Porencephaly
From Holoprosencephaly
Definition of Porencephaly
Porencephaly: A disorder of the central nervous system involving a cyst or cavity in a cerebral hemisphere of the brain. The cysts or cavities are usually the remnants of destructive lesions, but are sometimes the result of abnormal development. The disorder can occur before or after birth.
Porencephaly has a number of different causes including absence of brain development and destruction of brain tissue. The presence of porencephalic cysts can sometimes be detected by transillumination of the skull in infancy (when a strong light is shined through the head). The diagnosis may be confirmed by CT, MRI, or ultrasonography.
More severely affected infants show symptoms of the disorder shortly after birth, and the diagnosis is usually made before age 1. Signs may include delayed growth and development, spastic paresis (slight or incomplete paralysis), hypotonia (decreased muscle tone), seizures (often infantile spasms), and macrocephaly or microcephaly. Individuals with porencephaly may have poor or absent speech development, epilepsy, hydrocephalus, spastic contractures (shrinkage or shortening of muscles), and mental retardation. An extreme form of porencephaly is called hydranencephaly.
Treatment may include physical therapy, medication for seizure disorders, and a shunt for hydrocephalus.
The prognosis for individuals with porencephaly varies according to the location and extent of the lesion. Some patients with this disorder may develop only minor neurological problems and have normal intelligence, while others may be severely disabled. Others may die before the second decade of life.
Clinical Description
Prorencephaly is a term which describes a cerebral image (cysts or cavities in the brain). The disorder occurs before birth. Most infants show symptoms of the disorder shortly after birth and the diagnosis is usually made before one year of age. The clinical symptoms are variable and depend on the location and size of the lesion. Some patients may develop only minor neurological problems and have normal intelligence while others may be severely disabled. The commonest features are hemiplegic cerebral palsy, mental retardation and epilepsy. Other features encountered are: delayed growth, hypotonia, macrocephaly or microcephaly. Patients with porencephaly may have poor or absent speech development, hydrocephaly and limb spasticity.
Diagnostic methods
- Neuroimaging: computerized tomography (CT) and cerebral magnetic resonance imaging (MRI)
- Positive familial history
Etiology
According to their topography (which usually corresponds to territories supplied by cerebral arteries) porencephaly, like schizencephaly and polymicrogyria, is thought to result from an ischemic injury, occurring at mid-gestation. Most cases are sporadic and various risk factors have been identified: toxemia, maternal injuries, maternal infection, maternal diabetes, gemellarity, maternal intake of alcohol or cocaine, allo-immune thrombopenia, perinatal asphyxia.
However, some observations of familial recurrences have been reported, suggesting that genetic factors could be involved. The inheritance follows an autosomal dominant pattern with reduced penetrance. Genes involved in familial porencephaly have not yet been mapped. A first approach could be the search of mutations leading to a hypercaugulable state. Indeed, activated protein C (APC) resistance has been identified as a cause of hemiplegic cerebral palsy in children heterozygous for factor V Leiden mutation. The possible role of deficiencies in the protein C anticoagulant pathway in the pathogenesis of porencephaly was confirmed in a more recent study. Currently, the National Institute of Neurological Disorders and Stroke (NINDS) conducts a pilot study on abnormal acquired and genetic coagulation factors in children with porencephaly and stroke. In the family reported by Vilain et al, all tested affected members of the family were heterozygous for a mutation, which has been considered responsible for increased risk of thrombophilia either at a homozygous state or in combination with heterozygosity for another mutation. In this family, only one of four affected patients tested had the R506Q mutation in factor V Leiden and none of three affected patients tested had a deficiency in protein C. two of these patients were heterozygous for G20210A prothrombin gene mutation, one being also heterzygote for the C677T mutation in the mthylene tetrahydrofolate reductase (MTHFR) gene. Another patient was only heterozygote for the C677T MTHFR gene mutation. Considering the fact that the G20210A prothrombin gene mutation leads to hyperprothrombinmia, these data suggest that this mutation could play a role in the pathogenesis of porencephaly but is clearly not the only pathogenic factor. Similar conclusion emerged from studies designed to evaluate the risk of venous thromobosis in heterozygous carries of the 20210A allele: it was concluded that the risk of deep venous thrombosis and cerebral venous therombosis was increased only in patients who were heterozygous for both factor V Leiden and prothrombin gene mutations. Another study reported asymptomatic relatives of heterozygous carries of the 20210A variant with a history of theromboebolism who were homozygous for this variant. The pathogenic role of the C677T MTHFR gene mutation is very unlikely as the relationship between homozygostiy for this mutation and venous thrombosis remains controversial. However, increased frequency of combined MTHFR C677T and A1298C mutated alleles in spontaneous abort embryos have been reported.
Vilain Iet al.I have perposed that, in their family, there is a not yet identified mutation that would cause porencephaly in combination with a heterozygous state for a mutation involved in thrombophilia. This hypothesis would explain the authosomal dominant transmission and the low penetrance of the disorder. The candidate genes are homeobox genes. This is supported by the finding of mutations in the homebox gene EMX2, not only in sporadic cases of schizencephaly, also in two siblings with schizencephaly.
Mancini et al. reported the presence of patchy phyerintense white matter lesions on T2 MRI of patients and a asymptomatic abligate carrier, and suggested that these lesions could be a marker for the disease. However the specificic value of these MRI lesions seema very doubtfull. Indeed, periventricular hyperintense white matter lesions of variable size and extent are found in about 50% of normal controls aged 21 to 59 years and in nearly all normal controls above the age of 60 years.
Recently, mutations in the COL4A1gene have been described in four of the already published families and in one new unrelated family. Electromicroscopy of the skin biopsy can be helpful to rule out patients with COL4A1 gene mutations before asking for the molecular genetic diagnosis.
These mutations result in an abnoemal vascular basal membrane. Breedveld et al. Suggest that trauma and thrombophilia could represent factors influencing the accurence of cerebral bleeding in carriers of a muatation in the COL4A1 gene.
Genetic counseling
In the absence of a positive family history and increased risk factors for a hypercoagulable state, the recurrence risk of porencephaly is very low as familial poraencephaly is extremely rare. In case of positive family history, the mode of inheritance is autosmal dominant with reduced penetrance.
Antenatal diagnosis
Some cases may be diagnosed during pregnancy by fetal ultrasonography or MRI, usually in the third trimester.
Management including treatment
There is no specific treatment for this disorder. Symptomatic treatment includes physical therapy, medication for seizures (anti-epileptic drugs), and shunting procedures for treatment of hydrocephaly.
Prognosis
The prongonsis for children with porencephaly varies according to the location and extent of the cysts or cavities. Some children develop only mior neurological problems and have normal intelligence, while others may be severely disabled and may die before reaching adulthood.
Is there any treatment?
Treatment may include physical therapy, medication for seizures, and the placement of a shunt in the brain to remove excess fluid in the brain.
What is the prognosis?
The prognosis for children with porencephaly varies according to the location and extent of the cysts or cavities. Some children with this disorder develop only minor neurological problems and have normal intelligence, while others may be severely disabled and die before their second decade of life.
What research is being done?
The National Institute of Neurological Disorders and Stroke (NINDS) and other institutes of the National Institutes of Health (NIH) conduct research related to porencephaly in laboratories at the NIH and also support additional research through grants to major medical institutions across the country. Much of this research explores the complex mechanisms of normal brain development. The knowledge gained from these fundamental studies will provide a foundation for developing ways to prevent porecephaly and the other cephalic disorders.
<dive align="center">SPECIAL ISCHEMIC LESIONS PORENCEPHALY, SCHIZENCEPHALY, AND HYDRANENCEPHALY</center>
Fetuses and newborn infants suffer ischemic and hemorrhagic strokes with surprising frequency. Before birth, vascular occlusion may result from embolism from placental vessels, hereditary coagulopathies, maternal cocaine, and other causes, most of which remain unknown. Additional causes of stroke in the perinatal period are birth trauma, vascular spasm from subarachnoid hemorrhage, disseminated intravascular coagulation, and venous thrombosis. Systemic HIE can also cause focal lesions. The pathology of most of these strokes is similar to that of their adult counterparts. This section describes three special ischemic lesions that have their origin in fetal life.
Porencephaly (Gr.Poros a passage, ford, pore) was originally defined as a defect that creates a communication between the cerebral ventricles and the subarachnoid space but now, it it used to describe any fluid-filled cavity-a hole, as it were-in the fetal or neonatal brain. A thin membrane may separate the cavity from the lateral ventricle or the subarachnoid space. Such membranes rupture in life or during the autopsy. The pathology has its origin in fetal life. Most cases begin as ischemic infarcts that subsequently cavitate, and are usually located in the middle cerebral artery territory. Similar lesions may result from brain necrosis occurring in prenatal infections. The pathogenesis is no different from necrotic lesions that arise in late gestation or in the neonatal period. The main difference is that lesions arising early in gestation heal without gliosis, and the defect is frequently bordered by dysplastic cortex. On the other hand, lesions arising later are associated with gliosis, macrophage reaction, and calcification. A genetic angiopathy, caused by mutations of COL4A1, the gene that encodes Collagen 4A1 (a component of the vscular bsement membrane) causes porencephaly and cerebral hemorrhage in infants and lacunar infarcts, cerebral hemorrhage, and leukoencephalopathy in adults.
Schizencephaly(Gr.Scheizein to cleave, slit, split) was originally described by Yakovlev and Wadsworth as “congenital clefts in the cerebral mantle”, extending from the pial surface to the ventricles. The lips of the defects were closed in some cases, forming a seam (closed lip lissencephaly). In other cases, hydrocephalus caused the lips to separate, creating a gap in the cerebral mantle (open lip schizencephaly). As in porencephaly, the thin subpial and ependymal membranes along the outer and inner borders of open lip lesions may rupture, creating a communication between the lateral ventricles and the subarachnoid space. Yakovlev and Wadsworth emphasized the bilateral symmetry of the lesions and postulated that they were due to failure of development (agenesis) of brain tissue, dating back to the first two months of fetal life.
Schizencephaly can be unilateral or bilateral. The location of the lesions on the cerebral convexities suggests ischemic infarcts in the territories of the middle cerebral arteries, as in the 20 week gestation fetus above. Dysplastic cortex with changes of polymicrogyria is usually present along the sides of the seam and in the surrounding areas. Some patients have a schizencephaly in one hemisphere and polymicrogyria in the same distribution on the opposite hemisphere. The association of schizencephaly with polymicrogyria is so frequent that the two entities are now considered to be part of a spectrum.
The neurodevelopmental outcome correlates with the severity of pathology. Unilateral closed lip schizencephaly has the mildest clinical picture and bilateral open lip the most severe. The most prominent manifestations are motor deficits and seizures. Language function is less severely affected. Schizencephaly may be asymptomatic during the first year of life, and 17% of cases have minimal or no symptoms.
Many cases of schizencephaly, like the one in the 20 week fetus shown above, are probably ischemic infarcts that develop in utero. As they evolve, necrotic tissue is removed and the surrounding brain closes in around the defect. Neuropathologists have dismissed the agenesis hypothesis in favor of an encephaloclastic process and have even discouraged the use of the term schizencephaly. However, the term is used neuroradiologists, and, thanks to modern imaging, the frequency of schizencephaly appears to be considerably higher than had been previously appreciated. Also, perhaps opening the door for reconsideration of the agenesis hypothesis, familial forms of schizencephaly, associated with mutations of the EMX2 gene have been described recently. This homeobox gene is expressed in proliferating neuronal precursors along the walls of the ventricles and may play a role in brain development.
In hydranencephaly, the cerebral hemispheres are replaced by a thin-walled, fluid-filled cyst. The aqueduct is usually atretic, and increased fluid pressure causes the cyst (and the head) to enlarge. There is variable preservation of the inferior frontal, temporal, and occipital lobes, and of the basal ganglia and diencephalon. The brainstem and cerebellum are usually preserved. Hydranencephaly is not a malformation, but a disruption caused probably by ischemia in utero in the territories of the carotid arteries. Babies with hydranencephaly may appear normal initially because the brainstem is intact. The empty cranial cavity transilluminates.
References:
http://www.medterms.com/script/main/art.asp?articlekey=15543 http://www.orpha.net/data/patho/GB/uk-FamilialPorencephaly.pdf http://www.ninds.nih.gov/disorders/porencephaly/porencephaly.htm http://www.neuropathologyweb.org/chapter3/chapter3bPorencephaly.html
