Hansen Neuropathy: Still a Possible Diagnosis in the Investigation of a Peripheral Neuropathy.

INTRODUCTION: Leprosy is still one of the most frequent causes of peripheral neuropathy. Although regarded as eradicated in Portugal, is still documented in neuropathological study of patients with clinical peripheral neuropathy without proper diagnosis. MATERIAL AND METHODS: Review of the cases of Hansen disease neuropathy diagnosed in Neuropathology Unit of Centro Hospitalar do Porto between 1978 and 2013, atending to gender, age, clinical manifestations and neuropathological findings. RESULTS: Twenty one patients were identified with neuropathological diagnosis of Hansenâs disease neuropathy, predominantly male. The mean age at diagnosis was 52 years, and sensory symptoms predominate as neurological manifestation of disease. Interval between symptoms and diagnosis was 1-38 years. In most nerve samples tuberculoid type of disease was identified. Bacilli were detected in skin and nerve in 44% of cases. DISCUSSION: Mononeuritis is the most common presentation of leprosy but other clinical manifestations are possible, including skin lesions. Infection with M. leprae injures myelinated and unmyelinated fibres, with replacement of nerve tissue by collagen fibrosis. The diagnosis of leprosy is only achieved by neuropathological study of skin lesions and / or peripheral nerve, supported by the identification of the bacillus. CONCLUSION: Hansen disease remains a public health problem in tropical areas and, although rare, still described in Western countries reason why should still be considered as a diagnostic possibility in the investigation of peripheral neuropathy.

Introdução: A lepra continua a ser uma das causas mais frequentes de neuropatia periférica. Apesar de tida como erradicada em Portugal, ainda se documenta no estudo neuropatológico de doentes com clínica de neuropatia periférica sem diagnóstico etiológico definido.Material e Métodos: Revisão dos casos neuropatia por doença de Hansen diagnosticados na Unidade de Neuropatologia do Centro Hospitalar do Porto no período de 1978 e 2013 atendendo ao género, idade, manifestações clínicas e achados neuropatológicos.Resultados: Foram identificados 21 doentes com diagnóstico neuropatológico de neuropatia por doença de Hansen, com predomínio do sexo masculino. A idade média ao diagnóstico foi de 52 anos, sendo a sintomatologia sensitiva predominante. O intervalo entre sintomatologia e diagnóstico oscilou entre 1 a 38 anos. Na maioria foi identificada forma tuberculoide em biópsia de nervo e detetados bacilos em pele e nervo em 44% dos casos.Discussão: A mononeurite é a forma mais comum de apresentação de hanseníase, podendo cursar com outras manifestações clínicas incluindo lesões cutâneas. A infeção pelo M. leprae lesiona fibras mielinizadas e não mielinizadas, com substituição do tecido nervoso por colagénio resultando em fibrose. O diagnóstico da lepra é apenas conseguido por estudo neuropatológico das lesões cutâneas e/ou nervo periférico, adjuvado pela identificação do bacilo.Conclusão: A doença de Hansen continua a ser um problema de saúde pública em áreas tropicais e, apesar de rara, ainda descrita em países ocidentais, devendo ser considerada como uma hipótese de diagnóstico na investigação de neuropatia periférica.

[Current therapeutic indications of thalidomide and lenalidomide]. / Indicaciones terapéuticas actuales de la talidomida y la lenalidomida.

Thalidomide is a synthetic glutamic acid derivative first introduced in 1956 in Germany as an over the counter medications. It was thought to be one of the safest sedatives ever produced as it was effective in small doses, was not addictive, and did not have acute side-effects such as motor impairment, but was quickly removed from market after it was linked to cases of severe birth defects. The Food and Drug Administration approved use in the treatment of erythema nodosum leprosum. Further, it was shown its effectiveness in unresponsive dermatological conditions such as actinic prurigo, adult Langerhans cell hystiocytosis, aphthous stomatitis, Behçet syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma gangrenosum and others. In May 2006, it was approved for the treating multiple myeloma. New thalidomide analogues have been developed but lack clinical experience. This paper is a review of the history, pharmacology, mechanism of action, clinical applications and side effects of thalidomide and its analogues.

Innovative use of dapsone.

After synthesis of dapsone (4,4' diaminodiphenylsulfone) in 1908, the compound was known exclusively in chemistry. Following the epoch-making discovery of the antimicrobial potential for sulfonamides emerged, the sulfone class was included in the medical armamentarium. The therapeutic role of sulfones related to both pathogen-caused diseases and chronic inflammatory dermatoses has led to extensive use in dermatology. At present dapsone is the only sulfone congener available for clinical practice. The sulfone is used in rifampin-based multiple-drug regiments to treat multibacillary and paucibacillary leprosy and to treat Pneumocystis jiroveci pneumonia and prevent toxoplasmosis in individuals with AIDS. In dermatology, dapsone is the preferred drug for treating dermatitis herpetiformis (Duhring's disease) and is useful in the management of a broad range of chronic inflammatory entities, especially autoimmune bullous disorders. With proper administration and monitoring, the sulfone should be considered a useful and safe agent.

A case series of 48 patients treated with thalidomide.

INTRODUCTION: Thalidomide is approved by the Food and Drug Administration (FDA) for erythema nodosum leprosum, but has been used in many other dermatological conditions that are refractory to standard therapy. METHODS: The medical records of 48 patients treated with thalidomide at Baylor College of Medicine (Houston, TX) were retrospectively reviewed to determine the conditions treated with thalidomide, dosing, efficacy, treatment duration, side effects, adverse events, and reason for discontinuing therapy. RESULTS: Forty-eight patients (men = 18, women = 30) with a mean age of 49.6 years (range: 20-79) were included in this study. Patients were treated for prurigo nodularis, discoid lupus erythematosus, tumid lupus erythematosus, subacute cutaneous lupus erythematosus, systemic lupus erythematosus, lichen planus, lichen planopilaris, cutaneous sarcoidosis, and prurigo nodularis. All conditions were refractory to standard therapy. Patients were treated for a mean of 7.5 months (range: 3 days to 70 months). In most of the disorders, a majority of patients experienced clinical improvement. The most common reason for discontinuation of therapy was side effects, the most frequent being peripheral neuropathy. LIMITATIONS: This study was limited by being retrospective in nature. CONCLUSION: Thalidomide effectively treats some dermatologic conditions that are refractory to standard medications. There are inconveniences associated with obtaining the medication and it is expensive. Physicians must be vigilant for possible side effects, especially peripheral neuropathy.

Adverse effects of antiretroviral treatment.

BACKGROUND: The introduction of highly active antiretroviral therapy (HAART) has led to significant reduction in acquired immune deficiency syndrome (AIDS)-related morbidity and mortality. Adverse drug reactions (ADRs) to antiretroviral treatment (ART) are however, major obstacles in its success. AIMS: We sought to study the adverse effects of ART in a resource-restricted setting in India. METHODS: Hundred patients on ART were studied prospectively over a period of two years. All patients were asked to visit the clinic if they developed any symptoms or on a monthly basis. They were screened clinically and investigated suitably for any ADRs. RESULT: Out of the 100 patients, ten patients did not come for follow-up; only 90 cases were available for evaluation. ADRs were observed in 64 cases (71.1%) - the maximal frequency of ADRs was seen with zidovudine (AZT) (50%) followed by stavudine (d4T) (47.9%), efavirenz (EFV) (45.4%) and finally, Nevirapine (NVP) (18.4%). Most common ADRs were cutaneous (44.4%) followed by hematological (32.2%), neurological (31.1%), metabolic (22.2%) and gastrointestinal (20%). Most common cutaneous ADRs observed were nail hyperpigmentation (14.4%) and rash (13.3%). Immune reconstitution inflammatory syndrome (IRIS) was observed as a paradoxical reaction to ART in 20 (22.2%) cases. CONCLUSION: To optimize adherence and thus, efficacy of ART, clinicians must focus on preventing adverse effects whenever possible, and distinguish those that are self-limited from those that are potentially serious.

[The revival of thalidomide: an old drug with new indications]. / Le renouveau du thalidomide. Un vieux médicament aux nouvelles indications.

Thalidomide has several mechanisms of action: several immuno-modulatory properties, an anti-angiogenic action and a hypnosedative effect. Thalidomide has been used in several cutaneous inflammatory disorders (such as erythema nodosum leprosum in lepromatous leprosy, cutaneous lupus erythematosus, severe aphtosis), cancers (relapsed/refractory multiple myeloma) and inflammatory conditions. Several side effects are associated with thalidomide; some are major: teratogenicity, peripheral neuropathy and deep venous thrombosis; some are minor, such as somnolence or abdominal pain and endocrinologic disturbances. Use of thalidomide is strictly controlled with close adherence to a birth control program and close monitoring for early development of peripheral neuropathy.

Adverse effects of thalidomide administration in patients with neoplastic diseases.

Thalidomide, a glutamic acid derivative, was withdrawn from clinical use in 1962 due to its severe teratogenic effects. Its recent reinstitution in clinical practice was related to its benefits in leprosy and multiple myeloma. Moreover, the antiangiogenic and immunomodulatory properties of thalidomide have led to its evaluation in several malignant diseases, including myelofibrosis, renal cell cancer, prostate cancer, and Kaposi sarcoma. However, thalidomide use is associated with several side effects: somnolence and constipation are the most common, while deep vein thrombosis and peripheral neuropathy are the most serious. A combination of thalidomide with steroids or chemotherapy is being evaluated in several phase 2 studies. While it is not yet clear whether these combinations will enhance efficacy, they appear to increase the toxicity of thalidomide, and thalidomide analogs are being developed to minimize this toxicity. Ongoing studies will clarify the potential advantages of these agents in the treatment of neoplastic diseases.

[New pharmacological availability of thalidomide based on experience in patients with multiple myeloma].

Thalidomide was developed in the 1950s as a sedative having only a low toxicity. However, McBride and Lenz reported in 1961 a close correlation between oral administration of thalidomide by pregnant women and a particular deformity (phocomelia) of their babies. In the 1990s, the biological activities of thalidomide were determined to include the control of tumor necrosis factor-alpha production and inhibition of angiogenesis. In 1994, Folkman et al. reported that thalidomide exhibited a strong inhibition of angiogenesis in their experiments with rabbits and that this effect had a significant relationship to phocomelia. They suggested a utility of thalidomide as a therapeutic agent for diseases that involve angiogenesis, particularly tumorous diseases. Furthermore, in 1994, Vacca et al. reported that the bone marrow of multiple myeloma (MM) patients was rich in blood vessels and that there is a causal relationship between the activity of MM and marrow angiogenesis. According to these data, thalidomide was tested in many countries as a new therapeutic agent for MM. In this review, new pharmacological availability of thalidomide is described on the basis of our experiences.

Thalidomide: current and potential clinical applications.

More than three decades after its withdrawal from the world marketplace, thalidomide is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor (TNF)-alpha by accelerating the degradation of its messenger RNA. Thalidomide also inhibits angiogenesis. Recently, the drug was approved for sale in the United States for the treatment of erythema nodosum leprosum, an inflammatory complication of Hansen's disease. However, it has long been used successfully in several other dermatologic disorders, including aphthous stomatitis, Behçet's syndrome, chronic cutaneous systemic lupus erythematosus, and graft-versus-host disease, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with human immunodeficiency virus (HIV) infection; the drug is efficacious against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related diarrhea, and Kaposi's sarcoma. To prevent teratogenicity, a comprehensive program has been established to control access to the drug, including registration of prescribing physicians, dispensing pharmacies, and patients; mandatory informed consent and education procedures; and limitation of the quantity of drug dispensed. Clinical and, in some patients, electrophysiologic monitoring for peripheral neuropathy is indicated with thalidomide therapy. Other adverse effects include sedation and constipation. With appropriate safeguards, thalidomide may benefit patients with a broad variety of disorders for which existing treatments are inadequate.

Risk factors for type-1 reactions in borderline leprosy patients.

Type-1 or reversal reactions are the major cause of nerve damage and disability in leprosy. We wished to determine whether there were any clinical or laboratory markers that identified patients with an increased risk of type-1 reaction. 42 (31%) of 136 Nepalese borderline leprosy patients (97 male, 39 female; age range 7-73 years) had a type-1 reaction during the first 2 years of multi-drug therapy. Before therapy, 41 (98%) of the 42 patients were seropositive for antibodies to one of three mycobacterial antigens. Seropositivity for IgM antiphenolic-glycolipid-1 (PGL-1) antibodies, but not IgG anti-lipoarabinomannan or anti-Mycobacterium leprae 35 kDa protein antibodies, was significantly associated with subsequent manifestation of a type-1 reaction (p less than 0.001). The concentration of IgM anti-PGL-1 antibodies in serum was significantly higher in patients in whom a type-1 reaction developed. The risk attributable to anti-PGL-1 seropositivity was independent of leprosy class, skin smear positivity, and the presence of other anti-M leprae antibodies (adjusted odds ratio = 8.7, p less than 0.001). In the 87 patients who had a lepromin test, anti-PGL-1 seropositivity and lepromin reactivity were significant independent risk factors for subsequent reaction. 78% of patients with positive lepromin reactivity and IgM anti-PGL-1 antibodies had type-1 reactions. Patients with these risk factors should be carefully monitored during antimicrobial therapy to permit early initiation of anti-inflammatory treatment thus minimising permanent nerve damage and resultant disability.

Peripheral neuropathy and haemolytic anaemia with cherry red spot on macula in dapsone poisoning.

A young female presented with haemolytic anaemia due to dapsone overdosage. She developed peripheral neuropathy and marked visual impairment with a cherry red spot on the macula, possibly due to toxic retinal vascular damage; both these resolved in due course. Cherry red spot due to dapsone poisoning has not been reported previously.

Dapsone-induced neuropathy compounds Hansen's disease nerve damage: an electrophysiological study in tuberculoid patients.

In 17 previous cases of dermatological disorders, an axonal motor neuropathy was described as a dapsone (DDS) therapy side effect. In this study, we attempted to assess DDS-induced neuropathy in the ulnar and popliteal nerves of 39 tuberculoid Hansen's disease patients using electrophysiological recordings at the time of DDS withdrawal, owing to dermatological improvement, and 4 months after. Distal motor latencies, conduction velocities at forearm and leg and above the epicondyle and the neck of the fibula were improved at a highly significant level. Twenty-five percent of the patients presented abnormal values (outside of the 95% confidence interval) at the first recording session compared to those at the second session. By contrast, parameters exploring the degree of innervation of distal muscles showed a progressive denervation. These results lead to an impairment of Hansen's disease neuropathy during DDS therapy affecting the motor conduction velocities of one quarter of the patients, and are discussed in terms of physiopathological mechanisms.