protocol im

8/14/2019 Protocol IM

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CASE PROTOCOL

Maria Reyna Hospital

DEPARTMENT OF INTERNAL MEDICINE

November 27, 2008

Collera, Joanne M.Encong, Aubrey A.

Gullim, Carryll Lynne M.Hassannoor, Adlee W.


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OBJECTIVES

1. To present a case of erythema nodosum leprosum presenting as acute sinusitis

2. To discuss its diagnosis, pathophysiology and management

GENERAL DATA

A case of LR, 44-year-old, male, Filipino, Roman Catholic, married,

businessman; currently residing at Ebarle-Corrales Streets, Cagayan de Oro City; andadmitted for the first time last November 6, 2008 at 4:35 pm.

Informant: Patient

Reliability: 80%

CHIEF COMPLAINT

Nasal congestion

HISTORY OF PRESENT ILLNESS

9 days prior to admission (PTA), patient claimed to have noted on and off fever

with temperature ranging from 37.6C to 37.8C. There were no other associated

symptoms at this time. Patient self-medicated with Phenylpropanolamine +

Chlorphenamine maleate + Paracetamol (Nafarin-A), 1 tab every 4 hours for 5 doseswhich afforded relief.

4 days PTA, patient was very busy preparing for an incoming family event. He

was exposed under the heat of the sun for many hours, lifting and arranging heavymaterials in order to build a tent. Few hours after, he noted nasal stuffiness associated

with feverish feeling. There were no associated chills, headache, nausea and vomiting.

Non-pruritic, non-painful, erythematous nodule was also noted on his right lowerinfraorbital area. He just continued taking Paracetamol + Phenylpropanolamine HCl +

Phenyltoloxamine Citrate (Sinutab) 1 tablet every 4 hours with no relief. No consult was

done.3 days PTA, patient noted recurrence of fever, especially noted in the afternoon,

with highest temperature recorded at 39.9C. This time it was associated with chills, nasal

congestion, diaphoresis, loss of appetite and frontal headache, tearing in quality, non-

radiating, 7/10 in severity. Still, no consult was done. Instead, he just continued takingSinutab every 4 hours. However, no relief was noted.

1 day PTA, the right lower infraorbital nodule gradually increased in size. He also

noted onset of similar lesion on the opposite side, with no other associated symptoms.Morning PTA, fever, chills, and headache still persisted. However, there was now

associated difficulty of breathing brought about by the increasing severity of his nasal

congestion. This prompted him to seek consult at Maria Reyna Hospital as an out-patient.CBC was done revealing WBC of 16.9, Neutrophils of 80.4% and Lymphocytes of 6.3%.

X-ray of the paranasal sinuses showed that his sinuses are of normal lucency and that his

nasal septum is in the midline. There were no localizing signs. He was then seen by an

ENT specialist and was given Oxymetazoline HCl (Drixine) nasal spray without relief.

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Due to lack of response to the drug and the weakness noted by the ENT specialist, he was

advised admission to which he complied.

PAST MEDICAL HISTORY

Last December 2005, patient had multiple non-pruritic, erythematous and

hypopigmented patches first noted on his forehead which gradually progressed to involve

his upper and lower extremities and torso. He also noted hyperpigmented, non-pruritic,brownish-black macules on his lower extremities and right flank that were associated

with numbness, decreased sensation to pain, weakness and slight discomfort on affected

areas. He sought consult at Provincial Health Office and was diagnosed to have leprosywithout work-up being done. He was prescribed with Multidrug Therapy (Rifampicin,

Clofazipime, Dapsone) 4 tablets on first dose and 2 tablets daily for 1 month and the

cycle is again repeated every month for 1 year, with good compliance.

Two months after completion of treatment, he noted recurrence of multiplebrownish macules and hyperpigmented brownish-black patches, non-pruritic, non-painful

on upper and lower extremities, and torso associated with numbness, pinprick and

decrease sensation to pain. He sought consult at Provincial Health Office. Prednisone was

prescribed with unrecalled tapered dosages which he took for one week with goodcompliance. Noted regression of brownish macules.

Patient is a known hypertensive for 3 years, highest BP 160/110, usual BP140/100. No maintenance medications but was advised to exercise.

Patient is nondiabetic, non asthmatic with no history of previous hospitalizations

and operations.

FAMILY HISTORY

Patient claimed to have family history of hypertension and diabetes mellitus onhis paternal side. He denied any other heredo-familial diseases like asthma and cancer.

PERSONAL AND SOCIAL HISTORY

He was a chronic smoker for about 42 pack years and stopped just recently. He

was also an occasional alcoholic beverage drinker. He has no known allergy to drugs.

However, he claimed to have an allergy to chicken meat.He finished Bachelor of Science in Marine Transportation. He was once an

official in their barangay. He currently works with his wife in dry goods business.

He denied any exposure to or even contact with persons known to have any form

of skin disease. Patient loves outdoor activities like biking, hiking and jogging.

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REVIEW OF SYSTEMS

GENERAL:

(-) weight loss, fatigueSKIN

(-) pallor, lumps, itching, rashes, sores, jaundice

NAILS

(-) clubbing, color change

HEAD(-) lightheadedness, dizziness

NECK

(-) pain, swollen glands, lumps

EYES(-) pain, redness, itchiness

EARS

(-) hear loss, tinnitus, pain

NOSE & SINUSES(-) epistaxis, tenderness, discharges

MOUTH & THROAT

(-) dry lips, gumbleeding

RESPIRATORY

(-) dyspnea, chest pain

CARDIOVASCULAR

(-) palpitations, chest pain

GASTROINTESTINAL(-) abdominal pain, constipation, obstipation

URINARY

(-) frequency, hematuria, dysuria

MUSCULOSKELETAL

(-) stiffness, limitation of movement, joint pains

NEUROLOGIC

(-) tremors, memory deficits, seizures

HEMATOLOGIC

(-) anemia, easy bruising, bleeding

ENDOCRINE

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(-) weight change, heat intolerance, cold intolerance

PSYCHIATRIC(-) mood changes, suicidal ideation

PHYSICAL EXAMINATION

Examined patient awake, conscious, cooperative, ambulatory and not inrespiratory distress with the following vital signs:

BP: 160/80 mm Hg

HR: 80 bpmRR: 22 cpm

Temp: 39 C

O2 Sat: 100% at RA

Skin and Nails: warmth, good turgor

(+) 3 x 1 cm, erythematous nodule, non-painful, well-defined border with intactsensation at right lower infraorbital area

(+) 1 x 1 cm, erythematous nodule, non-painful, well-defined border with intactsensation at left lower infraorbital area

(+) 2 x 3 cm, hyperpigmented brownish- black patch, hyposthetic, ill-defined borderat posterior axillary line

(+) 10 x 6 cm, hyperpigmented blackish patch, hyposthetic, ill-defined border with

central clearing lesion, above the right superior iliac spine(+) 4 x 5 cm hyperpigmented blackish scaly patch with central hypopigmentation,

anesthetic, non-painful at the lateral distal third of the left lower extremity

No clubbing and cyanosis, with good capillary refill

HEENT:

Head: Hair is black, thick, and evenly distributed. Head is normocephalic andatraumatic with absent scalp lesions. Face is symmetrical.

Eyes: symmetrical, well-distributed eyelashes and eyebrows, anicteric sclerae, pink

palpebral conjunctivae

Pupils isocoric, equally round and reactive to light and accommodationEars: no discharges, lesions, tenderness on ears and mastoids

Nose: (+) nasal congestion, nasal septum midline, no internal lesions, no sinus

tenderness, watery discharges, turbinates not hyperemicMouth & pharynx: no gum bleeding, no ulcerations on oral mucosa, tongue midline,

uvula midline, no tonsillar inflammation, good dentitionNeck: supple, trachea midline, no thyroid gland enlargement, absent neck vein

distention, no lymphadenopathy

Thorax & Lungs: Posterior chest is symmetrical, no retractions, equal chest expansion

No adventitious breath sounds heard

Cardiovascular: Adynamic precordium, distinct heart sounds, normal rate and regular

rhythm, no murmurs

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Abdomen:globular, normoactive bowel sounds, soft, no tenderness on all four quadrants

GUT: Negative kidney punch sign

Musculoskeletal: (-) atrophy, (-) limitation of range of motion

Nervous:

Mental status patient is alert and cooperative, oriented to time, place, and person, awareof objects in the environment, has good thought content, and coherent. Patient

demonstrates proper affect, no mannerisms, able to repeat sequences of words, and

has good memory.

Cranial Nerves

I able to smell coffee in each nostril

II can read nameplate at 2 feet distance

II, III pupils equally round, reactive to light and accommodationIII, IV, VI extraocular movements full and equal

V temporal and masseter have good muscle toneVII face symmetrical; can raise both eyebrows; can frown; can show both upper

and lower teeth, and can puff out both cheeks

VIII able to hear whispered voice

IX, X good speaking voice; no hoarseness; can easily swallow; uvula midline; gagreflex intact

XI can shrug both shoulders against resistance; can turn head side to side

XII no tongue deviation, can protrude tongue; can move tongue side to side; canpush tongue against inside of cheek

Motor: Patient is aware of body position, absent involuntary movements, has goodoverall muscle bulk and tone. Muscle strength in all extremities of 5/5.

Sensory: unable to differentiate dull and sharp stimuli on patchy areas of the feetDecrease sensation on patchy areas of the trunk, upper extremities and face

Motor Sensory Deep Tendon Reflexes

5/5 5/5 100% 100%

5/5 5/5 100% 100%

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SALIENT FEATURES

History 44 years old male

came in due to nasal congestion associated with fever, chills, headache and

weakness

diagnosed with Leprosy last 2005 and completed 1 year treatment of Multidrug

Therapy (Rifampicin, Clofazipime, Dapsone) with good compliance

Physical Examination

high BP, febrile

erythematous nodules, non-painful, well-defined border with no decreasedsensation to pain at the lower infraorbital areas

multiple hyperpigmented brownish-black, hyposthetic to anesthetic, ill-definedbordered patches at the posterior axillary line, above the superior iliac spine and at

the lateral distal third of the left lower extremity

ADMITTING IMPRESSION

Acute Sinusitis

T/C Lepromatous Reaction

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DIFFERENTIAL DIAGNOSIS

1. PsoriasisRuled in:

erythematous nodule, sharply demarcated

fever

younger age of onset

Point against:

symmetry of lesions

extensor distribution (most common sites of involvement are scalp, elbows

and knees, hands, feet, trunk, and nails)

Auspitz sign

itchiness and silvery scales

2. Sarcoidosis

Ruled in:

erythematous nodule

fever, anorexia, headache, weaknessPoint against:

red, rounded patches, which become elevated and painful within days

skin plaques are purple, indolent lesions

blurring of vision

Subcutaneous nodules appear most often on the arms and legs

3. Leukemia cutis

Ruled in:

history of fever, chills, and lethargy

single or multiple nodulesPoint against:

pancytopenia

pallor

hepatosplenomegaly

4. Acute Febrile Neutrophilic Disorder (Sweets Syndrome)

Ruled in: Non-pruritic erythematous nodules

Fever, upper respiratory tract infections, headache

Point against:

Skin lesions causes pain and burning sensation

Extracutaneous manifestations (e.g pulmonary involvement which may

manifest as dyspnea or chronic cough)

Proteinuria, hematuria

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Decreased creatinine clearance

COURSE IN THE WARDS

On admission, patient had complaints of difficulty of breathing, nasal stuffiness,headache and fever. On physical examination, patient was febrile with temperature of

39.4C. There was non hyperemic turbinates noted with watery secretions. His face had

erythematous nodule, non-painful, well-defined border with no decreased sensation topain at both lower infraorbital areas. Subsequent physical examination revealed an area of

hyposthesia on the hyperpigmented patches with ill-defined border at the posterior axillary

line, above the right superior iliac spine and the lateral surface of the distal third of theleft lower extremity. CBC revealed leukocytosis at 16.9 with neutrophilic predominance of80.4% and lymphocytopenia at 6.3%, consistent with bacterial infection. Urinalysis revealed

turbid urine with high specific gravity at 1.030, +1 protein, and 3-5/hpf pus cells. Baseline

creatinine was within normal limits at 1.3 mg/dL. X-ray of the paranasal sinuses showed

normal lucency of the sinuses and midline nasal septum with no localizing signs. CT scanof PNS showed densities seen within the inferior aspect of the maxillary sinuses, theethmoids and the left frontal sinus with obliteration of the osteomeatal complexes. Mucus

retention cyst was seen at the left maxillary sinus too. The impression was acute sinusitis

to consider lepromatous reaction. He was started on D5LR 1L at 30 gtts/min. He was

given Amoxicillin + Sulbactam (Ultramox) 1,500 amp IVTT q 8 ANST, Celecoxib(Celebrex) 400mg cap, 1 cap OD, Midazolam 7.5mg PO at 8pm and Paracetamol 500mg

q 4, PRN for fever 37.8C.

Patient still complains of nasal congestion, fever, inability to sleep, headache anddecreasing difficulty of breathing on the 1st hospital day. He was given Oxymetazoline

HCl (Drixine) nasal spray, 2 sprays per nostril BID for 3 days and Loratadine +

Pseudoephedrine (Clarinase) 1 tab BID.On the 2nd hospital day, he was referred to an infectious specialist for co-

management and re-evaluation of persistent sinusitis and skin lesions. He was then

transferred to an isolation ward. Amoxicillin + Sulbactam (Ultramox) was discontinued

and started with Levofloxacin (Floxel) 500 mg 1 tab OD. Repeat CBC showed slightincrease in leukocytosis at 18.7 with neutrophilic predominance at 93%. ESR was

elevated at 128 mm/hr. ALT was 90 U/L. Typhidot and CRP were negative. Acute

sinusitis was improving. Hypersentivity reaction to Ultramox was considered regardinghis lesions.

From the 3rd hospital day onwards there was a note of progressing erythematous

nodules all over his body associated with fever. He was referred to a dermatologist on the5th hospital day with an impression of Erythema Nodosum Leprosum. Multibacillary drug

regimen recommended by WHO was started (Dapsone 100 mg tab OD, Rifampicin 600

tab once a month, and Clofazamine 50 mg tab OD and 300 mg once a month). This willbe for two years. Prednisone 30 mg 1 tab after breakfast was also given. Slit smear to

AFB staining was done which revealed negative for two takings.

On the 7th hospital day, patient had markedly improved with no more complaints

of nasal stuffiness, fever, headache and difficulty of breathing. However, there was stillerythematous nodules noted all over his body. He was advised for discharge, with the

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following final diagnosis of Sinusitis, Bacteremia, Staph species, Erythema Nodosum

Leprosum. Patients relatives were advised on the duration of treatment before the patient

becomes non-infectious and on chemoprophylaxis.

DISCUSSION:

Cutaneous lesions of leprosy are varied so that their true nature is often missed.

The nodular lesions at the infraorbital areas which appeared did not bother our patient to

seek medical consultation. Admission was done because of nasal congestion, fever,chills, headache and weakness. In the presence of nasal congestion, we often think of

more common diseases such as acute sinusitis and common colds. However, subsequentphysical examination revealed an area of hyposthesia on the hyperpigmented patches with ill-

defined border at the posterior axillary line, above the right superior iliac spine and the

lateral surface of the distal third of the left lower extremity. Only then was leprosysuspected.

Leprosy is a chronic granulomatous infection and its sequelae, caused byMycobacterium leprae. It involves primarily the skin and nerves, but also other organs or

systems, including eyes, respiratory tract, lymph nodes, testicles, and joints. It requires

demonstration of acid-fast bacilli in tissue or a characteristic nerve abnormality.

There are around 500,000 new cases yearly, worldwide. Leprosy has declined in

most of the countries in the Western Pacific Region. China, Philippines and Viet Nam

continue to report 1 000 or more new cases annually. The national prevalence rate of

leprosy has consistently been less than one per 10,000 population since 1998. This is thelevel at which leprosy is considered eliminated as a public health problem. The case

detection rate has continued to decrease from 1989 to 2004. Surveillance in 2004

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revealed that the prevalence of leprosy has gone down to 0.38 case per 10,000

population.

Despite the low prevalence rate of leprosy at the national level since 1998, 29

provinces were noted to have sub-national prevalence rates above one case per 10,000 in

the year 2000. However, five provinces did not meet the target and remained to havemore than one case of leprosy per 10,000 population in 2004. There are also eight cities

that have leprosy prevalence rate above one case per 10,000 population.

Leprosy is a very serious, multilating and stigmatizing disease in many parts of

the world and early diagnosis and therapy is the most important strategy for its control. It

is highly infective, but has low pathogenicity and low virulence with a long incubationperiod.

Leprosy reactions are immunological phenomena that occur before, during or

after the completion of multi-drug therapy (MDT). They contribute immensely to theburden of leprosy and need to be diagnosed and treated early to prevent nerve function

impairment and permanent disability.

Etiology

M. leprae, the cause of leprosy, is a non-cultivable, Gram-positive, obligate,

intracellular, acid-fast bacillus. In tissues or smears, M. leprae is quantified by the biopsy

index (BI), a logarithmic scale as to the number of bacilli per oil immersion field (OIF): aBI of 6 is 1000 or more bacilli/OIF; a BI of 5 is 100 to 1000/OIF; a BI of 4 is 10 to

100/OIF; a BI of 3 is 1 to 10/OIF; a BI of 2 is 1 bacillus/1 to 10 OIFs; a BI of 1 is 1

bacillus/10 to 100 OIFs; and a BI of 0 is no bacilli in 100 OIFs. Because a BI of 6

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indicates 109 bacilli per gram of granuloma, tissue with a BI of 0, may have as many as

103 organisms per gram.

A patient is considered to be paucibacillary if no acid-fast bacilli are found in

tissue or smears, and to be multibacillary if one or more acid-fast bacilli are found.

Pathogenesis

Phenolic glycolipid-1 (PGL-1) is a glycolipid in the capsule of Mycobacterium

leprae. PGL-1 contains an antigenically distinct trisaccharide unit that is not found in anyother bacteria. PGL-1 makes up to 2% of the total bacteria mass, suggesting that the

function of the sugar chains may be related to functions unique to Mycobacterium leprae.

PGL-1 binds to laminin-2, which facilitates PGL-1 binding to the basal lamina of axons

on Schwann cells and the resulting invasion of the cells. This might explain theneurotropism of these bacteria. Because this invasion can occur even when the bacteria

were dead, the invasion seems not to be driven by the bacteria, but by passive interaction

between glycolipids in the capsule of the cell wall and molecules in the basal lamina of

Schwann cells. If this binding could be blocked, a new therapeutic avenue might becomepossible. However, laminin-2 is also present in the basement membrane of other tissues.

The basement membrane in muscle is composed of laminin, type IV collagen,entactin/nidogen and heparan sulphate proteoglycan. One major component of the BM in

muscle is laminin-2, which is composed of a heavy chain laminin a2 and two light chains,

b1 and laminin g1. Other factors must also play a role in the fact that Mycobacterium

leprae has a predilection for neural tissue.

It has long been suspected that leprosy has a strong genetic component. A leprosy

susceptibility locus on chromosome 6 (region q25-q26) was discovered in 2004. ThisDNA stretch included the Parkinson's disease gene PARK2 and the co-regulated gene

PACRG. The PARK2 gene is expressed by human Schwann cells and macrophages,

which are the primary host cells ofMycobacterium leprae.

Pathophysiology

Leprosy is not a highly infectious disease. The principal means of transmission is by

aerosol spread from infected nasal secretions to exposed nasal and oral mucosa. Leprosyis not generally spread by means of direct contact through intact skin, although close

contacts are most vulnerable. The incubation period is 6 months to 40 years or longer.

The mean incubation period is 4 years for tuberculoid leprosy (TT) and is 10 years forlepromatous leprosy (LL).

The areas most commonly affected are the superficial peripheral nerves, skin, mucous

membranes of the upper respiratory tract, anterior chamber of the eyes, and the testes.

These areas tend to be cool parts of the body. Tissue damage depends on the degree towhich cell-mediated immunity is expressed, the type and extent of bacillary spread and

multiplication, the appearance of tissue-damaging immunologic complications (ie, lepra

reactions), and the development of nerve damage and its sequelae.

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M leprae is an obligate intracellular, acid-fast, gram-positive bacillus with an affinity for

macrophages and Schwann cells. For Schwann cells in particular, the mycobacteria bind

to the G domain of the alpha-chain of laminin 2 (found only in peripheral nerves) in thebasal lamina. Their slow replication within the Schwann cells eventually stimulates a

cell-mediated immune response, which creates a chronic inflammatory reaction. As a

result, swelling occurs in the perineurium, leading to ischemia, fibrosis, and axonal death.

The genomic sequence ofM leprae was only recently completed. One importantdiscovery is that although it depends on its host for metabolism, the microorganism

retains genes for the formation of a mycobacterial cell wall. Components of the cell wall

stimulate a host immunoglobulin M antibody and cell-mediated immune response, whilealso moderating the bactericidal abilities of macrophages.

The strength of the host's immune system influences the clinical form of the disease.

Strong cell-mediated immunity (interferon-gamma, interleukin [IL]2) and a weak

humoral response results in mild forms of disease, with a few well-defined nerves

involved and lower bacterial loads. A strong humoral response (IL-4, IL-10) butrelatively absent cell-mediated immunity results in LL, with widespread lesions,

extensive skin and nerve involvement, and high bacterial loads. Therefore, a spectrum ofdisease exists such that cell-mediated immunity dominates in mild forms of leprosy and

decreases with increasing clinical severity. Meanwhile, humoral immunity is relatively

absent in mild disease and increases with the severity of disease.

Toll-like receptors (TLRs) may also play a role in the pathogenesis of leprosy. M leprae

activates TLR2 and TLR1, which are found on the surface of Schwann cells, especially

with TT. Although this cell-mediated immune defense is most active in mild forms of the

disease, it is also likely responsible for the activation of apoptosis genes and,

consequently, the hastened onset of nerve damage found in persons with mild disease.Alpha-2 laminin receptors found in the basal lamina of Schwann cells are also a target of

entry forM leprae into these cells, while activation of the ErbB2 receptor tyrosine kinase

signaling pathway has been identified as a mediator of demyelination in leprosy.

The activation of macrophages and dendritic cells, both antigen-presenting cells, is

involved in the host immune response to M leprae. IL-1beta produced by antigen-

presenting cells infected by mycobacteria has been shown to impair the maturation andfunction of dendritic cells. Because bacilli have been found in the endothelium of skin,

nervous tissue, and nasal mucosa, endothelial cells are also thought to contribute to the

pathogenesis of leprosy. Another pathway exploited by M leprae is the ubiquitin-

proteasome pathway, by causing immune cell apoptosis and tumor necrosis factor(TNF)alpha/IL-10 secretion.

A sudden increase in T-cell immunity is responsible for type I reversal reactions. Type II

reactions result from activation of TNF-alpha and the deposition of immune complexes intissues with neutrophilic infiltration and from complement activation in organs. One

study found that cyclooxygenase 2 was expressed in microvessels, nerve bundles, and

isolated nerve fibers in the dermis and subcutis during reversal reactions.

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Diagnosis

Clinical tests: Certain tests can be performed in the clinic to aid in the diagnosis ofleprosy.

o Tissue smear testing/slit-skin smears: An incision is made in the skin, and the

scalpel blade is used to obtain fluid from a lesion. The fluid is placed on a glass

slide and stained by using the Ziehl-Neelsen acid-fast method or the Fite methodto look for organisms. The bacterial index is then determined as the number of

organisms at 100X with oil immersion. Skin smears have high specificity but low

sensitivity because 70% of all patients with leprosy have negative smears.However, this test is useful because it detects the most infectious patients.

o Histamine testing: This test is used to diagnose postganglionic nerve injury.

Histamine diphosphate is dropped on healthy skin and affected skin, and apinprick is made through each site. The site forms a wheal on healthy skin, but

not on skin where nerve damage is present.

o Methacholine sweat testing: An intradermal injection of methacholine

demonstrates the absence of sweating in leprous lesions. This test is useful in

dark-skinned patients in whom the flare with the histamine test cannot be seen.

Diagnostic criteria for leprosy: The diagnosis of leprosy is primarily a clinical one. In one

Ethiopian study, the following criteria had a sensitivity of 97% with a positive predictivevalue of 98% in diagnosing leprosy. Diagnosis was based on 1 or more of 3 signs:

o

Hypopigmented or reddish patches with definite loss of sensationo Thickened peripheral nerves

o Acid-fast bacilli on skin smears or biopsy material

Classification: The Ridley-Jopling classification is used to differentiate types of leprosy

and helps in determining the prognosis. Purely neuritic leprosy (asymmetrical peripheral

neuropathies with no evident skin lesions), with or without tenosynovitis and symmetricpolyarthritis, is also possible. A general classification of disease is based on the number

of skin lesions present and the number of bacilli found on tissue smears. Paucibacillary

disease (indeterminate leprosy and TT) has fewer than 5 lesions and no bacilli on smear

testing. Five or more lesions with or without bacilli (borderline leprosies and LL) is

considered multibacillary disease.

o Indeterminate leprosy: This early form causes one to a few hypopigmented or,

sometimes, erythematous macules. Sensory loss is unusual. Approximately 75%of affected persons have lesions that heal spontaneously. In some, the disease may

persist in this indeterminate form. In those with weak immunity, the disease

progresses to one of the other forms.

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o Tuberculoid leprosy: Skin lesions are few. One erythematous large plaque is

usually present, with well-defined borders that are elevated and that slope down

into an atrophic center. The lesions can become arciform or annular. They can befound on the face, limbs, or elsewhere, but they spare intertriginous areas and the

scalp. Lesions can be dry and scaly, hypohidrotic, and hairless. Another

presentation involves a large, asymmetric hypopigmented macule. Both types oflesions are anesthetic and involve alopecia.

Spontaneous resolution can occur in a few years, leaving pigmentary

disturbances or scars. Progression can also occur, leading to borderline-type leprosy. In rare instances in which a patient is untreated for many

years, the lepromatous type can develop.

Neural involvement is common in persons with TT; it leads to tender,

thickened nerves with subsequent loss of function. The great auricularnerve, common peroneal, ulnar, and radial cutaneous and posterior tibial

nerves are often prominent. Nerve damage can happen early, resulting in

wrist drop or foot drop.o

Borderline tuberculoid leprosy: Lesions in this form are similar to those in thetuberculoid form, but they are smaller and more numerous. The nerves are less

enlarged and alopecia is less in borderline tuberculoid leprosy than in other forms.Disease can remain in this stage, it can convert back to the tuberculoid form, or it

can progress to LL.

o Borderline borderline leprosy: Cutaneous lesions consist of numerous, red,

irregularly shaped plaques that are less well defined than those in the tuberculoid

type. Their distribution may mimic those of the lepromatous type, but they are

relatively asymmetric. Anesthesia is only moderate. Regional adenopathy may bepresent. Disease may remain in this stage, it may improve, or it may worsen.

o Borderline lepromatous leprosy: Lesions are numerous and consist of macules,

papules, plaques, and nodules. Annular punched-outappearing lesions that looklike inverted saucers are common. Anesthesia is often absent. As with the otherforms of borderline leprosy, the disease may remain in this stage, it may improve,

or it may regress.

o Lepromatous leprosy: Early cutaneous lesions consist mainly of pale macules.

Late infiltrations are present with numerous bacilli. Macular lesions are small,

diffuse, and symmetric. The skin may be smooth and shiny, but skin changes do

not occur in LL until late in the course. Therefore, early LL lesions have little orno loss of sensation, nerves are not thickened, and sweating is normal. Nerve loss

is slow and progressive.

Hypoesthesia occurs first over extensor surfaces of the distal extremities,

followed by weakness in the same areas. Alopecia affects the lateral aspects of the eyebrows (madarosis), spreading

to the eyelashes and then the trunk. Scalp hair remains intact. Lepromatous infiltrations can be diffuse, can occur as nodules (called

lepromas), or can be plaques. The diffuse type results in the thickened skin

appearance of a leonine facies. Neuritic lesions are symmetric and slow to

develop.

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Eye involvement occurs, causing pain, photophobia, decreased visual

acuity, glaucoma, and blindness.

Nasal infiltration can cause a saddle-nose deformity and impairedolfaction. Hoarseness ("leprous huskiness") and stridor are a result of

laryngeal involvement.

Oral lepromas, usually located on the hard and soft palate, uvula, tongue("cobblestoning"), lips, and gums, can progress to necrosis and ulceration.

Tissue destruction may result.

Infiltration of the helix or megalobule (elongation and wrinkling of theearlobe) may occur.

Lymphadenopathy and hepatomegaly can result from organ infiltration.

Testicular atrophy results in sterility and gynecomastia.

Aseptic necrosis and osteomyelitis can occur with repeated trauma afterjoint invasion.

Brawny edema of the lower extremities is a late finding.

Histoid leprosy is a recognized clinical variant of LL. It can occur as a

result ofM leprae resistance to monotherapy of MDT. One report of denovo histoid leprosy suggests that it may also possibly evolve from

indeterminate leprosy. Paucibacillary and multibacillary forms also exist. Unlike the other types of leprosy, LL cannot convert back to the less

severe borderline or tuberculoid types of disease.

Other: Lepra reactions are complications that occur in 50% of patients after the start

of therapy or occasionally before therapy

Management

The management of leprosy includes early pharmacotherapy and physical, social, andpsychological rehabilitation. The goals of pharmacotherapy are to stop the infection,reduce morbidity, prevent complications, and eradicate the disease. Since 1981, MDT has

been advocated by the World Health Organization (WHO) and the United States. MDT

prevents dapsone resistance, quickly reduces contagiousness, and reduces relapses,reactions, and disabilities.

The length of treatment ranges from 6 months to 2 years. Patients are considered

noninfectious within 1-2 weeks of treatment (usually after the first dose). These drugs are

conveniently packaged in monthly calendar blister packs. Monitor for drug resistance andadverse reactions to medications.

Paucibacillary disease can be treated with a combination of 2 drugs, whereas

multibacillary disease requires triple-drug therapy. Single skin lesions

(paucibacillary) can be treated with a single dose of 3 drugs. The length oftreatment depends on the type of disease and on the access to drugs.

WHO and US treatment regimens for paucibacillary and multibacillary disease

are listed below. Therapy for single skin lesions is not universal, because 80% of

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single skin lesions heal spontaneously. Therefore, only the WHO has a

recommended treatment.

Current WHO recommendations for treatment of leprosy are as follows:o Paucibacillary disease - Dapsone at 100 mg/d plus rifampin at 600 mg

once a month for 6 months

o

Multibacillary disease - Dapsone at 100 mg/d plus rifampin at 600 mgonce a month plus clofazimine at 300 mg once a month and 50 mg/d for 1

year

o Single skin lesion - A single dose of rifampin at 600 mg, ofloxacin at 400

mg, and minocycline at 100 mg

Current US recommendations for the treatment of leprosy are as follows:

o Paucibacillary disease - Dapsone at 100 mg/d plus rifampin at 600 mg/d

for 1 year

o Multibacillary disease - Dapsone at 100 mg/d plus rifampin at 600 mg/d

plus clofazimine at 50 mg/d for 2 years

In patients taking dapsone, the CBC count should be checked frequently early

during the therapy and then less frequently later during therapy. Skin lesions usually resolve within the first year of treatment, although some may

persist for up to 5 years in multibacillary disease.

Potential deformities can be prevented by educating patients about how to

minimize existing nerve damage and by treating any sequelae of this damage.

Close follow-up is important to ensure patient compliance.

Complications

Reactional states occur in approximately one third of patients and are acute

inflammations of the disease. They may be induced by MDT, physical or mental

stress, trauma, pregnancy, or surgical procedures. A leprous reaction should beconsidered a medical emergency and mandates immediate care. These states can

result in permanent neurologic sequelae, resulting in disability and deformity.

Patients at the highest risk are those with multibacillary leprosy and/or preexistingnerve impairment.

o Lepra type I (reversal)reactions usually affect patients with borderline

disease. Reversal reactions are a shift toward the tuberculoid pole after the

start of therapy, and they are type IV cell-mediated allergichypersensitivities, indicating an improvement in cell-mediated immunity.

Puberty, pregnancy, and childbirth can also precipitate type I reactions.

These reactions usually result in skin erythema, with edema and

tenderness of peripheral nerves. New skin lesions are common, and thepatient may have an acute febrile illness. The peak time for type I

reactions is during the first 2 months of therapy and for up to 12 months.Corticosteroid treatment is aimed at controlling acute inflammation,

relieving pain, and reversing nerve and eye damage. With treatment,

approximately 60-70% of the patient's nerve function is recovered. Ifneuritis is absent, NSAIDs may be helpful. MDT should be continued

during type I reactions.

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o Lepra type II reactions, or ENL, occur in approximately 10% of patients

with borderline lepromatous leprosy and in 20% of patients with LL.

These reactions are type III humoral (antibody-antigen) hypersensitivities,with a systemic inflammatory response to immune complex deposition.

The most common presenting symptoms are crops of painful erythematous

nodules of the skin and subcutaneous tissue. Bullae, ulcers, and necrosisalso may occur. Nerve damage is slower than in reversal reactions. The

reaction usually manifests after a few years of therapy, and, although a

single acute episode is possible, relapses occur intermittently over severalyears. Associated fever, malaise, arthralgias, neuralgia, iridocyclitis,

dactylitis, orchitis, and proteinuria may be present.

The use of clofazimine in MDT substantially reduces the incidence

of ENL to 5%. Clofazimine has also been used to treat ENL. Thalidomide is effective except in the case of neuritis or iritis, in

which case corticosteroids should be used.

Other treatment therapies reported to be effective include

colchicine, pentoxifylline, cyclosporine A, intravenousimmunoglobulin, and infliximab.

Lowering the dose of dapsone may decrease the severity of bullaeand ulcers.

o Lucio phenomenon is a cutaneous necrotizing vasculitis that is

sometimes designated a type II reaction. It is common in Mexico andCentral America and is characterized by erythematous, geometric,

irregular-shaped macules that rapidly progress to ulceration and necrosis

on acral areas or extremities of patients with diffuse LL. Systemic

symptoms such as hepatosplenomegaly, fever, arthritis, and nephritis areusually present. Thalidomide is ineffective in treating this type of reaction;

however, no consensus on treatment had been determined. Most patientswith Lucio phenomenon have not received MDT or were treatedirregularly; therefore, MDT is recommended. Azathioprine or

cyclophosphamide with corticosteroids with or without plasmapheresis

has also been used.

The real challenge in managing leprosy is the treatment of reactional states.

o If the course of MDT is not complete, continue taking those medications

as directed.

o Systemic steroids are effective in reducing inflammation and edema in

reversal reactions; therefore, they are the most helpful medications in

preventing nerve damage.

o

Prednisone at 40-80 mg/d should be given for 5-7 days then taperedslowly over 3-6 months. This long course is necessary to decrease the

severity of disabilities and deformities. One study recommended a low-

dose (30 mg/d) regimen for 20 weeks for controlling type I reactions.o Clofazimine can also be used as a steroid-sparing agent for reversal

reactions, alone or with corticosteroids.

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o Although the WHO does not support its use for ENL, thalidomide is

highly effective with ENL. It is ineffective for the treatment of reversal

reactions. Neuropathy induced by leprosy can result in trauma, pressure necrosis, or

secondary infection that goes unnoticed, leading to amputation of digits or limbs.

Wrist and foot drop are also common. Silent neuropathy can occur in the absenceof overt signs of nerve or skin inflammation. Even with corticosteroid treatment,

only approximately 60% of nerve function is recovered. Cyclosporine A may be

useful in controlling nerve impairment and pain.

Injuries can result in ulcerations, cellulitis, scarring, and bony destruction. Foot

ulcers discovered early should be treated with rest because they heal if they are

not subject to weight bearing.

Osteoporosis and fractures can result from bony changes due to leprosy.Risedronate and other bisphosphates may help improve lumbar bone mineral

density.

Contractures can develop and may result in fixation. Common sequelae include

clawing of hands and feet. Eye damage, especially in the anterior portion of the eye, can result in loss of the

corneal reflex, lagophthalmos, ectropion, entropion, and blindness. One studyfound the risk of ocular complications in patients with multibacillary disease, after

completion of MDT, to be 5.6%, with eye-threatening complications to be 3.9%.

Skin drying and fissures can be caused by autonomic disruption.

ERYTHEMA NODOSUM LEPROSUM

ENL or type 2 reaction is a serious, difficult to manage immunological complication ofborderlinelepromatous (BL) and lepromatous leprosy (LL). The majority of patients with ENL go

on to develop several episodes over many years, as multiple acute episodes orchronic ENL.

The cutaneous manifestation of ENL is widespread crops of erythematous, inflamednodules and papules, which may be superficial or deep.Ulcerated, necrotic, pustularand bullous forms have also been reported. Some nodules may persist as a chronicpainful panniculitis leading to fibrosis and scarring.

Neuritis, in the form of painful enlarged nerves and nerve function impairment, mayoccur as part of ENL. The neuritis may be less dramatic than in T1R but it isimportant to recognise nerve involvement early to prevent permanent loss offunction.

ENL may present as a systemic illness, with high fever, systemic upset and

prostration. Peripheral oedema and transient proteinuria can also occur. Iritis andepiscleritis can occur and may be sight threatening. Other features such as pain,photophobia and lacrimation may be absent. Orchitis, lymphadenopathy,organomegaly, joint involvement, dactylitis and bone tenderness, especially over thetibia, are well recognised features of ENL.

Epidemiology and risk factors

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There is wide geographic variation in the prevalence of ENL reactions. In Asiareported figures vary between 19-26% of BL and LL cases in Nepal, India and

Thailand.

ENL reactions occur most commonly during the first year of MDT.One third ofpatients with ENL have the diagnosis of leprosy made at the same time as theirreaction.

Lepromatous leprosy (LL) and a bacillary index (BI) greater than 4+ have been shownto be risk factors for ENL.Pregnancy, lactation, puberty, intercurrent infection,vaccination and psychological stress have been considered to precipitate ENLbutthese associations have not been confirmed in prospective studies.

Pathology of erythema nodosum leprosumThe inflammatory infiltrate in ENL is situated in the dermis and the subcutis. Theconstituent cells vary with the timing of the skin biopsy. In acute lesions where skinbiopsy is performed within 72 hours of occurrence, the predominant cell type is theneutrophil. Eosinophils and mast cells may also be present.Skin biopsies performedlater show fewer neutrophils and increasing numbers of lymphocytes, plasma cellsand histiocytes, representing a chronic inflammatory infiltrate.

The other histological features reported in ENL are edema of the dermis and subcutis,vasculitis and panniculitis.Changes due to leprosy will also be evident. The infiltratedue to LL may contain histiocytes with fatty change and foamy cells arrangeddiffusely. In biopsies from patients with BL leprosy the granuloma may containhistiocytes and lymphocytes.In both cases large numbers of acid fast bacilli, usuallygranular in appearance, will be found.

Immune complexes are important in the pathogenesis of ENL as demonstrated by the

presence of complexes of complement and M. leprae antigen in cutaneous lesions.High levels of circulating TNF have been found in some individuals with ENL.There isevidence of a cell mediated immune response in the pathogenesis of ENL. The major

T cell subtype in ENL is the CD4+ cell in contrast to lepromatous leprosy where CD8+cells predominate.TNF and IL-6 have been shown to be present in skin lesions of ENLwhile IL-4 is absent or low which supports a role for Th1 type T cells.

Treatment of erythema nodosum leprosumThe main aims in the management of ENL are the control of inflammation, pain reliefand prevention of further episodes.Mild cases of ENL can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs).

CorticosteroidsPrednisolone is commonly used for the management of moderate to severe ENL. TheWHO Global Strategy document does not give specific advice concerning the dosageof prednisolone.We commonly start at a dose of prednisolone 40-60 mg daily butsome leprologists use higher initial doses. The dose of prednisolone should be slowlyreduced according to response. The majority of patients require multiple orprolonged courses of prednisolone due to the natural history of the condition.

Tachyphylaxis to prednisolone may also develop.

Concerns about the use of corticosteroids in the management of reactions

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The use of potent immunosuppressants is potentially problematic in areas endemicfor severe infections such as tuberculosis. Immunosuppression may also lead to fatalstrongyloidiasis.

Analysis of the adverse events attributable to prednisolone in the three TRIPOD trialssuggests that the drug is safe when used under field conditions in standardisedregimes.The trials used a total prednisolone dose of 1.96g and 2.52g. The steroid

treated group were significantly more likely to experience minor adverse events butthere was no difference in the likelihood of major adverse events between theprednisolone and placebo groups. Three hundred of the 815 patients enrolled in thethree studies were followed for 24 months and none developed tuberculosis orhypertension during that time.

The long term adverse effects of corticosteroid therapy in individuals with leprosyreactions have not been studied. The amount of diabetes, cataract and hypertensionexperienced by this group is not known.

It has been reported that patients receiving steroids for ENL develop more adverseeffects compared to those with T1Rs which may be due to the longer duration oftreatment in this group.

ThalidomideThalidomide is very effective in the treatment of moderate to severe ENL. It has arapid onset of action. Its beneficial effect is thought to be due to its action on TNF butother mechanisms may also play a part. Prospective clinical trials have shown thattreatment with thalidomide has a quicker action of onset and reduces the number ofskin lesions, fever and systemic symptoms better than pentoxifylline, aspirin andplacebo.Treatment with thalidomide has also been shown to reduce the prednisolonerequirement of patients with chronic ENL.

We suggest using a starting dose of 400mg thalidomide at night in severe ENL and toreduce the dose to 300mg as soon as possible. This dose can then be reduced by100mg per month but a maintenance dose may be required in those with chronic

disease.Thalidomide should be used with extreme caution due to its teratogenicpotential. The System for Thalidomide Education and Prescribing Safety (STEPS)programme adopted by the FDA in the USA has been shown to be very effective inpreventing pregnancies in women taking thalidomide.There has been a recent reportof three cases of thalidomide embryopathy in Brazil and importantly tablet sharingwas a major contributory factor.

Women of child bearing potential who require thalidomide should be provided withinformation about its adverse effects and counselled on the importance of the needto avoid pregnancy. A negative pregnancy test should be obtained before startingthalidomide therapy and two methods of contraception should be prescribed. Thepregnancy test should be repeated every month. Only one months supply ofthalidomide should be prescribed.54 In many leprosy endemic countries such stringent

arrangements are not possible.

Somnolence and dizziness are the commonest adverse affects of thalidomide.Cutaneous adverse effects occur in 3% of individualsand may be exanthems or rarelyerythema multiforme and toxic epidermal necrolysis.Thalidomide causes a peripheralneuropathy but there are no data regarding thalidomide-induced neuropathy inpatients with ENL. Deterioration of nerve function in patients receiving thalidomideshould not be assumed to be due to their leprosy.

Clofazimine

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Clofazimine is a mild anti-inflammatory agent. It can be used for the treatment ofmild to moderate ENL but has a slow onset of action.The clofazimine component ofMB MDT probably reduces the incidence of ENL but this has not been formally tested.Clofazimine at a dose of up to 300mg daily can be given to help control ENL. It iscomplicated by increased pigmentation and the possibility of clofazimine crystalenteropathy.This higher dose should not be continued for more than 12 months.

Other drugsA recent Brazilian double blind RCT has shown that pentoxifylline is inferior tothalidomide in controlling cutaneous and systemic features of ENL. The pentoxifyllinewas also less well tolerated.Colchicine and chloroquine have been evaluated in smallstudies and their effect was marginal. There are case reports and case series on theuse azathioprine,methotrexate,oral zinc,and the chimeric anti-TNF monoclonalantibody, infliximab,for the treatment of ENL.

Involvement of the Paranasal Sinuses by Lepromatous Leprosy

The role of nasal infection in the transmission of leprosy has been extensively studied.

The paranasal sinuses play an important role in transmission of leprosy due to their largesurface area of mucous membrane and the constant flow of secretions. Leprosy can affect

the paranasal sinuses because the mucosal lining is in continuity with the nasal cavity.The paranasal sinuses can also be involved secondarily as a result of bacillaemia and they

act as a reservoir of infection. CT scan has become a major tool in investigating

pathology of the paranasal sinuses because it shows good soft tissue delineation andvisualization of bone. In one Indian study on CT images of untreated patients with

lepromatous leprosy, the pattern of mucosal pathology involving the paranasal sinuses

found out that the anterior group of ethmoidal air cells was more commonly involved(65%) than the posterior group (35%). Bilateral involvement was commonest (65%). In

this same study, they also found out that the ethmoid sinuses were mostly involved

followed by maxillary sinuses. In a 2007 study by Kiris et al on lepromatous leprosy

patients who had been treated, concluded that persistent infection was still commonlyencountered. They noted that paranasal sinus CT examination is a useful method for the

evaluation of patient response to treatment and follow up; however, a CT scan alone

cannot determine whether the leprosy is active.

Updates on treatment of ENL

Effective Treatment of Erythema Nodosum Leprosum with Thalidomide Is Associated

with Immune Stimulation

To elucidate the mechanism of action of thalidomide in this syndrome, we prospectively

investigated 20 patients with ENL who were treated with thalidomide for 21 days. All

patients responded to treatment, with the majority of them having complete resolution of

cutaneous lesions within 7 days. This response was associated with a marked buttransient increase in ex vivo mitogen-induced expression of interleukin (IL)2 and

interferon-g by CD4+ and CD8+ T cells that was observed on treatment day 7, but these

returned to pretreatment levels by day 21.

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Treatment of recurrent erythema nodosum leprosum with infliximab.

TNF- contributes to the pathogenesis of erythema nodosum leprosum in humans andthat TNF- blockade may be considered as a therapeutic alternative in patients with

severe erythema nodosum leprosum that has not responded to standard therapies.

However, because TNF- blockade carries an increased risk of M. tuberculosis andfungal infections, one needs to use infliximab in this setting with great care.

Double-blind trial of the efficacy of pentoxifylline vs thalidomide for the treatment of

type II reaction in leprosy.

In the present randomized double-blind clinical study we compared the effectiveness of

orally administered pentoxifylline vs thalidomide in treating type II reaction in 44patients. Daily doses of 300 mg thalidomide or 1.2 g pentoxifylline were administered for

30 days to multibacillary leprosy patients undergoing type II reaction. Randomly chosen

patients were included in the study before, during, and after specific multidrug therapy.

Clinical evaluations were performed on the 1st, 7th, 14th, 21st, and 30th days oftreatment and laboratory tests were carried out on the 1st and 30th days.

As expected, overall, thalidomide proved to be more effective in the treatment of type II

leprosy reaction. Nevertheless, continuous treatment with pentoxifylline was effective in

relieving the clinical signs of ENL, especially limb edema and systemic symptoms, in

62.5% of the patients.

Management of erythema nodosum leprosum by mycophenolate mofetil

Mycophenolate mofetil has been tried in 20 cases of chronic relapsing erythema

nodosum leprosum reaction where long use of systemic steroid produce complications or

are contraindicated. Excellent results have been observed in all the cases to arrest thereaction followed for a period of six to eight months duration.

These patients were started with Mycophenolate Mofetil at dose of 1 gram per day andin a few cases dosage increment to 2 grams per day were necessary for control and

subsequent maintenance. The liver function, kidney function and routine blood counts

were done during the course of therapy. These patients were monitored for a period of six

to eight months. In two patients treatment was discontinued within a month due to thesystemic side-effects of the drug like nausea and vomiting and other gastro intestinal

symptoms and drug did not produce desired results. Maintenance dosages of 500 mg per

day was effective to control the ENL in most cases.

REFERENCES:

Banerjee K, Banerjee R. Management of erythema nodosum leprosumby mycophenolate mofetil. Indian J Dermatol 2008;53:142-3

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Fitzpatricks Dermatology in General Medicine by Klaus Wolff, Lowell A.Goldsmith, Stephen I. Katz, Barbara A. Gilchrest, Amy Paller, and DavidJ. Leffell, 7th ed. New York, New York, McGraw-Hill Professional, 2007.

Faber WR, Jensema AJ, Goldschmidt WF. Treatment of recurrent

erythema nodosum leprosum with infliximab. N Engl J Med. Aug17 2006;355(7):739.

Fucci da Costa AP, Augusto da Costa Ner y J, Wan-del-Rey de OliveiraML, Cuzzi T, Ramos-e-Silva M. Oral lesions in leprosy. Indian J DermatolVenereol Leprol 2003;69:38 1-5.

Haslett PAJ, Roche P, Butlin CR, et al. Effective treatment of erythemanodosum leprosum with thalidomide is associated with immunestimulation. J Infect Dis 2005; 192:204553.

Kahawita IP, Walker SL, Lockwood DNJ. Leprosy type 1 reactionsand erythema nodosum leprosum. An Bras Dermatol. 2008;83(1):75-82.

Kiris A et al. 2007. Paranasal sinus computed tomography findings inpatients treated for lepromatous leprosy. J Laryngol Otol. 2007Jan;121(1):15-8. Epub 2006 Jul 31.

Ramos-e-Silva M, Rebello PF. Leprosy. Recognition and Treatment. Am J Clin

Dermatol. 2001;2(4):203-11)

Sales AM, de Matos HJ, Nery JA, Duppre NC, Sampaio EP, Sarno EN. Double-blindtrial of the efficacy of pentoxifylline vs thalidomide for the treatment of type II reactionin leprosy.Braz J Med Biol Res. Feb 2007;40(2):243-8.

Smith, S. et al. 2008. Leprosy. www.emedicine.com (November 20, 2008)

Srinivasan S et al. 1999. CT findings in involvement of the paranasalsinuses by lepromatous leprosy. Br J Radiol 1999;72(855):271-3.

World Health Organization. Global Strategy for Further Reducing the LeprosyBurden and Sustaining Leprosy Control Activities [Plan period: 2006-2010]. [Document

WHO/CDS/CPE/CEE/2005.53.] Geneva, World Health Organization, 2005.
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