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Sample_PPT.pptxCongenital, Acquired Pyogenic, and Acquired Viral Infection:
Infectious diseases can be conveniently divided into congenital/neonatal and acquired infections. There are unique infectious agents that affect the developing brain.
The stage of fetal development at the time of infection is often more important than the causative organism. The clinical manifestations of fetal and neonatal infection and long-term neurologic consequences compared with infections that affect the more mature or fully developed brain will be emphasized below.
We then delineate the first major category of acquired infections, i.e., pyogenic infections. We start with meningitis, the most common of the pyogenic infections. Abscess, together with its earliest manifestations (cerebritis), is discussed next, followed by considerations of ventriculitis (a rare but potentially fatal complication of deep-seated brain abscesses) and intracranial empyema.
Congenital Infections
Parenchymal calcifications are the hallmark of most congenital infections and have been reported with cytomegalovirus (CMV) (12-2A), toxoplasmosis (12-6A), congenital herpes simplex virus (HSV) infection (12- 8A), rubella (12-15), congenital varicella-zoster virus (12-17), Zika virus (12- 12B), and lymphocytic choriomeningitis virus (LCMV) (12-16).
Infections of the fetal brain result in a spectrum of injury and malformation that depends more on the timing of infection than the infectious agent itself. Infections early in fetal development (e.g., during the first trimester) usually result in miscarriage, severe brain destruction, and/or profound malformations such as anencephaly, agyria, and lissencephaly.
When infections occur later in pregnancy, encephaloclastic manifestations and myelination disturbance (e.g., demyelination, dysmyelination, and hypomyelination) predominate. Microcephaly with frank brain destruction and widespread encephalomalacia are common (12-11A).
With few exceptions (toxoplasmosis and syphilis), most congenital/perinatal infections are viral and are usually secondary to transplacental passage of the infectious agent. Zika virus is a relative newcomer to the list of viruses recognized as a cause of congenital CNS infection and is capable of causing profound brain destruction and resultant microcephaly. Zika virus infection represents the first reported congenital CNS infection to be mostly transmitted by mosquitoes.
Six members of the herpesvirus family cause neurologic disease in children: HSV-1, HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), CMV, and human herpesvirus 6 (HHV-6).
Aside from CMV, HSV-2, Zika virus, and congenital HIV (vertically transmitted), congenital CNS infections have become less common due to immunization programs, prenatal screening, and global infection surveillance.
Here, an overview of the TORCH infections and important non-TORCH congenital/perinatal CNS infections is presented, beginning with the most globally common of the congenital infections, congenital CMV infection.
TORCH Infections
Terminology
Congenital infections are often grouped together and simply called TORCH infections—the acronym for toxoplasmosis, rubella, cytomegalovirus, and herpes. If congenital syphilis is included, the grouping is called TORCH(S) or (S)TORCH.
Etiology
In addition to the recognized "classic" TORCH(S) infections, a host of new organisms have been identified as causing congenital and perinatal infections.
These include Zika virus, LCMV, human Parvovirus B19, human parechovirus, hepatitis B, VZV, tuberculosis, HIV, and the parasitic infection toxocariasis.
Imaging
CMV, toxoplasmosis, rubella, Zika virus, VZV, lymphocytic choriomeningitis virus, and HIV may all cause parenchymal calcifications.
The location and distribution of the calcifications may strongly suggest the specific infectious agent. CMV causes periventricular calcifications, cysts, cortical clefts, polymicrogyria (PMG), schizencephaly, and white matter injury.
Early CNS infection with Zika virus leads to severe microcephaly and calcifications at the gray matter-white matter junction. Rubella and HSV cause lobar destruction, cystic encephalomalacia, and nonpatterned calcifications. Congenital syphilis is relatively rare, causing basilar meningitis, arterial strokes, and scattered dystrophic calcifications.
Congenital HIV is associated with basal ganglia calcification, atrophy, and aneurysmal arteriopathy. TORCH(S), Zika virus, and LCMV infections should be considered in newborns and infants with microcephaly, parenchymal calcifications, chorioretinitis, and intrauterine growth restriction (12-1).
Congenital Cytomegalovirus
CMV is the leading cause of nonhereditary deafness in children and is the most common cause of congenital brain infection in developed countries.
Terminology and Etiology
Congenital CMV infection is also called CMV encephalitis. CMV is a ubiquitous DNA virus that belongs to the human herpesvirus family.
(12-2B) T2WI in the same patient shows ventriculomegaly, periventricular Ca++ ſt, and simplified gyral pattern (polymicrogyria) .
Pathology
The timing of the gestational infection determines the magnitude of brain insult.
Early gestational CMV infection causes germinal zone necrosis with subependymal cysts and dystrophic calcifications. White matter volume loss occurs at all gestational ages and can be diffuse or multifocal.
Malformations of cortical development are very common, with PMG having the greatest prevalence (12-2B).
Microscopic examination shows cytomegaly with viral inclusions in the nuclei and cytoplasm. Patchy and focal cellular necrosis, particularly of germinal matrix cells, is typical of first-trimester infection. Vascular inflammation and thrombosis are also common.
Clinical Issues
Epidemiology. CMV is the most common of all congenital infections. Between 0.25-1.00% of newborn infants shed CMV in their urine or saliva at birth. This translates to nearly 35,000 viral-shedding newborns annually. Of these, 10% develop CNS or systemic symptoms and signs. Up to 4,000 newborns in the USA are annually confirmed to have symptomatic CMV infection (e.g., congenital CMV disease). This later category has significant long-term neurodevelopmental sequelae.
Presentation and Natural History. With advances in fetal imaging, particularly fetal MR, many of the CNS imaging manifestations of congenital CMV infection that have been chronicled in the newborn and infant are elegantly depicted antenatally (e.g., PMG, germinolytic cysts, and cerebellar dysgenesis).
Symptomatic newborns and infants may exhibit microcephaly, jaundice, hepatosplenomegaly, chorioretinitis, and rash. Asymptomatic newborns with congenital CMV infection may show microcephaly and otherwise initially appear developmentally normal. Sensorineural hearing loss, seizures, and developmental delay are the major long-term risks.
Newborns with systemic manifestations (e.g., hepatosplenomegaly, petechiae, and jaundice) have a slightly worse overall prognosis. Greater than half of all neonates with systemic signs and symptoms also have CNS involvement. Many of these newborns that demonstrate microcephaly, ventriculomegaly, cortical malformations (e.g., PMG), white matter abnormalities, and parenchymal calcifications have major neurodevelopmental sequelae (e.g., cerebral palsy, epilepsy, and mental retardation).
Treatment Options. Early (before gestational week 17) maternal hyperimmunoglobulin therapy improves the outcome of fetuses from women with primary CMV infection. The use of antiviral agents is also being explored for the treatment of symptomatic congenital CMV beyond the neonatal period. Antiviral agents that specifically target CMV are ganciclovir, valganciclovir (VGVC), foscarnet, and cidofovir. VGVC is well tolerated and may improve or help preserve auditory function in infected infants.
Imaging
General Features. Imaging features of congenital CMV are protean, including microcephaly, ventriculomegaly, germinolytic cysts, cortical malformations (e.g., PMG), Ca++, cerebellar and hippocampal dysgenesis, and white matter abnormalities. As a rule, the earlier the fetal infection, the more severe the findings (12-1) (12-4).
CT Findings.
NECT scans show intracranial calcifications and ventriculomegaly in most symptomatic infants. Calcifications are predominantly periventricular, with a predilection for the germinal matrix zones, particularly the caudostriatal regions (12-2A).
Calcifications vary from numerous bilateral thick calcifications to faint punctate unilateral foci (12- 2A) (12-3A) (12-4A). Calcification may be entirely absent (e.g., some NECT series of proven congenital CMV CNS disease report the prevalence of intracranial Ca++ at 66%). Therefore, the absence of intracranial Ca++ does not exclude diagnosis of congenital CMV. NECT may also demonstrate cortical clefting and other features reflecting underlying cortical malformation (e.g., PMG).
MR Findings.
MR remains the most sensitive imaging tool and examination of choice to depict the magnitude of congenital CNS CMV findings. MR shows the broad range of CMV-induced CNS abnormalities. This includes microcephaly with ventriculomegaly, cortical migrational and organizational abnormalities (the most common of which is PMG), cysts (germinal zone and pretemporal), parenchymal calcifications, white matter abnormalities (dysplastic and demyelinating), hippocampal dysgenesis, and cerebellar dysgenesis.
It bears reemphasizing that cortical migrational and organizational abnormalities are present in approximately 10-50% of congenital CMV cases and range from minor dysgenesis with focal cortical clefting, simplified gyral pattern and "open" lateral cerebral/sylvian fissures (e.g. PMG), to more severe manifestations including agyria, lissencephaly, and schizencephaly.
PMG in most congenital CMV infection imaging reviews remains the most common imaging abnormality that will be detected, more common than calcification.
T1WI shows microcephaly and enlarged ventricles and cysts with a predilection for the periventricular germinal zones and pretemporal white matter. Cortical abnormalities such as cerebellar and hippocampal dysgenesis are well depicted (12-3C) (12-3D). Also, subependymal hyperintense foci of T1 shortening caused by the periventricular calcifications may be seen. White matter hypointensities correspond to regions of demyelination and dysplasia. Sagittal midline T1WI shows a diminished cranial-to-facial ratio, indicating microcephaly. 3D T1WI techniques (e.g., 3D-SPGR) with isotropic axial and coronal reformations aide
in detecting cortical, hippocampal, and cerebellar abnormalities (e.g., PMG)
(12-3) (12-4).
T2WI and FLAIR images show myelin delay, white matter destruction, demyelination, and white matter volume loss with focal, patchy, or confluent hyperintensities at sites of white matter abnormality. Periventricular (e.g., germinal zone and anterior temporal lobe) cysts are common (12-4) (12-5). The pretemporal white matter cysts often begin as regions of T1 and T2 prolongation (12-4C) (12-5C).
T2WI also demonstrates the indistinct gray matter/white matter interface characteristic of PMG and characterizes other patterns of cortical organizational and migrational disturbance (12-3C). Coronal T2WI and FLAIR demonstrate the patterns of vertically dysmorphic hippocampi and cerebellar dysgenesis (12-3).
Calcifications appear as foci of T2 shortening (e.g., hypo intensity) (12-1). SWIs, including SWI-filtered phase maps, are able to distinguish paramagnetic substances (blood products as hypointense) from diamagnetic substances (calcification as hyperintense). Thus, SWI represents a valuable MR sequence in the imaging evaluation of suspected congenital CNS infections.
Fetal MR is more sensitive than US in the early detection of CMV-associated CNS abnormalities.
Ultrasound:
Cranial sonography is useful for evaluation of the neonatal and infant brain (up to 6-8 months of age). In the setting of congenital CMV infection, cranial sonography may be technically challenging, as microcephaly (due to poor brain growth and brain destruction) is associated with overlapping sutures and diminished size of the anterior and posterior fontanelles, which represent the probe contact points for sonography. When an acoustic window is present, enlarged ventricles, periventricular hyperechogenic foci that correspond to the subependymal calcifications seen on NECT and MR (SWI), may be seen.
Other findings include germinal zone cysts (germinolytic), which may be present along the caudostriatal grooves in the periventricular zones and in the anterior temporal white matter. Lenticulostriate mineralizing vasculopathy appearing as linear and branching hyperechogenicities within the thalami and basal ganglia although not pathognomonic for CMV occurs in 25-30% of congenital CMV infections
