Mycobacterium leprae in neurons of the medulla oblongata and spinal cord in leprosy.

Peripheral neuropathy has been extensively studied in leprosy, a chronic disease caused by Mycobacterium leprae, but the central nervous system (CNS) is thought to be free from bacilli. Involvement of the CNS was explored in autopsy cases of clinically cured lepromatous leprosy (n = 67) and in non-leprosy cases (n = 15). Paraffin sections of the medulla oblongata and spinal cord were subjected to hematoxylin and eosin staining, Fite acid-fast staining, and anti-phenolic glycolipid-I (PGL-I) immunostaining. PGL-I-positive areas were microdissected from selected cases and nested polymerase chain reaction (PCR) targeting the M. leprae-specific repetitive sequence was performed. Of the 67 cases of leprosy, 44 (67%) had vacuolar changes of motor neurons either in medulla oblongata (nucleus ambiguous or hypoglossal nucleus) or spinal cord. Fite staining was negative, but PGL-I was positive in vacuolated areas. PCR revealed M. leprae-specific genomic DNA in 18 of 19 cases (95%) with vacuolated changes and 5 of 8 (63%) without vacuolated changes. All of above findings were negative in control cases. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining did not show a significant increase of apoptosis in the neurons. The PCR positivity had a significant correlation with PGL-I immunostaining (p < 0.05). The presence of vacuolar changes in the spinal cord was correlated with hand and feet deformity grades (p = 0.04). This study provides significant additional evidence to indicate that M. leprae is present in the CNS in a subset of patients. Further investigation is required to correlate this finding to motor dysfunction and silent neuropathy in leprosy.

Nerve damage in Mycobacterium ulcerans-infected mice: probable cause of painlessness in buruli ulcer.

Buruli ulcer is an emerging chronic painless skin disease found in the tropics and caused by Mycobacterium ulcerans; however, it remains unknown why the large and deep ulcers associated with this disease remain painless. To answer this question, we examined the pathology of BALB/c mice inoculated in the footpads with M. ulcerans African strain 97-107. On days 54 to 70 after inoculation, extensive dermal ulcers, subcutaneous edema, and numerous acid-fast bacilli were noted at the inoculate region. Nerve invasion occurred in the perineurium and extended to the endoneurium, and some nerve bundles were swollen and massively invaded by acid-fast bacilli. However, Schwann cell invasion, a characteristic of leprosy, was not observed. Vacuolar degeneration of myelin-forming Schwann cells was noted in some nerves which may be induced by mycolactone, a toxic lipid produced by M. ulcerans. Polymerase chain reaction analysis of microdissected nerve tissue sections showed positive amplification of M. ulcerans-specific genomic sequences but not of Mycobacterium leprae-specific sequences. Behavioral tests showed decrease of pain until edematous stage, but markedly ulcerated animals showed ordinary response against stimulation. Our study suggests that the painlessness of the disease may be partly due to intraneural invasion of bacilli. Further studies of nerve invasion in clinical samples are urgently needed.

Cured tuberculoid patients have a greater life expectancy than cured lepromatous patients in Japan.

Leprosy patients lack specific cellular immunity against Mycobacterium leprae, but other immunological functions are thought to be preserved. However, in a leprosy sanatorium in South Japan between 1982 and 2000, we found that the average age at death of cured lepromatous leprosy patients was about 5 yrs younger than that of cured tuberculoid patients; [male/lepromatous, 76.0 +/- 10.0 yrs old vs. male/tuberculoid, 79.7 +/- 9.4 yrs old, p = 0.026], and [female/lepromatous, 78.0 +/- 10.5 vs. female/tuberculoid, 85.3 +/- 9.8, p = 0.0001]. This trend was also observed in autopsy records of two other leprosy sanatoria in Japan. In a prospective study based on their age in 1982, among females in the age group between 60 and 69, lepromatous patients (75.3 +/- 6.0 yrs) died earlier than tuberculoid patients (81.0 +/- 5.1 yrs) (p < 0.01). These findings suggest that lepromatous patients have higher risk of death even in a post-chemotherapy era.