Neural Leprosy Research Articles

Isolated median neuropathy as the first symptom of leprosy

Focal peripheral neuropathy of the median nerve is mainly caused by a traumatic event or pressure, but it may also be produced by systemic illnesses. Among the latter, leprosy is a rare cause. Six cases of isolated median neuropathy as the first sign of leprosy were selected from patients with an exclusively neurological complaint as the initial symptom. The patients, evaluated at the National Leprosy Reference Center in Rio de Janeiro, Brazil, followed routine and specialized procedures. Three of the patients had pure neural leprosy, and 3 had skin lesions. Clinical median nerve function impairment was confirmed by neurophysiological testing and histopathology. Both mononeuritis and mononeuritis multiplex were observed. This case series demonstrates an additional form of presentation of leprosy, which, if not diagnosed and treated in time, may lead to permanent disability.

Extensive Ulnar Nerve Necrosis: A Complication of Tuberculoid Leprosy

Pure neural leprosy without cutaneous manifestations is a relatively rare manifestation of leprosy. It can present as a mono- or poly-neuritis with sensory and/or motor impairment. Neural leprosy may or may not be associated with thickening of the involved nerve. We report the case of a 14 year old boy with extensive ulnar nerve necrosis who was diagnosed to have tuberculoid leprosy. What makes this case unique is that we have here a case of pure neural leprosy with a single nerve turned 'necrotic'.

Estimation of serum level of interleukin-17 and interleukin-4 in leprosy, towards more understanding of leprosy immunopathogenesis

Combating Mycobacterium leprae is known to be via T-helper1 response. However, other T-helper effector cells; T-helper17 and T-helper2; play a role, particularly in the context of disease type. We aimed to evaluate serum levels of interleukin (IL)-17 (T-helper17 cytokine) and IL-4 (T-helper2 cytokine) in untreated patients with different types of leprosy, compared to controls. Using enzyme-linked immunosorbent assay, serum IL-17 and IL-4 levels were estimated in 43 leprotic patients and 43 controls. Patients were divided into six groups; tuberculoid, borderline cases, lepromatous, erythema nodosum leprosum (ENL), type 1 reactional leprosy, and pure neural leprosy. Patients were also categorized according to bacillary load and the presence or absence of reactions. Serum IL-17 was significantly lower in cases (4-61.5 pg/mL; median 19), compared to controls (26-55 pg/mL; median 36) (P < 0.001), and was significantly lower in each type of leprosy compared to controls, with the lowest level in lepromatous leprosy (4-61.5 pg/mL; median 12.5). Significantly elevated serum IL-4 was found in patients (1.31-122.4 pg/mL; median 2.31) compared to controls (1.45-5.72 pg/mL; median 2.02) (P = 0.008), with the highest level among lepromatous leprosy patients (2-87.2 pg/mL; median 28.9), and the lowest in type 1 reactional leprosy (1.4-2.5 pg/mL; median 1.87) (P = 0.006). Defective secretion of IL-17 is related to disease acquisition as well as progression toward lepromatous pole in leprosy patients. The overproduction of IL-4 in patients with lepromatous leprosy may infer their liability to develop ENL. Nevertheless, the small number of the studied population is a limitation.

Interesting and unusual clinical presentations in leprosy at a referral center

Background:Leprosy is a disease of declining global endemicity but is still an important health-care problem in India. Pure neural leprosy is an important subset of presentations of leprosy in India. Leprosy is a known disease of the skin and nerves, but cases of pure neural involvement are relatively less. We hereby present 10 cases of pure neural leprosy in which the diagnosis of leprosy was difficult with routine methods.Materials and Methods:The study was conducted at the main referral center and satellite clinics of our organization. A retrospective analysis of patient records for the last four years was undertaken to identify patients presenting with predominantly neurological manifestations and uncommon presentations including those without skin lesions. The medical records of the patients were used as source of data. All the patients were subjected to a detailed clinical examination and bacteriological examination with slit-skin smears. Investigations like nerve biopsy, electromyography, and nerve conduction studies were done in patients with diagnostic difficulties.Results:Patients presented with neurological symptoms like paresthesias (60%), diminished sensations (40%), nonhealing ulcers (30%), and blisters (20%). All except one had thickened nerves on clinical examination. Slit-skin smear was negative in all but one patient. Nerve biopsy confirmed the diagnosis of leprosy in seven cases.Conclusion:Pure neural leprosy is difficult to diagnose with routine methods. The diagnosis should be considered, especially by neurologists and dermatologists, who are more likely to see such patients with predominant neural manifestations. The diagnosis should be confirmed with nerve biopsy to prevent delay in therapy and associated complications.

Use of fine needle aspirate from peripheral nerves of pure-neural leprosy for cytology and PCR to confirm the diagnosis: A pilot study

The diagnosis of pure neural leprosy (PNL) remained subjective because of over-dependence of clinical expertise and a lack of simple yet reliable diagnostic tool. The criteria for diagnosis, proposed by Jardim et al., are not routinely done by clinicians in developing country as it involves invasive nerve biopsy and sophisticated anti-PGL-1 detection. We conducted a study using fine needle aspiration cytology (FNAC) coupled with Ziehl Neelsen staining (ZN staining) and Multiplex-Polymerase Chain Reaction (PCR) specific for M. leprae for an objective diagnosis of pure neural leprosy (PNL), which may be simpler and yet reliable. The aim of the study is to couple FNAC with ZN staining and multiplex PCR to diagnose pure neural leprosy patients rapidly, in simpler and yet reliable way. Thirteen patients of PNL as diagnosed by two independent consultants were included as case, and 5 patients other than PNL were taken as control in the study. Fine needle aspiration was done on the affected nerve, and aspirates were evaluated for cytology, ZN staining and multiplex-PCR. Out of the 13 cases where fine needle aspiration was done, M. leprae could be elicited in the nerve tissue aspirates in 5 cases (38.4%) with the help of conventional acid-fast staining and 11 cases (84.6%) with the help of multiplex PCR. On cytological examination of the aspirates, only 3 (23%) cases showed specific epithelioid cells, whereas 8 (61.5%) cases showed non-specific inflammation, and 2 (15.3%) cases had no inflammatory cells. Our study demonstrates that in the field of laboratory diagnosis of PNL cases, FNAC in combination with ZN staining for acid-fast bacilli (AFB) and Multiplex-PCR can provide a rapid and definitive diagnosis for the majority of PNL cases. FNAC is a less-invasive, outdoor-based and simpler technique than invasive nerve biopsy procedure. Thus, this study may enlighten the future path for easy and reliable diagnosis of PNL.

Pure Neural Leprosy: Clinical and Electrophysiologic Features of Patients Evaluated in a Brazilian Tertiary Centre of Neuromuscular Diseases (S07.004)

Pure Neural Leprosy: Clinical and Electrophysiologic Features of Patients Evaluated in a Brazilian Tertiary Centre of Neuromuscular Diseases (S07.004)

Histopathological examination of nerve samples from pure neural leprosy patients: obtaining maximum information to improve diagnostic efficiency

Nerve biopsy examination is an important auxiliary procedure for diagnosing pure neural leprosy (PNL). When acid-fast bacilli (AFB) are not detected in the nerve sample, the value of other nonspecific histological alterations should be considered along with pertinent clinical, electroneuromyographical and laboratory data (the detection of Mycobacterium leprae DNA with polymerase chain reaction and the detection of serum anti-phenolic glycolipid 1 antibodies) to support a possible or probable PNL diagnosis. Three hundred forty nerve samples [144 from PNL patients and 196 from patients with non-leprosy peripheral neuropathies (NLN)] were examined. Both AFB-negative and AFB-positive PNL samples had more frequent histopathological alterations (epithelioid granulomas, mononuclear infiltrates, fibrosis, perineurial and subperineurial oedema and decreased numbers of myelinated fibres) than the NLN group. Multivariate analysis revealed that independently, mononuclear infiltrate and perineurial fibrosis were more common in the PNL group and were able to correctly classify AFB-negative PNL samples. These results indicate that even in the absence of AFB, these histopathological nerve alterations may justify a PNL diagnosis when observed in conjunction with pertinent clinical, epidemiological and laboratory data.

Microfasciculation: a morphological pattern in leprosy nerve damage

To study Microfasciculation, a perineurial response found in neuropathies, emphasizing its frequency, detailed morphological characteristics and biological significance in pure neural leprosy (PNL), post-treatment leprosy neuropathy (PTLN) and non-leprosy neuropathies (NLN). Morphological characteristics of microfascicles were examined via histological staining methods, immunohistochemical expression of neural markers and transmission electronmicroscopy. The detection of microfasciculation in 18 nerve biopsy specimens [12 PNL, six PTLN but not in the NLN group, was associated strongly with perineurial damage and the presence of a multibacillary inflammatory process in the nerves, particularly in the perineurium. Immunoreactivity to anti-S100 protein, anti-neurofilament, anti-nerve growth receptor and anti-myelin basic protein immunoreactivity was found within microfascicles. Ultrastructural examination of three biopsies showed that fibroblast-perineurial cells were devoid of basement membrane despite perineurial-like NGFr immunoreactivity. Morphological evidence demonstrated that multipotent pericytes from inflammation-activated microvessels could be the origin of fibroblast-perineurial cells. A microfasciculation pattern was found in 10% of leprosy-affected nerves. The microfascicles were composed predominantly of unmyelinated fibres and denervated Schwann cells (SCs) surrounded by fibroblast-perineurial cells. This pattern was found more frequently in leprosy nerves with acid-fast bacilli (AFB) and perineurial damage while undergoing an inflammatory process. Further experimental studies are necessary to elucidate microfascicle formation.

Schwann Cells Producing Matrix Metalloproteinases UnderMycobacterium lepraeStimulation May Play a Role in the Outcome of Leprous Neuropathy

Matrix metalloproteinases (MMPs) mediate demyelination and breakdown of the blood-nerve barrier in peripheral neuropathies. Matrix metalloproteinases and tissue inhibitor of metalloproteinase 1 gene expression and secretion were studied in cells of the human Schwann cell line ST88-14 stimulated with Mycobacterium leprae and tumor necrosis factor (TNF) and in nerve biopsies from patients with neural leprosy (n = 21) and nonleprous controls (n = 3). Mycobacterium leprae and TNF induced upregulation of MMP-2 and MMP-9 and increased secretion of these enzymes in cultured ST88-14 cells. The effects of TNF and M. leprae were synergistic, and anti-TNF antibody blockage partially inhibited this synergistic effect. Nerves with inflammatory infiltrates and fibrosis displayed higher TNF, MMP-2, and MMP-9 mRNA than controls. Leprous nerve biopsies with no inflammatory alterations also exhibited higher MMP-2 and MMP-9; tissue inhibitor of metalloproteinase 1 was significantly higher in biopsies with fibrosis and inflammation. Immunohistochemical double labeling of the nerves demonstrated that the MMPs were mainly expressed by macrophages and Schwann cells. The biopsies with endoneurial inflammatory infiltrates and epithelioid granulomas had the highest levels of MMP-2 and MMP-9 mRNA detected. Together, these results suggest that M. leprae and TNF may directly induce Schwann cells to upregulate and secrete MMPs regardless of the extent of inflammation in leprous neuropathy.

Ulnar neuropathy as a first sign of HIV infection: a diagnostic challenge for leprosy endemic countries

Mycobacterium leprae and HIV are two infectious agents capable of infecting peripheral nerves and, as a result, inducing peripheral neuropathy. In leprosy endemic countries, more refined diagnostic procedures than are currently available are urgently needed to accurately a differential diagnosis between the peripheral neuropathies presenting in both HIV and leprosy since mononeuropathy simplex and multiplex as well as polyneuropathy are known to occur in both diseases (Jardim et al., 2003). Pure neural leprosy (PNL), for example, presents a particularly difficult diagnostic challenge. PNL patients have nerve deficit and/or enlargement of peripheral nerves with or without tenderness in the absence of any sign of skin disease or history of skin patches (Talwar et al., 1992). In this study, the case of a seropositive HIV patient admitted to our Leprosy Outpatient Clinic under suspicion of leprosy neuropathy is described.

Pure neural leprosy: steroids prevent neuropathy progression

Multidrug therapy (MDT), with rifampicin, dapsone, and clofazimine, treats leprosy infection but is insufficient in arresting or preventing the nerve damage that causes impairments and disabilities. This case-series study evaluates the benefits of the combined use of steroids and MDT in preventing nerve damage in patients with pure neural leprosy (PNL). In addition to MDT, 24 patients (88% male aged 20-79 years, median=41) received a daily morning dose of 60 mg prednisone (PDN) that was gradually reduced by 10 mg during each of the following 5 months. PNL was clinically diagnosed and confirmed by nerve histopathology or PCR. A low prevalence (8.3%) of reaction was observed after release from treatment. However, most of the clinical parameters showed significant improvement; and a reduction of nerve conduction block was observed in 42% of the patients. The administration of full-dose PDN improved the clinical and electrophysiological condition of the PNL patients, contributing to the prevention of further neurological damage.

Pure neural leprosy: Diagnostic value of the polymerase chain reaction

Pure neural leprosy (PNL) is often difficult to diagnose when acid-fast bacilli (AFB) cannot be detected. We undertook the present study to evaluate use of the polymerase chain reaction (PCR) in diagnosing PNL. Fifty-eight patients (41 men and 17 women) suspected of pure neural leprosy (PNL) were examined. Patients were classified as borderline tuberculoid (BT, 40 cases) and polar tuberculoid (TT, 18 cases) types. Nerve biopsy was performed and was positive for AFB in 20 patients (all BT patients), i.e., 34.5% of total cases. DNA was extracted from the nerve biopsy samples and amplified using PCR for a specific repeated sequence of DNA from Mycobacterium leprae. PCR analysis was positive in the nerve samples from 29 patients (50%), 27 of the BT type, and 2 of the TT type patients. Further, PCR analysis was positive in 14 of 38 cases that were negative for AFB by nerve biopsy, of which 12 were of the BT type and 2 the TT type. PCR analysis proved to be a useful method to investigate pure neural leprosy, enabling confirmation of the diagnosis in more than a third of the cases that were negative for AFB by nerve biopsy.

Role of PGL-I antibody detection in the diagnosis of pure neural leprosy

Pure neural leprosy (PNL) is difficult to diagnose because skin lesions and acid-fast bacilli (AFB) in slit smears are absent. At present, the gold standard for PNL diagnosis is the histopathological examination of a peripheral nerve biopsy. Even so, detection of bacteria is difficult and histological findings may be non-specific. Furthermore, nerve biopsy is an invasive procedure that is only possible in specialized centres. Therefore, there is a need for additional diagnostic methods that may help to confirm the clinical diagnosis of PNL. In the present study, an additional laboratory test, the ELISA for anti-phenolic glycolipid I (PGL-I) IgM antibodies, was performed on 103 individuals with clinical and neurophysiological signs of peripheral neuropathy, of which 67 were diagnosed as PNL patients and 36 remained as 'not diagnosed as PNL', as well as on a control group of 34 patients with other neurological diseases. An antibody response was present in 14/67 (21%) of the patients diagnosed as PNL as compared with 3/34 (9%) of controls. Anti-PGL-I positivity was observed in 5/8 (63%) of the AFB positive cases. Patients whose diagnosis was confirmed solely by Mycobacterium leprae PCR on the nerve sample had 4/25 (16%) seropositivity. In addition, anti-PGL-I antibodies were detected in 9/40 (23%) of the PNL patients who were PCR negative for M. leprae DNA. Moreover, two patients who showed clinical and eletrophysiological manifestations suggestive of PNL were diagnosed with the help of their positive test results in the anti-PGL-I ELISA. In conclusion, detection of antibodies against PGL-I in patients with peripheral neuropathy is useful as an additional laboratory test to help PNL diagnosis.

Clinical and diagnostic aspects of the primarily neural leprosy

A total of 33 patients, 28 males and five females, from nine to 87 years of age, wi th suspec ted leprosy associated peripheral neuropathy, without detectable skin lesion or positive skin bacilloscopy, were studied during the period of 1994 to 2004. Patients were s u bmi t t e d t o d e rma t o l o g i c a l a n d n e u r o l o g i c a l examination, electrophysiologic tests, Mitsuda reaction and nerve biopsy. Samples for histopathological examswere stained with hematoxillin-eosin, Faraco-Fite and immunohistochemistry with anti -BCG antibodies. Among patients with suspected leprosy, the clinical presentation of polyneuropathy occurred in 17 (51.51%) patients while 13 (39.39%) presented mononeuropathy mu l t ip l ex an d 3 ( 9 .1%) mo n o n e ur op a t hy . T h e hematoxillin-eosin and Faraco-Fite stainings confirmed the leprosy diagnosis in 10 (30.30%) patients. Three patients presented a borderline pattern, two tuberculoidpattern and no characteristic histological pattern was observed in the remaining five patients. The final classification depended on the clinical-histological correlation. Immunohistochemistry increased the diagnosis to 11 (33.33%) cases. Among the remaining 22 patients, three patients had leprosy confirmed increasing the diagnosis to 14 (42.43%) cases. One was clinicallyunderstood as a primarily neural leprosy, probably tuberculoid form of the childhood. From the remaining patients, 19 (57.57%) were excluded during the follow-up. The primarily neural leprosy (PNL) is an unusual leprosy presentation and a complex form to diagnose. The clinical follow-up accompanied by the improvement of histopathological examination of the nerve may add more accuracy to the investigation of the suspected leprosy neuropathies.

Criteria for diagnosis of pure neural leprosy.

The clinical diagnosis of pure neural leprosy (PNL) remains a public health care problem mainly because skin lesions-the cardinal features of leprosy-are always absent.Moreover, the identification of the leprosy bacillus is not easily achieved even when a nerve biopsy can be performed. In an attempt to reach a reliable PNL diagnosis in patients referred to our Leprosy Outpatient Clinic, this study employed a variety of criteria. The nerve biopsies performed on the 67 individuals whose clinical, neurological, and electrophysiological examination findings strongly suggested peripheral neuropathy were submitted to M. leprae identification via a polymerase chain reaction (PCR). Mononeuropathy multiplex was the most frequent clinical and electrophysiological pattern of nerve dysfunction, while sensory impairment occurred in 89% of all cases and motor dysfunction in 81%. Axonal neuropathy was the predominant electrophysiological finding, while the histopathological nerve study showed epithelioid granuloma in 14% of the patients, acid fast bacilli in 16%, and nonspecific inflammatory infiltrate and/or fibrosis in 39%. PCR for M. leprae was positive in 47% of the nerve biopsy samples (n=23). PCR, in conjunction with clinical and neurological examination results, can be a powerful tool in attempting to identify and confirm a PNL diagnosis.

Needle aspiration cytology of the nerve for the diagnosis of pure neural leprosy

Needle aspiration cytology of the nerve for the diagnosis of pure neural leprosy

Experimental leprosy in monkeys. I. Sooty mangabey monkeys: transmission, susceptibility, clinical and pathological findings.

A total of 31 sooty mangabey monkeys (SMM) (Cercocebus torquatus atys) inoculated by various routes with differing numbers of SMM-origin Mycobacterium leprae (ML) and 4 SMM inoculated with human-origin ML were observed for 4-12 years. SMM-origin ML was more pathogenic in SMM than human-origin ML. The spectrum of disease ranged from indeterminate to borderline and lepromatous in different animals. Some animals developed pure neural leprosy. Erythema nodosum leprosum (SNL) was also observed. Combined intravenous/intracutaneous (IV/IC) routes of inoculation more effectively induced advancing, disseminated lepromatous forms of leprosy; IV or IC routes alone were less effective at comparable doses. Total IV/IC doses of SMM-origin ML equal to or greater than 5 x 10(8), with morphologic indices (MIs) ranging from 5 to 10%, produced advancing, disseminated LL leprosy in 92% of SMM. Lower IV/IC doses and inoculations by a single IV or IC route produced fewer leprosy infections and more spontaneous regressions. As a species, captive SMM are highly susceptible to experimental leprosy and provide an excellent model for the longitudinal study of leprosy.

Efficacy and safety of multidrug therapy in paucibacillary leprosy in Singapore.

A total of 49 patients with paucibacillary leprosy (PB) who completed multidrug therapy (MDT) between 1985 and 1990 were analysed retrospectively for efficacy and complications; 20 (40.8%) patients had borderline-tuberculoid (BT), 13 (26.5%) had tuberculoid (TT), 1 (2.1%) had indeterminate (I) and 15 (30.0%) had pure neural (N) leprosy; 26 patients (76.5% of 34 non-neural leprosy) were skin biopsied for histological cure before MDT was stopped. Of these 26 patients, 19 had histological clearance at 6 months while the remaining 7 cleared beyond 1 year (18-36 months). The remaining 8 non-neural patients who refused rebiopsy had MDT for 6-8 months and the MDT was stopped when there was clinical clearance. Of the 15 neural (N) leprosy patients, 11 were given MDT for 6 months while the rest had 12-18 months of treatment; 1 patient with neural leprosy, who was treated for 6 months, relapsed with BT leprosy 18 months post-treatment. There were few complications among the 49 patients-4 (8.2%) patients developed reaction to dapsone, 1 (2.0%) had the dapsone syndrome, 2 (4.1%) had haemolytic anaemia and 1 (2.0%) had dapsone hepatitis; 7 (14.3%) patients had type I reaction.

T Lymphocyte Subsets in Leprosy

Phenotypic analysis was done on 24 Egyptian leprosy patients and 11 healthy controls. The type of leprosy, duration of disease at the time of testing, and age were found to affect T cell subset distribution. As compared with controls, neural leprosy tended to have a decreased total T cell percentage, borderline leprosy an increased T suppressor cell percentage, and reactional borderline leprosy an increased T helper/suppressor ratio. Patients with the disease for less than 1 year had a higher mean percentage of T suppressor cells and a lower mean T helper/suppressor ratio than patients with leprosy for more than 1 year. The same was true in older (50-70 years old) versus younger (12-41 years old) patients.

Pure Neural Leprosy Diagnosed in the United States

Pure Neural Leprosy Diagnosed in the United States