Acute Encephalopathy Associated with Inﬂ uenza A Infection in Adults

We report acute encephalopathy associated with in ﬂ uenza A infection in 3 adults. We detected high cerebrospinal ﬂ uid (CSF) and plasma concentrations of CXCL8/IL-8 and CCL2/MCP-1 (CSF/plasma ratios >3), and interleukin-6, CXCL10/IP-10, but no evidence of viral neuroinvasion. Patients recovered without sequelae. Hyperactivated cytokine response may play a role in pathogenesis. of 7,043.0 (4,025.1–1,2381.1), 992.1

by nasopharnygeal aspirate/IFA; patient 1 did not receive antiviral treatment. Both patients recovered in the next 2 days. Patient 3 had fever, severe chronic obstructive pulmonary disease exacerbation requiring noninvasive ventilatory support, complicated by acute coronary syndrome. He was given oseltamivir, 75 mg 2×/day, after infl uenza A infection was confi rmed. Agitation and confusion developed in the patient on day 3-4 of illness (onset after the third dose of oseltamivir), despite resolution of the patient's respiratory failure. These symptoms were followed by involuntary, tremulous movements involving all 4 limbs, while at rest and during movement. Brain CT scan was normal. Electroencephalogram showed generalized slowing. Oseltamivir was stopped after the ninth dose, but tremor persisted. CSF analyses showed no pathogen or pleocytosis. The patient's symptoms resolved in the next 3-4 days without sequelae.
Simultaneous CSF and plasma OC and OP concentrations were determined for patient 3, as symptoms progressed at 18 h after oseltamivir. The concentrations (mean ± SD) of OC in duplicate CSF and plasma samples were 18.3 ± 0.9 ng/mL and 143.8 ± 3.3 ng/mL, respectively; the CSF/plasma concentration ratio was 12%-13%. The OP plasma concentration was 1.05 ± 0.03 ng/mL; it was not detectable in the CSF.
Whether early viral suppression by antivirals can lead to attenuation of these cytokine responses and better outcomes warrants further study (7).
We measured oseltamivir concentrations because of the concerns over its neuropsychiatric side-effects in children and adolescents. However, only the active metabolite (OC) was detected in the CSF of patient 3; the CSF/plasma concentration ratio was 12%-13% (18.3/143.8 ng/mL) at 18-hours postdose. This degree of CSF penetration is similar to that observed among healthy patients, with a Cmax CSF/plasma concentration ratio of 3.5% (at ≈8 hours), and a ratio of ≈10% at 18 hours (concentration-time profi les for plasma/CSF differ). Assuming a similar ratio, the CSF OP concentration would have fallen below the assay's detection limit (0.25 ng/mL) by 18 hours (11,15). The low CSF drug-penetration, together with high cytokines in CSF and symptom progression despite drug withdrawal suggest that the manifestations of patient 3 may have been diseaserelated. Symptoms developed in patients 1 and 2 without antiviral exposure. Further investigations on the CNS effects of oseltamivir in the clinical setting are needed..
Our study is limited by the small patient number and the lack of feasibility in obtaining CSF for study/comparison in infl uenza patients without neurologic symptoms. Further studies on the clinical spectrum of infl uenza encephalopathy and encephalitis in adults (1,6) and their pathogenesis are indicated. In conclusion, acute encephalopathy may occur in adults with infl uenza. Exuberant  3) pg/mL, respectively. In CSF, in subjects without neurologic disease/infection, these cytokines/chemokines are either undetectable or present at low levels (8)(9)(10). In a pediatrics influenza cohort, CSF cytokine levels were substantially higher in encephalopathy cases when compared to those with febrile seizure; CSF/plasma concentration was <1 (8). †CSF cytokine concentrations above plasma reference ranges. ‡CSF/plasma cytokine concentration ratio consistently >3 (3.5-12.1), in addition to CSF cytokine concentrations being above the plasma reference ranges. For IFN-, IL-12p70, TNF-, IL-10, IL-1 and RANTES, because of their low/undetectable levels, the CSF/plasma ratios were not calculated. CSF specimens from patients 1 and 2 were collected at the peak of symptoms, and before antiviral treatment (if given); CSF from patient 3 was collected when persistent tremor developed 18 hours after the ninth dose of oseltamivir; the drug was stopped afterward.
cytokine/chemokine response may play an important role in its pathogenesis. respectively. The performance of the assay was demonstrated by analysis of 3 replicates of quality control samples at 3 levels. The coefficients of variation (CV%) during the analysis of OP were 4.1%,1.9% and 2.1% at 3 ng/mL, 20 ng/mL, and 150 ng/mL, respectively (limit of detection of OP, 0.25 ng/mL). The coefficients of variation (CV%) during the analysis of OC were 2.3%, 0.5%, and 3.1% at 30 ng/mL, 400 ng/mL, and 4,000 ng/mL, respectively.