PATHOLOGY3

<body topmargin=0 leftmargin=0 marginheight=0 marginwidth=0> <table cellpadding=0 cellspacing=0 border=0><tr> <td valign="top" colspan=2 height=22 BGCOLOR="#FFFFFF" TEXT="#080000" bgproperties="fixed" background="041000d2egerdp.gif"> <div> </div> </td> </tr><tr> <td valign="top" width=145 BGCOLOR="#333399" TEXT="#080000" background="040a2c00erkjzj.gif"> <div> <IMG SRC="0eba5ab0.jpg" border=0 width="165" height="171" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">DANIL HAMMOUDI.MD</div> </td> <td valign="top" height=458 BGCOLOR="#FFFFFF" TEXT="#080000"> <div> <FONT SIZE="5" COLOR="#336600" FACE="Times New Roman" ><I>NEUROPATHOLOGY</I></FONT><FONT SIZE="1" COLOR="#663399" FACE="Times New Roman" >    </FONT> |    <B> </B><FONT SIZE="2" COLOR="#0000BF" FACE="Times New Roman" ><A HREF="index.htm" TARGET="_top" TITLE="NEUROPATHOLOGY"><U><B>home</B></U></A></FONT></div> <div> <A HREF="id18.htm" TARGET="_top" TITLE="HISTOLOGY REVIEW"><U>HISTOLOGY REVIEW</U></A>   |   <A HREF="id19.htm" TARGET="_top" TITLE="PHYSIOLOGY REVIEW"><U>PHYSIOLOGY REVIEW</U></A>   |   <A HREF="id20.htm" TARGET="_top" TITLE="PATHOLOGY part1"><U>PATHOLOGY part1</U></A>   |   <A HREF="id22.htm" TARGET="_top" TITLE="pathology part2"><U>pathology part2</U></A>   |   <B>PATHOLOGY3</B>   |   <A HREF="id27.htm" TARGET="_top" TITLE="PATHOLOGY 4"><U>PATHOLOGY 4</U></A>   |   <A HREF="id21.htm" TARGET="_top" TITLE="PICTURES"><U>PICTURES</U></A>   |   <A HREF="id31.htm" TARGET="_top" TITLE="tumor gn"><U>tumor gn</U></A>   |   <A HREF="id30.htm" TARGET="_top" TITLE="multiple sclerosis"><U>multiple sclerosis</U></A>   |   <A HREF="id24.htm" TARGET="_top" TITLE="quiz"><U>quiz</U></A>   |   <A HREF="id23.htm" TARGET="_top" TITLE="quizanswer"><U>quizanswer</U></A>   |   <A HREF="id17.htm" TARGET="_top" TITLE="Contact Me and links"><U>Contact Me and links</U></A>   |   <A HREF="id29.htm" TARGET="_top" TITLE="info and news"><U>info and news</U></A></div> <div> <IMG SRC="04207040.gif" border=0 width="263" height="4" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></div> <div> <B>PATHOLOGY3</B></div> <DIV ALIGN="LEFT"></DIV> <div> <B>CONGENITAL ABNORMALITIES </B></div> <div> <B>OF THE CNS</B><FONT SIZE="4" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B>AND HYDROCEPHALUS</B><FONT SIZE="4" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>NEURAL TUBE DEFECTS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ANENCEPHALY</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">SPINA BIFIDA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ENCEPHALOCELE</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>HOLOPROSENCEPHALY</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>AGENESIS OF THE CORPUS CALLOSUM</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>NEURONAL MIGRATION DEFECTS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">LISSENCEPHALY-PACHYGYRIA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">POLYMICROGYRIA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>HYDROCEPHALUS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">CHIARI MALFORMATIONS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">AQUEDUCTAL ATRESIA AND STENOSIS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">DANDY- WALKER MALFORMATION</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">PATHOGENESIS OF BRAIN DAMAGE IN HYDROCEPHALUS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>SYRINGOMYELIA - HYDROMYELIA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <bR> <bR> <div> ========================================================================================================</div> <div> Congenital abnormalities are among the leading causes of infant morbidity and mortality and fetal loss. The leading sites of congenital abnormalities are the skeleton, skin and brain. </div> <div> Congenital abnormalities of the CNS can be divided into developmental malformations and disruptions. </div> <bR> <bR> <div> <B>Developmental malformations</B> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">result from flawed development of the brain. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This may be caused by chromosomal abnormalities and single gene defects that alter the blueprint of the brain or by imbalances of certain factors that control gene expression during development. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gene defects may be in the germline or develop after conception by spontaneous mutation or from the action of harmful physical or chemical agents. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Some malformations are caused by multiple genetic and environmental factors acting in concert (multifactorial etiology).</div> <bR> <div>  <B>Disruptions</B></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> result from destruction of the normally developed (or developing) brain caused by</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">environmental or intrinsic factors such as </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">fetal infection, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">exposure of the fetus to harmful chemicals,</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> irradiation, and fetal hypoxia.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> For instance, holoprosencephaly, a condition in which the forebrain is not divided into two hemispheres, is a malformation. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Hydranencephaly, in which massive destruction reduces the hemispheres into fluid-filled sacs, is a disruption. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The line between malformation and disruption is sometimes blurred because an extrinsic factor (e.g. irradiation) may not only cause physical injury but may also damage genes that are important for development. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In general, the pathological lesions of developmental malformations of the CNS are either midline or bilateral and symmetric and do not show gliosis.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> On the other hand, most disruptions are focal and asymmetric and are associated with gliosis and other reactive changes such as inflammation, phagocytosis and calcification. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">However, in disruptions occurring in the first trimester, these reactions are limited because the brain is immature.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> For these reasons, it is hard, sometimes, to distinguish malformation from disruption. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This distinction carries important implications.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Malformations carry a recurrence risk that can be calculated.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Disruptions do not recur, unless the exposure recurs or continues. </div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Exposure to teratogens, viral infections, etc., can occur throughout pregnancy.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The timing of exposure is critical for both, malformations and disruptions. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The earlier the exposure, the more severe the defect.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> For instance, fetal cytomegalovirus (CMV) infection before midgestation causes microcephaly and polymicrogyria. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">CMV infection in the third trimester causes an encephalitis, similar to postnatal CMV encephalitis.</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The most critical period for malformations and disruptions is the third to eighth week of gestation, during which most organs, including the brain, take form.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B> <A NAME="ntds"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>NEURAL TUBE DEFECTS</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The neural plate appears on the 17th day of gestation as a thickening of the embryonic ectoderm over the notochord.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> This <B>neuroectoderm</B> gives rise to the central nervous system.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> On day 18, the neural plate invaginates along the midline, forming the neural groove with the neural folds on either side. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The neural tube is formed by approximation and fusion of the neural folds by the end of the third week. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The cranial end of the neural tube closes by 24 days and the caudal by 25-26 days. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The neural tube then is covered dorsally by mesenchyme that forms the vertebrae and skull. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Closure of the vertebral arches is completed at 11 weeks of gestation. </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Defective closure of the neural tube results in neural tube defects (NTDs) which are classified as anterior (anencephaly, encephalocele) and posterior (spina bifida).</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <bR> <div>  <A NAME="anencephaly"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><FONT SIZE="3" COLOR="#000000" FACE="Verdana" ><B>Anencephaly</B></FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> is often accompanied by spina bifida. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In anencephaly, the brain protrudes through a defect in the cranial vault (<B>exencephaly]</B>and is gradually destroyed because of mechanical injury and vascular disruption<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG SRC="0dfe6650.gif" border=0 width="230" height="357" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="Arial" >Exencephaly. The brain protrudes outside the skull</FONT></div> <div> <IMG SRC="0e197720.jpg" border=0 width="407" height="370" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><IMG SRC="0e3f4120.gif" border=0 width="500" height="274" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">[MY FIRST DELIVRY DONE BY MY SELF AS AN EXTERN WAS AN ANENCEPHALY FOR AN 18 YEARS WOMEN THIS USUALLY STICK IN YOUR MEMORY]</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Eventually, all that is left is a small, vascular mass of disorganized neural tissue (cerebrovasculosa) mixed with choroid plexus. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The eyes evaginate from the forebrain before it is destroyed and are preserved. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The cranial vault is either absent or collapses over the base of the skull. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Loss of the hypothalamus and pituitary gland results in adrenal hypoplasia. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Anencephaly is incompatible with survival.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <bR> <div> <B> <A NAME="bifida"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Spina bifida</B> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">is a set of malformations of the spinal cord caused by failure of closure of the neural tube and defective fusion or lack of fusion of the vertebral arches, soft tissues, and skin that cover the back</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">. The lesion is usually in the lumbosacral area but sometimes it can be more extensive or involve the entire spinal cord.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f00000ff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In its mildest form, <B>spina bifida occulta</B>, the vertebral arches are absent, but there is a hairy patch of skin over the defect.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f00000ff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The spinal cord may be normal or the filum terminale may be tethered to subcutaneous tissue. <B>Meningocele</B> is a bulge in the lumbosacral area consisting of a meningeal sac protruding through the bone defect.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f00000ff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In <B>meningomyelocele</B>, the sac contains malformed spinal cord tissue.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f00000ff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In severe cases, there is no sac at all, and neural tissue from the open neural plate lies on the dorsal surface of the fetus.<FONT SIZE="3" COLOR="#FF0000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <IMG SRC="0e5f4530.gif" border=0 width="500" height="339" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">  <FONT SIZE="3" COLOR="#000000" FACE="System" >Meningomyelocele (left). Anencephaly and neural tube defect involving the entire length of the spine (right).</FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div>  SPINA BIFIDA AS SAW SO MANY OF THESE POOR BABIES DURING MY NEUROSURGICAL ROTATION AND NO MUCH WAS DONE IN THAT TIME FOR SOME OF THEM</div> <bR> <div> <B>Encephalocele</B> is a protrusion of brain through a defect of the skull, usually in the occipital area<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG SRC="0e7397f0.gif" border=0 width="313" height="383" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="System" >Occipital encephalocele.</FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The protruding part is destroyed because of mechanical disruption and ischemia. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The intracranial part of the brain around the defect is malformed and disrupted.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Large occipital encephaloceles are incompatible with life because of damage of the brainstem.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">NTDs are the most common congenital abnormalities of the CNS and, overall, the second most common congenital abnormality after congenital heart disease. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">They are a significant cause of fetal loss.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Live-born babies may have paralysis of the legs and loss of bladder and bowel function.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Open defects allow direct entry of bacteria into the CNS.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The same thing happens if the skin covering the meningomyelocele becomes necrotic and infected. Some meningomyeloceles are a component of a more complex malformation, the Chiari II malformation, which includes hydrocephalus and abnormalities of the posterior fossa structures.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f00000ff00.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Neural tube defects can be detected in utero by determination of </B><B>alpha-fetoprotein (AFP)</B><B> and </B><B>acetylcholinesterase</B><B> in the </B><B>amniotic fluid</B><B> and </B><B>maternal blood</B><B>. Alpha- fetoprotein</B><FONT SIZE="3" COLOR="#000000" FACE="Verdana" >, a major circulating fetal protein produced by the liver, peaks at 12-14 weeks of gestation and subsequently declines. </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">AFP leaks from the fetus into the amniotic fluid through exposed capillaries of the neural tube defect.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> This results in persistently high levels of AFP in the amniotic fluid and in the maternal blood.</div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Elevated AFP is also seen in other lesions where fetal capillaries are exposed to the amniotic fluid such as omphalocele and sacrococcygeal teratoma. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Acetylcholinesterase leaks directly from exposed neural tissue into the amniotic fluid.</B> </div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">NTDs develop during the third to<B><U> fourth week of gestation</U></B> and are due to a combination of genetic and environmental causes (multifactorial). </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The genetic causes are unknown. Environmental causes include diabetes mellitus and the antiepileptic drug valproate.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Administration of 0.4 mg of folic acid in the periconceptional period (4 weeks before to 8 weeks after conception) significantly reduces the occurrence of NTDs. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The mechanism of action of folic acid in preventing NTDs is not known. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Women who have children with NTDs are not overtly folate deficient. However, the rapidly dividing cells of the neural tube probably require a large amount of folate for DNA synthesis.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Supply of folate may be inadequate because of gene defects that result in subtle abnormalities of folate metabolism.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Two mutations of the folate dependent enzyme 5,10-Methylenetetrahydrofolate reductrase (MTHFR), MTHFR C677T and MTHFR A1298C, are associated with an increased risk for NTDs. </div> <bR> <bR> <div> <B> <A NAME="holo"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>HOLOPROSENCEPHALY</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Between the fourth to sixth week of gestation, the forebrain (prosencephalon) is divided into the two hemispheres. Absence of this cleavage results in a spectrum of malformations called holoprosencephaly (HPE). </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In the most severe form, alobar HPE, the brain consists of a <B>single spherical forebrain structure</B> with a single ventricle.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <DIV ALIGN="LEFT"></DIV> <div> <IMG SRC="0e9f4ee0.gif" border=0 width="500" height="238" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="Arial" >Holoprosencephaly. There is no interhemispheric fissure. There is a single ventricular cavity. The olfactory bulbs are absent</FONT></div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The brain in alobar HPE is small and the gyral pattern and cortical architecture are abnormal. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The eyes, which evaginate from the forebrain in the fourth week, are small and malformed or there is only one eye (cyclopia).</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Because the olfactory nerves which are part of the rhinencephalon are absent, the term <B>arrhinencephaly</B> has also been applied to this malformation. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">However, in alobar HPE, there is much more missing than the olfactory brain.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The brain malformations are accompanied by severe<B> midline facial anomalies </B>such as<B> </B>a proboscis (a trunk-like structure above the single eye), a single nostril, cleft lip, cleft palate, and others. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Alobar HPE is incompatible with survival.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In milder forms of HPE the brain is larger, and there is partial separation of the hemispheres.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Such cases are associated with variable psychomotor retardation depending on the pathology.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> .<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <DIV ALIGN="LEFT"></DIV> <div> <IMG SRC="0ed84a50.gif" border=0 width="388" height="421" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="Arial" >Facial malformation in holoprosencephaly</FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">HPE is rare among live born infants but is very common in embryogenesis. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">It has genetic and environmental causes. Most cases are sporadic but there are genetic forms that can be autosomal dominant, recessive, or X-linked.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> HPE also occurs as a component of multiple malformation syndromes and in several chromosomal abnormalities involving 12 chromosomes. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Genetic HPE is associated with four genes, the best known of which is Sonic Hedgehog (SHH) gene on7q36.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Mutations of this gene cause autosomal dominant HPE. Defective cholesterol synthesis inhibits SHH signaling resulting in HPE like malformations. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Retinoic acid participates in the HSS system.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Excess retinoic acid during embryogenesis (from administration of Accutane for acne) inhibits SHH and causes HPE and other malformations. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The HPE associated gene TG-interacting factor (TGIF) on 18p11, regulates retinoic acid. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Mutations of TGIF result in unrestrained retinoic acid activity and HPE. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The multitude of genes and chromosomal loci associated with HPE underline the complexity of genetic programs that are involved in embryonic patterning and the intricate interaction of genes with one another and with environmental factors. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The chemical messages that induce the forebrain to divide into two hemispheres arise in the preductal plate, an area rostral to the notochord that gives rise to facial mesoderm. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">So, the facial anomalies are probably primary. </div> <bR> <bR> <div> <B> <A NAME="agenesis"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>AGENESIS OF THE CORPUS CALLOSUM</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">At about 10 weeks gestation, a glial bridge (massa commisuralis) forms between the two hemispheres, at the bottom of the interhemispheric fissure. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Soon after, axons begin to cross this bridge, forming the corpus callosum (CC). </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This process is completed by 18 to 20 weeks gestation.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Agenesis of the corpus callosum (ACC) develops either if the bridge does not form or if axons fail to cross it.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> HPE, in which the forebrain does not divide into two hemispheres, can be mistaken for ACC. ACC is probably the most genetically diverse brain malformation. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">It occurs in tens of chromosomal abnormalities and malformation syndromes and in several inherited metabolic disorders.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> ACC is associated with mutations of the L1 cell adhesion molecule, a cell surface glycoprotein that is important for guidance of migrating neurons (see neuronal migration below). </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ACC may be complete or partial, involving only the posterior part of the CC (splenium). </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">It may occur as an isolated defect (in which case there may be no neurological deficit) or as part of a more complex malformation.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> When the CC is absent, the anterior horns of lateral ventricles have a bat wing shape and the posterior horns are dilated and parallel to one another.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The gap between the two hmispheres is filled sometimes by adipose tissue.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> Agenesis of the corpus callosum and pachygyria<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <DIV ALIGN="LEFT"></DIV> <div> <IMG SRC="0ee2cf90.jpg" border=0 width="300" height="249" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></div> <bR> <bR> <div> <B> <A NAME="nmds"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>MALFORMATIONS DUE TO ABNORMAL NEURONAL MIGRATION</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The neurons and glial cells that form the cerebral cortex are generated around the ventricles of the brain and migrate to the cortex. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Proliferating multi-potential precursor cells form a thick layer around the ventricles, the <B>proliferative neuroepithelium</B>. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The first wave of migration results in formation of a provisional cortex, the <B>preplate</B>. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This is replaced by the permanent cortical plate.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Neurons migrate to the cortex along the <B>radial glia</B>, a scaffold of astrocytic processes that strech from the ventricular wall to the pial surface. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">They are guided by adhesion molecules present on their membranes and on radial glial fibers and by chemical signals some of which are produced by the preplate. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Neurons that form the permanent cortical plate migrate in an <B>inside-out</B>, outside last pattern. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The precursor cells of the proliferative zone are organized into genetically related groups, the <B>proliferative units</B>.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The offspring of each proliferative unit migrate into adjacent positions at the cortex and are organized into a functional module, the <B>ontogenetic column</B>. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Thus, the cortex has a horizontal organization into five neuronal layers and a vertical arrangement into ontogenetic columns.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Neurogenesis in fish, amphibians, birds and rodents continues after birth. Until recently, it was thought that neurogenesis and migration in primates is completed by mid-gestation except for the hippocampus and granular layer of the cerebellum where it continues during early postnatal life.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Recent research shows that neurogenesis also occurs in the adult primate cortex. New neurons are generated in the periventricular area and migrate to the the neocortex. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The significance of this observation in terms of neuronal plasticity is not known.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The proliferative neuroepithelium produces more neurons than are necessary to populate the cerebral cortex. Neurons that do not make working synapses die</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">. Other neurons are eliminated by genetically programmed apoptosis.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The extent of programmed neuronal death in humans is not known.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG BORDER="0" SRC="Wing0a7300a800f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The surface of the hemispheres during the first trimester is smooth. </div> <div> <IMG BORDER="0" SRC="Wing0a7300a800f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Cortical folding begins during neuronal migration.</div> <div> <IMG BORDER="0" SRC="Wing0a7300a800f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The Sylvian fissure, central sulcus, calcarine fissure, and parieto-occipital fissure are formed by 26 weeks.</div> <div> <IMG BORDER="0" SRC="Wing0a7300a800f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The entire surface of the hemispheres is folded by 32 weeks.</div> <div> <IMG BORDER="0" SRC="Wing0a7300a800f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Defective neuronal migration results in the formation of a disorganized cerebral cortex in which neurons are not normally related or connected with one another. </div> <div> <IMG BORDER="0" SRC="Wing0a7300a800f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The gyral pattern is also abnormal and is the basis for the morphologic classification of neuronal migration defects into lissencephaly, pachygyria and polymicrogyria.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Wing0a7300a800f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The most severe migration defect is  <A NAME="lissencephaly"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><B>lissencephaly</B> (smooth brain) or <B>agyria</B>, in which cortical sulci are absent except, usually, for the Sylvian fissure.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG SRC="0f0f4e10.gif" border=0 width="500" height="225" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="System" >Lissencephaly.</FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The cortex, in type 1lissencephaly, is thick and consists of the molecular and three neuronal layers.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The depest of these layers is also the thickest and most cellular, presumably comprised of neurons that migrated a certain distance from the germinal matrix but failed to reach their normal destinations. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There is a small amount of white mater between the abnormal cortex and the ventricles. In type 2 lissencephaly, no layers are present and there are glioneuronal heterotopias in the subarachnois space.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> <B>Pachygyria</B> (thick gyri) is a milder variant of lissencephaly with a reduced number of broad gyri. Lissencephaly arises between 12 and 16 weeks of gestation.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Patients with lissencephaly-pachygyria have severe psychomotor retardation and intractable seizures.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <bR> <div> <B><U>Periventricular heterotopia (PH) </U></B></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">is characterized by unorganized islands of neurons under the ependyma of the lateral ventricles and may coexist with other migration defects. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">These neurons presumably failed to migrate and differentiated in their original positions. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Patients with PH have normal intelligence and seizures</div> <bR> <div> <U>In </U><B><U>subcortical band heterotopia (SBH)</U></B><B>,</B></div> <div>  misplaced neurons are arranged in a separate layer between the cortex and the ventricles. </div> <div> Patients with SBH have psychomotor retardation, seizures and behaviour problems.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <U>In </U><U> <A NAME="polymicrogyria"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U><B><U>polymicrogyria</U></B><U> (many small gyri)</U>, </div> <div> the surface of the cerebral hemispheres shows multiple small bumps, suggesting an excessive number of gyri.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The cortex consists of the molecular and one other broad neuronal layer (in some cases there are three poorly defined neuronal layers).</div> <div>  These layers are irregularly overfolded and fused, eliminating the sulci.</div> <div>  Patients with polymicrogyria have severe psychomotor retardation and seizures.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B><U>Focal cortical dysplasia – microdysgenesis</U></B> </div> <div> is characterized by a focally thickened cortex with a disordered cytoarchitecture, large abnormally oriented neurons and hypertrophic astrocytes. </div> <div> Such lesions are often seen in specimens resected for epilepsy. </div> <div> The lesion is thought to represent a focal abnormality of neuronal migration and differentiation.</div> <div>  It resembles the cortical lesions of tuberous sclerosis.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Major clinical-pathological phenotypes are distinct and relatively rare. </div> <div> Minor or focal abnormalities such as focal polymicrogyria, a single or a few subependymal heterotopic nodules and subarachnoid glioneuronal heterotopias are quite common.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <bR> <div> <B><U>ETIOLOGY-PATHOGENESIS OF NMDs</U></B> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Lissencephaly, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">SBH and PH have a genetic basis. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">PMG is thought to be a disruption.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B><U>Lissencephaly</U></B> </div> <div> occurs in two distinct genetic disorders, </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">X-linked lissencephaly-subcortical band heterotopia (XLIS-SBH) </B>and </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">the <B>Miller-Dieker syndrome (MDS)</B>.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> XLIS-SBH is caused by mutations of a gene on Xq22.3-q23 that codes for Doublecortin (DCX), a microtubule associated protein. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This suggests that XLIS-SBH is caused by an abnormality of the cytoskeleton of migrating neurons. XLIS-SBH is an X-linked dominant defect. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Affected males have type 1 lissencephaly. Due to random X-inactivation, affected females have a mosaic cellular phenotype, i.e. half of their cells are affected and the other half are not.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This results in a less severe malformation, SBH. </div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The <B>MDS</B> is caused by a microdeletion of 17q13.3 involving the LIS1 gene. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The product of this gene regulates Platelet Activating Factor Acetylhydrolase and is also thought to be involved in regulation of microtubules. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Deletion of one copy of the gene is suffficient to produce lissencephaly. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The MDS is characterized by type 1 lissencephaly, dysmorphic face, visceral abnormalities and polydactyly.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B><U>Periventricular Heterotopia </U></B></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">is an X-linked dominant defect which is lethal in males and causes PH in females.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The mutation involves the gene of Filamin I on Xq28. Filamin I, an actin-binding protein that crosslinks actin filaments, is important for the cytoskeleton and cellular locomotion.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B><U>NMDs WITH CONGENITAL MUSCULAR DYSTROPHY</U></B>: </div> <div> Three rare syndromes, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">the Walker-Warburg Syndrome,</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Fukuyama Congenital Muscular Dystrophy, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Muscle-Eye-Brain Disease are characterized by type 2 (unorganized) lissencephaly, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">subarachnoid glioneuronal heterotopias, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">hydrocephalus and retinal detachment.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B><U>NMDs ASSOCIATED WITH METABOLIC DISORDERS</U></B>: </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The main entities in this group are the Zellweger Syndrome (ZS),</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> neonatal adrenoleukodystrophy (NALD), </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> glutaric aciduria IIA.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Two key features of the ZS and NALD, deficiency of plasmalogens and elevated very long chain fatty acids, may cause membrane abnormalities that could impair guidance of migrating neurons. </div> <bR> <bR> <div> <B>Polymicrogyria</B> is thought to be a disruption caused, most frequently, by HIE and fetal infections. Layer 5 is damaged and layers superficial to it merge and overfold. The damage occurs either after neuronal migration is completed or after migration of layer 6 neurons. In the latter case, layer 4, 3 and 2 neurons pass through the damaged layer 5 and are arranged in an abnormal fashion superficial to it. The disruptive pathogenesis of polymicrogyria is supported by animal experiments. Polymicrogyria is seen frequently in a vascular distribution and in the borders of porencephalic cysts and schizencephaly defects. </div> <bR> <bR> <div> <B><U> <A NAME="hydro"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>HYDROCEPHALUS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><U> </U></FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Hydrocephalus is dilatation of the cerebral ventricles. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This dilatation results from a variety of causes, the common denominator of which is obstruction of CSF circulation. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Approximately 600-700 ml of CSF is produced daily by the choroid plexuses. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">From the lateral ventricles, CSF enters the third ventricle through the foramina of Monro and then flows into the fourth ventricle through the aqueduct.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> It exits from the fourth ventricle into the subarachnoid space through the foramina of Luschka and Magendie and then moves over the cerebral convexities to the arachnoid villi through which it is absorbed into the venous circulation.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Hydrocephalus may result from the following causes:<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="794" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#FFFF00 HEIGHT= 245 WIDTH="784"><div> <B>Hypersecretion of CSF</B>: choroid plexus papilloma<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Obstructive hydrocephalus</B> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Obstruction of the foramina of Monro (colloid cyst, tuberous sclerosis)<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Obstruction of the third ventricle (craniopharyngioma, pilocytic astrocytoma, germ cell tumors).<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Obstruction of the aqueduct (aqueductal stenosis or atresia, posterior fossa tumors).<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Obstruction of the foramina of Luschka or impairment of flow from the fourth ventricle (Chiari malformation, Dandy-Walker malformation, meningitis, subarachnoid hemorrhage, posterior fossa tumors).<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Fibrosis of the subarachnoid space (meningitis, subarachnoid hemorrhage, meningeal dissemination of tumors), obliteration of the subarachnoid space by glioneuronal heterotopias in the Walker-Warburg syndrome.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Defective filtration of CSF</B>: postulated for low-pressure hydrocephalus.</div> </tD> </tR> </TABLE></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Hydrocephalus per se is not a malformation, but a deformation due to increased pressure in the ventricles. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">As the above list shows, some forms of it are congenital and others develop later in life. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The most common congenital forms of hydrocephalus are those that are associated with the Chiari malformation, various aqueductal lesions and the Dandy-Walker malformation.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <bR> <DIV ALIGN="LEFT"></DIV> <div> <B><U> <A NAME="chiari_malformations"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><FONT SIZE="3" COLOR="#000000" FACE="Verdana" ><B><U>CHIARI MALFORMATIONS</U></B></FONT><B><U> </U></B></div> <div> The<B> Chiari type II malformation</B> is a syndrome or association of anomalies characterized by </div> <bR> <bR> <div> a) a neural tube defect, usually a <B>lumbosacral</B> <B>meningomyelocele</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG SRC="0f236a70.gif" border=0 width="310" height="423" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="Arial" >Chiari II malformation. Meningomyelocele and large head from hydrocephalus</FONT></div> <bR> <bR> <div> b) <B>abnormalities of the posterior fossa and craniocervical junction</B> </div> <bR> <bR> <div>  c) <B>hydrocephalus</B>. It is the most frequent congenital abnormality associated with hydrocephalus. </div> <div> The abnormality of the posterior fossa and its contents consists of a large foramen magnum, low insertion of the tentorium and a shallow posterior fossa. As a result of these deformities, the cerebellum and brainstem are crowded and displaced into the cervical canal</div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The medulla is elongated and folded dorsally.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The aqueduct and the fourth ventricle are collapsed. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There is often aqueductal atresia. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The foramina of Luschka lie in the spinal canal and the subarachnoid space around them is collapsed and fibrotic.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Blockage of CSF flow from these lesions causes hydrocephalus. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Severe hydrocephalus causes parts of the cortex that had been hidden in the cerebral sulci to become externalized. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The surface of the brain appears to have more gyri than normal and gives the false impression of polymicrogyria. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">However, unlike true polymicrogyria, the cortical cytoarchitecture is normal. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The pathogenesis of these complex abnormalities and the connection between the neural tube and posterior fossa defects is not known.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B>The Chiari type I </B>malformation is a milder variant of Chiari II. The volume of the posterior fossa is reduced leading to overcrowding of posterior fossa structures and herniation of the cerebellar tonsils and dorsal cerebellum into the spinal canal. Many patients have syringomyelia and some have hydrocephalus. Chiari I is a frequent finding in imaging studies. Some patients are asymptomatic but others have headache, dizziness, cranial nerve abnormalities, spinal cord disturbances and other symptoms.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B><U> <A NAME="aqueduct"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>AQUEDUCTAL ATRESIA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><U> </U></FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Aqueductal atresia is a disruption that occurs in utero. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">It may be caused by clots from intraventricular bleeding, infection and other pathologies that cause gliosis and obliterate the aqueduct. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Sometimes a few rudimentary ependymal-lined tubules are seen in place of the aqueduct (aqueductal forking).<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">These small channels are not enough to convey CSF from the third to the fourth ventricle. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Aqueductal atresia is usually associated with other disruptive brain lesions. </div> <bR> <bR> <div> <B>Aqueductal stenosis</B> (a narrow aqueduct without gliosis) occurs as an isolated, sporadic or X-linked abnormality<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> X-linked aqueductal stenosis is due to mutation of a gene on Xq28 that codes for an L1 adhesion molecule. Hydrocephalus and mental retardation in some cases of aqueductal stenosis are indolent and are discovered in adult life.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B> <A NAME="dw"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>DANDY-WALKER MALFORMATION</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The Dandy-Walker malformation is a syndrome of<B> hydrocephalus</B> and<B> agenesis of the cerebellar vermis</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There is obstruction of CSF flow out of the fourth ventricle, the mechanism of which is not understood. This obstruction causes severe dilatation of the fourth ventricle, balloons the membrane that joins the two cerebellar hemispheres and separates them. Agenesis of the corpus callosum is seen in some cases</div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Hydrocephalus ex vacuo</B> is dilatation of the cerebral ventricles <B>due to loss of brain tissue</B>. It is a common sequel of wasting brain diseases (leukodystrophies, cortical atrophy, multiple sclerosis, multiple strokes, Alzheimer disease, etc.).<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B><U> <A NAME="pathogenesis"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>PATHOGENESIS OF BRAIN DAMAGE IN HYDROCEPHALUS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B><U> </U></B></FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Initially, increasing pressure within the cerebral ventricles forces fluid through the ependymal lining into the periventricular white matter (<B>transependymal edema</B>).</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> This is seen on T2 MRI images.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG SRC="0f4649b0.gif" border=0 width="356" height="411" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="Arial" >Transependymal edema. T-2 MRI image</FONT></div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Pressure also causes the ventricles to dilate compressing brain tissue around them. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The brunt of the damage falls mainly on the periventricular white matter which loses myelin and axons.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Up to a certain point, the white matter changes are reversible, and often spectacular recovery is seen after shunting.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> If pressure is not relieved, permanent atrophy, first of the white matter and then of the cortex, develops.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> This causes spastic paralysis, loss of bladder function and dementia.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In severe hydrocephalus, the cortex and white matter may become paper thin<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG SRC="0f64ca70.gif" border=0 width="332" height="423" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="Arial" >Severe hydrocephalus. Atrophy of cortex and white matter</FONT></div> <div> and semitransparent such that the head transilluminates. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Pressure in the ventricles cannot continue to build indefinitely.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Something has to give or the patient will die from increased intracranial pressure. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In young children, before the sutures close, the head may enlarge significantly. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Sometimes the fibrosed subarachnoid space or a small aqueduct is forced open by increased pressure, thus relieving the obstruction. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This is <B>compensated hydrocephalus</B>.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Without relief, in extreme situations the cerebral mantle may break, releasing fluid into the subarachnoid space. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Today, with prompt diagnosis and shunting, permanent neurological damage can be prevented in most cases.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B><U> <A NAME="syrinx"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>SYRINGOMYELIA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B><U> </U></B></FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Syringomyelia (syrinx, Gk a tubular cavity) is a<B> tubular cavitation of the spinal cord</B> which usually affects the cervical and upper thoracic segments. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The cavity is in the central gray matter of the spinal cord<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Initially, it is separate from the central canal but later, as it enlarges it may communicate with it. Syringobulbia is an extension of the cavity from the spinal cord into the medulla </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">. The syrinx is lined by glial tissue. It contains CSF-like fluid which accumulates progressively under <B>pressure</B>, causing <B>atrophy of gray and white matter of the spinal cord</B>. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Symptoms from by compression and atrophy of the spinal cord usually begin in the second or third decade of life. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Initially there is<B> dissociated anesthesia</B> (segmental loss of pain and temperature sensation corresponding to the distribution of the syrinx with preservation of touch, vibration and position sense), denervation atrophy of muscle and kyphoscoliosis. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Dissociated anesthesia is due to damage of the spinothalamic axons which cross anterior to the syrinx. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">As the cavity enlarges, more severe neurological damage may occur.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Pressure may be relieved by shunting of the syrinx or by laminectomy. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Syringomyelia is often associated with the Chiari I malformation.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In such cases, it has been postulated that obstruction of the foramina of Lushka which are displaced into the cervical canal keeps the central canal open. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">However, the syrinx is not actually the dilated central canal and this mechanism does not apply to cases of syringomyelia without the Chiari I malformation or other craniocervical lesions. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Thus, the pathogenesis of syringomyelia is unknown and is probably diverse. Syringomyelia is often seen above spinal tumors such as ependymoma, pilocytic astrocytoma and hemangioblastoma.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Some of these tumors tend to be cystic and the syrinx may represent the cystic part of the tumor. Normally, the central canal closes postnatally, becoming a solid column of ependymal cells. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Cystic dilatation of the central canal (<B>hydromyelia</B>) is a feature of the Chiari II malformation.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div>  <A NAME="navigation"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> </td> </tr></table></body>