Final Diagnosis

Multibacillary Hansen’s disease

Patient Follow-up

The patient was treated with dapsone , rifampin and clofazimine for 2 years per the National Hansen’s disease program guidelines [1]. His sensory exam improved dramatically in the right hand and normalized in the left foot.

Four years after completing therapy, he returned for evaluation of worsening right-hand numbness, new weakness of the right hand, and new numbness and weakness of the right foot. He had partial recurrence of numbness in left lateral foot. His hemoglobin A1c was normal. Skin biopsy of the numb area of the right foot showed chronic perivascular and perineurial inflammatory infiltrates in the mid and deep dermis. One focus clearly involved a cutaneous nerve. No AFB could be identified by Fite stain. The patient was treated with prednisone, gradually tapering over several months. He was also treated with dapsone, rifampin and clofazimine for a year for possible recurrent infection. However, in retrospect, this episode most likely represented a reversal reaction [2], an increase in the body’s immune response to bacteria, which can be seen before, during or even years after completion of antibiotic treatment [3]. Nonviable bacteria are cleared from the body very slowly over years and may provoke an inflammatory response, producing new neuropathies, with or without pain. Reversal reactions can be successfully treated with steroids or other immune suppressants. The patient’s right hand weakness improved but did not return to baseline. His right foot numbness was unchanged.

Discussion

Leprosy , or Hansen’s disease, is a common cause of neuropathy in the developing world, but may be seen in immigrants to developed countries or in endemic regions of the United States. It is an infection caused by Mycobacterium leprae , affecting skin and nerves. Its neurotropism can be explained, at least in part, by its affinity for Schwann cells. The cell wall of M. leprae contains phenolic glycolipid-1 (PGL-1), which is not found in other mycobacteria [4]. PGL-1 binds to the laminin alpha-2 chain of the Schwann cell basal lamina, an interaction sufficient to induce the uptake of M. leprae into the Schwann cell [5]. Manifestations of the disease range on a spectrum from tuberculoid to lepromatous. Tuberculoid patients have a well-developed cell-mediated immune response, with disease limited to a few hypoesthetic skin lesions and at most a mononeuropathy. Lepromatous patients present with widespread rash and a symmetric polyneuropathy . Interestingly, deep tendon reflexes are typically preserved in leprous neuropathy. Patients may have loss of eyelashes and eyebrows, and inflammatory infiltration of ear lobes, nose and forehead, leading to the so-called “leonine facies ”. In between these polar extremes are patients with more asymmetric presentations, called borderline leprosy [6]. For treatment purposes, patients are classified as either paucibacillary (5 or fewer skin lesions) or multibacillary (more than 5 skin lesions) and treated according to World Health Organization protocols. Paucibacillary patients are treated with dapsone and rifampin for 6 months. Multibacillary patients are treated with dapsone, rifampin and clofazimine for 1 year [7]. In the United States, treatment is continued for 1 year for paucibacillary and 2 years for multibacillary disease per the National Hansen’s Disease Program recommendations [1].

One of the challenges of treating this disease is its propensity for causing autoimmune reactions, which can occur as long as the bacterial antigens are present in the body. These are of two types: type 1 or reversal reaction and type 2 or erythema nodosum leprosum (ENL). In reversal reaction, there is an increase in cell-mediated immune response, leading to increased erythema and swelling of skin lesions and new numbness or weakness , with or without pain. ENL is caused by deposition of antigen-antibody complexes in various tissues, leading to fever, painful skin nodules, hepatosplenomegaly, neuritis, nephritis, orchitis, and iridocyclitis [2]. Both reversal reaction and ENL are treated with prednisone, particularly when there is nerve involvement. In addition, thalidomide is used to treat ENL in non-pregnant patients. It is not helpful in treating neuropathy. Both male and female patients treated with thalidomide must use adequate contraception due to the well-known teratogenic effects of the medication.

Leprosy is typically diagnosed by biopsy of skin rash. In tuberculoid cases , well-formed epithelioid granulomas, sometimes caseating, may be seen with bacteria absent or only demonstrable by polymerase chain reaction (PCR) for M. leprae. In lepromatous cases , skin biopsy reveals disorganized inflammatory cells, including lipid-laden (“foamy”) macrophages containing many bacilli in clumps (“globi”). Destruction of sweat glands and hair follicles results in dry skin and loss of hair, respectively [2].

As illustrated in this case, “neuritic leprosy ” may occur, without associated skin hypopigmentation or rash. A high index of suspicion in patients from endemic areas (which include Texas and Louisiana in the United States) should prompt referral for biopsy. Skin biopsy in a symptomatic area may reveal inflammation involving dermal nerves, which is highly suggestive of leprosy by itself without AFB. If skin biopsy is not definitive, biopsy of an affected nerve may confirm the diagnosis.

Nerve biopsy shows variable degrees of inflammatory changes, involving some fascicles, sparing others. Perineurial inflammation is common, and its presence in any nerve biopsy should always prompt a search for acid fast bacilli. Animal studies have demonstrated that the mycobacteria collect in epineurial lymphatics, thus spreading to endoneurial blood vessels [8]. M. leprae may be seen in endothelial cells of human patients, suggesting a vascular entry through the perineurial sheath [9]. In tuberculoid disease, granuloma formation is prominent and destroys nerve. Staining with S-100 may be necessary to verify presence of nerve tissue. In lepromatous cases, the nerve structure may be relatively preserved and well-formed granulomas are absent. Myelin injury is best demonstrated in toluidine blue stained semithin resin-embedded semithin sections and in teased fiber preparations. The perineurium may be split into layers by sheets of foamy cells or edema, giving an “onion bulb” appearance [2].

Prognosis depends on the duration of symptoms and is good to excellent if the disease is diagnosed in early stages before significant nerve damage occurs. Close monitoring of patients is required during treatment and periodically after treatment is completed, in order to promptly detect and treat reactions that can lead to further nerve damage.

Pearls