eMedicine Specialties > Neurology > Neuromuscular Diseases

Neuropathy of Leprosy: Differential Diagnoses & Workup

Author: Ramaratnam Sridharan, MD, FRCP, FAAN, Head of the Department of Neurology, Professor, Neurology, Chennai Neurospeciality & Research Institute
Coauthor(s): Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants; Lakshmi Narasimhan Ranganathan, MD, Assistant Professor, Department of Neurology, Stanley Medical College, India; Srinivasaraman Govindarajan, DMRD, DNB, Staff Physician, Barnard Institute of Radiology, Madras Medical College, India
Contributor Information and Disclosures

Updated: Feb 27, 2007

Differential Diagnoses

Other Problems to Be Considered

Cervical myeloradiculopathies
Mononeuropathy multiplex due to rheumatoid arthritis
Symmetric polyneuropathy due to other causes
Small-fiber neuropathies due to amyloid or hereditary sensory neuropathy
Dapsone-induced motor polyneuropathy
Sensory perineuritis affecting subcutaneous sensory nerves
Hypertrophic neuropathies due to amyloidosis
Hypertrophic neuropathies due to recurrent trauma
Diseases characterized by trophic ulcers
Congenital indifference to pain
Hysterical and/or functional disease

Workup

Laboratory Studies

• Complete blood cell count
• Blood glucose, BUN, creatinine, liver function tests
• HIV serology, when appropriate
• Skin and nasal smears for AFB
• Immunologic tests
• • Lepromin test
    
    
    • Lepromin is a suspension of killed M leprae obtained from infected human or armadillo tissue. Following intradermal inoculation, early (48 h, Fernandez) reactions and late (3-4 wk, Mitsuda) reactions may be seen.
    • The Mitsuda reaction, a granulomatous response to the antigen, is more consistent. Patients with TT or BT leprosy have strongly positive (>5 mm) responses, whereas patients with LL disease do not respond.
    • The test is not useful in the diagnosis of leprosy because most of the population in both areas of endemic disease and areas in which disease is not endemic are Mitsuda positive.
    • The lepromin 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 (LTT) and lymphocyte migration inhibition test (LMIT). Response decreases steadily in the progression from subpolar TT to subpolar LL leprosy.
  • Tests based on detection of M leprae antibodies or antigens include serologic tests, tissue tests, and polymerase chain reaction (PCR)–based genetic tests.
  • Serologic tests
    
    
    • Major serologic assays include fluorescent antibody absorption test (FLA-ABS), radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), passive hemagglutination assay (PHA), serum antibody competition test (SACT), and particle agglutination assays (PAA).
    • Important serologic tests are FLA-ABS test and PGL-1 ELISA, which have been simplified further as dot ELISA and dipstick ELISA.
    • However, 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 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 their high rate of false-positive reactions, especially in tropical countries, has decreased their positive predictive value for activity of the disease.
  • Recombinant DNA and PCR techniques
    
    
    • Gene probes have been developed for demonstration of M leprae –specific sequences in various specimens, such as skin and/or nasal smears, biopsies, tissue sections, and blood.
    • DNA-targeting probes have sensitivity of 10,000-100,000 organisms. Hence, they are not likely to be useful for a PB leprosy relapse. The signals may persist after bacterial death.
    • RNA (ie, mRNA, rRNA) targeting probes: These probes can detect 100-1000 bacteria and correlate better than the DNA-targeting probes with the presence of viable organisms.
    • Various PCR techniques to amplify the DNA of M leprae have been described, and these amplified sequences of target DNA can be detected by either gel electrophoresis or specific gene probes.
    • Very low bacterial loads (<10 bacilli) can be detected.
    • About 60-75% of patients with smear-negative PB leprosy have positive results on PCR. After chemotherapy, signals become weaker; therefore, PCR can be used to monitor treatment, confirm relapses, or determine the need for chemotherapy in patients presenting with reactions.
    • PCR methods for identifying the DNA, which encodes M leprae proteins of 65 and 18 kd and repetitive sequences of M leprae have been developed.

Imaging Studies

• Chest radiography
• Radiography to detect bone involvement
• • Radiographs may reveal features of periostitis and osteomyelitis, commonly in the epiphyseal and metaphyseal regions of the small bones of the hands and feet, especially the phalanges.
  • The tubular bones of the extremities and the ribs may be rarely involved because of hematogenous spread.
  • Facial involvement may take the form of maxillary alveolar and nasal spine destruction resulting in a constellation of facial deformities known eponymously as Bergen syndrome. Symmetrical periostitis of the tibia, fibula and the ulna may occur.
  • In rare cases, leprous arthritis may result because of direct extension from a focus of leprous osteomyelitis.
  • Most commonly, neuropathy and secondary infection affects the joints of the hands and feet.
  • Motor denervation results in concentric atrophy and resorption of cancellous bone resulting in the licked–candy-stick appearance.
  • Neuropathic osteoarthropathy results in cartilage erosion and fragmentation, bony eburnation, fragmentation, and destruction with a large serous effusion.
  • Secondary infection may result in osteomyelitis.
• MRI or CT of neuropathic joints when appropriate
• Magnetic resonance (MR) neurography in special situations
• • MR neurography can be performed by using custom-made, high-resolution phased-array coils and a variety of fat-saturation sequences to study gross nerve morphology and internal fascicular architecture. This technique has been used to assess the presence of neuropathy, including active reversal reactions.
  • TT leprosy results in nerve thickening and abscesses that may be detected as thickened nerves with increased signal intensity on T2-weighted images.
  • Nerve entrapment in osseofibrous tunnels occur in leprosy. Compression of the nerve appears as flattening of the normal circular cross-sectional appearance of the nerve with increased signal intensity on T2-weighted images, and the presence and configuration of the osseofibrous tunnels may be apparent on MRI.
  • Alteration in the fascicular architecture, increased signal intensity on T2-weighted images, and gadolinium enhancement are observed in nerves affected by acute reversal reactions. With treatment, normal T2 signal intensity and reduced enhancement have been reported.
  • The fascicular architecture is completely lost in many patients with ENL.
• Ultrasonography and Doppler ultrasonography
• • High-frequency linear ultrasound probes can be used to demonstrate thickening of nerves and presence of osseofibrous compression.
  • Doppler study documents increased endoneurial blood flow in nerves in acute reversal reactions, which has been shown to resolve after treatment with steroids.

Other Tests

• Nerve-conduction studies
• • Abnormalities include the following:
    • Segmental slowing of conduction at common sites of entrapment (eg, elbow segment of the ulnar nerve)
    • Prolonged distal latencies
    • Reduced (sensory or motor) nerve conduction velocities
    • Reduced amplitude of compound muscle action potentials
    • Absent or low-amplitude sensory nerve action potentials
    • Pattern of abnormalities suggesting mononeuropathy, mononeuropathy multiplex, entrapment neuropathy, or generalized polyneuropathy
  • The ulnar, common peroneal, median, and tibial nerves are most commonly involved.
  • Changes in nerve conduction are more severe if the nerves are clinically affected than if they are not.
  • Nerve-conduction velocity may be decreased before any sensory deficit appears, and this finding can be used to detect asymptomatic nerve involvement.
  • Conduction velocity in the index branch of the radial cutaneous nerve can be reduced in early leprosy and even in the contacts of patients with leprosy.
  • Similar studies in the dorsal cutaneous branch of the ulnar and the great auricular nerves can also be useful.
  • In LL disease, nerve thickening is not correlated with impaired nerve conduction.
  • Palpably enlarged nerves may be functional, though they may eventually fail.
• Other neurophysiologic findings
• • Prolongation of the refractory period is considered a more sensitive parameter than conventional motor or sensory conduction in detecting early nerve damage in clinically asymptomatic nerves.
  • Abnormalities in visual and brainstem auditory evoked potentials have been reported in LL disease, suggesting CNS involvement.
• Autonomic tests
• • Sympathetic skin response (SSR) may be absent initially, but can be recorded in approximately 16% of patients after treatment.
  • Fingertip blood-flow velocity and its control by vasomotor reflexes (as tested by using a laser Doppler flowmeter), fingertip skin temperature, and SSR have been valuable in the evaluation of early leprous neuropathy. Findings may be abnormal even in preclinical infection.

Procedures

• Skin biopsy
• • May lead to a diagnosis when a skin patch is sampled
  • Useful for the diagnosis and proper classification of leprosy
  • Skin and nasal smears for AFB: Details regarding skin and nasal smears are given in the article on Leprosy.
• Nerve biopsy
• • Nerve biopsy occasionally reveals abnormalities, even in contacts of patients with leprosy.
  • Findings from nerve biopsy may rule out other diseases, such as polyarteritis nodosa, hereditary neuropathies, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Even in regions of endemic disease, not all persons with thickened nerves have leprosy.
  • In purely neuropathic leprosy, nerve biopsy is the only way to confirm the diagnosis.
  • Nerve biopsy is probably more sensitive than skin biopsy, although false-negative histologic findings may be seen when clinically uninvolved nerves are sampled.
  • Skin and nerve histologic findings are often incongruous. Patients with MB leprosy in the nerves may have PB in the skin.
  • The best results are obtained when the results are interpreted in laboratories with special expertise in these diseases.
  • Biopsy of a clinically involved cutaneous nerve may be more informative than routine biopsy of the sural nerve, radial cutaneous nerve, or dorsal branch of the ulnar nerve.
  • Sural nerve biopsy is usually performed at the level of the lateral malleolus, where it passes between the calcaneum and the lateral malleolus.
  • Biopsy of the radial cutaneous nerve or dorsal branch of the ulnar nerve is at the level of the dorsum of the wrist.
  • Fascicular nerve biopsy causes less sensory deficit than full-thickness biopsy.
  • The nerve-biopsy specimen is divided into 5 pieces, each treated with 1 of the following fixatives:
    • Formalin for hematoxylin and eosin and silver stains for axons
    • Flemming solution for myelin stains (Weigert-Pal technique)
    • Glutaraldehyde for electron microscopy
    • Formol-calcium solution for teased-fiber preparations
    • Frozen specimen for enzyme histochemical techniques
• Aspiration cytology
• • The first step is performing a nerve block proximal to the site of aspiration.
  • A syringe filled with isotonic saline and fitted with an 18-gauge needle is used.
  • The nerve to be aspirated is fixed between the clinician's thumb and index finger, and the needle is inserted into the nerve as parallel to the fascicles as possible.
  • The aspirated material may demonstrate AFB.
  • Cytologic studies of fine-needle aspirates from skin lesions and lymph-node aspirates of patients with LL disease may be diagnostically useful.

Histologic Findings

Histologic findings on skin biopsies vary according to the type of leprosy.

• Indeterminate leprosy
  • A few cells cuffing the dermal appendages and neurovascular bundles
  • A few M leprae in cutaneous nerves
• TT leprosy
  • Noncaseating granulomas formed by epithelioid cells, lymphocytes, and giant cells
  • Destruction of normal dermal nerves
  • Loss of normal skin organs (eg, sweat glands, hair follicles)
  • Bacilli frequently absent or difficult to demonstrate
• LL leprosy
  • Normal epidermis: The rete is flattened, and clear space separates the epidermis from the diffuse granulomatous reaction with macrophages, large foamy histiocytes (Virchow or lepra cells), and many intracellular AFB, which are frequently in spheroidal masses (globi).
  • Absent epithelioid cells and giant cells
  • Granulomas, most numerous around blood vessels, nerves, and skin appendages.
  • Plasma cells (occasional)
  • Easily visible dermal nerves
• BT leprosy
  • Epithelioid granulomas with lymphocytic preponderance
  • Dermal nerves mostly destroyed
  • Scanty or absent bacilli
• BB leprosy
  • Epithelioid granulomas
  • Possibly visible dermal nerves
  • More frequent bacilli than in BT leprosy
• BL leprosy
  • Granulomas formed by histiocytes
  • Dermal nerves visible
  • Bacilli seen in greater numbers than in other types
• Reversal reaction
  • Granulomas formed by epithelioid cells and lymphocytes
  • Extracellular edema in dermal collagen with dilated lymphatics and/or proliferation of fibrocytes
  • As the reactions clear, lesions healing with reduction or eradication of bacilli
• ENL reaction
  • Massive influx of polymorphonuclear cells
  • Possible deposition of complement and immunoglobulin in a granular pattern around dermal vessels
  • More numerous bacilli than in other reactions
  • Histologic studies not useful for assessing clinical activity because granulomas persist after clinical improvement.
• Nerve biopsy findings in LL
  • Light microscopy
    • Overall nerve structure is preserved.
    • Involvement is asymmetric between and within individual fascicles.
    • Nerve cross-sections show an inflammatory reaction affecting the epineurium and perineurium, causing increased nerve volume.
    • Macrophages and Schwann cells filled with organisms and debris (foamy cells) appear in the epineurium, endoneurium, and perineurium. In the perineurium, foamy macrophages infiltrate and separate individual layers, fibroblasts and perineurial cells proliferate, and collagen is deposited. This produces onion skinning of the nerve fascicles.
    • Proliferation of connective tissue (peri and endoneurial fibrosis) is not as prominent as in TL disease.
    • Lymphocytic vasculitis affects nerve blood vessels in all nerve compartments. The vessels remain permeable to blood. This feature is seen in persons who have received treatment for leprosy prior to the biopsy.
    • M leprae are extremely numerous, often found in globoid clumps on Ziehl-stained paraffin-embedded specimens. They are found in all nerve compartments and affect a large variety of cells, including perineurial cells, fibroblasts, cells of the macrophage histiocyte lineage, Schwann cells, and endothelial cells. Fite, auramine rhodamine, or toluidine blue (in plastic-embedded sections) also demonstrates M leprae. A few viable M leprae in Schwann cells persist even after treatment completion.
  • Myelin and silver (axon) stains
    • Small myelinated and unmyelinated fibers are lost in early stages. Large myelinated fibers are lost in later stages.
    • Symptomatic neuropathy is associated with severe axonal loss. Nerve fiber density decreases to 5% of the control, compared to 25-30% in silent hypertrophy of the radial cutaneous nerve.
  • Electron microscopy
    • Organisms are seen as membrane-bound, round- or rod-shaped, electron-dense structures. They often are surrounded by a clear halo, which is composed of bacterial metabolites and/or denatured host cytoplasmic components.
    • Bacteria are found easily in macrophages and Schwann cells of unmyelinated fibers but less frequently in Schwann cells associated with myelinated fibers.
    • In early leprous neuropathy, electron microscopy demonstrates naked or thinly myelinated axons, suggesting primary demyelination. Axonal pathology appears at a late stage.
    • Endothelial cells may appear swollen, with loss of cell junctions and other signs of damage to the blood-nerve barrier. Multilayering and thickening of the basement membrane around vessels occurs in all types of leprosy but is a nonspecific change of many chronic neuropathies.
  • Teased-fiber preparation
    • In patients with silent hypertrophy of the superficial radial cutaneous nerve, this preparation reveals segmental abnormalities of the myelin sheath, including segmental demyelination, a wide nodal gap between 2 internodes, and short remyelinated internodes.
    • Demyelinated fibers often are clustered and linked closely with debris-laden macrophages.
    • Axonal degeneration of nerve fibers predominates in some.
    • In experimental animals, segmental demyelination was predominant during early infection. Axonal degeneration was evident in advanced infections.
  • Pathological findings in PB (TT) leprous neuropathy
    • The nerve may be completely destroyed and normal nerve structures may not be identifiable.
    • Involvement also may be multifocal, with damaged fascicles found adjacent to entirely normal ones.
    • Perineurium is thickened markedly, often fused with the epineurium into a thick fibrotic mass and infiltrated by inflammatory cells and small vascular channels.
    • The entire endoneurium may be replaced by a single granuloma. Caseation necrosis may occur and may even progress to a nerve abscess.
    • Granulomas consist of epithelioid histiocytes, multinucleated giant cells, and variable numbers of lymphocytes and plasma cells.
    • Bacilli are absent in the lesions, but M leprae antigens may be demonstrated in nerves by immunohistochemical methods.
    • When no evidence of infection with M leprae can be found, differentiating sarcoid neuropathy from TT leprous neuropathy may be impossible. Immunologic and molecular techniques may be needed to confirm the etiology.

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