Neural tube defects: failure of the embryonic process of neurulation

Failure of neural tube closure results in malformations termed neural tube defects
(Copp, 1999). In craniorachischisis (Figure 8.4a), the most severe type of neural tube defect, the
neural tube fails to close along most of the body axis, although the forebrain usually closes
normally. If the neural tube fails to close specifically in the future brain, exencephaly results (i.e.
exteriorization of the brain folds), which is converted to anencephaly (i.e. absence of brain)
owing to neurodegeneration in later gestation. In contrast, if the low spine is primarily affected,
this leads to open spina

bifida (myelomeningocele; Figure 8.4b).

Related to these open CNS defects are a series of ‘closed’ defects, in which the
neural tube and/or meninges herniate through an opening in the skull or in the
neural arches of the vertebral column. Brain herniation yields a defect called
encephalocele, while herniation of the spinal cord is termed meningocele. A further
category of neural tube defects are so-called ‘occult’ spina bifida (also called spinal
dysraphism), which mainly affect the low spinal region and are skin-covered lesions in which the
spinal cord may be split or tethered to the surrounding tissues, often in
association with a bony spur or a fatty mass (lipoma). While covered lesions are
protected from the potentially toxic amniotic environment, open neural tube defect
lesions undergo erosion of the exposed neuroepithelium so that, by the late stages of
gestation, the region of affected nervous system is largely degenerate, leading to severe
disability or death after birth. Surgery on the human fetus during pregnancy, with the
aim of covering the neural tube defect lesion with muscle and skin, has shown that
this process of degeneration can be halted (Johnson et al., 2003), minimizing damage
to the exposed CNS but not recovering function.

Neural tube cacat: kegagalan proses embrio Neurulasi

Kegagalan hasil penutupan tabung saraf malformasi disebut cacat tabung saraf
(Copp, 1999). Dalam craniorachischisis (Gambar 8.4a), jenis yang paling parah cacat neural
tube, tabung saraf gagal menutup sebagian sepanjang sumbu tubuh, meskipun otak depan
biasanya menutup normal. Jika tabung saraf gagal menutup khusus di otak depan, hasil
eksensefali (exteriorization yaitu lipatan otak), yang dikonversi menjadi anencephaly (yaitu tidak
adanya otak) karena neurodegeneration dalam kehamilan nanti. Sebaliknya, jika tulang belakang
rendah terutama dipengaruhi, ini mengarah untuk membuka bifida
bifida (myelomeningocele; Gambar 8.4b).
Terkait dengan ini cacat SSP terbuka adalah serangkaian 'tertutup' cacat, di mana
tabung saraf dan / atau meninges herniate melalui lubang pada tengkorak atau di
lengkungan saraf tulang belakang dari kolom. Herniasi otak menghasilkan cacat yang disebut
encephalocele, sementara herniasi dari sumsum tulang belakang disebut Meningosel. A lebih
lanjut
kategori cacat tabung saraf yang disebut 'okultisme' spina bifida (juga disebut tulang belakang
dysraphism), yang terutama mempengaruhi daerah tulang belakang rendah dan lesi kulit yang
tertutup di mana sumsum tulang belakang mungkin akan dipecah atau ditambatkan ke jaringan
sekitarnya, sering kali dalam
asosiasi dengan sebuah bertulang memacu atau massa lemak (lipoma). Sementara lesi yang
dibahas adalah
dilindungi dari lingkungan ketuban berpotensi beracun, neural tube defect buka
lesi mengalami erosi neuroepithelium terkena sehingga, dengan tahap akhir
kehamilan, wilayah sistem saraf yang terkena sebagian besar merosot, yang mengarah ke parah
cacat atau meninggal setelah lahir. Operasi pada janin manusia selama kehamilan, dengan
tujuan untuk menutup lesi cacat tabung saraf dengan otot dan kulit, telah menunjukkan bahwa
proses degenerasi dapat dihentikan (Johnson et al, 2003.), meminimalkan kerusakan
ke SSP disinari tetapi tidak memulihkan fungsi.

Genetic basis of neural tube defects The high recurrence risk in siblings and in
close relatives of individuals with neural tube defects suggests a strong genetic basis,
although there is a marked lack of large families with neural tube defects, arguing
against causation based on single genes. It has been suggested, therefore, that neural
tube defects have a multifactorial causation, with many genetic variants interacting to
determine individual risk of neural tube defect, and with a marked contribution of
environmental factors, both exacerbating and preventive. Since neural tube defects
are relatively common malformations (Table 8.1), the predisposing genetic variants
themselves seem likely to be relatively common, or else there may be many different
combinations of rare genetic variants that can predispose to neural tube defect. In
mice, more than 80 different mutant genes cause non-closure of the mouse neural
tube, with different mutations affecting different rostro-caudal levels of the body axis,
thereby mimicking the human situation (Copp et al., 2003b). In contrast, only a few
of the mouse mutants exhibit closed neural tube defects, for example resembling
encephalocele. Despite the many genetic loci that have been implicated in mouse
neural tube defects, few human genes have so far been definitively shown to
predispose to human neural tube defects. The best known of these is the gene
encoding 5,10-methylene tetrahydrofolate reductase (MTHFR), an enzyme of folic
acid metabolism. MTHFR catalyses the reaction that produces 5-methyl tetrahydrofolate,
a methyl donor for homocysteine during its conversion to methionine. A
polymorphic, thermolabile variant of the MTHFR gene (the C677T variant) exhibits a
higher frequency among neural tube defect cases and their families than among
normal controls in several populations (Van der Put et al., 1997) and seems
responsible for imparting an increased risk of neural tube defect, especially in
combination with a low folate and/or vitamin B12 level during pregnancy.

Genetik dasar cacat tabung saraf Resiko rekurensi tinggi dalam saudara dan di
kerabat dekat dari perorangan dengan cacat tabung saraf menunjukkan dasar genetik yang kuat,
walaupun ada kekurangan ditandai keluarga besar dengan cacat tabung saraf, berdebat
terhadap penyebab berdasarkan gen tunggal. Ia telah mengemukakan, karena itu, bahwa saraf
cacat tabung memiliki penyebab multifaktorial, dengan banyak varian genetik berinteraksi untuk
menentukan risiko individual neural tube defect, dan dengan kontribusi ditandai
faktor lingkungan, baik memperburuk dan preventif. Sejak cacat tabung saraf
adalah malformasi relatif umum (Tabel 8.1), varian genetik predisposisi
sendiri tampaknya mungkin relatif umum, atau yang lain mungkin ada banyak berbeda
kombinasi varian genetik langka yang dapat mempengaruhi terhadap cacat tabung saraf. Dalam
tikus, lebih dari 80 gen mutan yang berbeda ini menyebabkan non-penutupan saraf mouse
tabung, dengan mutasi yang berbeda mempengaruhi tingkat rostro-ekor yang berbeda dari sumbu
tubuh,
dengan demikian meniru situasi manusia (Copp et al, 2003b.). Sebaliknya, hanya beberapa
dari mouse mutan pameran ditutup cacat tabung saraf, misalnya menyerupai
encephalocele. Meskipun banyak lokus genetik yang telah terlibat di mouse
cacat tabung saraf, gen manusia hanya sedikit yang sejauh ini telah secara definitif terbukti
predisposisi manusia cacat tabung saraf. Yang paling terkenal di antaranya adalah gen
5,10 encoding-metilen tetrahydrofolate reduktase (MTHFR), sebuah enzim folat
metabolisme asam. MTHFR mengkatalisis reaksi yang menghasilkan tetrahydrofolate 5-metil,
donor metil untuk homosistein selama konversi kepada metionin. A
polimorfik varian, termolabil gen MTHFR (varian C677T) menunjukkan suatu
frekuensi yang lebih tinggi di antara kasus cacat neural tube dan keluarga mereka dari antara
kontrol normal dalam beberapa populasi (Van der Put et al, 1997.) dan tampaknya
bertanggung jawab untuk menyampaikan peningkatan risiko neural tube defect, terutama di
kombinasi dengan folat rendah dan / atau tingkat vitamin B12 selama kehamilan.

Environmental effects on occurrence of neural tube defects Many environmental

factors have been demonstrated, in mice, to interact with the genotype to either
increase or decrease the risk of neural tube defect (Copp et al., 1990). Teratogenic (i.e.
malformation increasing) influences range from physical factors such as hyperthermia
to biologically active molecules such as retinoids (vitamin A derivatives). In
humans, several of these agents are also suspected of increasing neural tube defect risk
and the anti-epileptic drug sodium valproate, taken early in pregnancy, has conclusively
been demonstrated to predispose to spina bifida (Lammer et al., 1987). In
180 EMBRYOS, GENES AND BIRTH DEFECTS
contrast to these teratogenic influences, folic acid is well known to diminish the risk
of neural tube defects in a proportion of predisposed human pregnancies (Wald et al.,
1991) and in several mouse mutants with neural tube defect. While studies in mice
have demonstrated that folic acid acts directly on the developing embryo, its precise
mode of action remains elusive. Genetic predisposition to neural tube defect via the
C677T variant of MTHFR leads to elevated levels of homocysteine, a trend that is
reversed by administration of exogenous folic acid. Homocysteine has not been
found to directly cause neural tube defects in experimental animals, however,
suggesting that other embryonic defects, such as diminished embryonic cell proliferation
or excessive cell death, may be the primary target of folic acid in preventing
neural tube defects. A proportion of neural tube defects in both humans and mice do
not respond to folic acid therapy. In one folate-resistant mouse mutant, curly tail,
administration of the vitamin-like molecule inositol can prevent the great majority of
cases of spina bifida, through a molecular mechanism involving activation of specific
isoforms of the enzyme family protein kinase C (Cogram et al., 2004). It remains to
be determined whether inositol will also prove to exert a preventive effect against
human neural tube defects.

Lingkungan efek pada terjadinya cacat tabung saraf Banyak lingkungan

faktor telah ditunjukkan, pada tikus, untuk berinteraksi dengan genotipe baik
meningkatkan atau mengurangi risiko neural tube defect (Copp et al, 1990.). Teratogenik (yakni
kelainan meningkat) berkisar pengaruh dari faktor-faktor fisik seperti hipertermia
untuk biologis molekul aktif seperti retinoid (vitamin A derivatif). Dalam
manusia, beberapa agen ini juga diduga meningkatkan resiko cacat tabung neural
dan obat anti-epilepsi natrium valproate, diminum pada awal kehamilan, telah meyakinkan
telah ditunjukkan untuk mempengaruhi untuk spina bifida (Lammer et al, 1987.). Dalam
180 embrio, GEN DAN CACAT LAHIR
Berbeda dengan pengaruh teratogenik, asam folat dikenal untuk mengurangi risiko
cacat tabung saraf dalam proporsi kehamilan manusia cenderung (Wald et al.,
1991) dan di beberapa tikus mutan dengan cacat tabung saraf. Sementara penelitian pada tikus
telah menunjukkan bahwa asam folat bekerja langsung pada embrio yang berkembang, tepat nya
cara kerja tetap sukar ditangkap. Genetik predisposisi terhadap cacat neural tube melalui
varian C677T dari MTHFR menyebabkan peningkatan kadar homosistein, sebuah tren yang
terbalik dengan pemberian asam folat eksogen. Homosistein belum
ditemukan langsung menyebabkan cacat tabung saraf pada hewan percobaan, bagaimanapun,
menunjukkan bahwa cacat embrio lain, seperti proliferasi sel embrio berkurang
atau kematian sel yang berlebihan, mungkin menjadi sasaran utama asam folat dalam mencegah
cacat tabung saraf. Sebuah proporsi cacat tabung saraf di kedua manusia dan tikus melakukan
tidak menanggapi terapi asam folat. Dalam satu tikus mutan tahan folat, ekor keriting,
administrasi inositol molekul seperti vitamin dapat mencegah sebagian besar
kasus spina bifida, melalui mekanisme molekuler yang melibatkan aktivasi khusus
isoform dari keluarga enzim protein kinase C (Cogram et al, 2004.). Hal ini tetap
ditentukan apakah inositol juga akan membuktikan mengerahkan efek pencegahan terhadap
manusia cacat tabung saraf.

Embryonic mechanisms of neural tube defects In mice, the great majority of

neural tube defects arise from non-closure of the neural tube during neurulation.
Analysis of the types of mutant gene (especially gene knock-outs) that lead to mouse
neural tube defects has highlighted several embryonic mechanisms that appear
essential for closure of the neural tube. In some cases, experimental studies have
confirmed the importance of these developmental mechanisms in neurulation.
Craniorachischisis. In this most severe neural tube defect, both cranial and spinal
regions of the neural tube remain open (Figure 8.4a). The defect arises when the
initial event of neural tube closure (‘closure 1’) fails at the hindbrain–cervical
boundary. A small group of mouse mutant genes give rise to this neural tube defect
and recent work has implicated these genes in the so-called ‘planar cell polarity’
signalling pathway, in which Wnt/frizzled signals are transduced by a _-cateninindependent
mechanism (Copp et al., 2003a). Hence, loss of function of Vangl2 (also
called strabismus), Celsr1, Scrb1, Ptk7 and double mutants for dishevelled-1 and -2,
produce craniorachischisis in homozygous form. The planar cell polarity pathway is
required for ‘convergent extension’, a net medially-directed movement of cells, with
intercalation and rostro-caudal extension in the midline. Convergent extension fails
in mice with planar cell polarity mutations, leading to short, broad embryos in which
the neural folds are spaced widely apart. This wide spacing of the neural folds
prevents closure 1 and causes craniorachischisis (Greene et al., 1998).
Embrio mekanisme cacat tabung saraf Pada tikus, sebagian besar
cacat tabung saraf timbul dari non-penutupan tabung saraf selama Neurulasi.
Analisis jenis gen mutan (khususnya gen knock-out) yang mengarah pada tikus
cacat tabung saraf telah menyoroti mekanisme beberapa embrio yang muncul
penting untuk penutupan tabung saraf. Dalam beberapa kasus, peneliti juga
menegaskan pentingnya mekanisme ini perkembangan pada Neurulasi.
Craniorachischisis. Dalam hal ini cacat tabung saraf yang paling parah, baik tengkorak dan
tulang belakang
daerah dari tabung saraf tetap terbuka (Gambar 8.4a). Cacat muncul ketika
acara awal penutupan tabung saraf ('penutupan 1') gagal di-otak belakang leher rahim
batas. Sekelompok kecil dari mouse gen mutan ini menimbulkan neural tube defect
dan pekerjaan terakhir telah terlibat gen tersebut dalam 'polaritas sel planar' yang disebut
sinyal jalur, di mana Wnt / sinyal frizzled adalah transduced oleh cateninindependent-_
mekanisme (Copp et al, 2003a.). Oleh karena itu, hilangnya fungsi Vangl2 (juga
disebut strabismus), Celsr1, Scrb1, Ptk7 dan mutan ganda untuk kusut-1 dan -2,
menghasilkan craniorachischisis dalam bentuk homozigot. Jalur sel planar polaritas adalah
diperlukan 'ekstensi konvergen' untuk, gerakan medial-diarahkan bersih sel, dengan
interkalasi dan penyuluhan rostro-ekor di garis tengah. Konvergen ekstensi gagal
pada tikus dengan mutasi polaritas sel planar, yang mengarah ke pendek, embrio yang luas di
mana
lipatan saraf berjarak luas terpisah. Ini jarak luas saraf lipatan
mencegah craniorachischisis penutupan 1 dan menyebabkan (Greene et al, 1998.).

Exencephaly and anencephaly. Many mutant genes and a large number of teratogens
cause cranial neural tube defects in the mouse, with the neural tube failing to
close in the future brain (Figure 8.4b). Analysis of the genetic models has revealed
several critical events in cranial neurulation that are required for successful brain
CH 08 BRAIN AND SPINAL CORD 181
closure (Copp et al., 2003b). The initial elevation of the cranial neural folds requires
expansion of the cranial mesenchyme, as a result of cell proliferation and increase in
extracellular space. This causes the elevating neural folds to adopt a bi-convex
appearance, particularly in the midbrain. Mice with loss of function of the Twist or
Cart1 genes have cranial neural tube defects in which the principal defect is a
reduction in the proliferation and expansion of the cranial mesenchyme (Chen and
Behringer, 1995; Zhao et al., 1996).

Eksensefali dan anencephaly. Banyak mutan gen dan sejumlah besar teratogen
menyebabkan cacat tabung saraf kranial dalam mouse, dengan tabung saraf gagal
dekat di otak masa depan (Gambar 8.4b). Analisis model genetik telah mengungkapkan
kritis beberapa peristiwa di Neurulasi tengkorak yang diperlukan untuk sukses otak
CH 08 OTAK DAN sumsum tulang belakang 181
penutupan (Copp et al, 2003b.). Elevasi awal dari lipatan saraf kranial membutuhkan
perluasan mesenkim tengkorak, sebagai akibat dari proliferasi sel dan peningkatan
ruang ekstraselular. Hal ini menyebabkan neural mengangkat lipatan untuk mengadopsi bi-
cembung
penampilan, khususnya di otak tengah. Tikus dengan hilangnya fungsi Twist atau
Gen Cart1 memiliki cacat tabung saraf kranial dimana cacat utama adalah
pengurangan proliferasi dan perluasan mesenkim tengkorak (Chen dan
Behringer, 1995; Zhao et al, 1996)..

Once the bi-convex neural folds have formed, a second phase of cranial neurulation
occurs in which the dorsolateral aspects of the neural fold bend medially,
allowing the folds to adopt a bi-concave morphology and approach the dorsal
midline for fusion. This second phase is highly dependent on the actin cytoskeleton,
as illustrated by mice mutant for shroom, a gene involved in generating actin
microfilaments, which fail to close their brains (Hildebrand and Soriano, 1999).
The initiation of cranial neural crest emigration from the neural fold apices is also
required, as shown by mice overexpressing connexin 43, which exhibit defects of
cranial neural crest emigration and exencephaly (Ewart et al., 1997). A third
requirement for cranial closure is precise regulation of programmed cell death
(apoptosis). Knock-out mice with either increased (e.g. AP-2_, bcl10 and Tulp1)
or decreased (e.g. Apaf-1, caspase 9 and p53) apoptosis exhibit cranial neural tube
defects (Copp et al., 2003b). Apoptosis appears to synergize with neural crest cell
emigration, to enable the conversion from bi-convex to bi-concave morphology. In
addition, apoptosis at the neural fold tips may be necessary for midline epithelial
remodelling, once the neural folds have met in the midline, since inhibition of
apoptosis in the chick embryo prevents midline remodelling (Weil et al., 1997).
Cranial closure also requires precisely coordinated cell proliferation in the neural
tube: mice mutant for RBP-J_, Hes1 and Numb show premature differentiation of the
neuroepithelium and failure of brain closure (Copp et al., 2003b).

Setelah lipatan saraf bi-cembung telah membentuk, fase kedua Neurulasi tengkorak
terjadi di mana aspek dorsolateral dari lipatan neural tikungan medial,
memungkinkan lipatan untuk mengadopsi morfologi bi-cekung dan pendekatan punggung yang
midline untuk fusi. Tahap kedua ini sangat tergantung pada sitoskeleton aktin,
seperti yang digambarkan oleh tikus mutan untuk shroom, sebuah gen yang terlibat dalam
menghasilkan aktin
mikrofilamen, yang gagal menutup otak mereka (Hildebrand dan Soriano, 1999).
Inisiasi emigrasi puncak tengkorak syaraf dari Apeks flip saraf juga
diperlukan, seperti yang ditunjukkan oleh tikus overexpressing connexin 43, cacat pameran mana

emigrasi cranial neural crest dan eksensefali (Ewart et al, 1997.). Sepertiga
persyaratan untuk penutupan tengkorak adalah peraturan yang tepat dari kematian sel terprogram

(Apoptosis). Knock-out tikus dengan baik meningkat (misalnya AP,-2_ bcl10 dan Tulp1)
atau dikurangi (misalnya Apaf-1, caspase 9 dan p53) tabung menunjukkan apoptosis saraf
kranial
cacat (Copp et al, 2003b.). Apoptosis muncul untuk bersinergi dengan sel puncak neural
emigrasi, untuk mengaktifkan konversi dari bi-cembung untuk morfologi bi-cekung. Dalam
Selain itu, apoptosis di ujung saraf lipat mungkin diperlukan untuk epitel garis tengah
renovasi, setelah lipatan saraf telah bertemu di garis tengah, karena penghambatan
apoptosis dalam embrio ayam mencegah remodeling garis tengah (Weil et al, 1997.).
penutupan cranial juga membutuhkan tepat terkoordinasi proliferasi sel dalam saraf
tube: tikus mutan untuk RBP-J_, Hes1 dan Numb menunjukkan diferensiasi dini
neuroepithelium dan kegagalan penutupan otak (Copp et al, 2003b.).

Open spina bifida. A number of mouse mutants exhibit low spinal neurulation
defects leading to open spina bifida (Figure 8.4b). Here, the critical event appears to
be regulation of dorsolateral bending of the neural plate. In contrast to the cranial
region, dorsolateral bending in the spine does not require emigration of the neural
crest (which begins after neurulation in the spine) or function of the actin
cytoskeleton (Ybot-Gonzalez and Copp, 1999). Instead, sonic hedgehog (Shh)
signalling appears critical for regulation of dorsolateral bending. Shh is produced
by the notochord underlying the ventral neural plate and inhibits dorsolateral
bending (Ybot-Gonzalez et al., 2002). In the absence of Shh, for example in the
Shh mutant mouse, dorsolateral bending occurs as a default mechanism that ensures
spinal closure. Overstimulation of the Shh signalling pathway, on the other hand, is
incompatible with spinal closure. Hence in the Ptc1 and Opb mouse mutants,
dorsolateral bending is absent and homozygotes fail to close their low spinal neural
tube (Eggenschwiler and Anderson, 2000; Goodrich et al., 1997). In contrast, the curly
tail mutant does not lack dorsolateral bending but apposition of the neural folds is
hampered, owing to ventral curvature of the caudal body axis (Brook et al., 1991),
182 EMBRYOS, GENES AND BIRTH DEFECTS
secondary to an underproliferation of ventral cell types (Copp et al., 1988), so that a
proportion of homozygotes exhibit open spina bifida.

Buka spina bifida. Sejumlah tikus mutan menunjukkan Neurulasi tulang belakang rendah
cacat terkemuka untuk membuka spina bifida (Gambar 8.4b). Di sini, peristiwa penting
tampaknya
menjadi peraturan dorsolateral lentur dari pelat saraf. Berbeda dengan tengkorak
wilayah, dorsolateral membungkuk di tulang belakang tidak memerlukan emigrasi dari saraf
puncak (yang dimulai setelah Neurulasi di tulang belakang) atau fungsi actin yang
sitoskeleton (Ybot-Gonzalez dan Copp, 1999). Sebaliknya, sonic hedgehog (Shh)
muncul sinyal penting untuk peraturan dorsolateral lentur. Shh diproduksi
oleh notochord mendasari piring saraf ventral dan menghambat dorsolateral
membungkuk (Ybot-Gonzalez et al, 2002.). Dengan tidak adanya Sst, misalnya di
Shh mouse mutan, dorsolateral membungkuk terjadi sebagai mekanisme default yang
memastikan
penutupan tulang belakang. Overstimulation dari jalur Sst sinyal, di sisi lain,
tidak kompatibel dengan penutupan tulang belakang. Maka pada tikus mutan Ptc1 dan OPB,
dorsolateral bending tidak ada dan homozigot gagal untuk menutup saraf tulang belakang mereka
yang rendah
tabung (Eggenschwiler dan Anderson, 2000; Goodrich et al, 1997.). Sebaliknya, keriting
ekor mutan tidak kekurangan tapi lentur dorsolateral aposisi dari lipatan saraf tiruan adalah
terhambat, karena kelengkungan ventral sumbu tubuh ekor (Brook et al, 1991.),
182 embrio, GEN DAN CACAT LAHIR
sekunder ke underproliferation jenis sel ventral (Copp et al, 1988.), sehingga
menunjukkan proporsi homozigot spina bifida terbuka.

Figure 8.4 Neural tube defects and neuronal migration disorders. (a,b) Mouse fetuses at E15.5 to
illustrate the appearance of craniorachischisis, in a Celsr1 mutant (a) and exencephaly and open
spina bifida, in a curly tail mutant (b). In craniorachischisis, the neural tube is open from
midbrain
to low spine (between the thin arrows in A). Exencephaly in the curly tail fetus is restricted to the
midbrain (thin arrow in b), while the spina bifida affects the lumbosacral region (arrowhead in
b).
Note the presence of a curled tail in both fetuses (thick arrows in a and b). (c) The various types
of
neuronal migration disorder displayed diagrammatically on a coronal section of a postnatal
human
brain. The left side shows large-scale defects, while the right side shows typical focal lesions.
See
text for description of the different types of neuronal migration disorder. Parts (a) and (b) are
reproduced with permission from Copp et al. (2003b) and part (c) from Copp and Harding (1999)
Gambar 8.4 cacat tabung syaraf dan gangguan migrasi neuronal. (a, b) Mouse janin di E15.5
untuk
menggambarkan munculnya craniorachischisis, dalam Celsr1 mutan (a) dan eksensefali dan
terbuka
spina bifida, dalam ekor keriting mutan (b). Dalam craniorachischisis, tabung saraf terbuka dari
otak tengah
untuk tulang belakang rendah (di antara anak panah tipis di A). Eksensefali pada janin ekor
keriting adalah terbatas pada
otak tengah (panah tipis dalam b), sedangkan spina bifida mempengaruhi daerah lumbosakral
(panah di b).
Perhatikan adanya meringkuk ekor di kedua janin (panah tebal dalam a dan b). (c) berbagai jenis
gangguan migrasi neuronal ditampilkan diagram di bagian koronal manusia pascakelahiran
otak. Sisi kiri menunjukkan cacat besar-besaran, sementara sisi kanan menunjukkan lesi fokal
khas. Lihat
teks untuk deskripsi dari berbagai jenis gangguan migrasi neuronal. Bagian (a) dan (b) adalah
direproduksi dengan izin dari Copp et al. (2003b) dan bagian (c) dari Copp dan Harding (1999)

Dysraphism, or Rachischisis
(Encephaloceles and Spina Bifida)
Included under this heading are the large number of disorders of
fusion of dorsal midline structures of the primitive neural tube, a
process that takes place during the first 3 weeks of postconceptual
life. Exogenous factors are presumed to be operative in most cases.
The entire cranium may be missing at birth, and the undeveloped
brain lies in the base of the skull, a small vascular mass without
recognizable nervous structures. This state, anencephaly, has been
discussed earlier, under “Disturbances of Neuronal Migration,” and
it is the most frequent of the rachischises. It has many associations
with other conditions in which the vertebral laminae fail to fuse.
An eventration of brain tissue and its coverings through an
unfused midline defect in the skull is called an encephalocele.
Frontal encephaloceles may deform the forehead or remain occult.
Associated defects of the frontal cortex, anterior corpus callosum,
and optic-hypothalamic structures as well as CSF leakage into frontal
or ethmoid sinuses pose a risk of meningitis. Some of these
children are relatively normal mentally. Far more severe are the
posterior encephaloceles, some of which are enormous and are attended
by grave neurologic deficits. However, lesser degrees of the
defect are well known and may be small or hidden, such as a meningoencephalocele
connected with the rest of the brain through a
small opening in the skull. Small nasal encephaloceles may cause
no neurologic signs, but if they are mistaken for nasal polyps and
snipped off, CSF fistulae may result. The larger occipital ones are
associated with blindness, ataxia, and mental retardation.

Dysraphism, atau Rachischisis

(Encephaloceles dan spina bifida)
Termasuk dalam pos ini adalah jumlah besar gangguan
fusi struktur garis tengah dorsal tabung saraf primitif,
proses yang berlangsung selama 3 minggu pertama postconceptual
hidup. faktor eksogen yang diduga operasi dalam kebanyakan kasus.
Seluruh tengkorak mungkin hilang pada saat kelahiran, dan berkembang
otak terletak di dasar tengkorak, massa pembuluh darah kecil tanpa
dikenali gugup struktur. Keadaan ini, anencephaly, telah
dibahas sebelumnya, di bawah "Gangguan saraf Migrasi," dan
ini adalah yang paling sering dari rachischises. Ini telah banyak asosiasi
dengan kondisi lain di mana lamina vertebra gagal sekering.
Sebuah eventration dari jaringan otak dan penutup melalui sebuah
cacat garis tengah tidak disatukan dalam tengkorak disebut encephalocele sebuah.
encephaloceles Frontal mungkin cacad dahi atau tetap tersembunyi.
Asosiasi cacat dari korteks frontal, corpus callosum anterior,
optik-hipotalamus dan struktur serta kebocoran CSF ke frontal
atau sinus ethmoid menimbulkan risiko meningitis. Beberapa
anak-anak relatif normal mental. Jauh lebih parah adalah
posterior encephaloceles, beberapa di antaranya sangat besar dan dihadiri
oleh defisit neurologis kuburan. Namun, lebih rendah derajat dari
cacat sudah dikenal dan mungkin kecil atau tersembunyi, seperti meningoencephalocele
dihubungkan dengan sisa otak melalui
kecil membuka dalam tengkorak. encephaloceles hidung kecil dapat menyebabkan
tidak ada tanda-tanda neurologis, tetapi jika mereka keliru untuk polip hidung dan
dipotong off, fistula CSF akan terjadi. Yang oksipital yang lebih besar
terkait dengan kebutaan, ataksia, dan keterbelakangan mental.

A failure of development of the midline portion of the cerebellum,

referred to earlier, forms the basis of the Dandy-Walker
syndrome (Fig. 38-2). A cyst-like structure, representing the greatly
dilated fourth ventricle, expands in the midline, causing the occipital
bone to bulge posteriorly and displace the tentorium and torcula
upward. In addition, the cerebellar vermis is aplastic, the corpus
callosum may be deficient or absent, and there is dilatation of the
aqueduct as well as the third and lateral ventricles.
Even more frequent are abnormalities of closure of the vertebral
arches. These take the form of a spina bifida occulta, meningocele,
and meningomyelocele of the lumbosacral or other
regions. In spina bifida occulta, the cord remains inside the canal and
there is no external sac, although a subcutaneous lipoma or a dimple
or wisp of hair on the overlying skin may mark the site of the
lesion. In meningocele, there is a protrusion of only the dura and
arachnoid through the defect in the vertebral laminae, forming a
cystic swelling usually in the lumbosacral region; the cord remains
in the canal, however. In meningomyelocele, which is 10 times as
frequent as meningocele, the cord (more often the cauda equina) is
extruded also and is closely applied to the fundus of the cystic
swelling.

Sebuah kegagalan pengembangan bagian garis tengah otak kecil,

disebut sebelumnya, membentuk dasar dari Dandy-Walker
sindrom (Gbr. 38-2). Struktur kista seperti, mewakili sangat
dilatasi ventrikel keempat, memperluas di garis tengah, menyebabkan oksipital
tulang untuk tonjolan posterior dan menggantikan tentorium dan torcula
ke atas. Selain itu, vermis cerebellum adalah aplastik, korpus
callosum mungkin kekurangan atau tidak ada, dan ada dilatasi dari
saluran air serta ventrikel ketiga dan lateral.
Bahkan lebih sering adalah kelainan dari penutupan tulang belakang
lengkungan. Ini mengambil bentuk spina bifida occulta, Meningosel,
dan meningomyelocele dari lumbosakral atau lainnya
daerah. Pada spina bifida occulta, kabel tetap di dalam kanal dan
tidak ada kantung eksternal, meskipun lipoma subkutan atau sebuah lesung pipi
atau gumpalan rambut di kulit di atasnya dapat menandai lokasi
lesi. Dalam Meningosel, ada tonjolan hanya dura dan
arakhnoid melalui cacat dalam lamina vertebra, membentuk
pembengkakan kistik biasanya di daerah lumbosakral, kabel tetap
di kanal, namun. Dalam meningomyelocele, yang 10 kali
sering sebagai Meningosel, kabel (lebih sering bagian cauda equina) adalah
diekstrusi juga dan erat diterapkan pada fundus dari kistik
pembengkakan.

The incidence of spinal dysraphism (myeloschisis), like that

of anencephaly, varies widely from one locale to another, and the
disorder is more likely to occur in a second child if one child has
already been affected (the incidence then rises from 1 per 1000 to
40 to 50 per 1000). Exogenous factors (e.g., potato blight in Ireland)
have been implicated in the genesis of both myeloschisis and
anencephaly. Folic acid, given before the 28th day of pregnancy,
can be protective; vitamin A may also have slight protective benefit.
As with anencephaly, the diagnosis can often be inferred from
the presence of _-fetoprotein in the amniotic fluid (sampled at 15
to 16 weeks of pregnancy) and the deformity confirmed by ultrasound
in utero, as mentioned earlier in this chapter. Blood contamination
is a source of error in the fetoprotein test (Milunsky). Acetylcholinesterase
immunoassay, done on amniotic fluid, is another
reliable means of confirming the presence of neural tube defects.

Insiden dysraphism tulang belakang (myeloschisis), seperti itu

dari anencephaly, sangat bervariasi dari satu lokal ke yang lain, dan
gangguan yang lebih mungkin terjadi pada anak kedua jika seorang anak telah
sudah terpengaruh (kejadian kemudian naik dari 1 per 1000 untuk
40 sampai 50 per 1000). Faktor eksogen (misalnya, kentang hawar di Irlandia)
telah terlibat dalam asal-usul myeloschisis baik dan
anencephaly. Asam folat, diberikan sebelum hari ke 28 kehamilan,
dapat menjadi pelindung; vitamin A juga mungkin memiliki manfaat perlindungan sedikit.
Seperti anencephaly, diagnosis seringkali dapat disimpulkan dari
kehadiran _-fetoprotein dalam cairan ketuban (sampel di 15
sampai 16 minggu kehamilan) dan deformitas dikonfirmasikan dengan ultrasound
di dalam rahim, seperti yang disebutkan sebelumnya dalam bab ini. Darah kontaminasi
merupakan sumber kesalahan dalam uji fetoprotein (Milunsky). Acetylcholinesterase
immunoassay, dilakukan pada cairan ketuban, yang lain
berarti dapat diandalkan untuk mengkonfirmasi kehadiran cacat tabung saraf....

Some parents, on receiving this information, request abortion.

In the case of meningomyelocele, the child is born with a large
externalized lumbosacral sac covered by delicate, weeping skin. It
may have ruptured in utero or during birth, but more often the
covering is intact. There is severe dysfunction of the cauda equina
roots or conus medullaris contained in the sac. Stroking of the sac
may elicit involuntary movements of the legs. As a rule the legs
are motionless; urine dribbles, keeping the patient constantly wet;
there is no response to pinprick over the lumbosacral zones; and
the tendon reflexes are absent. In contrast, craniocervical structures
are normal unless a Chiari malformation is associated (see further
on). Differences are noted in the neurologic picture depending on
the level of the lesion. If it is entirely sacral, bladder and bowel
sphincters are affected but legs escape; if lower lumbar and sacral,
the buttocks, legs, and feet are more impaired than hip flexors and
quadriceps; if upper lumbar, the feet and legs are sometimes spared
and ankle reflexes retained, and there may be Babinski signs. The
two dreaded complications of these severe spinal defects are meningitis
and progressive hydrocephalus from a Chiari malformation,
which is often associated (see below). The subject of neural tube
defects has been reviewed by Botto and colleagues.

Beberapa orang tua, pada menerima informasi ini, permintaan aborsi.

Dalam kasus meningomyelocele, anak lahir dengan besar
externalized sac lumbosakral tertutup oleh halus, kulit menangis. Ini
mungkin telah pecah dalam rahim atau selama melahirkan, tetapi lebih sering
meliputi utuh. Ada disfungsi berat dari bagian cauda equina
akar atau medullaris konus yang terkandung dalam kantung. Membelai dari kantung
mungkin menimbulkan gerakan tak terkendali dari kaki. Sebagai aturan kaki
yang bergerak; urin menggiring, menjaga agar pasien tetap selalu basah;
tidak ada respon untuk cocokan peniti atas zona lumbosakral dan
refleks tendon tidak hadir. Sebaliknya, struktur craniocervical
adalah normal kecuali malformasi Chiari berhubungan (lihat lebih lanjut
aktif). Perbedaan dicatat dalam gambar neurologis tergantung pada
tingkat lesi. Jika seluruhnya sakral, kandung kemih dan usus
sphincters yang terpengaruh tapi kaki melarikan diri, jika lumbal lebih rendah dan sakral,
pantat, kaki, dan kaki lebih terganggu dari fleksor pinggul dan
quadriceps, jika lumbal atas, kaki dan kaki kadang-kadang diselamatkan
dan refleks pergelangan kaki dipertahankan, dan mungkin ada tanda-tanda Babinski. The
dua komplikasi ditakuti dari cacat tulang belakang parah meningitis
dan progresif hidrosefalus dari malformasi Chiari,
yang sering diasosiasikan (lihat di bawah). Subyek tabung saraf
cacat telah ditinjau oleh Botto dan rekan.

Treatment Opinions as to proper management vary considerably.

Excision and closure of the coverings of the meningomyelocele in
the first few days of life is advised if the objective is to prevent a
fatal meningitis. After a few weeks or months, as hydrocephalus
reveals its presence by rapid increase in head size and enlargement
of the ventricles on the CT scan, a ventriculoatrial or ventriculoperitoneal
shunt is required. Patients with high spinal lesions and
total paraplegia, kyphosis, hydrocephalus, and other major congenital
anomalies are usually not accepted for treatment. Less than 30
percent of such patients survive beyond 1 year, and the long-term
results of treating these patients have not been encouraging. Lorber
and others report that 80 to 90 percent of their surviving patients
are mentally retarded to some degree and are paraplegic—thus
totally dependent on others for their care. The decision to undertake
rather formidable surgical procedures is being questioned more and
more frequently. Exceptionally, the patient with meningomyelocele,
and most of those with lumbar meningocele, are mentally
normal. Clinical differentiation of this mental state is obviously
important.
Opini Perawatan untuk pengelolaan yang baik sangat bervariasi.
Eksisi dan penutupan penutup dari meningomyelocele di
beberapa hari pertama kehidupan dianjurkan jika tujuannya adalah untuk mencegah
fatal meningitis. Setelah beberapa minggu atau bulan, seperti hidrosefalus
mengungkapkan kehadirannya dengan peningkatan pesat dalam ukuran kepala dan pembesaran
dari ventrikel pada CT scan, sebuah ventriculoatrial atau ventriculoperitoneal
shunt diperlukan. Pasien dengan lesi tulang belakang tinggi dan
total paraplegia, kyphosis, hydrocephalus, dan besar lainnya bawaan
anomali biasanya tidak diterima untuk pengobatan. Kurang dari 30
persen pasien tersebut bertahan lebih 1 tahun, dan jangka panjang
hasil mengobati pasien ini belum menggembirakan. Lorber
dan lain-lain melaporkan bahwa 80 hingga 90 persen pasien mereka yang masih hidup
secara mental terbelakang untuk beberapa derajat dan lumpuh-sehingga
sepenuhnya tergantung pada orang lain untuk perawatan mereka. Keputusan untuk melakukan
prosedur pembedahan lebih tangguh sedang dipertanyakan lebih dan
lebih sering. Selain itu, pada pasien dengan meningomyelocele,
dan kebanyakan dari mereka dengan Meningosel lumbal, secara mental
normal. Diferensiasi klinis kondisi mental ini jelas
penting.

Other Developmental Spinal Defects and Delayed Effects of

Failure of Midline Fusion, Including Tethered Cord The
problems of meningomyelocele and its complications are so strictly
pediatric and surgical that the neurologist seldom becomes involved—
except perhaps in the initial evaluation of the patient—
in the treatment of meningeal infection, or in the case of shunt
failure with decompensation of hydrocephalus. Of greater interest
to the neurologist are a series of closely related abnormalities that
produce symptoms for the first time in late childhood, adolescence,
or even adult life. These include sinus tracts with recurrent meningeal
infections, lumbosacral lipomas with low tethering of the spinal
cord (“tethered cord”), and a delayed radicular or spinal cord
syndrome; diastematomyelia, cysts, or tumors with spina bifida and
a progressive myeloradiculopathy; and a Chiari malformation and
syringomyelia that first present in adolescence or adult life. These
abnormalities are described below.

Lain Spinal Defects Pembangunan dan Efek Penundaan

Kegagalan Fusion garis tengah, termasuk kabel tertambat The
masalah meningomyelocele dan komplikasi yang sangat ketat
pediatrik dan bedah yang ahli saraf jarang terlibat-
kecuali mungkin dalam evaluasi awal pasien-
dalam pengobatan infeksi meningeal, atau dalam kasus shunt
kegagalan dengan dekompensasi dari hydrocephalus. Dari kepentingan yang lebih besar
untuk ahli saraf adalah serangkaian kelainan erat terkait yang
menghasilkan gejala-gejala untuk pertama kalinya pada akhir masa kanak-kanak, remaja,
atau kehidupan bahkan dewasa. Ini termasuk saluran sinus dengan meningeal berulang
infeksi, lipoma lumbosakral dengan penarikan rendah dari tulang belakang
kabel ("kabel ditambatkan"), dan tali radikuler atau tulang belakang tertunda
sindrom; diastematomyelia, kista, atau tumor dengan spina bifida dan
sebuah myeloradiculopathy progresif, dan cacat Chiari dan
syringomyelia yang hadir pertama dalam kehidupan remaja atau dewasa. Ini
kelainan dijelaskan di bawah ini.
Another class of disorders involves an occult lumbosacral dysraphism
that is not inherited but is due to faulty development of
the cell mass that lies caudal to the posterior neuropore (normally
this undergoes closure by the 28th day of embryonic life). Occult
spinal dysraphism of this type is also associated with meningoceles,
lipomas, and sacrococcygeal teratomas. Another well-recognized
anomaly is agenesis of the sacrum and sometimes the lower lumbar
vertebrae (caudal regression syndrome). Interestingly, in 15 percent
of such cases, the mother is diabetic (Lyon and Evrard). Here
there is flaccid paralysis of legs, often with arthrogrypotic contractures
and urinary incontinence. Sensory loss is less prominent,
mental function develops normally, and there is no hydrocephalus.
Sinus tracts in the lumbosacral or occipital regions are of importance,
for they may be a source of bacterial meningitis at any
age. They are often betrayed by a small dimple in the skin or by a
tuft of hair along the posterior surface of the body in the midline.
(The pilonidal sinus should not be included in this group.) The
sinus tract may lead to a terminal myelocystocele and be associated
with dermoid cysts or fibrolipomas in the central part of the tract.
Cloacal defects (no abdominal wall and no partition between bladder
and rectum) may be combined with anterior meningoceles. Evidence
of sinus tracts should be sought in every instance of unexplained
meningitis, especially when there has been recurrent
infection or the cultured organism is of nosocomial dermal origin.
There are, in addition, other congenital cysts and tumors, particularly
lipoma and dermoid, that arise in the filum terminale and
attach (tether) the cord to the sacrum; progressive symptoms and
signs are produced as the spine elongates during development,
stretching the caudally fixed cord (Fig. 38-3). Some of these children
have bladder and leg weakness soon after birth. Others deteriorate
neurologically at a later age (generally between 2 and 16
years, sometimes later—see below). According to Chapman and
Davis, it is not the myelolipoma but the tethering of the cord that
gives rise to symptoms; removal of the tumor is of little benefit
unless the cord is untethered (detached from the sacrum) at the
same time. This may be difficult, for the lipoma may be fused with
the dorsal surface of the spinal cord.
Diastematomyelia is another unusual abnormality of the spinal
cord often associated with spina bifida. Here a bony spicule orfibrous band protrudes into the
spinal canal from the body of one
of the thoracic or upper lumbar vertebrae and divides the spinal
cord in two halves for a variable vertical extent. Or the division of
the cord may be complete, each half with its own dural sac and
complete set of nerve roots. This longitudinal fissuring and doubling
of the cord are spoken of as diplomyelia. With body growth,
it leads to a traction myelopathy, presenting with pain and progressive
sensory, motor, and bladder symptoms, sometimes as late
as adult life. Removal of the fibrous-bony spicule and untethering
of the spinal cord have been beneficial in some cases.
Several clinical syndromes of delayed progressive disease (in
adolescents or adults), due mainly to a tethered cord, have been
delineated:
1. Progressive cauda equina syndrome with lesions in the lumbosacral
region. In our experience this has been the most
common presentation of the tethered cord syndrome, with or
without a lipoma or dermoid. Complex disturbances of bladder
function that produce urgency and incontinence beginning
in the second or third decade may be the only manifestation,
or the bladder symptoms may be combined with
impotence (in the male) and numbness of the feet and legs or
foot drop (Pang and Wilberger). Several of our adult patients
have had unusual visceral reflex reactions, such as involuntary
defecation or priapism with stimulation of the abdomen
or perineum.
2. Progressive spastic weakness in some of the weak muscles
of the legs in a patient known to have had a meningocele or
meningomyelocele. Presumably the spinal cord, which is securely
attached to the lumbar vertebrae, is stretched during
the period of rapid lengthening of the vertebral column.
3. An acute cauda equina syndrome, following some unusual
activity or accident (e.g., rowing or a fall in a sitting position),
in patients who have had an asymptomatic or symptomatic
spina bifida or meningocele. The implicated sensory and
motor roots are believed to be injured by sudden or repeated
stretching.
4. Syringomyelia (page 1082). This is a developmental cavity
within the cervical cord, extending a variable distance caudally
or rostrally, associated with an Arnold-Chiari malformation
(see below). Also, there are a variety of neurologic
problems associated with spinal abnormalities in the high
cervical region [fusion of atlas and occiput or of cervical
vertebrae (Klippel-Feil syndrome), congenital dislocation of
the odontoid process and atlas, platybasia and basilar impression].
These abnormalities are reviewed in Chap. 44, with
other diseases of the spinal cord.
Chiari Malformation
Encompassed by this term are a number of congenital anomalies
at the base of the brain, the most consistent of which are (1) extension
of a tongue of cerebellar tissue, posterior to the medulla
and spinal cord, into the cervical canal and (2) displacement of the
medulla into the cervical canal, along with the inferior part of the
fourth ventricle. These and associated anomalies were first clearly
described by Chiari (1891, 1896). Arnold’s name is often attached
to the syndrome, but his contribution to our understanding of these
malformations was relatively insignificant. Use of the double eponym
Arnold-Chiari malformation is so entrenched that a dispute
over its propriety will not alter its usage. Chiari recognized four
types of abnormality. In recent years the term has come to be restricted
to Chiari’s types I and II—i.e., to the cerebellomedullary
malformation without and with a meningomyelocele, respectively.
Type III Chiari malformation is no more than a high cervical or
occipitocervical meningomyelocele with cerebellar herniation, and
type IV consists only of cerebellar hypoplasia. It should be emphasized
that a proportion of normal individuals have a small
tongue of the posterior cerebellum protruding below the opening
of the foramen magnum by a few millimeters; this is usually of no
significance and does not justify inclusion as a Chiari malformation.
Several other morphologic features are characteristic of the
true anomaly. The medulla and pons are elongated and the aqueduct
is narrowed. The displaced tissue (medulla and cerebellum) occludes
the foramen magnum; the remainder of the cerebellum,
which is small, is also displaced so as to obliterate the cisterna
magna. The foramina of Luschka and Magendie open into the cervical
canal, and the arachnoidal tissue around the herniated brainstem
and cerebellum is fibrotic. All these factors are probably operative
in the production of hydrocephalus, which is always
associated. Just below the herniated tail of cerebellar tissue there
is a kink or spur in the spinal cord, pushed posteriorly by the lower
end of the fourth ventricle. In this type of malformation, a meningomyelocele
is nearly always found. It should also be emphasized that hydromyelia or syringomyelia of the
cervical cord are
commonly associated findings.
Developmental abnormalities of the cerebrum (particularly
polymicrogyria) may coexist, and the lower end of the spinal cord
(i.e., filum terminale) may extend as low as the sacrum. There are
usually cranial bony abnormalities as well. The posterior fossa is
small; the foramen magnum is enlarged and grooved posteriorly.
Nishikawa et al have suggested that smallness of the posterior
fossa, with overcrowding, is the primary abnormality leading to the
brain malformation. Often the base of the skull is flattened or infolded
by the cervical spine (basilar impression).
Clinical Manifestations In type II Chiari malformation (with
meningomyelocele), the problem becomes one of progressive hydrocephalus.
Cerebellar signs cannot be discerned in the first few
months of life. However, lower cranial nerve abnormalities—
laryngeal stridor, fasciculations of the tongue, sternomastoid paralysis
(causing head lag when the child is pulled from lying to
sitting), facial weakness, deafness, bilateral abducens palsies—
may be present in varying combinations. If the patient survives to
later childhood or adolescence, one of the syndromes that occurs
with the type I malformation may become manifest.
In the more common type I Chiari malformation (without
meningocele or other signs of dysraphism), neurologic symptoms
may not develop until adolescence or adult life. The symptoms may
be those of (1) increased intracranial pressure, mainly headache,
(2) progressive cerebellar ataxia, (3) progressive spastic quadriparesis,
(4) downbeating nystagmus, or (5) cervical syringomyelia
(segmental amyotrophy and sensory loss, with or without pain). Or
the patient may show a combination of disorders of the lower cranial
nerves, cerebellum, medulla, and spinal cord (sensory and motor
tract disorders), usually in conjunction with headache that is
mainly occipital. This combination of symptoms is often mistaken
for multiple sclerosis or a foramen magnum tumor. The symptoms
may have an acute onset after sustained extension of the neck, as,
for example, after a long session of dental work, hairdressing in
women, or chiropractic manipulation. The physical habitus of such
patients may be normal, but about 25 percent have signs of an
arrested hydrocephalus or a short “bull neck.” When basilar impression
(a congenital abnormality of the occipital bone that invaginates
the posterior atlas into the cranial cavity) and a Chiari
malformation coexist, it may be impossible to decide which of the
two is responsible for the clinical findings.
The tongue of cerebellar tissue and the kinked cervical cord
obstruct the upward flow of dye and give a highly characteristic
radiologic profile, particularly on sagittal MRI (Fig. 38-4). Inspection
of the axial sections of CT scans at the level of the foramen
magnum also demonstrates crowding of the upper cervical canal
by inferiorly displaced cerebellar tissue, but one must be aware of
the variations in the normal position of the cerebellar tonsils at this
level. The low-pressure CSF syndrome may also lead to a slight
descent of the cerebellar tonsils that is reversible and in our experience
not indicative of a Chiari malformation. The CSF is usually
normal but may show an elevated pressure and protein level
in some cases.
Treatment The treatment of Chiari malformation (and basilar
impression) is far from satisfactory. If clinical progression is slight
or uncertain, it is probably best to do nothing. If progression is
certain and disability is increasing, upper cervical laminectomy and
enlargement of the foramen magnum are indicated. Often this procedure
halts the progress of the neurologic illness, arrests the hydrocephalus,
or results in some improvement. The outcome, in our
experience, has been less satisfactory when decompression was
performed mainly for intractable headache. The surgical procedure
must be done cautiously. Opening of the dura and extensive manipulation
of the malformation or excision of herniated cerebellum
may aggravate the symptoms or even cause death. The treatment
of an associated syringomyelia and other developmental abnormalities
in this region is discussed further on page 1082. We are
unable to comment on the use by a limited number of neurosurgeons
of posterior fossa decompression for the treatment of chronic
fatigue syndrome except to say that it is illogical, even when a
Chiari malformation is detected.

Figure 38-4. Chiari-type malformation and developmental syringomyelia.

T1-weighted MRI of the low-lying cerebellar tonsils below the foramen
magnum and behind the upper cervical cord (upper arrow) and the syrinx
cavity in the upper cord (lower arrow).