Imaging of central nervous system viral diseases

Herpes Simplex Virus Type 1 and 2

Herpes simplex encephalitis (HSE) is the most common cause of acute viral encephalitis. It is associated with high mortality and morbidity. Clinically, patients with HSE present with fever headache, seizures, focal neurologic signs, and impaired consciousness (6). HSV-1 has a predilection for the limbic system and spreads intra-cranially through meningeal branches of trigeminal nerve with frequent involvement of medial temporal and inferior frontal lobes. In addition, extra temporal involvement is seen in 55% of the patients and may be sole abnormality in minority of the patients (7, 8). HSV-2 localizes in the frontal and temporal lobe like HSV-1 and may also cause recurrent aseptic meningitis, myelitis, and radiculitis (6).

Initial CT is normal in up to 25% of HSE patients that may become positive after the second week. Areas of low attenuation with minimal mass effect may be detected in bilateral temporal lobes, which may progress to hemorrhagic lesions (8, 9). CT perfusion studies demonstrate an abnormal increase in regional cerebral blood flow (rCBF) in the involved areas (10). MR imaging is more sensitive than CT in the early detection of lesions within 48 h. Lesions are hyperintense on T2 and hypointense on T1-weighted imaging predominantly involving bilateral inferior and medial aspect of the temporal lobes and insula (Fig. 1). Cingulate gyrus and orbito-frontal regions are other commonly involved locations. Unilateral temporal lobe involvement is not unusual (Fig. 2). Leptomeningeal or gyriform enhancement may be observed with progression of the disease. A few weeks later there is severe atrophy and encephalomalacia involving most of the cerebral hemispheres (2, 11). Both CT and MRI may be useful for demonstration of hemorrhage in HSE but T2*W images are superior in detecting hemorrhage in acute as well as chronic phase (2, 12). Diffusion-weighted imaging (DWI) appears to be more sensitive than conventional imaging for early detection of HSE and correlates with disease activity and response to treatment (13). In acute stage, lesions show significant restricted diffusion with low mean apparent diffusion coefficient (ADC) values while facilitated diffusion with high average ADC values is observed in chronic stage. High ADC values may be associated with benign clinical course (14). Low ADCs value (less than 0.6 × 10⁻³ mm²/s) may help differentiate it from infiltrative temporal lobe tumor (15).

During acute phase ¹H-MRS reveals decreased level of N-acetyl aspartate (NAA) and NAA/creatine ratio and increased choline levels which may simulate infiltrative tumor. Follow up MRI allows differentiation of these two abnormalities, atrophy with encephalomalacic changes in encephalitis and progression of disease in neoplastic lesions (16). The technetium-99m-hexamethyl propylene amine oxime (HMPAO) scan shows focal hyperactivity of the affected brain (17). Diffusion tensor imaging (DTI) shows reduced mean diffusivity (MD) and increased fractional anisotropy (FA) values in the earliest phase and increased MD and reduced FA at day 14 or later (18). However, the imaging findings are sensitive for diagnosis of HSV encephalitis still there are few other rare conditions which also involve bilateral temporal lobes like paraneoplastic limbic encephalitis, Japanese encephalitis and neurosyphilis (19).

HSV-2 infection is usually seen in neonates because of maternal genital lesions which may be transmitted transplacentally or during birth. It rapidly disseminates along the white matter causes destruction of brain tissue and results in seizures, microcephaly, microophthalmia, ventriculomegaly, and multicystic encephalomalacia. Imaging findings resemble HSV-1 infection. In chronic cases atrophic changes with or without calcification in the subcortical white matter and periventricular regions are seen (6, 20).

Rarely HSV may involve brainstem. It shows symmetrical high signal intensity of the bilateral brainstem tegmentum, middle and inferior cerebellar peduncle on fluid attenuating inversion recovery (FLAIR), T2W, and DWI (21). Polymerase chain reaction (PCR) of CSF has a sensitivity of 98% and specificity of 94%. Although PCR is an excellent test and has replaced the routine brain biopsy but negative PCR test results of CSF can occur within the initial 72 h of illness. An early diagnosis is crucial in HSE patients to institute acyclovir therapy and reduce mortality rates. Although no signs are pathognomonic for HSV, it should be considered in the differential diagnosis of unexplained fever, altered sensorium, and seizures in patients who received radiotherapy and steroid treatment. In such cases, DW MRI seems to be better than PCR for early diagnosis of HSE (22).

Varicella Zoster Virus

Primary varicella zoster virus (VZV) infection usually results in chickenpox during childhood. Encephalitis, a rare neurologic complication, usually occurs acutely during the rash but may have a chronic course in an immunocompromised patient. CNS complications of acute varicella, include vasculopathy, aseptic meningitis, leukoencephalopathy, dorsal root or cranial nerve ganglionitis, polyradiculoneuritis, myelitis, ventriculitis, necrotizing angiitis, and meningoencephalitis and affect less than 0.1% of children with chickenpox. Once chickenpox has resolved VZV remains latent in ganglionic neurons (trigeminal and dorsal root ganglia) of the infected person. In approximately 10–20% of cases, VZV reactivates later in life producing a disease known as herpes zoster or shingles. Serious complications of shingles include postherpetic neuralgia, vasculopathy, myelopathy, retinal necrosis, and cerebellitis (23, 24). VZV may spread by means of blood vessels causing vasculitis which results in acute focal deficits and multifocal lesions at the gray–white matter junction and in deep white matter Manifestations of VZV vasculopathy are ischemic infarction of the brain and spinal cord, aneurysm, subarachnoid and cerebral hemorrhage, arterial ectasia and carotid dissection (25).

CT and MR imaging show areas of abnormal signal intensity and swelling of the cerebral cortex, basal nuclei, cortical-white matter junction or cerebellum. Plexitis or radiculitis is characterized by normal or thickened nerve roots with significant post contrast enhancement. In myelitis, long segment of diffuse cord intensity with mild cord expansion is seen on T2WI (26). VZV DNA and anti-VZV IgG antibody in the CSF together with reduced serum/CSF ratio of anti-VZV IgG is used for the confirmation of diagnosis (27).

Epstein-Barr Virus

Acute infectious mononucleosis is the commonest manifestation of Epstein-Barr Virus (EBV), which is usually a benign, self-limiting disease & rarely produces chronic active infection. CNS complications occurs in 7% and include meningitis, encephalitis, acute demyelinating encephalomyelitis (ADEM), cranial nerve palsies, cerebellitis, myelitis, Guillain-Barré syndrome (28). A potential pathophysiological relationship between EBV infection, leukoencephalopathy, and CNS lymphoma has been reported (29). There are few reports describing detailed neuroimaging of the CNS manifestation of EBV. MR imaging in a patient with clinical signs of encephalitis showed multiple diffuse hyperintensities on T2, FLAIR, and DWI especially in parieto-occipital, cortical areas, and splenium of corpus callosum, with low ADC values in these regions. Acute myeloradiculitis and subacute meningomyeloradiculitis show increased signal in the spinal cord and lumbosacral roots (30).

Neuroanatomic distribution of EBV encephalitis may be useful as a prognostic marker. Patients with isolated hemispheric gray or white matter involvement were reported to achieve good recovery while almost half of the patients with thalamic involvement developed late sequelae. The highest mortality rate was among patients with brainstem involvement (31). Definite diagnosis is usually based on fourfold rise in EBV-specific IgM antibodies against viral capsid antigen in serum and positive PCR for EBV DNA in CSF (32).

Cytomegalovirus

It is the most common cause of serious fetal or neonatal brain infection and spread by means of transplacental route. Serious complications occur during peninatal period and in immunocompromised patient. Intrauterine infection may lead to brain necrosis and hydrocephalus. CT and MRI provide complete extent of cerebral involvement. Calcified lesions seen better on CT in the walls of the lateral ventricles. The number of calcifications and extent of ventricular dilatation is much higher if the infection occurs within the first 3 months of intrauterine life (Fig. 3). In these cases, MRI may show lissencephaly, cerebellar hypoplasia, and marked ventriculomegaly (33). Fetuses infected with CMV have shown significantly lower temporal lobe/whole brain ratios with no obvious abnormality on conventional MRI (34).

Reactivation of the virus in the immunocompromised patients leads to dissemination of infection resulting in necrotising meningoencephalitis and ependymitis (35). It presents as ventriculo-encephalitis which involves deep white matter with areas of hemorrhage and necrosis. CT may be normal during the acute stage; however, MRI reveals area of high signal on T2W and low signal on T1W images without contrast enhancement (36). Delayed double-dose CT shows diffuse subependymal enhancement along the ventricular walls which is an important diagnostic sign (37). In patients with CMV retinitis, MRI visualizes thickening and prominent enhancement within membranes of the eye on FLAIR images. Polyradiculopathy is characterized by marked thickening, enhancement, and clumping of the cauda equina nerve roots (38).

Human Herpesvirus Type 6 and Type 7

HHV-6 causes exanthema subitum during childhood and associated with febrile seizures, meningitis and encephalitis in immunocompetent children and adults (39). The virus appears to be the major cause of “post transplant acute limbic encephalitis” which typically involves uncus, amygdala, hippocampal body, entorhinal cortex, and subiculum, with sparing of the parahippocampal gyrus. Involved areas show T2-weighted and FLAIR hyperintensity with restricted diffusion on DWI and faint postcontrast enhancement (40). Extra-hippocampal involvement of olfactory cortex, cortical and subcortical structures is also seen (41). HHV-7 is responsible for febrile seizures, meningoencephalitis, and necrotizing encephalitis involving basal ganglia, brainstem and cortical areas (42).

Japanese Encephalitis

Japanese Encephalitis (JE), a culex mosquito-borne flaviviral encephalitis, remains the single most important cause of acute viral encephalitis on a worldwide basis. It is the major health problem in Asia with case fatality ranging from 10% to 60% and frequent disabling neurologic deficits in the survivors (19). Common clinical features include fever, altered consciousness and seizures. The JE virus invades the nervous system by means of the hematogenous route and subsequent spread occurs along the dendritic axons (44).

On MR imaging, the lesions appear hypointense on T1 and hyperintense on T2WI, with or without hemorrhagic changes predominantly in the thalami but may also involve basal ganglia, brainstem, cerebellum, and cortical areas (44). JE and Wilson disease (WD) show similar topographical distribution of lesions, however, brainstem, anterolateral thalamic involvement is more frequent in WD while posteromedial part of the thalami in JE (45, 46).

Both JE and HSE should be considered in patients with acute encephalitis. The involvement of posterior part of hippocampus, thalami, substantia nigra (SN), basal ganglia, and sparing of anterior temporal lobe allow differentiation from HSE (Fig. 4) (44). DWI is helpful in characterization of the duration of the lesions. The results of DWI in JE are variable, which can be due to difference in stage, severity and duration of disease (3, 14). Some authors have reported that neurocysticercosis predisposes a person to JE infection (47). Others have found it just an incidental observation in areas of high endemicity (48). Laboratory tests may be the only way to differentiate JE from HSE, and it may be prudent to start antiviral therapy in the interim period (49).

West Nile Virus Encephalitis (WNV)

WNV is a mosquito-borne RNA virus of family Flaviviridae. It is maintained in a bird-mosquito transmission cycle. Human, horses and other non-avian vertebrates are usually incidental hosts. In humans, 80% of infections are asymptomatic and nearly 20% cause a mild self-limiting illness called WNV fever. CNS complications like encephalitis, meningitis, myelitis, radiculopathy, and peripheral neuropathy occurs in less than 1% of cases (50). Abnormal MRI findings have been reported in approximately one third of cases. It affects basal ganglia, thalami, mesial temporal structures, brainstem, and cerebellum which show areas of increased signal on T2WI and FLAIR images. DWI may show hyperintense signal with decreased ADC values in the early stages of illness, even when conventional magnetic resonance imaging is normal (Fig. 5) (51, 52).

Dengu Virus Encephalitis

It is a RNA arbovirus belonging to the family Flaviviridae and transmitted by Aedes. There are four different serologic types (dengue 1–4). Infection by any of these has been reported to result in dengue fever, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Various neurologic manifestations of dengue infection include headache, seizure, depressed sensorium, behavioral disorders, neck stiffness, delirium, paralysis, cranial nerve palsies (3).

The serotypes 2 and 3 are the principal agents causing CNS involvement. Neurologic involvement occurs in few patients of dengue infection which occur either by direct involvement of brain and spinal cord (encephalitis and myelitis) or secondary involvement (encephalopathy). A large retrospective study of confirmed cases of dengue has shown encephalitis like generalized cerebral edema, focal abnormalities involving globus pallidus, hippocampus, thalamus, internal capsule, pontine hemorrhage, and acute disseminated encephalomyelitis (Fig. 6). Isolated hippocampus involvement has also been reported (53). Intracranial bleeding is an infrequent finding (3). Transient pancallosal involvement has also been reported (54). Several new techniques like reverse-transcription polymerase chain reaction (RT-PCR) and anti-dengue virus IgM or IgG antibodies by enzyme-linked immunoassay (ELISA) have been developed for rapid diagnosis of dengue virus (55).

St. Louis Encephalitis

St. Louis encephalitis (SLEV) belongs to the family Flaviviridae, transmitted to humans by mosquitos. It is a common cause of epidemic encephalitis in the eastern and central United States (56). MRI shows isolated T2-weighted hyperintensity of the substantia nigra, which correlates with the pathological involvement of the substantia nigra. Although isolated involvement of substantia nigra has also been reported in JE, WNV encephalitis, Eastern equine encephalitis, and tick borne encephalitis, but involvement is usually more diffuse in these conditions (57).

Murray Valley Encephalitis

Also called as “Australian encephalitis,” is caused by infection with a flavivirus belonging to the JE antigenic complex with reported case fatality of 30% (58). Clinical features are nonspecific. MRI demonstrates extensive involvement of bilateral thalami with hypointense on T1 and hyperintense on T2WI, very similar to those seen in JE. Substantia nigra, red nucleus, reticular formation within the midbrain, with extensive involvement of the cervical spinal cord is also common (59). Murray Valley encephalitis (MVE) can mimic HSE, both clinically and radiologically. Hence, accurate and detailed travel history from patients where the risk of exposure to MVE virus is suspected, antibody testing of serum and CSF, and CSF for MVE-RNA should be undertaken (60).

Lyssavirus Encephalitis (Rabies)

It is caused by neurotropic RNA viruses in the family Rhabdoviridae Transmission to humans is mainly through bites of infected rabid dogs (worldwide), bats (America), cats, and other wild animals. The incubation time is usually weeks to months, with an average period of 40 days (3). A local sensory prodrome is thought to reflect a local ganglionitis. The virus replicates in muscle and infects the motor neurons that innervate the muscle, and then spreads to the CNS by means of reterograde axoplasmic flow. There are two form of canine rabies: furious (encephalitic) and dumb (paralytic). In paralytic rabies, the medulla and the spinal cord are mainly involved, whereas in the encephalitic form, brainstem, cerebrum, and limbic system are involved. As the disease has a rapid fulminant course, the available imaging data are sparse in the literature (61).

CT may show focal or diffuse areas of decreased attenuation in the basal ganglia, periventricular white matter, hippocampus, and brainstem. Diffuse cerebral edema may be seen in advanced cases (3). The predominant involvement of gray matter of the brain and spinal cord is a hallmark of rabies and is important in differentiating rabies from acute disseminated encephalomyelitis (Fig. 7) (62). The pattern of ill-defined mild hyperintensities on T2-weighted images in brainstem, hippocampi, thalami, and white matter in a clinical setting of acute encephalitis can be used to suggest rabies and to differentiate it from other mimicking conditions (63).

Measles Encephalitis

Measles is an acute, highly contagious infection caused by the rubeola virus of the paramyxovirus family. It results in three different forms of encephalitis: acute measles encephalitis, subacute sclerosing panencephalitis (SSPE), and measles inclusion body encephalitis (64). Acute measles encephalitis usually occurs in nonimmunocompromised patients, mostly in children and adolescents (65). Typically, patients recovering from measles present with an abrupt onset of renewed fever and a wide variety of neurologic symptoms that includes seizures, altered mental status, and multifocal neurologic signs (66).

Imaging data in acute measles encephalitis are sparse (64). Bilateral symmetric hyperintense lesions on T2-weighted images have been described in putamen and caudate nuclei and the centrum semiovale. DWI shows high signal with low ADC value in the abnormal areas (Fig. 8). Bilateral striatal necrosis, transient pseudoatrophy, and cerebral vein thrombosis have also been reported. Diagnosis is usually made on the basis of clinical course and positive IgM and IgG antibodies to measles in serum and CSF (64, 67, 68).

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a rare postinfectious progressive form of encephalitis usually occurs in children and adolescence as a sequel to early childhood measles infection. Following the original measles infection, the virus remains dormant intracellularly, and manifest as SSPE a decade or so later. The age at presentation is usually 8 to 11 years, with onset usually occurring 6 years after measles infection (69). SSPE is a dramatic disease, starting as minor disturbances in behavior followed by myoclonic attacks and dementia. The disease is incurable and usually causes death within 2 to 4 years of onset. Diagnosis is based on clinical findings, electroencephalogram results, and measles antibodies in the serum and CSF.

Conventional MRI reveals no abnormalities in early stage but widespread periventricular, cortical and subcortical asymmetrical hyperintense lesions may be observed on T2WI in the posterior parts of the brain (Fig. 9) (70). Even in normal appearing cerebral tissue of SSPE, MR spectroscopy studies have demonstrated metabolite alteration. In the early stages, it shows decreased NAA and an increase in choline, suggestive of demyelination and inflammation. Later stages are characterized by a decreased NAA/creatine ratio and increased choline/creatine and myoinositol/creatine ratios suggestive of gliosis and atrophy (71).

Voxel-based morphometery has demonstrated gray matter volume reduction in frontotemporal cortex of patients with SSPE without any apparent lesion on conventional MR imaging (72). Significantly decreased fractional anisotropy values are observed in periventricular white matter of all cerebral lobes with significantly increased mean diffusivity values in periventricular occipital and temporal white matter regions. The splenium of corpus callosum shows significantly low FA with no change in FA and MD values in the genu and mid-body of the corpus callosum and posterior limb of internal capsule. In patients with SSPE, DTI can detect early white matter damages even in the presence of normal findings on conventional imaging. These findings may have significant therapeutic implication (73). The clinical grading of SSPE is not possible on imaging. Tract-specific DTI measures from major white matter tracts correlates with clinical grade of SSPE and help in studying the disease progression and in assessing the therapeutic response. Curative therapy for SSPE is still undetermined (74). Combination therapy with intraventricular alpha-interferon plus isoprenosine gives temporary remission during first 2–4 years of treatment (75).

Mumps Encephalitis

Mumps is caused by a paramyxovirus, Earlier it was the single most common agent producing aseptic meningitis and mild encephalitis. Immunization has markedly decreased the incidence and subsequent complications. Neurologic manifestations of mumps include aseptic meningitis, acute encephalitis, chronic encephalitis, hydrocephalus, ataxia, transverse myelitis, Guillain-Barré syndrome, and deafness. Meningitis which usually has benign course and encephalitis though rare carries mortality rates of up to 22%. The leukoencephalitic pattern demonstrates low attenuation on CT and high signal intensity on T2WI. The diagnosis is usually based on demonstration of a fourfold rise of antibody titer in paired CSF samples (76, 77).

Nipah Encephalitis

Nipha virus a member of the Paramyxoviridae family was named after Kampung Sungai Nipah, the village in Malaysia where the encephalitis outbreak occurred during 1998–99 among pig-farm workers. Radiologic features simulate Japanese encephalitis, consist of multiple small, hyperintense lesions within the subcortical and deep white matter on T2W (Fig. 10). Multiple transient punctuate cortical T1 hyperintensities can also be seen in these patients. The periventricular region, corpus callosum, brainstem and thalamus involvement can also be seen. MR spectroscopy shows decreased NAA and elevated Choline levels during acute stage (78, 79).

Enteroviral Encephalitis

The enteroviruses include Coxsackie viruses A and B, poliovirus, echoviruses, and enteroviruses 68to71 (80). Following the eradication of Poliovirus, Enterovirus71 (EV71) has emerged as a major cause of neurological threat in the world. EV71 is a member of the Picornaviridae family. It may lead to hand-foot-mouth disease or herpangina, cerebellitis, brainstem encephalitis, opsoclonus-myoclonus syndrome, Guillain-Barré syndrome, and transverse myelitis. Enteroviral encephalomyelitis is characterized by symmetric bilateral T2 hyperintense lesion in the dorsal brainstem, dentate nuclei of the cerebellum and ventral horns of cervical spinal cord (80, 81). Enterovirus CSF PCR using “group-specific primers” may fail to reliably detect EV71 (82).

Human Parechoviruses Encephalitis

Human parechoviruses (HPeVs) are RNA virus of Picornaviridae family, cause a spectrum of diseases including aseptic meningitis, gastroenteritis, encephalitis, respiratory diseases, and neonatal sepsis-like disease in newborn infants Most cases of HPeVs infections are asymptomatic or subclinical. It may be detected even in the stool samples of healthy children. Almost all reported cases of HPeVs encephalitis are due to HPeV type 3. It was first isolated in the stools of an infant with transient paralysis in Japan in 2004 (83).

MR imaging shows diffuse punctate white matter lesions, suggestive of petechial hemorrhages on T1 and T2-weighted sequences. DWI provides additional information for early diagnosis and adverse motor outcome later on. Corpus callosum, optic radiation, internal capsule, and cerebral peduncle or rarely brainstem may show increased signal intensity on DWI. HPeV PCR is required to differentiate from EV because of letter may simulate the HPeV (84, 85).

Chikungunya Virus (CHIKV)

Chikungunya virus (CHIKV) is a RNA virus of family Togaviridae spreads by the Aedes mosquito. The disease is usually self-limiting and presents with fever, rash, arthralgia and with diverse neurological complications such as meningoencephalitis, meningoencephalomyeloradiculitis Guillain-Barré syndrome, and cranial nerve palsies. In a large study of 300 patients, neurological complications have been demonstrated in 16.3% (86). Ganesan et al have reported clinical and neuroimaging findings in 2 patients with Chikungunya encephalomyeloradiculitis. Bilateral fronto-parietal white matter lesions with restricted diffusion were seen on brain MR imaging. These lesions showed enhancement in one case. Spinal MR imaging demonstrated enhancement of cauda equine nerve roots (Fig. 11) (87). Various molecular tests such as PCR and RT-PCR have been used for its diagnoses which are rapid and cost-effective (86).

Hantavirus

It belongs to Bunyaviridae family. Puumala virus, a member of the Hantavirus genus has been identified as the etiologic agent for nephropathia epidemica (NE), a hemorrhagic fever with renal syndrome (HFRS). Pituitary hemorrhage can occur during or shortly after acute phase of the infection. Atrophy/panhypopituitarism occurs as a late complication with an empty sella appearance on MR imaging (88, 89).

Adenoviruses

Adenovirus is DNA virus belongs to the Adenoviridae family. They are subdivided into seven species, from A through G, and till date, 52 serotypes have been described. It commonly causes respiratory infections, conjunctivitis, and gastroenteritis especially in children but may become disseminated and life-threatening in the immunosuppressed. Several neurologic syndromes have been attributed to these agents, such as aseptic meningitis, myelitis, subacute focal encephalitis, and Reye-like syndrome. Imaging findings simulates HSV encephalitis. In children, hydrocephalus with periventricular changes and multiple parenchymal hypodensities and in the adults involvement of temporal lobes and bilateral limbic systems have been described on CT and MR imaging. Various available methods for diagnosis of adenovirus include viral culture, detection of adenoviral antigen or of viral DNA, histopathology, and serology (90, 91).

Rotavirus Encephalitis

It is a RNA virus of the family Reoviridae transmitted by feco-oral route and results in severe gastroenteritis in children. There are seven species and humans are primarily infected by species A, B and C (92). Neurological manifestations, ranging from benign convulsions to lethal encephalitis or encephalopathy, occur in approximately 2–5% of patients with rotavirus gastroenteritis. MRI may demonstrate an isolated splenium lesion with homogenously reduced diffusion and abnormal signal in the cerebellar white matter/nuclei. Letter on cerebellar cortical lesions appear followed by cerebellar atrophy (Fig. 12) (93). Diagnosis of infection with rotavirus A is made by identification of the virus in the patient's stool by ELISA. RT-PCR can detect and identify all species and serotypes of human rotavirus (94).

Swine Influenza (H1N1)

The recently emerged novel influenza A (H1N1) virus continues to spread globally. The clinical disease generally appears mild, but unfavorable outcomes have been reported. Neurological sequelae like seizures, encephalopathy, or encephalitis have been reported within 5 days of the initial illness in children with H1N1 infection for the first time from Dallas, Texas. Brain imaging was reported to be normal in these children. Influenza-associated acute encephalopathy/encephalitis (IAE) is an uncommon but serious complication with high mortality and neurological sequelae (95). The first case of neuroimaging abnormalities in H1N1 infection was first reported in a child presenting with acute necrotizing encephalitis with subsequently reporting of other cases from elsewhere. The imaging findings may resemble those with acute necrotizing encephalitis or may present as encephalitis with hemorrhage and typically involve bilateral thalami (Fig. 13) (96, 97). As these patients are known to recover completely on treatment, its early recognition will result in early institution of therapy specific to H1N1 and will possibly help in reducing the associated morbidity and mortality.