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Cranial imaging findings in dengue virus infection
JNS-13156; No of Pages 6 Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Cranial imaging findings in dengue virus infection Sanjeev Kumar Bhoi a, Suprava Naik b, Sunil Kumar b, Rajendra Vishnu Phadke b, Jayantee Kalita a,⁎, Usha Kant Misra a a b
Department of Neurology, Sanjay Gandhi Post Graduate Medical Sciences, Lucknow, India Department of Radiodiagnosis, Sanjay Gandhi Post Graduate Medical Sciences, Lucknow, India
a r t i c l e
i n f o
Article history: Received 3 January 2014 Received in revised form 10 March 2014 Accepted 11 April 2014 Available online xxxx Keywords: Magnetic resonance imaging Computed tomography Dengue encephalitis Dengue encephalopathy Thalamic lesion Basal ganglia
a b s t r a c t Background: The aim of this study is to evaluate cranial CT or MRI changes in dengue encephalitis and their correlation with clinical and biochemical findings. Methods: Twenty-one serologically confirmed patients with dengue with altered sensorium were included who underwent MRI (20)/CT (1) scan study. Their clinical details including seizure, hypotension, bleeding diathesis, focal neurologic deficit, and Glasgow Coma Scale (GCS) score were noted. Blood counts, hematocrit, renal and liver function tests, electrolytes, cerebrospinal fluid (CSF) and ECG were done. MRI findings on T1, T2, FLAIR, DWI and T1 gadolinium contrast were noted. Results: The median age of the patients was 30 (5–69) years and 5 were females. MRI was abnormal in 9(45%) and CT scan in 1 patient with dengue shock syndrome revealed cerebellar and subdural hematoma. The MRI lesions were in thalamic and basal ganglia in 3, focal cortical areas in 3, white mater in 2 and meningeal enhancement in 3 patients. Seven of these patients had CSF pleocytosis. The presence of abnormal imaging was not related to outcome. One patient died, 1 was bed ridden and 19 had complete recovery on discharge. Conclusion: Cranial imaging reveals nonspecific changes and is not related to hematological and biochemical changes or outcome. © 2014 Published by Elsevier B.V.
1. Introduction Dengue is the most important mosquito borne disease after malaria [1]. Its incidence has increased many folds in last half a century. About 4 billion people live in dengue endemic areas of Asia, Africa, Australia, America and Europe [1,2]. Dengue virus is a RNA virus of flaviviridae group and results in dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Dengue virus is a nonneurotropic virus but increasing number of studies on central nervous system (CNS) involvement in dengue virus infection has been reported [3–7]. The neurological involvement in dengue virus infection can occur due to metabolic alteration, such as liver or kidney dysfunction, hyponatremia, hemorrhagic diathesis in the CNS, DSS, hypoxia and hypotension, direct CNS invasion of dengue virus (DENV) producing encephalitis and post infective autoimmune mediated CNS injury [4–6]. Cranial MRI has provided information about the extent and nature of CNS injury in viral infections. There are characteristic MRI changes in viral encephalitis; frontotempoal changes in herpes simplex encephalitis; thalamus, basal ganglia and brain stem involvement in ⁎ Corresponding author at: Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareily Road, Lucknow 226014, India. Tel.: +91 522 2494167; fax: +91 522 2668811. E-mail addresses: [email protected], [email protected] (J. Kalita).
Japanese encephalitis (JE) and eastern equine encephalitis [8–10]. There are few reports of MRI changes in DENV infection and have revealed a wide variety of changes such as intra cerebral hemorrhage and thalamic, basal ganglia, cortical and sub cortical involvement [6, 11–15]. In the dengue endemic area, JE or other viral encephalitis are also prevalent; hence these MRI changes need to be critically evaluated. Prospective MRI studies using different sequences may help not only in localizing the abnormality but may also shed light on the underlying pathology, such as necrosis, edema, haemorrhage and demyelinating features. In the present study, we report the MRI/CT findings in patients with DENV infections and correlate these with their clinical and laboratory findings. 2. Material and methods The patients with abnormal cranial imaging (CT/MRI) were prospectively evaluated from our dengue registry maintained since 2003. The diagnosis of dengue encephalopathy was based on signs and symptoms of acute encephalitic syndrome with the presence of dengue antigen (NS1) and/or IgM antibody against dengue virus in serum. Patients with malaria, Leptospira, Chikungunya, JE, herpes simplex virus (HSV) encephalitis and Epstein Barr virus encephalitis were excluded. The patients were subjected to detailed clinical evaluation. The presence of fever, headache, vomiting, bleeding diathesis, hypotension, jaundice,
http://dx.doi.org/10.1016/j.jns.2014.04.018 0022-510X/© 2014 Published by Elsevier B.V.
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Fig. 1. Pt #1: Cranial MRI T2W (a) and FLAIR (b) image show areas of increased signal intensities in bilateral thalami. Same lesions appear hyperintense on DWI (c), and subtle hyperintensity was also appreciated in bilateral globi palidii in DWI. Lesions are hypointense on T1WI (d). Post contrast T1 (e) reveals meningeal enhancement.
oliguria and seizures were recorded. The level of consciousness was assessed by Glasgow Coma Scale (GCS) [16]. The presence of papilledema and cranial nerve palsy was noted. Muscle weakness (hemiplegia or quadriplegia) were graded into mild (MRC grade IV), moderate (MRC grade III-II) and severe (MRC grade I-0). Muscle tone and tendon reflex were noted. Sensations and cerebellar signs were tested in the patients who could cooperate. The presence of meningeal signs, chest rales, hepatosplenomegaly and cardiac abnormality were noted. 2.1. Investigations Blood counts, hemoglobin, activated partial thromboplastin time, prothrombin time, blood sugar, blood urea nitrogen (BUN), serum creatinine, bilirubin, transaminases, creatinine kinase (CK), sodium, potassium and calcium were done. Chest radiograph and ECG were carried out. Dengue antigen (NS1) and IgM antibody against dengue virus were tested in serum in all and in CSF in some patients by enzyme linked sorbent assay (ELISA). The diagnosis of JE was excluded by negative CSF IgM ELISA, and Leptospira and Chikungunya by serum IgM ELISA. Peripheral smear was examined for malarial parasite. Cerebrospinal fluid analysis was done when platelet count was N40,000/mm3and also examined for cells, protein and sugar. 2.2. Cranial imaging Cranial MRI was carried out using 3T Signa GE medical system, Wisconsin USA. All the patients underwent T1-weighted axial imaging (TR 1254, TE 11.6) and axial fast spin echo T2 weighted imaging
(TR 5600 and TE 95.5). For diffusion weighted imaging, diffusion sensitizing gradient was applied in three orthogonal plains (TR 5600, TE 72.4) and b value was set at 1000 s/mm2. The isotropic diffusion weighted images were reviewed. Fast fluid attenuated inversion recovery (T1 2200, TR 8802, TE 85.4) was simultaneously acquired. All the images in all sequences were 5 mm thick and inter-slice gap was 0.5 mm. Matrix size was 256 × 256 and acquisition was done after NEX = 1. Contrast enhanced studies were done using 0.1 mmol/kg body weight IV gadolinium (Gd-DTPA) in T1 sequence. All MR images were interpreted by a neuro-radiologist. In hemodynamic unstable and very critically ill patient CT scan was done using a 3rd generation CT scanner. 2.3. Treatment and outcome Patients were treated conservatively. Platelet and fresh frozen plasma were infused in the patients with severe thrombocytopenia (platelet count b10,000/mm3), coagulopathy or bleeding. Hospital mortality and one month functional outcome was assessed on the basis of activity of daily living [17]. 3. Results There were 21 patients with DENV infections who underwent cranial MRI or CT scan study (Figs. 1–4). Their median age was 30 (5–69) years and 5 were females; 3 patients were below the age of 15 years. The median GCS score was 12 (3–15) and eight patients had generalized tonic clonic seizures (Table 1). Systolic blood pressure was below 90 mm of Hg in 3 patients. Two patients had jaundice, 4 ecchymosis/petechiae
Fig. 2. Pt #2: Cranial MRI T2W (a) and FLAIR image (b) show subtle hyperintensity in genu and splenium of corpus callosum and right centrum semiovale which is more conspicuous in DWI (C). DWI also shows lesions in the posterior limb of internal capsule bilaterally that is not appreciable in T2 and FLAIR images. Lesions are hypointense to isointense on T1WI (d). No abnormal enhancement on post contrast scans (e).
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Table 1 Demographic and clinical characteristics of dengue patients with cranial imaging. Characteristics
Parameters n = 21 (%)
Age in years
33.05 ± 18.91 (median 30, range 5–69) 3 (16.7%) 16/5 (76.2/23.8%) 10.11 ± 4.2 (median 10, range 3–17) 8 (38.1%) 8 (100%) 20 (95.2%) 10.19 ± 4.05 (median 12, range 3–15) 3.29 ± 3.69 (median 1, range 1–16) 11 (52.4%) 4 (19.0%) 4 (19.0%) 1 (4.8%) 1 (4.8%) 6.76 ± 4.63 (median 6, range 1–20) 2 (9.5%) 11 (52.4%) 6 (28.6%) 2 (9.5%) 10 (47.6%)
Age b15 years Gender (male/female) Duration of illness in days Seizure GTCS Altered sensorium GCS score MRI/CT on days of admission
Fig. 3. Pt #4: Cranial MRI post gadolinium T1W image shows meningeal enhancement.
Within 24 h of admission 1–3 day 3–7 day 8–14 day N14 day MRI/CT done after onset of neurological symptoms in days b3 day 3–7 day 8–14 day N14 day MRI/CT scan abnormality
GCS = Glasgow Coma Scale; GTCS = generalized tonic clonic seizure.
and 2 had epistaxis and gum bleeding, 4 sub-conjunctival hemorrhage and 7 had melena. Ascites, pleural effusion and hepatosplenomegaly were present in 4 patients each. None of the patients had cranial nerve palsy. Tendon reflexes were brisk in 9 and reduced and normal in 6 patients each. One patient had extensor plantar response. Sensations and cerebellar tests were normal. 3.1. Investigations 11 patients were anemic (Hb b12 g/dl) and 13 had thrombocytopenia (platelet b100,000/mm3). Serum creatinine was raised (N1.6 mg/dl) in 5, SGPT (N45 U/L) in 21 and lactate dehydrogenase in (N450 U/L) 5
patients. Serum bilirubin was normal in all. Hyponatremia was present in 5 and hypokalemia in 3 patients. Activated partial thromboplastin time was prolonged in 12 and prothombin time in 13 patients. CSF examination was done in 20 patients and was abnormal in 13; pleocytosis (N10/mm3) in 11, elevated protein (45 mg/dl) in 13 and reduced sugar (b2/3rd of serum) in 3 patients (Tables 2 and 3).
3.2. Cranial imaging 20 patients had MRI and one had CT scan. Cranial imaging was abnormal in 10 patients; 9 had abnormality in MRI and one in CT scan. The later patient was critical and was on mechanical ventilation; therefore CT scan was obtained which revealed cerebellar and left subdural hematoma with midline shift. Cranial MRI/CT was done after a median duration of 11 (4 to 31) days of illness. In 3 patients MRI was done within 3–7, 11 patients within 1 to 2 weeks and in 7 patients after 2 weeks. The MRI abnormalities were T2 hyper intensity in thalami in 3 patients, cerebral cortex in 3, centrum semiovale in 2 and corpus callosum in 2 patients. FLAIR sequence showed similar findings as in T2. One patient with normal T2 sequence revealed abnormality in FLAIR sequence. Restricted diffusion was noted in 5 patients and was present in thalamus, globus pallidus, cerebral cortex, centrum semiovale and corpus callosum. Post contrast study revealed meningeal enhancement in 3 patients. The details of MRI findings are presented in Table 4.
3.3. Correlation
Fig. 4. Pt #10: Non contrast CT scan head of a patient with dengue encephalopathy on day 3 of illness shows acute or chronic left subdural hematoma with midline shift and mass effect. There is also acute cerebellar hemorrhage.
MRI was abnormal in all types of dengue virus infection; 6 patients had DF and 2 each had DHF and DSS. Intracranial hemorrhage was found in the patient with DSS. 5 patients had liver dysfunction and 2 each had renal impairment and mild hyponatremia. CSF pleocytosis was present in 7 patients suggesting dengue encephalitis. CSF IgM ELISA was possible in 5 patients and 4 were positive. The details are summarized in Table 5. The clinical and laboratory findings were not significantly different in the patients with and without MRI/CT abnormality.
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Table 2 Clinical features of dengue patients with abnormal MRI/CT findings. Patients number
Age (yrs)/ sex
Duration of illness
GCS score
Seizure Focal weakness
Platelet at admission
CNS manifestation
EEG
Diagnosis Outcome
1
5/m
8
11
GTCS
No
96,000
Encephalitis
DF
Recovered
2
16/m
12
8
–
QP
38,000
Encephalitis
DHF
Recovered
3
56/m
17
12
–
QP
78,000
Encephalitis
DF
Recovered
4 5
46/m 47/f
12 15
11 14
– –
No QP
130,000 180,000
Encephalitis Encephalitis
DF DF
Recovered Recovered
6 7
25/m 18/m
5 12
10 13
GTCS GTCS
No No
25,000 58,000
Encephalopathy Encephalitis
DHF DF
Recovered Recovered
8
9/f
3
5
GTCS
QP
36,000
Encephalopathy
DSS
9 10
24/m 48/m
4 3
4 3
GTCS –
QP Right HP
95,000 32,000
Encephalitis Dengue with ICH
Diffuse slowing Diffuse slowing Diffuse slowing Not done Diffuse slowing Not done Diffuse slowing Diffuse slowing Slowing Not done
Bed bound at 1 month Recovered Death
DF DSS
CNS = central nervous system; DF = dengue fever; DHF = dengue hemorrhagic fever; DSS = dengue shock syndrome; m = male; f = female; GCS = Glasgow Coma Scal; GTCS = generalized tonic clonic seizure; HP = hemiplegia; QP = quadriplegia.
3.4. Outcome One patient died, another was bed bound and the remaining had complete recovery at 1 month follow-up. The outcome in the patients with and without MRI abnormality was not different (p = 0.16). 4. Discussion In the present study on dengue encephalopathy or encephalitis, imaging was abnormal in 47.6% (10/21) patients (9 MRI and one CT). The MRI changes are non-specific and include intracerebral hemorrhage, thalamic involvement and cortico-subcortical white matter changes. This study evaluates the MRI changes in the patients with dengue encephalopathy or encephalitis and have correlated these changes with clinical and laboratory findings. MRI findings in dengue virus infection have also been reported in other studies. In a study on 27 children with dengue encephalopathy, MRI was carried out in 18 patients and 14 had abnormality. Majority of them had brain edema and focal scattered cortical changes and one had intracerebral hemorrhage [6]. In this study, CSF finding was normal which is unlikely in encephalitis. 21 patients had seizure which may also explain focal cortical changes and edema on MRI. Thrombocytopenia and coagulopathy in dengue are although common but reports of intracranial hemorrhage in dengue are less frequent than cutaneous and systemic hemorrhagic complications [6,11,12]. In our study as well as in the report by Cam et al., only one
patient each had intracranial hemorrhage in spite of thrombocytopenia in the majority and melena in 7 of our patients. In an epidemic of dengue, out of 1148 confirmed dengue hospitalized patients 3 (0.26%) had ICH [18]. In Brazil, only 1 out of 1585 patients with dengue had ICH [19]. There are isolated reports of intracranial hemorrhage in DHF. Intracranial hemorrhage more commonly occurs in elderly compared to young children. In the present study, the patient with ICH was above 40 years of age. Thrombocytopenia in dengue usually occurs during convalescent stage and there are reports of intracranial hemorrhage during this period emphasizing the need of monitoring these patients for few days after defervescence of fever [11,12]. One of our patients with DSS had ICH during the febrile period. Two of our patients had thalamic and basal ganglia involvement which were hyper intense in T2 and hypointense in T1 sequence. Both these patients had hypotension and respiratory failure necessitating artificial ventilation and one had seizure as well. The thalamic and basal ganglia changes in these patients; therefore, may be due to hypoxia or dengue per se. Thalamic lesion in MRI has also been reported in a patient with dengue who had respiratory distress and was on artificial ventilation for 2 days. His thalamic lesion improved on repeat scan after 2 weeks [13]. In our earlier study, we have reported thalamic involvement in 2 patients with dengue CNS involvement and one of them had JE co-infection. Basal ganglia and thalamus are vulnerable to hypoxia or ischemia and may be responsible for transient involvement of thalamus as reported by Kamble et al. [13]. We however have not done sequential studies which could have thrown light on the
Table 3 CSF, dengue antigen/antibody and biochemical findings in the patients with abnormal CT/MRI. Patients number
CSF total cells/cu mm
Lymphocyte in %
Protein (mg/dl)
Glucose (mg/dl)
Dengue serology (serum)
INR
Hepatic
Renal
Coagulopathy
Na (meq/L)
K (meq/L)
BP (mm Hg)
TLC (cu mm)
Duration of mechanical ventilation (in days)
1 2 3 4 5 6 7 8 9 10
10 30 70 100 200 0 200 0 10 –
100 60 95 80 95 0 90 0 90 –
68 109 46 250 70 30 159 40 50 –
47 81 99 39 59 85 69 60 57 –
Ag IgM IgM IgM IgM Ag/IgM IgM IgG NS1+,IgM IgM
0.94 1.41 1.27 0.97 .88 1.39 1.27 1.06 1 1.60
Absent Present Present Absent Absent Present Absent Present Absent Present
Absent Present Absent Absent Absent Absent Absent Absent Absent Present
Absent Present Present Absent Absent Present Present Absent Absent Present
127 160 138 125 136 143 141 130 135 136
4.6 6.0 3.1 3.0 4.9 4.4 5.4 4.5 4.5 4.3
90/60 110/70 140/100 130/90 110/70 100/70 140/90 90/50 110/70 70/20
9700 10,300 4500 12,200 8900 11,400 10,000 13,900 7400 9700
– 8 – – – 12 – 40 – 3
CSF = cerebrospinal fluid; Na = sodium; K = potassium; INR = international normalized ratio; TLC = total leucocyte count.
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Table 4 MRI findings in different sequence and CT scan findings in dengue patients with neurological manifestations. Patient MRI on number day of illness
T2W
FLAIR
DWI
T1W
Post contrast T1W
1
1
Bilateral thalamic hyperintensities
Bilateral thalamic hyperintensities
Increased signal in bilateral thalami and globus pallidi
Meningeal enhancement
2
3
3
7
4
6
Mild increase in signal in corpus callosum (genu and splenium) and centrum semiovale (rt) Increased signal intensities in bilateral centrum semiovale & splenium on left side Normal
Focal reduced signal in bilateral thalami Normal
5
1
6
8
7
1
8
1
9
2
10
CT-1
Mild increase in signal in corpus callosum (genu and splenium) and centrum semiovale (rt) Increased signal intensities in bilateral centrum semiovale & splenium on left side Small hyperintense lesion in right frontal area Few bilateral cortical hyperintensities Few bilateral cortical hyperintensities
Increased signal in genu and splenium, posterior limb of internal capsule and centrum semiovale bilaterally Increased signal in bilateral centrum semiovale, splenium on left, left caudate and bilateral corona radiata No diffusion restriction
Reduced signal in bilateral centrum semiovale Normal
No diffusion restriction
Normal
Bilateral thalamic & cortical hyperintensities Normal
Bilateral thalamic and cortical hyperintensities Normal
Bilateral thalamic & cortical hyperintensities Normal
Normal Normal
Increased signal in bilateral parietal region Increased signal intensities in bilateral thalamus & basal ganglia
Increased signal in bilateral parietal region Increased signal intensities in bilateral thalamus & basal ganglia
Increased signal in bilateral parietal region
Normal
No diffusion restriction
Reduced signal in bilateral basal ganglia
Normal
No abnormal enhancement Meningeal enhancement No abnormal enhancement No abnormal enhancement Meningeal enhancement No abnormal enhancement No abnormal enhancement
Acute on chronic left subdural hematoma with midline shift and mass effect. There is also acute cerebellar haemorrhage
DWI = diffusion weighted image; FLAIR = fluid attenuated inversion recovery; rt = right; lt = left.
mechanism of thalamic and basal ganglia involvement in dengue. Brain edema, nonspecific focal parenchymal brain lesions and meningeal enhancement have been reported on MRI in the patients with dengue [5, 6,20,21]. Dengue encephalitis is clinically similar to dengue encephalopathy and is characterized by the presence of CSF pleocytosis, IgM antibodies, NS1 antigen, or DENV RNA. DENV specific antibodies in the CSF are found in 22%–33% patients with dengue encephalitis [22]. Detection of DENV in the CSF may be limited by low sensitivity of RTPCR compared to serum due to low CSF viral load [23]. In view of these limitations combination of clinical symptoms, signs and CSF should be considered for the diagnosis of dengue encephalitis. Autopsy studies have reported cerebral congestion, edema, hemorrhage and only rarely histopathological evidence of encephalitis [24,25]. In an autopsy study of 75 fatal dengue
patients, meningitis was present in 9 and encephalitis in 3. Of the 41 patients with neurological complications, 23 had edema, 13 had cerebral congestion, 2 had brain necrosis, one had hemorrhage and 2 each had cerebellar congestion and edema [25]. In another study on 10 patients, autopsy revealed brain edema in 3, hemorrhage in 6 and normal in 1 [3]. Microscopic examination in another study however did not reveal mononuclear infiltrates [26]. On MRI, edema and congestion are hyperintense in T2 and FLAIR sequences. The MRI signal changes in hemorrhagic lesion depend on the stage of the bleed. DWI may reveal restricted diffusion in the presence of tissue hypoxia. In our patients, brain edema was not present which may be due to delay in MRI study and fewer numbers of DSS patients in whom capillary leakage is the maximum. The limitations of the present study are inclusion of hospitalized patients with
Table 5 Comparison of clinical and biochemical parameters in patients with normal and abnormal MRI/CT scan. Parameters
Abnormal (n = 10)
Normal (n = 11)
p value
Age in years Female/male Duration of illness (in days) MRI done on days of admission Systolic BP (mm of Hg) Diastolic BP (mm of Hg) Seizure ± GCS score Platelet/mm3 Leucocyte/mm3 INR Serum sodium meq/L Blood sugar mg/dl Total bilirubin (mg/dl) Hepatic dysfunction ± Renal dysfunction ± Coagulopathy CSF (cells/mm3) CSF (protein mg/dl)
29.40 ± 18.28 2/8 7.90 ± 5.07 3.10 ± 2.81 109.0 ± 22.83 69.0 ± 22.83 5/1 9.10 ± 3.90 76,800 ± 49,883.87 9800.0 ± 2584.14 1.18 ± 0.24 137.1 ± 9.89 115.60 ± 45.97 1.16 ± 0.48 5/5 2/8 5 68.89 ± 81.62 91.33 ± 71.79
36.36 ± 19.73 3/8 11.0 ± 7.10 3.45 ± 4.48 111.45 ± 21.80 74.55 ± 12.14 3/6 11.18 ± 4.09 149,727.27 ± 130,553.51 14,345.45 ± 6467.05 1.05 ± .13 138.0 ± 6.80 96.55 ± 28.49 0.80 ± 0.43 3/8 1/10 4 55.73 ± 101.44 52.82 ± 27.38
0.41 1.0 0.27 0.83 0.80 0.49 0.12 0.25 0.11 0.05 0.15 0.81 0.26 0.09 0.39 0.59 0.66 0.76 0.12
BP = blood pressure; CSF = cerebrospinal fluid; INR = international normalized ratio.
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Cranial imaging findings in dengue virus infection Sanjeev Kumar Bhoi a, Suprava Naik b, Sunil Kumar b, Rajendra Vishnu Phadke b, Jayantee Kalita a,⁎, Usha Kant Misra a a b
Department of Neurology, Sanjay Gandhi Post Graduate Medical Sciences, Lucknow, India Department of Radiodiagnosis, Sanjay Gandhi Post Graduate Medical Sciences, Lucknow, India
a r t i c l e
i n f o
Article history: Received 3 January 2014 Received in revised form 10 March 2014 Accepted 11 April 2014 Available online xxxx Keywords: Magnetic resonance imaging Computed tomography Dengue encephalitis Dengue encephalopathy Thalamic lesion Basal ganglia
a b s t r a c t Background: The aim of this study is to evaluate cranial CT or MRI changes in dengue encephalitis and their correlation with clinical and biochemical findings. Methods: Twenty-one serologically confirmed patients with dengue with altered sensorium were included who underwent MRI (20)/CT (1) scan study. Their clinical details including seizure, hypotension, bleeding diathesis, focal neurologic deficit, and Glasgow Coma Scale (GCS) score were noted. Blood counts, hematocrit, renal and liver function tests, electrolytes, cerebrospinal fluid (CSF) and ECG were done. MRI findings on T1, T2, FLAIR, DWI and T1 gadolinium contrast were noted. Results: The median age of the patients was 30 (5–69) years and 5 were females. MRI was abnormal in 9(45%) and CT scan in 1 patient with dengue shock syndrome revealed cerebellar and subdural hematoma. The MRI lesions were in thalamic and basal ganglia in 3, focal cortical areas in 3, white mater in 2 and meningeal enhancement in 3 patients. Seven of these patients had CSF pleocytosis. The presence of abnormal imaging was not related to outcome. One patient died, 1 was bed ridden and 19 had complete recovery on discharge. Conclusion: Cranial imaging reveals nonspecific changes and is not related to hematological and biochemical changes or outcome. © 2014 Published by Elsevier B.V.
1. Introduction Dengue is the most important mosquito borne disease after malaria [1]. Its incidence has increased many folds in last half a century. About 4 billion people live in dengue endemic areas of Asia, Africa, Australia, America and Europe [1,2]. Dengue virus is a RNA virus of flaviviridae group and results in dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Dengue virus is a nonneurotropic virus but increasing number of studies on central nervous system (CNS) involvement in dengue virus infection has been reported [3–7]. The neurological involvement in dengue virus infection can occur due to metabolic alteration, such as liver or kidney dysfunction, hyponatremia, hemorrhagic diathesis in the CNS, DSS, hypoxia and hypotension, direct CNS invasion of dengue virus (DENV) producing encephalitis and post infective autoimmune mediated CNS injury [4–6]. Cranial MRI has provided information about the extent and nature of CNS injury in viral infections. There are characteristic MRI changes in viral encephalitis; frontotempoal changes in herpes simplex encephalitis; thalamus, basal ganglia and brain stem involvement in ⁎ Corresponding author at: Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareily Road, Lucknow 226014, India. Tel.: +91 522 2494167; fax: +91 522 2668811. E-mail addresses: [email protected], [email protected] (J. Kalita).
Japanese encephalitis (JE) and eastern equine encephalitis [8–10]. There are few reports of MRI changes in DENV infection and have revealed a wide variety of changes such as intra cerebral hemorrhage and thalamic, basal ganglia, cortical and sub cortical involvement [6, 11–15]. In the dengue endemic area, JE or other viral encephalitis are also prevalent; hence these MRI changes need to be critically evaluated. Prospective MRI studies using different sequences may help not only in localizing the abnormality but may also shed light on the underlying pathology, such as necrosis, edema, haemorrhage and demyelinating features. In the present study, we report the MRI/CT findings in patients with DENV infections and correlate these with their clinical and laboratory findings. 2. Material and methods The patients with abnormal cranial imaging (CT/MRI) were prospectively evaluated from our dengue registry maintained since 2003. The diagnosis of dengue encephalopathy was based on signs and symptoms of acute encephalitic syndrome with the presence of dengue antigen (NS1) and/or IgM antibody against dengue virus in serum. Patients with malaria, Leptospira, Chikungunya, JE, herpes simplex virus (HSV) encephalitis and Epstein Barr virus encephalitis were excluded. The patients were subjected to detailed clinical evaluation. The presence of fever, headache, vomiting, bleeding diathesis, hypotension, jaundice,
http://dx.doi.org/10.1016/j.jns.2014.04.018 0022-510X/© 2014 Published by Elsevier B.V.
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Fig. 1. Pt #1: Cranial MRI T2W (a) and FLAIR (b) image show areas of increased signal intensities in bilateral thalami. Same lesions appear hyperintense on DWI (c), and subtle hyperintensity was also appreciated in bilateral globi palidii in DWI. Lesions are hypointense on T1WI (d). Post contrast T1 (e) reveals meningeal enhancement.
oliguria and seizures were recorded. The level of consciousness was assessed by Glasgow Coma Scale (GCS) [16]. The presence of papilledema and cranial nerve palsy was noted. Muscle weakness (hemiplegia or quadriplegia) were graded into mild (MRC grade IV), moderate (MRC grade III-II) and severe (MRC grade I-0). Muscle tone and tendon reflex were noted. Sensations and cerebellar signs were tested in the patients who could cooperate. The presence of meningeal signs, chest rales, hepatosplenomegaly and cardiac abnormality were noted. 2.1. Investigations Blood counts, hemoglobin, activated partial thromboplastin time, prothrombin time, blood sugar, blood urea nitrogen (BUN), serum creatinine, bilirubin, transaminases, creatinine kinase (CK), sodium, potassium and calcium were done. Chest radiograph and ECG were carried out. Dengue antigen (NS1) and IgM antibody against dengue virus were tested in serum in all and in CSF in some patients by enzyme linked sorbent assay (ELISA). The diagnosis of JE was excluded by negative CSF IgM ELISA, and Leptospira and Chikungunya by serum IgM ELISA. Peripheral smear was examined for malarial parasite. Cerebrospinal fluid analysis was done when platelet count was N40,000/mm3and also examined for cells, protein and sugar. 2.2. Cranial imaging Cranial MRI was carried out using 3T Signa GE medical system, Wisconsin USA. All the patients underwent T1-weighted axial imaging (TR 1254, TE 11.6) and axial fast spin echo T2 weighted imaging
(TR 5600 and TE 95.5). For diffusion weighted imaging, diffusion sensitizing gradient was applied in three orthogonal plains (TR 5600, TE 72.4) and b value was set at 1000 s/mm2. The isotropic diffusion weighted images were reviewed. Fast fluid attenuated inversion recovery (T1 2200, TR 8802, TE 85.4) was simultaneously acquired. All the images in all sequences were 5 mm thick and inter-slice gap was 0.5 mm. Matrix size was 256 × 256 and acquisition was done after NEX = 1. Contrast enhanced studies were done using 0.1 mmol/kg body weight IV gadolinium (Gd-DTPA) in T1 sequence. All MR images were interpreted by a neuro-radiologist. In hemodynamic unstable and very critically ill patient CT scan was done using a 3rd generation CT scanner. 2.3. Treatment and outcome Patients were treated conservatively. Platelet and fresh frozen plasma were infused in the patients with severe thrombocytopenia (platelet count b10,000/mm3), coagulopathy or bleeding. Hospital mortality and one month functional outcome was assessed on the basis of activity of daily living [17]. 3. Results There were 21 patients with DENV infections who underwent cranial MRI or CT scan study (Figs. 1–4). Their median age was 30 (5–69) years and 5 were females; 3 patients were below the age of 15 years. The median GCS score was 12 (3–15) and eight patients had generalized tonic clonic seizures (Table 1). Systolic blood pressure was below 90 mm of Hg in 3 patients. Two patients had jaundice, 4 ecchymosis/petechiae
Fig. 2. Pt #2: Cranial MRI T2W (a) and FLAIR image (b) show subtle hyperintensity in genu and splenium of corpus callosum and right centrum semiovale which is more conspicuous in DWI (C). DWI also shows lesions in the posterior limb of internal capsule bilaterally that is not appreciable in T2 and FLAIR images. Lesions are hypointense to isointense on T1WI (d). No abnormal enhancement on post contrast scans (e).
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Table 1 Demographic and clinical characteristics of dengue patients with cranial imaging. Characteristics
Parameters n = 21 (%)
Age in years
33.05 ± 18.91 (median 30, range 5–69) 3 (16.7%) 16/5 (76.2/23.8%) 10.11 ± 4.2 (median 10, range 3–17) 8 (38.1%) 8 (100%) 20 (95.2%) 10.19 ± 4.05 (median 12, range 3–15) 3.29 ± 3.69 (median 1, range 1–16) 11 (52.4%) 4 (19.0%) 4 (19.0%) 1 (4.8%) 1 (4.8%) 6.76 ± 4.63 (median 6, range 1–20) 2 (9.5%) 11 (52.4%) 6 (28.6%) 2 (9.5%) 10 (47.6%)
Age b15 years Gender (male/female) Duration of illness in days Seizure GTCS Altered sensorium GCS score MRI/CT on days of admission
Fig. 3. Pt #4: Cranial MRI post gadolinium T1W image shows meningeal enhancement.
Within 24 h of admission 1–3 day 3–7 day 8–14 day N14 day MRI/CT done after onset of neurological symptoms in days b3 day 3–7 day 8–14 day N14 day MRI/CT scan abnormality
GCS = Glasgow Coma Scale; GTCS = generalized tonic clonic seizure.
and 2 had epistaxis and gum bleeding, 4 sub-conjunctival hemorrhage and 7 had melena. Ascites, pleural effusion and hepatosplenomegaly were present in 4 patients each. None of the patients had cranial nerve palsy. Tendon reflexes were brisk in 9 and reduced and normal in 6 patients each. One patient had extensor plantar response. Sensations and cerebellar tests were normal. 3.1. Investigations 11 patients were anemic (Hb b12 g/dl) and 13 had thrombocytopenia (platelet b100,000/mm3). Serum creatinine was raised (N1.6 mg/dl) in 5, SGPT (N45 U/L) in 21 and lactate dehydrogenase in (N450 U/L) 5
patients. Serum bilirubin was normal in all. Hyponatremia was present in 5 and hypokalemia in 3 patients. Activated partial thromboplastin time was prolonged in 12 and prothombin time in 13 patients. CSF examination was done in 20 patients and was abnormal in 13; pleocytosis (N10/mm3) in 11, elevated protein (45 mg/dl) in 13 and reduced sugar (b2/3rd of serum) in 3 patients (Tables 2 and 3).
3.2. Cranial imaging 20 patients had MRI and one had CT scan. Cranial imaging was abnormal in 10 patients; 9 had abnormality in MRI and one in CT scan. The later patient was critical and was on mechanical ventilation; therefore CT scan was obtained which revealed cerebellar and left subdural hematoma with midline shift. Cranial MRI/CT was done after a median duration of 11 (4 to 31) days of illness. In 3 patients MRI was done within 3–7, 11 patients within 1 to 2 weeks and in 7 patients after 2 weeks. The MRI abnormalities were T2 hyper intensity in thalami in 3 patients, cerebral cortex in 3, centrum semiovale in 2 and corpus callosum in 2 patients. FLAIR sequence showed similar findings as in T2. One patient with normal T2 sequence revealed abnormality in FLAIR sequence. Restricted diffusion was noted in 5 patients and was present in thalamus, globus pallidus, cerebral cortex, centrum semiovale and corpus callosum. Post contrast study revealed meningeal enhancement in 3 patients. The details of MRI findings are presented in Table 4.
3.3. Correlation
Fig. 4. Pt #10: Non contrast CT scan head of a patient with dengue encephalopathy on day 3 of illness shows acute or chronic left subdural hematoma with midline shift and mass effect. There is also acute cerebellar hemorrhage.
MRI was abnormal in all types of dengue virus infection; 6 patients had DF and 2 each had DHF and DSS. Intracranial hemorrhage was found in the patient with DSS. 5 patients had liver dysfunction and 2 each had renal impairment and mild hyponatremia. CSF pleocytosis was present in 7 patients suggesting dengue encephalitis. CSF IgM ELISA was possible in 5 patients and 4 were positive. The details are summarized in Table 5. The clinical and laboratory findings were not significantly different in the patients with and without MRI/CT abnormality.
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Table 2 Clinical features of dengue patients with abnormal MRI/CT findings. Patients number
Age (yrs)/ sex
Duration of illness
GCS score
Seizure Focal weakness
Platelet at admission
CNS manifestation
EEG
Diagnosis Outcome
1
5/m
8
11
GTCS
No
96,000
Encephalitis
DF
Recovered
2
16/m
12
8
–
QP
38,000
Encephalitis
DHF
Recovered
3
56/m
17
12
–
QP
78,000
Encephalitis
DF
Recovered
4 5
46/m 47/f
12 15
11 14
– –
No QP
130,000 180,000
Encephalitis Encephalitis
DF DF
Recovered Recovered
6 7
25/m 18/m
5 12
10 13
GTCS GTCS
No No
25,000 58,000
Encephalopathy Encephalitis
DHF DF
Recovered Recovered
8
9/f
3
5
GTCS
QP
36,000
Encephalopathy
DSS
9 10
24/m 48/m
4 3
4 3
GTCS –
QP Right HP
95,000 32,000
Encephalitis Dengue with ICH
Diffuse slowing Diffuse slowing Diffuse slowing Not done Diffuse slowing Not done Diffuse slowing Diffuse slowing Slowing Not done
Bed bound at 1 month Recovered Death
DF DSS
CNS = central nervous system; DF = dengue fever; DHF = dengue hemorrhagic fever; DSS = dengue shock syndrome; m = male; f = female; GCS = Glasgow Coma Scal; GTCS = generalized tonic clonic seizure; HP = hemiplegia; QP = quadriplegia.
3.4. Outcome One patient died, another was bed bound and the remaining had complete recovery at 1 month follow-up. The outcome in the patients with and without MRI abnormality was not different (p = 0.16). 4. Discussion In the present study on dengue encephalopathy or encephalitis, imaging was abnormal in 47.6% (10/21) patients (9 MRI and one CT). The MRI changes are non-specific and include intracerebral hemorrhage, thalamic involvement and cortico-subcortical white matter changes. This study evaluates the MRI changes in the patients with dengue encephalopathy or encephalitis and have correlated these changes with clinical and laboratory findings. MRI findings in dengue virus infection have also been reported in other studies. In a study on 27 children with dengue encephalopathy, MRI was carried out in 18 patients and 14 had abnormality. Majority of them had brain edema and focal scattered cortical changes and one had intracerebral hemorrhage [6]. In this study, CSF finding was normal which is unlikely in encephalitis. 21 patients had seizure which may also explain focal cortical changes and edema on MRI. Thrombocytopenia and coagulopathy in dengue are although common but reports of intracranial hemorrhage in dengue are less frequent than cutaneous and systemic hemorrhagic complications [6,11,12]. In our study as well as in the report by Cam et al., only one
patient each had intracranial hemorrhage in spite of thrombocytopenia in the majority and melena in 7 of our patients. In an epidemic of dengue, out of 1148 confirmed dengue hospitalized patients 3 (0.26%) had ICH [18]. In Brazil, only 1 out of 1585 patients with dengue had ICH [19]. There are isolated reports of intracranial hemorrhage in DHF. Intracranial hemorrhage more commonly occurs in elderly compared to young children. In the present study, the patient with ICH was above 40 years of age. Thrombocytopenia in dengue usually occurs during convalescent stage and there are reports of intracranial hemorrhage during this period emphasizing the need of monitoring these patients for few days after defervescence of fever [11,12]. One of our patients with DSS had ICH during the febrile period. Two of our patients had thalamic and basal ganglia involvement which were hyper intense in T2 and hypointense in T1 sequence. Both these patients had hypotension and respiratory failure necessitating artificial ventilation and one had seizure as well. The thalamic and basal ganglia changes in these patients; therefore, may be due to hypoxia or dengue per se. Thalamic lesion in MRI has also been reported in a patient with dengue who had respiratory distress and was on artificial ventilation for 2 days. His thalamic lesion improved on repeat scan after 2 weeks [13]. In our earlier study, we have reported thalamic involvement in 2 patients with dengue CNS involvement and one of them had JE co-infection. Basal ganglia and thalamus are vulnerable to hypoxia or ischemia and may be responsible for transient involvement of thalamus as reported by Kamble et al. [13]. We however have not done sequential studies which could have thrown light on the
Table 3 CSF, dengue antigen/antibody and biochemical findings in the patients with abnormal CT/MRI. Patients number
CSF total cells/cu mm
Lymphocyte in %
Protein (mg/dl)
Glucose (mg/dl)
Dengue serology (serum)
INR
Hepatic
Renal
Coagulopathy
Na (meq/L)
K (meq/L)
BP (mm Hg)
TLC (cu mm)
Duration of mechanical ventilation (in days)
1 2 3 4 5 6 7 8 9 10
10 30 70 100 200 0 200 0 10 –
100 60 95 80 95 0 90 0 90 –
68 109 46 250 70 30 159 40 50 –
47 81 99 39 59 85 69 60 57 –
Ag IgM IgM IgM IgM Ag/IgM IgM IgG NS1+,IgM IgM
0.94 1.41 1.27 0.97 .88 1.39 1.27 1.06 1 1.60
Absent Present Present Absent Absent Present Absent Present Absent Present
Absent Present Absent Absent Absent Absent Absent Absent Absent Present
Absent Present Present Absent Absent Present Present Absent Absent Present
127 160 138 125 136 143 141 130 135 136
4.6 6.0 3.1 3.0 4.9 4.4 5.4 4.5 4.5 4.3
90/60 110/70 140/100 130/90 110/70 100/70 140/90 90/50 110/70 70/20
9700 10,300 4500 12,200 8900 11,400 10,000 13,900 7400 9700
– 8 – – – 12 – 40 – 3
CSF = cerebrospinal fluid; Na = sodium; K = potassium; INR = international normalized ratio; TLC = total leucocyte count.
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Table 4 MRI findings in different sequence and CT scan findings in dengue patients with neurological manifestations. Patient MRI on number day of illness
T2W
FLAIR
DWI
T1W
Post contrast T1W
1
1
Bilateral thalamic hyperintensities
Bilateral thalamic hyperintensities
Increased signal in bilateral thalami and globus pallidi
Meningeal enhancement
2
3
3
7
4
6
Mild increase in signal in corpus callosum (genu and splenium) and centrum semiovale (rt) Increased signal intensities in bilateral centrum semiovale & splenium on left side Normal
Focal reduced signal in bilateral thalami Normal
5
1
6
8
7
1
8
1
9
2
10
CT-1
Mild increase in signal in corpus callosum (genu and splenium) and centrum semiovale (rt) Increased signal intensities in bilateral centrum semiovale & splenium on left side Small hyperintense lesion in right frontal area Few bilateral cortical hyperintensities Few bilateral cortical hyperintensities
Increased signal in genu and splenium, posterior limb of internal capsule and centrum semiovale bilaterally Increased signal in bilateral centrum semiovale, splenium on left, left caudate and bilateral corona radiata No diffusion restriction
Reduced signal in bilateral centrum semiovale Normal
No diffusion restriction
Normal
Bilateral thalamic & cortical hyperintensities Normal
Bilateral thalamic and cortical hyperintensities Normal
Bilateral thalamic & cortical hyperintensities Normal
Normal Normal
Increased signal in bilateral parietal region Increased signal intensities in bilateral thalamus & basal ganglia
Increased signal in bilateral parietal region Increased signal intensities in bilateral thalamus & basal ganglia
Increased signal in bilateral parietal region
Normal
No diffusion restriction
Reduced signal in bilateral basal ganglia
Normal
No abnormal enhancement Meningeal enhancement No abnormal enhancement No abnormal enhancement Meningeal enhancement No abnormal enhancement No abnormal enhancement
Acute on chronic left subdural hematoma with midline shift and mass effect. There is also acute cerebellar haemorrhage
DWI = diffusion weighted image; FLAIR = fluid attenuated inversion recovery; rt = right; lt = left.
mechanism of thalamic and basal ganglia involvement in dengue. Brain edema, nonspecific focal parenchymal brain lesions and meningeal enhancement have been reported on MRI in the patients with dengue [5, 6,20,21]. Dengue encephalitis is clinically similar to dengue encephalopathy and is characterized by the presence of CSF pleocytosis, IgM antibodies, NS1 antigen, or DENV RNA. DENV specific antibodies in the CSF are found in 22%–33% patients with dengue encephalitis [22]. Detection of DENV in the CSF may be limited by low sensitivity of RTPCR compared to serum due to low CSF viral load [23]. In view of these limitations combination of clinical symptoms, signs and CSF should be considered for the diagnosis of dengue encephalitis. Autopsy studies have reported cerebral congestion, edema, hemorrhage and only rarely histopathological evidence of encephalitis [24,25]. In an autopsy study of 75 fatal dengue
patients, meningitis was present in 9 and encephalitis in 3. Of the 41 patients with neurological complications, 23 had edema, 13 had cerebral congestion, 2 had brain necrosis, one had hemorrhage and 2 each had cerebellar congestion and edema [25]. In another study on 10 patients, autopsy revealed brain edema in 3, hemorrhage in 6 and normal in 1 [3]. Microscopic examination in another study however did not reveal mononuclear infiltrates [26]. On MRI, edema and congestion are hyperintense in T2 and FLAIR sequences. The MRI signal changes in hemorrhagic lesion depend on the stage of the bleed. DWI may reveal restricted diffusion in the presence of tissue hypoxia. In our patients, brain edema was not present which may be due to delay in MRI study and fewer numbers of DSS patients in whom capillary leakage is the maximum. The limitations of the present study are inclusion of hospitalized patients with
Table 5 Comparison of clinical and biochemical parameters in patients with normal and abnormal MRI/CT scan. Parameters
Abnormal (n = 10)
Normal (n = 11)
p value
Age in years Female/male Duration of illness (in days) MRI done on days of admission Systolic BP (mm of Hg) Diastolic BP (mm of Hg) Seizure ± GCS score Platelet/mm3 Leucocyte/mm3 INR Serum sodium meq/L Blood sugar mg/dl Total bilirubin (mg/dl) Hepatic dysfunction ± Renal dysfunction ± Coagulopathy CSF (cells/mm3) CSF (protein mg/dl)
29.40 ± 18.28 2/8 7.90 ± 5.07 3.10 ± 2.81 109.0 ± 22.83 69.0 ± 22.83 5/1 9.10 ± 3.90 76,800 ± 49,883.87 9800.0 ± 2584.14 1.18 ± 0.24 137.1 ± 9.89 115.60 ± 45.97 1.16 ± 0.48 5/5 2/8 5 68.89 ± 81.62 91.33 ± 71.79
36.36 ± 19.73 3/8 11.0 ± 7.10 3.45 ± 4.48 111.45 ± 21.80 74.55 ± 12.14 3/6 11.18 ± 4.09 149,727.27 ± 130,553.51 14,345.45 ± 6467.05 1.05 ± .13 138.0 ± 6.80 96.55 ± 28.49 0.80 ± 0.43 3/8 1/10 4 55.73 ± 101.44 52.82 ± 27.38
0.41 1.0 0.27 0.83 0.80 0.49 0.12 0.25 0.11 0.05 0.15 0.81 0.26 0.09 0.39 0.59 0.66 0.76 0.12
BP = blood pressure; CSF = cerebrospinal fluid; INR = international normalized ratio.
Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018
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Please cite this article as: Bhoi SK, et al, Cranial imaging findings in dengue virus infection, J Neurol Sci (2014), http://dx.doi.org/10.1016/ j.jns.2014.04.018