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Friday, May 15, 2009

PHARMACOTHERAPY OF PARKINSON'S DISEASE



 
LEPROSY: A NEW LOOK AT AN OLD DISEASE
C. Muhammed NaslamHH, Anil Babu,
National College of Pharmacy, Manassery, Calicut

Cite this: N. M Nadim, Anil Babu, "PHARMACOTHERAPY OF PARKINSON'S DISEASE", B. Pharm Projects and Review Articles, Vol. 1, pp. 826-869, 2006. (http://farmacists.blogspot.in/)
 

 

 
1. INTRODUCTION
    Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The disease mainly affects the skin, the peripheral nerves, mucosa of the upper respiratory tract and also the eyes, apart from some other structures. Leprosy has afflicted humanity since time immemorial. It once affected every continent and it has left behind a terrifying image in history and human memory of mutilation, rejection and exclusion from society.

 
    At the beginning of 2005, Global registered prevalence of leprosy was 286 063 cases and the number of new cases detected during 2004 was 407 791. Among them, 47% were multibacillary cases, 12% were children, and 4% were diagnosed with severe disabilities.

 
    Full control of leprosy has eluded mainly in some parts of Angola, Brazil, Central African Republic, Democratic Republic of Congo, India, Madagascar, Mozambique, Nepal, and the United Republic of Tanzania. These countries have intensified their leprosy control activities.

 
    Access to information, diagnosis and treatment with multidrug therapy (MDT) is essential. The treatment is available free of charge from WHO and provides a simple yet highly effective cure for all types of leprosy21.

 
    Today, diagnosis and treatment of leprosy is easy. Essential work is being carried out to integrate leprosy services into existing, general health services. This is especially important for communities at risk for leprosy, which are often the poorest of the poor and under-served.

 

 
2. DEFINITION

 
    Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It is characterized by disfiguring skin sores, peripheral nerve damage, and progressive debilitation21.

 

 
3. CAUSATIVE ORGANISM

 
Mycobacterium leprae taken from a leprosy skin lesion

 
    The Etiological agent of leprosy is Mycobacterium leprae. It is a strongly acid-fast rod-shaped organism with parallel sides and rounded ends. In size and shape it closely resembles the tubercle bacillus. It occurs in large numbers in the lesions of lepromatous leprosy, chiefly in masses within the lepra cells, often grouped together like bundles of cigars or arranged in a palisade. Chains are never seen. Most striking are the intracellular and extra-cellular masses, known as globi, which consist of clumps of bacilli in capsular material. Under the electron microscope the bacillus appears to have a great variety of forms. The commonest is a slightly curved filament 3-10 m in length containing irregular arrangements of dense material sometimes in the shape of rods. Short rod-shaped structures can also be seen (identical with the rod-shaped inclusions within the filaments) and also dense spherical forms. Some of the groups of bacilli can be seen to have a limiting membrane26.
    It is believed that only leprosy bacilli which stain with carbol-fuchsin as solid acid-fast rods are viable and that bacilli which stain irregularly are probably dead and degenerating. The differences are valuable pointers in biopsy specimens to the effects of treatment.
    Two indices which depend on observation of M. leprae in smears from skin or nasal smears are useful in assessing the amount of infection, and the viability of the organisms and also the progress of the patient under treatment. They are the morphological index and the bacteriological index.

 
4. ETIOLOGY

 
    Leprosy is known to occur at all ages ranging from early infancy to very old age. The youngest age reported for occurrence of leprosy is three weeks in Martinique. The youngest case seen by the author was in an infant of two-and-a-half months, where the diagnosis of leprosy was confirmed by histopathology. Occurrence of leprosy, presumably for the first time, is not uncommon even after the age of seventy.

 
4.1 Method of Transmission of Leprosy

 
    The exact mechanism of transmission of leprosy is not known. At least until recently, the most widely held belief was that the disease was transmitted by contact between cases of leprosy and healthy persons. More recently the possibility of transmission by the respiratory route is gaining ground. There are also other possibilities such as transmission through insects which cannot be completely ruled out.

 
4.1.1 Transmission by contact

 
    The term 'contact' in leprosy is generally not clearly defined. All that we know at present is that individuals who are in close association or proximity with leprosy patients have a greater chance of acquiring the disease. It is with reference to this observation that the early workers appear to have used the term 'contact' as method of transmission. However, it is the definition of contact by later workers with qualifications such as 'skin to skin', 'intimate', 'repeated', etc. that has made it appear as if the disease could be acquired only under such conditions, and that the transmission involved some kind of 'inunction' or rubbing in of the organisms from the skin of affected persons into the skin of healthy subjects. Certainly, there is no proof that transmission takes place only through such inunction8.

 
    In general, closeness of contact is related to the dose of infection which in turn is related to the occurrence of disease. Of the various situations that promote close contact, contact within the household is the only one that is easily identified. In that area the relative risk for contacts was about four times that of non-contacts. The actual incidence among contacts and the relative risk for them appear to vary considerably in different studies. Attack rates for contacts of lepromatous leprosy have varied from 6.2 per 1000 per year in Cebu to 55.8 per 1000 per year in a part of South India.

 
4.1.2 Transmission through the respiratory route

 
    Transmission through the respiratory route is gaining increasing attention in recent years. It is interesting to note that as early as 1898 this possibility has also been discussed at some length. The possibility of transmission through the respiratory route is based on:
  1. The inability of the organisms to be found on the surface of the skin,
  2. The demonstration of a large number of organisms in the nasal discharge,
  3. The high proportion of morphologically intact bacilli in the nasal secretions,
  4. The evidence that M. leprae could survive outside the human host for several hours or days.

 
4.1.3 Transmission through insects

 
    With the available evidence on intracutaneous inoculation as a successful method of transmission of M.leprae in the mouse footpad model and a similar situation possibly existing in human beings, the question arises whether insects could play any role in natural infection1.
4.2 Factors determining clinical expression after infection
    There is sufficient evidence in leprosy that all people who get infected do not get the disease. The factors that determine clinical expression after infection appear to be as important as the factors that determine infection after exposure. Of the many possible factors that determine clinical expression of disease, a few are discussed below:
4.2.1 Genetic factors
    Genetic factors have been considered for a long time in leprosy. This is largely due to the observation of clustering of leprosy around certain families, and the failure to understand why certain individuals develop lepromatous leprosy while others develop non-lepromatous leprosy.
4.2.2 Route of Infection
Studies in the mouse footpad model suggest that the route of entry of the organism may, to some extent, determine the occurrence of leprosy. This is based on the observation that while intradermal administration of killed M.leprae sensitizes the animal, intravenous administration of killed M. leprae tends to tolerize the animal as studied through skin test reactivity. This also raises the possibility of tuberculoid and lepromatous leprosy being the result of different routes of entry of the organisms1.

 
4.2.3 Re-infection
The occurrence of leprosy, presumably for the first time, in older individuals in endemic areas has raised the possibility of re-infection in these individuals, since it is difficult to believe that they remained uninfected for such a long time in an endemic area. However, this occurrence in the older ages can also be explained by the possibility that the disease in these persons represents reactivation of old undetected primary disease following waning of previously acquired immunity. Since there is no evidence of a distinct primary disease occurring in leprosy as in tuberculosis, the hypothesis of re-infection gains some importance. Further, the occurrence of relapse in lepromatous leprosy also suggests, at least in a proportion of relapsed individuals, the possibility of re-infection. There is nothing to prevent these immune deficient inactive patients living in endemic areas from succumbing to fresh infection.

 
4.2.4 Prior infection with other mycobacteria
There is some evidence that as in tuberculosis, the atypical environmental mycobacteria and possibly M.tuberculosis play a role in the occurrence of leprosy. This is possibly due to antigenic overlap between M.leprae and other mycobacteria. The varying degrees of protection given by BCG against leprosy in different geographic areas, and the limited protection seen among natural tuberculin positive reactor in the BCG study in Uganda, support this possibility. The protective efficacy of BCG in different areas may be enhanced or diminished depending upon the local environmental mycobacteria, some acting synergistically with BCG and some antagonistically.

 
4.2.5 HIV infection and leprosy
It is now well recognized that the HIV infection has created a serious situation with regard to the incidence of tuberculosis. Case control studies carried out in several parts of Africa have clearly shown that the substantial increase in pulmonary tuberculosis is attributable to HIV infection. This is also true for atypical mycobacteriosis. Although a similar situation is possible with regard to leprosy there is no clear information on this so far. There have been a few anecdotal reports on leprosy and HIV infection occurring together. However, it is not clear whether or not this is a result of coincidence. Only good case control studies can provide an answer to the question of HIV infection s a risk factor for clinical leprosy. The prevalence of HIV infection to be significantly higher among patients with leprosy as compared with blood donors or surgical patients11

 
EPIDEMIOLOGY

 
5.1 The Prevalence Pool
The prevalence pool of leprosy in a population in general is in a constant flux resulting from inflow and outflow. The inflow is contributed by the occurrence of new cases, relapse of cured cases, and immigration of cases. The outflow is mainly through cure or inactivation of cases, death of cases, and emigration of cases. Of the various factors that influence the prevalence pool, the importance of inactivation of disease and mortality are less well recognized6.

 
5.2 Sex Distribution
Although leprosy affects both sexes, in most parts of the world males are affected more frequently than females often in the ratio of 2:1. This preponderance of males is observed in as diverse geographic situations as India, the Philippines, Hawaii, Venezuela and Cameroon.. The difference as a true difference due to higher incidence among males, and not due to differing duration of disease for the two sexes. It were the latter case, the sex-specific prevalence could be different even with the same sex-specific incidence. It should be pointed out that the male preponderance in leprosy is not universal and there are several areas, particularly in Africa, where there is either equal occurrence of leprosy in the two sexes, or occasionally even a higher prevalence among females. Such situations have been observed in Uganda, Nigeria, Malawi, Gambia, Burkina Faso, Zambia, Thailand and Japan.

 
5.3 Race
Leprosy occurs in all races. African blacks report a higher incidence of the tuberculoid form of leprosy. People with light skin and Chinese individuals have a greater tendency to have the lepromatous type of leprosy.
Leprosy is endemic in Asia, Africa, the Pacific basin, and Latin America (excluding Chile). It is more a rural disease than urban disease.

 

 
5.4 Age
Leprosy has a bimodal age distribution, with peaks in those aged 10-14 and in those aged 35-44 years. The disease is rare in infants. Children appear to be more susceptible to disease and tend to have the tuberculoid form.9
The incubation period ranges from 6 months to 40 years or longer. The average incubation period is 2-3 years.

 
5.5 Risk Groups
Those having close contacts with patients with untreated, active, predominantly multibacillary disease, and persons living in countries with highly endemic disease are at risk of contracting the disease. Recent research suggests that there is genetic variation in susceptibility. The region of DNA responsible for this variability is also involved in Parkinson's disease, giving rise to current speculation that the two disorders may be linked in some way at the biochemical level. In addition, men are two times more likely to contract leprosy than women.

 

 

 
6. PATHOPHYSIOLOGY

 
The areas most commonly affected by leprosy are the superficial peripheral nerves, skin, mucous membranes of the upper respiratory tract, anterior chamber of the eyes, and testes. These areas tend to be cooler parts of the body. Tissue damage is caused by the degree to which cell-mediated immunity is expressed, the extent of bacillary spread and multiplication, the appearance of tissue-damaging immunologic complications (ie, lepra reactions), and the development of nerve damage and its sequelae. M leprae is an obligate intracellular acid-fast bacillus with a unique ability to enter nerves1.

 
Leprosy damages the body in four main ways:
  • Peripheral neuritis: Leprosy is the most common cause of peripheral neuritis in the world. Nerve damage is due to the cell mediated response. Peripheral neuritis leads to loss of sensory, motor and autonomic function. The hallmarks of leprosy are skin lesions, skin anesthesia and enlarged peripheral nerves.
  • Bacillary infiltration: In lepromatous leprosy bacillary growth slowly damages the infiltrated major organs except the central nervous system and renders them liable to type 2 lepra reactions6.
  • Acute lepra reactions: Lepra reactions may be defined as episodes of inflammation in pre-existing lesions of leprosy. Reversal leprosy reactions episodes of immunological instability are now recognized as being of major importance in the pathogenesis of leprous nerve damage. Borderline leprosy patients are at particular risk of this complication.
  • Interacellular survival: Pathogens that live inside the host cells are not affected by antibodies, but are killed by a cellular immune response. Myco.leprate like myco.tuberculosis, surives and multipleies withn macrophages. These mycobacteria have an arsenal of defense that they use to escape killing by professional killing cells for example phenolic glycolipid, a surface lipid of myco.leprae has been implicated as defense against oxidative killing by macrophages. It is likely that the slow growth of myco.leprae, a hallmark characteristic of this pathogen, also contributes to the survival within the macrophages9.

 
6.1 Histologic Findings And Types Of Leprosy
Not all persons who are exposed to infection develop overt leprosy. Another observation is that family and household contacts of leprosy patients show myco.leprae in the normal skin, if a prolonged search is made and if special techniques are employed. The broad concept which emerges from the above observations is as follows. When myco.leprae enteres a new host, the more common outcome is that it is destroyed by the natural defences of the body (native resistance, mainly in the form of macrophages). A lepromin-neative host who has passed through such an experience usually becomes leprominpositive; he has acquired hypersensitivity (and probably immunity) to bacillary Ags. On the other hand, if the host is overwhelmed, the result is overt disease. Classification of the lesions produced is based on (1) The number of bacilli in the lesion, (2) The histological changes and (3) The results of the lepromin test (as an indicator of immunity)4.

 
6.1.1 Indeterminate leprosy (IL)
In the IL form, findings are nonspecific. Histiocytes and lymphocytes are scattered, with some concentration around dermal appendages and nerves. At times, an acid-fast bacillus can be observed in a nerve bundle. The number of
dermal mast cells may be increased.

 

  • This early form causes one to a few hypo pigmented, or sometimes erythematous, macules. Sensory loss is unusual.
  • Most cases evolve from this state into one of the other forms, depending on the patient's immunity to the disease. Those with strong immunity may become cured of disease. In some, the disease may persist in this indeterminate form. In those with weaker immunity, the disease progresses to one of the other forms18.

 
6.1.2 Tuberculoid Leprosy (TT)
In the TT form, well-developed epithelioid granulomas are observed in the papillary dermis, often around neurovascular structures. The granulomas are surrounded by lymphocytes, which extend into the epidermis. Langhans giant cells are common. Dermal nerves are destroyed or swollen because of the granulomas. Acid-fast bacilli are not observed.

 

 

 

 
Tuberculoid Lesion

 
  • Skin lesions are few in number. Usually, one erythematous large plaque is present, with well-defined borders that are elevated and slope down into an atrophic center. The lesions can become arciform or annular, and they can be found on the face, limbs or elsewhere, but spare intertriginous areas and the scalp.
  • Another presentation involves a large asymmetric hypo pigmented macule.
  • Both types of lesions are anesthetic and involve alopecia.
  • Spontaneous resolution can occur in a few years, leaving pigmentary disturbances or scars. Progression can also occur, leading to borderline-type leprosy. In rare instances in which a patient is untreated for many years, the lepromatous type can develop.
  • Neural involvement is common in TT; it leads to tender, thickened nerves with subsequent loss of function. The great auricular nerve and superficial peroneal nerves are often prominent.

 
Borderline Tuberculoid Leprosy (BT)
In the BT form, well-developed epithelioid cell granulomas are apparent and diffuse, but few or no Langhans giant cells are observed. Few lymphocytes are present in the epidermis in this form, compared with the TT form. Bacilli are absent or rare, but they can be found in dermal nerves as well as in the arrector pilorum. Nerves are moderately swollen26.

 
In the BB form, diffuse epithelioid granulomas that lack giant cells are observed in the dermis below the subepidermal grenz zone. Nerves are slightly swollen, and acid-fast bacilli are present in moderate numbers.

 

 

 
Borderline Tuberculoid Leprosy Skin Lesion

 

 

 
  • Lesions in this form are similar to those in the tuberculoid form, but they are smaller and more numerous. The nerves are less enlarged, and is less alopecia is present.
  • Disease can remain in this stage; convert back to the tuberculoid form, or progress.

 
6.1.4 Borderline Borderline Leprosy (BB)
  • Cutaneous lesions consist of numerous, red, irregularly shaped plaques that are less well defined than those in the tuberculoid type. Their distribution may mimic those of the lepromatous type, but they are more asymmetric. Anesthesia is only moderate. Regional adenopathy may be present.
  • Disease may remain in this stage, improve or worsen26.

 
6.1.5 Borderline Lepromatous Leprosy (BL)
In the BL form, smaller granulomas with some foamy changes and numerous lymphocytes are observed. Nerves often have an onion-skin appearance due to invasion of the perineurium. A few epithelioid cells may be observed8.
  • Lesions are numerous and consist of macules, papules, plaques, and nodules. Annular punched-out-appearing lesions that look like inverted saucers are common. Anesthesia is often absent.
  • As with the other forms of borderline leprosy, the disease may remain in this stage, improve, or regress.

 
6.1.6 Lepromatous Leprosy (LL)
In the LL form, a diffuse infiltrate of foamy macrophages is present in the dermis below a subepidermal zone of uninvolved papillary dermis (ie, grenz zone). An enormous number of acid-fast bacilli develop within the foamy macrophages, singly or in clumps called globi. Lymphocytes are scant, and giant cells are typically absent. Numerous bacilli invade the nerves, but these are fairly well preserved with little infiltrate. Nodular, or dermatofibroma-like lesions in LL, referred to as histoid leprosy, result in a diffuse fascicular arrangement of spindled cells in the dermis admixed with foamy macrophages that contain numerous bacilli10.

 

 

 

 
Lepromatous form - Left Arm

 
  • Early cutaneous lesions consist mainly of pale macules. Later, infiltrations are present, with numerous bacilli. Macular lesions are small, diffuse, and symmetric. The skin texture does not change, and little or no loss of sensation occurs. The nerves are not thickened, and sweating is normal.
  • The lateral eyebrows are affected by alopecia (ie, madarosis), which spreads to the eyelashes and then the trunk. Scalp hair remains intact.
  • Lepromatous infiltrations can be diffuse, nodules (called lepromas), or plaques. The diffuse type results in the appearance of a leonine facies. Neuritic lesions are symmetric and slow to develop.
  • Eye involvement occurs, causing pain, photophobia, decreased visual acuity, glaucoma, and blindness.
  • Testicular atrophy results in sterility and gynecomastia.
  • Lymphadenopathy and hepatomegaly can result from organ infiltration.
  • Stridor and hoarseness are a result of laryngeal involvement. Nasal infiltration can cause a saddle-nose deformity.
  • Aseptic necrosis and osteomyelitis can occur with repeated trauma after joint invasion.
  • Brawny edema of the lower extremities is a late finding.
  • Unlike the other types of leprosy, LL cannot convert back to the less severe borderline or tuberculoid types of disease.
  • Lepra reactions are complications that occur in 50% of patients after the initiation of therapy or, occasionally, before therapy10.

 

 

 
Flowchart of diagnosis and classification

 
6.2 Classification of Leprosy
Leprosy can be classified on the basis of clinical manifestations and skin smear results. In the classification based on skin smears, patients showing negative smears at all sites are grouped as paucibacillary leprosy (PB), while those showing positive smears at any site are grouped as having multibacillary leprosy (MB). However, in practice, most programmes use clinical criteria for classifying and deciding the appropriate treatment regimen for individual patients, particularly in view of the non-availability or non-dependability of the skin-smear services.The clinical system of classification for the purpose of treatment includes the use of number of skin lesions and nerves involved as the basis for grouping leprosy patients into multibacillary (MB) and paucibacillary (PB) leprosy4.
    While classifying leprosy, it is particularly important to ensure that patients with multibacillary disease are not treated with the regimen for the paucibacillary form of the disease. Only the solid-staining bacilli are viable. It is not unusual for solid-staining M. leprae to reappear for short periods in patients being successfully treated with drugs. It is important to recognize that measurement of MI is liable for observer variations and therefore not always reliable.

 
7 SIGNS AND SYMPTOMS

 
  • one or more hypopigmented (lighter than your normal skin color) skin lesions that have decreased sensation to touch, heat, or pain
  • skin lesions that do not heal after several weeks to months
  • numbness or absent sensation in the hands and arms, or feet and legs
  • muscle weakness resulting in signs such as foot drop (the toe drags when the foot is lifted to take a step)9

 
7.1 Signs Which Are Not Leprosy
  • Skin patches present from birth (i.e. birth marks);
  • Skin patches where there is normal feeling;
  • Skin patches that itch;
  • Skin patches that are white, black or dark red;
  • Skin patches with scaling of skin;
  • Skin patches that appear or disappear suddenly and spread fast.

 

 
8. MORBIDITY AND MORTALITY

 
8.1 Morbidity
If severe and left untreated, leprosy can cause significant debilitating deformity. Since 1943, when sulfone was introduced as the first effective treatment for leprosy, antibiotic treatment has dramatically improved patients' outcomes. Early diagnosis and effective antimicrobial treatment can arrest and even cure the disease8.

 
8.2 Mortality In Leprosy
Mortality in leprosy is often not considered important since the disease is rarely an immediate cause of death. However, leprosy patients are exposed to increase mortality risks due to its indirect effects. In a study in Cebu, Philippines, it was found that the mortality rate for lepromatous patients was four times more as compared with the general population, and that the situation for non-lepromatous patients was very similar to that of the general population. A comparative study of lepromatous patients, non-lepromatous patients, and the general population from the same rural area in South showed that the standardized death rate for lepromatous patients was three-and-a-half times that of the general population, the non-lepromatous patients themselves having a mortality risk which was twice that of the general population. In that population, leprosy was found to contribute to about 1% of all deaths8.

 

 
9. COMPLICATIONS
  • permanent nerve damage
  • cosmetic disfigurement
  • Reactional states are the most common complications. These states can result in permanent neurologic sequelae, resulting in disability and deformity.
  • Lepra type I reactions usually affect patients with borderline disease. A downgrading reaction represents a shift toward the lepromatous pole before the initiation of therapy. Reversal reactions are shifts toward the tuberculoid pole after the initiation of therapy16.
  • Lepra type II reactions, or ENL (erythima nodosum leprosum) is an immune complex–mediated reaction that occurs in patients with the BL or LL forms. The most common presenting symptoms are crops of painful erythematous nodules of the skin and subcutaneous tissue. The reaction usually manifests after a few years of therapy and resolves spontaneously after about 5 years. Associated fever, malaise, joint pain, nerve pain, iridocyclitis, dactylitis, and orchitis may be present.
  • A Lucio phenomenon is an unusual type II reaction that is sometimes designated a type II reaction. It common in Mexico and Central America and is characterized by cutaneous hemorrhagic infarcts in patients with diffuse LL.
  • Injuries can result in ulcerations, cellulitis, scarring, and bony destruction19.
  • Contractures can develop and result in fixation.
  • Eye damage can result in lagophthalmos, ectropion, and entropion.

 

10. DIAGNOSIS
Diagnosis of leprosy is most commonly based on the clinical signs and symptoms. These are easy to observe and elicit by any health worker after a short period of training. In practice, most often persons with such complaints report on their own to the health centre. Only in rare instances is there a need to use laboratory and other investigations to confirm a diagnosis of leprosy8.

 
In an endemic country or area, an individual should be regarded as having leprosy if he or she shows ONE of the following cardinal signs:
  1. Skin lesion consistent with leprosy and with definite sensory loss, with or without thickened nerves
  2. Positive skin smears

 
The skin lesion can be single or multiple, usually less pigmented than the surrounding normal skin. Sometimes the lesion is reddish or copper-coloured. A variety of skin lesions may be seen but macules (flat), papules (raised), or nodules are common. Sensory loss is a typical feature of leprosy. The skin lesion may show loss of sensation to pin pick and/or light touch. Thickened nerves, mainly peripheral nerve trunks constitute another feature of leprosy. A thickened nerve is often accompanied by other signs as a result of damage to the nerve. These may be loss of sensation in the skin and weakness of muscles supplied by the affected nerve. In the absence of these signs, nerve thickening by itself, without sensory loss and/or muscle weakness is often not a reliable sign of leprosy.

 
A person presenting with skin lesions or with symptoms suggestive of nerve damage, in whom the cardinal signs are absent or doubtful should be called a `suspect case' in the absence of any immediately obvious alternate diagnosis . Such individuals should be told the basic facts of leprosy and advised to return to the centre if signs persist for more than six months or if at any time worsening is noticed. Suspect cases may be also sent to referral clinics with more facilities for diagnosis30.

 

 

 

 
10.1 Tissue Smear Testing
  • An incision is made in the skin, and the scalpel blade is used to obtain fluid from a lesion. The fluid is placed on a glass slide and stained by using the Ziehl-Neelson acid-fast method to look for organisms.
  • The bacterial index (BI) is then determined7.

 
10.2 Skin Biopsy
  • The skin biopsy sample should be examined for morphologic features and the presence of acid-fast bacilli.
  • Biopsy is useful for determining the morphologic index (MI), which is used in the evaluation and treatment of patients. It is the number of viable bacilli per 100 bacilli in the leprous tissue.

 
10.2 Sensory Testing
  • Tactile and temperature sensations should be tested.
  • A wisp of cotton can be used to test for anesthesia of the lesions.

 
10.3 Lepromin Testing
  • This test indicates host resistance to M leprae. It results do not confirm the diagnosis, but they are useful in determining the type of leprosy.
  • A positive finding indicates cell-mediated immunity, which is observed in TT. A negative finding suggests a lack of resistance to disease and is observed in LL. A negative result indicates a poorer prognosis.
  • To perform this test, bacillary suspension is injected into the forearm. When the reaction is assessed at 48 hours, it is called the Fernandez reaction and indicates delayed hypersensitivity to antigens of M leprae or mycobacterium that cross react. When the reaction is read at 3-4 weeks, it is called the Mitsuda reaction and indicates that the immune system is capable of mounting an efficient cell-mediated response8.

 

 
10.4 Polymerase Chain Reaction (PCR) Analysis
  • PCR can be used to detect and identify M leprae.
  • The technique is used most often when acid-fast bacilli are detected but clinical or histopathologic features are atypical. It is not useful when acid-fast bacilli are not detectable by means of light microscopy21.

 
TREATMENT
The management of leprosy includes chemotherapy to stop the infection; treatment to minimize potential physical deformities; and physical, social, and psychological rehabilitation. Potential deformities can be prevented by educating patients about how to deal with existing nerve damage and by treating any sequelae of this damage. Close follow-up is important to ensure patient compliance. Monitor for drug resistance and adverse reactions to medications.

 
  1. Eyes, nerves, and the nose should be examined at follow-up to ensure the timely recognition of reactive disease.
  2. The real challenge in managing leprosy is the treatment of reactional states.
  • Systemic steroids are effective in reducing inflammation and edema in reversal reactions; thus, they are the most helpful medications in preventing nerve damage.
  • Prednisone should be given at a dose of 40-80 mg/d for 5-7 days and then tapered slowly over 3-6 months. This long course is necessary to decrease the severity of disabilities and deformities8.
  • Clofazimine can also be used as a steroid-sparing agent for reversal reactions.
  • Thalidomide is ineffective for the treatment of reversal reactions, but it is highly effective with erythema nodosum leprosum (ENL).

 
11.1 Surgical treatment
  • Emergency surgery may be necessary if a patient with profound nerve inflammation presents with a nerve abscess or loss of nerve function secondary to compression.
  • Prompt recognition and surgical drainage of the abscess can often restore nerve function.
  • Elective surgery may be required for correction of lagophthalmos (ie, inability to close the eye).
  • Reconstructive surgery can be used to repair nasal collapse in LL.
  • Other surgery may be needed to improve function or for cosmesis.
  • Contractures can be surgically repaired.
11.2 Consultations
Consultations with an ophthalmologist, plastic surgeon, orthopedic surgeon, otolaryngologist, neurosurgeon, and/or neurologist may be necessary. Reasons for a consultation with an ophthalmologist consult include the following:
  • Lagophthalmos
  • ENL-induced iritis
  • Direct invasion of the anterior chamber of the eye by M leprae
  • Corneal and conjunctival insensitivity
  • Infection or scarring from fifth and seventh cranial nerve involvement

 
Rehabilitation medicine, including physical and occupational therapy, can help reduce morbidity. Consultation with a prosthetics specialist may also be appropriate. In patients with bone or joint destruction, weight bearing should be minimized. Patients with anesthesia of limbs need to be educated about their condition, and they should wear appropriate footwear. Plantar ulceration requires rest and avoidance of weight bearing. Weakness or paralysis requires physical therapy to prevent contractures. The goals of pharmacotherapy are to reduce morbidity, prevent complications, and eradicate the disease27.

 
11.3 Drugs
11.3.1 Antimicrobials
Antimicrobials are used to eliminate organisms. The first-line drugs are dapsone, rifampin, and clofazimine. Other antibiotics include minocycline, ofloxacin, and clarithromycin.

 
For drug treatment purposes, infections are classified as paucibacillary or multibacillary. Paucibacillary disease can be treated with a combination of 2 drugs, whereas multibacillary disease requires triple-drug therapy. The length of treatment depends on the type of disease and the access to medicine. The recommendations of the World Health Organization (WHO) and those in the United States are both mentioned here.

 

 

 
11.3.1.1 Dapsone
Mechanism of action 
Acts by blocking folic acid synthesis and is weakly bactericidal. Was widely used as monotherapy for leprosy until resistance developed. Now used as part of a multidrug regimen to treat leprosy.
Adult Dose Paucibacillary:
WHO: 100 mg/d PO for 6 mo
U.S.: 100 mg/d for 3 y for IL and TT and 5 y for BT
Multibacillary: WHO: 100 mg/d PO for 24 mo
U.S.: 100 mg/d indefinitely
Pediatric Dose 
Not established 
Contraindications 
Documented hypersensitivity; known G-6-PD deficiency 
Interactions 
May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists such as pyrimethamine (monitor for agranulocytosis during the second and third months of therapy); probenecid increases toxicity; concurrent trimethoprim may increase toxicity of both; due to increased in renal clearance, levels may significantly decrease with concurrent rifampin
Pregnancy 
C - Safety for use during pregnancy has not been established. 
Precautions 
Obtain weekly blood counts in first month, then WBC monthly for 6 mo then semiannually; discontinue if platelet count, leukocyte count, or hematopoiesis significantly reduced; caution in methemoglobin reductase deficiency, G-6-PD deficiency, or hemoglobin M (high risk for hemolysis and Heinz body formation); caution in patients exposed to other agents or in conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy rare; phototoxicity may occur when patient is exposed to UV light

 
11.3.1.2 Rifampin
Mechanism of action 
Bactericidal for M leprae. Inhibits DNA-dependent RNA polymerase, interfering with bacterial RNA synthesis. Part of multidrug regimen to treat leprosy.
Adult Dose Paucibacillary:
WHO: 600 mg PO every mo (supervised) for 6 mo
U.S.: 300 mg PO bid for 6 mo
Multibacillary:
WHO: 600 mg PO every mo (supervised) for 24 mo
U.S.: 600 mg/d for 3 y
Pediatric Dose 
10-20 mg/kg PO/IV; not to exceed 600 mg/d; schedule as in adults6
Contraindications 
Documented hypersensitivity 
Interactions 
Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either alone (discontinue one or both if LFT results are altered)
Pregnancy 
C - Safety for use during pregnancy has not been established. 
Precautions 
Obtain CBCs and baseline clinical chemistries prior to and during therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy associated with thrombocytopenia (reversible if therapy discontinued as soon as purpura occurs); if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

 
11.3.1.3 Clofazimine
Mechanism of action 
Red, fat-soluble, crystalline dye. Inhibits mycobacterial growth, binds preferentially to mycobacterial DNA. Has antimicrobial properties, but mechanism of action is unknown. Weakly bacteriocidal against M leprae. Has anti-inflammatory properties.
Adult Dose Paucibacillary: Not necessary
Multibacillary: WHO: 300 mg PO every mo (supervised) and 50 mg PO qd for 24 mo
U.S.: 50 mg/d if dapsone resistance present
Pediatric Dose 
Not established
Contraindications 
Documented hypersensitivity 
Interactions 
Dapsone may inhibit anti-inflammatory activity 
Pregnancy 
C - Safety for use during pregnancy has not been established. 
Precautions 
Most noticeable adverse effect is skin discoloration; secretions also discolored; urine becomes red; ichthyosis of shins may be prominent; severe abdominal symptoms with rare reports of splenic infarction, bowel obstruction, and GI bleeding; autopsy reveals crystalline deposits of clofazimine in tissues, including intestinal mucosa, spleen, liver, and mesenteric lymph nodes

 
11.3.2 Corticosteroids
These are important anti-inflammatory agents used in the treatment of reactional leprosy. Corticosteroids are the reliable only in the treatment of reversal reactions. These medications can be used to treat leprosy reactions when a risk of neurologic deficits exists or when lesions occur in cosmetically important places. They can also be used to treat ENL.

 
11.3.2.1 Prednisone
Mechanism of action 
May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.
Adult Dose 
40-80 mg PO qd; taper slowly over weeks to months 
Pediatric Dose 
4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications 
Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease9
Interactions 
Coadministration with estrogens may decrease clearance; when used with digoxin, may increase digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy 
B - Usually safe but benefits must outweigh the risks. 
Precautions 
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; regardless of dosing schedule, avascular necrosis of long bones may occur; corticosteroid may aggravate insomnia, mood swings, depression, and psychosis

 
11.3.3 IMMUNOMODULATORS
These agents are used to modify the immune system response to diverse stimuli.

 
11.3.3.1thalidomide
Mechanism of action 
Immunomodulatory agent that may suppress excessive production of tumor necrosis factor-alpha (TNF-alpha) and downregulate selected cell-surface adhesion molecules involved in leukocyte migration. Can be used to treat recurrent or refractory ENL.
Adult Dose 
100-300 mg/d PO qd with water, preferably at hs and at least 1 h pc
Pediatric Dose 
Not established 
Contraindications 
Documented hypersensitivity; pregnancy 
Interactions 
May increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine; due to teratogenic effects, women must use 2 additional methods of contraception or abstain from intercourse
Pregnancy 
X - Contraindicated in pregnancy 
Precautions 
Caution in women of child-bearing age (because of severe birth defects with thalidomide use in pregnancy, the System for Thalidomide Educational Prescribing Safety [STEPS] program recommends serum pregnancy testing 24 h prior to starting medication, then every wk for first month, then monthly thereafter); other potential adverse effects include peripheral neuropathy (can be irreversible), sedation, bradycardia; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, from tanning beds)

 
11.3.4. Multidrug Therapy (MDT)
The drugs used in WHO-MDT are a combination of rifampicin, clofazimine and dapsone for MB leprosy patients and rifampicin and dapsone for PB leprosy patients. Among these rifampicin is the most important antileprosy drug and therefore is included in the treatment of both types of leprosy.

 
Treatment of leprosy with only one antileprosy drug will always result in development of drug resistance to that drug. Treatment with dapsone or any other antileprosy drug used as monotherapy should be considered as unethical practice21.

 
In developing WHO MDT regimens, three main principles were adhered to:
  • rifampicin should be one of the components of MDT
  • rifampicin 600 mg should be given at least once a month to all patients
  • at least two anti-leprosy drugs should be used in the MB regimen and one anti-leprosy drug should be used in the PB regimen, in addition to rifampicin, in order to prevent the occurrence of rifampicin-resistant M. leprae.

     
    Rifampicin
    The drug is given once a month. No toxic effects have been reported in the case of monthly administration. The urine may be coloured slightly reddish for a few hours after its intake, this should be explained to the patient while starting. 30

     
    Clofazimine
    It is most active when administered daily. The drug is well tolerated and virtually non-toxic in the dosage used for MDT. The drug causes brownish black discoloration and dryness of skin. However, this disappears within few months after stopping treatment. This should be explained to patients starting MDT regimen for MB leprosy.

     
    Dapsone
    The drug is very safe in the dosage used in MDT and side effects are rare. The main side effect is allergic reaction, causing itchy skin rashes and exfoliative dermatitis. Patients known to be allergic to any of the sulpha drugs should not be given dapsone.

     
    Rifampicin is an exceptionally potent bactericidal agent against M. leprae. A single dose of 600 mg is capable of killing 99.9% or more of viable organisms. However, the rate of killing is not proportionately enhanced by subsequent doses. It is also possible that rifampicin exerts a delayed antibiotic effect for several days, during which the organism is incapable of multiplying

     

     
    12. FOLLOW UP AND PROGNOSIS

     
    12.1 Follow up
    • WHO recommends 2 years of follow-up for paucibacillary disease and 5 years of follow-up for multibacillary disease. Patients should be monitored for possible lepra reactions.
    • In some regions of the world, self-administration of medications is difficult. Medical posts or mobile units can be set up for the administration of medications and management of health-related issues. Supervision may be required to achieve the maximum benefit from therapy.
    • In patients taking dapsone, the complete blood count should be checked at frequent intervals early during the therapy and at less frequent intervals later during therapy28.
    • Sensation and muscle strength in the hands, feet, and eyes should be checked on a regular basis.

     
    12.2 Prognosis
    • The prognosis depends on the stage of disease.
    • In borderline cases, the disease has the potential to be down-graded to LL; these patients may have nerve damage.
    • Even with corticosteroid treatment, neuritis may not be curable.
    • The prognosis also depends on the patient's access to therapy, the patient's compliance, and the early initiation of treatment.

     

     
    13. PREVENTION
    Household contacts of patients with lepromatous disease should be annually monitored for 5 years after diagnosis. Children especially should be observed for the development of disease. Dapsone prophylaxis is no longer advocated.

     
    Attempts have been made to develop a vaccine against leprosy. The bacille Calmette-Guerin (BCG) vaccine has variable results in protection7

     
    PATIENT COUNSELING
    14.1 About leprosy
    • They will be cured of leprosy if they take the drugs in the blister packs as advised.
    • They must complete a full course of treatment: 6 blisters for PB patients and 12 blisters for MB patients.
    • The drugs stop the disease from spreading.
    • Patients can lead normal lives. They can live at home, go to school, work, play, get married, have children, participate in social events4

     
    14.2 About their treatment
    • The MDT blister packs are free of charge.
    • They should keep the blister packs in a dry, safe, and shady place and out of the reach of children. If the drugs are spoiled (changed colour, broken), the health worker will replace them.

     
    14.3 About possible problems
    • The medicines will turn their urine red and their skin darker. Patients should not worry: both will return to normal once the treatment is completed.
    • They must go immediately to a health centre if they have any problems (pain, fever, malaise, new lesions, muscle weakness …).
    • They should return for a check-up after they complete their treatment. If they already have disabilities, tell them how to protect themselves from injuries

     
    14.4 Important Pointsabout MDT
    Safety
    • MDT is very safe and effective in curing leprosy.
    • MDT is safe during pregnancy.
    • MDT is safe for patients being treated for tuberculosis
    (TB) as well as those who are HIV-positive.
    • Rifampicin is common to the treatment of leprosy and
    TB and must be given in the doses required for TB.

     
    Treatment
    • Give MDT free of charge to all leprosy patients.
    • Help ensure that patients complete their treatment.
    • Give patients enough blister packs to last until their next visit.
    • Use Accompanied MDT for all patients who find it difficult to visit the health centre regularly.
    • If a person cured of leprosy presents new skin patches with definite loss of sensation, consider this as a case of relapse. Re-treat with appropriate MDT regimen.
    MDT supplies
    • Do not use MDT blister packs
      • beyond the expiry date
      • if the drugs are damaged, or have changed colour, or if a capsule is broken
    • Keep MDT blister packs in a cupboard or a wooden box.
    • If MDT blister packs for children are not available, remove tablets from an adult pack for the appropriate dose21.
    Common Side Effects of MDT
    • Red coloured urine
      This is due to the colour of rifampicin, which is taken once every month. This lasts for only a few hours aftertaking the drug. Please assure patient that it is harmless.
    • Darkening of skin
      This is due to clofazimine used daily for treating MB patients. This is harmless and will disappear withina few months after completing the treatment. Please encourage patient to take the medicines regularly.
    • Allergy
      As with any medicine, some patients may be allergic to one of the drugs in MDT. Most commonly there will be severe itching and red /dark spots on the skin. In such cases, ask the patient to stop taking the medicines and refer him or her to the nearest hospital.

     
    15. CONCLUTION

     
        The last two decades have been enormous progress in the treatment of leprosy. However, major challenges remain – we must ensure that leprosy care remains excellent, we must solve the important problems of preventing and ameliorating nerve damage. The nerve damage associated with leprosy is lifelong and may progress despite successful antibacterial treatment; currently it is estimated that there are seven million people with lepsory-associated nerve damage. These patients have completed their course of MDT so in WHO parlance, they are no longer 'leprosy patients', but their nerve damage remains for the rest of their lives putting them at risk of trauma. We remain poor at detecting and halting nerve damage in leprosy.

     
    Recently, three new drugs, namely, ofloxacin-a fluoroquinolone, clarithromycin-a macrolide and minocycline -a tetracycline, all acting by different mechanisms, have shown very promising antileprosy activity in experimental models and short-term clinical trials. These drugs offer the potential for increasing the effectiveness and shortening the duration of antileprosy chemotherapy. In addition, new drugs may prove useful against Mycobacterium leprae strains resistant to the drugs currently in use, especially the strains resistant to rifampicin.

     
    In addition to ofloxacin, two more drugs - minocycline (a tetracycline) and clarithromycin (a macrolide) - have shown very promising anti-leprosy activity in experimental animals and short-term clinical trials. These drugs offer the opportunity to develop and test new regimens which will not only be more effective but also more practicable and acceptable to the patient.

     

     

     

     

     

     

     
    REFERENCE

     
  1. Robins pathological basis of disease edited by Cotran, Kumar, Collins, 6th edition, Saunders, an imprint of Elsevier science, the curtiscentre independent squir west, Philadelphia, Pennsylvania, pg no.385-387.
  2. Clinical pharmacy and therapeutics edited by Roger Walker, Clive Edward, 3rd edition, Churchil Livingstone.
  3. Goodman and Ginmans pharmaceutical basis of therapeutics by Joel. G. Hardman, Lee E. Limbard 10th edition, McGraw Hill, New York, pg no. 1288-1291.
  4. Pharmacology and Pharmaco therapeutics by R.S. Sathoskar and S.D. Bhandarkar, 13th edtion, Popular Prakasan, Mumbai, pg no.745-751.
  5. Essentials of medicinal pharmacology by K.D. Tripati, 5th edition, Jay Pee Brothers Medical Publishers Pvt. Ltd., pg no.709 -714.
  6. Robins pathological basis of disease edited by Cotran, Kumar, Collins, 7th edition, Saunders, an imprint of Elsevier science, the curtiscentre independent squir west, Philadelphia, Pennsylvania, pg no. 56, 321.
  7. Text book of pathology, 5th edition, Harsh Mohan, Jay Pee Brothers Medical Publishers Pvt. Ltd., New Delhi, pg no. 163-167.
  8. General pathology and pathology of systems by S.G. Deodhare, Popular Prakasan, Mumbai, pg no. 943-946.
  9. Gokhale DS, Sohoni Veena, The human face of leprosy, Ameya Prakasan Pune, India, 1997.
  10. Noordeen SK, Epidemiology and control of leprosy – A review of progress over the last 30 years, Trans R Soc. Trop Med. Hyg 87:515.
  11. Jayalakshmi P, et. al. Autopsy findings in 35 cases of leprosy in Malasia, Int. J. Lepr. 55: 510.
  12. Storrs EE, Leprosy in the armadillo Science, 183:851.
  13. Rea TH et.al. Peripheral blood lymphocytes subsets in leprosy. Int J Lepr 52: 311.
  14. Novick RP. "Plasmids" Scientific American, vol 243, No 6, 1980
  15. Barksdale L "Concerning the NI (neuron invasion) gene of mycobacterium leprae" International Journal of Leprosy, 47, (1979)
  16. Cantacuzine J, Longhin S. "De l'Existence d'un Ultra-Virus chez le Bacille de la Lepre Humaine" CR Soc Biol, 1932, Vol 109, No 11
  17. Corcos MG "A Transposon in Hansen's bacillus?" Transactions of the Royal Society of Tropical Medicine and Hygiene, 87 (1993)
  18. Corcos, MG "Tuberculoid Contamination in Histoid Hanseniasis", International Journal of Leprosy, Vol 62, no 2 (1994)
  19. Rees RJ, Pearson JM, Waters MF (1970). "Experimental and clinical studies on rifampicin in treatment of leprosy". Br Med J 688 (1): 89-92. PMID 4903972.

 


Cite this: N. M Nadim, Anil Babu, "PHARMACOTHERAPY OF PARKINSON'S DISEASE", B. Pharm Projects and Review Articles, Vol. 1, pp. 826-869, 2006. (http://farmacists.blogspot.in/)

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