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Clinical Neurology and Neurosurgery 113 (2011) 104–106

Contents lists available at ScienceDirect

Clinical Neurology and Neurosurgery

journa l homepage: www.e lsev ier .com/ locate /c l ineuro

eurological involvement in patients with falciparum malaria;requency and prognostic value

ohammad Wasaya,∗, Asif Taqib, Huma Azizc, Iqbal Azamd, M. Asim Bege

Department of Neurology/Medicine, Aga Khan University, Stadium Road, Karachi 74800, PakistanDepartment of Neurology, University of Tennessee, Memphis, TN, USADepartment of Internal Medicine, University of Tennessee, Memphis, TN, USADepartment of Community Health Sciences, Aga Khan University, Karachi, PakistanDepartment of Pathology and Microbiology, Aga Khan University, Karachi, Pakistan

r t i c l e i n f o

rticle history:eceived 24 August 2009eceived in revised form5 September 2010ccepted 22 September 2010

eywords:alaria

erebralalciparumeizures

a b s t r a c t

Objective: The objective of this study was to evaluate the prognostic significance of neurological mani-festations in falciparum malaria.Methods: We analyzed adult patients with malaria admitted from 2001 to 2003, diagnosed by asexualforms of Plasmodium falciparum in peripheral blood films and identified cases of malaria with neurologicalinvolvement. A patient was classified as having neurological involvement if they reported or had one ormore of the following symptoms; headache, altered mental status, seizures, neck rigidity, brisk reflexes,cranial neuropathy and hyper or hypotonia.Results: A total of 454 patients were included in the study. Out of these, 123 (27%) were diagnosed ascomplicated (severe) malaria and 331 (73%) as uncomplicated malaria at admission. Overall 70 (15.4%)patients had evidence of neurological involvement at initial evaluation. Twenty-seven patients out of123 (22%) with complicated malaria and 43 patients out of 331 (13%) with uncomplicated malaria hadneurological involvement. Over all, 16 (4%) patients died, 13 (11%) had complicated malaria (n = 123)

and 3 (1%) had uncomplicated malaria (n = 381). Mortality in patients having neurological involvement(n = 70) was 9 (13%) as compared to 7 (2%) in patients with malaria having no neurological involvement(n = 384). This difference was statistically significant (p = 0.012). Seizure was identified as predictor ofmortality on Univariate analysis [OR 5.091 (1.835–14.121)].Conclusion: Fifteen percent of patients with falciparum malaria admitted to our hospital had neurologicalsymptoms and neurological involvement was associated with increased mortality.

. Introduction

Malaria is a common parasitic infection worldwide affecting 5%f the world’s population at any time [1]. More than two billioneople are exposed to Plasmodium falciparum in malaria endemicreas translating into 515 million malaria episodes and more thanne million malaria-related deaths each year [2].

Neurological involvement in falciparum malaria is well knownnd usually manifests as altered mental status, psychosis, seizures,

ocal deficits and coma [3,4]. The term cerebral malaria has longeen used in literature to describe any CNS disturbance in malar-

al infection. However a stricter case definition for cerebral malariaas suggested in the 1980s, defining cerebral malaria as a deep

∗ Corresponding author. Tel.: +92 21 4930051x4665/4681; fax: +92 21 4934294.E-mail addresses: mohammadwasay@hotmail.com,

ohammad.wasay@aku.edu (M. Wasay).

303-8467/$ – see front matter © 2010 Elsevier B.V. All rights reserved.oi:10.1016/j.clineuro.2010.09.010

© 2010 Elsevier B.V. All rights reserved.

level of unconsciousness in the presence of Plasmodium falciparumparasites, after exclusion of hypoglycemia, renal failure, sepsis,meningitis and other metabolic disturbances [5,6]. Coma in patientswith falciparum malaria is typically divided into two types; cerebralmalaria and secondary encephalopathy due to sepsis, renal failureand metabolic disturbances. One study looked at more than 19,000children with falciparum malaria, neurological involvement wasseen in 47.6% of children and manifested as seizures (37.5%), agi-tation (2.8%), prostration (20.6%), and impaired consciousness orcoma (13.2%) [7]. Others found 2.4% prevalence of cerebral malariaamong travelers with falciparum malaria [8].

In our clinical practice we observed that a number of patientslabeled as uncomplicated malaria had neurological symptoms and

brain involvement on neuroimaging. These patients could possiblyrepresent mild or early forms of cerebral malaria. Prognostic valueof neurological manifestations in uncomplicated malaria patientsis not well known. Thus the objective of our study was to deter-mine neurological manifestations of falciparum malaria in adults

M. Wasay et al. / Clinical Neurology and N

Table 1Neurological symptoms in patients with falciparum malaria (n = 70).

Variable Complicatedmalaria (n = 123)

Uncomplicatedmalaria (n = 331)

P-value

Patients with neurologicalsymptoms

27 (22%) 43 (13%) 0.9

Mental statusComa 14 (11%) 0Stupor 4 9 0.18Drowsiness 9 31 (10%) 0.06Confusion 0 3Headache 13 (10%) 23 (8%) 0.10Seizures 4 0

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malaria on admission (Table 1). Overall, 16 (4%) patients died of

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Neck rigidity 18 (15%) 9 0.16Brisk reflexes 12 (10%) 53 (16%) 0.05

nd evaluate the prognostic value of early neurological manifes-ations particularly in patients who presented as uncomplicated

alaria.

. Methods

A retrospective chart review of 454 adult patients with con-rmed diagnosis of falciparum malaria admitted from 2001 to003 at Aga Khan University Hospital, Karachi was undertaken.he Charts were identified by ICD-9 coding system. The diagnosisas confirmed by presence of asexual forms of Plasmodium falci-

arum in peripheral blood films. Patients with organ dysfunctionrenal failure, jaundice, pulmonary edema, coma, convulsions, andevere anemia) were labeled as complicated malaria (WHO guide-ines 2006).

Data was extracted from patients’ charts. Our Hospital uses atandardized Performa (admission form) which includes completeistory, review of systems, physical examination findings, initial

aboratory and radiological evaluation, provisional and differen-ial diagnosis, diagnostic and therapeutic plan and attending notes.

e reviewed all patients with falciparum malaria. Patients wereivided in two groups: complicated and uncomplicated malariaased on established criteria. Patients with falciparum malariare routinely admitted including uncomplicated cases for observa-ion as they can progress into complicated malaria. Additionally,ll patients were divided in two groups based on presence or

bsence of neurological symptoms (headache, altered mental sta-us, seizures, neck rigidity, brisk reflexes, cranial neuropathy andyper or hypotonia).

able 2omparison of patients with and without neurological symptoms.

Variables Patients with neurological involvement (n = 70)

Age (mean) years 44 ± 29Male sex 45 (65%)Complicated malaria 27 (39%)Uncomplicated malaria 43 (61%)Outcome, death 9 (13%)

able 3nivariate analysis of prognostic factors for mortality in falciparum malaria patients.

Survivors n = 438 (%) Died n =

Neck rigidity 21 (5) 6 (37)Seizures 1 3 (22)Headache 31 (7) 5 (30)Brisk reflexes 63 (13) 2 (10)Comatose 11 (3) 3 (21)Male sex 286 (65) 12 (75)

eurosurgery 113 (2011) 104–106 105

3. Results

A total of 454 patients were included in the study. Out of these,123 (27%) were diagnosed as complicated (severe) malaria and 331(73%) as uncomplicated malaria on admission. Overall 70 (15.4%)patients had evidence of neurological involvement at initial evalu-ation. Twenty-seven patients out of 123 (22%) with complicatedmalaria and 43 patients out of 331 (13%) with uncomplicatedmalaria had neurological involvement.

Demographic features, presentation and laboratory and imag-ing findings of these 70 patients with neurological symptoms wereas follows. Age range was 15–80 years (mean 44 ± 29 years). Forty-five (65%) were males. Mental status changes were present in allpatients and included coma in 14 (20%) patients, stupor in 13(19%) patients, drowsiness in 40 (59%) patients and confusion in3 (3%) patients. Other presenting neurological symptoms includedheadache in 13 (19%) patients and seizures in 4 (6%) patients.None of the patients presented with hemiparesis. Other findingsincluded neck rigidity in 18 (27%) patients, brisk reflexes in 12(16%) patients, hypertonia in 8 (11%) patients, bilateral up goingplantar responses in 6 (9%) patients and cranial nerve palsies in 3(5%) patients (Table 1). Sixteen patients (23% of those with neu-rological involvement) had CSF studies done. CSF was abnormalin 10 patients with average protein 41.9 mg/dL, average glucose81.9 mg/dL and average WBC’s 5.6 cells per cubic millimeter. Noneof these CSF samples showed organisms on staining or routine bac-terial cultures. CSF PCR done for HSV was sent for a few patientsonly and all results were negative. Twenty-one patients (30%) hadCT scans and 9 patients (13%) had MRI Brain scans. CT scan find-ings included normal (67%), diffuse cerebral edema (19%), infarcts(9%) and inter hemispheric hemorrhage (5%). MRI scan findingsincluded normal in 6 (55%) patients, diffuse cerebral edema in 1(11%) patient, hyper intense signals in corona radiata and centrumsemiovale on T2 and FLAIR images in 1 (11%) patient and hemor-rhages in 1 (11%) patient. EEG was performed in 13 (19%) patientsshowing diffused slowing in 77% of patients while 23% had normalEEGs.

Non-neurological features in patients with falciparum malariaincluded fever (97%), generalized weakness (67%), dehydration(61%), vomiting (45%), myalgia (42%), respiratory distress (38%) andabdominal pain (19%). Twenty-seven (39%) patients had compli-cated malaria and 43 patients (61%) were labeled as uncomplicated

which 13 (11%) were in the complicated malaria (n = 123) group and3 (1%) were in the uncomplicated malaria (n = 381) group. Mortalityin patient having neurological involvement (n = 70) was 9 (13%) as

Patients without neurological involvement (n = 384) P value

46 ± 30 0.10242 (63%) 0.679

96 (25%) 0.09288 (75%) 0.087

7 (2%) 0.012

16 (%) Odd ratio [95% CI] P value

1.997 (0.556–7.169) 0.0445.091 (1.83–14.12) 0.0131.588 (0.629–4.009) 0.050.29 (0.09–0.96) 0.112.19 (0.65–8.86) 0.181.476 (0.682–3.193) 0.05

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ompared to 7 (2%) in patients with malaria having no neurologicalnvolvement (n = 384). This difference was statistically significantp = 0.012) (Table 2). Seizure; OR 5.091 (1.835–14.121) was identi-ed as predictor of mortality on univariate analysis (Table 3).

. Discussion

Prognosis for adult cerebral malaria is known with mortalityates ranging from 20 to 25%. However, prognosis for patients withalaria and toxic, metabolic encephalopathy ranges from 30 to

0% [9]. Multiple prognostic factors have been identified includingespiratory distress, circulatory failure, hyporeflexia, high parasiteoad, coma, severe anemia and renal failure [10,11]. Neurologi-al and renal dysfunction were most important predictors of poorrognosis in one study [12].

Prognostic factors for severe (complicated) malaria and cerebralalaria are well reported. Multiple scoring systems demonstrating

xtent and severity of organ dysfunction in complicated malariaave been validated. Acidosis and cerebral malaria are identifieds main independent predictors of outcome [13]. Age was identi-ed as an independent risk factor for fatal outcome in falciparumalaria though incidence of anemia and seizures decrease with age

mong these patients [14]. Multiple convulsions at admission aressociated with neurological sequelae among children [10].

Little information is available on prognostic factors in patientsith uncomplicated malaria. A study from Thailand reported that

% patients with uncomplicated malaria progressed to complicatedalaria. This study found that parasitemia and dehydration to

e important predictors of progression [15]. We believe that it ismportant to identify these patients who present as uncomplicated

alaria and then progress to complicated malaria. Findings ofur study indicate that neurological involvement in patients withalciparum malaria predicted increased likelihood of mortalityspecially in complicated malaria group. Mortality was so low inhe uncomplicated malaria group that we were unable to identifyredictors of mortality in this group. Presence of headache, neckigidity and seizure in an otherwise uncomplicated malaria patientay represent early forms of cerebral malaria and potential for

rogression into severe or complicated malaria. Predictive value ofhese factors is however limited by wide confidence intervals withittle allowance for confounders. This is largely attributable to low

ortality in the presence of number of confounding variables ands a limitation in our study. These findings have to be confirmedn prospective studies with a larger number of patients. Currentefinition of cerebral malaria is only useful for prognosis andxcludes number of potentially treatable cases with early orilder forms of cerebral malaria. We strongly recommend that

efinition of cerebral malaria should include milder cases or earlyorms of cerebral malaria.

Most patients with neurological dysfunction did not undergoeuroimaging or CSF analysis. CSF analyses were performed to

dentify patients with co-existing meningitis but staining and cul-ures were negative for bacterial infection in all patients. The rolend yield of CSF analysis in these patients should be evaluated inrospective studies. CT/MRI (done in 43% patients) findings and CSFbnormalities (done in 23% patients) were not significant predictors

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eurosurgery 113 (2011) 104–106

of mortality on univariate analysis. Prognostic value of combinedheadache, neck rigidity, seizure abnormal CSF and abnormal MRImay be valuable in future studies with more extensive work upamong these patients.

Acknowledgements

These findings were presented in a preliminary form at theAmerican Neurological association meeting in Salt Lake City, Utahin 2006. Authors are grateful to Andreas Martensson (KarolinskaInstitute, Stockholm, Sweden) and Faisal Mahmood (Aga Khan Uni-versity) for manuscript review and suggestions.

Financial disclosure statement: Authors have nothing to disclosein terms of financial relationships or interests.

Funding: Study was supported by Department of Medicine, AgaKhan University.

Conflicts of interest: None disclosed.Contributors: Mohammad Wasay, MBBS, MD, FRCP, contributed

to study concept, design, data analysis and manuscript writing, AsifTaqi, MBBS, MD, and Huma Aziz, MBBS, MD, data acquisition, dataanalysis and manuscript writing and Iqbal Azam, MSc, and M. AsimBeg, MBBS, PhD, data analysis and manuscript writing.

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