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Flashcards in Peripheral neuropathies: leprosy Deck (47):
1

Leprosy (Hansen’s disease):

A chronic bacterial infection caused by Mycobacterium leprae.

Primarily involves peripheral nerves and skin in cooler regions of the body and mucus membranes and tissues of upper respiratory tract. Leprosy is the most common treatable cause of neuropathy in the world.

Not a reportable disease

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M. leprae:

4 strains exist today

Acid-fast bacillus rod (mycolic acids in cell wall),
Slow growth rate (estimated generation time is about 12 hours)
Grows best at 33oC, but can grow at higher temperatures -- relates to sites of infection.

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M. leprae: EC or IC pathogen?

An obligate intracellular pathogen, which grows in:
macrophages,
histocytes of skin,
Schwann cells of nerves

Cannot be cultivated in vitro (Never cultured in vivo for diagnostic purposes).

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M. lep incidence:
Most (70%) of 1 million cases occur in

Southeast Asia: India, Indonesia, Bangladesh, Myanmar (Burma).
The remaining cases are primarily in Brazil, Nigeria.

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M. lep Incidence in US:

200→400 cases; principally in immigrants.

Endemic in a few states.
with efficacious therapy, the numbers of registered cases have decreased significantly in the last 20 years, but the number of new cases remains unchanged (250K → 500K/y).


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It is estimated that only 10% of the world population is ?? to infection and of those, ?? will manifest with disease if exposed to the agent.

SUSCEPTIBLE
only about 1/2

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M. lep transmission

primarily from diseased patients (esp. those with *lepromatous form*) via:

aerosol route
Mucous membranes or broken skin on the one person makes direct contact with skin lesions on infected person


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M. lep age, seasonality

risk factors??

kids and oldies more than adults
no season

Exposure to infected person.


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M. lep most common clinical manifestation

Asymptomatic infection is far more common than disease.

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M. lep, With respect to Schwann cells (SC):

The organism binds laminin-2 to alpha-dystroglycan on Schwann cells (these binding proteins are not found in CNS) to enter Schwann cells. Only infects non-myelinating SC that surrounds bundles of small diameter sensory nerve fibers

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M. lep also causes ??

demyelination of peripheral nerves, which activates myelin-forming SC to *de-differentiate & become non-myelinated* (this is a normal physiological process for myelin-forming SC).
These de-differentiated SC are now susceptible to infection by M. leprae.

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M. lep.: Sensory nerve loss occurs:

initially confined to the skin rash (with losses to temperature greater than losses to pinprick and light touch. Proprioception and vibration modalities are often preserved).

then progress to multiple mono-neuropathies with large nerve sensory and motor involvement and distal painless injuries

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nerves affected by M. lep

primarily the pressure/trauma-dependent nerves, with the
*ulnar nerve at the elbow involved most often, followed in order by the
superficial radial cutaneous and median nerve at the wrist, sural, radial
Popliteal fossa - Common peroneal nerve
Great auricular nerve in the neck
branches of the facial nerve (facial paralysis/lagophthalmos)

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M. lep: lose DTRs??

Deep tendon reflexes generally preserved because the muscle spindles and large-fiber nerves are not involved.

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M. lep incubation period?

3 cardinal signs:

LONG: (3 →10 years) (difficult to follow)

Skin lesions.
Skin anesthesia
Peripheral nerve enlargement

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*** Peripheral nerve enlargement in M. lep leads to ?? ***

Deformities due to weakness and wasting of muscles (weakness and wasting occur pari passu [ie, at the same rate]) innervated by the affected peripheral nerves (eg, claw hand or foot drop secondary to muscle weakness)

Sensory symptoms, such as diminished to complete loss of sensation, paresthesias in the distribution of affected nerves, and neuralgic pain when the nerve is struck or stretched.

Spontaneous painless blisters, burns, and trophic ulcers on hands and feet, post sensory loss.

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Disease Classification is based on the immune response of host:

Ridley Jopling classification:
Tuberculoid (TT) form
Lepromatous (LL) form
Borderline (3) forms (borderline boarderline, BB, BT, BL)

World health organization uses:
Paucibacillary (PB) leprosy is defined as five or fewer skin lesions without detectable bacilli on skin smears = TT form.
Patients with only a single skin lesion are classified separately as single lesion PB = TT form.
Multibacillary (MB) leprosy is defined as six or more lesions and may be skin smear positive = LL form.

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Tuberculoid (TT) form – not contagious:
Damage to patient's skin and nerves occur via ??

CMI

Patients have a positive response to *lepromin (autoclaved material from lesions of human, animal). *Normal Ig levels are present.
the CMI response leads to sensory loss in the skin rash, multiple mono-neuropathies with large nerve sensory and motor involvement.
no caseous necrosis observed in skin lesions but it may be present in peripheral nerves.

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TT form: skin lesions- skin plaques:

granulomatous (CMI response to agent),
large, hypopigmented, flattened, dry, scaly center.
sharply demarcated, raised edge,
*no sensation in center of lesion or the whole area around the lesion due to invasion of the nerves*
with few acid-fast organisms present.
lesions tend to destroy the normal skin organs such as sweat glands and hair follicles (i.e. lose eyebrows)

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TT form: Sensory loss (see above) may progress to ??

multiple mono-neuropathies occasionally causing *extreme pain beyond endurance*

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Lepromatous (LL) form - Contagious: Damage to patient occurs via:

Innate immune response
Humoral immune response
Nerve damage like TT form occurs – Sensory loss

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(*damaging*) Innate immune response to LL M. lep:

Macrophages infiltrate the infection site where they along with histocytes engulf large numbers of bacilli, fill-up with lipid debris from bacilli, and enlarge, and are then designated as “foamy macrophages” → skin lesions but multiple, symmetrically distributed lesions throughout the body (nerves, eyes, and internal organs in addition to the skin).

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(*damaging*) Humoral immune response to LL M. lep:

A polyclonal hypergammaglobulinemia is common → joints and kidney inflammation due to deposition of Ag-Ab complexes deposition followed by inflammation – a *type III hypersensitivity* response at these sites.

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LL M. lep Patients specifically non-responsive (anergic) to ??
but is capable of a normal ?? to other agents, including other mycobacteria.

lepromin (Ag) and/or the organism (diff than TT form!)

CMI response

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Skin lesions a cardinal sign due to LL M. lep innate immune response and are:

extensive,
raised (papular or nodular lepromas skin lesions),
irregularly shaped, with poorly defined edges.
bilaterally symmetrical,
lesions can coalesce
high densities (109 → 1010 cells/g tissue) of M. leprae are present in each lesion.

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Other LL M. lep manifestations

extensive tissue destruction (e.g., nasal cartilage [saddle nose], perforated nasal septum, swollen enlarged ear lobes) occurs.
loss of body hair.
arthralgias.
myalgias
redness of the eyes (cannot close eyelids/*lagophthalmos*)
*severe neuropathy & sensory loss →claw hand and foot drop*
bone reabsorption & trauma result in loss of digits.
*Kidney failure (most common cause of death)*

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most common cause of death in LL M. lep

Kidney failure

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M. lep: Borderline (3) forms (borderline (BB, BT, BL):

Both types of lesions are present. Disease can go either way depending upon immune status of the patient.
*Most leprosy patients fall within the borderline forms*

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lab dx M. lep

Full thickness skin biopsy specimen from the advancing margin of an active lesion (fixed in formalin, embed in parafilm) and stained with H/E

Involvment of cutaneous nerves with identification of bacilli in nerves by Fite-Farco modification of the acid-fast (carbol fusin) stain

Lepromin test

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M. lep ddx

a “Zebra” among “horses” in U.S.

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M. lep skin biopsy

Histology of the lesion:

if organized epithelioid granulomas are present the patient has TT form.

if “foamy macrophages” are present then patient has LL form.

f disorganized epithelioid granulomas are present, the patient has the borderline form LT

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M. lep skin biopsy

Acid-fast staining by *Fite-Farco* modification of the acid-fast (carbol fusin) stain of skin biopsy specimen from the advancing margin of an active lesion:

Rare bacilli are present in a patient with TT form.

High densities (109 → 1010 acid-fast bacilli/g tissue in lesion” are present in a patient with LL form.

Numbers of bacilli falling within the range of a. and b. of above are present in a patient with boarderline form.

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M. lep skin biopsy:
Slit-skin smear can be used for ??

semiquantitive enumeration of bacilli in skin to assess patients during and after treatment.

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Lepromin tests observed both ??

2 or 3 days and then 3 to 4w after injection, results are expressed as size of induration in mm

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Lepromin tests results

Not diagnostic or prognostic (Not FDA approved, not available in US)
Not used to monitor progress in therapy.
Not used to determine infection or exposure to M. leprae (low sensitivity & specificity).
A negative response to the test is associated with a person with LL from and a positive response (actual granuloma formation) is associated with a person with TT form. (counter-intuitive?)
Is a DTH response (a measure of lymphocyte/macrophage accumulation/proliferation at injection site). (T IV hypersn. like tuberculin for Mtb)
*Is used to assess disease form, but skin biopsy is preferred means to determine Ds form.

36

M. lep tx

MDT is now the norm, due in part, to emerging resistance strains:

dapsone (sulfanilamide) and either or both of the two below:
rifampin.
clofazimine – a fat-soluble riminophenazine dye.

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clofazimine – a fat-soluble riminophenazine dye.

Antibacterial- inhibits DNA replication.

Anti-inflammatory- even immunosuppressive.

produces pink to brownish skin pigmentation in nearly all (75→100%) of patients within a few weeks, as well as similar discoloration of most bodily fluids and secretions.

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M. lep Treatment regimens are based on the disease form:

TT form: 6 months and 2 drugs.
LL form: 2 years and 3 drugs.

39

Patients are considered noninfectious within ??

Monitor drug therapy with ??

1→2 weeks of treatment (usually after the first dose)

microscopic examination of stained skin smears.

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Erythema nodosum leprosum (ENL):
Believed to be due to massive release of

bacterial antigens and can occur in absence of treatment.

Occurs in many (50% of) patients within 1 y of initiation of effective treatment.

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ENL characterized by ??

deep, tender→extremely painful, red papules or nodules (lepromas) on face, arms, thighs and a generalized systemic response including fever, joint pain, edema, proteinuria and malaise, neuritis

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FDA has approved ?? for treatment of the lepromatous form, specifically to reduce occurrence of ENL and because it eliminates the need for ??

?? is also used to moderate ENL.

Thalidomide




corticosteroid therapy.

Clofazimine

43

M. lep px

TT – good even without treatment, but treat anyway.

LL – poor without treatment.

B – depends upon if patient is BT or BL.

Ten-yr-post treatment:
15 → 40% of in LL patient with high numbers of bacilli relapse.

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M. lep prevention: vaccine?

Vaccine exists:
Available/approved in India, Brazil, etc.

Consist of BSG, other atypical mycobacteria.

Prevent infection if administered to neonates (~50% efficacy).

Some therapeutic value if used in combination with antimicrobial therapy.

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M. lep precautions?

No quarantine or hospitalization required for TT.

Respiratory isolation IS required for LL and the indeterminate forms until chemotherapy becomes effective

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M. lep: ppx for close contacts?

Chemoprophylaxis close contacts (esp. children) of pt. with lepromatous, undeterminant forms.

47

M. lep WHO Global Alliance goal

to eliminate leprosy from endemic countries by 2005

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