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Early therapeutic plasma exchange may lead to complete neurological recovery in moderate to severe influenza-associated acute necrotizing encephalopathy

Open AccessPublished:March 22, 2022DOI:https://doi.org/10.1016/j.braindev.2022.03.004

      Abstract

      Background

      Acute necrotizing encephalopathy (ANE) is a pediatric neurological disease, presumably caused by cytokine storms, with a poor prognosis. Immunomodulatory therapy, including therapeutic plasma exchange (TPE), could be an effective treatment.

      Cases

      Two patients with influenza-associated ANE were treated. The ANE severity scores were 3 and 8 in case 1 (a 3-y-old boy) and case 2 (a 7-y-old boy), respectively. In case 1, intravenous methylprednisolone and TPE were initiated at 8 and 16 h, respectively, after the onset of impaired consciousness. In case 2, multiple organ failure and septic shock persisted even after infusion of fluids and inotropic agents. Intravenous methylprednisolone and TPE were started at 5 and 9 h, respectively, after the onset of impaired consciousness, which improved the inotrope-refractory septic shock. Patient 1 and 2 achieved complete neurological recovery within 4 weeks and after 3 months, respectively.
      In both patients, cytokine levels were serially measured. There were increased serum interleukin (IL)-6 and IL-10 levels in both patients; patient 1 showed increased IL-6 levels in the initial cerebrospinal fluid sample. There was a post-treatment decrease in serum IL-6 levels in both cases.

      Discussion

      Early intensive immunomodulatory therapy with TPE may improve neurological outcomes in pediatric influenza-associated ANE. Further studies are required to establish the efficacy of TPE for ANE.

      Keywords

      1. Introduction

      Acute encephalopathy is a severe neurological complication of common childhood infections that are most frequently encountered in East Asia [
      • Mizuguchi M.
      • Ichiyama T.
      • Imataka G.
      • Okumura A.
      • Goto T.
      • Sakuma H.
      • et al.
      Guidelines for the diagnosis and treatment of acute encephalopathy in childhood.
      ,
      • Hoshino A.i.
      • Saitoh M.
      • Oka A.
      • Okumura A.
      • Kubota M.
      • Saito Y.
      • et al.
      Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes.
      ,
      • Okumura A.
      • Mizuguchi M.
      • Aiba H.
      • Tanabe T.
      • Tsuji T.
      • Ohno A.
      Delirious behavior in children with acute necrotizing encephalopathy.
      ,
      • Okumura A.
      • Mizuguchi M.
      • Kidokoro H.
      • Tanaka M.
      • Abe S.
      • Hosoya M.
      • et al.
      Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin.
      ,
      • Yamamoto H.
      • Okumura A.
      • Natsume J.
      • Kojima S.
      • Mizuguchi M.
      A severity score for acute necrotizing encephalopathy.
      ,
      • Howard A.
      • Uyeki T.M.
      • Fergie J.
      Influenza-associated acute necrotizing encephalopathy in siblings.
      ]. Treatment options for acute encephalopathy are largely empirical with little supporting evidence. A recent nationwide study in Japan has revealed that immunomodulatory treatments, including corticosteroids, intravenous immunoglobulins, cyclosporin A, and therapeutic plasma exchange (TPE), are widely used to treat acute encephalopathy [
      • Hayakawa I.
      • Okubo Y.
      • Nariai H.
      • Michihata N.
      • Matsui H.
      • Fushimi K.
      • et al.
      Recent treatment patterns and variations for pediatric acute encephalopathy in Japan.
      ]. Acute necrotizing encephalopathy (ANE) is among the most devastating clinical entities of acute encephalopathy, with 13%, 23%, 33%, and 28% showing full recovery, mild-to-moderate sequelae, severe sequelae, and death, respectively [
      • Mizuguchi M.
      • Abe J.
      • Mikkaichi K.
      • Noma S.
      • Yoshida K.
      • Yamanaka T.
      • et al.
      Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions.
      ].
      We present two patients with moderate and severe influenza-associated ANE who received both intravenous methylprednisolone and TPE within hours after the onset of impaired consciousness and achieved complete neurological recovery.

      2. Case 1

      A 3-y-old boy presented with disturbed consciousness for 8 h on the third day of fever due to the H1N1pdm2009 influenza virus. The fever onset was at approximately 4:00 PM on the first day. At noon on the second day, he had a simple generalized seizure for 5 min. Neurological examination at another hospital was reportedly normal. He remained conscious until he began groaning without eye contact at 9:00 PM on day 2 (the onset). At 3:00 AM on the third day (6 h after the onset of impaired consciousness), a head CT revealed a low-density area of the thalamus and supratentorial brain swelling (Fig. 1). He was transferred to our hospital at 5:00 AM on day 3. He had no prior medical or family history. He was taking oral oseltamivir (2 mg/kg twice daily), acetaminophen, diclofenac sodium suppositories (12.5 mg twice daily), carbocisteine, ambroxol, and pranlukast hydrate.
      Figure thumbnail gr1
      Fig. 1Imaging results. Case 1: (top row) from left, day 1 CT, day 10 T1-weighted image, day 10 T2-weighted image, day 10 fluid-attenuated inversion recovery, day 10 diffusion-weighted image. (bottom row) Case 2: from left, day 1 CT, day 4 CT, day 7 T1-weighted image, day 7 T2-weighted image, day 7 fluid-attenuated inversion recovery.
      Upon physical examination, his vitals were as follows: heart rate, 150 beats per minute (bpm); respiratory rate, 30 breaths per minute; blood pressure, 120/74 mmHg; Glasgow Coma Scale (GCS), E3V2M4; and body temperature, 40.0 °C. He did not have neck stiffness. He was continuously moaning and screaming without making eye contact. Light, ocular, and sensory reflexes were preserved. He had a positive jaw jerk. Tendon reflexes in the lower extremities were symmetrically exaggerated; there were bilaterally positive Babinski and Chaddock signs. He was diagnosed with ANE with a severity score of 3 (0–9, a higher score indicates a poor prognosis) (Supplemental Table) [
      • Yamamoto H.
      • Okumura A.
      • Natsume J.
      • Kojima S.
      • Mizuguchi M.
      A severity score for acute necrotizing encephalopathy.
      ].
      He received intravenous methylprednisolone and TPE with continuous hemodiafiltration (see Supplemental Methods for detail) [
      • Mizuguchi M.
      • Ichiyama T.
      • Imataka G.
      • Okumura A.
      • Goto T.
      • Sakuma H.
      • et al.
      Guidelines for the diagnosis and treatment of acute encephalopathy in childhood.
      ,
      • Fortenberry J.D.
      • Nguyen T.
      • Grunwell J.R.
      • Aneja R.K.
      • Wheeler D.
      • Hall M.
      • et al.
      Therapeutic plasma exchange in children with thrombocytopenia-associated multiple organ failure: the thrombocytopenia-associated multiple organ failure network prospective experience.
      ] at 8 h and 16 h after the onset, respectively (Fig. 1A). He underwent intensive neurocritical care for 1 week, with careful regulation of oxygenation, ventilation, and systemic blood pressure with continuous EEG monitoring. He was sedated to prevent fluctuations in intracranial pressure and was also strictly controlled to normal deep body temperature. His neurological status showed a marked improvement during hospitalization. On the 8th day of hospitalization, he showed symptoms of somnolence, drooling, and inability to roll over. At 2 weeks after admission, he was awake, could sit without support, and could reach for objects; additionally, he had started oral intake. He could walk with support and had fully recovered without neurological symptoms at 3 and 4 weeks after admission, respectively. He was discharged 4 weeks after admission. On the 10-months follow-up visit, MRI showed atrophy of the bilateral thalamus. He showed normal cognitive and behavioral development on the 3-years follow-up visit.

      3. Case 2

      A 7-y-old boy presented to our hospital with a 5-h coma on the second day of fever due to the H3Nx influenza virus. The fever had begun at 1:00 PM on the first day. On the next morning at 7:30 AM, his parents observed slight confusion and disorientation. At 11:00 AM, he became unresponsive and showed urinary and fecal incontinence (the onset). He did not experience convulsive seizures. At 1:00 PM he was taken to another hospital, where he was treated for uncompensated septic shock with low systemic blood pressure. He was in comatose with GCS of E1V1M2. A head CT revealed severe diffuse cerebral edema and slight bilateral thalamic low attenuation areas (Fig. 1). He vomited several times and was intubated. He was transferred to our hospital. He had no prior medical or family history.
      At 4:00 PM (5 h after coma development), he was in uncompensated septic shock with a heart rate of 170 bpm, respiratory rate of 25 breaths per minute, blood pressure of 80/40 mmHg, GCS E1VTM1, body temperature of 40.0 °C, and capillary refill time of 5 s. His extremities were cold and the pupils were 1.5 mm bilaterally. Light, ocular, and corneal sensory reflexes were preserved. Cerebrospinal fluids (CSF) samples were not obtained at admission due to brain edema. He was diagnosed with ANE (severity score = 8) (Supplemental Table).
      Upon ICU admission, there was rapid deterioration of the patient’s condition (Fig. 1B). Despite 70 mL/kg fluid infusion and infusion of norepinephrine 0.3 μg/kg/min, epinephrine 0.3 μg/kg/min, and arginine vasopressin 0.06 U/kg/h, he showed uncompensated shock state with progression of metabolic acidosis. EEG showed diffuse high-voltage delta range activity. No Cushing's phenomenon was observed. An intravenous methylprednisolone (30 mg/kg) administered 5 h after the onset, and he underwent TPE with continuous hemofiltration (see Supplemental Methods for detail) [
      • Mizuguchi M.
      • Ichiyama T.
      • Imataka G.
      • Okumura A.
      • Goto T.
      • Sakuma H.
      • et al.
      Guidelines for the diagnosis and treatment of acute encephalopathy in childhood.
      ,
      • Fortenberry J.D.
      • Nguyen T.
      • Grunwell J.R.
      • Aneja R.K.
      • Wheeler D.
      • Hall M.
      • et al.
      Therapeutic plasma exchange in children with thrombocytopenia-associated multiple organ failure: the thrombocytopenia-associated multiple organ failure network prospective experience.
      ] at 9 h after the onset. There was a marked improvement in the blood pressure after TPE initiation. Moreover, EEG showed marked improvement of background activities after TPE initiation. He was placed under intensive neurocritical care for 10 days, with careful regulation of oxygenation, ventilation and systemic blood pressure with continuous EEG monitoring. He was sedated to prevent fluctuations in intracranial pressure and was also strictly controlled to normal deep body temperature. MRI on the 7th day of admission revealed bilateral diffusion restriction in the thalamus and subcortical white matter of the parietal and temporal lobes (Fig. 2). During hospitalization, his neurological status showed significant improvement. At 2 weeks after admission, he presented with somnolence with a GCS score of E3V3M5, drooling, and inability to roll over. By the 4th hospitalization week, he was awake, started walking, and spontaneously used his arms. He had poor coordination and could not draw a simple rectangle. By the 7th week after admission, he could fluently speak, run, and draw pictures; however, he showed hypoesthesia and mild incoordination in the right lower and upper extremities, respectively, as well as decreased coordination during running. There were no involuntary movements or postural abnormalities. He was transferred to a rehabilitation hospital and discharged without sequelae at 3 months after onset. On the 10-mo follow-up visit, the Wechsler Intelligence Scale for Children - Fourth Edition showed normal results, and MRI showed slight atrophy of the bilateral thalamus. There were no cognitive or behavioral problems in daily life, including school life, on the 3-years follow-up visit.
      Figure thumbnail gr2
      Fig. 2The treatment course for case 1 (A) and case 2 (B). TPE and IVMP are depicted by large and small arrows, respectively. In both cases, TPE was performed twice and IVMP was performed twice (5 days for the first course and 3 days for the second course). Abbreviations: ANE-SS, acute necrotizing encephalopathy-severity score; CHDF, continuous hemodiafiltration; CHF, continuous hemofiltration; IVMP, intravenous methylprednisolone; ICU, intensive care unit; PPV, predicted plasma volume; TPE, therapeutic plasma exchange.

      4. Cytokine measurements

      Serum and CSF cytokines were serially measured using clinically obtained samples in both cases (Table, see Supplemental Methods for detail). Pro-inflammatory IL-6 and anti-inflammatory IL-10 levels were both increased in the initial serum samples obtained from both cases, and decreased rapidly after treatment. In contrast, serum pro-inflammatory cytokines tumor necrosis factor and IL-2 as well as a soluble receptor sIL-1R1 showed no marked changes during the disease course. CSF before treatment in case 1 showed high IL-6 levels but low IL-10 levels. Thus, there was discrepancy between serum and CSF IL-10 levels before treatment in case 1.

      5. Discussion

      Two cases of influenza-related ANE with severity scores of 3 and 8 points, respectively, showed complete recovery after TPE within hours of ICU admission, as well as rigorous neurocritical care. First, we ruled out the possibility of familial ANE in both cases. Familial ANE was considered as a differential diagnosis in both cases since there were marked abnormalities on MRI despite a good clinical course [
      • Ohashi E.
      • Hayakawa I.
      • Murofushi Y.
      • Kawai M.
      • Suzuki-Muromoto S.
      • Abe Y.
      • et al.
      Recurrent acute necrotizing encephalopathy in a boy with RANBP2 mutation and thermolabile CPT2 variant: The first case of ANE1 in Japan.
      ]. However, there was no recurrence of acute encephalopathy during the 3-y follow-up. Moreover, the patients lacked a family history of ANE.
      While cytokine storms are considered to be the primary pathogenic mechanism underlying ANE [
      • Mizuguchi M.
      • Ichiyama T.
      • Imataka G.
      • Okumura A.
      • Goto T.
      • Sakuma H.
      • et al.
      Guidelines for the diagnosis and treatment of acute encephalopathy in childhood.
      ,
      • Lyon J.B.
      • Remigio C.
      • Milligan T.
      • Deline C.
      Acute necrotizing encephalopathy in a child with H1N1 influenza infection.
      ,
      • Kansagra S.M.
      • Gallentine W.B.
      Cytokine storm of acute necrotizing encephalopathy.
      ], literature measuring actual CSF or serum cytokines in ANE patients in their acute phase is limited [
      • Ichiyama T.
      • Nishikawa M.
      • Yoshitomi T.
      • Hayashi T.
      • Furukawa S.
      Tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in cerebrospinal fluid from children with prolonged febrile seizures. Comparison with acute encephalitis/encephalopathy.
      ,
      • Ishiguro A.
      • Suzuki Y.
      • Inaba Y.
      • Komiyama A.
      • Koeffler H.P.
      • Shimbo T.
      Production of interleukin-10 in the cerebrospinal fluid in aseptic meningitis of children.
      ,
      • Kleiner G.
      • Marcuzzi A.
      • Zanin V.
      • Monasta L.
      • Zauli G.
      Cytokine levels in the serum of healthy subjects.
      ,
      • Virhammar J.
      • Kumlien E.
      • Fällmar D.
      • Frithiof R.
      • Jackmann S.
      • Sköld M.K.
      • et al.
      Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid.
      ,
      • Tabarki B.
      • Thabet F.
      • Al Shafi S.
      • Al Adwani N.
      • Chehab M.
      • Al Shahwan S.
      Acute necrotizing encephalopathy associated with enterovirus infection.
      ]. Our data emphasizes the possible contribution of IL-6 in the pathogenesis of ANE. Our serial cytokine measurements revealed marked changes in serum IL-6 and IL-10 in the early disease stages. There was a dynamic decrease in both serum pro-inflammatory IL-6 and anti-inflammatory IL-10 levels during treatment, while tumor necrosis factor, IL-2, and sIL-1R1 did not show marked changes. Moreover, IL-6, but not IL-10, was elevated in CSF before treatment in Case 1. These results suggest that IL-6 may be involved in the pathogenesis of ANE. Indeed, high serum IL-6 levels are correlated with poor prognosis in influenza-related acute encephalopathy [
      • Aiba H.
      • Mochizuki M.
      • Kimura M.
      • Hojo H.
      Predictive value of serum interleukin-6 level in influenza virus – associated encephalopathy.
      ]. Further, tocilizumab, a humanized anti-IL-6 receptor antibody, has positive clinical effects on patients with ANE [
      • Koh J.C.
      • Murugasu A.
      • Krishnappa J.
      • Thomas T.
      Favorable outcomes with early interleukin 6 receptor blockade in severe acute necrotizing encephalopathy of childhood.
      ].
      Given that brain damage in ANE progresses within hours, early and aggressive immunomodulatory therapy is crucial for a favorable prognosis. TPE is among the promising treatments for acute encephalopathy, including ANE [
      • Hayano S.
      • Amamoto M.
      • Takano K.
      • Kamizono J.
      • Yamashita Y.
      • Tomonoh Y.
      Successful management of acute necrotizing encephalopathy by prompt and intensive treatment: a case report.
      ,
      • Shirai H.
      • Ando H.
      • Mineo E.
      • Nonoda Y.
      • Iwasaki T.
      • Ishii M.
      Favorable neurological outcomes of immunomodulatory therapy for cerebral protection in two patients with acute necrotizing encephalopathy.
      ,
      • Koyama T.
      • Tanaka T.
      • Mizota T.
      • Tanimoto K.
      • Shoda T.
      • Segawa H.
      • et al.
      A case of acute necrotizing encephalopathy with severe liver dysfunction.
      ,
      • Miyake N.
      • Tanaka A.
      • Yamamoto K.
      • Nakayama M.
      • Aoki M.
      • Nakashita T.
      • et al.
      Acute necrotizing encephalopathy receiving plasmapheresis: a case report.
      ,
      • Li K.
      • Zhang T.
      • Liu G.
      • Jin P.
      • Wang Y.
      • Wang L.
      • et al.
      Plasma exchange therapy for acute necrotizing encephalopathy of childhood.
      ,
      • Aksoy E.
      • Öztoprak Ü.
      • Çelik H.
      • Özdemir F.M.A.
      • Özkan M.
      • Kayalioğlu H.
      • et al.
      Acute necrotizing encephalopathy of childhood: a single-center experience.
      ]. However, there are two barriers to timely TPE administration in patients with ANE. First, early ANE detection may be difficult. For example, the initial CT scan of case 2 showed slight thalamic abnormality with prominent supratentorial brain swelling, making ANE difficult to diagnose. Pediatric neurologists should recognize the exact gestalt of ANE and promptly initiate aggressive neurocritical care and immunomodulatory therapy if ANE is clinically suspected, even with minor imaging abnormalities. Second, there are a limited number of facilities that can rapidly introduce TPE in children. Therefore, there is a need to establish a rapid and safe inter-hospital transport system for critically ill children.Table.
      TableCytokine levels in the serum and cerebrospinal fluid of each case.
      IL-6

      (pg/mL)
      TNF

      (pg/mL)
      IL-2

      (pg/mL)
      IL-10

      (pg/mL)
      sIL-1R1

      (pg/mL)
      Case 1
       Day 2 CSF (before Tx)275.51.62.49.928.7
       Day 2 serum (before Tx)80.44.71.5226.71813.3
       Day 2 serum (after Tx)7.81.31.9142.51082.8
       Day 4 serum2.90.41.17.91908.3
       Day 14 serum3.63.24.09.31721.4
      Case 2
       Day 2 serum (after TPE once)223.53.32.2176.01832.6
       Day 3 serum (after TPE twice)4.55.02.69.31355.2
       Day 4 serum21.22.82.59.91748.9
       Day 15 serum4.34.22.95.91448.6
      Abbreviations: IL, interleukin; sIL-1R1, soluble IL-1 receptor 1; TNF, tumor necrosis factor; CSF; cerebrospinal fluids, TPE; therapeutic plasma exchange, Tx; treatment.
      This study has three limitations. First, cytokine analysis was performed using clinically obtained samples; therefore, there were limited data. Specifically, in patient 2, serum and CSF samples before the first TPE were unavailable. Nonetheless, we observed rapid and dynamic changes in both IL-6 and IL-10 within a few days after the onset. Second, Fluorescence-activated cell sorting of leukocytes was not available, and some cytokines, such as the soluble IL2 receptor, were not measured. This information may have provided a better overview of the immunological status in the acute phase of ANE. Third, since our facility routinely introduces continuous hemodiafiltration or hemofiltration in patients undergoing TPE, hemofiltration may have contributed to the removal of pro-inflammatory cytokines, including IL-6. Although cytokine removal by hemofiltration remains controversial, several studies have demonstrated that high-flow continuous hemofiltration decreases blood IL-6 levels [
      • Park J.T.
      • Lee H.
      • Kee Y.K.
      • Park S.
      • Oh H.J.
      • Han S.H.
      • et al.
      High-dose versus conventional-dose continuous venovenous hemodiafiltration and patient and kidney survival and cytokine removal in sepsis-associated acute kidney injury: a randomized controlled trial.
      ]. However, the filtration flow rate in our cases (36.4–53.3 mL/kg/h) is not considered high; thus, the changes in cytokine levels could be more attributed to TPE treatment rather than the effect of hemofiltration.

      6. Conclusion

      In children with influenza-associated ANE, early aggressive immunomodulatory therapy with TPE may improve neurological outcomes. Further clinical and translational research is required to establish the efficacy of TPE for ANE.

      Consent

      The authors obtained a written informed consent from parents for publication.

      Acknowledgements

      We appreciate Drs. Sato Suzuki-Muromoto and Tohru Uchiyama for cytokine measurements.

      Conflicts of Interest disclosures

      The authors declare no competing interests.

      Funding

      This research was supported by a Grant-in-Aid for Early-Career Scientists (19K17350) from the Japan Society for the Promotion of Science (IH). The funding source had no involvement in the publication of the manuscript.

      Author contributions

      Dr. Okajima: Manuscript preparation.
      Dr. Hayakawa: Study conceptualization, clinical evaluation, study design, and manuscript preparation.
      Drs. Tsuboi, Shimura, Ishiguro, and Abe: Study concept, critical manuscript revision, and study supervision.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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