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    Brain magnetic resonance imaging (fluid attenuation inversion recovery) and magnetic resonance angiography (MRA) findings. Brain MRA (time-of-flight angiography) findings on the 6th day of illness (A) reveal the narrowing of multiple cerebral arteries, indicated by a white arrowhead. On day 40 of illness (B), the arterial narrowing had improved, but diffuse cerebral atrophy had mildly progressed. (a) Right anterior communicating artery; (b) right internal carotid artery; (c) left anterior communicating artery; and (d) left internal carotid artery.

  • 1.

    Idro R, Marsh K, John CC, Newton CR, 2010. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res 68: 267274.

    • Search Google Scholar
    • Export Citation
  • 2.

    Dugbartey AT, Spellacy FJ, Dugbartey MT, 1998. Somatosensory discrimination deficits following pediatric cerebral malaria. Am J Trop Med Hyg 59: 393396.

    • Search Google Scholar
    • Export Citation
  • 3.

    Hawkes M, Elphinstone RE, Conroy AL, Kain KC, 2013. Contrasting pediatric and adult cerebral malaria: the role of the endothelial barrier. Virulence 4: 543555.

    • Search Google Scholar
    • Export Citation
  • 4.

    Miller TR, Shivashankar R, Mossa-Basha M, Gandhi D, 2015. Reversible cerebral vasoconstriction syndrome, part 1: epidemiology, pathogenesis, and clinical course. AJNR Am J Neuroradiol 36: 13921399.

    • Search Google Scholar
    • Export Citation
  • 5.

    Eisenhut M, 2015. The evidence for a role of vasospasm in the pathogenesis of cerebral malaria. Malar J 14: 405.

  • 6.

    Lindegaard K-F, Nornes H, Bakke SJ, Sorteberg W, Nakstad P, 1989. Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements. Acta Neurochir (Wien) 100: 1224.

    • Search Google Scholar
    • Export Citation
  • 7.

    John CC, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, Wu B, Boivin MJ, 2008. Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics 122: e92e99.

    • Search Google Scholar
    • Export Citation
  • 8.

    Varney NR, Roberts RJ, Springer JA, Connell SK, Wood PS, 1997. Neuropsychiatric sequelae of cerebral malaria in Vietnam veterans. J Nerv Ment Dis 185: 695703.

    • Search Google Scholar
    • Export Citation
  • 9.

    Carter JA, Mung’ala-Odera V, Neville BG, Murira G, Mturi N, Musumba C, Newton CR, 2005. Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children. J Neurol Neurosurg Psychiatry 76: 476481.

    • Search Google Scholar
    • Export Citation
  • 10.

    Holding PA, Stevenson J, Peshu N, Marsh K, 1999. Cognitive sequelae of severe malaria with impaired consciousness. Trans R Soc Trop Med Hyg 93: 529534.

    • Search Google Scholar
    • Export Citation
  • 11.

    Carter JA, Lees JA, Gona JK, Murira G, Rimba K, Neville BG, Newton CR, 2006. Severe falciparum malaria and acquired childhood language disorder. Dev Med Child Neurol 48: 5157.

    • Search Google Scholar
    • Export Citation
  • 12.

    John CC, Panoskaltsis-Mortari A, Opoka RO, Park GS, Orchard PJ, Jurek AM, Idro R, Byarugaba J, Boivin MJ, 2008. Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg 78: 198205.

    • Search Google Scholar
    • Export Citation
  • 13.

    Potchen MJ 2012. Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease. AJNR Am J Neuroradiol 33: 17401746.

    • Search Google Scholar
    • Export Citation
  • 14.

    Looareesuwan S, Wilairatana P, Krishna S, Kendall B, Vannaphan S, Viravan C, White NJ, 1995. Magnetic resonance imaging of the brain in patients with cerebral malaria. Clin Infect Dis 21: 300309.

    • Search Google Scholar
    • Export Citation
  • 15.

    Hajj-Ali RA, Calabrese LH, 2014. Diagnosis and classification of central nervous system vasculitis. J Autoimmun 48–49: 149152.

  • 16.

    Milner DA Jr, Whitten RO, Kamiza S, Carr R, Liomba G, Dzamalala C, Seydel KB, Molyneux ME, Taylor TE, 2014. The systemic pathology of cerebral malaria in African children. Front Cell Infect Microbiol 4: 104.

    • Search Google Scholar
    • Export Citation
  • 17.

    Ducros A, 2012. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 11: 906917.

  • 18.

    Mohanty S 2017. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the brain. mSphere, 2: doi: 10.1128/mSphere.00193-17.

    • Search Google Scholar
    • Export Citation
  • 19.

    Newton CR, Marsh K, Peshu N, Kirkham FJ, 1996. Perturbations of cerebral hemodynamics in Kenyans with cerebral malaria. Pediatr Neurol 15: 4149.

    • Search Google Scholar
    • Export Citation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Case Report: Reversible Cerebral Vasoconstriction Syndrome in Cerebral Malaria

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  • 1 Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan;
  • 2 Department of Tropical Medicine and Malaria, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan;
  • 3 Department of Rehabilitation Medicine, Jikei University School of Medicine, Tokyo, Japan

Cerebral malaria is a severe complication of falciparum malaria that occurs infrequently in adults. Here, we describe the case of a 21-year-old man who presented with fever and headache 13 days after returning from a 12-day trip to Kenya and was subsequently diagnosed with falciparum malaria. Complications of cerebral malaria developed within 1 day after the initiation of therapy with intravenous quinine, and the patient entered a deep coma. Magnetic resonance angiography (MRA) revealed multiple vasoconstrictions in his brain. The resulting neurocognitive disorders that persisted after parasite clearance improved gradually, as confirmed by MRA, enabling the patient to perform activities of daily living upon discharge. In this case of cerebral malaria, the MRA findings indicated the involvement of reversible cerebral vasoconstriction syndrome.

INTRODUCTION

Cerebral malaria is a severe complication of falciparum malaria that occurs more frequently in children than in adults. Although among adults, the rates of mortality attributable to cerebral malaria are equal to or higher than those in children, the incidence of neurological sequelae in adults is considered very low.13 These rare sequelae of adult cerebral malaria mainly include motor dysfunctions rather than cognitive ones.2 Here, we describe a patient with cerebral malaria who exhibited cognitive sequelae. Magnetic resonance angiography (MRA), which has not usually been performed for cases of cerebral malaria, revealed multiple vasoconstrictions that improved after the treatment of Plasmodium falciparum malaria. These MRA findings suggest an association of reversible cerebral vasoconstriction syndrome (RCVS)4 with malaria. Previous arterial tonometry and increased cerebral blood flow velocity findings indicate a potential association of arterial vasospasm with cerebral malaria.5,6 To our best knowledge, this case is the first reported case of falciparum malaria with RCVS, and our findings support the occurrence of cerebral artery vasospasm in cerebral malaria.

CASE REPORT

An otherwise healthy 21-year-old Asian man complained of fever and headache 13 days after traveling to Kenya and was subsequently referred and admitted to our hospital in April. He had only received a yellow fever vaccine in Japan and had not used a prophylactic agent for malaria or preventive measures apart from a mosquito net during his 12-day visit to the Kisumu Province of Kenya, near Lake Victoria. He had previously been admitted to another hospital on day 3 of his illness. He was referred to our hospital on day 5 of his illness with suspected falciparum malaria.

The patient presented with a low-grade fever, tachypnea, and severe lethargy but remained alert. He also had mild jaundice, facial edema, throbbing pain in the right hypochondriac region, and an enlarged spleen. Hematological investigations revealed the following: white blood cell count, 11.2 × 103 cells/μL; hemoglobin level, 12.4 g/dL; and platelet count, 48 × 103/μL. The total bilirubin level was slightly elevated to 1.6 mg/dL (reference range, 0.3–1.2 mg/dL), the lactate dehydrogenase level was elevated to 999 IU/L (reference range, 119–229 IU/L), and the C-reactive protein level was elevated to 12.0 mg/dL (reference range, 0–0.3 mg/dL). His renal function was within the normal limits. Arterial blood gas analysis revealed a pH of 7.44, pCO2 of 32 mm of Hg, HCO3 of 21.7 mEq/L, and lactic acid level of 4.3 mmol/L. A microscopic blood smear examination confirmed the presence of P. falciparum (parasitemia, 21.7%).

We started intravenous quinine (Quinimax®, Ambarès, France) therapy with a loading dose of 16 mg base/kg and 8-mg quinine base/kg doses every 8 hours thereafter. This agent was unlicensed in Japan and was provided under a clinical trial after receiving informed consent from the patient and his parents. The next morning, he suddenly presented with deep coma, decorticate rigidity, hyperreflexia, and a bilateral Babinski reflex. We excluded brain hemorrhage, bacterial meningitis, severe bacterial sepsis, uremia, and hypoglycemia based on a blood test, arterial blood gas analysis, brain computed tomography findings, and cerebrospinal fluid and blood bacterial cultures. Electroencephalography showed only a slow wave, with no spike wave suggestive of a subclinical seizure. He was diagnosed with cerebral malaria. Brain magnetic resonance imaging (MRI) and MRA on the 6th day of the illness revealed narrowing and dilatation in multiple cerebral arteries (Figure 1A). No lesion suggested malaria retinopathy.

Figure 1.
Figure 1.

Brain magnetic resonance imaging (fluid attenuation inversion recovery) and magnetic resonance angiography (MRA) findings. Brain MRA (time-of-flight angiography) findings on the 6th day of illness (A) reveal the narrowing of multiple cerebral arteries, indicated by a white arrowhead. On day 40 of illness (B), the arterial narrowing had improved, but diffuse cerebral atrophy had mildly progressed. (a) Right anterior communicating artery; (b) right internal carotid artery; (c) left anterior communicating artery; and (d) left internal carotid artery.

Citation: The American Journal of Tropical Medicine and Hygiene 98, 2; 10.4269/ajtmh.17-0665

Although the parasitemia was cleared within 4 days after starting treatment, the patient became afebrile after 7 days and developed mild hemolysis without acute kidney injury. We discontinued each of quinine gluconate and clindamycin up to 7 days. On day 12 of illness, the patient became afebrile and could open his eyes upon hearing his name. After discontinuing the antimalarial agents, the patient kept his eyes open without stimulation, but found it difficult to communicate with others and to walk independently. Rehabilitation improved both his physical and brain dysfunctions (Table 1). Although the MRA findings of vasoconstriction disappeared, mild diffuse cerebral atrophy progressed on day 40 of illness (Figure 1B), and he was transferred to a rehabilitation hospital for the residual cognitive disorder. Single-photon emission computed tomography (SPECT) of the brain yielded almost normal findings at approximately 2 months after treatment. Even now, the patient continues to receive physical and occupational rehabilitation to improve the cognitive sequelae that interfere with his daily life.

Table 1

Clinical course of the patient’s neurocognitive symptoms

Day of illnessNeurological and neuropsychological findings
1st weekPresents in a deep coma with muscle stiffness
2nd weekOpens eyes to verbal commands and makes meaningless vocal sounds
3rd weekSpeaks short words, is unable to communicate, is restless, and requires restraints
4th weekAnswers simple questions and greetings, is orientated to place and people, forgets some proper names, and cannot remain standing
5th weekDisplays careless behavior and walks using a walker
Trail Making Test (A), 513 seconds (normal, 66.9 ± 15.4 seconds)
6th weekUses a mobile phone and reads books, walks independently, and answers complicated questions
7th–8th weekWAIS-III Verbal IQ, 91; Performance IQ, 57 (with especially low scores in sensory integration and processing speed)
Trail Making Test (A), 136 seconds
WMS-R Verbal, 109; Visual, 73; General, 98; Attention, 69; and Delay, 100
10th monthWAIS-III Verbal IQ, 116 and; Performance IQ, 115
WMS-R Verbal, 112; Visual, 108; General, 112; Attention, 104; and Delay, 114

WAIS = Wechsler adult intelligence scale; WMS-R = Wechsler memory scale-revised.

DISCUSSION

In the present case, the patient experienced brain damage and a sustained cognitive disorder from severe cerebral malaria. The MRA findings, which are rarely obtained in such cases, indicated RCVS.4 Both adults and children may develop late-onset neurocognitive disorders after cerebral malaria.7,8 One prospective and two retrospective studies reported cognitive impairment rates of 14–25% among children.7,9,10 Another study reported that 11.8% of children who survived cerebral malaria reportedly acquired a language disorder.11 Although these neurocognitive disorders are common in children, they comprise a rare complication of cerebral malaria in adults.13 However, it remains unclear why this complication is more common in children, although neurocognitive disorders have been associated with tumor necrosis factor expression in the cerebrospinal fluid.12

Several case reports and case series describe the MRI findings of cerebral malaria. Potchen et al.13 reported the MRI findings of cerebral malaria in 120 children with malaria retinopathy. In that study, basal ganglia involvement was the most common finding and was present in 101 of 120 patients (84.2%), followed by white matter, thalamic, cortical, corpus callosum, posterior fossa, and pontine involvement in descending order. Conversely, in a previous report of adult patients, an increased brain volume was the most common MRI finding (22/24).14 During the acute phase, the MRA findings of our patient showed multifocal segmental narrowing of the cerebral arteries, suggestive of either central nervous system vasculitis (CNSV)15 or RCVS.4 CNSV occurs as a secondary complication in association with autoimmune rheumatic diseases, systemic vasculitis, or infection with varicella zoster virus, human immunodeficiency virus, herpes simplex virus, or fungal organisms. No previous report has described malaria-induced CNSV or presented histopathological evidence of cerebral vessel infiltration by inflammatory cells in the case of cerebral malaria.16 The MRI findings of cerebral parenchymal abnormalities are very common with CNSV, and these imaging-detected cerebrovascular abnormalities are frequently irreversible.15 To our knowledge, no other report has described cerebral vasoconstriction detected by MRA in the case of cerebral malaria. Given the reversibility of the cerebral abnormalities in the present case of cerebral malaria, the MRA findings were more likely due to RCVS.

RCVS has been defined as uniphasic, reversible, multiple cerebral artery vasoconstriction without aneurysm; this condition was associated with a thunderclap headache and triggered by various causes.4 Although the pathogenesis of RCVS is poorly understood, the suspected cause involved the deregulation of the cerebral vascular tone in response to sympathetic hyperactivity, endothelial dysfunction, and oxidative stress.4 As with RCVS, posterior reversible encephalopathy syndrome (PRES) involves changes in the cerebral vascular tone and endothelial dysfunction,4,17 and the clinical and radiographic features of these two entities overlap. Regarding the latter feature, the reversible multifocal cerebral vasoconstriction usually seen in cases of RCVS has also been identified in more than 85% of patients with PRES.17 Mohanty et al.18 reported that in 40.7% of patients with nonfatal cerebral malaria, brain MRI indicated findings of PRES or PRES-like vasogenic edema. Although RCVS was not described in this literature, it, like PRES, may be associated with cerebral malaria. Although the previously described finding of PRES was not noted in our case (Figure 1), such findings may depend on the timing of MRI, as almost all findings of PRES or PRES-like lesions in cerebral malaria patients were reported to improve within 48–72 hours.18

Although the pathogenesis of cerebral malaria may be associated with microcirculation dysfunction, damage to the blood–brain barrier, and the effects of cytokines, vasoconstriction of the great cerebral artery might also be involved. In addition, P. falciparum-parasitized red blood cells (RBCs), which adhere strongly to endothelial cells and causes endothelial dysfunction, play a key role.1 Indirect evidence of this vasoconstriction has been reported, although to our best knowledge, there is no report of imaging findings of arterial vasoconstriction related to cerebral malaria. Newton et al.19 reported that 15 of 50 children with cerebral malaria exhibited increased cerebral blood flow velocity suggestive of a narrowed vessel diameter.6 The concept of vasospasm in cerebral malaria was further supported by the following observations. These include the rapid reversal of coma and neurological deficits against a vascular obstruction; the findings of unilateral asymmetrical hemispheric changes on MRI and transient hemispheric changes on SPECT in some patients, which were described in some cases as a transient vasospasm in a large supplying artery; the observation of fatal cerebral malaria features without parasitized RBC sequestration or thrombi in the cerebral blood vessels on autopsy; and reactive hyperemia peripheral arterial tonometry exhibiting changes during malaria that were compatible with changes of nitric oxide bioavailability, which could predispose to and cause vasospasm.5

In conclusion, RCVS might be involved in cerebral malaria. As this report describes a single case, further case series or studies are needed to prove the association between the findings of vasoconstriction and cerebral malaria, especially in cases involving subsequent neurocognitive disorders.

Acknowledgment:

We are deeply grateful to Dr. Tomoyuki Noguchi of the Department of Radiology, National Center for Global Health and Medicine for his expert advice on the radiological findings.

REFERENCES

  • 1.

    Idro R, Marsh K, John CC, Newton CR, 2010. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res 68: 267274.

    • Search Google Scholar
    • Export Citation
  • 2.

    Dugbartey AT, Spellacy FJ, Dugbartey MT, 1998. Somatosensory discrimination deficits following pediatric cerebral malaria. Am J Trop Med Hyg 59: 393396.

    • Search Google Scholar
    • Export Citation
  • 3.

    Hawkes M, Elphinstone RE, Conroy AL, Kain KC, 2013. Contrasting pediatric and adult cerebral malaria: the role of the endothelial barrier. Virulence 4: 543555.

    • Search Google Scholar
    • Export Citation
  • 4.

    Miller TR, Shivashankar R, Mossa-Basha M, Gandhi D, 2015. Reversible cerebral vasoconstriction syndrome, part 1: epidemiology, pathogenesis, and clinical course. AJNR Am J Neuroradiol 36: 13921399.

    • Search Google Scholar
    • Export Citation
  • 5.

    Eisenhut M, 2015. The evidence for a role of vasospasm in the pathogenesis of cerebral malaria. Malar J 14: 405.

  • 6.

    Lindegaard K-F, Nornes H, Bakke SJ, Sorteberg W, Nakstad P, 1989. Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements. Acta Neurochir (Wien) 100: 1224.

    • Search Google Scholar
    • Export Citation
  • 7.

    John CC, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, Wu B, Boivin MJ, 2008. Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics 122: e92e99.

    • Search Google Scholar
    • Export Citation
  • 8.

    Varney NR, Roberts RJ, Springer JA, Connell SK, Wood PS, 1997. Neuropsychiatric sequelae of cerebral malaria in Vietnam veterans. J Nerv Ment Dis 185: 695703.

    • Search Google Scholar
    • Export Citation
  • 9.

    Carter JA, Mung’ala-Odera V, Neville BG, Murira G, Mturi N, Musumba C, Newton CR, 2005. Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children. J Neurol Neurosurg Psychiatry 76: 476481.

    • Search Google Scholar
    • Export Citation
  • 10.

    Holding PA, Stevenson J, Peshu N, Marsh K, 1999. Cognitive sequelae of severe malaria with impaired consciousness. Trans R Soc Trop Med Hyg 93: 529534.

    • Search Google Scholar
    • Export Citation
  • 11.

    Carter JA, Lees JA, Gona JK, Murira G, Rimba K, Neville BG, Newton CR, 2006. Severe falciparum malaria and acquired childhood language disorder. Dev Med Child Neurol 48: 5157.

    • Search Google Scholar
    • Export Citation
  • 12.

    John CC, Panoskaltsis-Mortari A, Opoka RO, Park GS, Orchard PJ, Jurek AM, Idro R, Byarugaba J, Boivin MJ, 2008. Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg 78: 198205.

    • Search Google Scholar
    • Export Citation
  • 13.

    Potchen MJ 2012. Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease. AJNR Am J Neuroradiol 33: 17401746.

    • Search Google Scholar
    • Export Citation
  • 14.

    Looareesuwan S, Wilairatana P, Krishna S, Kendall B, Vannaphan S, Viravan C, White NJ, 1995. Magnetic resonance imaging of the brain in patients with cerebral malaria. Clin Infect Dis 21: 300309.

    • Search Google Scholar
    • Export Citation
  • 15.

    Hajj-Ali RA, Calabrese LH, 2014. Diagnosis and classification of central nervous system vasculitis. J Autoimmun 48–49: 149152.

  • 16.

    Milner DA Jr, Whitten RO, Kamiza S, Carr R, Liomba G, Dzamalala C, Seydel KB, Molyneux ME, Taylor TE, 2014. The systemic pathology of cerebral malaria in African children. Front Cell Infect Microbiol 4: 104.

    • Search Google Scholar
    • Export Citation
  • 17.

    Ducros A, 2012. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 11: 906917.

  • 18.

    Mohanty S 2017. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the brain. mSphere, 2: doi: 10.1128/mSphere.00193-17.

    • Search Google Scholar
    • Export Citation
  • 19.

    Newton CR, Marsh K, Peshu N, Kirkham FJ, 1996. Perturbations of cerebral hemodynamics in Kenyans with cerebral malaria. Pediatr Neurol 15: 4149.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Kei Yamamoto, Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. E-mail: kyamamoto@hosp.ncgm.go.jp

Financial support: This study was supported in part by research grants from the Emerging/Re-emerging Infectious Diseases Project of Japan from the Japan Agency for Medical Research and Development, AMED (15fk0108046h0003 and 17fk0108209h002).

Authors’ addresses: Kei Yamamoto, Yasuyuki Kato, Koh Shinohara, Satoshi Kutsuna, Nozomi Takeshita, Kayoko Hayakawa, and Norio Ohmagari, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan, E-mails: kyamamoto@hosp.ncgm.go.jp, ykato@hosp.ncgm.go.jp, shinoharakoh@gmail.com, skutsuna@hosp.ncgm.go.jp, nozomitake@gmail.com, khayakawa@hosp.ncgm.go.jp, and nohmagari@hosp.ncgm.go.jp. Moritoshi Iwagami and Shigeyuki Kano, Department of Tropical Medicine and Malaria, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan, E-mails: miwagami@ri.ncgm.go.jp and kano@ri.ncgm.go.jp. Shu Watanabe, Department of Rehabilitation Medicine, Jikei University School of Medicine, Tokyo, Japan, E-mail: shuwata@jikei.ac.jp.

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