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A rare infective cause of stroke in an immunocompetent child

      Abstract

      Background

      Infections are a common cause of childhood stroke with variable presentation. The current case describes a rare infective cause of venous and arterial stroke in an immunocompetent girl with management implications.

      Case description

      A 12 year old girl, presented with history of fever for 10 days, painful swelling of right eye for 7 days and altered sensorium for 2 days. On examination, she had right eye orbital cellulitis and fullness of right paranasal area. On nervous system examination, she was delirious, had right eye ophthalmoparesis, left upper motor neuron facial palsy and signs of meningeal inflammation. Her contrast enhanced CT head and subsequent MRI brain with arteriography and venography revealed right cavernous sinus and distal internal carotid artery thrombosis. She was started on intravenous ceftriaxone and vancomycin and subcutaneous heparin. In view of persistent symptoms, endoscopic debridement of right nasal cavity was done, which showed growth of aspergillus flavus. Subsequently, she was started on intravenous voriconazole. Within a week, she was afebrile, her inflammatory and neurological signs started improving. She was discharged after 3 weeks of intravenous voriconazole which was continued for 3 more weeks orally. Her procoagulant and immunodeficiency work up were normal. At 4 months follow up, she showed both clinical and radiological resolution.

      Conclusions

      Despite high mortality described in sino-orbital aspergillosis, early and appropriate treatment led to optimal outcome. In deep seated infections, isolation of etiological organism should be attempted, particularly when patient doesn’t respond to conventional antimicrobial therapy.

      Keywords

      1. Introduction

      Childhood stroke is a leading cause of mortality and morbidity worldwide. Acute stroke is a neurological emergency. The overall incidence rates for stroke is 1.3–13/100,000 for children under 18 years [
      • Tsze D.S.
      • Valente J.H.
      Pediatric stroke: a review.
      ]. Infections cause stroke either by direct vascular involvement or indirectly by alteration of baseline tendency in the acute state as well as weeks to months later. Gradual evolution of symptoms, presence of fever, neck rigidity, meningeal inflammation and multi-focal ischemic infarcts in neuro-imaging should raise the suspicion of infectious etiology. Infections associated with arterial ischemic stroke (AIS) are mycobacterium tuberculosis, mycoplasma, toxoplasmosis, Lyme’s disease, cryptococcus, influenza A and enterovirus while cerebral sino-venous thrombosis is most commonly associated with head and neck infections like otitis, mastoiditis and sinusitis [

      Kirton A, deVeber G. Cerebrovascular Disease in Children. In: Swaiman KF, Ashwal S, Ferriero DM, Schor NF editors. Pediatric Neurology: Principles and Practice. New York: Elsevier; 2018. P.1395-1436.

      ].
      Isolation of causal organism and appropriate antimicrobial therapy is quintessential for the timely management of these children. A 12 year old girl with infection associated stroke is being described here in whom early identification of a rare infectious agent led to optimal recovery.

      2. Case description

      A 12 year old, premorbidly normal girl, presented with fever for 10 days, right eye pain and swelling for 7 days and altered sensorium for 2 days. On local examination, she had right eye swelling with erythema and fullness of right paranasal area with pustules. Her nervous system examination revealed a delirious state, right eye ptosis and ophthalmoparesis, left upper motor neuron (UMN) facial palsy, neck rigidity and positive Kernig’s sign. On the basis of clinical picture and contrast enhanced CT head (Fig. 1A) done in the emergency room, a possibility of cavernous sinus thrombosis secondary to right orbital cellulitis and sinusitis was kept. She was started on subcutaneous low molecular weight heparin (LMWH), intravenous ceftriaxone and vancomycin. Her hemoglobin was 10.4 gm/dl with a red blood cell mean corpuscular volume of 97 fL (normal reference value: 80–95 fL). The cerebrospinal fluid (CSF) examination revealed 25 cells (80% lymphocytes)/µL, protein of 75 mg/dl and sugar of 40 mg/dl against a corresponding blood sugar of 140 mg/dl. The CSF analysis in terms of bacterial culture, cryptococcal antigen and GeneXpert (Cepheid, Sunnyvale, California, USA) were negative. An MRI brain with angiography and venogram revealed right cavernous sinus and internal carotid artery (ICA) thrombosis with consequent right basal ganglia and cerebellar signal changes suggestive of infarcts (Fig. 1B–E). There was no radiological evidence of sinusitis. The fullness of the cheek could be secondary to soft tissue spread from orbital cellulitis.
      Figure thumbnail gr1
      Fig. 1A) Contrast enhanced CT of the brain shows enlarged right cavernous sinus with filling defect suggestive of thrombosis (large arrow). B) The right orbit shows inflammatory changes with prominent superior ophthalmic vein (small arrow). Contrast enhanced MR brain shows thrombosed right cavernous sinus (large arrow) and right superior ophthalmic vein (small arrow). Note the presence of inflammation along the meninges posterior to the cavernous sinus. C) MR angiogram shows partial thrombosis of the distal right internal carotid artery (arrow). D) T2 weighted axial MRI brain images show hyperintense signal changes in right cerebellar hemisphere. E) T2 weighted axial MRI brain images show hyperintense signal changes in right caudate and right putamen. Follow up MRI of the brain with contrast at 20 weeks follow up shows. F) MR venography with normal cavernous sinus with complete resolution of the inflammatory changes. G) MR angiogram with complete re-canalisation of the internal carotid artery. H) T2 weighted axial images with encephalomalacic changes in right cerebellum. I) T2 weighted axial images with encephalomalacic changes in right caudate and putamen.
      In view of persisting fever spikes and fullness of right cheek with crusting of nasal cavity even after 72 h of antibiotic therapy, endoscopic debridement of the crusts in right nasal cavity was done which revealed hyaline septate hyphae on potassium hydroxide (KOH) mount and grew Aspergillus flavus on culture (Fig. 2). Child was therefore started on intravenous voriconazole. Within 48 h, she became afebrile and right eye swelling started improving. Her HIV serology was negative and blood sugar values were normal. The percentage frequencies of T (CD3), B (CD19) and NK (natural killer) cells (CD56 and CD16) were within normal range. Her NK cell activity, frequency of granulocytes expressing leukocyte adhesion markers and neutrophil oxidative index (NOI) value in granulocytes were normal. Her methylene tetrahydrofolate reductase (MTFHR) gene and factor V Leiden mutation analysis were negative. Her beta 2 glycoprotein levels and echocardiography were normal. She had vitamin B12 deficiency (12.6 pmol/L, normal reference range: 25.1–165 pmol/L) with homocysteine levels of 29.49 µmol/L (normal reference range: 4.6–8.1 µmol/L). She was started on daily subcutaneous vitamin B12 1000 µg daily for 2 weeks followed by oral B12 1000 µg daily for 3 months with folic acid supplements. She was given 3 weeks of injectable voriconazole and advised further 3 weeks of oral voriconazole at discharge.
      Figure thumbnail gr2
      Fig. 2A) Potassium hydroxide-Calcofluor white stain of the biopsy showing septate hyphae. B) Typical yellow-green colony of A. flavus on potato dextrose agar. C) Lactophenol cotton blue mount from the colony showing conidiophore, vesicle and phialides covering upper two third part consistent with A. flavus. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
      Her neurological symptoms started improving 7 days into voriconazole therapy and at discharge (3 weeks of parenteral voriconazole therapy), she was alert, interactive, ambulatory with resolution of right eye inflammation. Her neurological deficits resolved except persistent limitation of abduction in right eye and resolving left facial palsy. At discharge, subcutaneous LMWH was continued.
      At 20 weeks follow up, she had complete resolution of symptoms and signs. Her repeat MRI brain with contrast with MR angiography and venogram revealed significant improvement with small areas of gliosis in right basal ganglia and cerebellum (Fig. 1F–I). Her procoagulant work up in the form of protein C, protein S, anti-thrombin III and activated protein C resistance (APC-R) is negative. Subsequently, LMWH has been discontinued. After 3 months of vitamin B12 therapy, serum vitamin B12 (114 pmol/L) and homocysteine (7.7 µmol/L) levels have normalized.

      3. Discussion

      Amongst the Aspergillus species, most common to cause human infection is Aspergillus fumigatus followed by Aspergillus flavus. Invasive aspergillosis is usually caused by inhalation of conidia and sinusitis is most common site of upper airway aspergillosis [
      • Schwartz S.
      • Thiel E.
      Clinical presentation of invasive aspergillosis.
      ]. Cerebral aspergillosis can arise either by hematogenous spread from usually a primary pulmonary focus or extension from surrounding structures like orbit, paranasal sinuses and middle ear. Cerebral aspergillosis is more common in immunocompromised patients [
      • Chatterjee D.
      • Radotra B.D.
      • Mukherjee K.N.
      Aspergillus arteritis of the right internal carotid artery resulting in massive stroke.
      ]. Primary immunodeficiencies associated with invasive aspergillosis are chronic granulomatous disorder, hyper-IgE syndrome, leukocyte adhesion deficiency, primary neutropenias and primary T cell deficiencies [
      • Almyroudis N.G.
      • Holland S.M.
      • Segal B.H.
      Invasive aspergillosis in primary immunodeficiencies.
      ]. In the current case, both primary and secondary immunodeficiency states were ruled out.
      To the best of our knowledge, the current case is the youngest case of invasive aspergillosis leading to cavernous sinus thrombosis. A case of cavernous sinus thrombosis due to rhino-orbital aspergillosis has been described in an eighteen year old [
      • Arora V.
      • Nagarkar N.M.
      • Dass A.
      • Dash A.
      • Kaur R.
      Fungal Cerebral Embolic Infarction by Rhino-Orbitocranial Aspergillosis.
      ]. All other cases described till date are in middle-aged and elderly adults. Some of the elderly adults had associated diabetes mellitus, but majority of them underwent only HIV serology to rule out associated immunodeficiency states [
      • Arora V.
      • Nagarkar N.M.
      • Dass A.
      • Dash A.
      • Kaur R.
      Fungal Cerebral Embolic Infarction by Rhino-Orbitocranial Aspergillosis.
      ,
      • Brenet E.
      • Boulagnon-Rombi C.
      • Nguyen Y.
      • Litre C.F.
      Cavernous sinus thrombosis secondary to aspergillus granuloma: A case report and review of literature.
      ,
      • Chan Y.C.
      • Ho K.H.
      • Chuah Y.S.
      • Lau C.C.
      • Thomas A.
      • Tambyah P.A.
      Eosinophilic meningitis secondary to allergic Aspergillus sinusitis.
      ,
      • Chandra S.
      • Goyal M.
      • Mishra N.K.
      • Gaikwad S.B.
      Invasive aspergillosis presenting as a cavernous sinus mass in immunocompetent individuals; report of 3 cases.
      ,
      • Dyken M.E.
      • Biller J.
      • Yuh W.T.C.
      • Fincham R.
      • Moore S.A.
      • Justin E.
      Carotid-cavernous sinus thrombosis caused by Aspergillus fumigatus: magnetic resonance imaging with pathologic correlation. A case report.
      ,
      • Huang Y.
      • Gui L.
      Cavernous sinus-orbital apex aspergillus infection in a diabetic patient.
      ,
      • Neil J.A.
      • Orlandi R.R.
      • Couldwell W.T.
      Malignant fungal infection of the cavernous sinus: case report.
      ]. In the current case, apart from HIV serology and blood sugar, both quantitative and qualitative tests for T, B and NK cell were performed to rule out commonly inherited causes of immunodeficiency.
      The ICA thrombosis in this child can either be part of the cavernous sinus thrombosis or secondary to cerebrovascular aspergillosis consequent to septic embolization [
      • Chatterjee D.
      • Radotra B.D.
      • Mukherjee K.N.
      Aspergillus arteritis of the right internal carotid artery resulting in massive stroke.
      ]. Aspergillosis induced stroke is the rarest manifestation of cerebral aspergillosis. The commoner presentations are aspergillomas, aspergillus abscess and necrotizing disseminated aspergillosis, latter two being seen in immunocompromised individuals. Cerebrovascular aspergillosis has been occasionally described in immunocompetent individuals with poor outcome [
      • Chatterjee D.
      • Radotra B.D.
      • Mukherjee K.N.
      Aspergillus arteritis of the right internal carotid artery resulting in massive stroke.
      ,
      • Hersh C.M.
      • John S.
      • Subei A.
      • Willis M.A.
      • Kosmorsky G.S.
      • Prayson R.A.
      • et al.
      Optic neuropathy and stroke secondary to invasive Aspergillus in an immunocompetent patient.
      ,
      • Kavi T.
      • Madan N.
      • Majic T.
      • Rosengart A.
      • Maya M.
      • Bannykh S.
      • et al.
      Angioinvasive Aspergillus-associated stroke in an immunocompetent host following cardiac surgery and ECMO.
      ].
      Combination of cavernous sinus and ICA thrombosis has been described in most of the previous reports [
      • Arora V.
      • Nagarkar N.M.
      • Dass A.
      • Dash A.
      • Kaur R.
      Fungal Cerebral Embolic Infarction by Rhino-Orbitocranial Aspergillosis.
      ,
      • Brenet E.
      • Boulagnon-Rombi C.
      • Nguyen Y.
      • Litre C.F.
      Cavernous sinus thrombosis secondary to aspergillus granuloma: A case report and review of literature.
      ,
      • Chandra S.
      • Goyal M.
      • Mishra N.K.
      • Gaikwad S.B.
      Invasive aspergillosis presenting as a cavernous sinus mass in immunocompetent individuals; report of 3 cases.
      ,
      • Dyken M.E.
      • Biller J.
      • Yuh W.T.C.
      • Fincham R.
      • Moore S.A.
      • Justin E.
      Carotid-cavernous sinus thrombosis caused by Aspergillus fumigatus: magnetic resonance imaging with pathologic correlation. A case report.
      ,
      • Neil J.A.
      • Orlandi R.R.
      • Couldwell W.T.
      Malignant fungal infection of the cavernous sinus: case report.
      ]. The current case showed evidence of lymphocytic meningitis. Eosinophilic and polymorphonuclear predominant meningitis has been described in previous cases [
      • Chan Y.C.
      • Ho K.H.
      • Chuah Y.S.
      • Lau C.C.
      • Thomas A.
      • Tambyah P.A.
      Eosinophilic meningitis secondary to allergic Aspergillus sinusitis.
      ,
      • Chandra S.
      • Goyal M.
      • Mishra N.K.
      • Gaikwad S.B.
      Invasive aspergillosis presenting as a cavernous sinus mass in immunocompetent individuals; report of 3 cases.
      ,
      • Dyken M.E.
      • Biller J.
      • Yuh W.T.C.
      • Fincham R.
      • Moore S.A.
      • Justin E.
      Carotid-cavernous sinus thrombosis caused by Aspergillus fumigatus: magnetic resonance imaging with pathologic correlation. A case report.
      ].
      In the present case, cerebellar infarcts without posterior circulation involvement can be explained by either petrosal sinus thrombosis [
      • Ruiz-Sandoval J.L.
      • Chiquete E.
      • Navarro-Bonnet J.
      • Ochoa-Guzman A.
      • Arauz-Gongora A.
      • Barinagarrementería F.
      • et al.
      Isolated vein thrombosis of the posterior fossa presenting as localized cerebellar venous infarctions or hemorrhages.
      ] or presence of an aberrant cerebellar artery originating from cavernous part of internal carotid artery which represents persistence of fetal anterior and posterior circulation communications [
      • Shoja M.M.
      • Loukas M.
      • Tubbs R.S.
      • Antoni D.
      • Di Landro A.
      • Cure J.K.
      An aberrant cerebellar artery originating from the internal carotid artery.
      ].
      The current case had low vitamin B12 levels and elevated homocysteine. Presence of macrocytic anaemia on peripheral smear and elevated serum homocysteine level prompted serum vitamin B12 testing. More than 40% adolescents in rural India have low vitamin B12 levels secondary to undernutrition and poor intake of micronutrients [
      • Chakraborty S.
      • Chopra M.
      • Mani K.
      • Giri A.K.
      • Banerjee P.
      • Sahni N.S.
      • et al.
      Prevalence of vitamin B12 deficiency in healthy Indian school-going adolescents from rural and urban localities and its relationship with various anthropometric indices: a cross-sectional study.
      ]. The current case was from a rural area in north India and belonged to lower socioeconomic class, which can explain the vitamin B12 deficiency in her. Low serum vitamin B12 levels impairs conversion of serum homocysteine to methionine. High serum homocysteine can facilitate stroke by endothelial dysfunction, oxidative stress, inflammation and smooth muscle proliferation [
      • Moretti R.
      • Caruso P.
      The controversial role of homocysteine in neurology: from labs to clinical practice.
      ]. Hyper-homocysteinemia could have been a contributory factor to both cavernous sinus thrombosis and arterial ischemic stroke in this case.
      Voriconazole is recommended as primary therapy for pediatric invasive aspergillosis. Other antifungals which can be used are amphotericin B, itraconazole and echinocandins. There is no consensus on duration of antifungal therapy, it is usually 6–12 weeks depending upon resolution of clinical disease and severity of immunosuppression. Diagnostic and therapeutic surgical procedures like sinus lavage culture or removal of necrotic material is crucial to the management [
      • Patterson T.F.
      • Thompson G.R.
      • Denning D.W.
      • Fishman J.A.
      • Hadley S.
      • Herbrecht R.
      • et al.
      Practice guidelines for the diagnosis and management of aspergillosis: Update by the Infectious Diseases Society of America.
      ]. The response rate to medical therapy is only 40–60% and mortality rate of invasive sino-orbital aspergillosis is 40–75% despite optimal surgical and medical management [
      • Choi H.S.
      • Choi J.Y.
      • Yoon J.S.
      • Kim S.J.
      • Lee S.Y.
      Clinical characteristics and prognosis of orbital invasive Aspergillosis.
      ]. In the present case, voriconazole was given for total duration of 6 weeks which led to complete clinical and radiological resolution. Early debridement of necrotic tissue, isolation of the causative organism and institution of appropriate antifungal is the most likely cause for successful outcome in a disease which otherwise has high mortality as described in literature. This fact is echoed by all previously reported cases as well [
      • Arora V.
      • Nagarkar N.M.
      • Dass A.
      • Dash A.
      • Kaur R.
      Fungal Cerebral Embolic Infarction by Rhino-Orbitocranial Aspergillosis.
      ,
      • Brenet E.
      • Boulagnon-Rombi C.
      • Nguyen Y.
      • Litre C.F.
      Cavernous sinus thrombosis secondary to aspergillus granuloma: A case report and review of literature.
      ,
      • Chan Y.C.
      • Ho K.H.
      • Chuah Y.S.
      • Lau C.C.
      • Thomas A.
      • Tambyah P.A.
      Eosinophilic meningitis secondary to allergic Aspergillus sinusitis.
      ,
      • Chandra S.
      • Goyal M.
      • Mishra N.K.
      • Gaikwad S.B.
      Invasive aspergillosis presenting as a cavernous sinus mass in immunocompetent individuals; report of 3 cases.
      ,
      • Dyken M.E.
      • Biller J.
      • Yuh W.T.C.
      • Fincham R.
      • Moore S.A.
      • Justin E.
      Carotid-cavernous sinus thrombosis caused by Aspergillus fumigatus: magnetic resonance imaging with pathologic correlation. A case report.
      ,
      • Huang Y.
      • Gui L.
      Cavernous sinus-orbital apex aspergillus infection in a diabetic patient.
      ,
      • Neil J.A.
      • Orlandi R.R.
      • Couldwell W.T.
      Malignant fungal infection of the cavernous sinus: case report.
      ].
      The clinical, treatment and outcome related features of the current case and all previous cases of aspergillosis with cavernous sinus and ICA thrombosis have been tabulated (Table 1) [
      • Arora V.
      • Nagarkar N.M.
      • Dass A.
      • Dash A.
      • Kaur R.
      Fungal Cerebral Embolic Infarction by Rhino-Orbitocranial Aspergillosis.
      ,
      • Chandra S.
      • Goyal M.
      • Mishra N.K.
      • Gaikwad S.B.
      Invasive aspergillosis presenting as a cavernous sinus mass in immunocompetent individuals; report of 3 cases.
      ,
      • Dyken M.E.
      • Biller J.
      • Yuh W.T.C.
      • Fincham R.
      • Moore S.A.
      • Justin E.
      Carotid-cavernous sinus thrombosis caused by Aspergillus fumigatus: magnetic resonance imaging with pathologic correlation. A case report.
      ,
      • Neil J.A.
      • Orlandi R.R.
      • Couldwell W.T.
      Malignant fungal infection of the cavernous sinus: case report.
      ,
      • Hersh C.M.
      • John S.
      • Subei A.
      • Willis M.A.
      • Kosmorsky G.S.
      • Prayson R.A.
      • et al.
      Optic neuropathy and stroke secondary to invasive Aspergillus in an immunocompetent patient.
      ].
      Table 1Comparison of current case with previous case reports.
      Author, YearAge and GenderUnderlying PathologyOrganismImmune status mentionedTreatmentOutcome
      Dyken ME et al. 1990
      • Dyken M.E.
      • Biller J.
      • Yuh W.T.C.
      • Fincham R.
      • Moore S.A.
      • Justin E.
      Carotid-cavernous sinus thrombosis caused by Aspergillus fumigatus: magnetic resonance imaging with pathologic correlation. A case report.
      73 years/MaleSphenoid sinusitisAspergillus fumigatusOn oral steroids for temporal arteritis, diabetesSphenoidotomy and intravenous amphotericin BDeath
      Chandra S et al. 2000
      • Chandra S.
      • Goyal M.
      • Mishra N.K.
      • Gaikwad S.B.
      Invasive aspergillosis presenting as a cavernous sinus mass in immunocompetent individuals; report of 3 cases.
      40, 42 and 34 years (all females)Sinusitis (ethmoidal and sphenoidal in two and maxillary in one), mastoiditis in one and osteomyelitis and focal meningitis in oneAspergillus fumigatus in all 3 casesNot on immunosuppression, no diabetes or HIV infection in any of the 3 casesNKNK
      Arora V et al. 2010
      • Arora V.
      • Nagarkar N.M.
      • Dass A.
      • Dash A.
      • Kaur R.
      Fungal Cerebral Embolic Infarction by Rhino-Orbitocranial Aspergillosis.
      18 years/MaleMaxillary, ethmoidal and sphenoidal sinusitisAspergillusNo diabetes, HIV infection, immunosuppressionIntravenous amphotericin BDeath
      Neil JA et al. 2015
      • Hersh C.M.
      • John S.
      • Subei A.
      • Willis M.A.
      • Kosmorsky G.S.
      • Prayson R.A.
      • et al.
      Optic neuropathy and stroke secondary to invasive Aspergillus in an immunocompetent patient.
      69 years/MaleSinusitisAspergillus fumigatusImmunocompetentOral voriconazole, cavernous sinus resection with external carotid artery and middle cerebral artery bypassRecovery
      Brenet E et al. 2016
      • Neil J.A.
      • Orlandi R.R.
      • Couldwell W.T.
      Malignant fungal infection of the cavernous sinus: case report.
      75 years/MaleSphenoidal sinusitisAspergillus fumigatusImmunocompetentOral voriconazole, endoscopic sphenoidotomyRecovery
      Current case12 years/FemaleOrbital cellulitisAspergillus flavusImmunocompetentOral voriconazole, endoscopic sinus debridementRecovery
      (NK: Not Known, HIV: Human Immunodeficiency Virus).
      Although, any putative risk factor for invasive aspergillosis was not present in this case, early identification and institution of appropriate antimicrobial therapy led to complete recovery, despite high mortality rates cited in literature. The current case highlights the importance of early isolation of causative pathogen in invasive infections, particularly when there is no clinical response to conventional antimicrobials.

      Acknowledgement

      None.

      Funding source

      None.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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