Lepromatous Neuropathy (Hansen's Disease)
This 40 year gentleman was referred to the Department of Neurology for evaluation of progressive numbness in his extremities which began approximately 13 years ago. He also gave a history of repeated trauma to his upper and lower extremities with an inability to recognize significant painful stimuli.
The patient's physical exam was pertinent for hair loss in his distal lower extremities and poorly healed skin lesions on his thigh, calf, and fingers which resulted from previous burns and injuries. On neurological examination, there was a significant glove-stocking loss of sensation to temperature, pinprick, and vibration; asymmetric loss of position sense; impairment of light touch; and minimal loss of sensation over the face. Other than very slight hypersensitivity, the sensation to the plantar surfaces of the feet was normal. The deep tendon reflexes were preserved and muscle strength and coordination were essentially normal.
The clinical picture in this case was in accord with a chronic sensory neuropathy. The unusual findings included preserved deep tendon reflexes and relatively normal sensation on the plantar surfaces of the feet in the presence of marked loss of sensation in the legs.
A chronic sensory neuropathy could be caused by endocrine, inflammatory, or metabolic processes. One of the most common neuropathies seen in patients over 50 years of age is diabetic neuropathy which usually manifests as a distal symmetric sensory impairment associated with persistent numbness and tingling. Trophic changes are common due to ulcerations from unnoticed injury or infection and subsequent osteomyelitis and/or the development of Charcot joints. However, the plantar surfaces of the feet are not spared.
Neuropathies associated with toxin/drug exposure, such as lead or vincristine, as well as vasculitis can also present with predominantly sensory compromise. However, there usually is not a dissociated loss of modalities, and reflexes are invariably depressed. This patient had no history of exposure to toxins nor did he have evidence of endocrinopathy or vasculitis.
The patient's symptoms and signs (symmetrical absence of pain and temperature and normal to slightly increased reflexes) could also be explained by syringomyelia. The onset was insidious and the patient presented in the same age range at which signs and symptoms usually present in patients with syringomyelia (35-45 years of age). The syrinx is most often located in the cervical region, but can be present at any level of the cord as well as in the brainstem. Cavitation of the cord can be associated with other developmental anomalies such as Type I Chiari malformations, thoracic scoliosis, or vertebral fusion. Patients may also present with segmental weakness or ataxia of the lower extremities secondary to corticospinal and posterior column tract involvement. MRI studies in this patient were negative for syringomyelia or any of the associated anomalies.
A hereditary neuropathy of a pure sensory or mixed type was also considered. In the autosomal dominant type, the onset is usually in the second decade of life and the patient usually presents with distal sensory loss affecting pain and temperature greater than touch. There is also autonomic impairment with loss of sweating, decreased sympathetic skin response, and decreased or absent reflexes. On exam, this patient, had marked sensory impairment of pain and temperature, yet reflexes were normal to slightly increased and the family history was negative.
Amyloid neuropathy can present either as an inherited or acquired disorder. In the familial form, the age of onset is between 25-35 years of age. The acquired form usually presents later in life with a mean age of 63 years. In both types, there is a prominence of autonomic effects and a reduction in pain and temperature more than tactile and position sense. Weakness is minimal and reflexes become diminished with progression of the disease.
Another consideration was Tangier disease which is a rare familial disorder presenting in childhood or infancy and associated with an asymmetrical sensorimotor neuropathy. Sensory loss is primarily for pain and temperature, reflexes are diminished or absent, and there is muscular weakness.
Leprous neuropathy is caused by invasion of nerves by the acid fast bacilli Mycobacterium leprae. The presentation is usually with loss of pain and temperature sensation in relatively cool areas, such as the pinnae of the ear, distal extremities, and the tip of the nose. Clinically, there is a symmetric loss of pain and temperature resulting in diffuse anesthesia, and subsequent injuries which may go unrecognized. Autonomic involvement is usually limited to loss of sweating, and tendon reflexes are invariably preserved. Skin lesions can vary, depending on host immunity as well as the pattern and degree of nerve inflammation. The disease is indigenous to certain regions of the United States including Texas, Louisiana, and parts of California. This patient had resided in a small town in southwest Texas for the majority of his life. As a child, he had extensive exposure to armadillos which are well known hosts for
The patient's workup included laboratory, electrophysiologic, and pathologic evaluation. Screening for a systemic inflammatory, endocrine, or metabolic disease was negative. An EMG/NCV confirmed a mixed demyelinating greater than axonal sensory polyneuropathy. A nerve biopsy was performed and was significant for prominent inflammatory reaction, severe depopulation of myelinated nerve fibers, marked proliferation of endoneural connective tissue, and several collections of acid-fast bacilli. All of these findings were in accord with the diagnosis of lepromatous (LL) neuropathy. The patient was subsequently evaluated for associated skin lesions with a skin punch biopsy which showed no evidence of active inflammation or infection.
After screening for G6PD deficiency was negative, the patient was started on multi-drug therapy with dapsone, clofazimine, and rifampin. At one month follow-up, the patient was tolerating the therapy and had no further progression of his symptoms. He will continue to be followed on a monthly basis with the Neurology service and the Hansen's Disease Center in the Dermatology department in Houston, Texas.
Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The microorganism primarily affects the cooler areas of the body, including the superficial portions of nerves, skin, upper respiratory tract, and testes.[1,5] It was first discovered by Gerhard Hansen in 1873, but the earliest written records describing leprosy date back to 600 B.C. from India. It was termed kustha roga and described as hypesthesia, anesthesia, formications, and deformities. During the years 1000-1500, leprosy was widely prevalent in Europe and Great Britain and considered an "unholy and loathsome disease". Similar attitudes still exist today in some cultures. To help minimize the stigma, the term Hansen's disease is often used instead of leprosy when referring to the disease.[4-6]
Leprosy is globally distributed, with the highest prevalence in Africa, South America, India, Southeast Asia, and the Philippine and South Pacific Islands. The World Health Organization (WHO) estimates ten to twelve million patients worldwide, with six thousand cases reported in the United States of America. Ninety percent of the patients in the United States are immigrant residents from endemic areas, yet the disease is indigenous to Hawaii, Louisiana, Texas, and possibly California.[4-6]
The male to female ratio is 2:1 to 3:1 in adults and 1:1 in children and occurs in all age groups. In areas where the prevalence is high, the onset has a peak within the second decade of life with a plateau in the 30-60 year populations.[5,6] There is no ethnic or racial predominance, yet genetic factors do appear to influence susceptibility, secondary to possible difference in genetic host defense factors. Specifically, certain HLA haplotypes are associated with specific forms of leprosy such as HLA-D3 with the tuberculoid form. Twin studies have shown a 60-85% concordance rate in monozygotic (identical) twins, and 15-25% in dizygotic (fraternal) twins.[4-6]
The mode of transmission is uncertain. Most authorities consider the respiratory tract as the major route of entry via aerosol droplets. Skin to skin transmission is also likely, but requires intimate contact, or contact with abraded or open skin of an infected individual. Despite these proposed modes of transmission, there is no increased incidence among spouses of patients. Spouses have a risk rate of 5-6%, which is only slightly higher than that for most populations (4%).[5,6]
Humans were considered the only reservoir until 1974 when 5-10% of armadillos in Louisiana and East Texas were found to have advanced lepromatous disease. Other known animal reservoirs, and subsequent animal models, include the mouse, rat, and Mongabey monkey. However, there is no proven evidence of transmission from these animals to humans in endemic areas.[4-6]
The cardinal symptoms and signs of the disease are hypesthetic skin lesions, anesthesia, enlarged peripheral nerves with associated neuropathy, and acid fast bacilli on skin smear or nerve biopsy. Prodromal symptoms are uncommon and the incubation period is usually 2-5 years, but can be as long as 30-40 years.
The disease has a wide spectrum of clinical and pathological features. In 1986, the World Health Organization devised a simplified system for classification based on the number of Mycobacterium leprae found in each patient: 1) paucibacillary, those with negative skin smears and clinical symptoms and 2) multibacillary, those with positive smears. Ripley and Jopling (1966) were the first to propose a classification based on immunologic, pathologic, and clinical features.[2,5,6]
Leprosy is the most common cause of neuropathy. Nerve fibers which lie superficially under the skin are the most severely affected because the cooler temperature allows for growth of the organism. The type of neuropathy can vary from either a multiple mononeuropathy to a symmetric sensory neuropathy, depending upon the form of leprosy and the host immune response.[1,4]
In the tuberculoid type, dermal nerve involvement is rapid, so virtually all skin lesions lose the ability to sweat and are anesthetic to light touch, temperature, and pain. Superficial nerves can become thickened and firm, and if the neuritis is active, they may be tender or painful. Nerves of predilection include the ulnar, superficial radial, and median nerves.[1,5,6]
In the lepromatous type, nerve compromise develops slowly beginning with normal sensation early in the disease to progression of a glove and stocking anesthesia which can involve the entire body surface except for areas which are warm (greater than 33 degrees centigrade), such as the hairy scalp, axillae, perineum, and inguinal regions. Fine terminal twigs of sensory and autonomic nerves are primarily affected, resulting in dysfunction in temperature, superficial pain, light touch, and sweating. Pressure, deep pain, and soft tissue vibration are affected late. Vibration sense from bone and proprioception are usually preserved. Tendon reflexes are normal, and there is commonly preserved sensation or even hypersensitivity of the plantar surfaces of the feet.[1,5,6]
Skin lesions also vary according to the type of leprosy. With lepromatous type, early manifestations are dermal rather than neural, yet the patient may not present until there is marked superficial glove and stocking anesthesia. The lesions are numerous, ill-defined, and symmetrically distributed over the body. In the tuberculoid type, skin lesions are few and asymmetric, anesthetic and dry, and are not usually associated with nerve involvement except in large lesions.[1,2,4-7]
Mycobacterium leprae is an acid fast bacillus (5 by 0.5 µm) which is taken up by histiocytes in skin and invades the perineural and endothelial cells. It has a predilection for Schwann cells associated with thinly myelinated and unmyelinated axons. Adhesion of the organisms to the Schwann cell involves the polysaccharides and lipids of the bacillary cell wall, although it is not known precisely how
The form of leprosy is dependent upon the host cell mediated immune response. In the tuberculoid type, the cellular immunity is well developed, resulting in limited growth of the bacilli. Nerve damage is either indirect from granuloma formation or direct via an active neuritis. On pathology, bacilli are rare and epithelioid formation is prominent in the dermis, subcutaneous tissue, and nerves. T helper cells are numerous and found concentrated in the central epithelial rich area with T-suppressor cells found in the peripheral mantle of the granuloma.[1,2,4-7]
In the lepromatous type, the cell mediated immune response is weak, and there is marked inflammation with infiltration of lymphocytes and macrophages which are admixed. The macrophages accumulate lipid and become vacuolated. AFB are abundant within the Schwann cells, vessel endothelial cells, arrectores pilorum muscles, and macrophages. T-suppressor cells are predominant.[5,6]
It is unknown what determines the difference in cell mediated immune response among tuberculoid and lepromatous patients. It is felt to be, in part, under genetic control via the HLA complex. HLA-D antigens influence the antigen presentation to T-helper lymphocytes, and therefore affect the immune response by the production of IL-2 and subsequent production of gamma-interferon. Of interest, in lepromatous leprosy, there is a failure to produce IL-2 with decreasing levels of gamma interferon and macrophage activation.[5,6]
Diagnosis is based primarily on the clinical examination with the support of skin and/or nerve biopsy. The four cardinal features for diagnosis include sensory loss, thickened peripheral nerves, skin lesions, and acid fast bacilli on biopsy or smear.[1,7] At least two of the first three cardinal features, or a positive biopsy, are necessary to make the diagnosis of leprosy. Unfortunately, in the United States, the diagnosis of leprosy is often delayed secondary to failure to recognize the early signs and symptoms. An index of suspicion should be raised if a patient presents with an unusual skin rash and/or peripheral neuropathy. The neuropathy can present as an acute neuritis or secondary to complication of sensory or motor nerve damage.[5-7]
Diagnostic tests used are based upon the pathologic findings, immunologic markers, and immune response of the patient. Biopsy of tissue is fundamental in confirming the diagnosis and includes specimens from skin lesions and nerves. Nerves which are commonly biopsied include the medial branch of the radial cutaneous nerve and the sural nerve. The probability of documenting acid fast bacilli is dependent upon the type of leprosy, as the load of AFB is greater in the lepromatous or multibacillary forms.[1,2,7]
Skin tests are also available which aid in documenting exposure and classification. The Lepromin test (response to the intradermal injection of 0.1 ml of standard suspension of killed
Other skin tests include the histamine and pilocarpine test. The histamine test reflects integrity of the sympathetic nerve fibers via the presence or absence of a wheal and flare response, and the pilocarpine test assesses the integrity of parasympathetic nerve fibers with a present or absent response of sweat glands.[7]
Other tests available utilize immunofluorescence for titers specific for antibodies to
These tests and assays are useful not only for diagnosis, but also for determining the presence of persistent and subclinical infection in asymptomatic untreated as well as treated patients.
Beginning in 1941 in Carillo, Louisiana, sulfonamides have been the mainstay of treatment. With the emergence of increasing dapsone resistant strains (now found in up to 50% of all diagnosed patients), the WHO now recommends multi-drug therapy.[5,6]
For multibacillary leprosy (lepromatous and borderline cases), treatment includes rifampicin, clofazimine, and dapsone. Treatment should be given for a minimum of two years, and preferably until the patient is skin smear negative (especially in patients with skin smear bacterial index greater or equal to 4.0). Relapse rates are less than 1%.[1,2,5-7]
For paucibacillary (borderline and indeterminate cases), treatment with both rifampicin and dapsone is recommended. Relapse rates are also less than 1%.[1,2]
Alternate regimens are seldom used, yet recommendations by WHO have been given in cases where there is contraindication to a drug, or an adverse side effect occurs. Ofloxocine, minocycline, and clarithromycin are all bactericidal for
Vaccination with Bacille Calmette-Guerin (BCG) has been shown to give some protection, yet it provides only 20% protection overall in highly endemic areas. Trials are presently in progress comparing the efficacy of autoclaved
Treatment for the neuritis and nerve function impairment includes corticosteroids which are used to prevent further damage and facilitate recovery. Therapy is most effective in recovery of nerve damage of less than six months, and recovery usually occurs within the first 3-4 months. Steroid treatment is given for about six months, with a slow taper over several months to a maintenance dose. No trials have been done to evaluate the efficacy of steroid treatment for nerve lesions of greater than six months.[1,2]
About 50% of patients experience acute or chronic immunologically mediated reactions. The majority of these reactions occur in patients receiving drug therapy, but are also common in untreated patients. These reactions are considered medical emergencies, and must be treated promptly to prevent permanent nerve damage. The three reactions recognized include:[1,2,4-6]
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