On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.79 no.2 Rio de Janeiro Mar./Apr. 2004
CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION
Silent neuritis in multibacillary leprosy evaluated through the development of disabilities before, during and after multidrug therapy*
Maria Inês Fernandes PimentelI; José Augusto da Costa NeryII; Esther BorgesIII; Rosângela RoloIV; Euzenir Nunes SarnoV
in Dermatology, Universidade Federal do Rio de Janeiro, titular professor of
Dermatology, Escola de Ciências Médica, Centro Universitário
de Volta Redonda (Uni-FOA), Volta Redonda, RJ
IIPh.D. in Infectious and Parasitic Diseases, Universidade Federal do Rio de Janeiro, M.D. at Ambulatório Souza Araújo, Fundação Oswaldo Cruz, Rio de Janeiro
IIIPhysiotherapist at Ambulatório Souza Araújo, Fundação Oswaldo Cruz, Rio de Janeiro
IVOccupational therapist, Ambulatório Souza Araújo, Fundação Oswaldo Cruz, Rio de Janeiro
VVice-president of Research, Fundação Oswaldo Cruz, Rio de Janeiro
Silent neuritis is defined as deterioration of the neural function without neural
pain, in contrast to overt neuritis, characterized by pain in the peripheral
nerve that may accompany damage to neural function. Its early detection is important
to prevent the development of leprosy disabilities.
OBJECTIVES: To evaluate the frequency of silent neuritis in multibacillary leprosy patients.
METHODS: One hundred and three patients (18.4% BB, 47.6% BL and 34% LL) were followed-up for an average of 64.6 months from diagnosis, during and after multidrug therapy, in relation to physical impairments and according to a disability grade.
RESULTS: Patients that presented a worsening of the disability grade by the end of treatment or at the end of follow-up compared to the baseline grade or to the end of treatment, were studied. Altogether we detected five patients (4.9% of the total) that developed silent neuritis, during or after multidrug therapy.
CONCLUSION: We recommend a careful regular neurological examination of multibacillary patients, with a view to prompt detection and treatment of silent neuritis.
Keywords: disability evaluation; leprosy; neuritis.
Neural involvement is present in all clinical forms of leprosy, from the initial forms of indeterminate leprosy with areas of cutaneous thermal anesthesia, to the well defined polar forms of the illness, such as the clear-cut edges of the insensitive lesions of tuberculoid leprosy, progressing from the dimorphic forms to glove and boot anesthesia, particular to the advanced forms of virchowian (lepromatous) leprosy, with involvement of multiple nerve trunks. Thus, neural involvement underlies all the forms of leprosy.1,2
The pathogenesis of nerve damage varies with the clinical form of leprosy. Such that, in tuberculoid leprosy, the nerve lesion is linked to retarded type hypersensitivity against the antigens of Mycobacterium leprae present in the nerves, with the formation of granulomas of epithelioid cells and, occasionally, necrosis.1,3 In the borderline forms of leprosy, there are several degrees of hypersensitivity to the mycobacterial antigens, with greater concentrations of bacilli in the nerves;1,3 forming focuses of epithelioid granulomas alongside areas with relatively preserved Schwann cells, although with bacilli present.3 In the lepromatous forms, a great amount of bacilli occurs in the entire nerve structure, with a slow and gradual insidious nerve destruction.1
Neuritis literally signifies "inflammation of the nerves". However, neuritis has a specific sense, meaning the presence of pain, whether spontaneous or on palpation of a nerve trunk, which may be associated with impairment of function; or even an isolated impairment of nerve function, as detected in the sequential exam of a patient without pain.1,3 Neuritis can present little or no nerve lesion.1
Neuritis occurs mainly during reactional episodes. In both type I or reverse reactions, associated with an increase in the immunological response against M. leprae antigens, there occurs an increase in intraneural granuloma and edema, with pain and thickening of the nerve course. The sudden compression can lead to a rapid functional impairment,1,3 and occasionally without pain.1 In type II reactions or erythema nodosum leprosum (ENL), the peripheral nerves can be painful for prolonged periods, though without major impairment of function.3 Occasionally, ENL lesions are seen in the nerves, with neutrophilic infiltration and formation of microabscesses, extensive neural destruction can occur.1
Silent neuritis was identified in the beginning of the 1980s, with the studies by Duncan and Pearson,4 who recognized the deterioration of nerve function without a history of objective signs or symptoms of overt neuritis. Later, it became a matter of concern among various leprologists,5,6,7 since it can only be detected by careful sequential neurological exam.
Here the concepts of overt neuritis will be used for cases of pain in the peripheral nerve trunks, whether accompanied or not by thickening of the nerve and/or alterations in the nerve function, and of silent neuritis for cases of changes in nerve function without pain in the corresponding nerve trunk.
Neural damage is well recognized and feared among paucibacillary patients (tuberculoid tuberculoid, TT; and borderline tuberculoid, BT). However, it has been verified that in relation to the multibacillary group, there is less concern in general among health workers regarding the occurrence of nerve lesion, with the exception of patients with dimorphic forms (borderline borderline, BB), that are susceptible to greater nerve damage due to their known predisposition to reverse reactions. Those with multibacillary forms of leprosy (borderline borderline, BB; borderline lepromatous, BL; lepromatous lepromatous, LL) appear to present appreciably more reactions and neuritis than the paucibacillary cases.8,9 Epidemiological studies on leprosy disability have demonstrated a higher risk for multibacillary patients and those with neuritis.10,11
The objective of the present study was to accompany a cohort of multibacillary patients in order to determine the occurrence of neurological damage without pain (silent neuritis).
MATERIAL AND METHODS
One hundred and three patients with multibacillary leprosy forms (19 BB - 18.4%; 49 BL - 47.6%; and 35 LL - 34%) 12 admitted consecutively for multidrug therapy (MDT - MB 24 doses) at the Souza Araújo Ambulatory, Fundação Oswaldo Cruz, Rio de Janeiro, between January 1990 and December 1992, were followed-up during and after drug therapy for a mean period of 64.6 months (range 28 - 90 months) starting from the diagnosis. All of them signed an informed consent to participate in research at the above mentioned institution.
Individuals were excluded from the study that had previously been submitted to any type of drug treatment for leprosy; that abandoned the treatment before its conclusion; and those with exclusively neural forms without cutaneous involvement.
Between January 1990 and December 1992, 168 patients with multibacillary forms of leprosy were accepted for treatment at the clinic, of these 65 patients were excluded from the study for the above mentioned reasons.
Evaluation of the physical disabilities
The evaluation of the physical disabilities was done by physiotherapists or occupational therapists experienced in leprosy, at the beginning of the treatment; monthly, during the multidrug therapy, and annually after its conclusion (or at smaller intervals in the light of reactional episodes or when considered necessary by the health team).
The evaluation of disabilities was made by calculating the degree of disability, using the form recommended by the CNDS (Coordenação Nacional de Dermatologia Sanitária / National Coordination of Sanitary Dermatology) for this finality.14 The following were evaluated: hands, feet and eyes, according to impairment of sensitivity (Semmes-Weinstein monofilament tests) or motor disability (VMT, voluntary muscle test).14 The evaluation of ocular sensitivity was done using the dental floss technique.14 The degree of disability for a given patient was considered to be the maximum grade found in the completion of the respective form, varying from zero (no disability related to the leprosy), to grades one, two or three. The disability grade was calculated for each patient at the time of diagnosis (disability grade before treatment, DGBT), at the end of the multidrug therapy (disability grade at the end of treatment, DGET), and at the end of the follow-up period (final disability grade, FDG).
Reactional states corresponded to acute episodes during the chronic course of leprosy, and were basically classified as type one (reverse reaction, RR) or type two (erythema nodosum leprosum, ENL; polymorphic erythema, PE), whether or not accompanied by neuritis.
All episodes of overt neuritis were carefully recorded, and considered to be the presence of pain in the peripheral nerve trunk, whether or not accompanied by neural thickening.
The patients that presented a worse disability grade at the end of the treatment (DGET) or final disability grade (FDG), in relation to the disability grade before treatment (DGBT) totaled 12 individuals (11.7% of the total). Of these, 11 (91.7%) had reactions during and/or after the treatment, and only one did not present any reactional episodes; 10 (83.3%) had episodes of overt neuritis, during or after the multidrug therapy. Chart 1 summarizes the disability grade of these patients and their reactional episodes during the course of the study. Two (patients 3 and 11) did not present episodes of overt neuritis in the follow-up period, although one presented a type two reaction during the treatment. These two patients that suffered a deterioration in their physical disabilities despite the absence of clinically detectable neuritis (neural pain) presented silent neuritis.
When observing the physical disabilities present at the beginning of the treatment, during the treatment and at the end of the follow-up period, two patients stood out that were classified as disability grade zero or one before treatment and that coursed to disability grade two by the end of the treatment. These cases are described below:
Patient 2: The patient, presented four episodes of overt neuritis during the treatment (on days 5, 16, 20 and 22 of the multidrug therapy). From the first episode of neuritis (dose 5) in the left fibular nerve, claw-foot to the left, indicating functional impairment due to overt neuritis. On this occasion, responsibility for the loss of nerve function was attributed to the late diagnosis of fibular neuritis and to delayed initiation of corticotherapy. In the fourth episode of overt neuritis, at dose 22, (right and left fibular nerves), the patient presented bilateral claw-foot, that persisted throughout the evaluation of disabilities to the end of treatment (DGET = 2). A further four episodes of overt neuritis were detected in the post-treatment period, in months 10, 14, 30 and 37 after multidrug therapy. On three of these occasions, the patient developed overt neuritis of one or both fibular nerves. However, by post-treatment month 14, there was a recovery in the function of the fibular nerves, and claw-foot was not detected in any of the subsequent exams up until the last evaluation in post-treatment month 48.
Patient 4: Five episodes of overt neuritis were presented during the multidrug therapy, at doses 11, 14, 20, 22 and 24. From the fourteenth dose on, the patient presented right ulnar overt neuritis, with right ulnar mobile claw-hand (disability grade = 2). At the twentieth dose, right claw foot was still detectable and without pain (silent neuritis of the right fibular nerve). On each occasion, intensive corticotherapy was initiated. There was remission of the right ulnar mobile claw-hand, however the right claw foot persisted until the exam at the end of treatment (DGET = 2) and post-treatment month 9 (Dg-f = 2), when the patient abandoned the follow up.
Patient 5: this patient had 17 episodes of overt neuritis, usually accompanying a type two reaction (ENL), of which seven occurred during the treatment and 10 in the period up to post-treatment month 7, thereby having persisted during almost the entire follow-up under corticotherapy. In the fifth episode of overt neuritis (right and left ulnar neuritis, right and left fibular neuritis), the patient presented ulnar mobile claw-hand to the left, claw-foot to the left and incapacity to extend the right and left hands (silent neuritis of right and left radial nerves), the latter three disabilities persisted until the exam at the end of treatment (DGET = 2). There was a recovery in the hand extension capacity soon afterwards (post-treatment month one), however the claw-foot to the left persisted, and there were repeated episodes of right and left ulnar overt neuritis that resulted in bilateral ulnar mobile claw-hand (disability grade = 2), although a certain improvement was observed later. The final disability evaluation showed bilateral ulnar-median amyotrophy (FDG = 2), without a claw.
Patient 11: the patient coursed without detection of episodes of overt neuritis, but developed bilateral lagophthalmos at the end of the treatment - silent neuritis of right and left supraorbital nerves (disability grade at the end of treatment, DGET = 2). The patient abandoned follow-up after post-treatment month one.
These data can be verified in Table 2.
As observed by the analysis of these four patients, a further two individuals were detected (patients 4 and 5) with silent neuritis during the multidrug therapy.
Cases were then analyzed that presented worsening of the final disability grade (FDG) in relation to the disability grade at the end of treatment (DGET), these totaled three people. Two of which presented episodes of overt neuritis after treatment, and one suffered a type one reaction in the same period, but with silent neuritis, as shown in Table 3.
Frequency of silent neuritis
In a cohort of 103 multibacillary patients observed continually for a mean period of 64.6 months, at least five (4.9%) experienced a deterioration in their physical capacities (measured by a worsening in the disability grade), without presenting overt neuritis, or in other words, they had silent neuritis. The nerves affected by silent neuritis, the resulting disabilities and those present at the end of the follow-up of these patients are given in Table 4.
Overt neuritis (acute and painful nerve involvement) has always been recognized by leprologists as dangerous and capable of impairing nerve function (sensitivity and/or motor). However, in 1976, Naafs et al. were already recommending corticotherapy for patients with reverse reaction, whether or not there was neural pain.15 Silent neuritis was only identified after the studies by Duncan & Pearson,4 that observed the occurrence of a deterioration in nerve function without objective signs or symptoms of overt neuritis. These were followed by the studies of Srinivasan et al.,5 that demonstrated good results using corticotherapy for cases of silent neuritis, and of Hamilton.6 that stressed the need for a sequential and repeated follow-up of sensitivity and motor function of leprosy patients, in order to precociously detect and treat neuritis without pain and thereby preventing the development of disabilities. Later, van Brakel & Khawas7 suggested the term "silent neuropathy", and discussed various pathogenic possibilities: lesion of the Schwann cells, nerve fibrosis, immunological reaction mediated by intraneural cells and intraneural ENL.7
When the 12 patients were observed that presented a worse disability grade at the end of treatment or after the total period of follow up, in relation to the initial exam, it was observed that 11 (91.7%) had reactional episodes, and 10 (83.3%) demonstrated overt neuritis. Among these, two patients (3 and 11 in Table 1) presented worsening of their disability grade (both began with DGBT = 0 and at the end of the follow up presented FDG = 2), without detection of overt neuritis. Both these individuals had subclinical neuritis, or that is, silent neuritis (Patient 3 in the right and left fibular, sural and posterior tibial nerves; and Patient 11 in the right and left supraorbital nerves). Analysis of those that presented a worse disability grade at the end of treatment (DGET = 2) demonstrated a further two patients with silent neuritis: patient 4, in the right fibular nerve, and patient 5, in the right and left radial nerves. One more patient presented worsening of the disability grade between the end of treatment and the end of the total follow-up period without detection of overt neuritis - patient 15 (Table 3) who had silent neuritis in the right posterior tibial, fibular and sural nerves and left posterior tibial nerve. Thus, in the cohort studied, at least five patients (4.9%) presented silent neuritis during the follow-up. (It is possible, however, that other patients had silent neuritis with a more or less rapid recovery from the resulting disabilities - for instance, during corticotherapy for treatment of reactional episodes - without these momentary disabilities being detected in the examinations to evaluate the disability grade, depending on the frequency observed).
It should also be emphasized that patient 11 developed bilateral lagophthalmos, with silent neuritis of the supraorbital nerves, this constitutes a serious situation, but nevertheless may be overlooked during an inattentive routine exam.
Silent neuritis has received several definitions: "deficiency of the nerve and/or motor function without pain or sensitivity of the nerve";4 "presence of a sensitivity or motor loss not accompanied by nerve pain, and which generally passes unnoticed by the patient and therefore is not a matter of complaint;6 "asymptomatic";1 and "sensitivity or motor deficiency without cutaneous signs of reverse reaction or ENL, without evident nerve sensitivity and without spontaneous complaints of nerve pain (ardor or sharp pains), paresthesia or paralysis".7 Its frequency can vary, therefore, with the definition used, in the study by van Brakel and Khawas,7 it reached 7% of the patients recently diagnosed with leprosy. There is, however, a great emphasis among the authors in affirming the importance of periodic exams to detect silent neuritis and initiate intensive corticotherapy, as this results in an improvement of the nerve function.1,5,6,16 Unfortunately, in Brazil, there is no routine treatment with corticoids when disabilities are detected in the sequential exam of leprosy patients, without the occurrence of overt neuritis. It is hard to give a clear notion of how many patients develop neurological sequels due to this omission in their treatment, many of which could be avoided by precocious corticotherapy and appropriate physiotherapy.
More serious still is the deficiency in the accompaniment of disabilities which should be routine during the patients' monthly attendance for multidrug therapy. Doctors and other health workers should be attentive to the involvement of peripheral nerves at each consultation, and proper training to be able to perform a simple but effective neurological exam should be underscored for all those involved in the neurological follow-up of leprosy patients. This becomes even more important, in view of the current discussion regarding the possibility of self-administered multidrug therapy, accompanied MDT (A-MDT), in that the patients would receive sufficient medication for their entire multidrug therapy and only be seen at the end of the treatment, to be discharged.
One can never under emphasize the importance of a careful routine and sequential attendance of multibacillary patients, during and after the drug therapy, since approximately half will develop neuritis, whether overt or silent, during and/or after multidrug therapy.17 Silent neuritis can only be detected by routine sequential exam and attentive evaluation of the physical disabilities. This would enable the use of therapeutic measures, such as corticotherapy and appropriate physiotherapeutic attendance, to try to revert the neural picture and to minimize neurological sequels, thereby reducing the onset of physical disabilities caused by leprosy. q
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15. Naafs B, Pearson JMH, Baar AJM. A follow-up study of nerve lesions in leprosy during and after reaction using motor nerve conduction velocity. International Journal of Leprosy 1976; 44(1 & 2): 188-197. [ Links ]
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17. Pimentel MIF. Neurites na hanseníase: significado de parâmetros clínicos e epidemiológicos na indução e agravamento das incapacidades físicas em pacientes multibacilares. Tese de doutorado. Universidade Federal do Rio de Janeiro, Rio de Janeiro, 1998, 98 p. [ Links ]
Maria Inês Fernandes Pimentel
Rua Dr. Satamini, 210 / 1004 - Bloco A - Tijuca
20270-231 Rio de Janeiro RJ
Tel.: (21) 2240-0013
in June, 05th of 2002
Approved by the Consultive Council and accepted for publication in December, 02nd of 2003
* Work done at the Fundação Oswaldo Cruz, Rio de Janeiro, RJ Brazil.