 |
|
Disorders of Cortical Development and Epilepsy
Brenda E. Porter, MD, PhD;
Amy Brooks-Kayal, MD;
Jeff A. Golden, MD
Arch Neurol. 2002;59:361-365.
ABSTRACT
| |
There has been an impressive increase in our ability to identify and
categorize patients with cortical development lesions over the past decade.
The clinical features associated with disorders of cortical development (DCD)
have been described, and epilepsy has been shown to be a frequent symptom.
In this review, we categorize DCD based on their structure and discuss their
underlying causes and clinical features. Just as the cause of each type of
disorder is thought to be unique, each disorder also has distinct types of
seizures, treatment strategies, and electroencephalographic features. Studies
in human tissue and animal models of DCD have begun to shed light on why DCD
are associated with epilepsy. Aberrant synaptic connections within the dysplastic
tissue and between the dysplastic tissue and more normal-appearing adjacent
tissue form an abnormal, hyperexcitable network that increases seizure susceptibility.
In the future, strategies for blocking formation of the aberrant networks
may prevent the development of epilepsy.
INTRODUCTION
The past decade has brought increased recognition that abnormal development
of the central nervous system produces malformations that are frequently associated
with refractory epilepsy. Through the use of high-resolution magnetic resonance
imaging (MRI), disorders of neuronal migration, cell survival, and differentiation
can be diagnosed in patients with epilepsy. According to MRI, 12% of adults
with refractory epilepsy also have disorders of cortical development (DCD).1 The true incidence is probably higher because MRI
fails to detect some DCD that are present on pathological inspection.2 Seizures are the most common clinical feature of DCD,
and they occur in 75% of children with DCD as diagnosed using MRI.3 This review will highlight recent advances in understanding
the causes of DCD, explain how DCD contribute to the formation of epilepsy,
and present current treatment strategies and possible future options.
To better understand DCD it is necessary to briefly discuss normal brain
development.4 The neocortex is derived from
a plate of rapidly dividing cells that line the ventricle wall. The newly
born cells migrate away from the ventricular region toward the pial surface.
Each neuronal precursor, depending on its date of birth, migrates a set distance
and develops a specific neuronal phenotype appropriate to its final location.
One recent discovery of particular relevance to epilepsy is that many or potentially
all inhibitory  -aminobutyric acid–expressing interneurons are
derived from the ganglionic eminence and migrate along a tangential path to
populate the neocortex.5-6 This
carefully orchestrated migration produces the highly structured, 6-layered
neocortex. Once an immature neuron arrives at its final location, it establishes
a specific set of connections by extending an axon and dendrites. Disruption
of neuronal development at each stage will potentially produce unique clinical
phenotypes. In this review, we describe 4 types of DCD that are often associated
with epilepsy.
LISSENCEPHALY, AGYRIA, AND PACHYGYRIA
Lissencephaly is a severe type of DCD. On gross inspection, the brain
appears smooth because of a paucity of gyri and sulci. Lissencephaly comprises
a spectrum of cortical structural abnormalities with subdivisions based on
histopathological criteria, extent of lesion, and syndromic features. In lissencephaly
type 1, the neocortex deviates from the normal 6 layers, most often having
only 4 poorly organized layers. In lissencephaly type 2, the cortex is unlayered,
with a cobblestone surface and thickened meninges. The extent of cortical
involvement varies from agyria, with a smooth cortex and no sulci, to pachygyria,
with focal areas of abnormally thickened and widened gyri surrounded by regions
of cortex with a more normal appearance. The terms lissencephaly, agyria,
and pachygyria are sometimes used interchangeably because of a lack of agreed-on
criteria for distinguishing among these abnormalities.
Clinically, the lissencephalies are a heterogeneous group of disorders;
Miller-Dieker syndrome (MDS) is the best-recognized syndrome associated with
lissencephaly type 1. There are variable clinical features in MDS, including
dysmorphic facies and heart and kidney abnormalities, and lissencephaly as
a constant feature. It is best understood as a contiguous gene deletion syndrome
on the short arm of chromosome 17. The primary gene responsible for MDS, LIS1, was identified in 1993.7
Mutations and deletions of LIS1 have been identified
in isolated lissencephaly and as a part of larger deletions associated with
the more extensive features of MDS. In addition to MDS, X-linked and other
familial forms of lissencephaly have been identified (Table 1). To date, in addition to the LIS1
gene, the molecular bases for one X-linked and one autosomal recessive form
of lissencephaly (doublecortin [DCX] and reelin [RELN] genes, respectively) have been characterized.8-10 Walker-Warburg syndrome
includes hydrocephalus, retinal dysplasia, muscle disease, and lissencephaly
type 2.11 Walker-Warburg syndrome and its related
disorders, muscle-eye-brain disease and Fukuyama type congenital muscular
dystrophy, all appear to be related to mutations in the fukutin (FCMD) gene.
|
|
|
|
Disorders of Cortical Development*
|
|
|
All forms of lissencephaly share several clinical features, including
mental retardation, motor delays, axial hypotonia, and seizures. The seizures
tend to start in the first months of life, with infantile spasms, large myoclonic
jerks, and tonic seizures being the most common types. There are reports of
pachygyria associated with adult-onset complex partial seizures that do not
appear to be inherited. An electroencephalogram (EEG) with persistent, rhythmic
fast-frequency discharges of very high amplitude (>100 µV) is characteristic
of lissencephaly.12 In the first years of life,
the frequencies increase from  and  range to predominantly 
and ß. The electrophysiologic bases of the high-frequency discharges
and seizures are poorly understood but should be aided by the recent development
of animal models deficient in lissencephaly-related genes.13
HETEROTOPIAS
Heterotopias are clusters of neurons and glia that form a nodule of
gray matter in an inappropriate location. They may be single or multiple and
may be found lining the ventricles, in the deep white matter, in the subcortical
white matter, or in the leptomeninges. The overlying cerebral cortex can be
normal or show a disruption of cortical layers or cellular organization. The
genetic bases for several familial forms of heterotopias have been identified.
Mutations in the DCX gene produce lissencephaly in
men and subcortical band heterotopia (previously called double cortex) in
women.8-9 DCX has a novel sequence and appears to stabilize microtubules. The genetic
basis for X-linked periventricular nodular heterotopia seen in women is now
known to result from mutations in filamin-1 (FLN1).14 The mechanism involved in the formation of the heterotopias
remains uncertain, but it may be related to FLN1's
actin-binding domains. Thus, the pathogenesis for both familial forms of heterotopia
appears to be related to abnormalities of the cytoskeleton. Single or unilateral
heterotopias have been associated with several metabolic diseases (Table 1), although most cases of heterotopia
appear to be sporadic.15
Heterotopias are frequently associated with refractory epilepsy, normal
findings on neurologic examination, and normal intelligence.15
The mean age of epilepsy onset is late childhood to early adolescence. Complex
partial seizures are the most common type, with generalized tonic-clonic seizures,
simple partial seizures, and infantile spasms being less common. On an EEG,
the epileptiform discharges are unilateral or bilateral depending on the location
of the heterotopias. The seizures are often refractory to medication and surgery
unless most heterotopias can be resected. On surface and intracranial EEGs,
the temporal lobe appears involved in the initiation or early propagation
of seizures in some patients with nodular heterotopias. Isolated temporal
lobectomies did not produce seizure freedom even when hippocampal sclerosis
was also present.16 Using tract-tracing techniques,
there appear to be neuronal connections among different heterotopias and among
the heterotopias and more normal-appearing adjacent cortex.17
This network of connections may explain why it is difficult to localize seizure
onset.
Two animal models of heterotopia, the methylazoxymethanol acetate teratogenic
model and the tish rat, have been useful in studying how heterotopias produce
epilepsy.18 Exposing pregnant rats to the alkylating
agent methylazoxymethanol acetate produces heterotopias by inhibiting cell
division and migration in the developing cortex. The animals have cognitive
problems as well as a lowered seizure threshold.19-20
There appear to be orthodromic and antidromic neuronal connections between
the heterotopia and the surrounding neocortex and hippocampus.21-22
The heterotopia and the surrounding cortex have altered excitatory and inhibitory
neurotransmitter receptor subunits, an increase in intrinsically bursting
neurons, and prolonged depolarization potentials.23
The tish rat is a spontaneous mutant with clinical seizures. Its morphologic
characteristics are most similar to those of humans with subcortical band
heterotopia. There is a subcortical ribbon of heterotopic gray matter separated
by a myelinated axon tract from a more normal-appearing cortex, as well as
functional synaptic connections between the heterotopia and the overlying
cortex that traverse the white matter.24 Surprisingly,
when these connections are severed, it is the overlying cortex that appears
to have a lower seizure threshold. In both the methylazoxymethanol acetate
and tish models, there are electrical connections between the heterotopia
and surrounding cortex.25 In addition, the
surrounding cortex has independent physiological abnormalities, suggesting
that it may be involved in the initiation of seizures.
POLYMICROGYRIA
Polymicrogyria, as the name suggests, is composed of many abnormally
small gyri. Histologically, the gyri have a decreased number of neurons, with
the neuronal loss most pronounced in the middle cortical layers, especially
layer V, although marked variability among cases is typical. The presence
of normal-appearing neuronal layers on either side of layer V suggests that
migration is grossly intact. The cause of most cases of polymicrogyria is
thought to be an intrauterine insult such as hypoxia-ischemia, fetal demise
of a twin, or cytomegalovirus infection (Table 1).26
In a few cases of polymicrogyria, a maternal respiratory or cardiac
arrest occurred during the early part of the second trimester just as neuronal
migration was finishing.27 There are numerous
reports of sporadic and familial cases of polymicrogyria that include unilateral,
bilateral, perisylvian, parieto-occipital, and diffuse types. The existence
of familial cases suggests a genetic cause, though to our knowledge, no genes
have yet been identified.28 Clinically, seizures,
mental retardation, and some evidence of upper motor neuron dysfunction such
as weakness or spasticity corresponding to the polymicrogyric cortex may be
present.29
Porencephaly and schizencephaly might be classified under polymicrogyria
or as separate categories. We include both here because the margins of the
porencephaly almost always contain polymicrogyria. Porencephaly is most often
believed to result from an insult to the developing brain. However, there
are reports of mutations in transcription factors in some families, raising
the possibility of another pathogenesis.
Several seizure types have been associated with polymicrogyria, including
infantile spasms and complex partial, hemimyoclonic, and myoclonic seizures.
The onset of epilepsy occurs during a wide range of ages from childhood to
middle age. The EEG tends to demonstrate sharp waves and slowing across a
relatively broad area that includes the polymicrogyria.
In the freeze lesion model of polymicrogyria, a rat pup has a small
region of cortex supercooled. If this is performed around the time of birth,
the supercooled area will become an abnormal 4-layered cortex. Although there
are no spontaneous seizures, slices of the cortex are hyperexcitable.30 There appears to be an excessive ingrowth of axons
with synapse formation in the area surrounding the lesion.31
The axons that would normally form synapses within the lesion instead innervate
the surrounding cortex. A lowered seizure threshold, as measured by prolonged
depolarizations, is not within the lesion but in the adjacent normal-appearing
cortex.30 There is an increased ratio of excitatory
to inhibitory postsynaptic potentials in the area surrounding the lesion.
Similar to the tish and methylazoxymethanol acetate models, abnormal synaptic
connections formed in the normal-appearing cortex adjacent to the freeze lesion
may be involved in the initiation of seizures.
CORTICAL DYSPLASIA
The original description of cortical dysplasia was based on 10 patients
who had resective surgery for refractory epilepsy.32
On histologic evaluation there was loss of the gray-white matter junction
due to increased neurons in the white matter, loss of lamination, and giant
abnormal cells with poorly organized processes. The cause of cortical dysplasia
is unknown and likely variable. The size of the dysplasia varies from small
microscopic lesions to hemimegalencephaly, where an entire hemisphere is grossly
dysplastic. The loss of lamination and increased neurons in the white matter
suggest that a defect in migration may underlie some cases. The large abnormal-appearing
cells may express immature neuronal markers or a mixture of neuronal and glial
markers, suggesting that an abnormality in cellular differentiation may be
involved.33 On MRI, common features include
loss of the gray-white matter junction and nonenhancing signal changes.
Clinically, focal epilepsy, with an onset in childhood or adolescence,
and some mental deficiencies are the most common symptoms of cortical dysplasia34 (Table 1).
Cortical dysplasia has been extensively studied in humans because 50% of children
and up to 18% of adults undergoing surgery for refractory epilepsy have cortical
dysplasia present on histologic examinations.35-36
Surface and intracranial EEGs have identified focal rhythmic sharp-wave discharges,
lasting from several seconds to almost continuously, as characteristics of
cortical dysplasia.37 While there usually is
overlap between an MRI-identified dysplasia and the EEG abnormality, there
often are extensive electrographic abnormalities outside the area of a visible
lesion.
The increasing use of surgical resection for the treatment of cortical
dysplasia provides epileptic tissue for histologic, molecular biological,
and electrophysiologic examination. Numerous abnormalities have been described
in dysplastic tissue. There is an overall decrease in some types of -aminobutyric
acid–inhibitory neurons and increases in certain subtypes of the glutamate N-methyl–D-aspartate (NMDA) receptors,2, 38-39
which suggests a loss of inhibition and a shift in the pattern of excitation.
Electrophysiologic examinations, performed on epileptic human brain slices,
found a large network of neurons undergoing prolonged repetitive depolarization.40 Blocking the excitatory NMDA and non-NMDA glutamate
receptors prevented depolarization. Similarly, blockade of the inhibitory -aminobutyric
acid receptors augmented depolarization. Further refinement of this technique
should facilitate the identification of receptor subtypes and the involved
cell types.
TREATMENT STRATEGIES
The DCD are often refractory to medical treatment, including polypharmacy.
Now that specific expression patterns of certain excitatory neurotransmitter
receptor subunits have been found in some DCD, a more specific pharmaceutical
approach to DCD-related epilepsy should be possible. Currently, the best treatment
option for seizure freedom is a tailored surgical resection. A good surgical
outcome, up to 60% seizure freedom, depends on careful mapping and removal
of all areas with epileptiform discharges.41
There appears to be an extensive electrical network among the DCD, adjacent,
and even distant cortical structures. Leaving portions of the network intact
may explain why half of patients continue to have seizures after surgery.
Although the DCD are present at birth, most patients do not develop
seizures until years later. This provides a window of time in which the formation
of epilepsy might be blocked. Hopefully, we should soon have a better understanding
of the molecular and cellular changes that DCD undergo leading to the formation
of epilepsy. This knowledge may allow a scientifically based therapeutic trial
for the prevention of epilepsy by focusing on blocking the formation of an
epileptiform network. One possible strategy is to block aberrant connections
between the DCD and the surrounding cortex. Already, a long list of cytokines
and growth factors appear to be altered by seizures and/or block seizures
in animal models of epilepsy and might be candidates for an epilepsy prevention
trial.42 Alternatively, increasing the number
of inhibitory synaptic connections within the DCD and between the DCD and
the normal cortex might be possible as molecular cues for inhibitory synapse
formation are identified.6 Treatment strategies
for DCD-related epilepsies should blossom during the next decade as our understanding
of their pathophysiologic characteristics increases.
AUTHOR INFORMATION
Accepted for publication June 25, 2001.
Author contributions: Study
concept and design; analysis and interpretation of data; drafting of the manuscript;
critical revision of the manuscript for important intellectual content; obtained
funding; administrative, technical, and material support; and study supervision
were provided by Drs Porter, Brooks-Kayal, and Golden.
Corresponding author and reprints: Brenda E. Porter, MD, PhD, Division
of Child Neurology, Children's Hospital of Philadelphia, Wood Bldg 6th Floor,
Philadelphia, PA 19104 (e-mail: porterb{at}email.chop.edu).
From the Pediatric Regional Epilepsy Program, Divisions of Child Neurology
(Drs Porter and Brooks-Kayal) and Neuropathology (Dr Golden), Children's Hospital
of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia.
REFERENCES
| |
1. Li LM, Fish DR, Sisodiya SM, Shorvon SD, Alsanjari N, Stevens JM. High-resolution magnetic resonance imaging in adults with partial or
secondary generalized epilepsy attending a tertiary referral unit. J Neurol Neurosurg Psychiatry. 1995;59:384-387.
ABSTRACT
2. Spreafico R, Battaglia G, Arcelli P, et al. Cortical dysplasia: an immunocytochemical study of 3 patients. Neurology. 1998;50:27-36.
FREE FULL TEXT
3. Leventer RJ, Phelan EM, Coleman LT, Kean MJ, Jackson GD, Harvey AS. Clinical and imaging features of cortical malformations in childhood. Neurology. 1999;53:715-722.
FREE FULL TEXT
4. Gleeson JG, Walsh CA. Neuronal migration disorders: from genetic diseases to developmental
mechanisms. Trends Neurosci. 2000;23:352-359.
FULL TEXT
|
ISI
| PUBMED
5. Lavdas AA, Grigoriou M, Pachnis V, Parnavelas JG. The medial ganglionic eminence gives rise to a population of early
neurons in the developing cerebral cortex. J Neurosci. 1999;19:7881-7888.
FREE FULL TEXT
6. Anderson S, Mione M, Yun K, Rubenstein JL. Differential origins of neocortical projection and local circuit neurons:
role of DLX genes in neocortical interneuronogenesis. Cereb Cortex. 1999;9:646-654.
FREE FULL TEXT
7. Reiner O, Carrozzo R, Shen Y, et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein
beta-subunit-like repeats. Nature. 1993;364:717-721.
FULL TEXT
| PUBMED
8. Gleeson JG, Allen KM, Fox JW, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly
and double cortex syndrome, encodes a putative signaling protein. Cell. 1998;92:63-72.
FULL TEXT
|
ISI
| PUBMED
9. des Portes V, Pinard JM, Billuart P, et al. A novel CNS gene required for neuronal migration
and involved in X-linked subcortical laminar heterotopia and lissencephaly
syndrome. Cell. 1998;92:51-61.
FULL TEXT
|
ISI
| PUBMED
10. Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated
with human RELN mutations. Nat Genet. 2000;26:93-96.
FULL TEXT
|
ISI
| PUBMED
11. Dobyns WB, Pagon RA, Armstrong D, et al. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet. 1989;32:195-210.
FULL TEXT
|
ISI
| PUBMED
12. Gastaut H, Pinsard N, Raybaud C, Aicardi J, Zifkin B. Lissencephaly (agyria-pachygyria): clinical findings and serial EEG
studies. Dev Med Child Neurol. 1987;29:167-180.
ISI
| PUBMED
13. Fleck MW, Hirotsune S, Gambello MJ, et al. Hippocampal abnormalities and enhanced excitability in a murine model
of human lissencephaly. J Neurosci. 2000;20:2439-2450.
FREE FULL TEXT
14. Fox JW, Lamperti ED, Eksioglu YZ, et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons
in human periventricular heterotopia. Neuron. 1998;21:1315-1325.
FULL TEXT
|
ISI
| PUBMED
15. Dubeau F, Tampieri D, Lee N, et al. Periventricular and subcortical nodular heterotopia: a study of 33
patients. Brain. 1995;118(pt 5):1273-1287.
16. Li LM, Cendes F, Andermann F, et al. Surgical outcome in patients with epilepsy and dual pathology. Brain. 1999;122(pt 5):799-805.
17. Hannan AJ, Servotte S, Katsnelson A, et al. Characterization of nodular neuronal heterotopia in children. Brain. 1999;122(pt 2):219-238.
18. Jacobs KM, Kharazia VN, Prince DA. Mechanisms underlying epileptogenesis in cortical malformations. Epilepsy Res. 1999;36:165-188.
FULL TEXT
|
ISI
| PUBMED
19. Banfi S, Dorigotti L, Abbracchio MP, et al. Methylazoxymethanol microencephaly in rats: neurochemical characterization
and behavioral studies with the nootropic oxiracetam. Pharmacol Res Commun. 1984;16:67-83.
PUBMED
20. Germano IM, Zhang YF, Sperber EF, Moshe SL. Neuronal migration disorders increase susceptibility to hyperthermia-induced
seizures in developing rats. Epilepsia. 1996;37:902-910.
FULL TEXT
|
ISI
| PUBMED
21. Yurkewicz L, Valentino KL, Floeter MK, Fleshman JW Jr, Jones EG. Effects of cytotoxic deletions of somatic sensory cortex in fetal rats. Somatosens Res. 1984;1:303-327.
PUBMED
22. Colacitti C, Sancini G, DeBiasi S, et al. Prenatal methylazoxymethanol treatment in rats produces brain abnormalities
with morphological similarities to human developmental brain dysgeneses. J Neuropathol Exp Neurol. 1999;58:92-106.
ISI
| PUBMED
23. Sancini G, Franceschetti S, Battaglia G, et al. Dysplastic neocortex and subcortical heterotopias in methylazoxymethanol-treated
rats: an intracellular study of identified pyramidal neurones. Neurosci Lett. 1998;246:181-185.
FULL TEXT
|
ISI
| PUBMED
24. Schottler F, Couture D, Rao A, Kahn H, Lee KS. Subcortical connections of normotopic and heterotopic neurons in sensory
and motor cortices of the tish mutant rat. J Comp Neurol. 1998;395:29-42.
FULL TEXT
|
ISI
| PUBMED
25. Chen ZF, Schottler F, Bertram E, Gall CM, Anzivino MJ, Lee KS. Distribution and initiation of seizure activity in a rat brain with
subcortical band heterotopia. Epilepsia. 2000;41:493-501.
FULL TEXT
|
ISI
| PUBMED
26. Iannetti P, Nigro G, Spalice A, Faiella A, Boncinelli E. Cytomegalovirus infection and schizencephaly: case reports. Ann Neurol. 1998;43:123-127.
FULL TEXT
|
ISI
| PUBMED
27. Barkovich AJ, Rowley H, Bollen A. Correlation of prenatal events with the development of polymicrogyria. AJNR Am J Neuroradiol. 1995;16(suppl 4):822-827.
28. Guerreiro MM, Andermann E, Guerrini R, et al. Familial perisylvian polymicrogyria: a new familial syndrome of cortical
maldevelopment. Ann Neurol. 2000;48:39-48.
FULL TEXT
|
ISI
| PUBMED
29. Guerrini R, Dravet C, Bureau M, et al. Diffuse and localized dysplasias of cerebral cortex: clinical presentation,
outcome, and proposal for a morphologic MRI classification based on a study
of 90 patients. In: Guerrini R, Andermann F, Canapicchi R, Roger J, Zifkin BG, Pfanner
P, eds. Dysplasias of Cerebral Cortex and Epilepsy.
Philadelphia, Pa: Lippincott-Raven; 1996:255-269.
30. Jacobs KM, Hwang BJ, Prince DA. Focal epileptogenesis in a rat model of polymicrogyria. J Neurophysiol. 1999;81:159-173.
FREE FULL TEXT
31. Jacobs KM, Mogensen M, Warren E, Prince DA. Experimental microgyri disrupt the barrel field pattern in rat somatosensory
cortex. Cereb Cortex. 1999;9:733-744.
FREE FULL TEXT
32. Taylor DC, Falconer MA, Bruton CJ, Corsellis JAN. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry. 1971;34:369-387.
ISI
| PUBMED
33. Vinters HV, Fisher RS, Cornford ME, et al. Morphological substrates of infantile spasms: studies based on surgically
resected cerebral tissue. Childs Nerv Syst. 1992;8:8-17.
FULL TEXT
|
ISI
| PUBMED
34. Palmini A, Andermann F, Olivier A, et al. Focal neuronal migration disorders and intractable partial epilepsy:
a study of 30 patients. Ann Neurol. 1991;30:741-749.
FULL TEXT
|
ISI
| PUBMED
35. Duchowny M, Levin B, Jayakar P, et al. Temporal lobectomy in early childhood. Epilepsia. 1992;33:298-303.
FULL TEXT
|
ISI
| PUBMED
36. Wolf HK, Campos MG, Zentner J, et al. Surgical pathology of temporal lobe epilepsy: experience with 216 cases. J Neuropathol Exp Neurol. 1993;52:499-506.
ISI
| PUBMED
37. Gambardella A, Palmini A, Andermann F, et al. Usefulness of focal rhythmic discharges on scalp EEG of patients with
focal cortical dysplasia and intractable epilepsy. Electroencephalogr Clin Neurophysiol. 1996;98:243-249.
FULL TEXT
|
ISI
| PUBMED
38. Crino PB, Duhaime AC, Baltuch G, White R. Differential expression of glutamate and GABA-A receptor subunit mRNA
in cortical dysplasia. Neurology. 2001;56:906-913.
FREE FULL TEXT
39. Ying Z, Babb TL, Mikuni N, Najm I, Drazba J, Bingaman W. Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in
dysplastic neurons of human epileptic cortex. Exp Neurol. 1999;159:409-418.
FULL TEXT
|
ISI
| PUBMED
40. Avoli M, Bernasconi A, Mattia D, Olivier A, Hwa GG. Epileptiform discharges in the human dysplastic neocortex: in vitro
physiology and pharmacology. Ann Neurol. 1999;46:816-826.
FULL TEXT
|
ISI
| PUBMED
41. Paolicchi JM, Jayakar P, Dean P, et al. Predictors of outcome in pediatric epilepsy surgery. Neurology. 2000;54:642-647.
FREE FULL TEXT
42. Jankowsky JL, Patterson PH. The role of cytokines and growth factors in seizures and their sequelae. Prog Neurobiol. 2001;63:125-149.
FULL TEXT
|
ISI
| PUBMED
SECTION EDITOR: DAVID E. PLEASURE, MD
RELATED ARTICLE
Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 2002;59(3):492-494.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Genetic Disruption of Cortical Interneuron Development Causes Region- and GABA Cell Type-Specific Deficits, Epilepsy, and Behavioral Dysfunction
Powell et al.
J. Neurosci. 2003;23:622-631.
ABSTRACT
| FULL TEXT
|
