A 66-year-old man comes to the clinic due to numbness and tingling in his hands and feet that developed over the last few weeks. The patient was healthy until he was diagnosed with pulmonary tuberculosis 3 months ago. He takes only isoniazid and rifampin. Temperature is 37.1 C (98.8 F), blood pressure is 126/80 mm Hg, pulse is 90/min, and respirations are 16/min. Cardiopulmonary examination is unremarkable. Neurologic examination shows ataxia and decreased pain sensation in the distal extremities. This patient's condition is most likely due to which of the following?
Drugs commonly used to treat tuberculosis | ||
Drug | Mechanism of action | Adverse effects |
Rifampin | Inhibition of bacterial DNA-dependent RNA polymerase | Gastrointestinal effects, rash, red-orange body fluids, cytopenia |
Isoniazid | Inhibition of mycolic acid synthesis | Neurotoxicity (give vitamin B6/pyridoxine), hepatotoxicity |
Pyrazinamide | Unclear | Hepatotoxicity, hyperuricemia |
Ethambutol | Inhibition of arabinosyl transferase (?) | Optic neuropathy |
This patient with tuberculosis has developed paresthesia and ataxia consistent with isoniazid-induced peripheral neuropathy. Isoniazid is structurally similar to pyridoxine (vitamin B6), a cofactor for enzymes involved in synthesis of certain neurotransmitters. Because of this similarity, isoniazid acts as a competitive inhibitor of pyridoxine and can cause dose-related peripheral neuropathy (eg, numbness and tingling in the hands and feet). Sensory ataxia (due to loss of peripheral proprioception) and decreased pain sensation are also common features.
Patients at increased risk of isoniazid-induced peripheral neuropathy include those who are elderly, are malnourished (eg, alcohol use disorder), or have liver or kidney dysfunction; management involves supplementation with pyridoxine.
(Choice A) Paresthesia is common in Guillain-Barré syndrome, an immune-mediated demyelinating disorder, but a progressive ascending paralysis would be seen. Multiple sclerosis is also an immune-mediated demyelinating disease, and ataxia can occur, but symmetric, bilateral paresthesia would not be expected. Neither condition is associated with Mycobacterium tuberculosis infection or isoniazid therapy.
(Choice B) Advanced glycation end products (eg, hemoglobin A1c) in patients with diabetes mellitus (DM) contribute to the development of peripheral nerve ischemia. This typically occurs in those with chronic (ie, >20 years), poorly controlled DM. In contrast, this otherwise healthy patient developed neuropathy within months of starting isoniazid without pyridoxine, making diabetic neuropathy far less likely.
(Choice C) Certain chemotherapeutic drugs (eg, vincristine) may directly cause peripheral neuropathy by inhibiting microtubule formation. In contrast, isoniazid is not directly toxic to neurons.
(Choice D) Infection with Mycobacterium leprae (ie, leprosy) can cause peripheral neuropathy from impaired myelin production (due to bacterial replication within infected Schwann cells); however, skin findings (eg, erythematous macules, nodules) are also characteristic but are not seen in this patient. In contrast, this patient has pulmonary tuberculosis caused by M tuberculosis, which does not affect myelin production.
Educational objective:
Isoniazid is structurally similar to pyridoxine (vitamin B6) and competes for binding sites on pyridoxine-dependent enzymes. This leads to decreased synthesis of certain neurotransmitters, which may result in peripheral neuropathy. Management involves pyridoxine supplementation.