INT J TUBERC LUNG DIS 7(4):347–353 © 2003 IUATLD

Peripheral neuropathy associated with treatment for multidrug-resistant tuberculosis S. S. Shin,*† A. M. Hyson,† C. Castañeda,‡ E. Sánchez,§ F. Alcántara,¶ C. D. Mitnick,† M. C. Smith Fawzi,† J. Bayona,†¶ P. E. Farmer,*† J. Y. Kim,*† J. J. Furin¶ * Brigham and Women’s Hospital, Boston, † Department of Social Medicine, Harvard Medical School, Boston, Massachusetts, USA; ‡ Department of Neurology, Universidad Peruana Cayetano Heredia, § National Tuberculosis Program, Ministry of Health, ¶ Socios En Salud—Sucursal Peru/Partners In Health, Lima, Peru SUMMARY OBJECTIVE:

To review the incidence and management of peripheral neuropathy in patients receiving therapy for MDR-TB. M E T H O D S : A case series with retrospective chart review of 75 patients who initiated individualized therapy for multidrug-resistant tuberculosis (MDR-TB) in Lima, Peru, between 1 August 1996 and 31 January 1999. R E S U L T S : All patients had confirmed MDR-TB and were receiving individualized therapy, comprised of an average of six drugs. Ten (13%) of these patients presented with symptoms of peripheral neuropathy, confirmed by electromyography. All symptoms were reported in the lower extremities, and all were sensory in nature. Median time to presentation from initiation of MDR-TB therapy was 9.1 months. No significant risk factors associated with development of peripheral neu-

ropathy were identified. Management strategies depended on the severity of symptoms and included the treatment of contributing co-morbidities, medications for neuropathic pain, and adjustment of doses of possible offending agents. All patients responded to management; three patients were left with mild residual symptoms. Patients whose neuropathy resolved had symptoms for a median of 7 months. C O N C L U S I O N S : Peripheral neuropathy was encountered in 13% of our cohort of MDR-TB patients. The diagnosis of peripheral neuropathy can be based on clinical presentation alone, and effective management of this side-effect is possible without sacrificing MDR-TB treatment efficacy. K E Y W O R D S : peripheral neuropathy; MDR-TB; Peru; tuberculosis

MULTIDRUG-RESISTANT tuberculosis (MDR-TB) is defined as a strain of Mycobacterium tuberculosis with in vitro resistance to at least isoniazid (INH) and rifampin (RMP), the two most powerful anti-tuberculosis drugs. Because second-line anti-tuberculosis drugs are less efficacious and more toxic than firstline agents, the treatment of MDR-TB is more challenging. Multidrug regimens, with a minimum of four to five drugs, are administered for prolonged periods, usually 18–24 months, with lower cure rates and higher rates of adverse reactions compared with the treatment of pan-susceptible disease.1 Nonetheless, acceptable cure rates can be achieved, as demonstrated by our community-based MDR-TB treatment program in Lima, Peru.2,3 In addition, we have reported low rates of serious adverse reactions and successful management of adverse effects encountered.4 Among the adverse reactions reviewed, peripheral neuropathy was the second most commonly encountered serious side-effect in our case series.

Peripheral neuropathy is a well-known adverse effect associated with TB therapy. While understanding of such toxicity is limited, a review of available literature cites certain anti-tuberculosis drugs as causal agents.5,6 INH causes both sensory and motor neuropathy, especially in slow acetylators,7 with an estimated incidence of 0.2%, although at higher doses (e.g., 10 mg/kg/d vs. 3–5 mg/kg/d), the incidence of neuropathy has been reported to be as high as 40%.8–11 Elderly, alcoholic, malnourished and pregnant individuals, as well as those with renal or hepatic dysfunction, are at greater risk of INH-associated neuropathy.12–14 Co-administration of pyridoxine is protective, although excessive pyridoxine doses can actually cause peripheral neuropathy.15,16 Streptomycin (SM) and ethambutol (EMB) are also recognized to cause peripheral neuropathy; a dose-response relationship has been observed with both drugs.6,17–20 In addition, several second-line drugs have been associated with peripheral neuropathies. Ethionamide

Correspondence to: Sonya S Shin, MD, Program in Infectious Disease and Social Change, Department of Social Medicine, Harvard Medical School, 641 Huntington Avenue, Boston, MA 02115, USA. Tel: (1) 617-432-3715. Fax: (1) 617-4326045. e-mail: [email protected] or [email protected] Article submitted 12 July 2002. Final version accepted 28 October 2002.

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(ETH) is known to cause a sensory neuropathy which may take several months to resolve upon discontinuation of the drug.21,22 The mechanism of ETHinduced peripheral neuropathy is speculated to be the same as that of INH, namely interference with pyridoxine metabolism.17 Cycloserine (CS) also possesses well-known central and peripheral nervous system toxicities by acting as a pyridoxine antagonist and increasing renal excretion of pyridoxine. The concomitant administration of INH and/or ETH, as well as concurrent alcohol use, may exacerbate the neurotoxic effects of CS.23 The fluoroquinolones have also occasionally been associated with sensory and motor peripheral neuropathies when used in combination with other neurotoxic drugs.24,25 Given the relatively common occurrence of this adverse effect in our patient population, we evaluated a case series of patients receiving MDR-TB therapy in order to review the incidence, characteristics, and management of peripheral neuropathy.

METHODS Study population All patients had documented MDR-TB and were enrolled to receive individualized therapy through a collaborative effort of two non-governmental organizations (Partners in Health in Boston and Socios en Salud in Lima, Peru) and the Peruvian National Tuberculosis Program. All patients in this cohort lived in northern Lima, an urban slum characterized by poverty, overcrowding, malnutrition, unemployment, and high rates of immigration from rural areas. Treatment protocol Patients received community-based directly observed therapy (DOT) delivered in health centers and at patients’ houses by community health workers.26,27 Drug resistance was confirmed by conventional or Bactec methods performed by the Massachusetts State Laboratory Institute on sputum specimens.28 Individualized therapy was based on each patient’s resistance pattern. All patients receiving individualized therapy in this program automatically received pyridoxine supplementation of 150 mg PO once daily throughout their MDR-TB therapy.29 Pyridoxine dosing was increased to up to 300 mg PO once daily if a patient experienced any neurologic toxicity, such as peripheral neuropathy, seizures, or severe headaches. Dosing of CS and ETH was usually between 750 and 1000 mg, depending on tolerance (usually limited by dizziness or psychiatric side-effects for CS and gastrointestinal side-effects for ETH); patients who weighed less than 50 kg received lower doses of both drugs. Patients were evaluated at least once a month by a physician trained in the management of MDR-TB. Those patients who reported symptoms consistent with peripheral neuropathy were referred to a neurol-

ogist and electromyography (EMG) study; thiamine, vitamin B6 and B12 levels were checked in all patients observed to have EMG-confirmed neuropathy. Symptoms were managed according to a protocol developed by the team of clinicians at Socios en Salud (Figure). All patients had completed treatment at the time of chart review. The follow-up period for all patients who were still alive was at least 18 months after completion of treatment. Study method A case series with a retrospective chart review was conducted for all patients who had initiated individualized treatment between 1 August 1996 and 31 January 1999. All charts were reviewed by two clinicians trained in the management of MDR-TB. The case definition of peripheral neuropathy was any patient who experienced signs or symptoms of peripheral neuropathy (numbness, tingling, burning or weakness in the extremities, diminished or absent deep tendon reflexes) and also had confirmation of peripheral neuropathy by EMG testing. Other variables extracted from the chart review for all patients were: age; sex; drugs in the individualized regimen; number of previous treatment regimens; presence of a co-morbid condition, including psychiatric illness, anemia, malnutrition, history of alcohol or drug abuse, epilepsy, diabetes

Figure Management of peripheral neurotoxicity in individualized MDR-TB therapy. MDR-TB  multidrug-resistant tuberculosis; HIV  human immunodeficiency virus; INH  isoniazid; ETH  ethionamide; CS  cycloserine.

Peripheral neuropathy in MDR-TB therapy

mellitus (DM), baseline gastritis, hepatitis, baseline hypothyroidism, human immunodeficiency virus (HIV); and treatment outcome. The charts of all cases of peripheral neuropathy were reviewed in more detail to document EMG results, presence of vitamin deficiencies, MDR-TB regimen at time of peripheral neuropathy diagnosis, timing of presentation of peripheral neuropathy symptoms, use of other neurotoxic drugs, and patient management with neuropathy response. Analysis All data were recorded in Microsoft Excel 97 (Microsoft Corporation, Seattle WA); all statistical analysis was performed using SAS, version 8.0 (SAS Institute, Cary NC).

RESULTS Baseline characteristics Seventy-five patients initiated treatment between August 1996 and January 1999. Charts were available and reviewed for all 75 cases. In our cohort of 75 patients, 10 (13.3%) had peripheral neuropathy confirmed by EMG; three other patients reported symptoms suggestive of neuropathy, but all three had very mild symptoms and were subsequently found to have normal EMGs. Among those with confirmed peripheral neuropathy, symptoms developed as early as the second month and as late as the sixteenth month of MDR-TB treatment. The median duration of MDR-

Table 1

TB treatment at the time of diagnosis with peripheral neuropathy was 9.1 months. Symptoms reported by these patients were similar to those reported in the literature, although to varying degrees of intensity. Patients reported paresthesias (tingling, burning, lancing pain) and/or anesthesia, usually beginning in the soles of the feet and spreading proximally. Some patients also complained of muscle pain and weakness of the legs. One advanced case presented with loss of proprioception, ataxia, and loss of temperature sensation. Three patients complained of severe leg pain and dysesthesias, with difficulty sleeping at night due to the pain and extreme discomfort on walking. Several patients had diminished or absent ankle jerks. All symptoms and EMG findings were present only in the lower extremities. Of the 10 patients with peripheral neuropathy, EMG studies demonstrated sensory involvement in all cases, while four also had motor involvement. While the majority of these neuropathies were axonal, two had demyelinating involvement; both patients had co-morbid disease (DM and alcoholism). Of the patients diagnosed with peripheral neuropathy, 100% were receiving a parenteral drug (SM, kanamycin [KM], capreomycin [CM], or amikacin [AMK]) at the time of diagnosis (see Table 1). Of the five patients receiving CM at the time of presentation with peripheral neuropathy, three had received at least 6 months of an aminoglycoside as part of their MDR-TB regimen before being switched to CM in order to minimize cumulative aminoglycoside toxic-

Characteristics and treatment regimens of nine MDR-TB patients diagnosed with peripheral neuropathy

Sex

Age at treatment initiation

1

F

25

2

M

22

3

F

55

4

M

61

5

M

44

6

M

24

7 8 9

M M M

59 31 61

10

F

18

Patient

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MDR-TB regimen* SM, CS 750, ETH 750, CPX, PAS, AC, CFZ KM  6 mo ➝ CM,† CS 1000, ETH 1000, CPX, PAS, AC SM, INH, PZA, CS 1000, ETH 1000, CPX SM  8 mo ➝ CM,† CS 750, ETH 1000, CPX, PAS, AC, CFZ KM  6 mo ➝ CM,† CS 750, ETH 750, CPX, PAS, CFZ SM, INH, EMB, CS 1000, ETH 1000, CPX, PAS CM, INH, CS 750, CPX, PAS, CFZ, AC CM, INH, PZA, CS 1000, CPX, PAS KM, INH, EMB, CS 1000, ETH 1000, CPX, PAS, AC, CFZ SM, CS 750, ETH 1000, SPX 400, PAS, AC, CFZ

Past medical history None

Months of MDR-TB treatment at the time of peripheral neuropathy diagnosis 7

HIV-positive

16

Malnutrition, gastritis, vitamin B12 and thiamine deficiency Type II diabetes mellitus Hypercholesterolemia Alcoholism, history of stroke, malnutrition Vitamin B12 and thiamine deficiency None

13 13 14 13

Epilepsy, vitamin B12 deficiency Vitamin B12 deficiency Thiamine deficiency

6 2 5

None

6

* Daily doses of medications were the following: KM 1000 mg, SM 1000 mg, CM 1000 mg, PZA 30 mg/kg, EMB 25 mg/kg, CPX 1500 mg, SPX 400 mg, PAS 12 g, AC 1500 mg, CFZ 300 mg. INH was administered at 900 mg twice weekly. Doses of CS and ETH were between 500–1000 mg/d (individual doses are specified above). All patients received supplemental pyridoxine (150 mg); this dose was increased to 300 mg in all patients diagnosed with peripheral neuropathy. † Aminoglycosides changed to CM due to toxicity. MDR-TB  multidrug-resistant tuberculosis; SM  streptomycin; CS  cycloserine; ETH  ethionamide; CPX  ciprofloxacin; PAS  para-aminosalicylic acid; AC  amoxicillin-clavulanic acid; CFZ  clofazimine; KM  kanamycin; CM  capreomycin; INH  isoniazid; PZA  pyrazinamide; SPX  sparfloxacin; HIV  human immunodeficiency virus.

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ity (patients 2 and 5 experienced otoxicity, while patient 4 had rising creatinine). Five patients (50%) were receiving INH (900 mg twice weekly), two (20%) were receiving EMB (25 mg/kg/d), eight (80%) were receiving ETH, and all (100%) were receiving CS as well as a fluoroquinolone. Seven of the patients (70%) who developed peripheral neuropathies had additional contributing conditions, including HIV, DM, alcoholism, and vitamin deficiencies. Risk factors Table 2 compares demographic and clinical variables of those who developed peripheral neuropathy with those who did not. Although there was a tendency for patients with peripheral neuropathy to be older, male and have co-morbid conditions, these variables were not statistically significant. Development of peripheral neuropathy was not associated with the number of drugs in the MDR-TB regimen, nor with the number of drugs or number of regimens received prior to individualized therapy. All patients had received previous anti-tuberculosis treatment with INH, EMB, and often an aminoglycoside. None had received pyridoxine with previous treatment. All patients received a parenteral agent in their

Table 2

MDR-TB regimen. Among agents associated with neuropathy, none were significantly associated with higher rates of peripheral neuropathy. Similarly, the dose of CS and ETH was similar among those who experienced peripheral neuropathy and those who did not. Management and evolution Given the high degree of drug resistance in the majority of these patients, every effort was made to manage peripheral neuropathy with minimal impact on the efficacy of the MDR-TB regimen. An entire regimen was never discontinued permanently. Table 3 shows the presentation and management strategy of the patients with peripheral neuropathy. For several patients, decreasing the dose of the suspected offending drug provided relief, and the dose was often successfully increased once pain control was achieved. In three cases (33.3%), one or more anti-tuberculosis drugs were discontinued altogether. Of these, SM was discontinued in one case after the patient had already received 7 months of injection therapy. In the other two cases, CS in one and INH in the other were discontinued only because the remaining regimen was felt to be adequate. While all three patients did improve after discontinuation of the aforementioned drugs,

Characteristics of 75 patients receiving individualized treatment for multidrug-resistant tuberculosis

Patient characteristics Age (years) mean  SD Number of drugs in MDR-TB regimen, mean  SD Number of drugs received prior to MDR-TB regimen, mean  SD Number of previous treatment regimens, mean  SD Male sex, n (%) Any co-morbidity, n (%) Drugs included in individualized regimen, n (%) INH SM KM CM EMB Fluoroquinolone, n (%) CS ETH Dose CS, n (%) 750 mg/d 1000 mg/d Dose ETH, n (%) 500 mg/d 750 mg/d 1000 mg/d Outcome, n (%) Cure Failure/abandonment/death

With peripheral neuropathy (n  10)

Without peripheral neuropathy (n  65)

P value

38.8  17.2 5.9  1.7 7.4  1.9 3.3  1.6 7 (70.0) 5 (50.0)

27.5  7.9 6.3  1.3 7.1  1.9 3.4  1.7 30 (46.2) 24 (36.9)

0.07* 0.42† 0.34† 0.93† 0.19‡ 0.50‡

5 (50.0) 5 (50.0) 2 (20.0) 7 (70.0) 3 (30.0) 10 (100) 10 (100) 8 (80.0)

24 (36.9) 22 (33.9) 27 (41.5) 44 (67.7) 16 (24.6) 65 (100) 64 (98.5) 54 (83.1)

0.50‡ 0.48‡ 0.30‡ 1.00‡ 0.70‡ n/a 1.00‡ 1.00‡ 0.33‡

4 (40.0) 6 (60.0)

37 (57.8) 27 (42.2)

0 (0.0) 3 (30.0) 5 (50.0)

1 (1.9) 28 (51.9) 25 (46.3)

9 (90.0) 1 (10.0)

46 (70.8) 19 (29.2)

0.54‡

0.27‡

* t-test for unequal variances. † t-test for equal variances. ‡ Fisher’s exact test. SD  standard deviation; MDR-TB  multidrug-resistant tuberculosis; INH  isoniazid; SM  streptomycin; KM  kanamycin; CM  capreomycin; EMB  ethambutol; n/a  not available; CS  cycloserine; ETH  ethionamide.

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Table 3 Presentation and management of nine patients diagnosed with peripheral neuropathy while receiving individualized therapy for MDR-TB Patient

Presentation

EMG results

1

Ataxia, leg pain and weakness, numbness, loss of temperature sensation

Sensory neuropathy

2

Leg pain, especially on walking and at night, leg weakness.

Sensory neuropathy

3

Leg pain and cramping

Sensory neuropathy

4

Leg cramps

5

Leg cramps, leg weakness

6

Leg pain, especially at night

Motor/sensory axonal neuropathy; slight demyelinating compromise Motor/sensory demyelinating neuropathy Sensory neuropathy

7

Leg pain and numbness, ankle jerks absent

Motor/sensory neuropathy

8

Numbness and tingling in feet

Sensory neuropathy

9

Mild burning in feet

Sensory neuropathy

Burning and numbness in feet; difficulty in walking due to pain

Motor/sensory neuropathy

10

Management and evolution Amitriptyline with little response; SM discontinued with partial response; CS decreased to 500 mg with improvement, then restored to 750 mg; resolution of symptoms except residual loss in temperature sensation Amitriptyline with partial response; CS discontinued with significant response; symptoms resolved in 7 months Amitriptyline with partial response; vitamin deficiency corrected; residual mild paresthesias of feet Amitriptyline with significant response; improved glucose control; symptoms resolved in 4 months Amitriptyline with significant response; alcohol use discontinued; vitamin deficiency corrected; symptoms resolved in 3 months Amitriptyline with partial response; INH discontinued; symptoms resolved in 4 months Amitriptyline with partial response, then discontinued due to seizure; gabapentin with significant response; vitamin deficiency corrected; persistent mild lower extremity pain, numbness Amitriptyline with complete response; vitamin deficiency corrected; symptoms resolved in 10 months No interventions given mild symptoms; vitamin deficiency corrected; symptoms resolved upon completion of MDR-TB therapy Amitriptyline with partial response; gabapentin and carbamazepine briefly administered, but both rejected by patient due to pill burden; symptoms resolved after completion of therapy

MDR-TB  multidrug-resistant tuberculosis; EMG  electromyography; SM  streptomycin; CS  cycloserine; INH  isoniazid.

the concomitant use of amitriptyline in these cases makes a causal association with an individual agent difficult. Co-morbid factors (including alcoholism, HIV, DM, and malnutrition) were aggressively managed. The patient with alcoholism was intensively counseled and successfully sought rehabilitation, the patient with HIV was followed closely, although he never met criteria for antiretroviral therapy, and tighter glucose control was achieved in the diabetic patient by incorporating finger stick checks into the DOT visits and adjusting oral hypoglycemic dosing accordingly. Those patients with malnutrition or vitamin deficiencies received necessary supplementation. Nine of the patients with peripheral neuropathy (90%) required pain control, with the majority (8/9) responding to a tricyclic antidepressant at low doses (25–75 mg/d). One patient (11.1%) responded to gabapentin. Potential drug-drug interactions between supplemental drugs and anti-tuberculosis drugs were taken into consideration when prescribing these additional medications.30 All patients responded symptomatically to management, and only three had residual symptoms on completion of therapy. Among the seven patients whose symptoms resolved completely, the median duration of symptoms was 7 months.

Follow-up EMGs were not performed, as results would not be likely to affect management given our goal to achieve symptomatic control. Nine of the 10 patients were cured; one patient (patient 4) abandoned therapy while still culture-positive, probably due to treatment non-adherence.

DISCUSSION Community-based treatment of MDR-TB is a feasible and attractive model for resource-poor settings.26 While adverse reactions are to be anticipated, their successful management can help to minimize default and treatment failure rates. Although peripheral neuropathy occurred in a relatively high proportion (13%) of patients in this cohort, an aggressive management strategy successfully allowed patients to continue to receive effective MDR-TB therapy. Through the treatment of co-morbid conditions, modification of MDR-TB regimens, and the addition of therapy for neuropathy itself, all patients reported symptomatic improvement of their neuropathy. The data presented here are limited in a number of ways. First, the number of patients studied is small, and thus the statistical power to identify risk factors for peripheral neuropathy was limited. We may have

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underestimated the incidence of peripheral neuropathy, because EMG was only performed on patients reporting a significant degree of symptomatology. Finally, the population described here is a young, relatively healthy cohort of individuals with chronic MDR-TB, and the results of this work may not be representative of other populations. In spite of these limitations, our experience has led us to identify several important factors regarding peripheral neuropathy in our cohort. First, the rate of peripheral neuropathy observed was higher than previously described.4 This higher incidence may be due to the chronic nature of our cohort. All patients had received multiple previous regimens, all containing INH, without pyridoxine supplementation, and 20% of our cohort was malnourished on initial evaluation. Second, a heightened awareness of peripheral neuropathy symptoms and screening for predisposing factors—such as malnutrition with vitamin deficiencies, diabetes, alcoholism, and previous anti-tuberculosis treatment—may facilitate more rapid diagnosis of peripheral neuropathy. No individual anti-tuberculosis medication was identified as an outstanding culprit; rather, peripheral neuropathy may be due to the neurotoxic effects of multidrug therapy. While this paper describes only EMG-confirmed cases, from experience we felt that the diagnosis of peripheral neuropathy could be based on clinical findings alone. In the case of the three patients with neuropathy symptoms and normal EMGs, the presenting symptoms were mild and did not require intervention. Therefore, exclusion of neuropathy by EMG did not change management. In resource-poor settings, we feel that EMG is not needed or may be used only for rare cases in which the diagnosis is unclear. Finally, adequate management of peripheral neuropathy can be achieved. Treatment of any contributing medical conditions is important in improving the course of neuropathic disease. In general, our patients responded symptomatically to tricyclic antidepressants: some response was usually observed within 2 weeks of initiation of amitriptyline. When changes in the MDR-TB regimens were necessary, careful attention was paid to preserving treatment efficacy: original doses were resumed whenever possible, and medications were suspended only in severe cases and only in cases where the regimen’s efficacy was not felt to be compromised. Other authors have mentioned that discontinuation of the offending agent results in improvement, but this has often been reported with first-line drugs.14,25 We have found that symptoms may have good response to low-dose tricyclic antidepressant therapy. Of note, all patients receiving INH, ETH or CS should receive at least 150 mg of pyridoxine daily. In our practice, all patients initiate MDR-TB therapy with 150 mg per day of pyridoxine; all patients with baseline neurologic disorders, subsequent evidence of neurotoxic side-effects, and those receiving 1000 mg

cycloserine receive a higher dose of B6, usually 300 mg/day. Despite the frequency and occasional severity of the neurotoxic effects of MDR-TB drugs, aggressive and prolonged treatment is recommended. Promising results in our cohort justify such an approach, especially given the high morbidity and mortality of untreated or poorly treated MDR-TB. All but one patient was cured in this cohort, and all responded symptomatically to peripheral neuropathy management. Among the three patients with residual symptoms of peripheral neuropathy, none reported any significant limitation of daily activities. As this paper shows, troubling adverse effects that commonly occur, such as peripheral neuropathy, can be managed even in resource-poor settings. Our experience in community-based treatment of patients with MDRTB demonstrates that MDR-TB can and should be made available to those who suffer from the disease and that occurrence of adverse effects should not be a deterrent to instituting proper therapy for MDR-TB. Acknowledgements The authors would like to thank Thomas White for his indefatigable support, as well as the Peruvian Ministry of Health for their collaborative efforts.

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14 Gohel D, Oza J J, Panicker M G. Pyridoxine and isonex. J Assoc Physicians India 1993; 41: 229. 15 Snider D E Jr. Pyridoxine supplementation during isoniazid therapy. Tubercle 1980; 61: 191–196. 16 Nisar M, Watkin S W, Bucknall R C, Agnew R A. Exacerbation of isoniazid induced peripheral neuropathy by pyridoxine. Thorax 1990; 45: 419–420. 17 Blain P G, Lane R J. Neurological disorders. In: Davies D M, Ferner R E, de Glanville H, eds. Davies’s Textbook of Adverse Drug Reactions, 5th ed. London, UK: Chapman and Hall Medical, 1998: 585–629. 18 Nair V S, LeBrun M, Kass I. Peripheral neuropathy associated with ethambutol. Chest 1980; 77: 98–100. 19 Forester D. Toxic effects of ethambutol. Chest 1980; 78: 496– 497. 20 Takeuchi H, Takahashi M, Tarui S, Sanagi S, Takenada H. Peripheral nerve conduction function in patients treated with antituberculotic agents, with special reference to ethambutol and isoniazid. Folia Psychiatr Neurol Jpn 1980; 34: 57–64. 21 Poole G W, Schneeweiss J. Peripheral neuropathy due to ethionamide. Am Rev Respir Dis 1964; 84: 890–892. 22 Leggat P O. Ethionamide neuropathy. Tubercle 1962; 43: 95–96. 23 Rivlin R S. Disorders of vitamin metabolism: deficiencies, metabolic abnormalities, and excesses. In: Wyngaarden J B, Smith L

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RÉSUMÉ O B J E C T I F : Revoir l’incidence et la prise en charge de la neuropathie périphérique chez des patients traités pour une tuberculose à germes multirésistants (TB-MR). M É T H O D E S : Il s’agit d’une série de cas ayant fait l’objet d’une revue rétrospective des dossiers chez 75 patients chez lesquels un traitement individualisé pour TB-MR avait été mis en route à Lima, Pérou, entre le 1er août 1996 et le 31 janvier 1999. R É S U L T A T S : Chez tous les patients, la TB-MR a été confirmée et un traitement individualisé a été administré, comportant une moyenne de six médicaments. Dix de ces patients (13%) ont consulté pour symptômes de neuropathie périphérique qui ont été confirmés par électromyographie. Tous les symptômes concernaient les extrémités des membres inférieurs et tous étaient de caractère sensoriel. La durée moyenne avant la consultation, calculée à partir du début du traitement de la TB-MR, a été de 9,1 mois. Nous n’avons pu identifier aucun fac-

teur de risque significatif qui fut associé avec le développement de cette neuropathie périphérique. Les stratégies de prise en charge ont dépendu de la sévérité des symptômes et ont inclus le traitement des co-morbidités responsables, des médications pour les douleurs neurologiques et l’ajustement des doses des médicaments potentiellement en cause. Tous les patients ont bien répondu à la prise en charge ; chez trois patients des symptômes résiduels discrets ont persisté. Les patients dont la neuropathie est arrivée à résolution avaient des symptômes depuis une durée moyenne de 7 mois. C O N C L U S I O N S : La neuropathie périphérique a été rencontrée dans 13% des patients de notre cohorte atteints de TB-MR. Le diagnostic de neuropathie périphérique peut se baser sur les seuls symptômes cliniques et la prise en charge efficiente de cet effet collatéral est possible sans sacrifier l’efficacité du traitement de la TB-MR.

RESUMEN

Revisar la incidencia y manejo de neuropatía periférica en pacientes que reciben terapia para TB-MDR. M É T O D O S : Una seria de casos con revisión retrospectiva de 75 pacientes que iniciaron tratamiento individualizado para TB-MDR en Lima, Perú, entre agosto 1996 y octubre 1998. R E S U L T A D O S : De los 75 pacientes que recibieron un tratamiento TB-MDR, 10 (15%) presentaron con síntomas de neuropatía periférica, confirmado por electromiografía. Todos los síntomas fueron reportados en los miembros inferiores y la mayoría eran trastornos de sensación. El OBJECTIVO :

tiempo promedio antes de buscar atención desde el comienzo del tratamiento TB-MDR fue 9,1 meses. No se identificó ningún factor de riesgo asociado con el desarollo de neuropatía periférica. Estrategias de manejo dependían de la severidad de síntomas e incluyeron el tratamiento de comorbilidades contribuyentes, medicaciones para el dolor neuropático y ajusto de dosis de posibles agentes culpables. C O N C L U S I O N E S : Neuropatía periférica fue encontrada en el 13% de nuestra cohorte de pacientes con TB-MDR ; sin embargo, manejo efectivo de este efecto secundario fue posible sin sacrificar la eficacia de tratamiento TBMDR.