Observations from a 'special selective drive' conducted under National Leprosy Elimination Programme in Karjat taluka and Gadchiroli district of Maharashtra.

The special selective drive (SSD) was conducted on a request from the Joint Director of Health Services (Leprosy and TB) Government of Maharashtra. The study team comprised the Foundation for Medical Research (FMR), assisted by a member of the Acworth Leprosy Hospital Society for Research, Rehabilitation and Education in Leprosy and two from Kushtrog Nivaran Samiti (KNS). The drive was conducted in select villages covered by 6 primary health centers (PHCs) in Karjat taluka of Raigad district and 45 PHCs in Gadchiroli district from March to May 2009 and had the cooperation of the district and PHC level staff. The aim was to train and deploy community level workers (CWs) for early leprosy case detection and through them, to create leprosy awareness in the community. A total of 1053 CWs (126 in Karjat taluka, 927 in Gadchiroli district) were given intensive training by the team. The CWs then carried out a one-day house-to-house leprosy awareness drive in their areas and listed persons such 'suspects' in both Karjat taluka (no. = 514) and Gadchiroli district (no. = 1325). Around 40% of 'suspects' presented themselves at the PHCs for examination by the medical team; of these 38 (29%) and 281 (45%) respectively turned out to be previously undetected definite cases of leprosy. The PHC-wise NCDR ranged from 5 - 27/10,000 in Karjat (14/10,000) and 2 - 35/10,000 in Gadchiroli (average 13/10,000), both rates being much higher than the reported State average of 1.1/10,000. There was a high proportion of child cases (14 and 24% respectively) and grade 2 disability (18% and 12% respectively) which indicate continued transmission of leprosy and delayed diagnosis of cases. The study also notes poor diagnostic skills among the PHC staff. Significant shortage and irregular disbursement of MDT from district store PHCs, combined with transport problem which probably contributed to delay in treatment in over 50% of the cases confirmed by the team.

The first international leprosy conference, Berlin, 1897: the politics of segregation.

The present paper examines the first attempts to internationalise the problem of leprosy, a subject hitherto overlooked by historians of imperialism and disease. The last decade of the nineteenth century saw many in the civilised countries of the imperialist West gripped by a paranoia about an invasion of leprosy via germ-laden immigrants and returning expatriates who had acquired the infection in leprosy endemic colonial possessions. Such alarmists clamoured for the adoption of vigorous leper segregation policies in such colonies. But the contagiousness of leprosy did not go unquestioned by other westerners. The convocation in Berlin of the first international meeting on leprosy revealed the interplay of differing and sometimes incompatible views about the containment of leprosy by segregation. The roles of officials from several countries, as well as the roles of five protagonists (Albert Ashmead, Jules Goldschmidt, Edvard Ehlers. Armauer Hansen, and Phineas Abraham) in the shaping of the Berlin Conference are here examined.

Do nerve growth factor-related mechanisms contribute to loss of cutaneous nociception in leprosy?

While sensory loss in leprosy skin is the consequence of invasion by M. leprae of Schwann cells related to unmyelinated fibres, early loss of cutaneous pain sensation, even in the presence of nerve fibres and inflammation, is a hallmark of leprosy, and requires explanation. In normal skin, nerve growth factor (NGF) is produced by basal keratinocytes, and acts via its high affinity receptor (trk A) on nociceptor nerve fibres to increase their sensitivity, particularly in inflammation. We have therefore studied NGF- and trk A-like immunoreactivity in affected skin and mirror-site clinically-unaffected skin from patients with leprosy, and compared these with non-leprosy, control skin, following quantitative sensory testing at each site. Sensory tests were within normal limits in clinically-unaffected leprosy skin, but markedly abnormal in affected skin. Sub-epidermal PGP 9.5- and trk A- positive nerve fibres were reduced only in affected leprosy skin, with fewer fibres contacting keratinocytes. However, NGF-immunoreactivity in basal keratinocytes, and intra-epidermal PGP 9.5-positive nerve fibres, were reduced in both sites compared to non-leprosy controls, as were nerve fibres positive for the sensory neurone specific sodium channel SNS/PN3, which is regulated by NGF, and may mediate inflammation-induced hypersensitivity. Keratinocyte trk A expression (which mediates an autocrine role for NGF) was increased in clinically affected and unaffected skin, suggesting a compensatory mechanism secondary to reduced NGF secretion at both sites. We conclude that decreased NGF- and SNS/PN3-immunoreactivity, and loss of intra-epidermal innervation, may be found without sensory loss on quantitative testing in clinically-unaffected skin in leprosy; this appears to be a sub-clinical change, and may explain the lack of cutaneous pain with inflammation. Sensory loss occurred with reduced sub-epidermal nerve fibres in affected skin, but these still showed trk A-staining, suggesting NGF treatment may restore pain sensation.

Correlation of quantitative tests of nerve and target organ dysfunction with skin immunohistology in leprosy.

Loss of nociception and hypohidrosis in skin are hallmarks of leprosy, attributed to early invasion by Mycobacterium leprae of Schwann cells related to unmyelinated nerve fibres. We have studied skin lesions and contralateral clinically unaffected skin in 28 patients across the leprosy spectrum with a range of selective quantitative sensory and autonomic tests, prior to biopsy of both sites. Unaffected sites showed normal skin innervation, when antibodies to the pan-neuronal marker PGP (protein gene product) 9.5 were used, with the exception of intraepidermal fibres which were not detected in the majority of cases. Elevation of thermal thresholds and reduced sensory axon-reflex flare responses in affected skin correlated with decreased nerve fibres in the subepidermis, e.g. axon-reflex flux units (means+/-SEM) for no detectable innervation; decreased innervation; and clinically unaffected skin, were 23+/-3.1; 41.2+/-7.3; and 84.5+/-4.0, respectively. Reduced nicotine-induced axon-reflex sweating was correlated with decreased innervation of sweat glands. Where methacholine-induced direct activation of sweat glands was affected, there was inflammatory infiltrate and loss of sweat gland structure. This study demonstrates a correlation between selective nerve dysfunction on clinical tests and morphological changes in skin, irrespective of the type of leprosy, and is the first to show that loss of sweating in leprosy may result either from decreased innervation and/or involvement of the sweat glands. The findings have implications for the selection and monitoring of patients with leprosy in clinical trials which aim to restore cutaneous function.

Severe pan-sensory neuropathy in leprosy.

The sensory loss which occurs in leprosy is essentially cutaneous, resulting from centripetally ascending infection, the host cellular response and fibrosis, from dermal to certain mixed nerves. The hallmark is pain/temperature and touch/pressure loss. Muscle denervation is a byproduct of mixed nerve involvement. Leprous sensory and motor neuropathy presents a stereotyped picture, with preservation of position sense, noninvolvement of the large girdle muscles, and retained deep tendon reflexes. We report clinical and investigative details of 7 patients (3 males, 4 females) with mild-to-moderate polyneuritic leprosy who manifested severe proprioceptive loss in the upper per limbs; the lower limbs were similarly affected in 4 of them. Tendon reflexes were absent in the ataxic limbs. No other cause was found for the ataxia. Electrophysiological studies confirmed damage to large cutaneous and muscle afferents, and a normal EMG pattern in hip and shoulder muscles. Of great interest was the histology of a lumbar sensory ganglion biopsied in a severely disabled patient. There was extensive neuron loss and degeneration and reactive proliferation of capsular cells ("nodules of Nageotte"), an inflammatory focus of lymphocytes, and no bacilli. This suggests to us that the proprioceptive loss in these patients could well be the result of an unusual "leprous ganglionitis." Further clarification of the mechanism of ganglion degeneration and the frequency of inflammation could come from immunohistology of tissues from African green monkeys with experimental polyneuritic leprosy.

Dapsone neuropathy--report of three cases and pathologic features of a motor nerve.

We report the clinical features, electrophysiologic findings, and dapsone and isoniazid excretion studies in three young people who ingested excessive amounts (2-4 times the prescribed dose) of dapsone for hypopigmented macules and who developed, subacutely, progressive motor neuropathy a few months later. Pathologic studies on a biopsied motor nerve confirmed the electrophysiologic conclusion of distal motor axonopathy. All made a rapid recovery in a few months after dapsone was stopped, although electrical abnormalities persisted. One patient was a rapid acetylator of isoniazid.

An attempt to influence nerve degeneration and regeneration by using macrophage cell homogenate.

The effect of the contents of activated macrophages on the degenerative/regenerative process in the mouse sciatic nerve was investigated as a possible model for leprosy. The whole cellular homogenate or saline was injected every week around physically impaired (to bypass the perineurial barrier) and normal nerves. Recovery of the nerve function was monitored clinically and electromyographically. After 14 weeks animals were sacrificed and nerves were processed for histology. The data obtained from 134 experimental and control nerves were rated and analysed statistically. The course of the nerve regeneration in the physically impaired nerve with and without homogenate was found to be similar. One of the reasons for this could be insufficient concentration of the homogenate in the endoneurial space.