A prospective study of magnetic resonance imaging patterns of central nervous system infections in pediatric age group and young adults and their clinico-biochemical correlation.

BACKGROUND: Infections of the central nervous system (CNS) are common and routinely encountered. Our aim was to evaluate the neuroimaging features of the various infections of the CNS so as to differentiate them from tumoral, vascular, and other entities that warrant a different line of therapy. AIMS: Our aim was to analyze the biochemical and magnetic resonance imaging (MRI) features in CNS infections. SETTINGS AND
DESIGN: This was a longitudinal, prospective study over a period of 1½ years. SUBJECTS AND METHODS: We studied cerebrospinal fluid (CSF) findings and MRI patterns in 27 patients of 0-20 years age group with clinical features of CNS infections. MRI was performed on MAGNETOM Avanto 18 Channel 1.5 Tesla MR machine by Siemens India Ltd. The MRI protocol consisted of diffusion-weighted and apparent diffusion coefficient imaging, turbo spin echo T2-weighted, spin echo T1-weighted, fluid-attenuated inversion recovery (FLAIR), and gradient-echo in axial, FLAIR in coronal, and T2-weighted in sagittal plane. Contrast-enhanced T1-weighted sequence and MR spectroscopy were done whenever indicated. RESULTS AND
CONCLUSIONS: We found that most of the children belong to 1-10 years age group. Fungal infections were uncommon, mean CSF adenosine deaminase values specific for tuberculosis and mean CSF glucose-lowered in pyogenic. Hemorrhagic involvement of thalamus with/without basal ganglia and brainstem involvement may indicate Japanese encephalitis or dengue encephalitis. Diffusion restriction or hemorrhage in not expected in the brainstem afflicted lesions of rabies. Congenital cytomegalovirus can cause cortical malformations. T1 hyperintensities with diffusion restriction may represent viral encephalitis. Lesions of acute disseminated encephalomyelitis (ADEM) may mimic viral encephalitis. Leptomeningeal enhancement is predominant in pyogenic meningitis. Basilar meningitis in the presence of tuberculomas is highly sensitive and specific for tuberculosis.

Introduction

Infections of the nervous system and adjacent structures are often life-threatening with devastating consequences. Neuroimaging is crucial in visualization of typical lesion patterns which not only allows for a rapid diagnosis but also subsequent therapeutic decisions. Particularly, recognition of certain atypical imaging features of common infections must be kept in mind to avoid a diagnostic dilemma and delay in appropriate therapy.[12]

In neonatal brain infections magnetic resonance imaging (MRI) is the preferred imaging modality over computed tomography, even in an emergency situation.[3] MRI techniques such as diffusion-weighted imaging, magnetic resonance spectroscopy (MRS) provide additional helpful information in the assessment of central nervous system (CNS) infectious lesions.[45]

This study was undertaken to evaluate the MRI patterns of various CNS infections in children and young adults and to correlate with clinical and biochemical findings to determine the etiology and extent of the lesions, so as to allow a rapid radiological diagnosis and thus early treatment.

Aims and objectives

Analysis of MRI features in CNS infections in pediatric population and young adults

To correlate them with cerebrospinal fluid (CSF)/biochemical findings to determine their etiology

Subjects and Methods

This study was conducted on suspected/previously diagnosed cases of CNS infections referred to the Department of Radiodiagnosis at Dayanand Medical College, Ludhiana.

Informed consents were obtained from all the subjects/guardians before the study. Detailed clinical history was taken along with special consideration to neurological examination. The spectrum of MRI findings was recorded.

Study design

A longitudinal, prospective study over a period of 1½ years.

MRI was performed on MAGNETOM Avanto 18 Channel 1.5 Tesla TM MR machine by Siemens India Ltd. Protocol consisted of localizers in coronal, axial, and sagittal plane after proper positioning of the patient. The sequences in the axial plane were:

Turbo spin echo (SE) T2-weighted sequence (repetition time [TR]/echo time [TE]/number of excitations n = 4050 ms/101 ms/3)

SE T1-weighted sequence (TR/TE/n = 652 ms/17 ms/1)

Fluid-attenuated inversion recovery (FLAIR) sequence (TR/TE/n = 9000 ms/90 ms/1; inversion time, 2500 ms)

Gradient-echo sequence (TR/TE = 761 ms/26 ms)

Followed by FLAIR sequence in coronal plane and T2-weighted in sagittal plane

Contrast-enhanced T1-weighted sequence, MRS were done, whenever indicated

Diffusion weighted and apparent diffusion coefficient imaging were performed using echo planar imaging sequence with TR/TE = 3500 ms/109 ms (minimum), field of view = 23 cm × 23 cm, number of excitations = 3, slice thickness = 5 mm, interslice gap = 1.5 mm, matrix size = 128 × 128. Diffusion sensitizing gradients were applied along the three orthogonal directions with diffusion sensitivity of b = 0, b = 500, and b = 1000 s/mm2.

The positive findings were recorded. MRI differentials were correlated with clinical differentials based on CSF/biochemical analysis.

Results

We found that most of the children (55.55%) with cerebral infections were in the 1–10 years age group. Fungal infections were uncommon (0%), whereas viral and postviral demyelination were more common (60%) in pediatric age group. Mean CSF adenosine deaminase (ADA) values are markedly raised (20.2) and are specific for tuberculosis. Mean CSF glucose was lowered in pyogenic infections (41.6 mg/dl), compared to (46.9 mg/dl) in tubercular and (70.7 mg/dl) in viral. Mean CSF protein in our study was raised in pyogenic (208 mg/dl) and tubercular (173 mg/dl) infections. CSF cytology showed that lymphocytes were predominant in tubercular and polymorphonuclear cells in pyogenic meningitis. Out of total 15 cases of viral infection, 6 were nonspecific, 2 each of dengue, rabies, and ADEM, and 1 each of Japanese encephalitis (JE), Reyes encephalopathy, and cytomegalovirus (CMV). Imaging features of pyogenic, tubercular, and viral infections were also recorded and analyzed [Tables 1 and 2].

Table 1

Imaging analysis of cases with pyogenic infection (n=9) and tubercular infection (n=3) of the central nervous system

Table 2

Imaging analysis of cases with viral infection of the central nervous system (n=15)

Discussion

The mean CSF ADA level in our study was significantly raised in tuberculous meningitis (20.2 U/L) as compared to other causes of CNS infections. This is similar to the study by Jasmin et al.,[6] which concluded that CSF ADA is cost-effective and highly sensitive; more specific single test to help a clinician for early and accurate diagnosis of tubercular meningitis in association with clinicopathological parameters.

Two patients presented with fever, altered sensorium and thrombocytopenia. Dengue serology was positive in both. MRI revealed bilateral thalamic involvement in both the patients [Figure 1a]. Diffusion restriction and hemorrhage were seen in one patient [Figure 1b and c]. Leptomeningeal enhancement was seen in one patient. Cerebellar and brainstem involvement [Figure 1d] were seen in another patient.

Figure 1

Magnetic resonance imaging in dengue encephalitis, axial T2-weighted image (a) reveals symmetrical hyperintense signal in thalami, blooming on gradient-echo (b) and diffusion restriction appearing hyperintense on b1000 (c) with lowered apparent diffusion coefficient values (not shown). Sagittal T2-weighted image (d) in another patient shows hyperintense signal in cerebellum and brainstem in addition to thalami

In a recent study by Bhoi et al. in serologically confirmed patients of dengue, lesions were seen in the thalamus and basal ganglia in 3, focal cortical areas in 3, white matter in 2, and meningeal enhancement in three patients. Both the cases in our study had complete clinical recovery and were subsequently discharged.[7]

One case of JE had abnormal T2/FLAIR hyperintensities with diffusion restriction in bilateral thalami, basal ganglia, and the midbrain. Hemorrhage was also seen in thalami.

Our imaging findings reciprocate the study of Kumar et al. who documented bilateral thalamic lesions in seven cases, which were hemorrhagic in five. Signal changes may extend to brainstem, cerebellum, and basal ganglia.[8] Diffusion restriction was seen in our case of JE.

Regarding restriction of water molecules in JE, the study by Prakash et al. showed that diffusion restriction can help in the characterization of the duration of the lesions in JE.[9]

In patients of dog bite, neuroimaging revealed T2/FLAIR hyperintensities in the brainstem, bilateral thalami, bilateral hippocampus, and hypothalamus in both the cases, bilateral basal ganglia in one case, and hyperintense signal in the spinal cord in one case. No diffusion restriction or hemorrhage was seen. One of the patients died shortly after admission due to respiratory complication.

Laothamatas et al. in 2003 described the MRI findings in five patients with rabies which was similar to the spectrum seen in our studies.[10] T2 hyperintensity in the hypothalamus was seen in our cases of rabies. This is similar to the findings of Rao et al. The authors also described the absence of diffusion restriction in the lesions, as was in our study, as a finding that helps to differentiate rabies from other entities such as JE and other viral rhombencephalitis.[11]

One patient presented with weakness of bilateral limbs. MRI revealed hyperintense signal without diffusion restriction in the midbrain, pons, medulla, cerebellum, and the cervicomedullary junction. His CSF workup had revealed 200 cells; hence, we proposed the diagnosis of encephalitis. The patient gradually improved and responded dramatically to steroids without antivirals; hence, the final diagnosis of ADEM was entertained. Antecedent history of fever was present in this case.

The location of the lesions of ADEM in our study follows the observation of Lukes and Norman, who reported the lesions in the cortex, deep white matter, basal ganglia, and in the brainstem.[12]

The study by Atlas et al. in patients with ADEM demonstrated multiple foci of demyelination in the brain stem, cerebrum, and cerebellum. Lesions were characteristic, in that they were few in number, frequently present in the brainstem and posterior fossa, nonhemorrhagic, asymmetric, and correlated with clinical symptoms and signs.[13]

Neuroimaging in six patients revealed punctate foci of T1 hyperintensity with diffusion restriction in bilateral cerebral hemispheres [Figure 2]. No evidence of lepto/pachymeningeal enhancement or hydrocephalus was seen. A possibility of viral encephalitis was entertained. CSF revealed only two cells. The patient was put on antivirals and improved. Similar spectrum of imaging has been described in the work of Verboon-Maciolek et al. who described T1 hyperintensities with diffusion restriction in bilateral cerebral hemispheres in an infant with parechovirus infection.[14]

Figure 2

Magnetic resonance imaging in nonspecific/parechoviral encephalitis, axial T1-weighted (a) image in 6 days old infant shows hyperintense focus in subcortical white matter in the right parietal region and in the left peritrigonal white matter (b). Axial diffusion-weighted (c) and apparent diffusion coefficient (d) shows diffusion restriction in these areas. T2-weighted images were normal in this case

In one neonate with microcephaly, neuroimaging revealed polymicrogyria and hydrocephalus. His workup for IgG CMV was positive. A tiny focus of calcification was seen in the neonate in the right cerebellar hemisphere.

Engman et al. observed that the number of congenital CMV infections in children with cerebral cortical malformations was higher (4/26) than expected with reference to their birth prevalence (0.2–0.5%).[15]

In six of our patients, no specific viral pathogen could be determined, and they were labeled as nonspecific viral encephalitis. As seen in many studies based on imaging of viral encephalitis, for example, the study of Misra et al., this group usually forms the largest number. This is because barring herpes encephalitis, and maybe in certain situations such as that of rabies, all the other viruses produce encephalitis with overlapping imaging features.[16]

In a 10-year-old boy presenting with fever and history of blood transfusion 1 month ago, imaging revealed symmetrical areas of hyperintensity in the subcortical white matter and in the cortex in watershed distribution. Deep gray nuclei were spared. Imaging differential of encephalitis versus ADEM was kept. It was only when his abnormal liver function tests, and the history of aspirin intake elicited, was the diagnosis of Reye's syndrome made. Our imaging findings and diagnosis in this case is similar to the case described by Param et al.[17] They reported similar clinical and biochemical features in Reye's syndrome where MRI revealed diffuse cerebral edema with signal alterations and diffusion restriction in the brainstem, bilateral thalami, medial temporal lobes, parasagittal cortex, cerebellar, and subcortical white matter.

MRI in tubercular infections revealed meningeal involvement as the most frequent imaging finding seen in all the patients. In most of the cases, the enhancement was either seen in the basal cisterns or in the basal and suprasellar cisterns both [Figure 3c]. Thus, basal meningitis was the universal finding. Other findings were ring enhancing granulomas [Figure 3a and 3b].

Figure 3

Magnetic resonance imaging in cerebral tuberculosis-axial T2-weighted (a) image shows hyperintense lesions with hypointense center and peripheral edema in bilateral temporo-occipital regions. Axial contrast-enhanced T1-weighted, (b) multiple ring enhancing lesions. Axial contrast-enhanced T1-weighted (c) image in another patient shows leptomeningeal enhancement in basal cisterns and along anterior temporal lobes. Sagittal contrast-enhanced T1-weighted (d) image shows thick rim enhancing abscess in the sphenoid sinus

This is consistent with the study by Uysal et al. in which they found meningeal enhancement in up to 90% of cases and considered it to be the most sensitive feature of tubercular meningitis.[18]

Similar results were also interpreted by Andronikou et al.[19] who showed sensitivity of basal enhancement to be as high as 89% in making the diagnosis of tubercular meningitis.

Hydrocephalus was seen in 2 patients. It was noted that hydrocephalus occurs in approximately two-third patients and has an unfavorable impact on the prognosis. In one of our patients who presented with nonresolving hydrocephalus, we demonstrated membranes in the foramen of luschka and in the cisterns. This was a patient who benefitted with neuroendoscopic intervention.

In a recent study by Dinçer et al.,[20] they stated that hydrocephalous may be caused by membranes, a finding often missed on conventional MR sequences. They showed that three-dimensional (3D) constructive interference in steady state sequence (CISS) detects these membranes.

One of our patients had tubercular abscess in the sphenoid and posterior ethmoid sinuses in addition to basal meningitis [Figure 3d].

Neuroimaging findings in pyogenic meningitis showed leptomeningeal enhancement, the most consistent feature seen in 5 (55.5%) of our patients. The predominant location of the leptomeningeal enhancement was in the cortical sulci [Figure 4]. Our result is similar to the study done by Oliveira et al. who in their study of MRI findings in 75 CSF bacterial culture positive infants showed leptomeningeal enhancement to be the most common finding present in 57% of the cases.[21]

Figure 4

Axial postgadolinium enhanced T1-weighted image shows marked leptomeningeal enhancement along bilateral frontoparietal regions

Pachymeningeal enhancement was seen in 2 (22.22%) patients. The paucity of pachymeningeal enhancement in pyogenic meningitis correlates well with the study by Kioumehr et al.[22] Pachymeningeal enhancement was observed by them in meningeal carcinomatosis (83% of cases) and in 100% of the reactive cases (due to trauma, shunt, surgery). In contrast, all the cases of infectious meningitis and 78% cases of the chemical meningitis subgroups had leptomeningeal enhancement.[22]

Vasculitic infarcts were seen in 2 (22.22%) of our patients. The location of the vasculitic infarct was gray-white matter interface in one, and brainstem and basal ganglia in other patient.[23]

Associated hydrocephalous was seen in 5 (55.55%) patients. All the patients had reduced Glasgow coma score and poor clinical outcomes. These findings correlate well, the study of Wang et al. in whom the authors described poor outcomes in this specific group of patients.[24]

A well-developed abscess with smooth peripheral enhancement and central diffusion restriction was seen in the right cerebellum of a child who presented with drowsiness but no fever [Figure 5]. In the study by Luthra et al. in 91 cases of bacterial abscess, it was opined that bacterial abscess shows central diffusion restriction with smooth walls of the abscess in 55 and lobulated walls in 36 out of the 91 cases. They attributed the central diffusion restriction to the viscous nature of pus.[25]

Figure 5

Axial fluid-attenuated inversion recovery (a) fluid signal intensity lesion in the right cerebellar hemisphere with surrounding edema and upstream hydrocephalous. Sagittal postgadolinium enhanced T1-weighted image (b) shows thick smooth peripheral enhancement and diffusion restriction in its central part in image (c)

Conclusions

In our study of 27 patients,

Most of the patients either had viral (55.55% of total cases) or pyogenic (33.33% of total cases) infection of the CNS. Tubercular infection is less common, and fungal infection was not seen

Raised CSF ADA levels are highly characteristic in CNS tuberculosis

Mean CSF glucose in our study was lowered in pyogenic (41 mg/dl) infections when compared with other groups

In the viral group, mean CSF protein (70.1 mg/dl) was slightly raised and the mean glucose level (61.1 mg/dl) was within normal limits.

Lymphocytic pleocytosis was seen in the viral and tubercular group, with tuberculosis showing the maximum number of lymphocytes per tap (117 cells). Polymorphonuclear pleocytosis was seen in the pyogenic group

In viral encephalitis and ADEM, fever, and altered sensorium were the most common presenting symptoms. Neuroimaging revealed:

Hemorrhagic involvement of thalamus with/without basal ganglia and brainstem involvement may be seen in JE, as well as in dengue encephalitis

Diffusion restriction or hemorrhage in not expected in the brainstem afflicted lesions of rabies

Congenital CMV can cause cortical malformations which may present as delayed development

T1 hyperintensities with diffusion restriction in neonates may suggest parechovirus encephalitis

Lesions of ADEM may be indistinguishable from viral encephalitis. An antecedent history of fever and response to steroids often helps to solve the clinical dilemma.

In pyogenic meningitis, fever was the most common presenting symptom. Neuroimaging revealed:

Meningeal enhancement and hydrocephalus are the predominant features in pyogenic meningitis with leptomeningeal enhancement seen more than pachymeningeal enhancement and cortical sulcal enhancement seen more than basal enhancement

Pyogenic infections may also cause vasculitis, abscess, and infarcts.

Neuroimaging in tubercular infections revealed:

Basilar pattern of meningeal enhancement is most common. When coupled with the presence of tuberculomas, the findings are highly sensitive as well as specific for the tubercular nature of infection

Vasculitic infarcts in tuberculosis involve the basal ganglia, contrary to the distribution of pyogenic vasculitic infarcts which were seen involving both the deep gray and white matter

The classification of hydrocephalous into communicating or noncommunicating may be misleading as obstructing membranes may be present in the ventricular system, and its exit foramina with concomitant accentuation of the CSF flow void proximal to the membrane. These cases benefit from neuroendoscopic intervention, and the visualization of membranes may be missed on conventional MRI sequences and be visualized only on 3D CISS sequences.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.