Neurologic Complications of Leprosy

Keywords

leprous neuritis, lepromatous leprosy, tuberculoid leprosy, borderline leprosy, Mycobacterium leprae , drug treatment of leprosy, erythema nodosum leprosum

The acid-fast organism Mycobacterium leprae , the cause of leprosy, was the first pathogen conclusively linked to a human disease, a discovery made by Dr. G. Armauer Hansen in 1874. The genome of the organism underwent dramatic “reductive evolution” with loss of the metabolic machinery that other mycobacteria retain. The organism is an obligate intracellular pathogen. Single nucleotide polymorphisms indicate that leprosy originated in East Africa and passed on to Europe and Asia before explorers brought the disease to West Africa. The genome has also been found in ancient remains of the Near East from biblical times.

The number of active cases in the world has fallen dramatically from 10 to 20 million in 1970 to under 200,000 in 2012 because patients are now rapidly classified as “cured” with brief courses of multidrug therapy (MDT). The long-term validity of this encouraging trend, however, relies on the assumption that the relapse rate will be very low. No corresponding drop in incidence has yet occurred, but the hope of the World Health Organization program is to eliminate leprosy by effecting a critical decrease in infectious bacteria within the population.

The leprosy bacillus is unique in two important ways. First, it is the only bacterial pathogen that regularly invades peripheral nerves. The molecular biology underlying this neurotropism of M. leprae is unique among bacteria. An α-dystroglycan in the G domain of the α ₂chain of laminin in the basal lamina of the Schwann cell–axon unit is a specific binding target for M. leprae. After entering the Schwann cell, the organism commandeers the MEK kinase cascade, causing proliferation of more potential victim Schwann cells. Macrophages are the other major target cell.

Second, M. leprae multiplies at temperatures that are 7° to 10°C lower than the core body temperature of 37°C. These two factors account for several important clinical features of the disease. All patients with leprosy have some degree of nerve involvement, making leprous neuritis a significant cause of treatable neuropathy in the world. Visible deformities from involvement of facial structures, eyes, nerves, bones, and skin result in stigmatization and social ostracism. The diagnosis of leprosy is often missed by physicians, leading to a delay in treatment during which progressive neuropathy, visual loss, and deformity may occur.

General Manifestations

Leprosy may be spread by aerosol or rarely by skin-to-skin contact; fortunately, more than 95 percent of individuals are naturally immune. Animal reservoirs have been found in chimpanzee, sooty mangaby, cynomolgus macaque, and armadillo. In susceptible patients, the organisms rapidly gain access to cooler dermal tissues, primarily cutaneous and subcutaneous nerves and nerve networks, skin appendages, sweat glands, and erector pili muscles.

Leprosy occurs in three major forms: tuberculoid, borderline, and lepromatous. The type of leprosy that develops depends on the degree of host resistance rather than on the bacterium. There are some genetic variations in M. leprae , but these do not play a role in the severity of the disease, which is the same for all three types.

In patients with high resistance, the leprosy that develops is called tuberculoid (or TT) or paucibacillary. A single patch of skin is involved by a granulomatous infiltrate, often with enlargement of underlying nerve trunks, but systemic dissemination does not occur, bacterial organisms are few, and self-healing is the rule. The skin lesions have raised edges and may have one or more satellite lesions ( Fig. 42-1 ). Within these lesions, nerves are destroyed in an epithelioid granulomatous reaction. Often, a superimposed inflammatory response, known as a reversal reaction, occurs within the lesion either spontaneously or in response to drug treatment. Such a reaction reflects altered immunologic responsiveness by the host to the organism and often results in bacteriologic clearing of the lesions.

In contrast, patients with multibacillary leprosy (called lepromatous or LL) have little or no resistance, and bacilli are disseminated throughout the body through a continuous bacteremia, multiplying to extremely high numbers. There is little histologic evidence of host resistance; histiocytes are literally packed with huge numbers of organisms that proliferate in cool areas of the body: the skin, upper respiratory tract, anterior one-third of the eye, superficial nerves, testes, and other tissues. Beading of corneal nerves may be seen. Although bacilli may be deposited passively in the deeper, and therefore warmer, vital organs, such as the lungs, heart, liver, kidneys, and brain, there is little evidence of bacterial proliferation or pathologic tissue reaction at those sites. Clinically, patients present with skin infiltration, particularly prominent in the cool areas, such as facial promontories, ears, dorsal forearms, legs, nasal mucosa, and scrotum ( Fig. 42-2 ). Biopsy sample examination and skin scrapings of such tissues reveal innumerable acid-fast organisms. Without treatment, lepromatous leprosy continues to progress, eventually leading to severe deformities in most cases. At times spontaneously, but more often in response to antibacterial treatment, a reaction known as erythema nodosum leprosum occurs. Clinically, this is a very severe form of erythema nodosum and is a result of the deposition of antigen-antibody complexes in the walls of small arteries. Erythema nodosum leprosum occurs in areas where large amounts of mycobacterial antigen are present. The resulting inflammatory lesions can be devastating to the cornea and anterior eye, peripheral nerves, testes, and skin, producing multiple painful erythematous nodules ( Fig. 42-3 ), leading to frank ulceration in some cases. During the course of erythema nodosum leprosum, iritis, neuritis, and orchitis occur and may be more damaging than the underlying leprosy itself. Erythema nodosum leprosum is a complex immunologic reaction occurring with the production of cytokines such as tumor necrosis factor α (TNF-α). It is ironic that the circulating antibodies to mycobacterial antigen, constituting the host’s only immunologic responsiveness to the offending organism, appear not to benefit the host, but paradoxically to result in additional tissue damage.

In the third type of leprosy, called borderline leprosy (or BB), a variable spectrum of disease occurs, depending on the degree of host resistance. In patients having low resistance, the disease resembles lepromatous disease (BL), whereas in those with higher resistance it resembles tuberculoid disease (BT). Patients with borderline leprosy have less skin involvement than those with lepromatous disease and may have more circumscribed skin lesions, but they have more skin lesions than patients with tuberculoid disease ( Fig. 42-4 ). A form of “pure neuritic” leprosy occurs without visible skin lesions. Since few mycobacteria may be present, the diagnosis is confirmed by immunohistochemical techniques. Increasingly in leprosy work, the terms paucibacillary and multibacillary are used in an attempt to simplify disease classifications and treatment decisions.

In the spectrum of borderline leprosy, immunity may change, with patients worsening, their disease becoming more like lepromatous (BL) disease (downgrading reaction), or evolving more toward the tuberculoid (BT) form (reversal reaction). Such shifts in the spectrum of disease may occur spontaneously or in response to drug treatment or intercurrent medical conditions, such as underlying neoplasms or secondary infections. Considering the extent of infection with human immunodeficiency virus (HIV) in leprosy-endemic areas, it is fortunate that no increase in leprosy has been associated with acquired immunodeficiency syndrome (AIDS), which may, however, precipitate reversal or downgrading reactions in leprosy patients. CD8 ⁺T cells are implicated in triggering reversal reaction in HIV/ leprosy patients.

Neuropathology

In tuberculoid leprosy, the few organisms present in peripheral nerves evoke a strong granulomatous response with early and severe nerve damage, fortunately limited to the few nerves involved. In lepromatous leprosy, the overwhelming majority of organisms are present in Schwann cells ( Fig. 42-5 ), but neuropathologic and electrophysiologic data indicate that there is substantial axonal destruction, and some of the demyelinating lesions themselves may be secondary to axonal changes. Complex immunologic parasite–host interactions are gradually emerging as the basis for nerve damage.

In addition to the damage to nerves caused by the invasion of M. leprae , there are several types of leprosy reactions in which there is a sudden and often sustained increase in immune response to bacilli or products released by dead bacilli. Erythema nodosum leprosum occurs only in multibacillary leprosy and appears to be a clinical example of the Arthus phenomenon, with consumption of complement and an intense vasculitis. The vasculitis is most severe in the regions of greatest bacterial density and therefore may result in a devastating acute neuritis. There is a high amount of TNF-α in the blood with debilitating systemic symptoms. Although the nerve lesions of leprosy tend to be permanent, prompt treatment of reactions may improve neurologic deficits. It is also unclear to what extent or by what mechanisms erythema nodosum leprosum produces nerve damage, but it is likely that cytokines released by immunocompetent cells are important. Exogenous interferon-γ (IFN-γ) used in an attempt to treat leprosy has caused erythema nodosum leprosum in patients, who then have increased release of TNF. Thalidomide, which controls erythema nodosum leprosum, reduces TNF secretion. Thalidomide also reduces elevated numbers of CD4 ⁺lymphocytes in the blood of patients with erythema nodosum leprosum. During erythema nodosum leprosum, there is a loss of suppressor cell function and an increase in interleukin-2 (IL-2) production. Cyclosporine suppresses erythema nodosum leprosum and restores suppressor cell activity, possibly by its effect on macrophages. Infliximab, a monoclonal antibody that inhibits the production of TNF-α, has reportedly suppressed erythema nodosum leprosum in a patient in whom corticosteroid and thalidomide therapy had failed. ^.

In the higher-resistance tuberculoid and borderline cases, reactions are related to increase in tissue-mediated immune factors. There is infiltration of the lesions with IFN-γ and CD4 lymphocytes producing TNF-α, which causes local redness, swelling, and rapid loss of function in any nerve coursing through the lesion.

Leprous Neuritis

A meticulous neurologic examination yields definitive diagnostic information of this treatable neuropathy. The diagnosis is based on the recognition of two interplaying themes that, although they produce limitless combinations in individual cases, capture the unique nature of this neuropathy once they are discerned. Both of these themes rest on the fact that M. leprae is the only bacterium that consistently invades peripheral nerves.

The first of the two diagnostic themes is based on the biologic feature that M. leprae has a highly thermosensitive growth rate that is optimal at 27° to 30°C. The organism does not reproduce at all at core body temperature. This feature limits leprosy to involvement of only superficial nerves. The distinction between the “superficial” neuropathy of leprosy and a distal polyneuropathy is vital for correct diagnosis. This has been a source of confusion because long nerves tend to innervate cooler parts of the body. In leprosy, nerve damage is limited to intracutaneous nerve endings and networks and to the named nerves of gross anatomy at certain segments along their length where they course closest to the cooler surface of the body. Since M. leprae cannot proliferate at core body temperature, peripheral nerves that are situated in deep tissues under or close to muscles, nerve roots, and the central nervous system (CNS) are not actively involved.

The second diagnostic theme relates to host factors that determine the immune resistance to the invasion and proliferation of bacilli. This host resistance has resulted in the classification of leprosy into the three subtypes mentioned earlier and is the other major determinant of the clinical features including nerve damage.

In a study of Chinese patients with leprosy, a genetic basis for vulnerability to infection by M. leprae was found involving 93 single-nucleotide polymorphisms in five genes ( CCDC122 , C13orf31 , TNFSF15 , HLA-DR , and RIPK2 ). An additional polymorphism in the LRRK2 gene was associated with the multibacillary form of leprosy. HLA-DR allows M. leprae antigen to contact and activate CD4 lymphocytes.

Leprosy bacilli are intracellular human pathogens with very limited growth in animals with the exception of the armadillo, and they do not grow in culture. Examination of the genome of M. leprae has shown great stability so that the large variation in clinical features of the disease must depend upon host factors. Populations vary widely in vulnerability to the infection and even in the frequency of the various subtypes, presumably because of underlying genetic differences in human hosts.

Lepromatous Leprosy

There is very little evidence of tissue-mediated immune responses to M. leprae in lepromatous leprosy, and lepromin skin testing is negative. The organism proliferates most rapidly in the coolest tissues, and there is a constant blood-stream dissemination of organisms. In untreated cases, this type of leprosy becomes widespread and symmetric within superficial tissues and may involve large areas of the skin, the anterior chamber of the eye, the upper respiratory tract, and the testes, as well as superficial nerves. Sensory loss is largely due to destruction of intracutaneous nerve endings and first appears in cool areas, such as the dorsal surfaces of the hands, dorsomedial surfaces of the forearms, dorsal surfaces of the feet, and ventrolateral aspects of the legs, as well as in the pinnae of the ears, especially the helices and earlobes ( Fig. 42-6 ). The tip of the nose, malar areas, and buttocks are often the next to show intracutaneous sensory loss ( Fig. 42-7 ). There is a stage with sparing of the soles of the feet and palms of the hands, which may be due in part to the insulating effect of the thickened corium in these areas. If the patient is examined at the right stage, a distinct change in sensation at the cuticular border can sometimes be found in the hands or feet. When the intracutaneous pattern has evolved to this point, nerve trunk deficits supervene. Involvement of a 10- to 15-cm segment of the ulnar nerve proximal to the olecranon groove is most common, but the segment just proximal to the wrist may also be affected. Further paralysis is seen with damage to (1) the median nerve in the segment where it assumes a superficial position just proximal to the transverse carpal ligament ( Fig. 42-8 ), (2) the fibular (peroneal) nerve where it courses around the fibular head, (3) the branch of the fibular nerve to the extensor digitorum brevis, and (4) the posterior tibial nerve at the level of the ankle. There is also a unique patchy involvement of the most superficial facial nerve twigs, causing lagophthalmos and paralysis of some segments of the orbicularis oris and of the medial aspects of the corrugators of the forehead.