A novel free radical scavenger may show promise for treating HHV-6 encephalopathy
Edaravone, a free radical scavenging drug clinically used in Japan to treat acute ischemic stroke, has shown initial promise for treating HHV-6 encephalopathy and seizures.
A group of investigators from Tokyo tested the impact of this drug on a subset of encephalopathy cases that present with a febrile seizure or status epilepticus followed by a cluster of complex seizures on days 4-6. These patients typically don’t show abnormalities on an MRI immediately but demonstrate “reduced diffusion” (a sign of swelling) starting on the third day. Known as AESD or Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion, it is the most common cause of encephalopathy in Japan, and HHV-6 is the most common pathogen preceding AESD (Hoshino 2012). Although the fatality rate is low, the rate of neurological damage is high with approximately 70% suffering permanent sequelae.
The Tokyo group analyzed cerebrospinal fluid (CSF) samples from 16 patients with HHV-6 AESD, 10 patients with HHV-6 complex febrile seizures, and 16 controls with HHV-6 fever but without central nervous system infection. They measured common markers of oxidative stress as well as tau protein, TNF-a, IL-6, and IL-10. The group found that none of the patients with seizures ending after the initial attack went on to develop permanent brain injuries. On the other hand two-thirds of patients who progress to AESD (with a second set of seizures and brain swelling after 3-6 days) end up with a permanent disability.
The group found that the markers of oxidative stress (such as CSF 8-OHdG) in patients with either HHV-6 induced AESD or complex FS were twice as high as those found in controls. This finding suggests that HHV-6 infection induces oxidative stress within the brain. It was also demonstrated that HHV-6 AESD encephalopathy patients had elevated levels of IL-6 and TNF-a in the CSF, while those with short-lived HHV-6 febrile seizures did not.
CSF levels of tau protein, considered a useful biomarker of axonal damage, were also found to be significantly higher in HHV-6 encephalopathy patients (13,905.6±14,201.1 pg/mL) compared to HHV-6 complex FS patients (654.7±213.7 pg/mL) and controls (609.0±342.0 pg/mL). Moreover, these tau levels in HHV-6 encephalopathy patients were found to be significantly increased between days 3–8 (19,856.9±13,121.9 pg/mL) compared to days 1–2 (520.4±229.6 pg/mL). These results suggest the possibility that axonal injury may be the reason for the high incidence of neurological sequelae in patients with AESD. However, as no correlation was found between increased levels of tau protein and neurological sequelae, it can be concluded that tau protein may help identify an HHV-6 infection, but it is difficult to use this biomarker as an early sign of acute encephalopathy.
Edaravone reduces apoptotic neuronal cell death and improves cerebral function after traumatic brain injury or ischemic stroke by inhibiting oxidation and limiting peroxynitrite. This in turn reduces endothelial injury and edema and limits neuronal damage during ischemia and reperfusion, thus improving recovery from neurological deficits (Itoh 2010, Yoshida 2006). Administration of edaravone to mice immediately after brain injury suppresses traumatic axonal injury and reduces trauma-induced memory deficits (Ohta 2013).
The Tokyo group treated 6 patients with edaravone in addition to conventional therapy, 5 with HHV-6 encephalopathy and 1 with HHV-6 complex FS. The CSF levels of 8-OHdG in these patients decreased after treatment with edaravone suggesting that edaravone may have been partially effective in treating HHV-6–associated encephalopathy.
Limitations of the study included the fact that treatment was delayed until after the diagnosis of AESD; it is not possible to differentiate between complex febrile seizures and AESD during the initial seizures. The authors comment that a clinical trial would be difficult because of the difficulty of using a placebo in patients with a severe condition.
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