Peripheral Neuropathy Associated with Ethambutol

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Peripheral Neuropathy Associated with Ethambutol* Vi;ayachandran S. Nair, M.D., F.C.C.P.;•• Michel LeBmn, M.D.; .. and lroing Kass, M.D., F.C.C.P.t

A woman developed periphenl neuropathy and optic neuritis while receiving ethambufol in the retreatment of drug-resistant pulmonary tuberculosis. There was prompt improvement in periphenl neuropathy and th~ ocular symptoms following the withdrawal of the drug. The clinical events in this case suggest that occasionally symptoms of perlphenl neuropathy may precede the development of optic · neuritis by sevenl months, and thus serve as a warning for the subsequent development of the more serious visual toxicity. of its superior tuberculostatic activity, lower Because incidence of toxic side effects, and better patient acceptance, ethambutol has largely supplanted paraamino salicyclic acid in the initial drug therapy as well as the retreatment of tuberculosis. 1 • 2 Recently, this drug has also been shown to be an equally effective substitute for streptomycin, as a companion drug for isoniazid in the intermittent therapy for tuberculosis. 3 Optic neuritis is a well-recognized complication of ethambutol therapy, especially when daily doses higher than 30 mg/kg of body weight are used.' Peripheral neuropathy is mentioned as a rare side effect related to ethambutol therapy. 1 •2 •5 We report the case of a woman who showed evidence of both optic neuritis and 'Peripheral neuropathy while receiving ethambutol and in whom there was prompt improvement following the withdrawal of the drug. Pertinent data in the literature °From the Division of Pulmonary Diseases, Department of Internal Medicine, University of Nebraska College of Medicine, Omaha. • 0 Assistant Professor of Medicine. tLarson Professor of Medicine and Head, Division of Pulmonary Diseases. Reprint requests: Dr. Nair, Unit>ef'sfty of Nebraska Medical Center, 42nd and Dewey, Omaha 68105

concerning the neurologic changes associated with ethambutol are reviewed. CASE REPORT

This 57-year-old white woman was referred to the University of Nebraska Medical Center on March 5, 1978, for reactivation of pulmonary tuberculosis. She had no symptoms other than a chronic cough with small amounts of mucoid sputum. Since the initial diagnosis and drug therapy for bilateral apical pulmonary tuberculosis in 1950, she had been treated for reactivation of the disease in 1956, 1964, and 1969 with adequate courses of streptomycin, isoniazid, kanamycin, pyrazinamide, ethionamide, cycloserine, para-aminosalicyclic acid, and ethambutol. In addition, a right upper lobectomy and right thoracoplasty were performed in 1956. The chest roentgenogram on March 5, 1978, showed a fibrocavitary infiltrate and apical pleural thickening in the left upper lobe in addition to the changes of thoracoplasty on the right side. Several initial sputum specimens showed numerous acid fast bacilli on smear and later grew out Mycobacterium tuberculosis. The patient was started on isoniazid, pyridoxine, ethambutol and streptomycin while awaiting drug sensitivity results. Later, isoniazid was discontinued because of drug resistance and rifampin added to the therapeutic regimen. Details regarding her antituberculosis therapy are given in Table 1. Following an oral dose of 1400 mg ethambutol, the serum level was 2.25 µg/ml at three hours and 3 µg/ml at seven hours. All the sputum smears and cultures for mycobacteria organisms remained negative since May 10, 1976. At the clinic visit on July 23, 1976, she complained of occasional ataxia and numbness in both legs. There were no complaints pertaining to her vision or hearing. Neurologic examination revealed no abnormalities. When seen on March 18,1977, the paresthesias in the lower extremities was much worse. She also experienced paresthesias in both hands. In addition, there was marked deterioration in the acuity of vision in the left eye. The color vision was normal. Results of serial Snellen chart testing for visual acuity are given in Table 2. Neurologic examination showed diminished response to pin prick in a "glove and stocking" distribution in both upper and lower extremities. The vibratory sense was impaired in a "stocking" distribution in the lower extremities. Ankle jerks were diminished bilaterally. Results of serial nerve conduction studies in the various peripheral nerves are given in Table3. Ethambutol was discontinued promptly and rifampin continued. A reassessment of vision four days after withdrawal of ethambutol showed moderate improvement in the para-

Table I-..4ntituberculoaia Therapy

Drug

Daily Dose

3-9-76

4-20-76

7-23-76

Streptomycin

1 gm (5 days/wk)

Started

Continued

Completed

Isoniazid

600mg

Started

Terminated

Ethambutol

1,200 mg

St.arted

Dose increased to 1,400 mg/day

Continued

Rifampin

600 mg

Started

Continued

Continued Continued

98 NAIR, L£ BRUN, KASS

3-18-77

2-6-78

Remarks Total of 100 gm No side effects Organism from original culture found to be resistant Peripheral neuropathy and ocular toxicity

Terminated

Completed

No side effects

CHEST, 77: 1, JANUARY, 1980

Table 2-Acui'7 of Yi.ion by Snellen Claare

Right Eye

Left Eye

Remarks

4-15-76

20/30

20/30

No visual symptoms while receiving ethambutol

7-23-76

20/25

20/25

Occasional ataxia and paresthesias in legs

12-17-76

20/25

20/30

Paresthesias in legs persistent, no visual symptoms

3-1~77

20/30

Counting fingers at ~10 feet

Paresthesias much worse; cannot recognize faces at distances beyond 10 feet; paracentral scotoma in left temporal visual field. Ethambutol stopped

3-22-77

20/25

20/400

Vision in left eye shows improvement

7-24-77

20/25

20/30

No scotoma on perimetry

11- 4-77

20/25

20/30

Minimal paresthesias in legs; vision improved markedly

Date

Table 3--NenJe Conduction Stud:r

Date

Right Posterior Tibial Nerve

Right Sural Nerve

Left Sural Nerve

Distal Latency Nerve Conduction Velocity (M/sec) (msec)

Distal Latency Nerve Conduction Velocity (M/sec) (msec)

Distal Latency Nerve Conduction Velocity (M/sec) (msec) Not performed

4-1-77

4.22

38.3 (normal 37-57) No conduction in nerve

11-2-77

4.6

42.9

3.0

46.7 (normal 43-50)

3.3

50.0 (normal 43-50)

5-4-78

4.2

48.8

2.8

51.8

2.8

50.0

central scotoma in the left eye. In succeeding months, there was progressive improvement in the ocular symptoms and the paresthesias. Mild numbness in both legs and a slight decrease in the vibratory sense in the toes bilaterally were the only residual abnormalities in the neurologic evaluation on May 8, 1978. DISCUSSION

Our patient developed both peripheral neuropathy and ocular toxicity while receiving ethambutol in a dose of 20 mg/kg of body weight daily. It is interesting to note that symptoms of peripheral neuropathy preceded the visual disturbance by seven months. Also of note is the fact that she had received ethambutol previously without untoward side effects. Peripheral neuropathy is mentioned in the literature as a rare complication of ethambutol therapy, 1 • 2 •5 but there have been few published reports concerning its true incidence and clinical manifestations. Donomae and Yamamoto1 noted numbness in the legs in seven of their 187 patients who received ethambutol. However, two of these patients also received isoniazid along with ethambutol. The authors noted that there was a higher incidence of paresthesias among those patients who received ethambutol either as a fixed dose of 1 gm daily or 25 mg/kg of body weight per day. Tugwell and James8 reported peripheral neuropathy in three patients receiving ethambutol in doses of 13 to 50 mg/kg of body weight daily. The withdrawal of ethambutol was followed by prompt improvement in peripheral neuropathy. Schmidt7 demonstrated widespread degenerative changes in the central nervous system in Rhesus monkeys treated with large doses of ethambutol and related

CHEST, 77: l, JANUARY, 1980

the appearance of the various neurologic symptoms to blood levels of the drug. Contrary to the above reports, the use of ethambutol in doses of 50 mg/kg of body weight twice weekly up to 78 weeks, in the intermittent therapy of tuberculosis, has not been associated with visual impairment or peripheral neuropathy. 3 Even though the cx;ular toxicity from ethambutol has been shown to be dose related, 4 the occurrence of peripheral neuropathy at low doses of ethambutol on one hand, 8 and the absence of neurologic symptoms on high dose intermittent ethambutol therapy on the other, would lead one to doufa high serum levels of the drug as the only signiflcant factor in the development of ethambutol-induced neurotoxicity. The serum ethambutol level in our patient was well in the normal range. Individual susceptibility may play a role in the development of ethambutol-induced peripheral neuropathy. Nevertheless, we feel that it is wise to limit the daily dose to 15 mg/kg of body weight in the initial treatment of pulmonary tuberculosis. The clinical course in the present case suggests that symptoms of peripheral neuropathy may at times precede the onset of ethambutol-induced ocular toxicity by several months, and thus serve as an early warning for the subsequent development of the serious visual impairment. ACKNOWLEDGMENT: The authors wish to thank Drs. Robert Shoumaker and Neil Joseph for their assistance in the neurological and ophthaJinological evaluations, respectively. REFERENCES

1 Donomae I, Yamamoto K: Clinical evaluation of ethambutol in pulmonary tuberculosis. Ann NY Acad Sci 135: 849-879, 1966

PERIPHERAL NEUROPATHY ASSOCIATED WITH ETHAMBUTOL •

2 Wilson TM : Clinical experience with ethambutol. Antibiot Chemother 16:222-229, 1970 3 Albert AK, Sbarbaro JA, Hudson LD, et al: High dose ethambutol: Its role in intermittent chemotherapy. Am Rev Respir Dis 114:699-704, 1976 4 Leibold JE: The ocular toxicity of ethambutol and its relation to dose. Ann NY Acad Sci 135:904-909, 1966 5 AMA Council on Drugs: Evaluation of a new antituberculous agent, ethambutol hydrochloride. JAMA 208:24632464, 1969 6 Tugwell P, James SL: Peripheral neuropathy with ethambutol. Post Grad Med J 48:667-670, 1972 7 Schmidt IG: Central nervous system effects of ethambutol in monkeys. Ann NY Acad Sci 135:759-774, 1966

graphic and isotopic findings was obtained by contrast angiograms. Surgical pathologic findings defined the tumor as a poorly Berentiated sarcoma.

Drimary sarcomatous tumors of the heart are rare. C Some primary cardiac tumors can be removed surgically or irradiated but usually are not amenable to therapy and may produce intractable heart failure and death. We would like to report the unusual clinical presentation of a 17-year-old white male patient with sarcoma of the right atrium and right ventricle, in whom noninvasive evaluation led to the diagnosis of poorly differentiated sarcoma. CASE REPORT

Primary Right Cardiac Tumor* Detection by Echocardiographic and Radioisotopic Studies Dennis G. Caralis, M.D., F.C.C.P.; Harold L. Kennedy, M.D., F.C.C.P.; Ian Bailey, M.B., B.S.; and Bernadine H. Bulkley, M.D.

A primary tumor of the right atrium Md ri&ht ventricle was detected in a 17-year-old male patient by noninvasive techniques, ie, M-mode echocanliograms and gated blood-pool cardiac scan combined with myocardial fm. aging with radioactive 201 thallium. The cUnical presentation was unusual, and validation of the ecbocardio-

°From

the Department of Clinical Investigations (Cardiology), Public Health Service Hospital and the Johns Hopkins Medical Institutions, Baltimore. Reprint requests: Dr. Caralls, USPHS Hospital, 3100 Wyman Park Drive, Baltimore 21211

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A 17-year-old white male sailor was admitted to the Public Health Service Hospital in Baltimore for evaluation of fever, facial edema in the morning, easy fatigability, dyspnea, and vague exertional tightness in the anterior portion of the chest of two weeks' duration. Three months before the onset of illness, he had enlisted in the US Coast Guard and was in exoellent health. On admission his temperature was 38.6°C ( 101.5°F), the pulse rate was 130 beats per minute, his weight was 7 4 kg ( 163 lb), and his height was 168 cm ( 5 ft 6 in). The patient had mild bilateral periorbital edema. The neck was supple and obese. A right ventricular lift was palpable, and the second heart sound was felt in the second left intercostal space. The first and second heart sounds were loud, and a third heart sound was heard along the left lower sternal border; a grade 1-2/6 midsystolic murmur, which was unrelated to respiration, was audible along the lower left sternal border. Prominent superficial veins were seen over the abdomen. A smooth firm edge of the liver was palpable 3 cm below the right costal margin; the span of the liver was 11 cm. Abnormal laboratory findings included the following: hematocrit reading, 34 percent; hemoglobin level, 10.7 gm/

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FIGURE 1. Echocardiogram obtained with transducer pointed in direction of bicuspid valve (top ) ; mass of ultrasonic reftections is seen posterior to tricuspid valve ( anows) . Mitra) valve appears to be normal.

100 CARALIS ET AL

CHEST, 77: 1, JANUARY, 1980