Case 1-2004 — A 49-Year-Old Woman with Asymmetric Painful Neuropathy
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《新英格兰医药杂志》
Presentation of Case
A 49-year-old left-handed woman was evaluated in the neurology clinic because of painful asymmetric neuropathy.
The patient had been well until several years earlier, when numbness developed in the right hand. A right carpal-tunnel–release operation had been performed eight months before the current evaluation, but without benefit. During the four months before the evaluation, she experienced increasing burning pain in the same hand, and similar symptoms developed in the left hand. She frequently observed blisters on the first, second, and third digits of the right hand, without any recollection of injury. She had decreased sensation in the legs, particularly a decreased sensation of temperature, and feelings of "pins and needles." There were intermittent, lancinating pains in the distal portion of the left leg and pain over the left side of the face after it was touched. She also had hearing loss, which was more prominent in the left ear than in the right. She recalled two episodes of pruritic rash on the back. More recently, she had observed swelling of the feet and ankles, especially on the left side.
The patient had immigrated to the United States from India 13 years earlier. She had worked in an office until the hand pain forced her to retire. She had a long history of low back pain but no history of arthralgia or articular swelling, although the fingers became swollen and stiff at times and the right hand sometimes became "purple and cold." She experienced frequent constipation, seasonal allergies, and "chronic anemia." There were no other gastrointestinal symptoms or changes in bladder function, changes in weight, fevers, chills, chest pain, palpitations, respiratory symptoms, or night sweats. Her medications were vitamin B, oxycodone–acetaminophen, and a calcium supplement; in the past, she had also received vitamin B12 injections. She had had three uneventful pregnancies. A sister and a brother were well, as were her children; no one in her family had neurologic problems.
Laboratory tests performed at another hospital two days before the current evaluation showed that the thyrotropin level was normal, and tests for rheumatoid factor and antinuclear antibodies were negative. At the same hospital, nerve-conduction studies were performed in the left peroneal and left and right posterior tibial nerves and elicited right and left H reflexes; the sensory nerves were not tested. An examination of motor-nerve conduction revealed a normal amplitude in the right tibial response and decreased amplitude in the left tibial and left peroneal motor responses; on needle examination, there were fibrillation potentials in the left extensor digitorum brevis, left abductor hallucis, and left flexor digitorum longus; on the right side, fibrillations were seen only in the abductor hallucis. The conduction velocities were normal. The patient was referred to this hospital for further evaluation.
On physical examination, the patient appeared well and wore a glove on the right hand. The skin of the right-hand digits was slightly shiny and atrophic. The second and third fingers of the right hand were swollen; there were hyperpigmented areas that she related to previous blisters, and there was a subtle, flat area of hypopigmentation on the right side of the back. There was mild pedal edema bilaterally. The head, lungs, heart, and abdomen were normal.
On neurologic examination, the pupils were equal and reactive, and the retinas were normal. Extraocular movements were full, with normal saccades and no nystagmus. Facial sensation was normal except for areas of mildly decreased sensation of a pinprick in the left V2 distribution (the distribution of the second branch of the fifth cranial nerve or the maxillary division of the trigeminal nerve); the facial movements were normal. The remaining cranial-nerve functions were preserved. The strength of the arms and hands was normal. No enlarged peripheral nerves were palpated. Sensation of all types was severely diminished in the first, second, and third digits of the right hand. The sensation of a pinprick was decreased over the dorsum of both hands, and there was a distal-to-proximal gradient of pinprick and temperature sensation in all the fingers, with sensation better in the palms than in the fingers.
The strength of the legs was normal except for toe-extension strength, which was 4/5 bilaterally. Vibratory sensation was markedly reduced in the toes and intact at the ankles; the sensation of a pinprick was decreased distal to the left ankle and in the right toes. The deep-tendon reflexes were ++ and symmetric throughout; the plantar responses were flexor. There was no tremor. The results of finger-to-nose testing were normal. She could walk on her heels or toes and performed tandem walking well. The result of Romberg's test was negative. Tinel's sign was absent at the right carpal tunnel and elbow.
The results of laboratory tests are shown in Table 1. Serum protein electrophoresis yielded a normal pattern with a slight, diffuse increase in the gamma globulin level. Tests for antibodies against myelin-associated glycoprotein and neuronal nuclear antigen were negative, and DNA sequencing of alleles 1 and 2 of the gene encoding transthyretin was negative for mutations associated with amyloidosis. Tests for the sulfatide autoantibody and the GALOP (gait disorder, autoantibody, late-age onset, and polyneuropathy) autoantibody were negative, indicating that the patient did not have a late-onset immune neuropathy. Gabapentin was prescribed for the painful dysesthesias, and a follow-up examination was scheduled.
Table 1. Hematologic and Other Laboratory Values.
At the follow-up examination two and a half months later, the patient said that the swelling in her feet had improved, but that the pain in her left foot was radiating into the leg. She again had a small blister over the second finger on the right hand and said that the right hand occasionally turned "purple and red." She was taking oxycodone–acetaminophen and calcium and iron supplements but was not taking the gabapentin regularly because it sedated her.
On examination, sensation of a pinprick and of temperature was decreased distally in all the extremities, particularly in the right hand and left foot, and there was anesthesia with respect to all types of sensation in the right median-nerve distribution. Vibratory sensation was reduced in the left foot. Strength was normal throughout all the muscle groups on detailed examination. The deep-tendon reflexes were ++ and symmetric, and the plantar responses were flexor. Cerebellar function remained normal.
The urine was normal. Tests for antinuclear antibodies, anti–Jo-1 antibodies, anti–Scl-70 antibodies, and anti–hepatitis B core antibodies were negative. The results of additional laboratory tests are shown in Table 1.
An electromyographic study was performed on the right arm and both legs. There was evidence of a sensorimotor axonal neuropathy; sensory responses were absent. The disorder was asymmetric, with a low-amplitude motor response in the tibial nerve on the left side and normal-amplitude responses on the right side. Needle-electromyographic examination showed only slight changes in reinnervation in the tibialis anterior and extensor digitorum brevis on the left side and the abductor pollicis brevis on the right side.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. David A. Chad: This 49-year-old woman presented with a painful peripheral neuropathy. We must first define the attributes of the neuropathy and then develop a differential diagnosis.
Characterizing a Peripheral Neuropathy
We begin by reviewing the defining characteristics of the neuropathy.1,2,3 The most important of these are the time course, the type of neuron or fiber involved, the clinical and anatomical pattern of the deficits, the type of nerve-fiber abnormality, the type of neuropathy (inherited or acquired), and the availability of clues to the possible presence of an associated systemic disease (Table 2).
Table 2. Defining Characteristics of the Patient's Peripheral Neuropathy.
The record indicates that the neuropathy in this patient is chronic. Her right hand had been numb for several years, and the burning paresthesias in her hands and feet had been present for four months. Small sensory fibers were predominantly affected, and the neuropathy was painful, with trophic changes in the skin of the right hand. There was a loss of large-fiber vibratory sensation, particularly in the territory of the median nerve in the right hand and in both feet. The presence of intact reflexes indicates that the large-diameter, heavily myelinated 1A afferent neurons were spared. Some motor-fiber involvement was evident both on physical examination and on electromyography.
The clinical and anatomical pattern of the patient's deficits is complex. There is bilateral but asymmetric involvement of the upper and lower extremities (with the distal extremities much more affected than the proximal extremities). In addition, the electromyogram points to at least two superimposed mononeuropathies: a painful mononeuropathy of the right median nerve, with the site of involvement probably above the transverse carpal ligament, because of some loss of sensation in the palm, and with features resembling those of causalgia, and both sensory and motor neuropathy of the left tibial nerve. Finally, there appears to have been involvement of the maxillary division of the left trigeminal nerve. This pattern suggests the presence of an evolving mononeuritis multiplex that is passing through the stage of overlapping mononeuropathies on its way to a mostly distal, symmetric polyneuropathy.4
The nerve-fiber abnormality appears to be a mix of axon loss and demyelination. Axonal involvement of the motor fibers is indicated by the slight changes in motor-unit potential in the territories of the right median and left peroneal nerves and by the reduced amplitude of the left tibial motor response. There are also features of demyelination, since the motor velocities are reduced more than can be explained by loss of amplitude alone. Pronounced sensory involvement, with relative sparing of the motor responses, may be caused by loss of the neurons of the dorsal-root ganglia,5 their axons, or both, but in this instance it is more likely a result of damage to the nerve fibers rather than to the cell bodies.
The neuropathy in this patient is more likely to be acquired than inherited. The absence of a family history, the age at onset, and both its duration and the fact that it is asymmetric, with prominent paresthesias, are features typical of acquired peripheral neuropathy.2
There are clues that a systemic disorder may be present. The episodes of color changes in the right hand suggest Raynaud's phenomenon, and the mild polyclonal hypergammaglobulinemia suggests immune activation. The mild abnormalities in the levels of aspartate aminotransferase and alanine aminotransferase suggest that there is inflammation of the liver. These features raise the possibility of an underlying connective-tissue disorder. The fact that the patient had emigrated from India and the subtle, hypopigmented skin lesion raise the possibility of infection by Mycobacterium leprae.
The Process of Differential Diagnosis
Table 3 lists the diagnoses that would match the characteristics I have described: a chronic, acquired, painful, overlapping mononeuritis multiplex that predominantly affects sensory fibers, with a combination of axon loss and demyelination and with some features suggesting a connective-tissue disease and others that raise the possibility of leprosy. Table 3 also lists the reasons for including or ruling out each possible diagnosis.
Table 3. Considerations in the Differential Diagnosis of the Peripheral Neuropathy in the Current Case.
A predominantly sensory neuropathy presenting in midlife raises the possibility of a paraneoplastic manifestation.5 Because small dorsal-root ganglia may be targeted initially, the disorder may begin with painful asymmetric paresthesias, commonly in the hand or arm, but, unlike the disorder seen in this case, evolves to affect large sensory fibers, with pronounced sensory ataxia and attenuation or loss of tendon reflexes. The predominance of small-fiber involvement in the current case suggests sensory perineuritis10,11 and other forms of small-fiber sensory neuropathy in which the reflexes remain intact.12,13,14 Their relatively benign nature, or relapsing–remitting character, however, suggests that they are unlikely candidates for the diagnosis in this case.
A predominantly small-fiber neuropathy in primary systemic amyloidosis is classically manifested as a distal, symmetric polyneuropathy with prominent autonomic signs and major-organ involvement. It is a consideration here for several reasons: it is characterized by sensory symptoms that spread very rapidly to the hands, with carpal tunnel syndrome as the presenting feature in 25 percent of patients15; cranial neuropathy, including trigeminal involvement, may occur; and perhaps most important, tendon reflexes are preserved until the condition is in its advanced stages — a point emphasized by David Dawson at one of these conferences in 1979.16 He pointed out that preservation of tendon reflexes narrows the range of diagnostic possibilities to just a few conditions: amyloidosis, leprosy, and slowly advancing sensory diabetic neuropathy. There are no clinical or laboratory findings in this case, however, that would support a diagnosis of amyloid neuropathy.
Narrowing the Differential Diagnosis
The process of differential diagnosis leads to a consideration of vasculitic neuropathy in the context of systemic vasculitis or connective-tissue disease and leprous neuropathy. Although cryoglobulinemic neuropathy is associated with Raynaud's syndrome and although it may produce painful asymmetric neuropathy and be associated with liver dysfunction due to hepatitis C infection,17 the absence in this case of skin lesions suggesting leukocytoclastic vasculitis and the absence of serum protein abnormalities make this diagnosis unlikely. Vasculitic neuropathy occurs in Sj?gren's syndrome, a chronic autoimmune disorder of the exocrine glands. Patients with Sj?gren's syndrome may have Raynaud's phenomenon and hypergammaglobulinemia, and the peripheral nerves may be affected.18 One of the major manifestations of the neuropathy of Sj?gren's syndrome is a sensory ganglionopathy that is manifested predominantly as a sensory ataxia, although there may also be vasculitic involvement of individual nerve trunks. Sj?gren's syndrome is one of the few connective-tissue disorders that affects the trigeminal ganglion.1 Peripheral neuropathy may predate or overshadow symptomatic glandular involvement,18 and testing for anti-SSA and anti-SSB autoantibodies is helpful but not definitive. In the current case, I initially favored a diagnosis of vasculitic neuropathy, possibly in the context of Sj?gren's syndrome.
The patient was known, however, to have come from a region where leprosy is endemic, and she presented with a predominantly small-fiber neuropathy and intact reflexes. These factors, along with the presence of a subtle, hypopigmented skin lesion, raise the possibility of leprous neuropathy.19 Several features of the case are not typical of this diagnosis, including the severe pain and causalgia, large-fiber sensory involvement, and absence of demonstrable enlargement of peripheral nerves.
However, there was a greater reduction of pinprick sensation over the dorsal surfaces of the hands than over the palmar aspects — regions equidistant from the trunk and served by the same upper-limb nerves. Indeed, the pattern in this case, as outlined by Sabin in his classic description of sensory loss in leprosy,
. . . attracts attention because it does not follow the distribution of the named subcutaneous sensory nerves, of the mixed nerve trunks, of the sensory roots, or of the distal symmetrical sensory loss with fading upper borders commonly associated with the various hereditary, toxic and metabolic neuropathies. Comparison of this pattern of sensory loss with thermographic pictures of the arm suggests that local temperature differences might provide an explanation for this unique configuration of sensory loss.20
Figure 1 shows Sabin's examples of temperature-linked sensory loss in lepromatous neuropathy. In addition, the allodynia and sensory loss on the face involve the malar region, an area that is cooler than other regions of the body. Thus, the involvement that I originally considered a manifestation of a trigeminal neuropathy could be viewed as temperature-linked cutaneous sensory loss. The intact deep-tendon reflexes and preserved H reflexes in the face of pronounced sensory loss in the feet for small- and large-fiber modalities (pain and light touch, respectively) in the absence of sensory-nerve action potentials point to very distal (intracutaneous) sensory-nerve involvement, which is typical of lepromatous neuropathy.19,21 There is also evidence of lesions involving more proximal portions of the peripheral nerves — specifically, the right median nerve and the left tibial nerve. Such mononeuropathies may also be seen in leprous neuropathy.19,21
Figure 1. Temperature-Linked Sensory Loss in Lepromatous Neuropathy.
The upper part of the figure shows an example of the pattern of sensory loss in the forearm and hand on routine pinprick examination. The palmar surface of the hand is spared, whereas the dorsum is affected. The lower part of the figure shows sites selected for temperature measurements. The odd-numbered member of each pair (1, 3, 5, and 7) is always warmer than the even-numbered counterpart (2, 4, 6, and 8); warmer sites are spared from sensory loss, whereas cooler sites are affected. The blue lines demarcate regions with different degrees of sensory loss. (Adapted from Sabin,20 with the permission of the publisher.)
The causative organism of leprosy is M. leprae, an acid-fast, obligate, intracellular gram-positive bacillus that reproduces maximally at 27°C to 30°C.15 Consequently, infection is most prominent in cooler regions of the body (34°C to 35°C).19,21 The organism infects the skin and cutaneous nerves, its principal target being the Schwann-cell basal lamina.22
Five major clinical subtypes of leprosy, which reflect the immunologic status of the host, have been defined.19,21 Tuberculoid leprosy occurs in persons with relatively intact cell-mediated immunity to the organism, limiting the spread of the disease. Typically, there are a small number of skin lesions in cool regions, with adjacent nerve-trunk involvement. Histopathological examination of the skin and nerves shows granulomas but no or few bacilli. Lepromatous leprosy occurs in persons with no immune response to M. leprae. Large numbers of bacilli are found in the skin, nerves, and nasal mucosa. Borderline leprosy is intermediate in its manifestations between those two subtypes and is subdivided into forms that more closely resemble tuberculoid leprosy (so-called borderline tuberculoid leprosy) and forms that are closer to lepromatous leprosy (so-called borderline lepromatous leprosy).
In tuberculoid leprosy, sensory loss is pronounced in the skin lesions as a result of damage to the dermal nerves. There may be damage to nerve trunks in the vicinity of the skin lesions, and on occasion painful mononeuropathies develop in swollen or enlarged nerves.19 In lepromatous leprosy, a progressive symmetric polyneuropathy favoring cool regions is the chief manifestation.19 There is also damage to peripheral-nerve trunks, resulting in superimposed mononeuropathies that may evolve into mononeuritis multiplex. The incidence of neuropathic complications is probably highest in patients with borderline leprosy.19,21 These patients have an unstable immune response to the organism, so that the clinical manifestations vary along the tuberculoid-to-lepromatous spectrum. Impaired immunity results in extensive spread of the organism, whereas retained immunity generates a destructive inflammatory granulomatous response.
Leprous neuropathy explains several key clinical manifestations in this case. The painful dysesthesias affecting the hands, with sensory loss more pronounced on the dorsal than on the palmar surfaces, can be explained by temperature-dependent invasion of dermal nerves by M. leprae. The exquisitely painful right median neuropathy in the forearm is related to involvement of the proximal median-nerve trunk. The retention of the deep-tendon reflexes probably indicates that the deep-seated 1A afferent nerves were spared. The absence of sensory responses stems from very distal axon loss in intracutaneous nerves. Finally, motor-nerve conduction velocities that have decreased out of proportion to amplitude loss reflect demyelination due to the destruction of Schwann cells.
I believe that the likeliest diagnosis in this case is leprous neuropathy and that the diagnostic procedure was a sural-nerve biopsy. Because the clinical features are most consistent with the presence of borderline leprosy, I expect that examination of the biopsy specimen revealed both poorly defined granulomas and numerous bacilli.
Dr. E. Tessa Hedley-Whyte: Dr. Dawson, what was your clinical impression before the diagnostic procedure?
Dr. Katherine T. Dawson (Neurology): Our clinical impression was very close to that described by Dr. Chad. We were concerned about vasculitis, but we were also concerned about leprosy because of the skin lesions. We presented the patient to Dr. Anthony Amato at our interhospital neuromuscular conference.
Dr. Anthony Amato (Neurology, Brigham and Women's Hospital, Boston): My initial impression was that this patient's disorder was most likely leprous neuropathy. We decided to perform a sural-nerve biopsy. Under the optimal lighting of the operating room, the skin lesions on the back and arm were much more evident than they had been in the clinic, and I believed that they were typical of leprosy.
Clinical Diagnosis
Leprosy.
Dr. David A. Chad's Diagnosis
Borderline leprosy.
Pathological Discussion
Dr. Hedley-Whyte: The diagnostic procedure was a sural-nerve biopsy, which was performed by Dr. Amato.
Examination of the paraffin sections reveals a dense inflammatory infiltrate around the blood vessels and beneath the perineurium (Figure 2A). Some poorly circumscribed collections of histiocytes but no true granulomas were found (Figure 2B). The trichrome stain showed that myelin was preserved in some fascicles but that in adjacent fascicles there was myelin loss and endoneurial fibrosis. Fite's modification of the Ziehl–Neelsen acid-fast stain for mycobacteria revealed innumerable bacilli in Schwann cells (Figure 2C).
Figure 2. Sural-Nerve Biopsy Specimen.
There is a brisk inflammatory reaction in two nerve fascicles and a lesser inflammatory action in a third fascicle (Panel A, hematoxylin and eosin, x31). The inflammatory infiltrate consists of plasma cells and lymphocytes with rare, poorly formed aggregates of histiocytes (arrow) (Panel B, hematoxylin and eosin, x250). The inflammatory infiltrate is accentuated in the subperineurial area. Staining with Fite's modified Ziehl–Neelsen acid-fast stain shows that numerous Schwann cells contain acid-fast bacilli (arrows, Panel C, x500; inset, x1200). (Slides courtesy of Dr. Hart Lidov, Brigham and Women's Hospital, Boston.)
On ultrastructural examination, bacilli consistent with M. leprae were found in Schwann cells, particularly in those associated with unmyelinated axons (Figure 3A). There was a loss of unmyelinated axons, manifested by the presence of so-called empty Schwann-cell stacks (Figure 3B). These findings confirm the diagnosis of leprosy and are somewhat more characteristic of the lepromatous type than of the tuberculoid type.23
Figure 3. Electron Micrograph of the Sural-Nerve Biopsy Specimen.
A Schwann cell that is responsible for unmyelinated axons contains numerous bacilli (Panel A). The Schwann cells responsible for the unmyelinated axons are the ones predominantly infected with the bacilli. The total number of unmyelinated fibers has decreased, as evidenced by the presence of so-called Schwann-cell stacks, which are layers of collapsed Schwann-cell membrane (arrow). The bacilli are concentrated in the Schwann-cell cytoplasm (arrow, Panel B). Adjacent Schwann cells do not contain bacilli. (Images courtesy of Dr. Joseph C. Corbo, Brigham and Women's Hospital, Boston.)
The diagnosis of leprosy in the United Kingdom and the United States is often delayed.21,24 The median time from the onset of symptoms to diagnosis in a series of 28 patients at the Hospital for Tropical Diseases in London between 1995 and 1998 was 1.5 years (range, 0.2 to 15.2). Forty-three percent of the patients came from the Indian subcontinent, and 25 percent from Africa. Misdiagnosis of the condition as another dermatologic or neurologic disease was an important reason for the delay. The time from entry into the United Kingdom to diagnosis ranged from 0.2 to 47.8 years. Points at which the diagnosis was delayed were identified as evaluation by a general practitioner (10 of the 28 patients), orthopedic surgeon (5 of the patients), or neurologist (3 of the patients) or evaluation at the Hospital for Tropical Diseases (2 of the patients). Two of the patients had not reported a previous diagnosis of leprosy. Twenty-one of 28 patients seen by a dermatologist were "promptly" given the diagnosis. Similarly, Nations et al.21 pointed out that physicians in the United States may lack familiarity with the disease, with resulting delays in diagnosis.
Dr. Nesli Basgoz (Infectious Disease): This patient was referred to the infectious-disease clinic. On examination, she was found to have a large hypopigmented area with heaped-up borders on her back and a similar, smaller lesion on her left arm (Figure 4). Both were anesthetic. She recalled having been told 15 years ago that she had a small hypopigmented area on her back. This protracted time course illustrates the fact that the cutaneous and nerve-related manifestations of leprosy can progress very slowly, because of the slow growth of the organism.
Figure 4. Photographs of the Skin Lesions.
There is a large, faintly hypopigmented area on the back (arrows, Panel A), which has slightly raised edges. A similar, smaller lesion is present on the left arm (arrows, Panel B). Both lesions were anesthetic.
Most patients with leprosy have borderline leprosy. Our patient had some features of tuberculoid leprosy, including a small number of skin lesions with elevated edges and some evidence of granuloma formation on biopsy. However, she also had a polyneuropathy and shiny skin, which are consistent with some dermal infiltration, and there were many acid-fast bacilli in the nerve-biopsy specimen — features more suggestive of the lepromatous form of the disease. Therefore, she most likely had borderline leprosy.
As was the case with this patient, most cases of leprosy are not diagnosed by infectious-disease specialists but, rather, by internists, neurologists, and dermatologists. If any physician sees a patient from an area where this infection is endemic (Asia, Africa, the Pacific Islands, or South America) who has unexplained skin lesions, particularly if they are anesthetic or if there are accompanying neuropathies, it is important to consider leprosy. Early diagnosis and treatment can help prevent the neuropathic and other complications of untreated leprosy.
Although leprosy is a much-feared disease, it is not particularly infectious. The organisms are present in the skin at the level of the dermis, so touching the surface of the skin is without risk. The most likely mode of transmission is respiratory, through contact with nasal secretions. In areas where the infection is endemic, clinical disease will develop in only about 1 in 350 people who are infected with M. leprae. Once treatment is initiated, there is a rapid disappearance of organisms from the nose, so there is no indication for isolation.
In the current case, we treated the patient with dapsone and rifampin. After nine months of treatment, she continues to have slow improvement in the pain and numbness in her hands and feet, as well as improvements in motor strength. The skin lesions have become less distinct. Treatment will continue for several years.
Anatomical Diagnosis
Borderline leprosy.
Addendum
At follow-up 14 months after the initiation of treatment, the patient's skin lesions had almost completely resolved. The anesthetic areas on the dorsum of the hands and feet had become sensitive to touch. Her motor strength was normal.
Editor's note: Dr. William Fennel McNeely retired as Associate Editor of the Case Records of the Massachusetts General Hospital on January 1, 2004. His concise and precise writing style and meticulous attention to detail have set the standard for the preparation of a case history for 30 years. The current and former editors of the Case Records are grateful for his contributions.
Source Information
From the Department of Neurology, UMass Memorial Health Care, and the Departments of Neurology and Pathology, University of Massachusetts Medical School, Worcester (D.A.C.); and the Department of Pathology, Division of Neuropathology, Massachusetts General Hospital, and the Department of Pathology, Harvard Medical School (E.T.H.-W.).
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A 49-year-old left-handed woman was evaluated in the neurology clinic because of painful asymmetric neuropathy.
The patient had been well until several years earlier, when numbness developed in the right hand. A right carpal-tunnel–release operation had been performed eight months before the current evaluation, but without benefit. During the four months before the evaluation, she experienced increasing burning pain in the same hand, and similar symptoms developed in the left hand. She frequently observed blisters on the first, second, and third digits of the right hand, without any recollection of injury. She had decreased sensation in the legs, particularly a decreased sensation of temperature, and feelings of "pins and needles." There were intermittent, lancinating pains in the distal portion of the left leg and pain over the left side of the face after it was touched. She also had hearing loss, which was more prominent in the left ear than in the right. She recalled two episodes of pruritic rash on the back. More recently, she had observed swelling of the feet and ankles, especially on the left side.
The patient had immigrated to the United States from India 13 years earlier. She had worked in an office until the hand pain forced her to retire. She had a long history of low back pain but no history of arthralgia or articular swelling, although the fingers became swollen and stiff at times and the right hand sometimes became "purple and cold." She experienced frequent constipation, seasonal allergies, and "chronic anemia." There were no other gastrointestinal symptoms or changes in bladder function, changes in weight, fevers, chills, chest pain, palpitations, respiratory symptoms, or night sweats. Her medications were vitamin B, oxycodone–acetaminophen, and a calcium supplement; in the past, she had also received vitamin B12 injections. She had had three uneventful pregnancies. A sister and a brother were well, as were her children; no one in her family had neurologic problems.
Laboratory tests performed at another hospital two days before the current evaluation showed that the thyrotropin level was normal, and tests for rheumatoid factor and antinuclear antibodies were negative. At the same hospital, nerve-conduction studies were performed in the left peroneal and left and right posterior tibial nerves and elicited right and left H reflexes; the sensory nerves were not tested. An examination of motor-nerve conduction revealed a normal amplitude in the right tibial response and decreased amplitude in the left tibial and left peroneal motor responses; on needle examination, there were fibrillation potentials in the left extensor digitorum brevis, left abductor hallucis, and left flexor digitorum longus; on the right side, fibrillations were seen only in the abductor hallucis. The conduction velocities were normal. The patient was referred to this hospital for further evaluation.
On physical examination, the patient appeared well and wore a glove on the right hand. The skin of the right-hand digits was slightly shiny and atrophic. The second and third fingers of the right hand were swollen; there were hyperpigmented areas that she related to previous blisters, and there was a subtle, flat area of hypopigmentation on the right side of the back. There was mild pedal edema bilaterally. The head, lungs, heart, and abdomen were normal.
On neurologic examination, the pupils were equal and reactive, and the retinas were normal. Extraocular movements were full, with normal saccades and no nystagmus. Facial sensation was normal except for areas of mildly decreased sensation of a pinprick in the left V2 distribution (the distribution of the second branch of the fifth cranial nerve or the maxillary division of the trigeminal nerve); the facial movements were normal. The remaining cranial-nerve functions were preserved. The strength of the arms and hands was normal. No enlarged peripheral nerves were palpated. Sensation of all types was severely diminished in the first, second, and third digits of the right hand. The sensation of a pinprick was decreased over the dorsum of both hands, and there was a distal-to-proximal gradient of pinprick and temperature sensation in all the fingers, with sensation better in the palms than in the fingers.
The strength of the legs was normal except for toe-extension strength, which was 4/5 bilaterally. Vibratory sensation was markedly reduced in the toes and intact at the ankles; the sensation of a pinprick was decreased distal to the left ankle and in the right toes. The deep-tendon reflexes were ++ and symmetric throughout; the plantar responses were flexor. There was no tremor. The results of finger-to-nose testing were normal. She could walk on her heels or toes and performed tandem walking well. The result of Romberg's test was negative. Tinel's sign was absent at the right carpal tunnel and elbow.
The results of laboratory tests are shown in Table 1. Serum protein electrophoresis yielded a normal pattern with a slight, diffuse increase in the gamma globulin level. Tests for antibodies against myelin-associated glycoprotein and neuronal nuclear antigen were negative, and DNA sequencing of alleles 1 and 2 of the gene encoding transthyretin was negative for mutations associated with amyloidosis. Tests for the sulfatide autoantibody and the GALOP (gait disorder, autoantibody, late-age onset, and polyneuropathy) autoantibody were negative, indicating that the patient did not have a late-onset immune neuropathy. Gabapentin was prescribed for the painful dysesthesias, and a follow-up examination was scheduled.
Table 1. Hematologic and Other Laboratory Values.
At the follow-up examination two and a half months later, the patient said that the swelling in her feet had improved, but that the pain in her left foot was radiating into the leg. She again had a small blister over the second finger on the right hand and said that the right hand occasionally turned "purple and red." She was taking oxycodone–acetaminophen and calcium and iron supplements but was not taking the gabapentin regularly because it sedated her.
On examination, sensation of a pinprick and of temperature was decreased distally in all the extremities, particularly in the right hand and left foot, and there was anesthesia with respect to all types of sensation in the right median-nerve distribution. Vibratory sensation was reduced in the left foot. Strength was normal throughout all the muscle groups on detailed examination. The deep-tendon reflexes were ++ and symmetric, and the plantar responses were flexor. Cerebellar function remained normal.
The urine was normal. Tests for antinuclear antibodies, anti–Jo-1 antibodies, anti–Scl-70 antibodies, and anti–hepatitis B core antibodies were negative. The results of additional laboratory tests are shown in Table 1.
An electromyographic study was performed on the right arm and both legs. There was evidence of a sensorimotor axonal neuropathy; sensory responses were absent. The disorder was asymmetric, with a low-amplitude motor response in the tibial nerve on the left side and normal-amplitude responses on the right side. Needle-electromyographic examination showed only slight changes in reinnervation in the tibialis anterior and extensor digitorum brevis on the left side and the abductor pollicis brevis on the right side.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. David A. Chad: This 49-year-old woman presented with a painful peripheral neuropathy. We must first define the attributes of the neuropathy and then develop a differential diagnosis.
Characterizing a Peripheral Neuropathy
We begin by reviewing the defining characteristics of the neuropathy.1,2,3 The most important of these are the time course, the type of neuron or fiber involved, the clinical and anatomical pattern of the deficits, the type of nerve-fiber abnormality, the type of neuropathy (inherited or acquired), and the availability of clues to the possible presence of an associated systemic disease (Table 2).
Table 2. Defining Characteristics of the Patient's Peripheral Neuropathy.
The record indicates that the neuropathy in this patient is chronic. Her right hand had been numb for several years, and the burning paresthesias in her hands and feet had been present for four months. Small sensory fibers were predominantly affected, and the neuropathy was painful, with trophic changes in the skin of the right hand. There was a loss of large-fiber vibratory sensation, particularly in the territory of the median nerve in the right hand and in both feet. The presence of intact reflexes indicates that the large-diameter, heavily myelinated 1A afferent neurons were spared. Some motor-fiber involvement was evident both on physical examination and on electromyography.
The clinical and anatomical pattern of the patient's deficits is complex. There is bilateral but asymmetric involvement of the upper and lower extremities (with the distal extremities much more affected than the proximal extremities). In addition, the electromyogram points to at least two superimposed mononeuropathies: a painful mononeuropathy of the right median nerve, with the site of involvement probably above the transverse carpal ligament, because of some loss of sensation in the palm, and with features resembling those of causalgia, and both sensory and motor neuropathy of the left tibial nerve. Finally, there appears to have been involvement of the maxillary division of the left trigeminal nerve. This pattern suggests the presence of an evolving mononeuritis multiplex that is passing through the stage of overlapping mononeuropathies on its way to a mostly distal, symmetric polyneuropathy.4
The nerve-fiber abnormality appears to be a mix of axon loss and demyelination. Axonal involvement of the motor fibers is indicated by the slight changes in motor-unit potential in the territories of the right median and left peroneal nerves and by the reduced amplitude of the left tibial motor response. There are also features of demyelination, since the motor velocities are reduced more than can be explained by loss of amplitude alone. Pronounced sensory involvement, with relative sparing of the motor responses, may be caused by loss of the neurons of the dorsal-root ganglia,5 their axons, or both, but in this instance it is more likely a result of damage to the nerve fibers rather than to the cell bodies.
The neuropathy in this patient is more likely to be acquired than inherited. The absence of a family history, the age at onset, and both its duration and the fact that it is asymmetric, with prominent paresthesias, are features typical of acquired peripheral neuropathy.2
There are clues that a systemic disorder may be present. The episodes of color changes in the right hand suggest Raynaud's phenomenon, and the mild polyclonal hypergammaglobulinemia suggests immune activation. The mild abnormalities in the levels of aspartate aminotransferase and alanine aminotransferase suggest that there is inflammation of the liver. These features raise the possibility of an underlying connective-tissue disorder. The fact that the patient had emigrated from India and the subtle, hypopigmented skin lesion raise the possibility of infection by Mycobacterium leprae.
The Process of Differential Diagnosis
Table 3 lists the diagnoses that would match the characteristics I have described: a chronic, acquired, painful, overlapping mononeuritis multiplex that predominantly affects sensory fibers, with a combination of axon loss and demyelination and with some features suggesting a connective-tissue disease and others that raise the possibility of leprosy. Table 3 also lists the reasons for including or ruling out each possible diagnosis.
Table 3. Considerations in the Differential Diagnosis of the Peripheral Neuropathy in the Current Case.
A predominantly sensory neuropathy presenting in midlife raises the possibility of a paraneoplastic manifestation.5 Because small dorsal-root ganglia may be targeted initially, the disorder may begin with painful asymmetric paresthesias, commonly in the hand or arm, but, unlike the disorder seen in this case, evolves to affect large sensory fibers, with pronounced sensory ataxia and attenuation or loss of tendon reflexes. The predominance of small-fiber involvement in the current case suggests sensory perineuritis10,11 and other forms of small-fiber sensory neuropathy in which the reflexes remain intact.12,13,14 Their relatively benign nature, or relapsing–remitting character, however, suggests that they are unlikely candidates for the diagnosis in this case.
A predominantly small-fiber neuropathy in primary systemic amyloidosis is classically manifested as a distal, symmetric polyneuropathy with prominent autonomic signs and major-organ involvement. It is a consideration here for several reasons: it is characterized by sensory symptoms that spread very rapidly to the hands, with carpal tunnel syndrome as the presenting feature in 25 percent of patients15; cranial neuropathy, including trigeminal involvement, may occur; and perhaps most important, tendon reflexes are preserved until the condition is in its advanced stages — a point emphasized by David Dawson at one of these conferences in 1979.16 He pointed out that preservation of tendon reflexes narrows the range of diagnostic possibilities to just a few conditions: amyloidosis, leprosy, and slowly advancing sensory diabetic neuropathy. There are no clinical or laboratory findings in this case, however, that would support a diagnosis of amyloid neuropathy.
Narrowing the Differential Diagnosis
The process of differential diagnosis leads to a consideration of vasculitic neuropathy in the context of systemic vasculitis or connective-tissue disease and leprous neuropathy. Although cryoglobulinemic neuropathy is associated with Raynaud's syndrome and although it may produce painful asymmetric neuropathy and be associated with liver dysfunction due to hepatitis C infection,17 the absence in this case of skin lesions suggesting leukocytoclastic vasculitis and the absence of serum protein abnormalities make this diagnosis unlikely. Vasculitic neuropathy occurs in Sj?gren's syndrome, a chronic autoimmune disorder of the exocrine glands. Patients with Sj?gren's syndrome may have Raynaud's phenomenon and hypergammaglobulinemia, and the peripheral nerves may be affected.18 One of the major manifestations of the neuropathy of Sj?gren's syndrome is a sensory ganglionopathy that is manifested predominantly as a sensory ataxia, although there may also be vasculitic involvement of individual nerve trunks. Sj?gren's syndrome is one of the few connective-tissue disorders that affects the trigeminal ganglion.1 Peripheral neuropathy may predate or overshadow symptomatic glandular involvement,18 and testing for anti-SSA and anti-SSB autoantibodies is helpful but not definitive. In the current case, I initially favored a diagnosis of vasculitic neuropathy, possibly in the context of Sj?gren's syndrome.
The patient was known, however, to have come from a region where leprosy is endemic, and she presented with a predominantly small-fiber neuropathy and intact reflexes. These factors, along with the presence of a subtle, hypopigmented skin lesion, raise the possibility of leprous neuropathy.19 Several features of the case are not typical of this diagnosis, including the severe pain and causalgia, large-fiber sensory involvement, and absence of demonstrable enlargement of peripheral nerves.
However, there was a greater reduction of pinprick sensation over the dorsal surfaces of the hands than over the palmar aspects — regions equidistant from the trunk and served by the same upper-limb nerves. Indeed, the pattern in this case, as outlined by Sabin in his classic description of sensory loss in leprosy,
. . . attracts attention because it does not follow the distribution of the named subcutaneous sensory nerves, of the mixed nerve trunks, of the sensory roots, or of the distal symmetrical sensory loss with fading upper borders commonly associated with the various hereditary, toxic and metabolic neuropathies. Comparison of this pattern of sensory loss with thermographic pictures of the arm suggests that local temperature differences might provide an explanation for this unique configuration of sensory loss.20
Figure 1 shows Sabin's examples of temperature-linked sensory loss in lepromatous neuropathy. In addition, the allodynia and sensory loss on the face involve the malar region, an area that is cooler than other regions of the body. Thus, the involvement that I originally considered a manifestation of a trigeminal neuropathy could be viewed as temperature-linked cutaneous sensory loss. The intact deep-tendon reflexes and preserved H reflexes in the face of pronounced sensory loss in the feet for small- and large-fiber modalities (pain and light touch, respectively) in the absence of sensory-nerve action potentials point to very distal (intracutaneous) sensory-nerve involvement, which is typical of lepromatous neuropathy.19,21 There is also evidence of lesions involving more proximal portions of the peripheral nerves — specifically, the right median nerve and the left tibial nerve. Such mononeuropathies may also be seen in leprous neuropathy.19,21
Figure 1. Temperature-Linked Sensory Loss in Lepromatous Neuropathy.
The upper part of the figure shows an example of the pattern of sensory loss in the forearm and hand on routine pinprick examination. The palmar surface of the hand is spared, whereas the dorsum is affected. The lower part of the figure shows sites selected for temperature measurements. The odd-numbered member of each pair (1, 3, 5, and 7) is always warmer than the even-numbered counterpart (2, 4, 6, and 8); warmer sites are spared from sensory loss, whereas cooler sites are affected. The blue lines demarcate regions with different degrees of sensory loss. (Adapted from Sabin,20 with the permission of the publisher.)
The causative organism of leprosy is M. leprae, an acid-fast, obligate, intracellular gram-positive bacillus that reproduces maximally at 27°C to 30°C.15 Consequently, infection is most prominent in cooler regions of the body (34°C to 35°C).19,21 The organism infects the skin and cutaneous nerves, its principal target being the Schwann-cell basal lamina.22
Five major clinical subtypes of leprosy, which reflect the immunologic status of the host, have been defined.19,21 Tuberculoid leprosy occurs in persons with relatively intact cell-mediated immunity to the organism, limiting the spread of the disease. Typically, there are a small number of skin lesions in cool regions, with adjacent nerve-trunk involvement. Histopathological examination of the skin and nerves shows granulomas but no or few bacilli. Lepromatous leprosy occurs in persons with no immune response to M. leprae. Large numbers of bacilli are found in the skin, nerves, and nasal mucosa. Borderline leprosy is intermediate in its manifestations between those two subtypes and is subdivided into forms that more closely resemble tuberculoid leprosy (so-called borderline tuberculoid leprosy) and forms that are closer to lepromatous leprosy (so-called borderline lepromatous leprosy).
In tuberculoid leprosy, sensory loss is pronounced in the skin lesions as a result of damage to the dermal nerves. There may be damage to nerve trunks in the vicinity of the skin lesions, and on occasion painful mononeuropathies develop in swollen or enlarged nerves.19 In lepromatous leprosy, a progressive symmetric polyneuropathy favoring cool regions is the chief manifestation.19 There is also damage to peripheral-nerve trunks, resulting in superimposed mononeuropathies that may evolve into mononeuritis multiplex. The incidence of neuropathic complications is probably highest in patients with borderline leprosy.19,21 These patients have an unstable immune response to the organism, so that the clinical manifestations vary along the tuberculoid-to-lepromatous spectrum. Impaired immunity results in extensive spread of the organism, whereas retained immunity generates a destructive inflammatory granulomatous response.
Leprous neuropathy explains several key clinical manifestations in this case. The painful dysesthesias affecting the hands, with sensory loss more pronounced on the dorsal than on the palmar surfaces, can be explained by temperature-dependent invasion of dermal nerves by M. leprae. The exquisitely painful right median neuropathy in the forearm is related to involvement of the proximal median-nerve trunk. The retention of the deep-tendon reflexes probably indicates that the deep-seated 1A afferent nerves were spared. The absence of sensory responses stems from very distal axon loss in intracutaneous nerves. Finally, motor-nerve conduction velocities that have decreased out of proportion to amplitude loss reflect demyelination due to the destruction of Schwann cells.
I believe that the likeliest diagnosis in this case is leprous neuropathy and that the diagnostic procedure was a sural-nerve biopsy. Because the clinical features are most consistent with the presence of borderline leprosy, I expect that examination of the biopsy specimen revealed both poorly defined granulomas and numerous bacilli.
Dr. E. Tessa Hedley-Whyte: Dr. Dawson, what was your clinical impression before the diagnostic procedure?
Dr. Katherine T. Dawson (Neurology): Our clinical impression was very close to that described by Dr. Chad. We were concerned about vasculitis, but we were also concerned about leprosy because of the skin lesions. We presented the patient to Dr. Anthony Amato at our interhospital neuromuscular conference.
Dr. Anthony Amato (Neurology, Brigham and Women's Hospital, Boston): My initial impression was that this patient's disorder was most likely leprous neuropathy. We decided to perform a sural-nerve biopsy. Under the optimal lighting of the operating room, the skin lesions on the back and arm were much more evident than they had been in the clinic, and I believed that they were typical of leprosy.
Clinical Diagnosis
Leprosy.
Dr. David A. Chad's Diagnosis
Borderline leprosy.
Pathological Discussion
Dr. Hedley-Whyte: The diagnostic procedure was a sural-nerve biopsy, which was performed by Dr. Amato.
Examination of the paraffin sections reveals a dense inflammatory infiltrate around the blood vessels and beneath the perineurium (Figure 2A). Some poorly circumscribed collections of histiocytes but no true granulomas were found (Figure 2B). The trichrome stain showed that myelin was preserved in some fascicles but that in adjacent fascicles there was myelin loss and endoneurial fibrosis. Fite's modification of the Ziehl–Neelsen acid-fast stain for mycobacteria revealed innumerable bacilli in Schwann cells (Figure 2C).
Figure 2. Sural-Nerve Biopsy Specimen.
There is a brisk inflammatory reaction in two nerve fascicles and a lesser inflammatory action in a third fascicle (Panel A, hematoxylin and eosin, x31). The inflammatory infiltrate consists of plasma cells and lymphocytes with rare, poorly formed aggregates of histiocytes (arrow) (Panel B, hematoxylin and eosin, x250). The inflammatory infiltrate is accentuated in the subperineurial area. Staining with Fite's modified Ziehl–Neelsen acid-fast stain shows that numerous Schwann cells contain acid-fast bacilli (arrows, Panel C, x500; inset, x1200). (Slides courtesy of Dr. Hart Lidov, Brigham and Women's Hospital, Boston.)
On ultrastructural examination, bacilli consistent with M. leprae were found in Schwann cells, particularly in those associated with unmyelinated axons (Figure 3A). There was a loss of unmyelinated axons, manifested by the presence of so-called empty Schwann-cell stacks (Figure 3B). These findings confirm the diagnosis of leprosy and are somewhat more characteristic of the lepromatous type than of the tuberculoid type.23
Figure 3. Electron Micrograph of the Sural-Nerve Biopsy Specimen.
A Schwann cell that is responsible for unmyelinated axons contains numerous bacilli (Panel A). The Schwann cells responsible for the unmyelinated axons are the ones predominantly infected with the bacilli. The total number of unmyelinated fibers has decreased, as evidenced by the presence of so-called Schwann-cell stacks, which are layers of collapsed Schwann-cell membrane (arrow). The bacilli are concentrated in the Schwann-cell cytoplasm (arrow, Panel B). Adjacent Schwann cells do not contain bacilli. (Images courtesy of Dr. Joseph C. Corbo, Brigham and Women's Hospital, Boston.)
The diagnosis of leprosy in the United Kingdom and the United States is often delayed.21,24 The median time from the onset of symptoms to diagnosis in a series of 28 patients at the Hospital for Tropical Diseases in London between 1995 and 1998 was 1.5 years (range, 0.2 to 15.2). Forty-three percent of the patients came from the Indian subcontinent, and 25 percent from Africa. Misdiagnosis of the condition as another dermatologic or neurologic disease was an important reason for the delay. The time from entry into the United Kingdom to diagnosis ranged from 0.2 to 47.8 years. Points at which the diagnosis was delayed were identified as evaluation by a general practitioner (10 of the 28 patients), orthopedic surgeon (5 of the patients), or neurologist (3 of the patients) or evaluation at the Hospital for Tropical Diseases (2 of the patients). Two of the patients had not reported a previous diagnosis of leprosy. Twenty-one of 28 patients seen by a dermatologist were "promptly" given the diagnosis. Similarly, Nations et al.21 pointed out that physicians in the United States may lack familiarity with the disease, with resulting delays in diagnosis.
Dr. Nesli Basgoz (Infectious Disease): This patient was referred to the infectious-disease clinic. On examination, she was found to have a large hypopigmented area with heaped-up borders on her back and a similar, smaller lesion on her left arm (Figure 4). Both were anesthetic. She recalled having been told 15 years ago that she had a small hypopigmented area on her back. This protracted time course illustrates the fact that the cutaneous and nerve-related manifestations of leprosy can progress very slowly, because of the slow growth of the organism.
Figure 4. Photographs of the Skin Lesions.
There is a large, faintly hypopigmented area on the back (arrows, Panel A), which has slightly raised edges. A similar, smaller lesion is present on the left arm (arrows, Panel B). Both lesions were anesthetic.
Most patients with leprosy have borderline leprosy. Our patient had some features of tuberculoid leprosy, including a small number of skin lesions with elevated edges and some evidence of granuloma formation on biopsy. However, she also had a polyneuropathy and shiny skin, which are consistent with some dermal infiltration, and there were many acid-fast bacilli in the nerve-biopsy specimen — features more suggestive of the lepromatous form of the disease. Therefore, she most likely had borderline leprosy.
As was the case with this patient, most cases of leprosy are not diagnosed by infectious-disease specialists but, rather, by internists, neurologists, and dermatologists. If any physician sees a patient from an area where this infection is endemic (Asia, Africa, the Pacific Islands, or South America) who has unexplained skin lesions, particularly if they are anesthetic or if there are accompanying neuropathies, it is important to consider leprosy. Early diagnosis and treatment can help prevent the neuropathic and other complications of untreated leprosy.
Although leprosy is a much-feared disease, it is not particularly infectious. The organisms are present in the skin at the level of the dermis, so touching the surface of the skin is without risk. The most likely mode of transmission is respiratory, through contact with nasal secretions. In areas where the infection is endemic, clinical disease will develop in only about 1 in 350 people who are infected with M. leprae. Once treatment is initiated, there is a rapid disappearance of organisms from the nose, so there is no indication for isolation.
In the current case, we treated the patient with dapsone and rifampin. After nine months of treatment, she continues to have slow improvement in the pain and numbness in her hands and feet, as well as improvements in motor strength. The skin lesions have become less distinct. Treatment will continue for several years.
Anatomical Diagnosis
Borderline leprosy.
Addendum
At follow-up 14 months after the initiation of treatment, the patient's skin lesions had almost completely resolved. The anesthetic areas on the dorsum of the hands and feet had become sensitive to touch. Her motor strength was normal.
Editor's note: Dr. William Fennel McNeely retired as Associate Editor of the Case Records of the Massachusetts General Hospital on January 1, 2004. His concise and precise writing style and meticulous attention to detail have set the standard for the preparation of a case history for 30 years. The current and former editors of the Case Records are grateful for his contributions.
Source Information
From the Department of Neurology, UMass Memorial Health Care, and the Departments of Neurology and Pathology, University of Massachusetts Medical School, Worcester (D.A.C.); and the Department of Pathology, Division of Neuropathology, Massachusetts General Hospital, and the Department of Pathology, Harvard Medical School (E.T.H.-W.).
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