What are the neurological side effects of anti-tuberculosis (TB) drugs?

Neurological Side Effects of Anti-TB Drugs

The most serious neurological complications of anti-TB drugs include peripheral neuropathy from isoniazid, optic neuropathy from ethambutol, ototoxicity from aminoglycosides (streptomycin, kanamycin, amikacin), and central nervous system toxicity (psychosis, seizures) from cycloserine, with isoniazid being the most frequently implicated agent overall. 1, 2

First-Line Anti-TB Drugs

Isoniazid

Isoniazid causes the most frequent neurological adverse effects among first-line agents. 1, 3

• Peripheral neuropathy is the most common toxic effect, occurring in a dose-related manner and most frequently in malnourished patients, alcoholics, diabetics, and "slow inactivators" 1
• The neuropathy is usually preceded by paresthesias of the feet and hands 1
• Prevention with pyridoxine (vitamin B6) 10 mg/day is essential to prevent neuropathy 1
• Seizures can occur, particularly with overdose or in susceptible patients 1, 3
• Toxic psychosis and memory impairment may develop 1
• Optic neuritis and atrophy are uncommon but serious complications 1
• Toxic encephalopathy can occur with conventional doses 1

Ethambutol

Ethambutol's primary neurological toxicity is retrobulbar (optic) neuritis, which is dose-related. 2

• At 15 mg/kg/day with normal renal function, optic neuritis is very rare 2
• At 25 mg/kg/day or with impaired renal function, frequency increases to almost 3% 2
• Patients experience blurred vision, red/green color blindness (early symptoms), and later central scotomata 2
• Visual acuity monitoring is mandatory before starting ethambutol and whenever visual symptoms appear 2
• The drug must be stopped immediately if visual symptoms develop 2
• Optic atrophy is usually reversible if detected early 2
• Peripheral neuritis in the legs may occasionally occur 2
• Use with extreme caution in children due to difficulties monitoring visual acuity 2

Rifampin

Rifampin has minimal direct neurological toxicity but can cause drug interactions affecting neurological medications 2

• Reduces serum levels of phenytoin, carbamazepine, and other hepatically-metabolized drugs 2
• Dose adjustments of concurrent neurological medications may be necessary 2

Injectable Agents (Aminoglycosides and Polypeptides)

Streptomycin

Ototoxicity from irreversible damage to the vestibular branch of the eighth cranial nerve is the main neurological side effect. 2, 4

• Vestibular symptoms predominate: vertigo, ataxia, nystagmus 2
• Hearing loss can occur but is less common than with other aminoglycosides 2, 4
• Risk increases with cumulative doses above 100-120 grams 4
• Neuromuscular blockade can occur, particularly potentiating neuromuscular blocking agents during anesthesia 2
• Contraindicated in patients with auditory nerve impairment and myasthenia gravis 2
• Dosage must be reduced in elderly patients and those with renal impairment 2
• Serum levels should not exceed 4 mg/mL 2

Kanamycin and Amikacin

These aminoglycosides have higher risk of cochlear (hearing) toxicity compared to streptomycin. 4

• Amikacin has the highest reported incidence of hearing loss among aminoglycosides 4
• High-frequency hearing loss occurs early and requires regular audiometry 4
• Nephrotoxicity, ototoxicity, and neuromuscular blockade are the major side effects 2
• Baseline audiogram and monthly renal function monitoring are essential 4

Capreomycin

Capreomycin has the lowest reported incidence of ototoxicity among injectable agents but still carries significant risks 4

• Nephrotoxicity, ototoxicity, and neuromuscular blockade remain concerns 2
• Dosage reduction required in renal impairment 2

Second-Line Anti-TB Drugs

Cycloserine

Cycloserine causes the most serious central nervous system adverse effects among all anti-TB drugs, which are dose-related. 2

• Psychosis is a major limiting toxicity 2
• Depression occurs frequently 2
• Seizures can develop, particularly at doses >500 mg/day 2
• Headache and vertigo are common 2
• Alcoholics and patients receiving >500 mg/day are at highest risk 2
• Sedatives and anticonvulsants are effective in controlling symptoms 2
• Blood level monitoring to keep levels <30 μg/mL is recommended, especially with impaired renal clearance 2

Ethionamide/Prothionamide

These agents can potentiate cycloserine's central nervous system side effects. 2

• When used together with cycloserine, CNS toxicity increases 2
• Gastrointestinal effects are more common than neurological effects 2

Fluoroquinolones (Ofloxacin, Ciprofloxacin)

Neurological side effects are rare (3-7%) and usually mild 2

• Dizziness and headache are the most common neurological symptoms 2
• Seizures and delirium are rare 3

Linezolid

Linezolid causes significant neurological toxicity with prolonged use in MDR-TB treatment. 5

• Peripheral neuropathy develops in 32% of patients, with 78% having irreversible neuropathy at 12 months after treatment completion 5
• Optic neuropathy occurs in 74% of patients undergoing ophthalmologic evaluation, though most cases fully reverse 5
• Neurologic or ophthalmologic signs develop in 58% of patients receiving linezolid 5
• Close monitoring for neurologic signs is essential 5
• Trough concentrations >2 mg/L are associated with 88% adverse effect rate 5

Risk Factors and Prevention Strategies

High-Risk Populations

• Elderly patients: increased risk of ototoxicity with aminoglycosides and peripheral neuropathy with isoniazid 2
• Alcoholics: higher risk of isoniazid neuropathy and cycloserine CNS effects 2
• Diabetics: increased susceptibility to peripheral neuropathy 1
• Malnourished patients: higher risk of isoniazid-induced neuropathy 1
• Renal impairment: increased toxicity risk for aminoglycosides, ethambutol, and cycloserine 2

Monitoring Requirements

• Baseline audiogram and vestibular testing before starting aminoglycosides 4
• Monthly renal function assessment during aminoglycoside therapy 4
• Visual acuity testing before and during ethambutol therapy 2
• Regular questioning about auditory, vestibular, and visual symptoms 4
• Serum drug level monitoring for aminoglycosides and cycloserine 2, 4

Prevention Measures

• Pyridoxine (vitamin B6) 10 mg/day supplementation for all patients on isoniazid 1
• Dose reduction in elderly and renally impaired patients 2, 4
• Single daily dosing of aminoglycosides preferred over divided doses to minimize toxicity 4
• Avoid concurrent use of multiple ototoxic or nephrotoxic drugs 2

Management of Neurological Toxicity

Immediate Actions

• Stop the offending drug immediately when serious neurological toxicity develops 2, 1
• For isoniazid neuropathy: increase pyridoxine supplementation 1
• For cycloserine CNS effects: add sedatives or anticonvulsants 2
• For ethambutol optic neuritis: immediate discontinuation usually results in reversibility 2

Long-Term Considerations

• Hearing loss from aminoglycosides is often permanent and requires hearing aids and support services 2, 4
• Peripheral neuropathy from linezolid is frequently irreversible (78% at 12 months) 5
• Children with permanent hearing or vision loss need developmental assessments and educational support 2
• Physical therapy and occupational therapy for patients with severe neurological sequelae 2