immediately prior to training, at three months (mid-way through the training) and at six months (at the end of training).

Evaluation of Adaptation Practice

Half of those GPs who applied for the course were unable to attend because of prior commitments on the days planned for the course. These acted as a control group. Those who attended the course were the study group. All those who attended were also assessed in private by the authors immediately before and throughout the course. At the end of the course the doctors wrote anonymous self-assessments.

Training in Adaptation Practice

Those attending the course were taught not to express and suppress upsetting and disturbing emotion, not to distract their attention from it (including not to think about it and not to analyse it) and not to numb themselves to it with chemicals (alcohol, recreational drugs or prescribed medication). Instead, they learned how to engage with their moods and feelings physically, not cognitively, and how not to engage with thoughts about them. They were instructed to practise this six days a week with whatever they were doing, wherever they were. They were all offered unrestricted confidential telephone and e-mail support from the authors between training sessions and after the course had finished.

Statistical Analyses

The results are reported as means ± standard errors of the means. The scores were normally distributed and the data were analysed by analysis of variance with additional paired comparisons within periods, using the LSD method. Correlations were determined using Pearson’s correlation. The analyses were carried out using the statistical software programme SPSS 17.0 for Windows.

RESULTS

Recruitment

Of 314 registered GPs, 225 (72%) responded to our initial contact, and of these 152 (68%) said they would be interested in participating in the training course. Recruitment was restricted to those with HADS scores ≥ 8. Of the 225 who responded there were 71 (32%) for anxiety, 35 (16%) for depression, and 79 (35%) for both. 29 (13%) applied to attend the course. All were experienced GPs. 15 of these attended and 14 were not able to attend because of pre-existing commitments on the course dates. They asked for alternative dates but these were not available.

At the initial assessment (one month before the course started) there were significant correlations between the scores for anxiety and depression (P < 0.001), anxiety and stress (P < 0.001) and depression and stress (P < 0.001). At the second assessment immediately before the course started these correlations remained highly significant.

Effects of Adaptation Practice

All those who attended the course reported a subjective improvement in their abilities to cope with their own stress, anxiety and depression, and in their sense of well-being.

Anxiety

There were no significant differences between the control and study groups either one month before the start (P=0.949) or immediately before the first session (P=0.914). The anxiety scores in both groups remained greater than 8 at both assessments (Figure 1). At the mid-point of the course the mean score had fallen slightly in the study group (Figure 1) but the difference was not significant (P=0.652) By the end of the course the mean anxiety score in the study group was significantly lower (P=0.008) than that of the control group (Figure 1). The mean scores for anxiety decreased over the 4 assessments. This tendency was significant in the study group (P=0.002) but not in the control group (P=0.567).

Figure 1: The mean anxiety scores and standard errors of the means (SEM) for a control group and a study group of doctors with pre-existing signs of anxiety, assessed twice before, once during and once at the end of a six-month course in Adaptation Practice.

Depression

There were no significant differences between the control and the study groups either one month before the start (P=0.310) or immediately before the first session (P=0.880). The mean HADS scores for depression before training were all greater than 8 (Figure 2). At three months (the mid-point of the course) the difference between the mean scores in the two groups was not significant (P=0.631). At the end of the course the mean depression score in the study group was significantly lower (P=0.046) than the control group (Figure 2). The mean scores for depression decreased over the 4 assessments. This tendency was significant in the assessment group (P=0.003) but not in control group (P=0.689).

Figure 2: The mean depression scores and standard errors of the means (SEM) for a control group and a study group of doctors with pre-existing signs of depression, assessed twice before, once during and once at the end of a six-month course in Adaptation Practice.

Stress

There were no significant differences between the control group and the study group either one month before the course started (P=0.234) or immediately before it started (P=0.505). The stress scores were all greater than 8 (Figure 3). At three months (the mid-point of the course) the difference between the mean scores between the two groups was not significant (P=0.621). At the end of the course the mean stress score in the study group was lower (P=0.077) than that of the control group (Figure 3). The mean assessment scores for stress decreased over the 4 assessments. This decrease was significant for the assessment group (P=0.001) but not for the control group (P=0.425).

Figure 3: The mean stress scores and standard errors of the means (SEM) for a control group and a study group of doctors with pre-existing signs of stress, assessed twice before, once during and once at the end of a six-month course in Adaptation Practice.

Correlations

At all four assessments there were correlations among all three psychological parameters. At the initial assessment the correlation between anxiety and depression (r2= 0.405; P = 0.029) and between depression and stress (r2= 0.800; P < 0.0001) were significant but the correlation between anxiety and stress was not (r2= 0.253; P = 0.185). At the commencement of the course the correlation between anxiety and depression (r2= 0.479; P = 0.009), between depression and stress (r2= 0.765; P < 0.0001) and between anxiety and stress (r2= 0.486; P = 0.007) were all significant.

At three months (the mid-point) the correlation between anxiety and depression (r2= 0.526; P = 0.003), between depression and stress (r2= 0.622; P < 0.0001) and between anxiety and stress (r2= 0.790; P < 0.0001) were all significant and similarly at the and of the course: the correlation between anxiety and depression (r2= 0.604; P = 0.001), between depression and stress (r2= 0.577; P =0.001) and between anxiety and stress (r2= 0.740; P < 0.0001) were also all significant.

Assessments of the doctors’ psychological states and methods of coping

The doctors attending the course were assessed individually in private. They variously complained of stress, anxiety and depression. Notable findings included suicidal thoughts, plans for suicide, self-medication, excessive consumption of alcohol and an intention to leave the medical profession because of the unbearable pressures involved.

By the end of the course all these signs and symptoms had improved and the doctors felt confident in their ability to cope not only with pressures from outside but also with emotion, moods and feelings inside. One doctor still wanted to leave the profession but less adamantly than before, and stayed.

There was no qualitative assessment of the control group.

Qualitative Self-assessments

The anonymous self-assessment reports give meaningful, subjective accounts of what the doctors experienced individually. They fall into four main themes. There were no negative comments.

Connecting with emotion physically in the body

The following comments indicate contact with emotion:

‘I am more aware of my feelings.’

‘It is difficult to say “Yes” to unpleasant or upsetting feelings and situations. I have always preferred to avoid them and I have had a lifetime of suppressing emotions, so it is very difficult to say “Yes” to them, but this is what I am now doing.’

‘Since I’ve been more aware of my feelings there has been an enormous improvement in concentration.’

Developing inner emotional strength and coping.

A number of comments indicate the need to develop the strength to contain emotion physically in the body:

‘I am more accepting of daily stresses at work.’

‘I try to deal with problems instead of feeling so desperate and so wronged by them.’

‘I am calmer, and I lose my temper less often and less dramatically.’

‘The Practice was difficult initially because of my own resistances to it.’

‘I’ve always avoided seeking help for myself. I often feel worse than the patients I prescribe antidepressants for. I can now cope and I feel stronger but I don’t feel I’ve been treated and I now realise I didn’t need treatment: I needed to learn what to do and how to do it.’

Dealing with unpleasant, unwanted thoughts.

These comments illustrate the doctors’ new reactions to thoughts as they started to address the underlying emotion that normally drives worrying thoughts:

‘I now have less ruminations.’

‘As a long-standing ruminator I now realise these thoughts are the source of many anxieties. Thoughts were the main problem for me.’

‘I have learned to deal with obsessional thoughts by not giving time to them.’

General well-being.

The doctors commented on their sense of general well-being and ability to cope:

‘I am less tense and less anxious.’

‘I am now coping with episodes of work overload much better.’

‘I am feeling better generally.’

‘This has given me confidence to pursue the course of action I knew was correct.’

‘There are all-round improvements because of adapting myself to work and other people.’

‘I am happier and more content, optimistic and much less negative.’

DISCUSSION

Varying degrees of stress, anxiety or depression are universal.^{16, 26} Only about half of those thought to be clinically affected by these conditions seek help for them.²⁶ If put into practice, sound medical knowledge and training can be beneficial to doctors’ own health.^{1, 11, 15} This does not seem to be true for stress, anxiety and depression.²² Too little is known about emotional and psychological problems, and treatment for them is inadequate.^{2, 9, 15, 17, 19, 21, 23, 28, 29}

In this study, there was a high level of interest in how to deal with stress, anxiety and depression. Almost one third of respondents had scores on the HADS and SSS that suggested worrying levels of emotional and psychological problems amongst these working GPs. The fact that 152 doctors (68% of respondents) declared an interest in a six-month evening course (90 minute sessions after work on Thursday evenings) to learn how to deal with these conditions, suggests that:

• stress, anxiety and depression are significant problems either amongst their patients or for the GPs themselves, or both
• GPs are not confident in their ability to deal with them and want to learn more
• although they have a strong tendency not to admit that they cannot cope and not to seek help, doctors are willing to attend a course to train and to learn.¹¹

Most doctors tell their patients to seek professional help and to talk about their feelings but do not do so themselves.^{3, 5} They prescribe drugs for their patients that either the doctors will not take themselves or that they take but find ineffective. Of the 15 GPs on the course only one had mentioned psychological difficulties to a colleague and one to a partner and both only reticently. ¹⁶

ADAPTATION PRACTICE

Adaptation Practice strongly discourages self-disclosure, except in private to the Adaptation Practice teacher, which is necessary in order to assess the nature and severity of any problems and to lay the foundations for a rapport. Adaptation Practice sessions involve detailed discussion of moods and feelings as physical sensations and powerful forces that affect behaviour in all human beings. The ethos in Adaptation Practice is for participants to learn from their own experience how they are affected by emotion and how they can change this by containing themselves and not letting the emotion control them. It is not to criticise, judge, blame or condemn. Consequently, without the causes of stigmatisation, there is no prejudice and no stigma; instead there is respect and dignity and a pragmatic attitude to change.¹⁶

Adaptation Practice trains individuals to bear and endure upsetting, disturbing emotion by not expressing it, not suppressing it, not distracting themselves from it and not numbing themselves to it with drugs (alcohol, recreational drugs or prescribed medication). Bearing it this way develops emotional strength and resilience.

The high level of interest, the willingness to attend in groups and the positive results from this study indicate that Adaptation Practice is an acceptable way of teaching doctors how to cope with their own stress, anxiety and depression, that makes sense intellectually and emotionally. This, as well as the pragmatic approach mentioned above, makes Adaptation Practice radically different from other approaches.

GENERAL COMMENTS

Given that those who could not attend asked for an alternative day to attend, gave us reason to assume that the manner in which the study group and the control group were selected – individual availability on a given week night – would not have biased the sampling procedures and it seems reasonable to assume that the two groups did not differ in any meaningful way that would have biased the outcome.

Not surprisingly, there were strong positive correlations between anxiety and depression and between depression and stress on all assessments and between anxiety and stress on all but the first assessment, suggesting a strong association among these parameters of psychological states.

The mean scores for anxiety, depression and stress fell significantly in the participating GPs compared with the control group. The subjective reports from both the medical assessments and the self-assessments support these changes in the study group.

This study begs a number of important questions:

• if doctors are prejudiced and stigmatise mental illness amongst themselves then what are their conscious, or unconscious, attitudes to mental illness in their patients? ^{3, 5, 9, 24}
• if doctors cannot cope with emotional problems themselves then whom are they and their patients to turn to for help? This is not the same as doctors suffering from physical conditions requiring surgery, or medications such as insulin or antibiotics.^{3, 5} Doctors expect, and are expected, to be able to cope with their emotions and, if necessary, that the treatment they give their patients will also work effectively for themselves
• what are doctors to do and what are their patients to do, when doctors succumb to their own moods and feelings?

Adaptation Practice could be integrated in the medical curriculum at undergraduate and postgraduate levels, including Continuing Professional Development (CPD). Not only GPs but all doctors and other healthcare staff (nurses, physiotherapists, occupational therapists, social workers, etc.) could develop emotional resilience – which the GMC have proposed in recent years – and a better understanding of emotional and psychological problems and mental illnesses.

It is hoped that this preliminary study will stimulate and encourage a new way of looking at and investigating emotional and psychological problems and lead to further evaluation of Adaptation Practice.^{29, 30}

With adequate training doctors and psychologists could teach Adaptation Practice.

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

Incidence

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

Table1. Patients’ Response to AVH

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

Measurements for Assessment

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

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

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

Table 2. Measurement scales

Treatments

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

Pharmacotherapy

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

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

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

Table 3. Drug Treatment

Clozapine

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

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

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

Table 4. Cautions & Contraindications of Clozapine

Table 5. Benefits and risks of Clozapine

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

Psychological Interventions

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

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

Table 6. Psychological Interventions

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

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

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

Table 7. Goals of CBT

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

Newer Psychological Interventions

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

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

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

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

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

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

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

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

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

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

Repetitive Trans-cranial Magnetic Stimulation

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

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

Avatar Therapy

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

Sound Therapy

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

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

Future Directions

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

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

Discussion

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

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

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

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

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

The Issues

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

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

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

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

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

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

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

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

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

How it could be introduced:

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

Monitoring:

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

Funding:

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

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

Conclusion:

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

INTRODUCTION

Ventilator-associated pneumonia (VAP) is a type of nosocomial pneumonia that occurs in patients who receive mechanical ventilation and is usually acquired in the hospital setting approximately 48–72 hours after mechanical ventilation.¹ VAP is one of the most frequent hospital-acquired infections occurring in mechanically ventilated patients and is associated with increased mortality, morbidity, and health-related costs. Several risk factors have been reported to be associated with VAP, including the duration of mechanical ventilation, and the presence of chronic pulmonary disease, sepsis, acute respiratory distress syndrome (ARDS), neurological disease, trauma, prior use of antibiotics, and red cell transfusions.² VAP occurrence is closely related to intubation and the presence of the endotracheal tube (ETT) itself.

Since there are inadequate objective tools that are utilized to make an assessment of bacterial-induced lung injury in a heterogeneous group of hosts, the diagnosis of VAP is challenging. Around 90% of ICU-acquired pneumonias occur during mechanical ventilation, and 50 % of these ventilator-associated pneumonias begin in the first 4 days after intubation.³ VAP has a cumulative incidence of 10-25% and accounts for approximately 25% of all ICU infections and 50% of its antibiotic prescription, making it the primary focus for risk-reduction strategies.^1,4 For all these reasons, early diagnosis and prevention of VAP has held a prominent position on the research agenda of intensive care medicine in the past 25 years, with an ultimate goal of improving patient outcome, preferably by reducing mortality.

The keywords, ‘ventilator-associated pneumonia,’ in PUBMED revealed a total of 3612 titles and 625 review articles within the search limit of 10 years, between 2005 and 2014. Only articles in English were chosen.

PATHOGENESIS

Understanding the pathogenesis of VAP is the first step in the formulation of its appropriate preventive and therapeutic strategies. The initial step in the pathogenesis of VAP is bacterial colonization of the oropharynx and gastric mucosa, followed by translocation of the pathogens to lower respiratory tract. The most common means of acquiring pneumonia is via aspiration which is promoted by supine position and upper airway and nasogastric tube placement.^2,5 In a mechanically ventilated patients, aspiration occurs around the outside of the endotracheal tube rather than through the lumen. Secondly, aerobic Gram-negative bacteria presumably reach the lower airway via aspiration of gastric contents or of upper airway secretions. Other means by which VAP can be acquired include aspiration from the stomach or nose and paranasal sinuses. Figure 1 depicts the essential elements favoring colonization of lower respiratory tract with the bacterial pathogens with subsequent development of pneumonia.^2,5,6

Figure 1: Pathogenesis of Ventilator-associated pneumonia⁵
*Gastric alkalinization; prior antimicrobials; ICU stay; intubation; supine position; circuit/airway manipulation and mishandling; device cross-contamination; sedation; diminished cough reflex; and malnutrition predispose to colonization and aspiration. As the duration of ICU stay increases, colonization with MDR Gram-negative pathogens like Pseudomonas and Acinetobacter increases.
†Via contaminated nebulizers/aerosols
Reproduced with permission from the publisher.

COMMON CAUSES

The specific microbial causes of VAP vary widely depending in epidemiological and clinical factors. Common pathogens include aerobic gram negative bacteria such as Pseudomonas aeruginosa and members of family Enterobacteriaceae, staphylococci, streptococci, and Haemophilus species. Microorganisms like Pseudomonas spp., Acinetobacter spp. and Methicillin-Resistant Staphylococcus aureus occur commonly after prior antibiotic treatment, prolonged hospitalization, mechanical ventilation or when other risk factors are present.^6,7

Moreover, deliberated ill patients may have defect in phagocytosis and behave as functionally immunosuppressed even prior to emergence of nosocomial infection as seen by many recent studies.^8,9

DIAGNOSIS

Clinical Diagnosis

No gold standard of diagnosis for identifying VAP is there inspite of variety of proposed definitions. VAP has traditionally been diagnosed by clinical criteria of Johanson and colleagues (appearance of new or progressive pulmonary infiltrates, fever, leucocytosis and purulent tracheobronchial secretions), which are non-specific. When findings on histologic analysis and cultures of lung samples obtained immediately after death were used as references, a new and persistent (>48-h) infiltrate on chest radiograph plus two or more of the three criteria (i) fever of >38.3°C, (ii) leukocytosis of >12 × 10⁹/ml, and/or (iii) purulent tracheobronchial secretions had a sensitivity of 69% and a specificity of 75% for establishing the diagnosis of VAP.¹⁰

Because of the poor specificity of the clinical diagnosis of VAP and of qualitative evaluation of ETAs, Pugin et al. developed a composite clinical score, called the clinical pulmonary infection score (CPIS), based on six variables: temperature, blood leukocyte count, volume and purulence of tracheal secretions, oxygenation, pulmonary radiography, and semi-quantitative culture of tracheal aspirate. The score varied from 0 to 12. A CPIS of >6 had a sensitivity of 93% and a specificity of 100%.¹¹ Accuracy of CPIS in diagnosis of VAP is debated, despite of its clinical popularity. In one meta-analysis study evaluating the accuracy of CPIS in diagnosing VAP reported pooled estimates for sensitivity and specificity for CPIS as 65 % (95 % CI 61-69 %) and 64 % (95 % CI 60-67 %), respectively.¹² The poor accuracy of clinical criteria for diagnosing VAP is due to purulent tracheobronchial secretions in patients receiving prolonged mechanical ventilation which are rarely caused by pneumonia. Moreover, in pneumonia systemic signs such as fever, tachycardia, and leukocytosis are nonspecific; they can be caused by any state that releases the cytokines interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor alpha (TNFα), and gamma interferon.^13,14 The weak point of CPIS is probably the inter-individual variability (kappa= 0.16), since a subjective evaluation is required when we are judging the quality of tracheal secretion (purulent/not purulent) and the presence of infiltrate at chest ray.¹⁵

Radiologic Diagnosis

Radiographical evidence of pneumonia in ventilated patients is also notoriously inaccurate. In a study of autopsy proven VAP, of the total population, only air bronchograms correlated with pneumonia and no specific roentgenographic sign correlated with pneumonia in patients with adult respiratory distress syndrome. The differential diagnoses of VAP based on radiographical appearance, include adult respiratory distress syndrome, congestive heart failure, atelectasis, pulmonary embolism and neoplastic infiltration.¹⁶

Microbiologic Diagnosis

The type of specimen that should be obtained for microbiologic processing as soon as VAP is suspected is another area of importance. The use of quantitative cultures is one of the main issues for any diagnostic laboratory because there is oropharyngeal bacterial contamination of all respiratory secretion samples, despite this is not always undertaken in many hospitals today.^16,17

Blood cultures

Blood cultures have limited value because organisms isolated from blood in suspected VAP cases are often from extrapulmonary sites of origin.¹⁸ Blood cultures in patients with VAP are clearly useful if there is suspicion of another probable infectious condition, but the isolation of a microorganism in the blood does not confirm that microorganism as the pathogen causing VAP.

Quantitative cultures of airway specimens

Simple qualitative culture of endotracheal aspirates has high percentage of false-positive results due to bacterial colonization of the proximal airways observed in most patients in the ICU.²⁰ Quantitative culture techniques suggest that endotracheal aspirate cultures (QEA) may have an acceptable overall diagnostic accuracy, similar to that with several other, more invasive techniques including BAL, protected BAL (pBAL) ,protected specimen brush (PSB) or tracheobronchial aspirate(TBA).^7,19,20 Threshold values often employed for diagnosing pneumonia by quantitative cultures are ≥10⁵ to 10⁶, ≥10⁴, and ≥10³ CFU/ml for QEA, bronchoscopic BAL, and PSB, respectively, with ≥10⁵ CFU/ml being the most widely accepted value for QEA.^21,22,23 Also, blind aspiration sampling can lead to errors but bronchoscope also carries risks, such as inducing cardiac arrhythmia, hypoxemia, bleeding, pneumothorax, along with greater costs both in terms of time and resources. It is accepted that before administering the first dose of antibiotic or before any change in treatment patient specimens for culture should be taken, so that the results interpreted are valid.²⁴ Lalwani et al., in their study, observed that culture results of a properly collected tracheal aspirate should be taken into consideration along with Centre for Disease Control and Prevention (CDC's) diagnostic criteria to maximize the diagnosis of VAP.²⁵

The recent guidelines of Society for Healthcare Epidemiology of America/ Infectious Diseases Society of America (SHEA/IDSA) recommend Gram staining of endotracheal aspirates. However, the sensitivity (57-95%) and specificity (48-87%) of this technique are highly variable. The role of procalcitonin and other biomarkers for the diagnosis of VAP is yet unsubstantiated.^5,26

Since VAP diagnosis founded on radiographic findings of pneumonia, which have intrinsic variability in technique, interpretation, and reporting, and on clinical signs and symptoms- that are subjective- in 2011 a Working Group of the CDC proposed a new approach to surveillance for Ventilator-Associated Events (VAE). Table 1 According to the new CDC definition algorithm, VAP is an Infection-related Ventilator-Associated Complication (IVAC) occurring after 3 days of mechanical ventilation and 2 days before or after the onset of worsening oxygenation, if purulent respiratory secretions with positive cultures or objective signs of respiratory infection have been found.²⁷

Table 1: CDC Algorithm for VAP diagnosis³⁰

Table 2: Practices for which insufficient evidence or no consensus exists about Efficacy^8,57

STRATEGIES FOR VAP PREVENTION

There are multiple recommended measures for prevention of VAP. Practices for which insufficient evidence or no consensus exists about efficacy are summarized in Table 2. Preventive VAP strategies can be grouped into two classes: non-pharmacologic strategies, which are focused on preventing aspiration, and pharmacologic strategies, which are aimed at preventing colonization.

Non-Pharmacologic Strategies

Staff Education in the Intensive Care Unit

Various barriers to adhering to VAP prevention recommendations include disagreement with the reported results of source studies, resource paucity, elevated costs, inconvenience for nurses, fear of potential adverse effects and patient discomfort. There is considerable variability in practice between countries regarding humidification systems, intubation route, endotracheal suction system, kinetic therapy beds, subglottic secretion drainage and body position. For efficient patient care staffing must be sufficient while ensuring that staff is able to comply with essential infection control practices and other prevention strategies.^17,28

Hand Hygiene

Microorganisms can be spread easily from patient to patient on the hands of healthcare workers. Moreover, wrist watches, rings, bangles and other jewelry commonly act as reservoirs for organisms, and impede effective hand cleaning. Moreover, healthcare workers compliance to hand hygiene is low, and high workload decreases their compliance.²⁹

Impact of patient position

Patients positioned semi-recumbently 45 degrees have significantly lower incidence of clinically diagnosed VAP compared to patients positioned supinely.³⁰ Moreover, the incidence of clinically diagnosed VAP among patients positioned prone, does not differ significantly from the incidence of clinically diagnosed VAP among patients positioned supine.^31,32

Kinetic Beds

Critical patients often for a long time remain immobile in the supine position so the functional residual capacity is decreased because of alveolar closure in dependent lung zones and impaired mucociliary clearance. This leads to the accumulation of mucus, atelectasis onset and ensuing infection.³³ Rotational therapy uses a special bed designed to turn continuously, or nearly continuously, the patient from side to side; specific designs include kinetic therapy and continuous lateral rotation therapy (CLRT).^34,35

Artificial Airway Management

Oral vs Nasal Intubation: Both nasogastric and nasotracheal tubes can cause oropharyngeal colonization and nosocomial sinusitis. Thus, use of the oral route for both endotracheal and gastric intubation should be considered to decrease the risk of VAP.³⁶

Endotracheal tube cuff pressure: The secretions that pool above inflated endotracheal tube cuffs may be a source of aspirated material and ensuing VAP. The pressure of the endotracheal tube cuff should be optimized in order to prevent the leakage of colonized subglottic secretions into the lower airways. Persistent pressures into the tube cuff below 20 cm H₂O have been associated with the development of VAP.³⁷

Silver-Coated Endotracheal Tubes: Silver-coated endotracheal tubes appear to be safe, reduces bacterial biofilm formation, has bactericidal activity, reduces bacterial burden and can delay airway colonization. However, further studies are needed to for determing its efficacy.^38,39

Mechanical Ventilation Management

Ventilator Circuit Change: The CDCs recommendation was ‘do not change routinely, on basis of duration of use, the breathing circuit that is in use on an individual patient. Change the circuit when it is visibly soiled or mechanically malfunctioning.⁴⁰

Humidification With Heat and Moisture Exchangers: The effect of HME in preventing VAP is still controversial and recent studies have failed to show a significant difference in rates of infection.⁴¹

Subglottic secretion drainage: Intermittent subglottic secretions drainage using inspiratory pause during mechanical ventilation results in a significant reduction in VAP.⁴² SSD reduces VAP in patients ventilated for >72 hours and should be considered with other recommended strategies such as semi-recumbent positioning.⁴³

Pharmacologic Strategies

Modulation of Oropharyngeal Colonization

Policies encouraging routine tropical oral decontamination with chlorhexidine for patients merit reevaluation. It is a cheap measure, but whether is it a safe one − it does not select resistant microorganisms − remains to be investigated.^8,44

Selective Decontamination of the Digestive Tract

Selective decontamination of the digestive tract (SDD) is the decontamination ofpotentially pathogenic microorganisms living in the mouth and stomach, whilst preserving the indigenous anaerobic flora. SDD is an effective and safe preventive measure in ICUs where incidence rates of MRSA and VRE are low, but in ICUs with high rates of multi-resistant microorganisms it is a measure that is effective but not safe.^45,46

Stress Ulcer Prophylaxis

Patients at risk from important gastrointestinal bleeding (shock, respiratory failure requiring mechanical ventilation or coagulopathy) should receive H₂ antagonists such as ranitidine rather than sucralfate.⁴⁷

Ventilator sedation protocol

In patients receiving mechanical ventilation and requiring sedative infusions with midazolam or propofol, the use of a nurse-implemented sedation protocol decreases the rate of VAP and the duration of mechanical ventilation.⁴⁸ An objective assessment-based Analgesia-Delirium-Sedation (ADS) protocol without daily interruption of medication infusion decreases ventilator days and hospital length of stay in critically ill trauma patients.⁴⁹

Antibiotic Policy and Infection Control

Rational antibiotic policy is a key issue for better patient care and preventing antimicrobial resistance.^50,51 Infection control programs like using a scheduled switch of antibiotic class have demonstrated efficacy in reducing nosocomial infection rates and restraining multidrug resistant (MDR) microorganism emergence.⁵²

VAP prevention in low resource/developing countries

Though the incidence of VAP has declined in the developed countries, it continues to be unacceptably high in the developing world. Its incidence in these countries is 20 times that in the developed nations with significant morbidity, mortality, and increase in ICU length of stay, which may represent an additional burden on the scarce resources in developing countries.⁵³ Insufficient preventive strategies and probably inappropriate antibiotics administration may have lead to this scenario. Since microbiology and resistance pattern in India is different from other countries, there is need for data from our country to choose appropriate antimicrobials for management.⁵⁴ Simple and effective preventive measures can be instituted easily and at minimal costs. Such measures might include hand hygiene, diligent respiratory care, elevation of head, oral and not nasal cannulation, minimization of sedation, institution of weaning protocols, judicious antibiotics use, de-escalation, and leveraging PK/PD characteristics for antibiotics administered. More costly interventions should be reserved for appropriate situations. Strategies to prevent VAP, probably by emphasis on practical, low-cost, low technology, easily implemented measures is need of the hour.

Ventilator-associated events (VAE) surveillance: an objective patient safety opportunity

Surveillance for ventilator-associated pneumonia is challenging and contains many subjective elements, including the use of chest x-ray evidence of pneumonia. In January 2013, CDC convened a VAP Surveillance Definition Working Group which transitioned VAP surveillance to ventilator-associated event (VAE) surveillance in adult inpatient settings.⁵⁵ The VAE algorithm—which is a surveillance algorithm and not intended for use in the clinical management of patients—consists of 3 tiers of definitions: Tier 1, Ventilator-Associated Conditions (VAC); Tier 2, Infection -related Ventilator-Associated Complications (IVAC); and Tier 3, Possible and Probable VAP.²⁷ The tier 1, VAC attempts to identify sustained respiratory deterioration episodes, and capture both infectious and noninfectious conditions and complications occurring in patients receiving mechanical ventilation. The tier 2, IVAC, is intended to identify the subset of VACs that are potentially related to pulmonary and extra pulmonary infections of sufficient severity to trigger respiratory deterioration. The tier 3, possible and probable VAP, attempts to identify IVAC patient subsets with respiratory infections as manifested by objective evidence of purulent respiratory secretions (where purulence is defined by using quantitative or semi-quantitative criteria for the number of neutrophils on Gram stain) and/or positive results of microbiological tests done on respiratory specimens. Because of the wide range of the lower respiratory tract specimens, their collection procedure as well as in laboratory processing and reporting of results, the Working Group of CDC determined that it was not appropriate to include these data elements in the VAC and IVAC definitions.⁵⁶

This 3 tier approach is ineffective to accurately identify VAP for surveillance purposes and focuses on more mechanical ventilation complications. This approach may also reduce the likelihood of manipulation that could artificially lower event rates. Most VAEs are caused by pneumonia, pulmonary edema, atelectasis, or acute respiratory distress syndrome. In few recent studies concordance between the VAE algorithm and VAP was found to be poor.⁵⁷ Thus, more studies are needed to further validate VAE surveillance compared with conventional VAP by using strong microbiologic criteria, particularly bronchoalveolar lavage with a protected specimen brush for diagnosing VAP and to better characterize the clinical entities underlying VAE.

Bundle approach to prevention of VAP

One of the five goals of the ‘Saving 100,000 Lives’ campaign, launched by the Institute for Healthcare Improvement is to prevent VAP and deaths associated with it by implementing a set of interventions for better patient care known as the ‘ventilator bundle’. The interventions should have scientific support of effectiveness, based on randomized controlled trials. All the elements of the bundles must be executed at the same time. The bundles for VAP includes four components: (a) elevation of the head end of the bed to 30-45º, (b) daily interruption of sedation, (c) daily assessment of readiness to extubate and (d) prophylaxis for deep venous thrombosis and peptic ulcer disease. The bundle approach to prevention of VAP has been found to be highly effective in reducing the incidence, mortality and ICU stay.^5,58,59 The ventilator bundle should be modified and expanded to include specific processes of care that have been definitively demonstrated to be effective in VAP reduction. A multidimensional framework with a long-lasting program can successfully increase compliance with preventive measures directly dependent on healthcare workers bedside performance.

CONCLUSION

Ventilator Associated Pneumonia is one of the most common nosocomial infections in ICU presenting with non specific symptoms and clinical signs. Quantitative culture obtained by different methods, including EA, BAL, pBAL, PSB or TBA seem to be rather equivalent in diagnosing VAP. Clinical criteria used in combination, may be useful in VAP diagnosis; however, inter-observer variability and the moderate performance are to be considered.

Preventive strategies should focus on better secretion management and on reduction in bacterial colonization. Further research on targeted interventions is needed to effectively reduce VAP incidence. For VAP an approach based on multidisciplinary group is required including setting preventive benchmarks, establishing goals and time lines and providing appropriate education and training, audits and feedback to the staff, while continually updating themselves based on relevant clinical and preventive strategies.

INTRODUCTION

During my placement in Psychiatry at the Brooker Centre, Runcorn, UK, I have come into contact with a wide array of psychiatric disorders, none more so than borderline personality disorder (BPD). It is undoubtedly one of the most prevalent problems in the area which the Brooker Centre serves. I can recall an example of a patient with BPD who had been quite unwell for a prolonged period of time and had struggled with affective instability. This patient had been quite successfully treated with Lithium therapy, has exhibited stability and is happy on the current treatment. There is a pattern of pharmacological treatment in BPD patients despite the fact that guidelines suggest otherwise…

Personality disorders are defined as ‘an enduring pattern of inner experience and behaviour that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adulthood, is stable over time, and leads to distress or impairment’ . Personality disorders are representative of long-term functioning and are not considered in terms of episodes of illness ¹.

The Diagnostic and Statistical Manual of Mental Disorders, 5^th edition (DSM-5), groups the various personality disorders into three clusters based on their descriptive similarities.

Cluster A includes the Paranoid, Schizoid, and Schizotypal personality disorders which are categorised as ‘odd/eccentric’;

Cluster B includes the Antisocial, Borderline, Histrionic, and Narcissistic personality disorders which are categorised as ‘dramatic/emotional/erratic’;

Cluster Cincludes the Avoidant, Dependent, and Obsessive-compulsive personality disorders which are categorised as ‘anxious/fearful’ ².

The International Classification of Diseases, 10^th edition (ICD-10), specifies the condition of emotionally unstable personality disorder which has two subtypes: The impulsive type and the borderline type. The borderline type in essence overlaps with the DSM-5 definition ³.

It has proven difficult to provide robust clinical recommendations with regards to the treatment of personality disorder. This is, in part, due to the fact that study populations are diverse but also compounded by the use of different assessment criteria. Furthermore, it is important to consider that personality disorders often present with a great deal of psychiatric comorbidity. Of the personality disorders, particular attention has been paid to borderline personality disorder (BPD) as the symptom clusters which it involves have been shown to improve considerably with treatment ⁴.

Figure 1: Diagnostic Criteria for Borderline Personality Disorder according to DSM-5 ²:

Borderline personality disorder is characterised by a pervasive instability in mood, interpersonal relationships, self-image and behaviour. The condition was first recognised in the United States by Adolf Stern in 1938. He described that these are a group of patients who neither fit into psychotic or psychoneurotic group, which gave rise to the term ‘borderline’. BPD is often diagnostically comorbid with depression and anxiety, eating disorders (notably bulimia), post-traumatic stress disorder, substance misuse and bipolar affective disorder. Furthermore, psychotic disorders have also been found to overlap. Due to this extent of comorbidity it is rare to see a patient who has a pure BPD ⁵.

The pharmacological treatments of BPD are tailored according to the symptom clusters that present. These include impulsivity, affective instability, transient stress-related psychotic symptoms and suicidal & self-injurious behaviours ^5,6.

Recommended Psychological and Pharmacological treatment, 2009 National Institute for Health and Clinical Excellence (NICE) guidelines on Borderline Personality Disorder ^{5, 7}:

Psychological

NICE guidelines state that when offering psychology for BPD or for the individual symptoms of the disorder, brief psychological interventions (i.e. less than a 3 month period) should not be used. It states that the frequency of psychotherapy sessions should be adapted to the patient’s needs and ‘context of living’ and suggests that twice-weekly session may be considered. The guidelines also specify that for women with BPD for whom recurrent self-harm is a priority, a comprehensive dialectical behaviour therapy programme should be considered. NICE recommends that when psychological treatment is provided in BPD, the effects should be monitored using a broad range of outcomes. These should include personal functioning, drug and alcohol use, self-harm, depression and the symptoms of BPD.

Pharmacological

The NICE guidance states that drug treatment should not be used specifically for BPD or for the individual symptoms or behaviour associated with the disorder (e.g. repeated self-harm, marked emotional instability, risk taking behaviour and transient psychotic symptoms). It goes on to suggest that antipsychotics should not be used for the medium- and long term treatment of BPD. However, with regards to the management of comorbidities, it specifies that drug treatment may be considered and that in each case, the NICE guidelines for each comorbid condition must be referred to. Antidepressants, mood stabilisers and antipsychotics are commonly used in clinical practice. The guidelines mention that short-term use of sedative medication may be considered in a crisis. ‘Short-term’ denotes treatment lasting no longer than one week.

With regards to drug treatment during a period of crisis, NICE recommends that there should be a consensus among prescribers and other involved professionals about the proposed drug treatment and also that a primary prescriber should be identified. There should be an appreciation of the likely risks of prescribing, including alcohol and illicit drug use. NICE emphasises that the psychological role of prescribing (both from the patient’s and prescriber’s perspective) should be taken into account, and the impact that such prescribing decisions may have on the therapeutic relationship and overall care plan. NICE recommends that a single drug be used and that polypharmacy is to be avoided as much as possible.

In a crisis NICE recommends prescribing ‘a drug that has a low side-effect profile, low addictive properties, minimum potential for misuse and relative safety in overdose.’ The minimum effective dose is favourable, prescribing fewer tablets more frequently if there is a significant risk of overdose and also agreeing with patient on the symptoms that are being targeted. NICE suggests that following a crisis, a plan should be made to stop drug treatment that was started during a crisis. If this is not possible, a regular review of the effectiveness, side effects, misuse and dependency of the drug is advised. BPD patients can often have concomitant insomnia and for this, NICE details basic advice regarding sleep hygiene and forwards on to the guidance on the use of zaleplon, zolpidem and zopiclone for the short-term pharmacological management of insomnia.

AIMS AND OBJECTIVES

This report will review the current guidelines specifically regarding the management of borderline personality disorder and explore the literature according to the research recommendations that are set by NICE. The report is to focus on the two aspects of the management of BPD – The psychological/psychosocial aspect and the pharmacological aspect.

CURRENT NICE GUIDELINES ON PSYCHOLOGICAL AND PHARMACOLOGICAL TREATMENT OF BPD ⁷:

Psychology

Mentalisation-based therapy and dialectical behavioural therapy are proposed in the setting of a ‘well structured, high quality community based service’ e.g. a day hospital setting or a community mental health team. NICE suggests that these techniques should be compared with ‘high-quality community care delivered by general mental health service without the psychological intervention for people with BPD’ in order to measure efficacy. For outpatients, cognitive analytic therapy, cognitive behavioural therapy, schema-focussed therapy and transference focussed therapy are suggested and are catered to those with less severe BPD (i.e. fewer comorbidities, higher level of social functioning, greater ability to depend on self-management methods). Randomised controlled trials reporting medium term outcomes (e.g. quality of life, psychosocial functioning, employment outcomes and BPD symptomatology) of a minimum of 18 months are recommended

Pharmacology

Mood stabilisers are proposed as it is detailed that emotional instability is a key feature in BPD. In particular, topiramate and lamotrigine are mentioned as they have been shown to produce encouraging results in small-scale studies. A randomised placebo-controlled trial with medium to long-term follow up is recommended.

ANALYSIS

Psychology: Dialectical Behaviour Therapy (DBT)

Dialectics can be defined as the art of investigating the relative truth of opinions, principles, and guidelines ⁸. Dialectical in DBT refers to a means of arriving at the truth by examination of the argument i.e. the ‘thesis’ and ‘antithesis’ and resolving the two into a rational synthesis. DBT was introduced in 1991 by Marsha Linehan (a psychology researcher) and colleagues tailored as a treatment for BPD. In this, patients are supported in understanding their own emotional experiences and are taught new skills for dealing with their stresses. A combination of individual and group sessions are used. More adaptive responses and effective problem-solving techniques are integrated to improve functioning and quality of life as well as improving morbidity and mortality ^{9, 10}.

A study published in 2015 by M. Linehan et al detailed a randomized clinical trial that set out to compare

1) Standard DBT (DBT group skills training + DBT individual therapy) with

2) A treatment that evaluated DBT group skills training with manual case management (i.e. with the removal of DBT individual therapy) and

3) A treatment that removed DBT skills training by providing only DBT individual therapy with an activities group and prohibited individual therapists from teaching DBT skills.

All 3 versions of the treatment were found to be comparably effective at reducing suicide attempts, suicidal ideation, medical severity of intentional self-harm, use of crisis services owing to suicidality and improving reasons for living ¹¹.

Psychology: Mentalization based therapy

Mentalization is ‘the process by which we make sense of each other and ourselves, implicitly and explicitly, in terms of subjective states and mental processes.’ It is a social construct suggesting that we are attentive to the mental states of those we are with, physically or psychologically ¹². Mentalization based treatment is a psychosocial treatment for BPD in which therapists monitor attachment and mentalizing capacity, and use interventions that aim to reinstate or maintain the capacity of patients to mentalize ¹³.

A longitudinal study, published in 2008, involving an eight-year follow-up of patients treated for BPD evaluated the effect of mentalization-based treatment (MBT) with partial hospitalization compared with treatment as usual. Five years after discharge from MBT, the MBT group exhibited clinical and statistical superiority to treatment as usual measured on suicidality, diagnostic status, service use, medication use, global function and vocational status ¹⁴. A more recent review article, published in 2015, emphasises the consideration of disruptions in three closely related domains in individuals with BPD. These are ‘in attachment relationships, in different polarities of mentalizing, and in the quality of epistemic vigilance and trust’. It is suggested that this approach allows seemingly paradoxical features of BPD patients appear more coherent. It is supposed that this approach provides a clear focus for the therapist enabling them to monitor the therapeutic process in terms of imminent mentalizing impairments and epistemic mistrust due to activation of the attachment system.

The article goes on to assert that the effectiveness of MBT in BPD may be elucidated due to the fact that it ‘enables the therapist to maintain and foster a mentalizing stance, even–and perhaps particularly–under high arousal conditions that are so characteristic of work with these patients’ ¹⁵.

Psychology: Cognitive analytic therapy (CAT)

CAT is a brief focal therapy that is informed by cognitive therapy, psychodynamic psychotherapy and elements of cognitive psychology. It was originally developed by Anthony Ryle tailored towards the needs of the NHS ¹⁶. It is based on a collaborative therapeutic position which sets out to create narrative and diagrammatic reformulations with patients concerning their difficulties. The theory centres on descriptions of sequences of linked external, mental and behavioural events. At first, the emphasis was on how such procedural sequences prevented revision of dysfunctional ways of living. More recently, this has been extended to understanding the origins of reciprocal role procedures in early life and their repetition in current relationships and self-management ¹⁷.

One study detailed a randomised controlled trial which aimed to investigate the effectiveness of time-limited CAT for participants with personality disorder. The study found that participants receiving CAT exhibited reduced symptoms and showed considerable improvement compared with the control group who showed signs of deterioration during the treatment period. They concluded that CAT is superior to treatment as usual in improving outcomes associated with personality disorder ¹⁸.

Psychology: Cognitive behavioural therapy (CBT) and Schema-focussed therapy

CBT is a time-limited, problem focussed psychotherapy that has been applied to a wide range of psychiatric disorders. The development of this technique was born out of the observation that patients referred for psychotherapy often would hold ingrained, negatively skewed assumptions of themselves, their future and their environment. The therapy is based on the notion that disorder is caused not by life events, but by the view the patient adopts of events. The therapy focusses on current problems and helps to develop new skills to provide symptom relief and sustain recovery ^{9, 19}.

Initially CBT was predominantly insight-orientated, using introspection to bring about change. Beck et al began to integrate a range of behavioural techniques to improve the impact on dysfunctional controlling belief systems (schemas). The goal of treatment is not to replace the dysfunctional schemas; it aims to modify beliefs and develop new ones allowing the patient to cope more effectively in challenging situations ^{20, 21}.

A 2013 review article that set to explore schema-focussed therapy concluded that schema-therapy is based on a ‘cohesive theoretical model’ and that there seems to be sufficient evidence supporting its validity. Regarding effectiveness, it goes on to indicate that one should be encouraged by the results of studies, however it points out that due to the small number of ‘methodologically-good efficacy studies’ it is difficult to be certain. The article claims that when evaluated against other psychotherapeutic treatments, specifically DBT and MBT, schema-therapy requires more investigation ²². A pilot study (2013) set out to monitor the effects of group schema-based CBT on global symptomatic distress in young adults with personality disorders or features of personality disorder. Their findings provide preliminary evidence that schema-based CBT might be an effective treatment ²³.

Furthermore, there is a multicentre randomized controlled trial being conducted with the aim of investigating schema-focussed therapy versus treatment as usual in BPD, which has a closing date of 1^st February 2016 ²⁴.

Psychology: Transference focussed therapy (TFT)

The classic use of the term transference originates in psychoanalysis and comprises “the redirection of feelings and desires and especially of those unconsciously retained from childhood toward a new object” ²⁵. Transference-focussed psychotherapy is an evidence-based manualised treatment using a psychodynamic approach with a focus on object relations theory ²⁶. TFT aims to ‘facilitate the reactivation, under controlled circumstances, of the dissociated internalised object relations in the transference relationship to observe the nature of the patient’s split polarised internal representations, and then, through a multistep interpretive process, work to integrate them into a fuller, richer, and more nuanced identity ²⁷.

Yeomans et al produced an article in 2013 consisting of vignettes to illustrate the techniques used in TFT with the view to evaluate its use in treating BPD. Their findings supported the validity of TFT in treating BPD patients who specifically had difficulty with relationships.

They distilled TFT down to three important components ²⁸:

1) The treatment contracting/setting the frame

2) Managing one’s affective response

3) The interpretative process

Pharmacology

A Cochrane intervention review assessing the effects of drug treatments in BPD, included twenty-eight randomised control trials, published in the period 1979-2009 (20 of 28 trials dating from 2000 or later), involving a total of 1742 participants ²⁹.

Figure 2: The pharmacological agents that were tested included the following:

The authors arrived at the conclusion that pharmacotherapy in BPD ‘is not based on good evidence from trials’. The review found that there is support for the use of Second-generation antipsychotics (in improving cognitive-perceptual symptoms and affective dysregulation); Mood stabilisers (in diminishing affective-dysregulation and impulsive-aggressive symptoms); and Omega-3 fatty acids.

However, these claims were made based on single study effects and therefore require replication. No drug was found to significantly affect the symptom clusters, specific to BPD, including avoidance of abandonment, chronic feelings of emptiness, identity disturbance, and dissociation.

One noteworthy finding was that Olanzapine was associated with an increase in self-harming behaviour. Furthermore, the review states that ‘special attention’ is needed in BPD when prescribing tricyclic antidepressants (due to toxic effects in overdose) and hypnotics & sedatives (due to there being potential for misuse or dependence). Another problem that was highlighted was that in comorbid eating disorders the use of Olanzapine can contribute to weight gain and Topiramate can produce weight loss.

The review goes on to elucidate that there is not any evidence from randomised controlled trials that any drug reduces the severity of BPD and that it consists of ‘distinct pathology facets’. They recommend that the pharmacotherapy of BPD should be targeted at ‘defined symptoms’ and that polypharmacy is not supported by the latest evidence and should be avoided as much as possible.

The authors end by reaffirming that the evidence is not robust and that the studies may not satisfactorily reflect certain characteristics of the clinical environment. They propose that further research is needed in order to produce reliable recommendations. They detail the complications that arise from the ‘polythetic nature’ of BPD i.e. each patient is likely to experience different aspects of the disorder. There lacks a consensus among researchers about a common battery of outcome variables and measures. They comment that there is a fragmentary view on drug effects and that it is unknown as to how the alteration of one symptom affects another.

Comorbidity

Comorbidity is a foremost concern in the interpretation of data concerning personality disorders ³⁰. A majority of individuals diagnosed with one personality disorder often meet criteria for at least one other personality disorder ³⁰. A large proportion of patients with personality disorder have one axis I ³¹ disorder comorbidly, mostly depression, anxiety and alcohol and substance use disorders ³². [Axis I is a reference to the multi-axial classification system used in the Diagnostic and Statistical Manual of Mental Disorders that was removed in the latest version, DSM-5 ²

It is important to consider therefore that, an improvement in the symptom clusters in personality disorders might be an improvement in comorbid axis I disorder symptoms. It is reported that the rates of depression are very high in BPD ³³ and that the response to antidepressants in depressed individuals with comorbid personality disorders appears lower than in those without comorbid personality disorder ³².

The most recent guidance on the treatment of BPD from the National Health and Medical Research Council of Australia (NHMRC), which reviewed the literature and integrated a series of meta-analyses, details that pharmacotherapy does appear to be effective in altering the nature and course of BPD and that evidence does not warrant the use of pharmacotherapy as a sole or first-line treatment for BPD ³⁴.

DISCUSSION

All of the aforementioned psychotherapy techniques are shown to produce promising results when applied to the treatment of BPD, with some standing out, such as DBT and MBT, due to the presence of a relatively robust evidence base. With such a wide variety of different approaches that all show some propensity for successful treatment of BPD it is clear that these approaches must be taken more seriously in clinical practice. These treatments have been shown to considerably improve symptomatic outcomes however there is a shortcoming in that they have failed to significantly improve social functioning. Each of the therapies follow distinct theories, however, when each treatment modality is applied to BPD, similar effects are seen. This is intriguing and should be explored further.

An analysis of these therapies revealed some common features which are now suggested as core requirements for all effective psychotherapeutic treatments:

Figure 3: Five common characteristics of evidence-based treatments for BPD ^{35, 36}.

An update to the aforementioned Cochrane review ²⁹ was published in 2013. The update focussed on the psychotherapies that are available for the treatment of BPD and included a total of 1804 participants spread over 28 studies. The psychotherapies discussed were divided into ‘comprehensive’ if they substantially involved an individual psychotherapy element or as ‘non-comprehensive’ if they did not. The comprehensive therapies included dialectical behaviour therapy, mentalization-based therapy (delivered in either a partial hospitalisation or outpatient setting), transference-focussed therapy, cognitive behavioural therapy, dynamic deconstructive psychotherapy, interpersonal psychotherapy and interpersonal therapy for BPD. These were assessed against a control condition and also with some direct comparisons against each other. Non-comprehensive psychotherapies included DBT-group skills training, emotion regulation group therapy, schema-focussed group therapy, systems training for emotional predictability and problem solving for borderline personality disorder (STEPPS), STEPPS plus individual therapy, manual assisted cognitive treatment, and psychoeducation ³⁷.

The authors concluded that both comprehensive and non-comprehensive therapies indicated beneficial effects for the core pathology of BPD and associated general psychopathology. The authors identified that dialectical behaviour therapy had been studied the most comprehensively followed by mentalization-based therapy, transference-focussed therapy, schema-focussed therapy and STEPPS. However, the authors do state that none of the treatments presented a very robust evidence base and that there are concerns over the quality of individual studies ³⁷.

In terms of pharmacotherapy, the NICE and NHMRC guidelines agree with the 2006 Cochrane interventional review among others ^{38, 39} that there is some evidence that some second-generation antipsychotics (aripriprazole and olanzapine) and some mood stabilisers (topiramate, lamotrigine and valproate) could improve BPD symptoms in the short term. However, for some of these agents, it is necessary to balance risks against benefits as they have considerable long-term risks (e.g. with antipsychotics, extrapyramidal side effects such as tardive dyskinesia can persist even after withdrawal of the drug ⁴⁰). Such risks are not a problem in psychological treatments and it is probable that this influences guidelines. In practice, off-label use of psychotropics is widespread, despite the fact that the NICE guidance negates their use. It is arguable that clinicians should preferentially use pharmacological treatments that have the strongest evidence base (i.e. antipsychotics and mood stabilisers) and refrain from using agents with the least evidence (i.e. antidepressants and benzodiazepines).

CONCLUSION

Specialist treatments, in particular DBT and MBT substantiate the use of psychotherapy in BPD and these findings support the validity of the NICE guidance. However, the array of such treatments must be amalgamated with the view to provide a comprehensive, multi-faceted treatment approach. Each treatment must be broken down in order to outline the components that are particularly useful in BPD with the view to understand the condition in greater depth and to provide more focussed therapies.

The 2013 Cochrane review ³⁷ highlights that further psychotherapies are available and have been shown to successfully treat BPD core pathology, however, as it is clearly stated the evidence base lacks robustness and there is a need for further studies that can replicate results. The therapies that have been included in this Cochrane review that have not been covered in the guidelines (e.g. STEPPS) may prove to be superior to those put forward by NICE, and I recommend that these be explored thoroughly when the guidelines are due for update.

While the NICE guidance emphasises that the use of psychotropics is reasonable in the management of comorbidities, it worth noting that to understand BPD, it is necessary to explore both the underlying aberrant psychological processes and biological processes that manifest in the disorder. This will enable the use of more specific pharmacological therapies in targeting the symptoms of BPD in the future.

Case Summary

Three and half year old male child presented to PICU, Narayana health BANGALORE, with a short history of fever of 8 days with headache  and  cough for 2 days. At admission the child was febrile, dull looking, haemodynamically stable with no meningeal signs or focal neurological deficit. He was admitted and evaluated for the cause of fever. Same day child developed generalized seizures along with fever, hence a possibility of meningitis or electrolyte imbalance (hyponatremia) kept as child had initial serum sodium of 128meq/l. The cause of hyponatremia was looked into and child managed with antiepileptic drugs and 3% normal saline infusion. The initial sepsis screen was in-conclusive and CSF analysis showed 3 lymphocytes with low glucose and elevated protein levels, hence partially treated meningitis was considered (as h/o admission to a hospital for 3 days prior to admission in our hospital). The antimeningitic dose of IV antibiotics were given.  On day 3 of admission child developed meningeal signs with worsening sensorium, hence  neuro imaging was done (MRI brain) which showed multiple well defined ring enhancing lesion at bilateral central and cerebrallar hemisphere, thalamus, pons with mild perilesional edema. This radiological picture suggested a possibility of nerucysticercosis, however the clinical picture did not match with the same, hence pediatric neurology opinion was taken and simultaneous workup for tuberculosis were started. Child was also started on IV steroid. A strong possibility of CNS toxoplasmosis was kept by neurologist based on radiological picture. The workup for TB was inconclusive (negative mantoux, normal ESR, negative gastric aspirate for AFB) however child was empirically started on category II ATT in view of deteriorating clinical state. Repeat CSF evaluation showed increasing cell counts and similar biochemical picture as before, the sample was also send for Gene-Xpert (DNA amplification study). On day 6 of admission child developed lethargy and drowsiness hence antiedema measures were initiated. Same day he developed tonic posturing with unequal pupil, hypertension and bradycardia indicating raised Intracranial pressure (ICP), for which he was intubated and ventilated and urgent repeat CT head was done which showed increase in ventricular size and hydrocephalus. Immediately EVD was put by neurosurgeons after which there was gradual improvement in child’s condition and he was extubated within 48 hours. The reports showed negative HIV and toxoplasma serology and positive CSF gene study for AFB confirming the diagnosis of CNS tuberculosis, hence ATT and antiedema measures were continued and the EVD was later converted into VP shunt. Child by 2^nd week of illness became afebrile with improved sensorium and function.

Fig 1 & 2: MRI showing multiple ring enhancing lesions

Discussion

Tuberculosis remains a leading cause of morbidity and mortality in the developing world. CNS involvement is thought to occur in 2-5% of patients with tuberculosis and up to 15% of those with AIDS related tuberculosis ^1,2. Although CNS involvement by tuberculosis is seen in all age groups, there is a predilection for younger patients, with 60-70% of cases occurring in patients younger than 20 years of age ^2. Haematogeneous spread from the lungs or gastrointestinal tract is most common, leading to small subpial or subependymal infective foci. These are termed Rich foci and form a reservoir from which intracranial manifestations may arise ^3,4. Tuberculomas often present with symptoms and signs of focal neurological deficit without evidence of systemic disease. The radiologic features are also nonspecific and differential diagnosis includes malignant lesions, sarcoidosis, pyogenic abscess, toxoplasmosis and cysticercosis.^5,6

Regarding treatment, the Center for Disease Control and Prevention recommends 12 months of treatment for CNS TB when the MT strain is sensitive to all drugs.⁷ However numerous variables can affect the response of the disease to therapy and it has been suggested that treatment duration should be tailored to the radiological response.⁸ After 12 months of treatment more than two-thirds of the patients still have contrast enhancing lesions. Although it is not clear if this represents an active lesion or just inflammation, continuing treatment is probably prudent. Total resolution of the tuberculoma is observed when scans demonstrate no enhancing lesions or only an area of calcification.⁸

In the case described above child had tubercular mengitis, multiple tuberculous, hydrocephalus and raised ICP. Although clinical presentations were suggestive of same, however the radiological picture and initial CSF finding raised suspicion is diagnosis. As tuberculoma and NCC shows many common clinical features, there are few distinguishing features such as the cysticercosis is smaller, less perilesional edema, multiple numbers and less of midline shift as compared to tuberculoma. However in our patient the multiple tuberculi gave a suspicion of NCC. It was only gene expert which confirmed our diagnosis.

Hence clinical cases like Tuberculoma, the radiological findings of which can usually be distinguished from other common illness like Neurocysticercosis or Toxoplasmosis, sometimes pose challenge in terms of radiological diagnosis suggesting the need for detailed evaluation to reach the diagnosis and guide treatment.

Introduction

Meningiomas are common intracranial neoplasms with a wide range of histopathological appearances. The WHO classification of tumours of the central nervous system recognises 15 subtypes of meningiomas, of which meningothelial, fibrous and transitional subtypes are most common. Lymphoplasmacyte-rich meningiomas (LPM) are rare WHO subtype that belong to Grade I meningiomas.¹ The estimated incidence is less than 1% of all meningiomas.² LPM usually occurs in young and middle age patients, with most common locations being cerebral con­vexities, skull base, parasagittal area within the superior sagittal sinus, cervical canal, optic nerve and tentorium.³ Histopathological examination shows extensive infiltrates of lymphocytes and plasma cells often obscuring the meningothelial component.

Case report

A 21-year-old man presented with a history of headache since 4 months. It was a dull pain not associated with vomiting, seizures or visual symptoms. The patient did not have any features suggestive of cranial nerve involvement. Physical examination was unremarkable except for the presence of papilloedema. Non-contrast CT scan showed a large isodense lesion with peri- lesional oedema and eccentric enhancing nodular component in the right fronto-parietal region (Figure 1). A radiological diagnosis of glioma with mass effect and shift to left was rendered. A right frontoparietal free bone flap craniotomy was performed. Operatively, a well encapsulated tumour probably arising from the dura mater was found. Gross total removal of the tumour was done and the excised tumour was sent for histopathological examination with a provisional clinical diagnosis of meningioma.

Histopathological examination revealed a tumour arranged as sheets and whorls of meningothelial cells without any mitoses or atypia. A dense infiltrate of lymphocytes and plasma cells was seen in large areas of the tumour (Figure 2).

On immunohistochemistry, tumour cells were positive for epithelial membrane antigen (EMA) (Figure 3) and vimentin. The lymphoplasmacytic infiltrate contained mixture of CD3 and CD20 positive lymphocytes. A diagnosis of lymphoplasmacyte- rich meningioma was given.

Figure 1. Non-contrast CT scan showing a large isodense cystic lesion with perilesional oedema and eccentric enhancing nodular component in the right frontoparietal region

Figure 2: Tumour arranged as sheets and whorls of meningothelial cells without any mitoses or atypia. A dense infiltrate of lymphocytes and plasma cells seen in large areas of the tumour (H & E x 100)

Figure 3: Tumour cells positive for epithelial membrane antigen (x 200)

Discussion

Meningiomas are common neoplasms accounting for 24-30% of all primary intracranial tumours. They arise from the arachnoidal cells, and are typically attached to the inner surface of the duramater.¹ Most of the meningiomas are benign, corresponding to WHO grade I and associated with a favourable clinical outcome. LPM is a rare low grade histopathological subtype of meningioma, usually seen in younger patients, with the mean age of onset being 34 years.^4,5 The patients with LPM have variable clinical manifesta­tions according to the location of the tumour. The common presentations include headache, hemiparesis, seizure, vomit­ing, dizziness, visual disturbance, dyscalculia, dysgraphia and slurred speech.³ Although the natural history of LPM is often over one year, few cases might occur in short duration due to inflammatory cell infiltration and oedema.⁶ Systemic haematological abnormalities such as hyperglobulinemia and iron refractory anaemia have been documented in some patients with LPM, believed by some to be due to the plasma cell infiltrate.^3,6,7

Radiologically, LPMs are usually globular, highly vascular, contrast- enhancing, and dural based tumours. The typical characters of LPM on MRI are isointense lesions on T1-weighted images and hyperintense lesions on T2-weighted images, with a strong homogenous enhancement after the administration of gadolinium; obvious peritumoural brain oedema and dural tail signs.³ Sometimes, cystic component and heterogeneous enhance­ment may also be encountered, making pre­-operative diagnosis difficult, as in our case.⁸

On microscopic examination, this tumour is characterised by a conspicuous infiltrate of lymphocytes and plasma cells, sometimes completely obscuring the tumour cells. The massive infiltration of lymphocytes and plasma cells has been postulated to play a central role in the development of brain oedema associated with LPM. The origin of this tumour (neoplastic or inflammatory) is unclear, so it is considered closer to intracranial inflammatory masses rather than typical meningiomas.⁷

The differential diagnoses include collision tumour of meningioma and plasmacytoma, inflammatory pseu­dotumour, idiopathic hypertrophic pachymeningitis (IHP), and intracranial plasma cell granuloma.^3,7 The use of staining for EMA and vimentin is useful in indicating the meningothe­lial origin of the tumour, and differentiates LPM from other intracranial lesions.⁹

The pathological findings of IHP usually include thickened fibrotic dura mater with marked infiltration of lymphocytes and plasma cells, occasionally accompanied with small islands of meningothe­lial proliferation mimicking those of LPM. Localised nodular lesion can some­times rule out this diagnosis in that IHP usually shows diffused lamellar thickenings or plaque-like features.⁴

Chordoid meningiomas often contain regions that are histologically similar to chordoma, with cords or trabeculae of eosinophilic, vacuolated cells in a background of abundant mucoid matrix background.³ Detailed histological studies can aid the dif­ferential diagnosis. The plasma cell component is not neoplastic and thus plasmacytoma with reactive meningothelial hyperplasia or a collision tumour involving meningioma and plasmacytoma can both be excluded.¹⁰

The knowledge of this rare entity is important to avoid its underdiagnosis as an inflammatory pseudotumour or plasma cell granuloma and overdiagnosis as a plasmacytoma.

A 38 year old BMI 20.2 ASA 2 female underwent an elective robotic-assisted laparoscopic extirpation of endometriosis and dissection of endometriomas. Her medical history included hypertension, migraine, atopic dermatitis, sciatica, cervical spine spondylosis and dysplastic spondylolisthesis of L4/5. Of note, the patient had allergies to Aspirin (causing angioedema), Morphine and Tramadol (both causing generalized rash).

An 18gauge IV cannula was inserted into the cephalic vein at the left wrist, and connected to a bag of Hartmann’s solution. The patient was induced with Propofol 100mg, Rocuronium 30mg and a Remifentanyl infusion running at Ce 1ng/mL. Cefazolin 2g and Dexamethasone 4mg were also administered post-intubation. No rashes were noted on the patient’s skin, and her arms were subsequently enclosed with green towels by her sides for the duration of the surgery. During the procedure, the patient was sustained in a steep trendelenberg position, with her face and eyes checked periodically. No rashes were noted on any exposed skin. Peri-operatively, she was maintained with O₂/air/Desfluorane, top-up doses of Rocuronium, and titration of the Remifentanyl infusion. At the end of the surgery, the patient was administered Ondansetron 4mg and Pethidine 50mg (in 2mL), and reversed with Neostigmine 2.5mg and Glycopyrrolate 0.4mg. The patient’s arms were subsequently exposed in preparation for transfer, and it was noted that she had developed severe erythema and inflammation in specific tributaries of the cannulated vein (Figure 1). The patient was extubated uneventfully five minutes later, and did not complain of any symptoms systemically or pertaining to the cord inflammation. She was monitored in recovery for three hours post-op, and the inflammation subsided significantly 90 minutes post-op (Figure 2) and completely 150 minutes post-op (Figure 3).

There have not been many reports of such a reaction in published materials, and we take this opportunity to provide further pictorial evidence of the possible sequelae of IV administration of a high concentration Pethidine solution. The variances in analgesia effectiveness and potential side effects between Morphine and Pethidine are negligible². As such, and given that Pethidine is commonly used as a mode of analgesia on our wards and in the peri- and immediate post-operative periods when other classes of drugs are contraindicated, we hope to provide further pictorial support of such an extraordinary reaction for other interested clinicians. It is also interesting to note that in both cases the patient was female, around 40 years old, had a thin body structure, had an atopic tendency, and the concentration of injected solution was higher than 10mg/mL. Additionally, these are known factors believed to increase reaction severity^{3 4}. We acknowledge that 3 other drugs were administered at the same approximate time as Pethidine, and as such any of the 4 medications could be culprit to the reaction, although this is unlikely as our patient had been given those medications in previous procedures with no issues or complications.

Figure 1: Post-op, Figure 2: 90 mins post-op, Figure 3: 150 mins post-op

CASE REPORT

A 61-year-old lady underwent a modified radical mastectomy and axillary clearance in 2008 for a carcinoma of the left breast. Histopathology examination revealed two tumours within the left breast; a 16mm Grade 2 lobular carcinoma with probable vascular invasion and a 9mm Grade 1 infiltrating ductal carcinoma with no vascular invasion. She had clear resection margins. 21 out of 34 removed lymph nodes were positive for metastatic deposits. The tumour was oestrogen receptor positive and HER2 negative. She was staged as T1 N3a Mx and the tumour had a Nottingham Prognostic Index of 5.32. Metastatic workup revealed no distant metastasis.

Postoperatively, she required aspiration of a seroma but her recovery was otherwise satisfactory. She received adjuvant chemotherapy in the form of three cycles of Fluorouracil, Epirubicin and Cyclophosphamide and 3 cycles of Docetaxel. In addition, she had postoperative radiotherapy to the chest wall and supraclavicular fossa (40 Gy in 15 Fractions over 3 weeks) and hormonal therapy with Letrozole 2.5mg once daily.

The patient opted to undergo a prophylactic right mastectomy in 2010. She was regular in follow up and appeared to be free of disease recurrence for 6 years.

Her past surgical history included abdominal hysterectomy and bilateral salpingo-ophorectomy for fibroid disease as well as varicose vein stripping. She is a non-smoker and doesn’t consume alcohol. She had a family history of colon and cervical cancer in her uncle and sister respectively.

The patient visited the surgical outpatient clinic complaining of abdominal cramps, altered bowel habits and fatigue of a few months duration. There was no associated rectal bleeding, haematemesis, melaena, weight loss or urinary symptoms. Physical examination was unremarkable but she was noted to have gradually worsening renal function. Her symptoms were at first attributed to side effects of intravenous antibiotic treatment, which she received during an admission for cellulitis. She had already undergone an upper GI endoscopy which showed oesophagitis and ulceration; biopsies were within normal limits. She received treatment with proton pump inhibitors but her symptoms persisted.

A non-contrast abdominal CT scan was done, on account of her poor renal function, which showed bilateral hydronephrosis and thickening of the postero-superior aspect of the bladder wall. Considering the limitations of the non-contrast study, there were no other abnormalities. A colonoscopy was also done to investigate her altered bowel habit and it revealed a benign-looking stricture in the sigmoid about 25cm from the anal verge which was easily bypassed by the scope.

Figure 1. Benign stricture on flexible sigmoidoscopy

Biopsies of the sigmoid stricture showed an infiltrate of small to medium sized tumour cells in the submucosa, which had an Indian file pattern. They were positive for AE1/AE3 (pancytokeratins) and negative for CD68. They were positive for CK7 and negative for CK20, strongly positive for oestrogen receptors and HER2 negative. Taken in conjunction with the patient’s past history of an invasive lobular carcinoma of the breast, the appearance was consistent with a metastatic lobular carcinoma.

Figure 2. Clusters and cords of cells with positive cytoplasm for the cytokeratin immunostain CK7. Although the classical ‘Indian filing’ of lobular carcinoma is not well seen, the image clearly demonstrates that the large bowel glands are negative (normally CK20+, CK7-) and that the infiltrate is beneath the glandular mucosa (i.e. not originating from dysplastic glands within the mucosa and raising the possibility of infiltration from outside the bowel wall). The magnification is x200. Lobular carcinoma is usually CK7 +, CK20 -, ER +.

Figure 3. The same cells with their nuclei staining positively with an immunostain to oestrogen receptors. There are a few short chains of ‘Indian filing’ with the cells appearing rather rectangular in shape with straight margins. You can make out slight ‘moulding’ of the nuclei as they press against one another. The magnification is x 400.

Figure 4. Haematoxylin and Eosin section at 400 magnification. This shows a diffuse infiltrate of single cells with eccentric nuclei.

The patient required a right nephrostomy and a cystoscopy with left double J ureteric stent insertion to address her hydronephrosis and deteriorating renal function before undergoing restaging of her disease.

DISCUSSION

In patients with history of breast cancer, isolated GI metastases are less common than benign disease processes or second primaries of the GI tract.^1.2 In a retrospective review, 73 out of 12001 cases of breast cancer had gastrointestinal metastases, out of which 24 were to the colorectum³ and invasive lobular carcinoma was the commonest histological subtype. ^3.4 However, sixteen percent of patients with breast cancer have GI metastases at postmortem examination¹.

There might be a long interval of time between the diagnosis of breast cancer and development of gastrointestinal metastasis which together with their rare occurrence and nonspecific clinical and radiological manifestations adds to the diagnostic challenge. The median interval between the diagnosis and the development of GI metastasis was reported to be 6 years (range 0.25 to 12.5 years) by Schwarz et al ⁵with 25 years being the longest reported in the literature.⁶ Because of this long interval the history of a primary breast cancer can be missed. This also highlights the importance of long term follow up and maintaining an index of suspicion when these patients develop GI symptoms.

In our case, the interval between the diagnosis of breast cancer and colonic metastasis was 81 months. Her GI symptoms were initially attributed to side effects of antibiotic treatment for cellulitis and dyspepsia before investigating her with a colonoscopy. Even at colonoscopy the appearance was that of a smooth benign-looking stricture which did not seem to harbour any sinister pathology

Histological examination is probably the most reliable tool to make a diagnosis and it is prudent in such cases to compare the specimen with the original breast tumour. In this case, there were two primary tumours; an invasive ductal carcinoma as well as a lobular carcinoma but the metastatic disease favoured the lobular component, which is consistent with other published reports in the literature. The reasons why metastases favour lobular carcinoma are poorly understood. One explanation is the loss of E-cadherin expression, a molecule involved in cellular adhesion, in invasive lobular carcinoma⁷. A similar case in which the primary was a mixed ductal and lobular type with lobular subtype colonic metastasis was reported by Uygun et al.⁸ Immunohistochemistry can also help in establishing a diagnosis. Metastatic breast cancers tend to be positive for Oestrogen or Progesterone receptors as well as Gross Cystic Disease Fluid Protein-15.^{9, 10} It is, however, worth noting that primary colonic cancers can be oestrogen receptor positive in 30 to 70% of cases.¹¹

Accurate histopathological diagnosis probably saved our patient an unnecessary surgical treatment for a primary colonic neoplasm as the main focus of her treatment should be systemic therapy for metastatic breast cancer.

CONCLUSION

GI tract metastases from breast cancer are a rare occurrence. The patients may present after a long interval from the original diagnosis and the clinical and radiological features are nonspecific with the diagnosis often established on histological examination. Moreover, the history of breast cancer may not be elicited in all cases and these patients may present to a gastroenterologist or colorectal surgeon rather than a breast surgeon or oncologist. Therefore, remaining vigilant to this possibility is advised in any patient with a history of breast cancer who presents with unexplained GI symptoms.

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.