Immune trafficking across the BBB

Immune surveillance of the CNS is carried out by peripherally activated T-cells which traverse the BBB to gain access to the perivascular and subarachnoid spaces, even in normal physiological states. ^{Reference Meyer, Martin-Blondel and Liblau16} This is due to the special properties of the BBB, which, unlike peripheral endothelium, lacks P-selectin protein and expresses an atypical chemokine receptor 1 (ACKR1). ^{Reference Mapunda, Tibar, Regragui and Engelhardt13} The physiological immune entry is restricted to just T-cells which are independent of these trafficking cues. ^{Reference Mapunda, Tibar, Regragui and Engelhardt13} T-cell entry is a complex, multistep process involving initial tether (capture) onto the endothelium, followed by selectin-facilitated rolling, effectively reducing the speed of the T-cells. ^{Reference Nourshargh and Alon17} Chemotactic cues are later recognized allowing integrin-mediated cell arrest, crawling and finally diapedesis across the BBB. ^{Reference Nourshargh and Alon17}

During neuroinflammation, endothelial cells upregulate vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM1). These interact with αLβ2 and α4β1 on CD4+ T-cells, resulting in T cell arrest. ^{Reference Kadry, Noorani and Cucullo18} Multiple studies have proposed that activated leukocyte cell adhesion molecule (ALCAM), melanoma cell adhesion molecule (MCAM) and nerve injury-induced protein (ninjurin-1) also play a role in the migration of T-cells across the BBB in conditions such as autoimmune encephalomyelitis and multiple sclerosis. ^{Reference Mapunda, Tibar, Regragui and Engelhardt13,Reference Ifergan, Kebir and Alvarez19} It must be mentioned that the precise migration mechanisms of other immune cells (B cells, neutrophils, monocytes and dendritic cells) across the BBB are not fully understood. ^{Reference Mapunda, Tibar, Regragui and Engelhardt13} B cell migration is thought to be mediated by endothelial ICAM-1 with α4β1integrin, chemokines (CCL2 and CXCL8) and ALCAM. ^{Reference Marchetti and Engelhardt20}

Parechovirus encephalitis

The Parechovirus A (PeV-A) or the Human Parechovirus (HPeV), is a single-stranded RNA virus belonging to the Picornaviridae family. ^{Reference Sridhar, Karelehto, Brouwer, Pajkrt and Wolthers26,Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27} Of the 19 known genotypes, PeV-A3 commonly affects young infants. ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27} It is contracted via respiratory or gastrointestinal routes; CNS infection is secondary to hematogenous dissemination. ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27} Maternofetal transmission is not uncommon (30%-50%). ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27}

Symptomatology may vary from minor gastroenteritis or respiratory symptoms to fever, rash, irritability and sepsis with occasional CSF pleocytosis. ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27} Children < 2 years of age are at the highest risk of infection, with illness being particularly severe in children < 6 months of age (27). ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27}

Following infection, innate and adaptive immune responses are triggered. PRRs (TLRs, retinoic acid inducible gene I, and melanoma differentiation-associated gene 5) form the main defense mechanisms. ^{Reference Sridhar, Karelehto, Brouwer, Pajkrt and Wolthers26} TLR7 and TLR8 identify the viral RNA and activate the NF-κβ signalling pathway leading to the secretion of pro-inflammatory cytokines (IFN-β, TNF-α, IL-6). ^{Reference Sridhar, Karelehto, Brouwer, Pajkrt and Wolthers26} The role of T-cell immunity in parechoviral infection is not understood, though an increased T-cell proliferation has been noted in response to PeV-A1 capsids. ^{Reference Sridhar, Karelehto, Brouwer, Pajkrt and Wolthers26} Owing to the immature immune system in neonates, the elevated levels of pro-inflammatory cytokines and systemic inflammatory response have been linked to the severe pathogenesis of parechoviral infection. ^{Reference Sridhar, Karelehto, Brouwer, Pajkrt and Wolthers26} Neonatal sepsis (systemic inflammatory response syndrome) is a severe, but common, manifestation of PeV-A3 and is associated with increased vascular permeability and reduced BBB function, allowing leakage of the virus into the CNS. ^{Reference Sridhar, Karelehto, Brouwer, Pajkrt and Wolthers26} Preferential neuroaxonal tropism may be one cause of the distinct imaging pattern of the white matter involvement. ^{Reference Westerhuis, Koen and Wildenbeest28} Given the radiating pattern of involvement, the hypothesis of perivenular invasion or venous ischemia has also been proposed. This is supported by the postmortem examinations of two premature neonates, in which only periventricular inflammatory changes with marked macrophage infiltration and moderate astrocytosis were observed. ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27,Reference Bissel, Auer and Chiang29}

On cranial ultrasound, hyperechogenicity in the periventricular and deep white matter may be seen. On MRI, diffuse, multifocal signal abnormality and restricted diffusion in the subcortical white matter, with a frontal predominance, is a common finding ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27} (Fig. 7). Branching T1- and T2 shortening along the deep medullary veins is also a common finding. ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27} Thalamic involvement may be seen while the basal ganglia, hippocampal formations and posterior fossa structures may be spared. ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27} Additionally, a lactate peak may be encountered on MR spectroscopy; however, contrast-enhanced MRI, MR angiography and MR venography are typically normal. ^{Reference Sarma, Hanzlik, Krishnasarma, Pagano and Pruthi27}

Figure 7.

Parechoviral infection in a neonate presenting with fever and seizures. Diffusion-weighted imaging (DWI; A-F) reveals near symmetric restricted diffusion (ADC not shown) extensively involving the cerebral white matter bilaterally. Note the linear, radiating pattern of the signal abnormality (arrows) towards the subcortical and juxta-cortical white matter. Restricted diffusion is also noted in the corpus callosum (dotted arrows in C) and the dorsolateral thalami (dotted arrows in D), suggestive of preWallerian degeneration ADC = apparent diffusion coefficient.

Cerebral malaria

Malaria is a mosquito-borne disease, transmitted through the bite of a Plasmodium-infected female Anopheles mosquito. While multiple species are known to cause malaria, P. falciparum and P. vivax are the main cause of complications in humans, including cerebral malaria (CM). ^{Reference Schiess, Villabona-Rueda, Cottier, Huether, Chipeta and Stins30} CM commonly presents with impairment in consciousness and encephalopathy, with or without seizures, eventually progressing to coma. ^{Reference Schiess, Villabona-Rueda, Cottier, Huether, Chipeta and Stins30} Despite treatment, focal neurological signs and symptoms may persist, with signs of brainstem dysfunction being common in pediatric survivors. ^{Reference Schiess, Villabona-Rueda, Cottier, Huether, Chipeta and Stins30}

Understanding the pathogenesis of CM has been confounded by the fact that plasmodium-infected red blood cells (PRBCs) remain within the vascular lumen and do not physically damage the parenchyma. ^{Reference Schiess, Villabona-Rueda, Cottier, Huether, Chipeta and Stins30} It is now known that cerebral microcirculatory disturbances cause the clinical manifestations of CM ^{Reference Shikani, Freeman, Lisanti, Weiss, Tanowitz and Desruisseaux31} PRBCs undergo a process known as sequestration, by virtue of which they adhere to the endothelium with the help of a specific cell-surface ligand (P. Falciparum erythrocyte membrane protein 1). ^{Reference Shikani, Freeman, Lisanti, Weiss, Tanowitz and Desruisseaux31} It is encoded by a variable gene (var-gene) and interacts with host adhesion receptors (ICAM-1, EPCR, CD36). ^{Reference Schiess, Villabona-Rueda, Cottier, Huether, Chipeta and Stins30} Sequestration subsequently leads to multiple downstream cerebrovascular effects such as vasoconstriction, cerebral blood flow impediment, luminal obstruction and BBB disruption. ^{Reference Shikani, Freeman, Lisanti, Weiss, Tanowitz and Desruisseaux31} Apart from these mechanical effects, an alternate hypothesis related to cytokine storm has also been proposed based on the observation of increased neutrophil activation and increased production of cytokines (TNF, IFN-γ, IL-2, IL-6, IL-8 and IL-10) ^{Reference Schiess, Villabona-Rueda, Cottier, Huether, Chipeta and Stins30} (Fig. 8).

Figure 8.

Pathophysiology of cerebral malaria. The rupture of infected red blood cells leads to the release of merozoites which activate macrophages and dendritic cells which in turn causes the release of TNF and IFN-γ. These increase the expression of VCAM1 and ICAM1 on the endothelial cells in the BBB which further recruits more infected RBS, hence promoting inflammation and stimulating pro-coagulation pathways. PRRs detect malarial PAMPs and trigger the secretion of cytokines including IL-6, IL-12, and TNF. This also leads to increased recruitment of basophils, neutrophils, and NK cells. Upon activation these cells release chemokines (MIP-1 α and MIP-1β) which damage the integrity of the BBB. In addition, the endothelial cells of the BBB present the malarial antigen to CD8+ T cells in the brain which incites CD8+ T cell–mediated endothelial cell death (mediated by granzyme B). Following BBB breakdown, parasite-derived proteins and peripheral immune cells gain access to the brain. This triggers astrocyte and microglial activation which increases proinflammatory cytokines and chemokines production (e.g., MAP kinase-mediated cytotoxic pathway) which causes axonal loss. (Created with BioRender.com). BBB = blood–brain barrier; NK = natural killer; PRRs = pattern recognition receptors.

The neuroimaging features of CM are variable, especially due to isolated case reports and small case series. Typical imaging findings include diffuse neuroparenchymal swelling with increased T2 signal intensity, affecting the cerebral hemispheres more than the posterior fossa structures. ^{Reference Kampondeni, Potchen, Hommel and Kremsner33} In a cohort of 120 Malawian patients with CM, Potchen et al found moderate-to-severe cerebral edema, resulting in narrowing of CSF spaces and uncal herniation, was the most prevalent finding (47.5%). ^{Reference Potchen, Kampondeni and Seydel32} Some variability in the distribution was also noted, with 24.6% and 7.0% demonstrating supratentorial and infratentorial swelling respectively. ^{Reference Potchen, Kampondeni and Seydel32} In a study of pediatric patients admitted with CM by Seydel et al, 21 (81%) out of the 25 patients who died demonstrated MRI evidence of severe brain swelling at the time of admission (odds ratio for brain swelling among patients who died vs. survivors was 14.0; 95% CI, 4.5–43.4). These patients died as a result of respiratory arrest, consistent with the effects of elevated intracranial pressure. However, in this study, it was notes that brain swelling in the setting of CM does not always translate into fatality as the authors found that approximately 65% of the patients with severely increased brain volume survived with long-term outcomes similar to survivors with normal brain volumes. They concluded that interventions to decrease brain swelling and to sustain respiration temporarily could reduce mortality without an increased in morbidity. ^{Reference Seydel, Kampondeni and Valim34}

Signal alterations in the deep gray nuclei have also been described. Hyperintense T2 signals in the basal ganglia was common in the study conducted by Potchen et al (84.2%); predominant involvement of the globus pallidus was seen in a few cases. ^{Reference Potchen, Kampondeni and Seydel32} Restricted diffusion in the basal ganglia was also seen (42%). ^{Reference Potchen, Kampondeni and Seydel32} Thalamic involvement (64.2%) was observed, but associated restricted diffusion was uncommon. ^{Reference Potchen, Kampondeni and Seydel32} Petechial cerebral hemorrhagic foci may also be noted on susceptibility weighted images (SWI). ^{Reference Kampondeni, Potchen, Hommel and Kremsner33}

Potchen et al also described T2-hyperintense cortical swelling (61.7%), typically not following a vascular distribution, however, cortical restricted diffusion was noted in 20.8% of cases. ^{Reference Potchen, Kampondeni and Seydel32} These areas of restricted diffusion resolve in survivors, with no sequalae after a month, but persist or worsen in patients who succumb to the illness. The etiology of this phenomenon is still not completely understood. ^{Reference Kampondeni, Potchen, Hommel and Kremsner33}

Increased T2 signal in the white matter (71.7%) was commonly accompanied by DWI abnormalities (45.0%) in the study by Potchen et al. ^{Reference Potchen, Kampondeni and Seydel32} Callosal T2 hyperintensity was also seen in (49.2%) commonly in the absence of other white matter changes. ^{Reference Potchen, Kampondeni and Seydel32} In their cohort, cerebellar involvement was not uncommon (49.2%), ranging from diffuse involvement to multifocal areas or unifocal lesions, while restricted diffusion in the cerebellum was uncommon. ^{Reference Potchen, Kampondeni and Seydel32} In our experience, we have encountered a case of CM showing restricted diffusion and T2-prolongation involving the juxta- and subcortical white matter, with a near symmetric distribution (Fig. 9).

Figure 9.

Cerebral malaria in patient presenting to the emergency department in deep coma. Axial DWI (A, C) and corresponding ADC (B, D) images show restricted diffusion involving the juxta- and subcortical white matter bilaterally. A diagnosis of CM was made based on peripheral smears and the patient survived after intensive treatment with anti-malarial regimens and supportive management. ADC = apparent diffusion coefficient; CM = cerebral malaria; DWI = diffusion-weighted imaging.

Approximately 30% of those who survive CM develop structural brain abnormalities and are often associated with seizures, developmental delay, behavioral problems and multiple neurological deficits. ^{Reference Kampondeni, Potchen, Hommel and Kremsner33} Volume loss of the brain parenchyma is the most common finding, seen as early as within 2 weeks after coma resolution. Periventricular and subcortical T2 hyperintense signal abnormality in almost 47 % and 18 % of all cases, respectively. Focal areas of cerebral cortical defects / encephalomalacia and isolated vermian atrophy may also be encountered. ^{Reference Kampondeni, Potchen, Hommel and Kremsner33}

Febrile infection-related epilepsy syndrome (FIRES)

Status epilepticus (SE) is a common neurological condition, occasionally preceded by febrile illness in some patients. ^{Reference Gaspard, Hirsch and Sculier35} This entity has various names including new-onset refractory SE (NORSE), febrile illness-related epilepsy syndrome (FIRES), acute encephalitis with refractory repetitive partial seizures (AERRPS) and devastating epilepsy in school-age children (DESC). ^{Reference Gaspard, Hirsch and Sculier35} NORSE is defined as a clinical presentation, not a specific diagnosis, in patients with new onset of refractory SE without a clear acute /active structural or toxic-metabolic etiology. ^{Reference Gaspard, Hirsch and Sculier35} FIRES, a subcategory of NORSE, present following a febrile illness with fever occurring 2 weeks to 24 hours prior to onset of refractory SE. ^{Reference Gaspard, Hirsch and Sculier35} The exact etiology of FIRES is unknown. While few cases have tested positive for mycoplasma and adenovirus, however, no pathogen has been isolated in a vast majority of cases. ^{Reference Reppucci and Datta36} Autoimmunity has also been implicated with reports of anti-glutamate receptor antibodies or anti-glutamic acid decarboxylase antibodies and IL6/IL8 obtained from CSF. ^{Reference Reppucci and Datta36} Genes including SCN2A and PCDH19 have been reported. ^{Reference Kessi, Liu and Zhan37} Febrile illness causes the release of pro-inflammatory cytokines and chemokines which lower the seizure threshold secondary to ion channel function modification while promoting neuronal excitability. ^{Reference Reppucci and Datta36} These may also prime innate immunity activation in seizure-prone areas of the brain and alter cellular components in the BBB, thereby triggering a neuroinflammatory cascade. ^{Reference Reppucci and Datta36} Activation of microglial NLRP3 inflammasome/IL1 axis has been proposed, leading to a proinflammatory-proconvulsive milieu. ^{Reference Reppucci and Datta36} FIRES also shows elevation of pro-inflammatory profile including interleukin IL-6, C-X-X motif chemokine ligand 8 (CXCL8) and C-C motif ligand L3 and 4 (CCL4 and CCL3) as well as IL-1β. ^{Reference Reppucci and Datta36,Reference Kessi, Liu and Zhan37} IL-1β in particular lowers the seizure threshold and is endogenously antagonized by IL-1Ra, encoded by the IL1RN gene. ^{Reference Saitoh, Kobayashi and Ohmori38} Patients with the variable number of tandem repeat (VNTR) allele of the IL1RN, RN2, carry a higher risk of FIRES as the presence of RN2 is associated with reduced IL1RN-mRNA expression and enhanced IL-1β production. ^{Reference Saitoh, Kobayashi and Ohmori38} FIRES typically affects children at a median age of 6–8 years. FIRES has 3 stages of disease evolution. ^{Reference Reppucci and Datta36} The initial prodromal stage (approximately 13 days) is characterized by febrile illness (respiratory or gastrointestinal infection). ^{Reference Reppucci and Datta36,Reference Kessi, Liu and Zhan37} This is followed by a new onset of seizures, which increase in frequency, eventually evolving into refractory SE. ^{Reference Reppucci and Datta36} At this stage, most patients have recovered from fever. ^{Reference Reppucci and Datta36} The final chronic stage ensues with patients requiring multiple anti-seizure medications with varying grades of residual disability. Seizures are typically multifocal or generalized, evolving into super-refractory SE reaching up to several seizures each day. ^{Reference Reppucci and Datta36,Reference Vezzani, Häusler, Kluger and van Baalen39}

The major role of MRI, in patients with FIRES, is to exclude other clinical mimics. The NORSE Institute recommends a contrast-enhanced MRI of the brain with MR angiography and MR venography within the first 24 hours of symptom onset. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Most patients have an unremarkable initial MRI examination, though unilateral or bilateral temporal lobe signal abnormalities have been reported. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Description of the spatial involvement of the temporal lobe is heterogeneous in literature, with authors reporting hippocampal, mesial temporal or just temporal lobe involvement. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Cortical edema with T2/FLAIR hyperintensity and/or restricted diffusion may also be noted reflecting impairment of the Na/ATPase pump function ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} (Fig. 10). Bilateral involvement of the basal ganglia is another frequent abnormality reported in the acute FIRES. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Basal ganglia involvement may affect the striatal inhibitory function and reduce the seizure threshold, however, the exact mechanism leading to signal alterations in the basal ganglia is unclear. Involvement of the insular/peri-insular regions and the cerebral cortices (focal or diffuse) may also be noted. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Symmetric T2/FLAIR hyperintensity involving the claustrum, referred to as the ‘claustral sign’ has been reported, however, this is neither diagnostic nor pathognomonic for NORSE or FIRES ^{Reference Di Dier, Dekesel and Dekeyzer41} (Fig. 11). Involvement of thalami, brainstem and cerebellum is rare. Following contrast administration, parenchymal or leptomeningeal enhancement may be seen. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40}

Figure 10.

FIRES in a 10-year-old presenting with acute failure of verbalization, reduced ambulation and poor intake along with abnormal repetitive movements of hands and pursing of lips. Axial FLAIR sequence (A-C) shows extensive, symmetric, gyriform hyperintense cortical swelling in the temporal lobes (A), the insula (B), and the frontal lobes (with a mesial predominance; C). Similar hyperintense swelling is seen involving the lentiform nuclei bilaterally. Axial DWI (D) and ADC (E) sequences show corresponding gyriform restricted diffusion in the temporal lobes. There was no restricted diffusion seen in the rest of the affected brain parenchyma. Coronal contrast-enhanced 3D-T1sequence (F) reveals no evidence of contrast enhancement. A differential diagnosis of infection, including viral etiologies such as herpes, as well as anti-NMDAR encephalitis were considered at the time of initial presentation. A biopsy of the temporal lobe revealed focal spongiotic changes with apoptotic neurons and neuronal loss but no immunohistochemistry was negative. Based on the clinical presentation and the pathological results, FIRES was considered and the patient was treated with methylprednisolone, IV immunoglobulin and plasma exchange (PLEX). ADC = apparent diffusion coefficient; DWI = diffusion-weighted imaging; FIRES = febrile infection-related epilepsy syndrome.

Figure 11.

Claustral sign in a 3-year-old with suspected FIRES presenting with multiple seizures, following a bout of febrile illness. Axial FLAIR (A) and coronal T2-weighted (B) sequences reveal hyperintensities in the subinsular regions/claustrum bilaterally (arrows). Axial DWI (C) and axial contrast-enhanced 3D-T1 sequence (D) demonstrate no corresponding restricted diffusion or contrast enhancement, respectively. DWI = diffusion-weighted imaging; FIRES = febrile infection-related epilepsy syndrome.

Imaging in the chronic phase may reveal normal MRI appearances or global parenchymal atrophy with ex-vacuo dilation of the ventricles. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Atrophy and/or T2 hyperintensity within the mesial temporal lobes is not uncommon. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Abnormal white matter T2/FLAIR hyperintensities may be seen in the deep and/or subcortical white matter. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Similar signal changes may be seen in the insular and peri-insular as well as the deep grey nuclei and cortices. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40} Ependymal enhancement and signal abnormalities in the substantia nigra and corticospinal tracts have been described in single case reports. ^{Reference Culleton, Talenti, Kaliakatsos, Pujar and D’Arco40}

Rasmussen’s encephalitis (RE)

RE is a rare chronic neurological disorder of unknown origin, classically causing drug-resistant focal epilepsy with progressive unihemispheric atrophy. ^{Reference Tang, Luan and Li42,Reference Varadkar, Bien and Kruse43} RE may begin anytime between infancy and adulthood, with a median age of 6 years. ^{Reference Varadkar, Bien and Kruse43} Some may present with a prodromal period of hemiparesis or episodic seizures progressing to the acute phase characterized by frequent seizures arising from one cerebral hemisphere. ^{Reference Varadkar, Bien and Kruse43} Nearly half the patients present with epilepsia partialis continua. ^{Reference Varadkar, Bien and Kruse43} Untreated patients develop hemiparesis, hemianopia, cognitive decline and dysphasia (when the language dominant hemisphere is affected). ^{Reference Varadkar, Bien and Kruse43}

At present there is no obvious cause known to trigger RE. Viral infections were considered to be a trigger, however, to date no study has proved viral replication in the brain parenchyma of patients with RE. ^{Reference Tang, Luan and Li42,Reference Bien44} Autoantibodies against GluR3 were considered, however, these were found only in a few patients with proven RE. ^{Reference Varadkar, Bien and Kruse43} More recently, cytotoxic T cells have been evaluated in the pathogenesis of RE; pathological specimens have revealed that cytotoxic CD8+ T cell lymphocytes form the majority of infiltrated T cells in RE with 10% of which are granzyme-B positive CD8+ T cells. ^{Reference Tang, Luan and Li42} This is viewed as compelling evidence of neuronal destruction and astrocytic degeneration caused by cytotoxic T cells, which gives rise to seizures. ^{Reference Tang, Luan and Li42} Research has also shown certain genes (encoding interferon-γ, CCL5, CCL22, CCL23, CXCL9, CXCL10 and Fas ligand) were expressed in RE which are related to the activation and recruitment of T cells to sites of inflammation. ^{Reference Varadkar, Bien and Kruse43} Activation of microglia has also been evaluated; their activation closely follows the T-cell infiltration patterns and progression of cortical damage. ^{Reference Tang, Luan and Li42,Reference Varadkar, Bien and Kruse43} Activated microglia release interleukin 1 and other pro-inflammatory cytokines which participate in the seizure induction. Activated microglia may also take part in complement-mediated synaptic dysfunction which increases neuronal excitability. ^{Reference Tang, Luan and Li42,Reference Varadkar, Bien and Kruse43}

MRI forms the mainstay in the evaluation of RE. Typical MRI features include preferential atrophy of the frontal lobe and insula with volume loss of the caudate head, together leading to ex-vacuo enlargement of the CSF spaces ^{Reference Tang, Luan and Li42} (Fig. 12). Volume loss typically ensues 4 months following symptom onset. Intra- and/or subcortical T2/FLAIR may also be observed ^{Reference Tang, Luan and Li42,Reference Bien44} (Fig. 13). Areas of increased signals have been shown to correspond to sites of increased T cells, microglial nodules and GFAP + astrocytes. Most tissue loss is noted within the initial 12 months of disease onset; with disease progression, cortical atrophy develops in the rest of the hemisphere. ^{Reference Tang, Luan and Li42,Reference Bien44} Fluorodeoxyglucose-positron emission tomography shows hypometabolism in the affected hemisphere while single photon emission computed tomography may show interictal hypoperfusion and ictal hyperperfusion of focal parenchymal lesions in patients with RE. ^{Reference Tang, Luan and Li42}

Figure 12.

Rasmussen encephalitis in a 6-year-old patient presenting with sudden onset absence-like complex partial seizures originating from the right hemisphere. Axial FLAIR sequence (A, B) shows areas ill-defined areas of hyperintense signal involving the cortex and the juxtacortical white matter of the right parietal (A) and frontal (B) lobes. DWI (not shown) revealed no restricted diffusion in these locations. Corresponding contrast-enhanced 3D-T1 sequence (C, D) reveals no evidence of enhancement in these regions. DWI = diffusion-weighted imaging.

Figure 13.

Evolution of Rasmussen encephalitis. Axial FLAIR (A) and axial T2-weighted (B) sequences reveal a small nonspecific focus of hyperintensity in the right frontal lobe (dotted arrows). Axial 3D-T1 sequence (C) shows normal volume of the right cerebral hemisphere. Follow-up MRI (D-F) obtained after 3 years due to medically refractory focal epilepsy, occurring multiple times daily, and emerging left hemiparesis. Axial FLAIR (D), axial T2-weighted (E), and axial 3D-T1 (F) sequences reveal marked volume loss of the right cerebral hemisphere, seen in the form of ex-vacuo dilation of the right lateral ventricle and prominence of the sulcal spaces. Note, apart from non-specific FLAIR/T2 hyperintensity along the right frontal horn, there is no other signal abnormality seen in the rest of the brain parenchyma.

Anti-NMDAR encephalitis

The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, centered in the postsynaptic compartment. ^{Reference Skrenkova, Hemelikova and Kolcheva45} It is comprised of two GluN1 and two GluN2 or GluN3 subunits; GluN1 and GluN3 bind glycine while GluN2 binds glutamate. ^{Reference Skrenkova, Hemelikova and Kolcheva45} Autoantibodies against the GluN1 subunit of the NMDAR are the most common form of autoimmune encephalitis, especially in children. ^{Reference Ding, Jian, Stary, Yi and Xiong46,Reference de Bruijn, Bruijstens and Bastiaansen47}

Tumors and post-viral states are common immunologic triggers linked to anti-NMDAR encephalitis. ^{Reference Huang, Xie, Hu and Tang48} However, in nearly half of the cases, the immunologic triggers remain unknown. ^{Reference Huang, Xie, Hu and Tang48} Tumors containing nervous tissues expressing NMDAR (e.g., ovarian teratomas) incite expansion of T and B cells while virus-induced neuronal damage leads to direct transport of the receptors to draining lymph nodes or APC uptake stimulating memory B expansion. ^{Reference Ding, Jian, Stary, Yi and Xiong46} Upon exposure to NMDAR, naïve B cells are activated and enter the CNS via the choroid plexus. ^{Reference Huang, Xie, Hu and Tang48} Tumors also present potential ligands for the innate PRRs, including, but not limited to TLRs. ^{Reference Ding, Jian, Stary, Yi and Xiong46} The activation of innate immunity-mediated cytokines and TLR ligands leads to BBB disruption, allowing B cell infiltration. ^{Reference Ding, Jian, Stary, Yi and Xiong46} Interaction with the autoantibodies causes internalization of the NMDARs leading to decreased receptor density on cell surfaces and eventual imbalance between excitatory and inhibitory neurotransmitters ^{Reference Skrenkova, Hemelikova and Kolcheva45} (Fig. 14).

Figure 14.

Pathophysiology of anti-NMDAR encephalitis. (A) Simplified diagrammatic representation of neurotransmission at a glutamatergic synapse and (B) simplified diagrammatic representation of antibodymediated internalization. Binding of antibodies to the GluN1 subunit causes crosslinking of NMDAR, hence forming clusters (not shown). These are removed from the post-synaptic surface by endocytosis (receptor internalization). This eventually leads to a decreased density of NMDAR at the postsynaptic membrane. The net result is slowing down of glutamate evoked postsynaptic impulses. (Created with BioRender.com). NMDAR, N-methyl-D-aspartate receptor.

NMDAR encephalitis often shows a progressive clinical worsening. An initial viral-like prodrome may be encountered (fever, malaise, headache, etc). ^{Reference Kelley, Patel, Marin, Corrigan, Mitsias and Griffith49} This is subsequently followed by psychiatric symptoms (anxiety, depression, schizophrenia, psychosis) with progression to temporal lobe dysfunction (amnesia and seizures). ^{Reference Kelley, Patel, Marin, Corrigan, Mitsias and Griffith49} Ultimately, severe residual neurologic deficits may be seen (impairments of memory and psychiatric symptoms). ^{Reference Kelley, Patel, Marin, Corrigan, Mitsias and Griffith49} Early diagnosis and treatment may be associated with a good prognosis and neurological outcomes, with patients returning to baseline. ^{Reference Kelley, Patel, Marin, Corrigan, Mitsias and Griffith49}

Most patients with anti-NMDAR encephalitis have normal brain MRI examinations at presentation (89%) and on follow-up (79%) ^{Reference Kelley, Patel, Marin, Corrigan, Mitsias and Griffith49} Non-specific T2/FLAIR hyperintensity involving grey and/or white matter with variable supra- and infratentorial distribution has been described. ^{Reference Kelley, Patel, Marin, Corrigan, Mitsias and Griffith49} In a study of 53 patients with anti-NMDAR encephalitis, including pediatric and adult patients, Zhang et al divided brain lesions into 4 groups: type 1 (normal MRI; 53%), type 2 (isolated hippocampal involvement; 13%), type 3 (lesions sparing the hippocampus; 13%) and type 4 (combined hippocampus and other focal brain involvement’ 21%). ^{Reference Goldman and Prinz5} . Apart from the hippocampus, lesions were found in the frontal lobes, cingulate gyri, middle cerebellar peduncles, corpus callosum, insula, basal ganglia, thalami and brainstem. ^{Reference Zhang, Duan and Ye50} They found no statistical difference in the imaging manifestations between pediatric and adult groups (p = 0.982). ^{Reference Zhang, Duan and Ye50} Hippocampal involvement was associated with a poor neurological outcome. ^{Reference Zhang, Duan and Ye50} The presence of restricted diffusion is uncommon and should prompt further evaluation of the etiologies including seizures, infectious encephalitis and vasculitis. ^{Reference Van Mater51,Reference Budhram, Britton and Liebo52} (Fig. 15). Rare manifestations include isolated contrast enhancement of the leptomeninges and cranial nerve enhancement ^{Reference Van Mater51,Reference Budhram, Britton and Liebo52} (Fig. 16).

Figure 15.

Imaging findings in a 12-year-old patient with anti-NMDAR encephalitis. Axial FLAIR (A) and T2 (B) images reveal abnormal hyperintense swelling of the left frontal cortices (arrow), with resultant effacement of the left frontal sulci. Abnormal signal is also seen involving the subjacent white matter. Axial ADC (C) obtained at the corresponding level shows patchy areas low signals representing restricted diffusion (arrow) on the background of hyperintense signals representing vasogenic edema. Coronal FLAIR (D), axial T2 (E), axial ADC (F) images obtained through the temporal lobes reveals similar hyperintense swelling of the left anterolateral temporal cortices (arrows). Contrast was not administered as the patient was suffering from concomitant chronic renal failure. ADC = apparent diffusion coefficient; NMDAR = N-methyl-D-aspartate receptor.

Figure 16.

Atypical imaging presentation of anti-NMDAR encephalitis in a 2-year-old presenting with new-onset seizures, behavioral changes, aphasia, and fever. Axial (A) and coronal oblique FLAIR (B) sequences reveal hyperintense signal abnormality within the hippocampal formations bilaterally (arrows) as well as gyriform, FLAIR hyperintense swelling of the left occipitotemporal gyrus (dotted arrow in A) and the left parahippocampal gyrus (dotted arrow in B). Contrast-enhanced axial FLAIR images (C, D) reveal diffuse leptomeningeal enhancement (stepped arrows) along both cerebral hemispheres. The patient received high-dose intravenous steroids with clinical status reaching back to baseline within a few weeks. NMDAR = N-methyl-D-aspartate receptor.

Acute necrotizing encephalopathy (ANE) vs acute necrotizing encephalopathy 1 (ANE1)

ANE is a distinct parainfectious encephalopathy, triggered by a viral infection (influenza A, influenza B, novel influenza A/H1N1, parainfluenza, human herpes virus 6, herpes 7, etc.). While the pathomechanisms of ANE are still unclear, it is thought to be an exaggerated immune response to the viral infection (cytokine storm), resulting in multisystem involvement. The CNS manifestation of this is seen in the form of increased BBB permeability. ^{Reference Wu, Wu, Pan, Wu, Liu and Zhang53} Research shows, that a CD56+ natural killer (NK) may be involved. ^{Reference Wu, Wu, Pan, Wu, Liu and Zhang53} Elevation of other cytokines has also been described, with IL-6 and TNF-α playing a major role in neurotoxicity and BBB endothelial damage, respectively. ^{Reference Wu, Wu, Pan, Wu, Liu and Zhang53} The outcome of ANE varies depending on the causative organism. In a study by Khamis et al, the rate of pediatric intensive care unit admission was 100% and 77% for influenza and non-influenza cases, respectively. The authors also found a higher mortality rate in patients with ANE secondary to influenza infection (42% vs 11% among those due to non-influenza infection) ^{Reference Khamis, Brown, Kaliakatsos, Eyre and Lim54}

ANE was initially thought to have a geographic distribution but is now considered a global phenomenon. Multiple cases of recurrent and/or familial ANE were reported suggesting an inherited disposition. Missense mutations in the Ran Binding Protein 2 (RANBP2), the gene encoding the nuclear pore protein, were found to be the susceptibility allele for familial/recurrent cases, with an autosomal dominant inheritance. ^{Reference Wu, Peng, Jiang, He, Jiang and Hu55} This form of ANE has since been classified as “ANE1”. ^{Reference Wu, Wu, Pan, Wu, Liu and Zhang53} Mutations in SCNIA R1575C and carnitine palmitoyl transferase II genes have also been linked to ANE1. ^{Reference Neilson, Adams and Orr56–Reference Kumakura, Iida, Saito, Mizuguchi and Hata61}

RANBP2 is located on the cytoplasmic surface of the nuclear pore. It performs several functions such as protein transport facilitation, intracellular trafficking, neuronal energy maintenance and regulation of specific subsets of mRNAs. ^{Reference Wu, Wu, Pan, Wu, Liu and Zhang53,Reference Mahadevan, Zhang and Akef62} Specifically, RANBP2 is a small ubiquitin-related modifier (SUMO) pathway protein that attaches and stabilizes target proteins (SUMOylation), thus enabling them to perform vital cellular functions. ^{Reference Malik and Shroff24} In this context, RANBP2-mediated SUMOylation of Argonaute or AGO proteins ensure the silencing of ANE-related cytokines (IL-6, TNFα), STAT1 activity and type 1 interferon. ^{Reference Malik and Shroff24} Failure of these silencing mechanisms leads to persistent cytokine production increased glutaminergic CNS excitotoxicity and eventual CNS injury ^{Reference Levine, Ahsan, Ho and Santoro63,Reference Ichiyama, Endo, Kaneko, Isumi, Matsubara and Furukawa64} (Fig. 17).

Figure 17.

Schematic of the ANE1 pathophysiology. The nuclear pore complex is a complex macromolecule located in the nuclear envelope. It serves as an important conduit for transport across the nuclear membrane. Argonaute (AGO protein) is involved in messenger RNA (mRNA) silencing, by facilitating attachment of micro-RNA (miRNA-induced silencing complex; a silencing RNA) to the target IL6 mRNA. The RANBP2-mediated SUMOylation ensures a stable attachment of during AGO to IL-6 mRNA passage during its transport across the nuclear pore protein. The SUMOylated AGO bound IL-6 mRNA later attaches to miRNA-induced silencing complex, thereby ceasing the production of IL-6. While the exact role of mutated RANBP2 interaction in this sequence of events is not clearly delineated, but failure of miRNA-induced silencing complex attachment to an otherwise unstable AG0 bound IL-6 mRNA complex may lead to sustained production of cytokines and hypercytokinemia. Adapted from reference 24. (Created with BioRender.com) ANE1 = acute necrotizing encephalopathy.

ANE1 is usually preceded by a nonspecific infection which triggers downstream hyperinflammatory mechanisms. Clinically, the disease is divided into 3 phases prodrome (fever, diarrhea, vomiting, upper respiratory tract infection), acute encephalopathy (seizure, altered consciousness, focal neurologic deficits) and recovery. ^{Reference Park, Hwang, Kim, Lee and Ko65} The clinical course is diverse ranging from mild encephalopathy to a fulminant course leading to death. ^{Reference Park, Hwang, Kim, Lee and Ko65}

Neuroimaging manifestations include symmetric involvement of bilateral thalami with a characteristic trilaminar pattern This pattern refers to a central core of T2 hyperintensity representing perivascular hemorrhage and neuronal/glial necrosis, surrounded by a zone of cytotoxic edema, seen as restricted diffusion, due to vascular congestion and oligodendrocyte swelling. ^{Reference Wu, Peng, Jiang, He, Jiang and Hu55} The outermost zone represents extravasation/vasogenic edema and demonstrates T2-shine through ^{Reference Wu, Peng, Jiang, He, Jiang and Hu55} (Fig. 18). ANE1 has an increased predisposition to involve amygdala, hippocampus and medial temporal lobes compared to sporadic ANE. ^{Reference Neilson, Adams and Orr56} Involvement of the cerebral hemispherical white matter, brainstem and cerebellum may also be noted. ^{Reference Mizuguchi, Yamanouchi, Ichiyama and Shiomi66–Reference Vanjare, Selvi and Karuppusami68} Uncommon manifestations include isolated involvement of the cerebral parenchyma, internal capsule and the corpus callosum. ^{Reference Handryastuti, Silvana, Yunus, Taufiqqurrachman and Rafli69} The presence of cavitation and hemorrhage is linked to adverse clinical outcomes in pediatric ANE1. ^{Reference Wong, Simon, Zimmerman, Wang, Toh and Ng70}

Figure 18.

ANE1 due to RANBP2 mutation in a 4-year-old child presenting with acute encephalopathy. Axial T2-weighted sequence (A) shows symmetric involvement of bilateral thalami (solid arrows). An evolving trilaminar pattern can be identified with a central area of T2 hyperintensity surrounded by a rim of intermediate signal and a peripheral rind of hyperintensity. A small focus of T2-weighted hyperintensity is also noted along the posterior aspect of the right lentiform nucleus (dotted arrow in A). Axial DWI sequence (B) shows patchy areas of restricted diffusion in the core of the thalamic lesions. Axial multiplanar gradient recalled (MPGR) sequence (C) shows areas of susceptibility within the left thalamic lesion suggesting foci of hemorrhage. Axial FLAIR sequence (D) shows homogeneous hyperintense swelling of the thalami as well as the right lentiform nucleus posteriorly. Axial (E) and coronal (F) contrastenhanced 3D-T1 sequence shows subtle enhancement within the thalamic lesions. DWI = diffusion-weighted imaging.

Familial hemophagocytic lymphohistiocytosis (FHLH)

Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disorder with various subtypes (deficient genes): FHL1 (unknown), FHL2 (PRF1), FHL3 (Munc13-4 protein on UNC13D), FHL4 (Syntaxin 11 protein on STX11) and FHL5 (Munc18-2 protein on STXBP2) (71). PRF1 encodes perforin, contained in cytotoxic granules of lymphocytes. ^{Reference Canna and Marsh72} Upon exposure to infected cells, CD8+ cytotoxic T cells and NK cells release these perforin-containing cytotoxic granules and granzymes resulting in target cell membrane destabilization and apoptosis. ^{Reference Canna and Marsh72} Perforin deficiency leads to the inability of granule content to enter into target cells. ^{Reference Canna and Marsh72} A prolonged synapse time ensues between perforin-deficient cytotoxic lymphocytes and target cells causing overproduction of pro-inflammatory cytokines. ^{Reference Canna and Marsh72} APCs continue to accumulate and stimulate T cell activation and proliferation leading to excessive lymphohistiocytic proliferation and hypercytokinemia ultimately causing widespread tissue damage and hyperinflammation. ^{Reference Canna and Marsh72} UNC13D, STX11 and STXBP2 gene products are important for normal cytotoxic granule exocytosis. ^{Reference Canna and Marsh72} Defects in these genes limits the granule contents from being released into the immunological synapse, hence target cells are not destroyed. ^{Reference Canna and Marsh72} HLH is also a manifestation of other genetic diseases, including pigmentary disorders (RAB27A, LYST and AP3B1 mutations), X-linked lymphoproliferative diseases (SH2D1A and XIAP mutations), CDC42 mutations, gain-of-function mutations in NLRC4 and Epstein-Barr virus (EBV) susceptibility disorders (MAGT1, ITK, CD27, CD70, CTPS1, RASGRP1 gene deficiency). ^{Reference Canna and Marsh72} Discussion of their pathomechanisms is beyond the scope of this article, but summarized in Figure 19.

Figure 19.

Schematic representation of HLH pathogenesis. (Circuit #1) in patients with familial HLH and some other forms of HLH related to primary EBV infection, genetic defects of virucidal property (e.g., Perforin 1 (PERF1) deficiency) causes sustained presentation of antigens and activation CD8+T cells, amplified by IFN-γ release and MHC-I upregulation. Prolonged IFN-γ release is also though to cause tissue macrophage/monocyte activation consequently leading to release of inflammatory mediators (IL-1b, IL-6, IL-18, IL-12). (Circuit #2) macrophages/monocytes are activated by activated by chronic inflammation and TLR stimulation (infection). In HLH associated with malignancies, malignant cells may drive HLH through autonomous cytokine release or presentation of EBV antigen. Drug (CAR-T cell therapy) induced occurs due to activation of therapeutic CD8+ CAR-T cells. (Created with BioRender.com). EBV = Epstein–Barr virus; CAR-T = Chimeric antigen receptor T cell; HLH = hemophagocytic lymphohistiocytosis.

CNS involvement is common in all forms of HLH. The reported incidence of CNS involvement in FHLH is ranges between 18-75% in FHLH. ^{Reference Cooray, Sabanathan and Hacohen73} In a case series (n = 38), ataxia/gait disturbances (74%), seizures (50%), headache (47%), visual alterations (45%) and motor impairment (42%) were reported (74). Cranial nerve palsies, papilledema, dysmetria, dysarthria, sensory deficits and behavioral alterations were also reported. ^{Reference Blincoe, Heeg and Campbell74} Histopathologically, pediatric CNS HLH shows meningeal lymphocytic and macrophage infiltration (stage 1), advancing to perivascular inflammatory infiltrate (stage 2), leading to diffuse parenchymal infiltration, multifocal necrosis and astrogliosis (stage 3). ^{Reference Henter and Nennesmo75}

MRI is the neuroimaging modality of choice for patients with CNS-HLH. ^{Reference Cooray, Sabanathan and Hacohen73} In a study of 179 pediatric patients, CNS imaging findings were seen in up to 50% of cases with systemic HLH, most of which belonged to the FHLH group. ^{Reference Zhao, Zhang and Li76} At neuroimaging, pediatric CNS-HLH presents with differing imaging patterns affecting various brain regions including multifocal cerebral and cerebellar white matter lesions, CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) like brainstem lesions and diffuse cerebellar involvement similar to cerebellitis. ^{Reference Malik, Antonini and Mannam77} Atypical findings include diffuse hemorrhagic transformation with bilateral basal ganglia, thalamus and brainstem involvement. ^{Reference Pak, Selehnia and Hunfeld78} Other findings reported in CNS-HLH are nodular or ring-enhancing lesions with restricted diffusion, leptomeningeal enhancement, diffuse cerebral edema, subdural collections as well as calcification and cerebral atrophy in late stages ^{Reference Fitzgerald and MacClain79–Reference Rego, Severino and Micalizzi81} (Fig. 20).

Figure 20.

HLH in a 12-year-old with long-standing immune dysregulation (fever, cytopenia, splenomegaly). Axial FLAIR (A, B) images reveal bilateral, near-symmetric, gyriform FLAIR hyperintensity with cortical swelling with similar signal abnormality in the juxtacortical white matter in the frontal and parietal lobes (arrows in A, B). Axial FLAIR (C) reveals patchy hyperintensities in the cerebellar hemispheres as well (C). Contrast-enhanced axial 3D-T1 sequences (D-F) reveal multiple, punctate foci of cortical enhancement, most accentuated in the frontal lobes, more on the left (arrows in D), with few foci of enhancement in the right parietal lobe (arrow in E), and left cerebellum (arrow in F).

Acute and subacute neurological complications

Acute encephalopathy or encephalitis typically presents with ill-defined areas of T2/FLAIR hyperintensity of the cortex and hemispherical white matter with gyral swelling; rare deep grey nuclei involvement; microbleeds; and variable contrast enhancement. ^{Reference Orman, Desai and Kralik86–Reference Lindan, Mankad and Ram88} Occasional reports of cerebellitis have also been published ^{Reference O’ Neill and Polavarapu89} (Fig. 21). Parainfectious immune-mediated Guillain-Barre syndrome and Miller-Fisher variants are characterized by cauda equina nerve root thickening/enhancement and lower cranial nerve enhancement ^{Reference Malik and Shroff24} (Fig. 22). On the other hand, endothelial injury and thrombosis lead to vasculitis, acute arterial stroke, venous thromboembolism, microbleeds and parenchymal hemorrhage. Moreover, cytokine and inflammatory mediators result in cerebral endothelial damage and blood-brain barrier disruption leading to posterior reversible encephalopathy syndrome. ^{Reference Korkmazer, Ozogul and Hikmat90}

Figure 21.

COVID-related cerebellitis in a 6-year-old patient presenting with fever, headache, ataxia and decreased mental status. Axial DWI (A) and ADC (B) sequences reveal extensive restricted diffusion involving both the cerebellar hemispheres (arrows) with a focus of profound restricted diffusion in the left middle cerebellar peduncle (dotted arrows). Axial FLAIR (C) and T2-weighted (D) sequences reveal hyperintense swelling of the cerebellum with effacement of the interfolial spaces and the cerebellopontine angle cisterns. Contrast-enhanced axial 3D-T1 sequence (E) demonstrates no abnormal parenchymal enhancement. Delayed coronal contrast enhanced T1-weighted sequence (F) reveals leptomeningeal enhancement along the cerebellar hemispheres bilaterally. The patient was treated with intravenous immunoglobulins for 10 days along with 10 cycles of plasma exchange (PLEX). ADC = apparent diffusion coefficient; DWI, diffusion-weighted imaging.

Figure 22.

Guillain-Barré syndrome (GBS) in a 2-year-old presenting with COVID infection detected on nasopharyngeal swab analysis, presenting with generalized weakness and gait disturbance. Sequential craniocaudal contrast-enhanced axial (A, B) and coronal (C) T1 sequences through the lumbar spine demonstrate enhancing thickening of the ventral cauda equina nerve roots. The patient was treated with a 3-day course of intravenous immunoglobulins.

Delayed neurological complications

The cytotoxic lesions of the corpus callosum splenium are associated with hyperinflammatory illness i.e., pediatric multisystem inflammatory syndrome in children (MIS-C); and the myositis of the neck and face typically occurs weeks after COVID-19 infection. On imaging, splenial lesions may be seen in up to 60% of children and demonstrate T2 FLAIR hyperintensity with restricted diffusion and postulated to represent intramyelinic edema due to cytokine-mediated glutamate toxicity. ^{Reference Abdel-Mannan, Eyre and Löbel91}

Cytokine storm-induced neuronal and autoimmune injury encompassing acute disseminated encephalomyelitis (ADEM) like phenotype, acute necrotizing encephalopathy (ANE) and transverse myelitis are reported in all phases (Fig. 23). Rarely, ADEM-like imaging phenotype in SARS-CoV-2 occurs due to immune-mediated encephalitis associated with anti-myelin oligodendrocyte (MOG) and Anti-NMDAR antibodies. Pediatric COVID-19-associated ADEM-like phenotype shows better treatment response and outcome on treatment with steroids compared to increased association with severe disease, risk of intracranial hemorrhage and poor outcome in adults. ^{Reference Monti, Giovannini and Marudi92,Reference Manzano, McEntire, Martinez-Lage, Mateen and Hutto93}

Figure 23.

MRI in an 8-year-old patient presenting with fever and decreased level of consciousness. The patient tested positive for COVID infection. Axial DWI (A) and apparent diffusion coefficient (ADC; B) show areas of restricted diffusion involving both the thalami (arrowheads) with peripheral areas of facilitated diffusion (dotted arrows in B). Axial FLAIR (C) and coronal T2-weighted (D) sequences demonstrate marked swelling of the thalami (arrows). In addition, confluent T2-weighted hyperintensity is seen in the pons (stepped arrow in D), extending into the medulla. Corresponding FLAIR hyperintensity was noted in the affected brainstem (not shown). Contrast-enhanced axial (E) and coronal (F) 3D-T1 sequences show faint irregular enhancement in the thalami (arrows), with a nonenhancing core, corresponding to the areas of restricted diffusion. Subtle, irregular, ring-like enhancement is also seen in the right hemipons (stepped arrow in F). These imaging manifestations suggest a parainfectious CNS complication (ANE) following COVID-19 infection occurring due to a hyperimmune response. ANE = acute necrotizing encephalopathy; CNS = central nervous system; DWI = diffusion-weighted imaging.