Pattern Recognition Approach to Brain MRI Findings in Patients with Dengue Fever with Neurological Complications
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.294556
Source of Support: None, Conflict of Interest: None
Keywords: Dengue, encephalitis, MRI
Dengue virus is a single stranded, non-segmented, ribonucleic acid (RNA) virus, belonging to the flaviviridae family. Four closely related dengue virus serotypes (DENV1–V4) exist and are known to cause dengue fever, a mosquito-borne disease. The disease is endemic in almost all tropical and subtropical countries with the highest incidences being noted in Asia and in Central and South America. Previous WHO classification of symptomatic dengue infections into dengue fever, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) was in vogue several decades and was the cornerstone clinical decision making and management., However, this classification was found to have low sensitivity and very high specificity and was revised in 2009 which included the severe organ manifestations in order to include severe cases requiring intensive care treatment and monitoring. In the new classification, the disease was classified as dengue without warning signs, dengue with warning signs, and severe dengue, with one definition for severe dengue as involvement of the central nervous system (CNS) with impaired consciousness. Classically, dengue is not regarded as a neurotropic virus. Therefore, previously it was not considered as a sentinel encephalitis virus. However, dengue encephalitis is recognized as a distinct clinical entity nowadays and is considered as one of the leading causes of encephalitis in endemic areas,,,, and the disease may primarily manifest as encephalitis.
The neurological complications of dengue are variable and include encephalitis, encephalopathy, meningitis, ischemic and hemorrhagic stroke, cerebellar involvement, longitudinally extensive transverse myelitis, immune mediated syndromes, myositis, and neuro-ophthalmological disorders., The neurological involvement in dengue virus infection can lead to encephalitis as a result of direct invasion of CNS by the virus, whereas encephalopathy can occur or precipitated by several factors like prolonged shock (in cases of DSS), anoxia, cerebral edema, metabolic abnormalities such as hyponatremia, renal or hepatic dysfunction, systemic, or cerebral hemorrhagic diathesis., Postinfectious immune-mediated CNS injury can also lead to neurological manifestations in dengue fever.,
Magnetic resonance imaging (MRI) of brain is crucial for identifying the extent and nature of injury in dengue patients with neurological symptoms. Multiple cranial MRI findings such as ganglio-thalamic, cortical, subcortical and cerebellar involvement, intracerebral hemorrhage, meningitis, and acute disseminated encephalomyelitis (ADEM) have been described in the literature.,,,,,,,,,, Multiparametric MRI is an integral diagnostic tool in the setting of dengue fever presenting with neurological symptoms. Not only does it help in identification of disease nature and extent, it can also identify the underlying pathological processes such as hemorrhage, necrosis, demyelination, and edema and thereby helping in treatment decision and prognostication of the disease. However, the MRI features in the setting of dengue need to be evaluated with caution as other viral encephalitis like Japanese encephalitis (JE) may have similar imaging features and is endemic in dengue endemic areas. In the current study, we describe the cranial MRI findings in dengue patients presenting with neurological signs and symptoms.
In this retrospective study, 36 serologically proven dengue patients presenting with neurological symptoms and undergoing brain MRI over a 6-month period between July and December 2017 were included. The diagnosis of dengue encephalopathy or encephalitis was established by presence of signs/symptoms of acute encephalitic syndrome with the presence of IgM antibody against dengue antibody in the serum and/or presence of dengue antigen (NS1) in serum. Any patients found to have positive serological test for malaria, leptospirosis, scrub typhus, Chikungunya, JE virus, and Herpes simplex virus (HSV) encephalitis were excluded from the study.
Detailed clinical examination was done for all the patients. The presence of fever (along with pattern and periodic temperature recording), headache, nausea, vomiting, pallor, icterus, edema, bleeding diatheses, sensorium, and seizure (with number of episodes and pattern of seizure) were recorded. Vital parameters such as pulse, blood pressure, respiratory rate, temperature, and urine output were recorded. The level of consciousness was assessed using Glasgow Coma Scale (GCS). General systemic examination was done for all patients. Detailed neurological examination was done for all patients as far as feasible. Fundus examination was done for all patients to look for presence of papilledema. In cooperative patients, sensation and cerebellar signs were tested as well.
Hemoglobin, hematocrit level, total and differential white blood cell counts, coagulation profile (platelet count, prothrombin time, activated partial thromboplastin time), blood sugar, blood ammonia, blood urea nitrogen, serum creatinine, bilirubin, transaminases, sodium, potassium, chloride, and calcium were done for all patients. Chest X-ray, electrocardiogram, and ultrasound of abdomen were done as well. Cerebrospinal fluid (CSF) analysis was done in patients with platelet count at least >40,000/mm3 and was examined for cells, sugar, and proteins. IgM antibody against dengue virus and dengue antigen (NS1) were tested in serum in all patients. The diagnosis of JE was excluded by negative CSF IgM ELISA, and Leptospira and Chikungunya by serum IgM ELISA. Peripheral blood smear was examined for malarial parasite as well as rapid dual antigen test for malaria parasite.
The MRI included following sequences: 2D axial T2 and FLAIR sequences for brain, pre- and postcontrast 3D T1 spoiled gradient recalled sequence, postcontrast 3D FLAIR sequence, diffusion weighted images, and susceptibility weighted images. The diffusion weighted images were acquired using single-shot fast spin-echo echoplanar sequence with sensitizing gradients applied in all three orthogonal planes with b values of 50 and 1000 s/mm2. The 2D sequences were acquired using a slice thickness of 4 mm, whereas the 3D sequences were acquired using a slice thickness of 0.9 mm. Intravenous gadolinium (Gd-DTPA) was injected at a dose of 0.1 mmol/kg of body weight for postcontrast sequences unless the use of gadolinium-based contrast agents was contraindicated in the patient. All the MR images were evaluated by an experienced neuroradiologist having 10 years of experience in evaluating brain MRI.
A total of 36 patients (23 men, 13 women; mean age of 29.84 years and age range of 2–70 years) were included in this study. Nine patients (25%) were in the pediatric age group (<18 years of age) whereas the rest were in the adult age group.
Classification of the patients as per WHO classification (2009)
Five patients were classified as dengue without warning signs, nine were classified as dengue with warning sign, and the rest were classified as severe dengue.
Indication for MRI
Twenty cases underwent MRI for acute onset of altered sensorium, whereas six patients underwent MRI for altered sensorium with associated seizure. Rest of the patients underwent MRI for acute onset severe headache and/or concomitant suspicion for intracranial hemorrhage.
The clinical and demographic profiles of the patients undergoing brain MRI are summarized in [Table 1].
Of 36 cases, 11 cases were found to have no significant abnormality on MRI. Varying degrees of abnormality were found in rest of the 25 patients. The imaging findings are described based on a pattern recognition approach.
Of 25 cases having positive MRI finding, 12 were found to have MRI abnormality consistent with an encephalitic pattern. The diagnosis was considered when there was involvement of basal ganglia, thalami, cerebellar structures, brainstem and cortical gray or subcortical white matter in isolation or combination. In five patients, involvement of basal ganglia, thalami, cerebellar structures, and brainstem was seen. Involvement of cortex and subcortical white matter in addition to involvement of basal ganglia, thalami, brainstem, and cerebellum was seen in three patients. Involvement of cerebellum and brainstem without ganglio-thalamic involvement was seen in three patients. Isolated cerebellar involvement was noted in one patient. Altered signal intensity (SI) was noted in the form of T2/FLAIR hyperintensity and T1 hypointensity in the structures involved in all the patients. True diffusion restriction with hypointensity on corresponding apparent diffusion coefficient (ADC) maps was noted in the areas of altered SI in all the cases. Interspersed hemorrhage was seen in the area of altered S.I in 8 of the 12 patients. Mild patchy postcontrast enhancement was seen in four of the cases in the areas of altered SI. Six of the 12 patients in this group had platelet count less than 20,000/mm3, whereas rest 6 had platelet count below 50,000/mm3. A typical case demonstrating the encephalitic pattern is shown in [Figure 1].
Encephalopathy pattern including posterior reversible encephalopathy syndrome
Two patterns of MRI brain changes consistent with encephalopathy were encountered– seizure-related/metabolic encephalopathy and posterior reversible encephalopathy syndrome (PRES). Two patients were found to have diffuse cerebral edema with altered S.I in bilateral hippocampi, whereas in one patient, white matter structures (periventricular and frontoparietal deep and subcortical white matter and corpus callosum) were involved without features of cerebral edema. These features are consistent with seizure-related encephalopathic changes. The posterior parieto-occipital subcortical white matter predominant pattern of involvement suggesting PRES was found in one patient. The prototypical patterns of different variants of encephalopathic pattern are shown in [Figure 2].
Acute disseminated encephalomyelitis
Three patients showed presence of multifocal, asymmetrical, non-enhancing, fluffy T2/FLAIR hyperintensities involving the bilateral periventricular and frontoparietal white matter which is suggestive of an imaging diagnosis of ADEM. Brainstem, cerebellar, and involvement of gangliothalamic complexes are not seen in any of the cases. In two of these cases, diffusion restriction was present within the lesions, whereas in one patient, true diffusion restriction was absent; and the lesions showed increased mean diffusivity and appeared bright on both diffusion weighted imaging (b = 1000) and ADC map. The imaging for this group of patients was done at 8th, 10th, and 13th day after onset of fever. The prototypical case is shown in [Figure 3].
Six of the 25 patients with positive MRI findings showed presence of either intracranial macro- or micro-hemorrhage or both. The cases of hemorrhagic encephalitis are not considered under this group. Only cases with isolated intracranial hemorrhage are considered under this subgroup. All the six patients were found to have thrombocytopenia (<20,000/mm3 in five of the cases and <30,000/mm3 in one of them). In four patients, multiple punctate foci of micro-hemorrhages, which appeared as foci of blooming on susceptibility weighted imaging (SWI) sequence, were seen scattered in bilateral cerebral and cerebellar hemispheres and brainstem. One patient had right frontal intra-parenchymal hematoma with multifocal micro-hemorrhages in basal ganglia, thalami in addition to bilateral cerebral and cerebellar hemispheres [Figure 4]. In another patient, isolated intra-parenchymal hemorrhage was seen at right parietal region. The imaging findings in different patterns are summarized in [Table 2].
Outcome of the cases
Of the 36 cases included in the study, 16 had a good outcome and were discharged from the hospital in after acute episode in a fairly satisfactory status. In the rest of the 20 patients, 8 hospital deaths were encountered. Four patients were discharged with decreased sensorium (GCS >12), whereas eight patients were discharged in a conscious, oriented state with residual deficit (four with hemiparesis, two with swallowing difficulty requiring nasogastric feeding, and two with truncal ataxia). Of the 10 patients having normal MRI, 9 had good outcome, whereas1had poor outcome.
Causes of death
Autopsy was not performed in any of the patients. The cause of death in all eight patients was attributed to multi-organ dysfunction.
Follow-up MRI was available in five cases at a mean interval of 3.6 months. Two patients were form the encephalitis group which showed volume loss with gliosis in the areas involved in the index scan. Follow-up imaging of one case of each of ADEM and seizure-related encephalopathy was available and showed no residual abnormality. One case of macro-hemorrhage also had a follow-up scan which showed evolution of the hematoma to a chronic stage with surrounding gliosis.
Dengue is a RNA virus, which has four closely related serotypes and is the causative agent for the dengue fever which is endemic in almost all tropical and subtropical countries. The disease is a significant burden to society as it is associated with high morbidity and mortality. Dengue fever generally manifests as fever with associated myalgia and arthralgia, retro-orbital or frontal headache, rash, nausea, and vomiting. Varying degree of thrombocytopenia is generally encountered in patients with dengue fever. Although multi-organ involvement is a common feature of complicated dengue infection, the neurological manifestations are of particular significance because of long-standing disabilities associated with it. Traditionally, the dengue virus is considered to be a non-neurotropic virus. However, the neurological complications associated with dengue are on the rise and it is more frequent with the DENV2 and DENV3 serotypes. The neuro-invasive capability of dengue virus has been established by demonstration of dengue IgM antibodies in CSF. Direct invasion of the blood–brain barrier leading to its disruption and CSF migration of the infected macrophages from the peripheral blood are the two proposed mechanisms of CNS invasion by dengue virus. Isolation of dengue antigen from the brain was also possible in postmortem studies. However, the actual mechanism of neurological involvement in dengue is controversial and can be attributable to direct viral invasion, metabolic imbalance, hemorrhagic diathesis, or postinfectious autoimmunity activation. Broadly based on these pathophysiologic mechanisms, the neurologic manifestations of dengue can be broadly classified into three subtypes –encephalitis/meningitis/myelitis secondary to direct neuro-invasion by the virus, systemic complications manifesting with neurological features –metabolic/seizure-related encephalopathy and hemorrhagic stroke secondary to thrombocytopenia, and lastly, postinfectious activation of autoimmunity leading to ADEM and myelitis.
MRI plays a definitive role in the setting of dengue fever as it can accurately and noninvasively diagnose the degree and extent of involvement of the CNS. In addition, with the help of multi-parametric MRI, it is possible to identify the underlying pathophysiologic mechanism. Based on this, a pattern reorganization approach has been proposed in our study.
Dengue encephalitis is one of the leading causes of encephalitis in endemic countries.,, Although the definitive diagnosis of encephalitis can be done by histopathological analysis only, the presence of focal lesions instead of global lesions on MRI generally favors a diagnosis of encephalitis over encephalopathy. Most commonly affected brain structures in the encephalitic process in the setting of dengue are basal ganglia, thalami, brainstem, cerebellum, cortical gray matter, and subcortical and deep white matter. In our study, predominant involvement of basal ganglia, thalami, brainstem, and cerebellar involvement was noted in 8 of the 12 patients of encephalitis group, whereas brainstem and cerebellar involvement without ganglio-thalamic involvement was seen in 3 patients. One patient was found to have isolated cerebellar involvement. Concomitant involvement of cortex and subcortical WM in addition to basal ganglia, thalami, midbrain, and cerebellum was noted in three patients. These findings are similar to previous case reports, case series, and studies.,,,,,,,,, In most of the larger studies, a predominant pattern of involvement of basal ganglia, thalami, brainstem, and cerebellum were described.,, In one of the previous case series, eight cases of predominant cerebellar involvement were described. In one of the studies, commoner involvement of posterior structures like brainstem and cerebellum has been described which is similar to that found in our study. The involvement of peripheral cerebellar structures was found to be more common than central cerebellar structures in the same study. However, similar propensity of involvement of peripheral and central cerebellar structures was not noted in our study. Only three of the cases in our encephalitis were found to have involvement of cortex and subcortical white matter, which is comparatively less compared to previous studies., The asymmetric pattern of involvement of cerebral white matter and superficial to deeper gradient of involvement of white matter, observed in one of the previous studies, were also noted in our study population; however, the patients with cerebral white matter involvement in our study population were relatively less making it difficult to opine definitely.
In all the cases in the encephalitis group, T2/FLAIR hyperintensity and T1 hypointensity were noted in the affected structures. True diffusion restriction was noted in at all the areas of altered S.I in all the cases in our series. Presence of diffusion restriction in the setting of dengue encephalitis in the involved structures has been described in the literature.,,, While most of these studies found diffusion restriction in variable number of cases,,, one of the studies found diffusion restriction in all the cases – similar to our study. Interspersed hemorrhage in the areas of altered signal intensity was found in 8 of the 12 cases in the encephalitis group. Dengue virus is a well-known and established cause of hemorrhagic viral encephalitis. The presence of hemorrhagic foci in the areas of altered SI has been well described in previous case series and literature.,,,,, Mild patchy heterogeneous postcontrast enhancement is seen in 4 of the 12 cases in this group, which is likely attributable to disruption of blood–brain barrier in the setting of dengue encephalitis.
Common differential diagnoses that must be taken into consideration while dealing with the encephalitic pattern of dengue infection include JE and HSV encephalitis and ADEM. Bilateral involvement of ganglio-thalamic complex is the typical anatomical site for JE, whereas bilateral involvement of temporal and basifrontal lobes is common in HSV encephalitis., Although presence of hemorrhagic foci is not a common finding in JE, it has been reported in literature., Thus, the presence of hemorrhage may favor a diagnosis of dengue over JE; however, it cannot be entirely conclusive. On the other hand, the presence of hemorrhagic foci is a relatively common finding in HSV encephalitis. Therefore, the differentiation between different viral encephalitis based on MRI features can be extremely difficult. The possibility of dengue encephalitis has to be considered particularly in the endemic region, especially during the seasons of outbreaks. Serological analysis and CSF analysis as well as patient's clinical profile must be taken into consideration before reaching a final diagnosis and good clinico-radiological concordance must be established prior to reaching a final diagnosis. Differentiating features between postinfectious ADEM and dengue encephalitis are discussed latter.
Isolated cerebellitis, as found in one of our cases, can be a presentation of dengue. One notable case series described the presence of predominant cerebellar involvement in dengue patients presenting with cerebellar symptoms. Although cerebellar involvement in dengue is considered to be due to postinfectious autoimmune process, viral antigens have been demonstrated in cerebellar cells in patients infected with dengue. Thus, primary cerebellar involvement can be considered when encountered in acute phase of disease. Other infectious causes of cerebellitis include listeria, Epstein–Barr virus, Coxsackie virus, Varicella-zoster virus, mumps, measles, herpes, and rarely, JE. Our case of isolated cerebellitis presented with fever and rash and had positive cerebellar signs and was found to be seropositive for dengue; hence, a diagnosis of dengue cerebellitis was made.
The term dengue encephalopathy is reserved for the cases where the brain MRI findings are secondary to systemic complications associated with dengue fever and not the result of direct neuronal invasion by virus. The plausible systemic complications that can be associated with brain MRI abnormalities include febrile seizure/status epilepticus-induced hypoxia, cerebral hypoperfusion secondary to shock, hepatic encephalopathy, electrolyte abnormalities, and leaky capillaries causing cerebral edema or PRES. In our study population, two cases were found to have diffuse cerebral edema with T2/FLAIR hyperintensities in bilateral hippocampi. Both the patients were seropositive for dengue and were having features of DSS as well as having repeated episode of status epilepticus. The presence of cerebral edema in these patients may be partly attributable to seizure and partly to leaky capillaries associated with DSS. Another patient in our study population, who was seropositive for dengue and having repeated seizure episodes, was found to have confluent areas of T2/FLAIR hyperintensity involving the bilateral periventricular and frontoparietal white matter and corpus callosum with intense diffusion restriction and is likely a sequel of profound seizure-related hypoxia.
PRES is found in one patient in our study group. The findings of PRES in the setting of dengue have been described in literature and are likely secondary to leaky capillaries.,, In our case, bilateral posterior parietal subcortical white matter T2/FLAIR hyperintensity was noted which was showing facilitated diffusion. Thus, the brain MRI findings in dengue that are related to the systemic complication of dengue fever are a distinct entity from the findings of dengue encephalitis that occurs due to neurotropism of the dengue virus.
Acute Disseminated Encephalomyelitis
ADEM refers to immune complex-mediated white matter injury, encountered during convalescent phase of viral illness or after vaccination. Involvement of cerebral white matter and deep gray nuclei is typically seen in ADEM. Incidence of hemorrhage is relatively low in ADEM. Distinguishing between dengue encephalitis and post-infectious ADEM can be extremely difficult at times. The most important distinguishing feature in this setting is the temporal relationship between the onset of fever and the appearance of lesions on MRI. Although the diagnosis of dengue encephalitis is more likely during the acute phase of the disease, the diagnosis of ADEM is more likely in the convalescent period of the disease. The onset of post-dengue ADEM has been described from 3 to 19 days of dengue infection in one meta-analysis.
Few studies and case reports of dengue-associated ADEM are available in literature.,,,, In our study population, three cases of ADEM were diagnosed. MRI has been done on 8th, 10th, and 13th day of onset of fever in all the patients. Multifocal, asymmetrical, non-enhancing, fluffy T2/FLAIR hyperintensities involving the bilateral periventricular and frontoparietal white matter were noted in all the cases. Diffusion restriction was noted in two of the cases, whereas facilitated diffusion was noted in one of the cases. Diagnosis of post-dengue ADEM and its distinction from dengue encephalitis is of paramount importance as the former requires treatment in the form of immunosuppressive drugs like corticosteroids, whereas the treatment of later is generally supportive.
Despite the presence of thrombocytopenia associated with dengue, the incidence of intracranial hemorrhage (ICH) associated with dengue is significantly less compared to cutaneous and systemic hemorrhagic complications.,,, Only 3 patients (0.26%) had an ICH out of 1148 confirmed dengue hospitalized patients in an epidemic of dengue while in Brazil, only 1 patient was diagnosed with ICH out of 1585 patients with dengue. In our study population, six patients had intracranial hemorrhage of which four had multifocal petechial micro-hemorrhages. One patient had multifocal micro-hemorrhages with associated lobar macro-hemorrhage and one patient had isolated lobar macro-hemorrhage. The relatively higher incidence of ICH in our study population is possibly because of inclusion of dengue-seropositive patients with neurological symptoms rather than general dengue-seropositive population without neurological symptoms and also because of use of SWI sequence which has better sensitivity in diagnosing micro-hemorrhages compared to conventional MRI sequences.
The major limitation of our study stems from the fact that our study population represents only a very small population of dengue-seropositive patients who underwent MRI brain because of their neurological symptoms. Therefore, similar results can be expected in the comparable patient population. The other major limitation of our study is lack of follow-up imaging in majority of the patients. Better insight into the pathophysiology of the disease could have been obtained if follow-up imaging were performed.
MRI is an important tool for demonstrating the degree of brain involvement in dengue infection. Although the findings are not entirely unique to dengue, it can help to narrow down the list of differential diagnosis particularly when coupled with serological tests and CSF analysis. A pattern-based approach to evaluating the brain MRI in combination with patient's clinical details in the setting of dengue can help the radiologist to identify the definitive underlying pathologic process. This is of particular significance in differentiating between dengue encephalitis and post-dengue ADEM because of their different treatment strategies.
Ethical approval: All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]