Brainstem mechanisms of autonomic dysfunction in encephalopathy-associated Shiga toxin 2 intoxication

Acute encephalopathy is the major determinant of death in an early stage of Shiga toxin (Stx)-producing Escherichia coli infection. Rapid progress toward refractory hypotension and dysfunction of breathing implies autonomic center dysfunction of patients. To clarify whether autonomic dysfunction becomes an ultimate cause of death in Shiga toxemia, we injected purified Stx2 (20 μg/kg) intravenously into rabbits, and monitored changes in cardiovascular and respiratory function together with renal sympathetic nerve activity (RSNA) in the conscious state. After an approximately 24-hour silent (lag) period, all rabbits given Stx2 developed hemorrhagic diarrhea (25.7 ± 1.1 hours) and limb paralysis (31.2 ± 1.3 hours). This limb paralysis was observed initially in the hind legs, and then it gradually extended to the forelegs. After 23.2 ± 2.3 hours, RSNA increased gradually, and arterial blood pressure was maintained within normal limits together with an increase in the maximum gain of baroreflex response. Severe hypotension developed within 34.8 ± 2.2 hours, without any increase in heart rate; RSNA significantly increased by 39.5 ± 0.9 hours. In the final stage, RSNA decreased concurrently with decreases in arterial blood pressure, heart rate, and baroreflex response, suggesting dysfunction of the baroreflex control system. Thereafter, all rabbits died within 47.8 ± 1.2 hours after the intravenous Stx2 injection. Magnetic resonance imagings of the central nervous system (T2-weighted images) showed high-intensity areas in the dorsal two-thirds of the cervical spinal cord and brainstem 48 hours after Stx2 administration. These results show that the cause of death is circulatory failure caused by impairment of the cardiovascular center in the medulla. We believe that this animal model helps to clarify the mechanism of rapid progress to death of patients with Shiga toxin–producing E coli infection. Ann Neurol 1999;45:716–723