eMedicine Specialties > Neurology > Neurological Infections

Leprosy: Differential Diagnoses & Workup

Author: Ramaratnam Sridharan, MBBS, MD, Head, Department of Neurology, Professor of Neurology, Chennai Neurospeciality and Research Institute, India
Coauthor(s): Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants; Lakshmi Narasimhan Ranganathan, MD, Tutor, Institute Of Mental Health, Chennai, India; Senior Civil Assistant Surgeon, Tamil Nadu Medical Services; Srinivasaraman Govindarajan, DMRD, DNB, Fellow in Radiology, Barnard Institute of Radiology, India
Contributor Information and Disclosures

Updated: Feb 27, 2007

Differential Diagnoses

Neurofibromatosis, Type 1
Neurofibromatosis, Type 2
Wegener Granulomatosis

Other Problems to Be Considered

Skin lesions - Flat and hypopigmented
Localized scleroderma
Onchocerciasis
Pityriasis alba
Pityriasis versicolor
Post Kala-Azar dermal leishmaniasis
Vitiligo
Yaws
Skin lesions - Raised and pigmented
Acquired syphilis
Atypical necrobiosis of the face
Cutaneous leishmaniasis
Follicular mucinosis
Granuloma annulare
Granuloma multiforme
Kaposi sarcoma
Lupus vulgaris
Lupus erythematosus
Mycobacterium marinum infection
Neurofibromatosis
Pityriasis rosea
Psoriasis
Sarcoidosis
Tinea corporis
Wegener granulomatosis
Generalized thickening of skin
Myxoedema
Pachydermoperiostitis
Scleroderma

Workup

Laboratory Studies

• Blood cell counts
• Blood glucose level
• Urea
• Creatinine
• Liver functions
• HIV status, especially in nonresponders
• Skin and/or nasal smears for AFB
• Family and/or contact screening for evidence of leprosy

Imaging Studies

• Chest radiography

Other Tests

• Immunologic tests
  • Lepromin test
    • Lepromin is a suspension of killed M leprae obtained from infected human or armadillo tissue. Following intradermal inoculation, early reactions (48 h, Fernandez) as well as late reactions (3-4 wk, Mitsuda) may be seen. The Mitsuda reaction, a granulomatous response to the antigen, is more consistent. Patients with TT or BT leprosy have strongly positive responses (>5 mm), whereas patients with LL do not respond.
    • The test is not useful in the diagnosis of leprosy because of the population, regardless of whether they live in an area of endemic disease, are Mitsuda positive. The test is a guide to the cell-mediated immunity of the individual. Lepromin is not available in the United States.
  • Cellular immune response against M leprae also can be studied by lymphocyte transformation test and lymphocyte migration inhibition test (LMIT). Response continuously decreases from subpolar TT to subpolar LL leprosy.
• Tests based on detection of M leprae antibodies or antigens
  • Serologic tests
    • Major serologic assays include fluorescent antibody absorption test (FLA-ABS), radioimmunoassay (RIA), ELISA, passive hemagglutination assay (PHA), serum antibody competition test (SACT), and particle agglutination assay (PAA).
    • Important serologic tests are FLA-ABS test and PGL-1 ELISA, which have been further simplified as dot ELISA and dipstick ELISA.
    • Serologic responses persist for considerable time after subsidence of disease and are not useful in assessing disease activity.
  • Estimation of M leprae –specific components in tissues
    • M leprae –specific antigens, nucleic acids, and M leprae –specific lipids are assessed with thin-layer chromatography, high-pressure liquid chromatography, gas-liquid chromatography, and mass spectrometry.
    • Lipids such as mycolic acid and phenolic glycolipid are characteristic of mycobacteria, including M leprae.
    • Tests to detect the epitope on M leprae antigens by using monoclonal antibodies or ELISA have been devised, but the frequent occurrence of false-positive reactions, especially in tropical countries, has decreased their positive predictive value for activity of the disease.
• Recombinant DNA and polymerase chain reaction (PCR)
  • Gene probes have been developed for demonstration of M leprae –specific sequences in various specimens: skin and/or nasal smears, biopsies, tissue sections, and blood.
  • DNA targeting probes have sensitivities of 10,000-100,000 organisms. Hence, they are not likely to be useful for a PB relapse. The signals may persist after bacterial death.
  • Regarding RNA (mRNA and rRNA) targeting probes because RNA has a shorter half-life and correlates better with viable organisms, these probes can detect 100-1000 bacteria.
  • PCR techniques to amplify the DNA of M leprae have been described, and these amplified sequences of target DNA can be detected by using gel electrophoresis or specific gene probes. Low bacterial loads ( <10 bacilli) can be detected. About 60-75% of smear-negative patients with PB leprosy have positive results on PCR. After chemotherapy, signals become weaker; therefore, PCR can be used to monitor treatment, diagnose relapses, or determine the need for chemotherapy. PCR methods for identifying DNA that encodes 65- and 18-kd M leprae proteins and repetitive sequences of M leprae have been developed.
• Despite the availability of several investigatory tools, the diagnosis of leprosy is essentially based on clinical grounds.
• Abnormalities on nerve conduction studies include the following:
  • Segmental slowing of conduction is seen at sites of entrapment (eg, elbow segment of the ulnar nerve), prolonged distal latencies, reduced (sensory or motor) nerve conduction velocities
  • Reduced amplitude of evoked motor responses (ie, compound muscle action potentials [CMAPs]) or absent or low-amplitude sensory potentials. The pattern of abnormalities may suggest mononeuropathy, mononeuropathy multiplex, or an entrapment neuropathy.
  • The nerves most commonly involved include the ulnar, common peroneal, median, and tibial nerves.
  • When the nerves are clinically affected, changes in nerve conduction are more obvious than they otherwise are. At times, the nerve conduction velocity may be decreased before any sensory deficit becomes apparent, and this finding can be used to detect asymptomatic nerve involvement. Conduction study in the index branch of the radial cutaneous nerve has been reported to reveal reduction in conduction velocity in people with early leprosy and even in contacts of those of leprosy.
  • Similar studies in the dorsal cutaneous branch of the ulnar and great auricular nerves may also be useful. In LL, thickening of the nerve is not correlated with impairment of nerve conduction. Although palpably enlarged nerves may function well, they may eventually fail.

Procedures

• Skin smears for AFB
  • These smears are made by nicking the skin with a sharp scalpel and scraping it. Obtained fluid and tissue are thickly spread on a slide, stained by using the Ziehl-Neelsen method, and partially decolorized with 1% acid alcohol.
  • Two indices (bacillary index and morphologic index), which depend on observation of M leprae in smears from skin or nasal discharge, are useful in assessing amount of infection, viability of organisms, and patient progress.
  • The bacillary index is an expression of the extent of bacterial loads. It is calculated by counting 6-8 stained smears under the X100 oil immersion lens. The depth of the skin incision, the thoroughness of the scrape, and the thickness of the film affect the bacillary index. Results are expressed on a logarithmic scale, as follows:
    • 1+ indicates 1-10 bacilli in 100 fields.
    • 2+ indicates 1-10 bacilli in 10 fields.
    • 3+ indicates 1-10 bacilli in every field.
    • 4+ indicates 10-100 bacilli in every field.
    • 5+ indicates 100-1000 bacilli in every field.
    • 6+ indicates more than 1000 bacilli in every field.
    • A more accurate and reliable index of the bacillary content of a lesion is given by the logarithmic index of biopsy results. These indices help to assess a patient's infection at the beginning of treatment and to assess progress.
  • The morphologic index is calculated by counting solid-staining acid-fast rods. Leprosy bacilli that stain with carbol-fuchsin as solid, acid-fast rods are believed to be viable; bacilli that stain irregularly are probably dead and degenerating. Measurement of the morphologic index is affected by observer variations and therefore not always reliable.
  • Fluorescent diacetate-ethidium bromide (FDA-EB) staining, laser microprobe mass analysis (LAMMA), bioluminescent technology, and macrophage-based assays may also be useful in detecting viable organisms.
• Nasal smears for AFB
• Skin biopsy
  • Skin biopsy should include the dermis and the epidermis, and samples are usually obtained from the edge of the lesion. A biopsy punch or scalpel may be used.
  • Skin biopsy is useful for the diagnosis and proper classification of leprosy.
• Nerve biopsy
  • Nerve biopsy occasionally reveals abnormalities even in contacts of patients with leprosy. The results may rule out other diseases such as polyarteritis nodosa, hereditary neuropathies, or chronic inflammatory demyelinating polyradiculoneuropathy. Recognizing that not all people with thickened nerves, even those of in regions of endemic disease, have leprosy is important. In purely neuropathic forms, nerve biopsy is the only way to confirm the diagnosis.
  • Nerve biopsy is probably more sensitive than skin biopsy, though false-negative histologic results may be seen when clinically uninvolved nerves are sampled. Skin and nerve histologic results are often incongruous; results in patients with MB leprosy in nerve may show PB leprosy in skin. The best results of nerve biopsy are obtained when the findings are interpreted in laboratories with special expertise in such diseases.

Histologic Findings

Histologic findings of skin obtained from leprosy-involved areas may be helpful. Histologic findings vary according to the type of leprosy. Indeterminate leprosy is characterized by a few cells cuffing the dermal appendages and neurovascular bundles and a few M leprae within cutaneous nerves.

In TT leprosy, epithelioid cells, lymphocytes, and perhaps giant cells form noncaseating granulomas. Dermal nerves are destroyed. Normal skin organs (eg, sweat glands, hair follicles) are lost. Bacilli are frequently absent or difficult to demonstrate.

In LL leprosy, the epidermis is normal and the rete flattened. A clear space separates the epidermis from diffuse granulomatous reaction with macrophages; large, foamy histiocytes (Virchow or lepra cells); and many intracellular AFB, which are frequently in spheroidal masses (ie, globi). Epithelioid cells and giant cells are not found. Granulomas are most numerous around blood vessels, nerves, and skin appendages. In some cases, many plasma cells are found. Dermal nerves are easily visible.

In BT leprosy, granulomas are epithelioid, with a preponderance of lymphocytes. Dermal nerves are mostly destroyed. Bacilli may be scanty or absent.

In BB leprosy, granulomas are epithelioid, dermal nerves may be visible, and bacilli are seen more often than in BT leprosy.

In BL leprosy, histiocytes form granulomas, dermal nerves are visible, and bacilli are seen in greater numbers than in other types.

In a reversal reaction, epithelioid cells and lymphocytes form granulomas. Extracellular edema is noted in the collagen of the dermis with dilated lymphatics or a proliferation of fibrocytes. As reactions clear, lesions heal with reduction or eradication of bacilli.

ENL reaction is characterized by a massive influx of polymorphonuclear cells. Complement and immunoglobulin may be deposited in a granular pattern around dermal vessels. Bacilli become more numerous. Histologic studies are not useful for assessing clinical activity because granuloma persists for a long time after clinical activity subsides.

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