Histological changes in the nerve, skin and nasal mucosa of patients with primary neuritic leprosy.

Primary neuritic leprosy (PNL) presents as a peripheral neuropathy with no visible skin patches and skin smears negative for acid fast bacilli. The pathogenesis of PNL is poorly understood. The aim of the study was to document the histological changes in the nerve, apparently normal skin and nasal mucosa in PNL and to study its significance to the pathogenesis of leprosy lesions. The study is based on a cohort of 208 PNL patients registered at the Schieffelin Leprosy Research and Training Centre, Karigiri. All patients had a nerve biopsy, 196 had a skin biopsy and 39 had a nasal mucosal biopsy. The findings reveal that PNL patients exhibit a spectrum of disease histologically in the nerve ranging from lepromatous to tuberculoid leprosy with a significant proportion (46%) manifesting a multibacillary leprosy histology. Findings in the apparently normal skin and nasal mucosa reveal that there are widespread changes due to leprosy in tissues such as the skin and nasal mucosa even when the disease appears clinically confined to a few nerves. PNL may be an early stage in the pathogenesis of the disease before the appearance of skin lesions. The number of nerves enlarged and lepromin status did not give any clue to the nature of underlying disease.

Histological studies in primary neuritic leprosy: changes in the nasal mucosa.

The nasal mucosae of 39 cases of primary neuritic leprosy (PNL) registered at Karigiri were studied histologically to determine nasal mucosal involvement in PNL and its relevance to the pathogenesis of the disease. Specific changes of leprosy were seen in 20 (51%) biopsies, ranging from macrophage granulomas with acid fast bacilli, to epithelioid granulomas and nerve inflammation. The remaining biopsies revealed chronic inflammatory changes of the mucosa or mild non-specific nerve changes. These findings show that there are widespread effects of the disease even in PNL patients in whom the disease is believed to be confined to the peripheral nerves. The findings also show that early leprosy involvement can be found in the nasal mucosa even before lesions become apparent in the skin or other parts of the body. The nasal mucosa could be one of the sites for the primary lesion in leprosy. Clinical and histological examination of the nasal mucosa may be useful and important in the early diagnosis of leprosy and especially in contacts.

Histological studies in primary neuritic leprosy: changes in the apparently normal skin.

The visually normal skin of 196 patients diagnosed clinically to have primary neuritic leprosy was studied histologically to determine whether there were any specific changes due to the disease in this site. Histological changes due to leprosy were seen in 32.1% of the patients, and included, indeterminate leprosy in 19.4%, borderline tuberculoid leprosy in 6.6% and borderline lepromatous leprosy in 6.1%. The remaining biopsies showed mild non-specific dermal inflammation, mild nerve changes or no significant lesion. The nerve inflammation and/or granulomas were mostly in the deep dermal nerves or neurovascular complexes. This study shows that there is a cutaneous component to primary neuritic leprosy and the disease is not totally confined to nerves. The absence of visible hypopigmented patches in these patients is probably related to the deep location of the dermal inflammation.

Rifampin in drug-incorporated diet: effect of duration and temperature of storage. Relevance to drug-susceptibility testing in mice inoculated with M. leprae.

This paper is in two parts. Plasma concentrations of rifampin were assayed at 11 time points in 24 hr in mice fed one of three dosages of rifampin, either by gavage or by dietary incorporation. The drug-mixed diets had been stored for a maximum of 3 weeks at 4 degrees C or at room temperature (30 degrees C-35 degrees C). The peak concentration of rifampin produced by gavage was approximately 11/2 times higher than the maximum plasma concentration of the corresponding dosage in fresh diet. Plasma concentrations decreased with the increasing duration of storage of the drug-mixed diet, irrespective of whether the diet was stored at 4 degrees C or at room temperature. This decrease was less when the diet was stored at 4 degrees C than at room temperature. Drug levels were also assayed in another set of mice selected from ongoing drug-susceptibility experiments; these mice were fed a rifampin-incorporated diet stored at room temperature. The plasma concentrations in these mice, assayed at the time of foot pad harvest, were generally higher than in the 24-hr experiment. The harvest results from these mice were compared with the harvest results from a third set of mice, also from ongoing drug-susceptibility experiments, but fed a rifampin-mixed diet stored at 4 degrees C. Multiplication of Mycobacterium leprae in mouse foot pads was prevented by rifampin mixed in the diet at a dosage of greater than or equal to 0.003%, whether stored at room temperature or at 4 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Reactional states in the nasal mucosa: a clinical and histopathological study.

Twenty leprosy patients in the reactive phase of the disease were studied clinically and histologically for evidence of reactive lesions in the nasal mucosa. Ten of 14 patients with erythema nodosum leprosum (ENL) showed characteristic polymorphonuclear leukocytic infiltration and two patients showed vasculitis. The histological changes of reversal reactions in the nasal mucosa, one with upgrading reaction and the other with downgrading reaction, are reported.

An ultrastructural study of dermal nerves in early human leprosy.

Skin biopsies from the cutaneous lesions of seven patients with indeterminate, BT, BL, and LL leprosy of less than 1 year's duration were examined by light and electron microscopy. Inflammatory cells, which marked the location of Mycobacterium leprae in bacilliferous cases (BL and LL) were most frequently and consistently found in relation to dermal blood vessels, neurovascular bundles, nerves, arrector pili muscles, and skin adnexa. The number of bacilli and inflammatory cells in the epineurium was in great excess of those in the perineurium and endoneurium. Perineurial infiltration by lymphocytes and bacillated macrophages was seen to occur through gaps between the constituent cells of a loosened and sometimes proliferated perineurium. Bacillation of Schwann cells and associated inflammation in the endoneurium was minimal. M. leprae were identified in endothelial cells, arrector pili muscles, macrophages and Schwann cells. At this stage, inflammatory destruction of nerve fibers was not encountered. It is concluded that M. leprae which are extruded from the circulation into the epineurium (or perineurium) may be carried in inflammatory cells across the perineurium which is loosened and rendered permeable to inflammatory cells as a consequence of chronic inflammation in the adjacent epineurium. This is suggested as a very probable route for M. leprae to enter nerves.

Relapse rates in lepromatous leprosy according to treatment regularity.

In Gudiyatham Taluk, South India, 1008 lepromatous (LL) and borderline lepromatous (BL) patients were studied. They had previously been smear positive, had attained smear negativity, and continued on DDS monotherapy. "Relapse" was defined as the reappearance of Mycobacterium leprae in skin smears. The area is endemic for leprosy. The lower relapse rates in the first three years of smear negativity alone were associated with more-regular treatment during both past smear positivity and smear negativity. From the fourth year of smear negativity onward, only the more-regular treatment during smear negativity was associated with lower relapse rates; whereas patients with more-regular treatment during past smear positivity had no lower risk of relapse than those with less-regular treatment. The finding that regularity of treatment during smear positivity seems to have no effect on relapse rates beyond the third year of smear negativity is discussed. In a leprosy-endemic area, it is argued that beyond the first three years of smear negativity in an LL or BL patient, sources of M. leprae outside the patient may be more responsible for relapse than the patient's own bacilli.

An ultrastructural study of the response of traumatized rabbit tibial nerve to epineurial infection with Mycobacterium leprae.

Crushed rabbit tibial nerves were inoculated with a suspension of living Mycobacterium leprae at and just distal to the site of nerve trauma. The resulting changes occurring over a period of time from 40 min to 72 hr post-inoculation were studied electron microscopically. Bacilli were seen in perineurial cells and in macrophages that had infiltrated the perineurium adjacent to epineurial deposits of M. leprae. It is suggested that trauma may weaken the perineurial barrier and facilitate the transperineurial passage of phagocytes, some of which may be laden with M. leprae, and may thus be a means whereby M. leprae enter the endoneurium of peripheral nerves.

Computerized mathematical model of M. leprae population dynamics during multiple drug therapy.

A computerized mathematical model of M. leprae populations during multiple drug therapy (MDT) was constructed. Relevant published information available to date was fed into it, and reasoned assumptions were made. From the model, it seems likely that MDT steadily selects bacteria resistant to the most powerful of the three drugs used: unless the individual bactericidal potencies of the drugs balance one another. If the drugs used have differing potencies, cure probably hinges on treatment being continued until all metabolically active bacteria are killed. Withdrawal of treatment before that could lead to relapse with bacteria resistant to the most powerful of the drugs used.

"Drug-resistant proportion test" for M. leprae to quantify the proportion of drug-resistant M. leprae in a sample using the mouse foot pad.

The mouse foot pad test has not previously been used quantitatively to discriminate between samples of Mycobacterium leprae with differing proportions of drug-resistant M. leprae. The "drug-resistant proportion test" is a simple modification of the routine mouse foot pad test. It is demonstrated to distinguish between samples of M. leprae with a tenfold difference in the proportion of dapsone-resistant M. leprae.

The mouse footpad test--sensitive to small proportions of drug-resistant bacilli in a sample of M. leprae.

In experiments at the Radda Barnen Research Laboratories of the SLR & TC Karigiri, the mouse footpad test was demonstrated to detect DDS-resistant M.leprae even if as few as 0.1% (1 in 1000) of the M. leprae tested were DDS-resistant. The mouse footpad test appears to be sensitive to minute proportions of drug-resistant bacilli in samples of M. leprae tested.

DDS-resistant infection among leprosy patients in the population of Gudiyatham Taluk, South India. Part 3. Prevalence, incidence, risk factors, and interpretation of mouse foot pad test results.

At the Schieffelin Leprosy Research and Training Centre, Karigiri, India, a study of the population of Gudiyatham Taluk revealed that the prevalence of dapsone (DDS)-resistant infection among lepromatous (LL) and borderline lepromatous (BL) leprosy patients treated for a minimum of three years was 3.3% (33 per 1000), with an average annual incidence of 0.28% per year. DDS-resistant infection was diagnosed when review of skin smear readings showed a continuing increase in the number of Mycobacterium leprae in successive smears despite adequate DDS treatment. The attainment of smear negativity in an LL or BL patient was found to be a favorable prognostic sign, indicating a reduced risk of DDS-resistant infection. No association was found between the incidence of DDS-resistant infection on the one hand and either the regularity or the initial dosage of DDS treatment on the other. Ninety-five (88.0%) out of 108 successful mouse foot pad tests on patients with a Bacterial Index (BI) greater than or equal to 2+ detected DDS-resistant M. leprae. The mouse test detected bacilli resistant to 0.01% w/w DDS in mouse diet not only among patients deteriorating despite adequate DDS monotherapy, but also among patients improving on DDS monotherapy. Since the mouse test as presently used does not measure the proportion of M. leprae in a sample that are resistant to DDS, the detection of DDS-resistant bacilli in the mouse test may not always indicate that the patient will fail to respond to DDS monotherapy.

The significance of dapsone (DDS)-resistant Mycobacterium leprae in untreated patients.

In a stable rural population of South India, 18 consecutive untreated persons newly discovered to have leprosy with a Bacterial Index (BI) greater than or equal to 2+ were tested for Mycobacterium leprae resistant to dapsone (DDS) by the mouse foot pad test. Of 12 successful tests, five detected resistant M. leprae. Known contact with a treated patient in the ten years preceding the diagnosis of leprosy was not found to increase the risk of DDS-resistant M. leprae occurring in an untreated, newly diagnosed patient. This data is consistent with the bulk of evidence in the field of bacteriology, which makes it seem unlikely that treated patients are the only source, or even the major source, of resistant M. leprae in untreated patients. Bacterial mutants resistant to a drug have been shown to precede initial use of the drug. Tests for drug-resistant bacteria in untreated patients before a drug is widely used in a community are likely to be important for subsequent evaluation of resistance to the drug in that community.

Response to dapsone (DDS) monotherapy in leprosy patients of Gudiyatham Taluk, South India: comparison between the 1960s and the 1970s.

At the Schieffelin Leprosy Research and Training Centre, Karagiri, India, 148 lepromatous (LL) and borderline lepromatous (BL) leprosy patients registered for treatment in the years 1971 to 1973 were found to respond as well to dapsone (DDS) monotherapy as 391 LL and BL patients registered in 1964 to 1966, as indicated by clearance of Mycobacterium leprae from skin smears during the initial seven years of therapy in each patient. Apparently, the efficacy of DDS monotherapy has not been progressively diminishing since the introduction of DDS monotherapy into the area.