Yaws, Bejel, and Pinta

Epidemiology and Etiology

Epidemiology

Yaws (most common):

• Prevalent in hot, humid areas of: 
  • South Asia ASIA Spinal Cord Injuries
  • Indonesia
  • Pacific Islands
  • Africa
  • South America
• Children > adults

Bejel:

• Prevalent in arid regions of:
  • Middle East
  • Central and South Africa
• Children > adults

Pinta:

• Very rare
• Occurrence has declined.
• May still be endemic in:
  • South America
  • Central America
• Teenagers and adults > children

Etiology

• Causative organisms: 
  • Subspecies of Treponema Treponema Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema pallidum:
    • Yaws: T. pallidum pertenue T. pallidum pertenue Treponema
    • Bejel: T. pallidum endemicum T. pallidum endemicum Treponema
  • Pinta: T. carateum T. carateum Treponema
• Basic Treponema Treponema Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema characteristics:
  • Spirochete Spirochete Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema ( spiral shaped Spiral shaped Treponema)
  • Gram negative Gram negative Bacteria which lose crystal violet stain but are stained pink when treated by gram’s method. Yersinia spp./Yersiniosis
  • Average length: 6–15 μm; average width: 0.1–0.2 μm

Pathogenesis

Reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli

Humans are the only reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli.

Transmission

• Yaws: skin-to-skin contact with lesions
• Bejel:
  • Skin-to-skin contact with lesions
  • Mouth-to-mouth contact with oral lesions
  • Fomites Fomites Inanimate objects that carry pathogenic microorganisms and thus can serve as the source of infection. Microorganisms typically survive on fomites for minutes or hours. Common fomites include clothing, tissue paper, hairbrushes, and cooking and eating utensils. Adenovirus (e.g., utensils for eating and drinking)
• Pinta: skin-to-skin contact with lesions

Pathophysiology

• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions contact with an infected lesion → spirochete Spirochete Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema adheres to the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions or mucosal membranes
• Production of hyaluronidase Hyaluronidase Bacteroides → allows for tissue invasion
• Organisms coat themselves in the host’s fibronectin Fibronectin Glycoproteins found on the surfaces of cells, particularly in fibrillar structures. The proteins are lost or reduced when these cells undergo viral or chemical transformation. They are highly susceptible to proteolysis and are substrates for activated blood coagulation factor VIII. The forms present in plasma are called cold-insoluble globulins. Connective Tissue: Histology → prevents phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation and recognition by the immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs
• Travel to lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy → dissemination through the bloodstream
• Host immune response → disease manifestations

Clinical Presentation

Yaws

Primary phase:

• Localized papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes at the site of inoculation (“mother yaw”):
  • Most commonly occurs on the lower extremities
  • Painless
  • May be pruritic
• Evolution:
  • Progresses to a large, yellow nodule Nodule Chalazion
  • Possible ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers with red granulation Granulation Wound Healing tissue at the ulcer base
  • Regresses spontaneously into a hyperpigmented scar Scar Dermatologic Examination

Secondary phase:

• Secondary lesions:
  • After lymphatic spread of the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology
  • Appear weeks to 2 years after primary phase
• Morphology:
  • Solitary, ulcerated nodules resembling primary yaws
  • Multiple smaller nodules
• Painful palmar and plantar papilloma Papilloma A circumscribed benign epithelial tumor projecting from the surrounding surface; more precisely, a benign epithelial neoplasm consisting of villous or arborescent outgrowths of fibrovascular stroma covered by neoplastic cells. Cowden Syndrome or plaques
• Arthralgias
• Osteoperiostitis:
  • Nocturnal bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Dactylitis Dactylitis Ankylosing Spondylitis

Tertiary phase:

• Rare
• Late lesions forming ≥ 5 years after initial infection
• Gummatous lesions (destructive, granulomatous lesions) of:
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
  • Bones
• Destructive, mutilating lesions can lead to:
  • Long-bone malformations (e.g., bowed tibia Tibia The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the fibula laterally, the talus distally, and the femur proximally. Knee Joint: Anatomy)
  • Juxtaarticular cutaneous or subcutaneous lesions
  • Ulcerations of the nasopharynx Nasopharynx The top portion of the pharynx situated posterior to the nose and superior to the soft palate. The nasopharynx is the posterior extension of the nasal cavities and has a respiratory function. Pharynx: Anatomy and palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy (“rhinopharyngitis mutilans”)
  • Exostosis of the nasal portion of the maxilla Maxilla One of a pair of irregularly shaped bones that form the upper jaw. A maxillary bone provides tooth sockets for the superior teeth, forms part of the orbit, and contains the maxillary sinus. Skull: Anatomy (“goundou”)

Bejel

Primary phase:

• Small, primary papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes, patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes, or ulcer on the oral mucosa Oral mucosa Lining of the oral cavity, including mucosa on the gums; the palate; the lip; the cheek; floor of the mouth; and other structures. The mucosa is generally a nonkeratinized stratified squamous epithelium covering muscle, bone, or glands but can show varying degree of keratinization at specific locations. Stomatitis
• Not commonly seen due to small size
• Resolves spontaneously

Secondary stage:

• Painless ulcers or patches Patches Vitiligo:
  • Can affect:
    • Mucous membranes
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions (particularly warm, moist regions)
  • Become condylomatous before eventually healing
• Periostitis Periostitis Inflammation of the periosteum. The condition is generally chronic, and is marked by tenderness and swelling of the bone and an aching pain. Acute periostitis is due to infection, is characterized by diffuse suppuration, severe pain, and constitutional symptoms, and usually results in necrosis. Reactive Arthritis → bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
• Laryngitis Laryngitis Laryngitis is an inflammation of the larynx most commonly due to infection or trauma that can be either acute or chronic. In this condition, the 2 folds of mucous membranes that make up the vocal cords become inflamed and irritated. The inflammation results in a distortion of the voice produced, resulting in a hoarse sound or aphonia. Laryngitis → hoarseness Hoarseness An unnaturally deep or rough quality of voice. Parapharyngeal Abscess 
• Nasopharyngeal ulcers
• Possible genital ulcer similar to that seen in syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis

Tertiary phase:

• Gummatous lesions of:
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
  • Bones
• Destructive lesions result in:
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types deformities
  • Nasopharyngeal destruction
  • Juxta-articular nodules

Pinta

Primary phase:

• Initial red papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes or plaque Plaque Primary Skin Lesions:
  • Pruritic
  • Scale-like
  • ≥ 10 cm in diameter
  • Commonly on lower extremities
  • Satellite lesions may be present.
• Regional lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy

Secondary phase:

• Pintids:
  • Appear months after primary phase
  • Multiple pruritic plaques
  • Undergo a color change from red to gray to black
• Similar to the initial skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesion of the primary phase

Tertiary or late phase Late Phase Sepsis in Children:

• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions discoloration and depigmentation Depigmentation Vitiligo
• Atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation

Diagnosis and Management

Diagnosis

Because these treponemal species are morphologically indistinguishable, the diagnosis is based on the combination of demographics, geographic region, clinical presentation, and laboratory findings.

Serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus:

• Nontreponemal tests:
  • Options:
    • Rapid plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products reagin
    • VDRL VDRL Treponema
  • Titers should decline after treatment. 
• Treponemal tests:
  • Options:
    • Fluorescent treponemal antibody absorption test Fluorescent treponemal antibody absorption test Serologic assay that detects antibodies to treponema pallidum, the etiologic agent of syphilis. After diluting the patient’s serum to remove non-specific antibodies, the serum is mixed on a glass slide with nichol’s strain of treponema pallidum. An antigen-antibody reaction occurs if the test is positive and the bound antibodies are detected with fluoresceinated antihuman gamma-globulin antibody. Syphilis (FTA-ABS)
    • Microhemagglutination test Microhemagglutination test Treponema for antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions to T. pallidum ( MHA-TP MHA-TP Treponema)
    • T. pallidum particle agglutination test
    • T. pallidum enzyme immunoassay Enzyme immunoassay HIV Infection and AIDS
    • Chemiluminescence immunoassay Chemiluminescence Immunoassay Syphilis
  • Cannot differentiate between current and previous infection (titers stay positive after treatment)

Direct methods:

• PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR):
  • Detect Treponema Treponema Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • Specimen: swabs of an ulcer
• Dark-field microscopy Dark-field microscopy Treponema:
  • A microscopy technique that illuminates specimens against a dark background
  • Motile spirochetes Spirochetes An order of slender, flexuous, helically coiled bacteria, with one or more complete turns in the helix. Treponema will be seen.

Management

Treatment is the same for all of these infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease. Options include:

• Intramuscular benzathine penicillin Penicillin Rheumatic Fever G (preferred with bejel and pinta)
• Oral azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides

Differential Diagnosis

• Syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis: a sexually transmitted bacterial infection caused by T. pallidum subspecies pallidum. Syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis has 3 stages. Primary syphilis Primary Syphilis Syphilis presents with a painless genital ulcer called a chancre Chancre The primary sore of syphilis, a painless indurated, eroded papule, occurring at the site of entry of the infection. Syphilis. Secondary syphilis Secondary Syphilis Syphilis presents with diffuse rash Rash Rocky Mountain Spotted Fever, condylomata lata Condylomata Lata Syphilis, and flu-like symptoms Flu-Like Symptoms Babesia/Babesiosis. Tertiary syphilis Tertiary Syphilis Syphilis presents with neurological and cardiac involvement. Diagnosis is with nontreponemal and treponemal serological tests. The mainstay of treatment is intramuscular benzathine penicillin Penicillin Rheumatic Fever G.
• Chancroid Chancroid Chancroid is a highly transmissible STD caused by Haemophilus ducreyi. The disease presents with painful ulcer(s) on the genital tract (termed chancroid or “soft chancre”). Up to 50% of patients will develop painful inguinal lymphadenopathy. Chancroid: a sexually transmitted infection Sexually Transmitted Infection Sexually transmitted infections (STIs) are infections that spread either by vaginal intercourse, anal sex, or oral sex. Symptoms and signs may include vaginal discharge, penile discharge, dysuria, skin lesions (e.g., warts, ulcers) on or around the genitals, and pelvic pain. Some infections can lead to infertility and chronic debilitating disease. Sexually Transmitted Infections (STIs) caused by Haemophilus ducreyi Haemophilus ducreyi A species of Haemophilus that appears to be the pathogen or causative agent of the sexually transmitted disease, chancroid. Haemophilus. Chancroid Chancroid Chancroid is a highly transmissible STD caused by Haemophilus ducreyi. The disease presents with painful ulcer(s) on the genital tract (termed chancroid or “soft chancre”). Up to 50% of patients will develop painful inguinal lymphadenopathy. Chancroid presents with painful genital ulcers and suppurative inguinal lymphadenopathy Inguinal Lymphadenopathy Lymphadenopathy ( buboes Buboes Chancroid). Diagnosis is usually clinical, though PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR) and cultures can help (if available). Treatment is with macrolide antibiotics.
• Leishmaniasis Leishmaniasis Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. The mildest form is cutaneous leishmaniasis (CL), characterized by painless skin ulcers. The mucocutaneous type involves more tissue destruction, causing deformities. Visceral leishmaniasis (VL), the most severe form, presents with hepatosplenomegaly, anemia, thrombocytopenia, and fever. Leishmania/Leishmaniasis: an infection caused by Leishmania Leishmania Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. The disease is endemic to Asia, the Middle East, Africa, the Mediterranean, and South and Central America. Clinical presentation varies, dependent on the pathogenicity of the species and the host’s immune response. Leishmania/Leishmaniasis species, which are obligate intracellular parasites transmitted by the sandfly Sandfly Leishmania/Leishmaniasis. The mildest form is cutaneous leishmaniasis Cutaneous leishmaniasis An endemic disease that is characterized by the development of single or multiple localized lesions on exposed areas of skin that typically ulcerate. The disease has been divided into old and new world forms. Old world leishmaniasis is separated into three distinct types according to epidemiology and clinical manifestations and is caused by species of the l. Tropica and l. Aethiopica complexes as well as by species of the l. Major genus. New world leishmaniasis, also called american leishmaniasis, occurs in south and central america and is caused by species of the l. Mexicana or l. Braziliensis complexes. Leishmania/Leishmaniasis, which is characterized by painless skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions ulcers. The mucocutaneous type involves more tissue destruction and deformities. Visceral leishmaniasis Visceral leishmaniasis A chronic disease caused by Leishmania donovani and transmitted by the bite of several sandflies of the genera phlebotomus and lutzomyia. It is commonly characterized by fever, chills, vomiting, anemia, hepatosplenomegaly, leukopenia, hypergammaglobulinemia, emaciation, and an earth-gray color of the skin. The disease is classified into three main types according to geographic distribution: indian, mediterranean (or infantile), and african. Leishmania/Leishmaniasis (VL) presents with hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. Management is based on clinical severity. Systemic treatment ( amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes) is needed for VL. 
• Leprosy Leprosy Leprosy, also known as Hansen’s disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy: a chronic bacterial infection caused by Mycobacterium leprae Mycobacterium leprae A species of gram-positive, aerobic bacteria that causes leprosy in man. Its organisms are generally arranged in clumps, rounded masses, or in groups of bacilli side by side. Mycobacterium complex. Symptoms primarily affect the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and peripheral nerves Peripheral Nerves The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. Nervous System: Histology, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Diagnosis is established clinically and supported with skin biopsy Skin Biopsy Secondary Skin Lesions. Management includes long-term multidrug antibiotic combinations.