834 SECTION VI Pediatric Critical Care Neurologic disease, resection is necessary With prompt immunotherapy and tumor resection, when necessary, full recovery or significant re covery with only mild d[.]
834 S E C T I O N V I Pediatric Critical Care: Neurologic disease, resection is necessary With prompt immunotherapy and tumor resection, when necessary, full recovery or significant recovery with only mild deficit is anticipated.149 Prognosis The prognosis of patients with meningoencephalitis is quite variable—it depends on the causative agent as well as degree of CNS and extraneurologic organ injury sustained One recent single-center study showed that almost 80% of patients with encephalitis had persistent neurologic symptoms on long-term follow-up.156 MRI abnormalities and presence of seizure correlated with lower quality-of-life scores In the same study, seizure at presentation was associated with ongoing seizure disorder While antivirals have improved mortality for neonatal HSV encephalitis, the long-term cognitive and neurodevelopmental consequences of HSV encephalitis and disseminated HSV disease are significant, including static encephalopathy, cognitive deficits, autism, cortical blindness, and epilepsy Currently, serial neuroimaging and close neurologic follow-up can aid in counseling families long term However, more large-scale studies are needed to develop more robust prognostic indicators and to help identify which patients may benefit from more intensive early post-PICU followup measures to maximize functional neurologic outcome Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis (ADEM) is an immunemediated demyelinating CNS disorder characterized by new-onset neurologic symptoms, often including encephalopathy, coupled with neuroimaging evidence of multifocal demyelination ADEM occurs most frequently in childhood, with a median age of onset of 6.5 years and a slightly male predominance The incidence of ADEM is estimated to be 0.8 in 100,000 patients annually.157 Until recently, the definition of ADEM varied widely Initial attempts at establishing a uniform diagnostic criterion began in 2007 by the International Pediatric Multiple Sclerosis study group These were later revised in 2013.158 The latest ADEM criteria now required are summarized as follows: • An initial multifocal clinical CNS event with a presumed inflammatory demyelinating cause • Encephalopathy (alteration in consciousness or behavior unexplained by fever, systemic illness, or postictal symptoms) • Brain MRI abnormalities consistent with demyelination during the acute (3 months) phase • No new clinical or MRI findings months or more after clinical onset ADEM typically is a single event that resolves over the course of months Recently, the diagnosis of “recurrent ADEM” was removed from the 2013 criteria and replaced by the term multiphasic disseminated encephalomyelitis (MDEM).159 MDEM requires two separate clinical events consistent with ADEM but separated by a period of at least months ADEM is not an acute infectious process but rather a post- or parainfectious complication This comes from the observation that ADEM typically develops following a defined or suspected viral illness.160 Additionally, exposure to an ill sibling in the month before onset of symptoms is also considered a risk factor.161 Nonspecific upper respiratory tract infections are the most often cited association with childhood cases of ADEM.162 Serologic studies for viral or bacterial pathogens causing antecedent or coincident infections are positive in less than 20% of cases.161 A prodromal viral illness occurs in 50% to 75% of patients with childhood ADEM Historically, vaccines were often cited as a risk factor for ADEM However, two recent studies demonstrated little to no correlation with ADEM and vaccinations.163,164 Further, ADEM tends to occur in pediatric populations who are no longer receiving active vaccinations Neurologic symptoms of ADEM can begin as early as to weeks following a febrile event ADEM’s initial clinical presentation is often nonspecific Patients may initially experience headaches, malaise, vomiting, lethargy, and low-grade fevers Acute onset of encephalopathy with polyfocal neurologic defects follows, often within to days Patients often exhibit ataxia, inability to walk, slurred speech, or decreased speech output Cranial neuropathies (especially of extraocular movements) and abnormal reflexes (typically hyperreflexia) are common findings Altered mental status— including agitation, delirium, nonresponsiveness, and seizure activity—is noted in up to 60% of patients Up to 25% of children require ICU admission for their initial management.165 No specific laboratory criteria exist for the diagnosis of ADEM CSF examination is commonly performed at the time of clinical presentation in most ADEM patients and is often normal A mild pleocytosis with lymphocyte predominance and moderately elevated protein levels are common Oligoclonal bands are rare in ADEM and may only be present transiently, which is in sharp contrast to multiple sclerosis (MS).166 EEGs typically show diffuse slowing, especially when the patient exhibits altered level of consciousness The radiologic study of choice for diagnosing ADEM is MRI Abnormalities are most frequently identified on T2-weighted and FLAIR sequences ADEM-associated MRI lesions are often multiple and asymmetric The lesions are often of different sizes (Figs 67.12 and 67.13) ADC values consistent with vasogenic edema are noted in a majority of ADEM lesions MRI findings of spinal cord involvement are noted in up to 30% of patients.167 CT scanning does not usually detect the lesions noted in most ADEM patients One-third of MRI abnormalities completely resolve, while a partial resolution is noted in 35% to 50% of patients.160,162,168,169 In monophasic ADEM, new MRI lesions will not develop after months of initial presentation Delayed development of MRI lesions in deep gray matter and brainstem may herald a prolonged clinical course and poor response to medical management.170 • Fig 67.12 Brain axial T2-weighted magnetic resonance image of acute disseminated encephalomyelitis showing bilateral multiple sized lesions CHAPTER 67 Central Nervous System Infections and Related Conditions • Fig 67.13 Brain axial fluid-attenuation inversion recovery magnetic reso- nance image sequence of acute disseminated encephalomyelitis lesions showing cytotoxic edema From a radiologic perspective, the lesions of ADEM can often be confused with those found in patients with MS However, there are unique histopathologic findings in both ADEM and MS MS lesions are heterogeneous in terms of lesion age MS lesions are characterized by confluent demyelination associated with sheets of macrophage infiltration and with reactive astrocytes In contrast, ADEM lesions are almost always of similar age and consist of mostly one distinct pattern.171 The inflammation tends to cluster around small vessels (particularly veins) in both white and gray matter Histopathology demonstrates perivenular demyelination associated with inflammatory infiltrates of myelinladen macrophages, T and B lymphocytes, plasma cells, and granulocytes.172 In addition, there is perivascular edema, endothelial swelling, and vascular endothelial infiltrations Demyelination may not be present in the acute lesions, but tends to develop later in the lesion’s evolution, often in a sleeve-like pattern confined to the area of inflammation Damage to the axon itself is rare Lesions in ADEM, like MS, can occur anywhere in the brain from subpial locations to the deep cortex While the exact pathophysiologic mechanism of ADEM is uncertain, the concept of molecular mimicry is one of the most prevalent theories.173 It is believed that certain amino-acid sequence homologies and antigenic epitopes are shared between an invading pathogen and the host CNS protein The pathogen is neither recognized as “foreign” in order to be eliminated nor as “self,” which would result in immune tolerance Initially, the pathogenic material is processed at the site of infection or inoculation The adaptive immune response causes T-cell activation and, ultimately, production of antigen-specific B cells These autoreactive T cells and B cells are capable of entering the CNS During routine immune surveillance, they may encounter the homologous myelin protein Following local reactivation by antigen-presenting cells, an inflammatory immune reaction against the presumed foreign antigen is elicited Thus, a physiologic immune response causes detrimental autoimmunity distant from the original site of infection or inoculation Another theory on the pathogenesis of ADEM concerns release of CNS autoantigens following infection.174 After a direct CNS infection with a neurotropic pathogen (such as measles), 835 CNS tissue may be damaged and the blood-brain barrier disrupted This may result in systemic leakage of CNS-confined autoantigens into the systemic circulation, where they are processed in systemic lymphatic organs, causing breakdown of tolerance with subsequent emergence of a self-reactive T-cell response Subsequent expression of proinflammatory cytokines may perpetuate CNS inflammation even further Interestingly, although there appears to be an immune response component in the pathophysiology of ADEM, the CSF of ADEM patients has significantly less interferon-g and IL-10 concentrations when compared with patients with CNS enteroviral infections.161 A majority of patients have a single event Although most episodes of ADEM are solitary with no further clinical relapse or new radiographic findings, recurrences have been reported.160 These patients may develop additional areas of demyelination with localizations that differ from those of the initial episode In these patients, the diagnosis of multiple sclerosis is often considered once they reach adulthood Some patients have recurrent episodes in temporal proximity to or with the same localizations as the initial presentation These very early, temporally circumscribed relapses are thought to represent part of the same acute monophasic immune process, and the terms MDEM and relapsed ADEM are occasionally used to describe these cases.169 MDEM is characterized by older age of patients at onset (typically 10 years), more severe and prolonged local neurologic symptoms, marked extrapyramidal signs, and distinct demyelination patterns on MRI.175 Since there is no single radiologic study or serologic test to confirm ADEM, a differential diagnosis must be entertained in all suspected cases Meningoencephalitis, Behỗet disease, CNS vasculitis, CNS neoplasia or metastases, and mitochondrial encephalopathies are a few diseases that can potentially present with clinical symptoms similar to ADEM However, the most important and most common differential diagnosis regarding therapeutic options and prognosis is MS In a recent study from Germany, the authors noted that the incidence of MS was fivefold higher than ADEM in the pediatric age population While the diagnosis of ADEM and MS were virtually identical in number during childhood, MS was far more prevalent in adolescence.176 The MS clinical picture is often indistinguishable from ADEM, although CSF findings are much more likely to show oligoclonal banding Cerebellar and brainstem clinical signs are the most frequent initial presentation of pediatric onset MS, occurring far more frequently than in adult-aged controls with MS.176 Children with ADEM are generally younger and present with systemic symptoms, such as fever, vomiting, malaise, and headaches A recent study indicated that initial MRI findings might be helpful in distinguishing MS from ADEM in children While total lesion number did not differentiate ADEM from MS, periventricular lesions were more frequently found in children with MS Further, the authors noted that the presence of two or more periventricular lesions combined with either the absence of a diffuse bilateral lesion pattern or the presence of nonenhancing lesions on T1-weighted images (black holes) was highly sensitive and specific to MS in children.177 There are currently no randomized studies for the treatment of ADEM Given its presumed autoimmune origin, high-dose steroid therapy remains the mainstay of treatment The Infectious Disease Society of America recommends methylprednisolone for a 3- to 5-day course.178 Although there are no studies comparing efficacy, many authors recommend methylprednisolone 30 mg/kg per day with a maximum dose of g/day Clinical improvement is generally noted with 24 hours of initiation of therapy Relapses are common, occurring in 25% to 35% of patients Some authors 836 S E C T I O N V I Pediatric Critical Care: Neurologic advocate IVIG or plasmapheresis as a treatment option for patients with ADEM, especially when the course is aggressive or the patient has severe disease that has not responded to corticosteroids.170 Most pediatric patients recover following an ADEM event More than 70% of children with ADEM, including many with significant neurologic deterioration upon admission to the PICU, recovered completely, generally within months.168,179 Typically, neurologic improvement is seen within days of initiation of corticosteroid therapy A small but important subset of patients with ADEM will subsequently be diagnosed with relapsing disorders, including neuromyelitis optica spectrum disorders and MS A positive anti-aquaporin-4 immunoglobulin G titer or presence of myelin oligodendrocyte glycoprotein antibodies supports the diagnosis of ADEM complicated by neuromyelitis optica.180,181 Key References Banerjee AD, Pandey P, Devi BI, Sampath S, Chandramouli BA Pediatric supratentorial subdural empyemas: a retrospective analysis of 65 cases Pediatr Neurosurg 2009;45:11-18 Brouwer MC, van de Beek D Epidemiology, diagnosis and treatment of brain abscesses Curr Opin Infect Dis 2017;30:129-134 Kulik DM, Uleryk EM, Maguire JL Does this child have meningitis? A systemic review of clinical prediction rules for children with suspected bacterial meningitis J Emerg Med 2013;45:508-519 Ouchenir L, Renaud C, Khan S, et al The epidemiology, management, and outcomes of bacterial meningitis in infants Pediatrics 2017; 140:e20170476 Pellegrino P, Carnovale C, Perrone V, et al Epidemiological analysis on two decades of hospitalizations for meningitis in the United States Eur J Clin Microbiol Infect Dis 2014;33:1519-1524 Piccirilli G, Chiereghin A, Gabrielli L, et al Infectious meningitis/ encephalitis: evaluation of a rapid and fully automated multiplex PCR in the microbiological diagnostic workup New Microbiol 2018; 41(2):118-125 Pohl D, Alper G, Van Haren K, et al Acute disseminated encephalomyelitis: updates on an inflammatory CNS syndrome Neurology 2016;87:s38-s45 Rao S, Elkon B, Flett KB, et al Long-term outcomes and risk factors associated with acute encephalitis in children J Pediatric Infect Dis Soc 2017;6(1):20-27 Venkatesan A, Murphy OC Viral encephalitis Neurol Clin 2018; 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Meningoencephalitis, Behỗet disease, CNS vasculitis, CNS neoplasia or metastases, and mitochondrial encephalopathies are a few diseases that can potentially present with clinical symptoms similar to ADEM However,... pathogen (such as measles), 835 CNS tissue may be damaged and the blood-brain barrier disrupted This may result in systemic leakage of CNS-confined autoantigens into the systemic circulation,