Sex: F
Vaccine: FLUX, PNC15, PPV
Symptoms: Cytogenetic analysis abnormal, Cytokine increased, Cytokine storm, Enteral nutrition, Generalised tonic-clonic seizure
Clinical narrative: new-onset refractory status epilepticus that followed routine vaccine administration and ensuing cytokine storm/ this patient's cytokine-mediated response to vaccination in the setting of PCDH19 dysfunction led to her severe NORSE presentation; new-onset refractory status epilepticus that followed routine vaccine administration and ensuing cytokine storm/ this patient's cytokine-mediated response to vaccination in the setting of PCDH19 dysfunction led to her severe NORSE presentation;  This literature marketed report has been received from the authors of a published article, titled as stated above, and refers to a 7-month-old girl with no previous medical history.  On an unspecified date, the patient was with vaccinated with the third dose of the pneumococcal vaccine, polyvalent (23-valent) (PNEUMOVAX23) injection (strength, dose description, lot #, expiry date, and route of administration were not provided) or pneumococcal 15v conj vaccine (crm197) (VAXNEUVANCE) injection (strength, dose description, lot #, expiry date, and route of administration were not provided) and second dose of influenza vaccine (INFLUENZA VACCINE) (strength, formulation, dose description, lot #, expiry date, and route of administration were not provided) without documented fever.  On an unspecified date (1 day after vaccination). the patient presented to the hospital for frequent clusters of seizures for 1 day. The patient was noted to have multiple episodes of seizures consisting of behavioral arrest, cyanosis, and generalized tonic-clonic and tonic activity. In the emergency department, seizures evolved into refractory status epilepticus (SE) despite use of multiple antiseizure medications (ASMs) necessitating pentobarbital-induced coma to achieve burst suppression twice after seizures were refractory to midazolam and ketamine infusions. She was admitted to the hospital and additionally started on a 3:1 ketogenic diet due to the refractory nature of her SE, which escalated to 4:1 ketogenic ratio at the peak of her seizure frequency. Extensive initial evaluation for infectious, metabolic, and structural causes of epilepsy was unrevealing. Given the patient's fulminant onset of refractory SE, she was diagnosed with new-onset refractory status epilepticus (NORSE). Given presumed immunologic factors that lead to NORSE  in general, she was treated symptomatically with IV methylprednisolone and IV immunoglobulin (IVIg). Initial serum cytokine panels revealed elevated serum interleukin (IL)-1, IL-1ß, IL-2, IL-4, IL-8, IL-10, IL-13, and IL-17 levels and CSF IL-6 and IL-13 levels. On an unspecified date at hospital day 12: interleukin 1 beta was 14.9 pg/mL; reference range less or equal to 6.7 pg/mL, elevated Interleukin 2 was less than 2.1 pg/mL; reference range less or equal to 2.1 pg/mL; Interleukin 2 receptor, soluble was 1868.2 pg/mL; reference range 175.3858.2 pg/mL, elevated; Interleukin 4 was 5.2 pg/mL; reference range less or equal to 2.2 pg/mL, elevated; Interleukin 5 was less than 2.1 pg/mL; reference range less or equal to 2.1 pg/mL; Interleukin 6 was 5.7 pg/mL; reference range less or equal to 2.0 pg/mL, elevated; Interleukin 8 was 538.1 pg/mL; reference range less or equal to 3.0 pg/mL, elevated; interleukin 10 was 13.6 pg/mL; reference range less or equal to 2.8 pg/mL, elevated; Interleukin 12 was less than 1.9 pg/mL; reference range less or equal to 1.9 pg/mL; interleukin 13 was 58.1 pg/mL; reference range less or equal to 2.3 pg/mL, elevated; interleukin 17 was 8 pg/mL; reference range less or equal to 1.4 pg/mL, elevated; tumor necrosis factor alpha was 22.3 pg/mL; reference range less or equal to 7.2 pg/mL; interferon gamma 8.3 pg/mL; reference range less or equal to 4.2 pg/mL, elevated. Interleukin 1 beta (on date unspecified, hospital day 29) was less than 6.5 pg/mL; reference range less or equal to 6.7 pg/mL, elevated; interleukin 2 (date unspecified, hospital day 29) was less than 2.1 pg/mL; reference range less or equal to 2.1 pg/mL; interleukin 2 receptor, soluble (date unspecified, hospital day 29) was 3488.5 pg/mL; reference range 175.3858.2 pg/mL, elevated; interleukin 4 (date unspecified, hospital day 29) was 2.6 pg/mL; reference range less or equal to 2.2 pg/mL, elevated; interleukin 5 (date unspecified, hospital day 29) was 2.2 pg/mL; reference range less or equal to 2.1 pg/mL, elevated; interleukin 6 (date unspecified, hospital day 29)was less than 2.0 pg/mL; reference range less or equal to 2.0 pg/mL; interleukin 8 (date unspecified, hospital day 29)was less than 3 pg/mL; reference range less or equal to 3.0 pg/mL; interleukin 10 (date unspecified, hospital day 29)was 11.6 pg/mL; reference range less or equal to 2.8 pg/mL, elevated; interleukin 12 (date unspecified, hospital day 29) was less than 1.9 pg/mL; reference range less or equal to 1.9 pg/mL; interleukin 13 (date unspecified, hospital day 29) was less than 1.7 pg/mL; reference range less or equal to 2.3 pg/mL; interleukin 17 (date unspecified, hospital day 29) was 3.9 pg/mL; reference range less or equal to 1.4 pg/mL, elevated; tumor necrosis factor alpha (date unspecified, hospital day 29) was 13.7 pg/mL; reference range less or equal to 7.2 pg/mL; interferon gamma (date unspecified, hospital day 29) was less than 4.2pg/mL; reference range less or equal to 4.2 pg/mL. On an unspecified date, on hospital day 29: Interleukin 1 beta was less than 6.5 pg/mL; reference range less or equal to 6.7 pg/mL, elevated Interleukin 2 was less than 2.1 pg/mL; reference range less or equal to 2.1 pg/mL; interleukin 2 receptor, soluble was 4921.6 pg/mL; reference range 175.3858.2 pg/mL, elevated; interleukin 4 was 2.5 pg/mL; reference range less or equal to 2.2 pg/mL, elevated; interleukin 5 was less than 2.1 pg/mL; reference range less or equal to 2.1 pg/mL; interleukin 6 was less than 2.0 pg/mL; reference range less or equal to 2.0 pg/mL; interleukin 8 was less than 3 pg/mL; reference range less or equal to 3.0 pg/mL; Interleukin 10 was 10.5 pg/mL; reference range less or equal to 2.8 pg/mL, elevated; interleukin 12 was less than 1.9 pg/mL; reference range less or equal to 1.9 pg/mL; interleukin 13 was 2.3 pg/mL; reference range less or equal to 2.3 pg/mL interleukin 17 was 3.2 pg/mL; reference range less or equal to 1.4 pg/mL, elevated; tumor necrosis factor alpha was 20.3 pg/mL; reference range less or equal to 7.2 pg/mL; interferon gamma less than 4.2pg/mL; reference range less or equal to 4.2 pg/mL. Given the elevated cytokine levels, an evaluation for secondary hemophagocytic lymphohistiocytosis was performed and was negative. A rapid epilepsy gene panel revealed the pathogenic PCDH19 variant c.1211C>T, resulting in the p.T404I amino acid substitution. The treatment included requiring clobazam 20 mg nightly (2 mg/kg/d), brivaracetam 50 mg twice a day (10 mg/kg/d), phenobarbital 97 mg 3 times a day (30 mg/kg/d), and cannabidiol 100 mg nightly (10 mg/kg/d). Given the elevated cytokine levels, anakinra was started with dose escalation (520 mg/kg/d) and slowly weaned off, guided by repeat cytokine panels. She was successfully weaned off pentobarbital with subsequent cytokine panels showing continued improvement of the inflammatory markers. Following an attempt to reduce the anakinra dose seizures recurred, and cytokine levels were rechecked, showing residual cytokine elevation notably in markers of adaptive immunity, such as IL-4, IL-5, and proinflammatory IL-17, which led to retitration of anakinra. Eventually, seizures abated, and anakinra was weaned off successfully with no recurrence of seizures. After 52 days, the patient was discharged home on 5 ASMs:clobazam, cannabidiol, and fenfluramine and the ketogenic diet that were maintained and phenobarbital and brivaracetam that were actively being weaned. She remained seizure-free at 6-month follow-up therefore the outcome of the event of status epilepticus was assessed as recovered. She has progressed from nasogastric tube feeding to oral intake of pureed feeds, has shown improved strength, and is achieving some developmental milestones, such as sitting up with support, with speech, physical, occupational, and feeding therapies in place. at the time of the report, the outcome of cytokine storm was unknown.  The events of status epilepticus and cytokine storm were assessed as related to suspected vaccines.  The events of status epilepticus and cytokine storm were determined to be medically significant.  A copy of the published article is attached as further documentation of the patient's experience.