Leprosy is a curable granulomatous disease caused by Mycobacterium leprae, whose symptoms ..... tingling, numbness, pins and needles or piercing pain (4).
MSc Project Report 2014-2015 A Cross-Sectional Study Of The Prevalence Of Neuropathic Pain And Its Impact On The Functional Capacity And General Health Of Patients With Leprosy Who Have Been Treated In Indonesia
Supervisor: Prof. Diana Lockwood
Candidate number: 108571 Word count: 9760 Project length: Standard
Submitted in part fulfilment of the requirements for the degree of MSc in Tropical Medicine and International Health September 2015
TABLE OF CONTENTS 1. TABLE OF CONTENTS…………………………………………………………………………..I 2. LIST OF TABLES ............................................................................................................... III 3. LIST OF FIGURES ............................................................................................................. III 4. ABSTRACT ....................................................................................................................... IV o
BACKGROUND ............................................................................................................. IV
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METHODS .................................................................................................................... IV
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RESULTS ..................................................................................................................... IV
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CONCLUSION ............................................................................................................... IV
5. ACKNOWLEDMENTS…………………………………………………………………….……...V o
ACKNOWLEDGEMENT OF ACADEMIC SUPPORT ............................................................... V
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ACKNOWLEDGEMENT OF OTHER SUPPORT .................................................................... V
6. INTRODUCTION ................................................................................................................. 1 o
EPIDEMIOLOGY: GLOBAL SITUATION ............................................................................... 1
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EPIDEMIOLOGY: FOCUS ON INDONESIA ........................................................................... 1
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GENDER DISTRIBUTION .................................................................................................. 2
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TRANSMISSION .............................................................................................................. 2
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INCUBATION PERIOD ...................................................................................................... 2
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PATHOGENESIS ............................................................................................................. 3
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CLINICAL PRESENTATIONS ............................................................................................. 3
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SKIN .............................................................................................................................. 3
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NERVES......................................................................................................................... 3
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OTHERS ........................................................................................................................ 4
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CLASSIFICATION ............................................................................................................ 4
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WHO CLASSIFICATION ................................................................................................... 4
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RIDLEY-JOPLING CLASSIFICATION .................................................................................. 5
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DIAGNOSIS .................................................................................................................... 6
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REACTIONS ................................................................................................................... 7
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MANAGEMENT ............................................................................................................... 8
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TREATMENT................................................................................................................... 8
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CHEMOTHERAPY............................................................................................................ 9 I
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PREVENTION OF DISABILITY ........................................................................................... 9
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TYPES OF PAIN IN LEPROSY ............................................................................................ 9
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NEUROPATHIC PAIN (NP)............................................................................................. 10
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IMPACT OF NP ON FUNCTIONAL CAPACITY AND GENERAL HEALTH ................................. 11
7. AIMS AND OBJECTIVES ................................................................................................. 12 8. MATERIALS AND METHODS .......................................................................................... 13 o
STUDY DESIGN............................................................................................................. 13
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STUDY SETTING ........................................................................................................... 13
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STUDY POPULATION .................................................................................................... 13
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CASE DEFINITIONS………………………………………………………………………………………...…..14
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INFORMED CONSENT.................................................................................................... 14
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CLINICAL EXAMINATION AND DATA COLLECTION .......................................................... 15
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NERVE ASSESSMENT ................................................................................................... 15
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DISABILITY ASSESSMENT ............................................................................................. 16
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NEUROPATHIC PAIN ASSESSMENT AND ITS IMPACT USING THE DN4, BPI-SHORT, SALSASHORT AND GHQ-12 QUESTIONNAIRES........................................................................ 16
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STATISTICAL ANALYSIS ............................................................................................... 17
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ETHICAL APPROVAL ..................................................................................................... 17
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POSSIBLE ETHICAL ISSUES ........................................................................................... 18
9. RESULTS…………………………………………………………………………………………19 o
DEMOGRAPHY……………………………………………………………………………….…………………19
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CLINICAL FINDINGS…………………………………………………………………………………………...19
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NEUROPATHIC PAIN…………………………………………………………………………………………..21
10. DISCUSSION .................................................................................................................. 27 o
LIMITATIONS OF STUDY ................................................................................................ 29
11. RECOMMENDATIONS………………………………………………………………………..30 12. REFERENCES ................................................................................................................ 31 13. APPENDIX
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2. LIST OF TABLES Table 1: Overall summary of patients’ demographics and clinical findings ………...………..20 Table 2: BPI - worst pain and pain interference in daily functions in patients with NP .…….23 Table 3: Summary of Salsa Score in patients with NP …………………………………………23 Table 4: Summary of logistic regression NP – Salsa Score and thickened nerves …………24 Table 5: Clinical features of patients with NP …………………………………………………...25
3. LIST OF FIGURES Figure 1: Disease Spectrum …………………………………………………………………..……6 Figure 2: Ridley-Jopling Classification and the relationship with host immunity …………..….7 Figure 3: Map of Surabaya (East Java)…………………………………………………………..13 Figure 4: Symptoms and signs of NP (DN4 Criteria) …………………………………………...21
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4. ABSTRACT Background Leprosy is a curable granulomatous disease caused by Mycobacterium leprae, whose symptoms continue to persist or worsen after completion of chemotherapy. There is a dearth of information on neuropathic pain (NP) and little is known of its impact on the patients’ lives. We carried out a cross-sectional study on the prevalence of NP, using the Douleur Neuropathique 4 Questionnaire (DN4), in patients who have completed their multi-drug therapy (MDT) in Indonesia. We also looked at the burden of pain using the Brief Pain Inventory (BPI-short) and assessed the impact of NP on the patients’ functional capacity and general health using the Salsa short questionnaire and the General Health Questionnaire 12 (GHQ-12) respectively. This is probably the first study to administer the Salsa score to screen for activity limitations and safety awareness in patients with NP.
Methods A total of 71 leprosy patients who have completed their MDT were recruited from the Leprosy Clinic at The Soetomo Hospital, Surabaya. All patients had a detailed history and careful examination of their skin and nerves to map areas of pain and motor and sensory loss. The researcher administered the DN4, BPI, Salsa and GHQ-12 in Bahasa Indonesia to identify patients with neuropathic pain and to study its impact on their lives.
Results Eighteen (25.4%) patients were diagnosed with NP based on the DN4 criteria. The majority of them reported symptoms of numbness (100%), burning sensation (83.3%), tingling sensation (66.7%) and 83.3% had touch hypoesthesia on clinical examination. NP was associated with nerve thickening (100%) and tenderness (77.8%) and 7 (38.9%) patients were having a reaction at the time of interview. The mean BPI score for the intensity of pain at its worst was 8 (severe) and mood and sleep were worst affected by pain. There were 12 (66.7%) who reported moderate to extreme limitation of their daily activities on the Salsa Score and 17 (94.4%) had psychological morbidity on GHQ-12 score.
Conclusion It is important that NP is diagnosed as early as possible so that treatment can be prescribed early to prevent further nerve damage and deformities, which may lead to physical and psychological morbidities that may impact on their quality of life. Further research on NP is recommended to expand our knowledge on this disabling condition. IV
5. ACKNOWLEDGEMENTS Acknowledgement of academic support I am grateful to Professor Diana Lockwood, my project supervisor, for providing the opportunity to undertake this project. Her guidance and invaluable contribution, support and encouragement at every stage of this project have been tremendous. I had several meetings with Prof Lockwood from the inception to discuss and plan the project. She suggested some reading materials to help me with my understanding of neuropathic pain and with the definitions of the nerve terminologies. We kept our communication open via email while I was in Surabaya for project updates. I would like to thank her for her time and comments on parts of the report. I would also like to thank Prof Andrew Rice and Dr Omer Haroun for their valuable time and advice at the initial stage of the project.
Acknowledgement of other support I am also grateful to Dr Yulianto Listiawan and the staff of Soetomo General Hospital for their interest and kind support of my project. I am appreciative of all the help from the Junior Residents and the Clinic Manager at the Leprosy Clinic in Surabaya. I am grateful to all the participants of this project for their cooperation and time to make it a success. I would like to thank Dr Eka Widyadharma, Udayana University, Bali for the translated DN4 questionnaire in Bahasa Indonesia. To my Tutor, Prof David Moore and TMIH Course Director, Prof Robin Bailey, their encouragement throughout the course is greatly appreciated. I am grateful to LSHTM who provided financial support to cover part of the cost of the flight to Surabaya and the travel reimbursements for the patients who participated in the study.
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6. INTRODUCTION Leprosy is a chronic, granulomatous disease caused by Mycobacterium leprae (1), which is a strongly acid-fast rod-shaped bacillus that has a predilection for cooler parts of the body such as the skin, nasal mucosa and superficial nerves. Although the bacteria is slow growing and the disease has a low mortality rate, it is associated with immunological damage. Patients are at high risk of tissue destruction and nerve impairment leading to severe deformities and disabilities (1). Leprosy is a disease of poverty and the disabling complications of leprosy may lead to significant socioeconomic burden to patients and their families. They may cause patients to suffer social stigma, ostracisation and lead to reduced quality of life (2). Neuropathic pain (NP) is now recognised as one of the complications of leprosy (3, 4).
Epidemiology: global situation Leprosy is common throughout the tropics and subtropics and continues to pose a serious public health challenge. In 2013, the World Health Organisation (WHO) reported that there were 215656 new cases worldwide (5). India, Brazil, and Indonesia are the most highly endemic countries for leprosy and the majority (81%) of all new cases have been reported in these countries (6). The number of new cases has remained fairly stable over the years, hence indicating ongoing transmission of the disease. However, fewer countries are now reporting a prevalence greater than 1 case per 10000 (7). This apparent fall in global prevalence may be an underestimation of cases due to a disparity in the number of observed and reported cases or due to the shortened duration of treatment or patients being removed from the records when they have completed their treatment (8). This large number of unreported cases may increase the burden of infection in the community and hinder leprosy control (8, 9).
Epidemiology: Focus on Indonesia In 2014, the number of new cases in Indonesia was reported to be 14771 (10) compared to 16856 in 2013 (5). This puts Indonesia as the third highest burden country for leprosy in the world, after India and Brazil (6). The proportion of children with leprosy was 10.2%, which indicates continued transmission of disease in the community (10). There are pockets of high endemicity in some regions of Java, Sulawesi, Madura, Maluku and West Papua. In twelve of the thirty-four provinces, the new case detection rates are 1
above 10/100,000 population with West Papua reporting above 100/100,000. This may be due to poverty, isolation and lack of health facilities (11). Historically, the first leprosy asylum in Indonesia was built in 1655, on one of the islands off Java. Due to increasing number of patients, the number of asylums grew to 45. In 1932, the compulsory isolation of leprosy cases was abolished, which resulted in the closure of these asylums (12). The government then introduced a national registry of leprosy patients and patients were encouraged to be treated at outpatient clinics. They were isolated at home if necessary and not in institutions (12). The Government subsequently implemented the National Leprosy Control Programme and since 1969 has integrated leprosy control in the general health services. This led to the establishment of leprosy clinics at the community level, commonly now known as Pukesmas to the locals (11, 13).
Gender distribution Leprosy affects both men and women but a higher prevalence of men has been reported in most countries in the ratio of 2:1. It can occur at all ages and tends to affect young adults at their most productive stage of life. In women, pregnancy can precipitate clinical leprosy (14).
Transmission Humans are the primary reservoir of M. leprae but it is known to occur naturally in the wild in nine-banded armadillos (15). The transmission of M. leprae from leprosy patients to healthy contacts is thought to be by the upper respiratory route - via airborne droplets or nasal discharge (16). The nose is a major portal of exit/entry of M. leprae of a person affected by leprosy. M. leprae has been demonstrated in abundance in nasal secretions of patients with untreated lepromatous leprosy (14). The transmission of M. leprae through the skin is less certain. Although there have been some cases reported via skin tattooing, leprosy cannot be acquired by touch (1, 17).
Incubation Period The incubation period can be variable ranging from 3 to 12 years with an average of about 5 - 7 years (18).
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Pathogenesis The host immune response to M. leprae determines the type of disease. The immune response and clinical effects vary across a spectrum between two poles. Cell-mediated immunity is a protective immune response, which kills M. leprae. It is strong in tuberculoid leprosy (TT). Few bacilli are found in tissues and Th1 response predominates (1, 19). Humoral antibodies are produced in response to various antigens of M. leprae, but do not eliminate the organism. They are abundant in lepromatous leprosy (LL). There is diffuse infiltration with proliferation of bacilli in skin and nerves and a predominance of CD8+ T cells in situ. There is absence of granuloma formation. Patients with LL leprosy have a predominantly Th2 type response with a CD4:CD8 ratio of 1:2 (1, 19). The borderline forms are clinically unstable, and may either decline towards the lepromatous type or show reversal reactions (1).
Clinical Presentations The cardinal signs of leprosy (1) •
Hypopigmented or erythematous skin lesions showing definite reduction in sensation
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Enlarged and clinically impaired nerves
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Acid-fast bacilli in slit-skin smears
Skin Lesions can be found anywhere on the body - the face, trunk, buttocks and extremities including the palms and soles but usually sparing the scalp, axillae and groin. The skin lesions are usually macules or plaques, less commonly, papules and nodules (1). The number of skin lesions indicates the effectiveness of the host immune response to limit the spread of the bacilli. Sensory loss within skin lesions is typical of leprosy, usually tested by light touch and/or pin prick, temperature and anhidrosis (1). Nerves The principal sites of peripheral nerve damage are ulnar, median, radial cutaneous, lateral popliteal, posterior tibial, sural and facial nerves. These nerves may be thickened and tender and impairment varies according to the type of leprosy (1). LL patients often present with
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glove and stocking sensory loss (1, 20, 21). Nerve function impairment (NFI) may occur before, during and after treatment (1, 22). Leprosy can cause sensory loss in the affected skin lesions and in the arms and legs. Motor impairment can occur due to muscle imbalance especially of the intrinsic muscles of the hands and feet (1). Patients may present with difficulty closing eyes, ulcers on the feet, clawed hands and toes, wrist and foot drop (20). Autonomic nerve involvement may present with mild oedema of the hands and feet, which later may become dry and puffy with loss of sweating (1). Despite the MDT having a high cure rate of about 98% (23) where bacteria infection is cleared quite easily, it has been reported that 30% of MB patients may develop further nerve damage during treatment – this maybe related to on-going inflammation in the nerves, which is difficult to switch off (24). In some of them, pain may present as a new disabling condition even after adequate treatment and bacteriological cure (25). Others Leprosy can also affect the eyes causing lagopthalmos, exposure keratitis, acute/chronic iritis and cataracts. It is important that patients are monitored closely as onset is often insidious. Mucous membranes may also be involved especially the upper respiratory tract causing nasal stuffiness and nasal discharge. In LL saddle nose may develop because of nasal collapse (1).
Classification WHO Classification According to WHO, for the purpose of treatment, leprosy patients can be classified into paucibacillary (PB) and multibacillary (MB) leprosy based on clinical criteria and the number of skin lesions. In the PB group there are usually 5 skin lesions or less. MB has 6 or more skin lesions. In some leprosy programmes, they also look at the number of nerves involved and the slit-skin smears (26). When skin smears are available and reliable, patients who have positive skin smears, irrespective of their clinical picture, must be classified and treated as MB leprosy with the MDT regimen (27).
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Ridley-Jopling Classification Alternatively, the clinical presentation of leprosy can be classified as a spectrum of disease (Fig 1) from tuberculoid (TT) type to a more widespread lepromatous (LL) type (28, 29). This classification made by Ridley–Jopling in 1966 was based on the host immune system, clinical, histological and immunological differences in the disease (29). Tuberculoid leprosy (TT) is localized, well-defined and asymmetrical, characterized by a single or very few macules or plaques with scanty M.leprae. They can be dry and scaly, with loss of sweating and hair, hyper or hypopigmented and frequently anaesthetic. Thickened cutaneous nerves are common in the proximity of the skin lesions. They usually have good prognosis (29). Lesions in borderline tuberculoid (BT) leprosy are usually numerous and involve larger areas of a limb or trunk, with margins, which are less defined and less infiltrated. These patients tend to suffer from Type 1 reactions (T1R), which may result in further nerve damage and deformities (29). In borderline leprosy (BB), the skin lesions are larger, numerous, macular, papular or plaque-like with ill-defined borders and ‘punched-out’ centres. Nerve damage is common involving several peripheral nerve trunks. This is the most unstable type, which can progress unpredictably to either pole (29). Borderline lepromatous leprosy (BL) is usually widespread, symmetrical, small macular lesions, which may become progressively more infiltrated and papules and nodules may develop. Skin lesions may not have obvious sensory loss. Patients may suffer reversal or ENL reactions (29). Lepromatous disease (LL) has an insidious onset with ill-defined skin lesions, widely and symmetrically distributed macules that have an abundance of bacteria. They may gradually become infiltrated and nodules may develop causing thickened earlobes and leonine facies. There is loss of sensation, anhidrosis and hair loss and symmetrical damage to peripheral nerves. LL is seen in people with poor immune response to the M.leprae (29).
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Fig 1: Disease Spectrum
Source: HPA (2012) Memorandum on Leprosy
Diagnosis Early diagnosis and treatment of leprosy are essential to minimise nerve damage and reduce the occurrence of deformities and disabilities. The diagnosis of leprosy is a clinical one based on its cardinal signs (1). The skin must be examined carefully and any lesions should be tested for anaesthesia to touch, pinprick and temperature. Peripheral nerves must be examined for thickening and tenderness. Motor function should be assessed by testing the small muscles of the hands and feet. The Semmes Weinstein monofilaments (MF) or a ballpoint pen (1) may be used for testing sensation. Slit skin smears are able to assess bacterial load and should be sampled from the earlobes or edges of active lesions. They help to identify the most infectious patients and those at greatest risk of relapse. It has high specificity but low sensitivity and many patients have negative result. Skin biopsy may help with accurate classification and may detect presence of neural inflammation. The histopathological picture may be pathognomonic of leprosy even in the absence of the bacilli (1). Phenolic glycolipid I (PGL-I) is still the only M. leprae-specific antigen and it has been used for the serodiagnosis of leprosy. It is detectable in 90% of lepromatous and 40-50% of tuberculoid patients. It has been shown that anti-PGL-I IgM antibodies and circulating PGL-I antigen levels reflect the bacterial loads in untreated leprosy patients. It may be useful at diagnosis and in monitoring patients following chemotherapy. It is not commonly available and its use is therefore limited (30).
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PCR is a sensitive test to detect the presence of very few bacilli, which are not recognized by slit-skin smear. It is not routinely used because of cost and availability but may be beneficial for diagnosis of difficult cases and treatment follow-up. There is no serological test that is reliable across the leprosy spectrum (31).
Reactions Reactions (Fig. 2) are immune mediated complications of leprosy and can occur before, during or after treatment.
Fig 2: The Ridley–Jopling classification and the relationship with host immunity. S. L. Walker, and D. N. J. Lockwood Br Med Bull 2006;77-78:103-121
T1R is a delayed hypersensitivity reaction to M. leprae, usually occurring in the first 2 months of treatment; characterized by oedema, erythema and tenderness of existing skin lesions, formation of new skin lesions and severe peripheral nerve damage with loss of sensory and motor function. They can occur in all borderline patients and post-partum women (32, 33). Prednisolone 40 mg/day on reducing scale over 6 months is often prescribed. Patients will also benefit from physiotherapy (32, 33). Type 2 (T2R) or erythema nodosum leprosum (ENL) are immune complex reactions, which cause tender and inflamed erythematous skin nodules all over the body with systemic illness that includes fever, malaise, neuritis, arthritis, orchitis, lymphadenopathy and renal disease. Patients with ENL have significant Ag-Ab mediated vasculitis with deposition of immune complexes in the vessel walls and multiple tissues like skin, bones and nerves (33). They
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tend to affect patients in the lepromatous pole of the spectrum. They usually occur in first year of MDT and may recur and prove difficult to treat (33, 34). Treatment requires high dose prednisolone 60-80 mg daily but about 50% of patients recur and require further courses of corticosteroids (24). Thalidomide, clofazimine, azahioprine and pentoxifylline may also be used to treat ENL (35) but thalidomide is generally not used in Indonesia. Neuritis may present as acute or chronic nerve inflammation that may occur on its own or with Type 1 or 2 reactions. Since the nerve damage is immune mediated, treatment with steroids is needed to stop the inflammation. Prednisolone 40 mg/day reducing slowly over several months is often effective. Neuritis of more than 6 months may not respond to steroid treatment (1, 34).
Management Leprosy is a curable disease with anti-bacterial treatment. The key to effective management of leprosy is early diagnosis and treatment with MDT consisting of rifampicin, dapsone, and clofazimine. The antibiotic combination is highly effective with relapse rates of only 1% (36). Early recognition and management of reactions and nerve damage are essential to avert disability. Patients who have been released from treatment should be followed up closely to detect any possible relapses or complications (37). It is essential to promote effective health education, public awareness and to encourage patients to present themselves early to a health facility if symptomatic (36).
Treatment The introduction of Dapsone in the late 1940’s was the first effective treatment for leprosy but was later shown to develop secondary resistance (18). MDT was introduced in 1981 and since1995, WHO has supplied MDT free to all leprosy patients. The combination drugs are very effective and the bacilli are killed within a few days of starting treatment. There has not been any reported resistance to rifampicin or clofazimine. Patients generally receive either dual or triple drug therapy for 6 to 12 months depending on their type of disease. Alternative drugs like ofloxacin 400 mg and minocycline 100 mg have been used as second-line treatment (38).
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Chemotherapy Dapsone 100 mg daily (adult) is one of the primary drugs used in combination with at least another drug in the treatment of leprosy. It is weakly bactericidal and prevents the formation of folic acid; inhibiting the organism’s replication. It has been known to cause hypersensitivity reactions and may trigger haemolysis especially in G6PD patients causing their haemoglobin to drop. It is known to cause photosensitivity (39). It is combined with rifampicin 600 mg monthly, which is one of the main drugs in tuberculosis treatment. It is a potent bactericidal antibiotic for M. leprae as it inhibits DNA-dependent bacterial RNA polymerase. It is well absorbed orally and cross-resistance may occur. It should be used with caution in severe liver disease and may cause red-orange discoloration of urine or body fluids (39). Clofazimine 300 mg monthly, 50 mg daily is an antimicrobial that inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. Its mechanism of action is unclear but may cause increased melanin production, resulting in discolouration and dryness of skin and gastrointestinal symptoms. It has good anti-inflammatory properties and has been used to treat ENL. Dapsone is known to inhibit its anti-inflammatory activity (39). All three medications are taken orally depending on the stage of disease and can be administered on an out-patient basis (39).
Prevention of disability It is important for leprosy patients to be monitored regularly for NFI. They should be advised regarding proper footwear. They must look after their skin and pressure points and to perform self-care practices to prevent ulcerations and infections. They should be provided with protective aids and offered rehabilitation and support. Patients should also be referred to the surgeons for reconstructive or cosmetic surgery if needed (40).
Types of pain in leprosy Patients with leprosy are known to have reduced awareness of pain in areas of deformity causing them to neglect the presence of pain (23, 41). They may experience nociceptive pain due to tissue inflammation, caused by noxious stimuli, which often occurs during episodes of immune activation (23). NP is caused by a lesion or disease of the somatosensory system, either at central or peripheral level; without any noxious stimuli (42). 9
Mixed pain is difficult to diagnose but is now increasingly recognized and indicates the coexistence of nociceptive and neuropathic pain in the same patient (23).
Neuropathic Pain (NP) The diagnosis of NP is usually made clinically, based on a detailed medical history and a neurological examination. It can be diagnosed if the distribution of pain described by patient followed the sensory distribution of the nerve, which is then confirmed by clinical examination (42, 43). It may occur early in the treatment but normally many years after completion of MDT, indicating chronic and irreversible damage to the nerves (43). The pain is often of varying patterns for example intermittent or continuous, burning sensation or electric shocks, tingling, numbness, pins and needles or piercing pain (4). There is generally very little information about NP in leprosy and the mechanisms responsible for its occurrence remain largely unknown (41). The pathophysiology of neuropathic pain associated with leprosy is thought to involve repetitive inflammatory attacks on the peripheral nervous system leading to nerve damage. Recent literature has highlighted some of the main risk factors such as the presence of MB leprosy and T2R (ENL) (25, 44). The level of nerve damage is high in MB patients and many already have nerve damage at the time of diagnosis (24). In patients with chronic NP, it usually affects the distribution of 1 or more major nerves with a symmetrical glove and stocking distribution. Peripheral nerve thickening especially ulnar and common peroneal nerves are common (4, 45). In their study in Mumbai, Lasry-Levy and her co-authors (21) found the DN4 to be a good screening tool and reported 21.8% of the patients recruited had NP. They showed NP was associated with nerve thickening and tender nerves, painful skin lesions and psychological morbidity. The Brazilian study showed 56% of 358 leprosy patients had NP with a glove and stocking distribution (20). Saunderson,et al. (25) established 29% of the 96 Ethiopian patients, treated more than 10 years earlier had NP. There are now several screening tools that have been found to be accurate for NP and the Douleur Neuropathique 4 (DN4) has been tried and validated in leprosy patients (21, 44). It can be now be successfully used in the field combined with careful medical history and clinical examination (46). It consists of 7 items related to symptoms and 3 items related to clinical signs and a score of 4 or more suggests the presence of NP (21, 44).
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This will allow leprosy patients with NP, who have been released from therapy (RFT) to be diagnosed earlier to address their ongoing needs especially pain management and supportive treatment (23).
Impact of NP on functional capacity and general health It is well established that people who suffer from chronic conditions like leprosy have an increased risk of poor general health particularly affecting their mental health (47) as they may suffer from depression and disturbance of sleep. The stigma associated with their disfigurement and disability follows even after their RFT (47-49). There are several screening questionnaires that can be used to assess the burden of NP on patients’ lives. The brief pain inventory (BPI-short) is a pain measurement tool. There are 4 questions asking about pain severity and 7 on pain interference of daily functions. It has been validated for clinical pain assessment and effectiveness of pain treatment (50). Psychological morbidity is dependent on multiple factors and is an unpleasant experience that can affect the patient’s wellbeing and quality of life (48). The 12-Item General Health Questionnaire (GHQ-12) is extensively used as a screening instrument for common mental disorders; looking at the patients’ confidence, sleep disturbance, happiness level and their self worth (51). NP may affect the patients physically and could impair their functional capacity (13). It can be a very disabling condition and patients may find their mobility limited and unable to carry out their normal daily chores. This may also affect their social life and their interpersonal relationships (13). The Salsa short questionnaire was used here to assess the impact of NP on their functional capacity. It is a useful tool, comprising of 20 items of daily activities, which are related to mobility, self-care and normal daily work (52). The goals of this study are to improve our understanding of neuropathic pain in leprosy patients and the effects on their lives. We expect that the results will fill in the gaps in our current knowledge and contribute to a proper system of diagnostic triage, which will result in earlier diagnosis and treatment of leprosy patients with NP. Many of them may be missed or misdiagnosed because it was only recently that NP has been recognised as a complication of leprosy. This awareness is anticipated to reduce the morbidity of the patients with nerve related complications. They will also influence the rehabilitation programmes and social support, which will reduce the challenges in the longterm management of leprosy. 11
7. AIMS AND OBJECTIVES The aim of this study was to ascertain the prevalence of neuropathic pain in leprosy patients in Indonesia who have been treated with multi drug therapy using the DN4 questionnaire. This study also looked at the impact of neuropathic pain on the patients’ lives, functional capacity, general health and psychological wellbeing. The objectives of this study were: 1. To identify patients with NP using the DN4 questionnaire. 2. To assess the pain intensity of NP and its effects on the day-to-day activities. 3. To assess the impact of NP on functional capacity. 4. To determine whether psychological wellbeing is associated with NP.
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8. MATERIALS AND METHODS Study design This cross-sectional study was conducted on leprosy patients who have completed their treatment in Indonesia to ascertain the prevalence of NP and its impact on their functional capacity and their general health particularly psychological wellness.
Study Setting The study was executed at Soetomo General Hospital in Surabaya, the second largest city in Indonesia with a population of 3.1 million. The hospital is the largest public hospital in East Java with 1505 beds. It is a tertiary referral centre, which also functions as the teaching hospital of Airlangga University, Surabaya. The leprosy service is run as part of the Dermatology services and serves the surrounding areas like Gresik, Lamongan and Madura Island.
Fig 3: Map of Surabaya (East Java)
Map reference: lppm.petra.ac.id
Study Population The study had planned to recruit a sample size of 100 patients from those attending the leprosy outpatients’ clinic for follow up in June - August 2015. This sample size was based on the estimation of previous studies that 20% of these patients might have neuropathic pain. Patients who attended the clinic during this study period and had completed their MDT including those released from treatment, who were recalled for follow up were all invited to
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participate in the study. The duration of time from when they completed their MDT was not specified. However, the recruitment numbers were low because of the Muslim Holy month of Ramadan and they had a week of national holidays for the Eid festivities. A total of 76 patients were recruited but 5 had to be excluded because they did not meet the age criteria. The following inclusion criteria were used for recruitment. Leprosy patients – •
who have completed their MDT
•
18 years old and above
•
who provided informed consent
Those with severe mental or physical conditions that would interfere with their assessment were excluded. Patients who were found to have neuropathic pain were included in the case group and the rest were in the control group. There was no matching of cases to controls.
Case Definitions Neuropathic pain (NP) is defined as a score of 4 or more on the DN4 questionnaire (21, 44). It is initiated or caused by a lesion or disease affecting the somatosensory system causing pain in the nerve distribution that is neuro-anatomically plausible and is confirmed by clinical examination (43). Nociceptive pain is defined as pain arising from injury or tissue damage, which results in the nerves being activated and transmitting pain signals via the peripheral nerves or spinal cord to the brain (43). Neuritis is defined as inflammation of a nerve trunk, which may/may not lead to nerve function impairment (34, 41). Mixed pain is when both nociceptive and neuropathic pain are present at the same time especially in those who are in transition of developing chronic neuropathic pain (41). Nerve function impairment (NFI) is defined as having loss of motor and/or sensory functions (53).
Informed Consent On recruitment, all patients were given a detailed explanation of the study in Bahasa Indonesia by the researcher in the presence of the clinic staff before being invited to sign the
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consent form, which has been translated into Bahasa Indonesia. They were informed that their participation was completely voluntary and they had the option to withdraw at any time and reassured that their decision to participate will not affect their treatment at the hospital. Patients were not offered any reimbursements for participation except for their travel expenses.
Clinical Examination and Data Collection Patients were given a blank body chart to record the location of the painful sites. The researcher used the same to mark the skin lesions, thickened or tender nerves and map the painful areas. The patient’s demographic information – their age, gender, marital status, education, employment including past medical history, classification of leprosy, MDT, and previous leprosy reactions and treatment were recorded. Their medical records were reviewed to confirm details of the medical history and treatment.
Nerve Assessment A comprehensive assessment of the skin and neurological examination was carried out to look for thickened and tender nerves in the main peripheral nerves – ulnar, median, lateral popliteal, posterior tibial and great auricular nerves. The sensory function was tested using the MF (0.02g to 300g) at 6 points in the hand to assess skin areas supplied by the ulnar and median nerves and 4 points in the foot to assess the posterior tibial nerve. Patients were asked to respond with a yes or no answer. The normal sensory threshold is set at 0.2 g using the Semmes-Weinstein monofilaments (MF) on the hands, face and skin lesions and 2.0 g on the foot. Sensory loss is diagnosed if the MF threshold is increased by 3 or more levels from the normal on any site, 2 levels on 1 site and at least 1 level on another site or 1 level on 3 or more sites for 1 nerve. Motor involvement was assessed by testing for muscle weakness: •
abductor digiti minimi (ulnar)
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abductor pollicis longus (median)
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wrist extensors (radial)
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extensor hallucis longus (lateral popliteal)
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foot dorsiflexors (Lateral popliteal)
•
orbicularis oculi (facial) 15
The motor power was tested using the Medical Research Council (MRC) scale for muscle strength on a scale between 0-full paralysis to 5- full ROM, full resistance. Motor loss is considered present when there is a muscle score below 5 in any of the muscles on voluntary muscle testing.
Disability Assessment Disability was classified according to WHO Disability Criteria: •
Grade 0 –No disability
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Grade 1 – loss of sensation
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Grade 2 – obvious abnormalities like clawed hands and toes, trophic or traumatic ulcers, wrist drop, foot drop and lagopthalmos.
Neuropathic pain assessment and its impact using the DN4, BPI-short, Salsashort and GHQ-12 Questionnaires The questionnaires were initially piloted on 5 eligible patients to allow for adjustments in the content, time needed and administration process. The researcher found that most of the patients needed help and required clarification of the terms used in the questionnaires. Their data were not included in the results. For the actual study, the researcher, who was fluent in Bahasa Indonesia, administered these 4 questionnaires to every patient, to overcome the challenges of comprehension and literacy of the patients and to ensure standardisation of the terms used. This study is believed to be the first to use the Salsa-short questionnaire to evaluate the functional capacity of leprosy patients with neuropathic pain. It is a good screening tool for activity limitation and safety awareness. It measures in a standardised way the impact of disease on the patients’ ability to carry out his daily activities. Patients were asked to evaluate their own limitations. They can score a maximum of 80, which were grouped into no limitations (10-24), mild (25-39), moderate (40-49), severe (50-59) and extreme (60-80) (52). There were 7 questions in the DN4 that were related to sensory description – burning, cold pain, electric shock, tingling, pins and needles, numbness and itchiness and 3 questions were based on clinical examination. Light touch with the finger was applied to the area of pain and a non-painful area simultaneously to elicit touch hypoaesthesia. The 300g MF was used to test for pricking hypoaesthesia and a piece of cotton wool was used to assess for allodynia. It was easy to score and a total of 4 or more out of maximum 10 indicated presence of neuropathic pain. 16
The BPI (short) was used to assess the severity of pain and its effects on the patient’s daily functions. It used a numeric rating scale (NRS) between 0-(No pain) to 10-(Pain as bad as you can imagine). It measured the intensity of pain (worst, least, average and current) in the last 24 hours and its interference in daily functions including mood, sleep, relationships, general activity, normal work, walking ability and enjoyment of life. It allowed the patients to rate the severity of their pain, how it had affected their daily routine and the effectiveness of the treatment given. The pain was rated 0 (none), 1-4 (mild), 5-6 (moderate) and 7-10 (severe) and the same rating used for the daily activities (50, 54). The GHQ-12, a 12-item questionnaire, was used to assess the patients’ psychological wellbeing. They were asked how they had felt in the past 4 weeks and what they attributed their symptoms to. Interpretation of the answers was based on a 4-point response scale. (Symptoms present: less than usual=0, as usual=0, more than usual=1, much more than usual=1). A score of 4 or more indicated the presence of psychological morbidity without diagnosing the exact pathology (51).
Statistical Analysis A database was created using Microsoft Excel spreadsheet and this was cleaned and analysed using Stata 13. A univariate analysis using the Pearson χ2 test was used to compare all the variables to the outcome variables neuropathic pain (DN4>=4) and nonneuropathic pain (DN4
