1. Abstract Background Acutestrokeinbacterialmeningitisinchildrencontributestohigh morbidityandmortality.Theincidenceofstrokeinpediatricmeningitisisvaried,withreportsbetween8-42%,andassociatedmortality as high as 25%. The majority of these are arterial ischemic strokes(80-93%).Cerebralarterialvasospasmhasbeenproposed. We present the first case of intrathecal nitroprusside used to treat refractoryvasospasminachildwithbacterialmeningoencephalitis complicated by acute ischemic stroke. Case Presentation A7-year-old, vaccinated male with a past medical history of autism spectrum disorder and developmental delay was admitted to PICU with GCS of 3T, and CSF findings of streptococcal meningitis.SeveretranscranialdopplerandMRIrevealedvasospasm in bilateral middle cerebral artery (MCA) and basilar artery, despite aggressive hemodynamic intervention, IV nimodipine, IV milrinone infusion. The patient was started on novel intra-thecal (IT) nitroprusside.After 4 doses, the patient's TCD markedly improved. A trial of discontinuing IT nitroprusside was attempted, however,wasabortedduetoneurologicalstatusdeteriorationand it was restarted. After 10 doses of IT nitroprusside, TCD values normalized and clinical improvement was observed, and the patient was eventually discharged. Conclusion This case highlights the use of IT vasodilator therapy in bacterial meningoencephalitis for refractory vasospasm with case-reproducibility and good outcome emphasizes the need for further studies and consensus guidelines on monitoring for vasospasm to prevent stroke in meningitis. Background Theincidenceofstrokeinbacterialmeningoencephalitis(BME)is 27- 42%, with 80-93% being arterial ischemic stroke (AIS) and a 25% mortality rate in children [1-3]. Cerebral arterial vasospasm (CAV) is a proposed etiology for BME-associated AIS (BMEAIS),however,preventingBME-AIShasprovendifficultwithfirst line therapies [1-6]. Transcranialdoppler(TCD),establishedinsub-arachnoidhemorrhage (SAH) for detectingAIS, has emerging evidence for utility in BME [1-3]. In a study involving 94 adults with BME, TCD detectedBME-associatedCAV(BME-CAV)in41patients,which was associated with AIS and mortality [4 -9]. Additionally, in a studyinvolving20childrenwithBME,TCDaideddifferentiation of hyperemia, hypoperfusion, and vasospasm [10]. Initialevidence ofAIS prevention in BME-CAVsuggestseffective therapy may require a prolonged duration of action through permanent, repeated, or sustained contact of therapeutic agents and the arterial vessels involved.Although enteral and IVnimodipine haveprovenbeneficialinpatientswithSAH,thesewereofnoben- efit in the aforementioned trial involving 94 adults [11, 12]. Furthermore, small case series using intra-arterial (IA) percutaneous transluminalangioplastyandIAnicardipineandverapamiltotreat BME-CAV demonstrate promising results [13 - 15]. Insearchofalessinvasivetreatmentwithamoresustainedeffect, wepresentthefirstcaseofBME-CAVtreatedwithintrathecal(IT) nitroprusside.
Keywords: Vasospasm; Meningoencephalitis; Stroke; Intrathecal; Nitroprusside
2. Case Report A7-year-old male with autism and developmental delay presented secondary to acute onset neurologic deficit with an admission Glasgow coma score (GCS) of 3T and cerebral spinal fluid suggesting streptococcal meningitis. TCDonhospitalday2showedvasospasmoftherightmiddleceTable1:SerialTranscranialDopplerResults. rebral artery (R-MCA) (Table 1). MRI revealed small, multifocal lenticulostriate AIS, ventriculitis and moderate hydrocephalus withunremarkableinitialMRangiography(MRA).Despiteexter- nal ventricular drain (EVD) insertion and systemic antibiotics, he continued to have only trace pain response, and status epilepticus developed on day 3. Beginning day 6, serialTCDs and MRAs revealed bilateral MCA and basilar artery vasospasm refractory to enteral nimodipine and IV milrinone. Four-vessel angiogram on day 9 confirmed severe widespreadvasospasmandIAverapamilyieldednoimprovement. Due to widespread severe vasospasm, evidence ofAIS, and continueddeteriorationdespiteallpriortreatments,ITnitroprusside4 mg every 12 hours via EVD was started on day 10. Nitroprusside was selected due to evidence of benefit in the adult literature for treatmentofCAVsecondarytoSAHandtheavailabilityofapreservative-freeformulation.TCDfindingsimprovedmarkedlyfollowingthefirstdosewithsustainedsuppressionofvasospasmand clinicalimprovementover4dosesthroughday12.Adiscontinuationtrialwasconductedandabortedwithin36hoursduetodeteriorationinneurologicstatusandworseningvasospasmbyTCDand MRA(herein defined as case-reproducibility). Clinical status and vasospasm improved within 24 hours of reinitiating therapy. Ten totaldosesweregivenwithsideeffectsconsistingofself-resolving hypertensive episodes and emesis. Thereafter TCD values remained within normal limits and IT nitroprussidewasdiscontinuedonday17.Byday21thepatientwas extubated,milrinoneinfusionweanedoff,andtheEVDremoved. Atthattime,hehadimprovedencephalopathy(GCS11)andbrisk localizationtostimulation.Onday23hetransferredoutoftheICU followedby4weeksofinpatientrehabilitation.Duringafollow-up appointment four months after presentation, he was speaking in short phrases and walking unassisted (GCS 15) with no apparent extension of his original AISs clinically or by imaging.
3. Discussion Toourknowledge,thisisthefirstreportofITvasodilatorfortreatmentofBME-CAV.Theauthorswereinitiallyconcernedthelack ofimprovementwithIVandIAvasodilatorsindicatedafixedanatomicalnarrowingofvesselsfromarteritisversustruevasospasm. Despitethis,therisk-benefitratiofavoredtreatmentastheimaging wasmoreconsistentwithvasospasm(smoothregularnarrowingof arterial walls). Confirming this hypothesis, arterial velocities and clinical exam improved quickly after IT nitroprusside initiation, worsened after treatment discontinuation, and again quickly improved with re-initiation. Ultimately, the etiology of AIS in BME is unknown. Causative factors include anatomical obstructions from thrombi, vasculitis, andvasospasmthatcauseincreasedbloodflowvelocitiesbuthave different appearance on imaging [1-4]. ThepathophysiologyofBME-CAVispoorlyunderstoodandmay be caused by decreased nitric oxide secondary to bacterial consumption [5, 6]. The authors hypothesize nitroprusside, a nitric oxide donor, was effective for this child’s refractory vasospasm duetoincreasedcontacttimebetweenthedrugandmajorcerebral arteries secondary to the IT route of administration. Treatmentdurationofactionisimportantinvasospasmfromany
4. Conclusion This sentinel case report of ITantispasmodic therapy in BME for refractoryvasospasmwithcase-reproducibilityandgoodoutcome highlightstheneedforfurtherstudies.Escalationofanti-spasmodictherapyinBMEtoITnitroprussidemaybeconsideredinthose withrefractoryvasospasmorwithcontraindications,orlackofaccess, to IA treatment when indicated.
References 1. DunbarM,ShahH,ShindeS.StrokeinPediatricBacterialMeningi- tis: Population-Based Epidemiology. Pediatr Neurol. 2018; 89:11-18.
2. Pryde K, Walker WT, Hollingsworth C. Stroke in paediatric pneumococcalmeningitis:across-sectionalpopulation-basedstudy.Arch Dis Child. 2013; 98(8): 647-649.
3. SnyderRD,StovringJ,CushingAH,DavisLE,HardyTL.Cerebral infarctioninchildhoodbacterialmeningitis.JNeurolNeurosurgPsychiatry. 1981; 44(7): 581-585.
4. KleinM,KoedelU,PfefferkornT,ZellerG,WoehrlB,PfisterH-W. Arterialcerebrovascularcomplicationsin94adultswithacutebacte- rial meningitis. Crit Care. 2011; 15(6): R281.
5. EisenhutM.VasospasminCerebralInflammation.IntJInflam. 2014; 2014.
6. WeirB.Thepathophysiologyofcerebralvasospasm.BritishJournal of Neurosurgery. 1995; 9(3): 375-390.7. KumarR,PathakA,MathuriyaSN,KhandelwalN.Intraventricularsodi um nitroprusside therapy: A future promise for refractory subarachnoid hemorrhage-induced vasospasm. Neurology India. 2003;51(2): 197.
8. Raabe A, Zimmermann M, Setzer M, Vatter H, Berkefeld J, Seifert V. Effect of Intraventricular Sodium Nitroprusside on Cerebral Hemodynamics and Oxygenation in Poor-gradeAneurysm Patients withSevere,MedicallyRefractoryVasospasm.Neurosurgery.2002; 50(5): 1006-1014.
9. Thomas Jeffrey E. McGinnis Gerri. Safety of Intraventricular Sodium Nitroprusside and Thiosulfate for the Treatment of Cerebral Vasospasm in the Intensive Care Unit Setting. Stroke. 2002; 33(2): 486-492.
10. Ducharme-CrevierL,MillsMG,MehtaPM,SmithCM,Wainwright MS. Use of Transcranial Doppler for Management of Central Nervous System Infections in Critically Ill Children. Pediatr Neurol. 2016; 65: 52-58.e2.
11. OktenA,AhmetoğluA, Dilber E. Cranial Doppler ultrasonography asapredictorofneurologicsequelaeininfantswithbacterialmeningitis. Invest Radiol. 2002; 37(2): 86-90.
12. Liu GJ, Luo J, Zhang LP. Meta-analysis of the effectiveness and safetyofprophylacticuseofnimodipineinpatientswithananeurys- mal subarachnoid haemorrhage. CNS Neurol Disord Drug Targets. 2011; 10(7): 834-844.
13. Buechner D, Gelfand MS, Cleveland KO. Percutaneous transluminal angioplasty in a patient with vasospasm due to staphylococcal meningitis. J Neurosurg. 2012; 117(1): 103-106.
14. HuYC, Newman CB, Bristol R, McDougall CG,Albuquerque FC. Percutaneous transluminal angioplasty in a patient with vasospasm secondary to coccidioidal meningitis: case report and review of the literature. J Neurointerv Surg. 2011; 3(1): 62-65.
15. Taqui A, Koffman L, Hui F. Intra-arterial vasodilator therapy for parainfectious cerebral vasospasm. J Neurol Sci. 2014; 340(1-2): 225-229.
Maria Jose Gonzalez. Refractory Vasospasm andArterial Ischemic Stroke in Meningoencephalitis: Novel Intrathecal Nitroprusside Treatment. Annals of Clinical and Medical Case Reports 2021