In This Case Study
- A 28-year-old male presented with a week of nausea, vomiting, headache, photophobia and weakness, and he was treated for suspected conditions
- After he was treated and discharged, the patient returned to the hospital with edema and weakness, as well as a lactic acid level of 5.7 mmol/L
- The Pathways Consul Service at Massachusetts General Hospital took up the case and investigated whether the development of lactic acidosis on linezolid therapy could provide insight into why he had developed such a severe case of encephalitis
A 28-year-old male presented with a week of nausea, vomiting, headache, photophobia and weakness. He was found to have a fever of 102.4° F, neck stiffness and photophobia, and inflamed spinal fluid with 660 white blood cells (65% lymphocytes, 35% monocytes), elevated protein and normal glucose. Over the course of the next week, he was empirically treated with ceftriaxone, vancomycin, acyclovir, isoniazid, rifampin, ethambutol and amikacin, but continued to deteriorate. Brain MRI showed diffusely increased signal in the cerebral sulci consistent with meningoencephalitis. Extensive virologic serologies and TB testing were negative. He became obtunded and high-dose steroids and linezolid were added. Over the next weeks, his mental status substantially improved and he was discharged from the hospital.
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However, on the day of discharge, he returned to the hospital with lower extremity edema and weakness and was found to have a lactic acid level of 5.7 mmol/L with normal vital signs. The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on the key question of whether the development of lactic acidosis on linezolid therapy could provide insight into why he had developed such a severe case of encephalitis.
Investigation and Diagnosis
The great majority of cases of encephalitis are caused by viruses, including herpes, enteroviruses, mosquito-borne viruses (e.g., West Nile) and tick-borne viruses, according to a study published in the New England Journal of Medicine. The study found that most patients with encephalitis have relatively mild flu-like symptoms including headache and fever, although some develop far more severe diseases. Although the type of virus can be associated with the severity of symptoms, much of the variation in clinical presentation is poorly understood and does not appear to be driven by variation in the viral genome. Variation in host response has been hypothesized to drive most of the variation in disease severity, with potential pathways including differences in immune response and tissue damage that may reflect underlying variation in the immune system or mitochondrial function, according to findings published in The Lancet, Infectious Diseases and Neurology.
Linezolid acts by binding to bacterial 23S rRNA, but also binds to host cell mitochondrial 16S rRNA and inhibits mitochondrial protein synthesis. Because the mitochondrial activity is central to clearing lactic acid, it is hypothesized that the decrease in mitochondrial protein synthesis can lead to a decrease in mitochondrial enzymatic activity and an accumulation of lactic acid, according to findings published in Clinical Infectious Diseases. Although this effect should occur across all patients exposed to linezolid, the risk of significant lactic acidosis from linezolid is thought to be quite low with one series reporting ~2% incidence among patients begun on linezolid, according to findings published in Nature Communications. Furthermore, standard risk factors such as age, kidney failure and diabetes do not appear to explain who develops this complication—raising the possibility that the development of lactic acidosis is a sign of baseline mitochondrial dysfunction that is exacerbated by the addition of linezolid. This hypothesis is supported by a report of rapid onset linezolid associated lactic acidosis in a patient with an underlying mitochondrial defect and MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome, as reported in Mitochondrion. Thus, the occurrence of a pronounced lactic acidosis from linezolid in this patient raises the possibility that he has a previously unrecognized predisposition to mitochondrial dysfunction from an underlying mitochondrial defect.
If the patient does have an underlying mitochondrial defect, could it have contributed to the severity of the meningoencephalitis?
Mitochondrial damage is known to release mitochondrial-associated molecules into the cytosol and extracellular space, which can function as damage-associated molecular patterns (DAMPs) and trigger an adaptive immune response, according to findings published in Antioxidants and Redox Signaling. For example, unmethylated CpG repeats in both microbial DNA and mitochondrial DNA are recognized by toll-like receptor 9 (TLR9) and trigger a proinflammatory cascade including cytokine release, neutrophil chemotaxis and phagocytosis, as reported in Nature Reviews Immunology. To the extent that viral infections of the central nervous system (CNS) create cellular stress and mitochondrial damage, variation in this pathway may both contribute to the severity of the presentation and be driven by underlying variation in mitochondrial function. While this "two-hit" mechanism may be applicable to any organ, the CNS may be particularly susceptible to damage given the background rate of CNS involvement in mitochondrial diseases.
Summary and Next Steps
We are beginning to see the adult-onset of genetic diseases identified previously as pediatric with mutations in the same genes having lower levels of penetrance, perhaps because of mutation-specific effects, modifying genes or differences in environmental exposures. It seems conceivable that this patient has a mitochondrial sensitivity, possibly (although not proven) as genetic, and may have had an exaggerated response to another encephalitic stressor. A muscle biopsy may be useful to seek an underlying mitochondrial defect through histological and electron microscopy of mitochondrial structure, as would DNA sequencing for both nuclear and mitochondrial-encoded mitochondrial genes. While it is unlikely that such information would change his clinical management currently, it might be useful for informing decisions about therapeutics in the future.
Learn more about the Pathways Consult Service at Mass General
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