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Developmental dyslexia Four consecutive patients with cortical anomalies.

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Developmental Dyslexia: Four Consecutive
Patients with Cortical Anomahes
Albert M. Galaburda, MD, Gordon F. Sherman, PhD, Glenn D. Rosen, PhD,
Francisco Aboitiz, MBiol, and Norman Geschwind, MD+
We report the neuroanatomical findings in 4 consecutively studied brains of men with developmental dyslexia. The
patients, who ranged in age between 14 and 32 years, were diagnosed as dyslexic during life. Nonrighthandedness and
several autoimmune and atopic illnesses were present in the personal and family histories. All brains showed developmental anomalies of the cerebral cortex. These consisted of neuronal ectopias and architectonic dysplasias located
mainly in perisylvian regions and affecting predominantly the left hemisphere. Furthermore, all brains showed a
deviation from the standard pattern of cerebral asymmetry characterized by symmetry of the planum temporale. The
neuroanatomical findings in these 4patients are discussed with reference to developmental cortical anomalies, cerebral
asymmetries, reorganization of the brain after early lesions, and the association between learning disorders, left
handedness, and diseases of the immune system.
Galaburda AM, Sherman GF, Rosen GD, Aboitiz F, Geschwind N: Developmental dyslexia: four
consecutive patients with cortical anomalies. Ann Neurol 18:222-233, 1985
Although there is controversy as to whether developmental dyslexia is a single entity, there is widespread
agreement that there is a notable portion of the school
age population who, despite normal intelligence, emotional stability, and adequate family and educational
opportunities, share common difficulties in learning
how to read and write C13, 31).
Since the first descriptions of developmental dyslexia near the end of the nineteenth century C28, 29,
371, many advances have been made in the description
and classification of the functional characteristics of this
condition. Among the disabilities frequently associated
with dyslexia one finds specific linguistic anomahes affecting semantic, phonological, and syntactic processes
133, 55, 56, 58); there is often evidence of anomalous
cerebral dominance affecting a wide variety of performances, e.g., the lateralization of speech sounds, the
awareness of right and left, and handedness C31, 42,
43, 571. Some authors, on the other hand, have
stressed the high rate of certain cognitive talents in the
dyslexic population C24, 25, 441.
Several authors have described neurological abnormalities present in association with dyslexia. These
findings, consisting of sensorimotor deficits, alterations
in eye movements, electroencephalographic changes,
and aberrations in evoked potentials IS, 7 , 30, 501,
have generally been regarded as controversial (see
[lo]) and do not consistently account for the reading
deficit. Consequently clear-cut alterations in brain
structure were almost universally assumed not to be
present. In 1979 our laboratory reported a detailed
neuroanatomical study of the brain of a young man
with severe developmental dyslexia [161. Since that
time we have had the opportunity to study 3 additional
patients and have become aware of 2 other descriptions of anatomical findings in the literature. The purpose of this report is to review the available information on the anatomical nature of developmental
dyslexia and to discuss the possible importance of
these findings.
From the Dyslexia Research Laboratory and the Charles A. Dana
Research Institute. Reth Israel Hospital., and the Department of
Neurology, Beth Israel Hospital and-Harvard Medical School, 330
Brookline Ave, Boston, MA 022 15.
Received Dec 10, 1984, and in revised form Jan 29, 1985. Accepted
for publication .Jan 29, 1985.
Patient Histories
Patient 1
A detailed account of this patient has been published previously 1161. A 20-year-old left-handed man died as the result
of a fall. History revealed speech delay until after age 3 years.
Diagnosis of specific reading disability was made soon after
school entrance, and thereafter the patient received special
education until 18 years of age. Despite these efforts, his
reading and writing competency never reached beyond the
fourth-grade level (see Table). At age 16 he developed
nocturnal seizures, though the electroencephalogram was
normal. He subsequently entered an apprenticeship program in sheet metal work and became a skillful metal sculptor.
Family history revealed several members, all male, with developmental dyslexia, as well as left handedness, ambidexterity,
rheumatoid arthritis in the mother, and migraine headaches.
Address reprinI requests to Dr Galaburda,
"Deceased.
222
Results of Reading and Intelligence Testing
Patient 2
Patient 1
Tests
Age 13
Age 19
Gray Oral Reading"
Wide-Range Achievement Test"
Reading
Spelling
Arithmetic
Intelligence Quotientb
Verbal
Performance
Full Scale
1.6
4.0
Age 11
Age 13
Patient 4
Age 14
1.8
2.6
NA
3.5'
79
93
85
105
125
117
1.9
6.0
3.3
4.3
95
83
88
Patient 3
Age 18
94
91
91
"All reading scores are given in grade levels.
bIQ for Patient 1 was determined by the Wechsler Intelligence Scale for Children, Patient 2 by the Wechsler Intelligence Scale for Children,
Revised, and Patients 3 and 4 by the Wechsler Adult Intelligence Scale.
'Results of an informal spelling test. Tutor said ". . . performance was like that of children in the third grade."
NA = not administered.
Patient 2
A 14-year-old right-handed boy (ambidextrous until age 2 to
3 years) with the diagnosis of developmental dyslexia died
suddenly. Postmortem examination revealed acute myocarditis, and it was presumed that an arrhythmia was the cause
of death. There was severe reading disability in an older
brother, and the diagnosis of dyslexia was made in Patient 2
at an early age. He was placed in special education programs
near the start of his elementary education. The results of
several reading and intelligence tests are summarized in the
Table. In addition to developmental dyslexia, his family history included left handedness, athletic giftedness both in the
dyslexic brother and in the patient, juvenile rheumatoid arthritis in the mother, thyroid disease of unknown type in the
father, asthma, multiple food allergies, migraine headaches,
and mitral valve prolapse in the dyslexic brother, in a sister,
and in the mother.
Patient 3
A 20-year-old right-handed dyslexic man died in a motor
vehicle accident. His learning disability was noted at the age
of 5, and by age 8 notable language difficulties had been
documented in spite of normal intelligence and special education. Results of his tests are provided in the Table. At age
14 he fell from an eight-foot wall and sustained a linear
fracture of the left temporal bone but no loss of consciousness. At age 15 he was evaluated for daytime drowsiness, and
was found on electroencephalography to have paroxysmal
slowing over the right hemisphere. At the age of 19 his
reading competency did not exceed the second-grade level.
Two younger left-handed twin brothers had reading difficulties, but no additional medical information was made
available.
Patient 4
A 32-year-old ambidextrous West German man died of a
massive subarachnoid hemorrhage. The official medical record is somewhat sketchy, although the mother and the
school psychologist provided very careful histories. H e was
late in acquiring speech and later repeated two grades despite
higher than average intelligence in areas other than reading.
He was diagnosed as dyslexic at an early age, although very
little special education was available to him. His performance
on oral tests was always much better than that on written
examinations. Just before his death he had completed the
requirements for the postgraduate degree of doctor of engineering. Available psychometric test results are provided
in the Table. Family history included left handedness, a
mathematically talented father who was almost certainly an
undiagnosed dyslexic, and a mother with idiopathic thrombocytopenic purpura.
Neuroanatomical Studies: Methods
Except for Patient 1, the brains were received through the
Orton Dyslexia Society Brain Bank. This program comprises
several thousand dyslexic persons and their relatives, all of
whom have agreed to donate their brain in the event of their
death, and many of whom have filled out detailed questionnaires covering medical, social, and educational histories.
At postmortem examination the brain in each case is carefully removed, making every effort to avoid injury to the
Cortex. The specimen is suspended in 10% formalin solution
to avoid distortion of the hemispheres; the formalin solution
is changed in each of 3 successive weeks. The brain is then
shipped in a crush-proof container to the neuroanatomical
laboratory, where, after an additional 3 to 4 weeks of formalin fixation, it is weighed before it is embedded whole in
celloidin. After approximately 10 months of embedding in
progressively higher concentrations of celloidin (see the
method of Yakovlev [bl]), the brain is cut in gapless histological sections at a thickness of 35 p. Every twentieth section is stained for cell bodies using cresyl violet, and the
adjacent section using the Loyez method for myelinated
fibers.
Descriptions of gross morphological features are based on
photographs taken before embedding and on optical reconstructions made from the serial sections with the aid of a
distortion-free apparatus. It is thus possible to determine the
Galaburda et al: Cortical Anomalies in Dyslexia 223
shape and length of the sylvian fissures and of the planurn
temporale (the triangular region lying immediately caudal to
the transverse gyrus of Heschl on the dorsal surface of the
temporal lobe and containing auditory association fields), as
well as the topographical distribution of the microscopical
findings.
Analysis of the sections is carried out with a stereomicroscope, and additional architectonic characterization with the
help of standard and comparison compound microscopes. In
special instances additional stains are employed on appropriate spare sections to outline other histological features such
as glia and blood vessels.
Similarly prepared age- and sex-matched control brains are
available in this laboratory and through the Yakovlev Collection at the Armed Forces Institute of Pathology, Washington, DC.
Results
Patient 1
Fig 1. Topography ofectopias and dysplasias (solid circles), a
brain wart (w), and micropolygyria (shaded area) in the
planurn temporale (inset) and cortical convexities of the left (L)
and right (R)hemispheres of Patient I . Note the symmetvy of
the pkzna and the preponderance of anomalies in the left hemisphere. (PT = planum temporale; H = HeschPs gyrus.)
224 Annals of Neurology Vol 18 No 2 August 1985
The formalin-fixed brain weight was 1,576 gm. Gross
examination disclosed no abnormalities. Reconstruction of the planum temporale on the two sides disclosed plana that were nearly symmetrical in size and
shape (inset, Fig 1).
Microscopical examination of the stained serial sections revealed two types of abnormalities in the cortex:
architectonic dysplasias and neuronal ectopias. The
Fig 2. Micropolygyria (arrows) in the left planurn temporale of
Patient 1 . (Bar = 1 mm.)
C
Fig 3. Examples of ectopias (arrows)and dysprasias (arrowheads) in (A) Patient 4, (B) Patient I , (C) Patient 3, and (0)
Patient 2. In C, artery (a) and cell-free area accompany a brain
wart. (Bar = 500 p.J
cortical dysplasias consisted, in their mildest form, of
focal architectonic distortions rending to obscure the
normal lamination and columnar organization typical
of a given field. In the typical dysplasia, there were
excessive numbers of large cells, often disoriented with
respect to the axis perpendicular to the pia. The most
severe form of dysplasia was an instance of micropolygyria involving the region of the left planum temporale
and posterior superior temporal g y m , characterized
by excessive folding, fused laminae, and absent columnar organization (Fig 2 ) .
Ectopias consisted of nests of cells (medium-sized
neurons based on Nissl appearance), most commonly
located in layer I (for example, see Fig 3); in the normal state this layer is virtually free of neurons in comparable architectonic areas. Ectopic collections of
neurons were occasionally seen in the white matter
subjacent to the cortex. Ectopic nests were frequently
seen in the vicinity of dysplastic cortex. The topo-
D
graphical distribution of the lesions is shown in
Figure 1.
Patient 2
General postmortem examination disclosed focal inflammatory infiltrates involving the myocardium and
conduction pathways. There was also borderline hypothyroidism determined by postmortem measurements of T3, Tq, and thyroid-stimulating hormone. The
thymus was believed to be enlarged at 40 gm, and
there were generalized lymphadenopathy and acute
laryngotracheobronchitis and epiglottiditis.
The brain weighed 1,597 gm after formalin fixation.
There were several reversals or deviations from the
usual pattern of gross anatomical asymmetry: (1) the
posterior end of the right sylvian fissure was lower
than that of the left; ( 2 ) the pars opercularis of the
right inferior frontal gyrus was larger in surface than
the corresponding structure on the left; ( 3 ) the former
also contained a more branched ascending sylvian sulcus; (4) the reconstructions of the plana temporale revealed nearly symmetrical structures on the two sides
(inset, Fig 4).
Microscopical analysis of the serial sections disclosed
multiple instances of cortical dyspiasia and ectopia (for
Galaburda
et
al: Cortical Anomalies in Dyslexia 225
Fig 4 . Topography of ectopias and dysplasias (solid circles) and
brain warts (w) zn the planum temporale (inset) and cortical
convexities of the ldt (L) and right (R) hemispheres of Patient 2.
(FT = pkznum temporale; H = Hescbl's gyrus.)
example, see Fig 3 ) involving both hemispheres but
clearly more prominently the left. The dysplasias and
ectopias were of the same type as those described in
Patient 1 except for the absence of micropolygyria. As
in the other patients, ectopias and dysplasias could often be found adjacent to one another, and occasionally
assumed the form of cortical excrescences known as
brain warts 1431. The distribution of lesions in Patient
2 is illustrated in Figure 4 .
Patient 3
General postmortem findings included extensive intraperitoneal and retroperitoneal hemorrhage, ruptured spleen, ruptured right kidney, and lacerated right
renal vein and artery. There were fresh fractures of the
right mandible, the roof of the left orbit, and the
greater and lesser wings of the left sphenoid bone. The
fresh brain weighed 1,450 gm; the specimen was embedded before the formah-fixed weight could be recorded. There was a small subdural blood collection
and evidence of fresh subarachnoid bleeding. On gross
inspection old contusions were seen involving right
and left midtemporal regions as well as both orbitofrontal surfaces. The sylvian fissures appeared symmetrical in shape and length, and the opercular portions of
226 Annals of Neurology Vol 18 No 2 August 1985
F i g 5 . Topography of ectopias and dysplasias (solid circles),
brain warts (w), and damage tamed by trauma (black) in the
planum temporale (inset) and cortical convexzties of the left (L)
and right (R) hemispheres of Patient 3. (FT = planum temporale; H = Heschl's gyrus.)
the frontal lobes were similar in size and complexity of
folding on the two sides. Reconstruction of the plana
temporale from the serial sections showed them to be
roughly symmetrical in size and shape (inset, Fig 5).
Microscopical examination of the serial sections revealed agonal changes characterized by perivenous microhemorrhages and dilatation of small cerebral veins
in areas of focal hemorrhage, including Duret hemorrhages in the mesencephalon. There were also extensive areas of old trauma corresponding in topography
to the gross descriptions (Fig 5 ) . These areas of old
contusion revealed various abnormalities ranging from
hemosiderin deposits, neuronal loss, and gliosis to
frank cavitation. These lesions showed the typical pattern of brain trauma, i.e., they tended to involve the
crests of gyri and spare the depths of sulci.
In addition to the findings of old and new parenchymal trauma, the brain showed evidence of developmental cortical anomalies, again characterized by the
presence of ectopias and dysplasias. There were
numerous examples of dysplastic cortical architecture
and ectopic collections of neurons in layer I (for example, see Fig 3 ) affecting the inferior frontal and
superior temporal regions. The distribution of these
lesions is illustrated in Figure 5 , which also shows the
asymmetry of lesion numbers in favor of the left side.
Fig 6. Topography of ectopias and dysplasias (solid circles) and
a brain wart (w) in the planurn temporale (inset) and cortical
convexities of the ldt (L)and right (R) hemispheres of Patient 4.
A small number of additional ectopias and dysplasias were present on the medialsu$aces of both hemispheres anteriorly. (PT =
planurn temporale; H = HeschI's gyrus.)
Patient 4
The formalin-fixed brain weighed 1,680 gm. Overseas
transportation produced notable distortion of the curvature of the convexity, especially over the right dorsal
surface. There was extensive subarachnoid bleeding,
especially involving the left inferior convexity. Examination of the branches of the circle of Willis failed to
show aneurysms or disruption of vessel walls. A medical examiner's coronal section at the level of the pars
opercularis of each frontal lobe revealed small ventricles, flattened gyri, and congested veins in the white
matter. There was evidence of bilateral uncal herniation that was more pronounced on the left. Artifactual
parietal distortion precluded any conclusions about the
nature of sylvian fissure asymmetry. The plana temporale, however, clearly corresponded to the symmetrical
type (inset, Fig 6).
Microscopical examination of the serial sections revealed an area of intraparenchymal bleeding, with
marked surrounding tissue destruction, involving the
left anterior mesial temporal region. Trichrome staining of adjacent sections disclosed multiple muscular
vessels with perivascular hemorrhages, but it was not
possible to demonstrate an actual angiomatous malfor-
mation. Additional analysis showed multiple examples
of dysplasia and ectopia in the cortex (for example, see
Fig 3); there were occasional brain warts containing
dysplastic cortex tissue and ectopic neurons; there was
a small instance of micropolygyria involving the undersurface of the left temporal lobe anteriorly. Both hemispheres contained the architectonic anomalies, but the
left was more severely affected (Fig 6).
The thalamus was surveyed in all 4 brains; the
findings in Patient 1 have been detailed in a previous
publication I151. They consisted mainly of architectonic distortion of the medial geniculate and posterior lateral nuclei hilaterally. The distortions were
characterized by abnormalities in nuclear outline,
abnormalities in the patterns of myelination, and
primitiveness of cytoarchitecture as evidenced by the
presence of large cells diffusely distributed in the nuclei. In Patient 2 there were slight distortions in the
external configurations of the medial geniculate nuclei,
but the internal architecture was preserved in a l l the
nuclei composing the posterior thalamus. Patient 3
showed no abnormalities in the thalamus, whereas Patient 4 showed a magnocellularity in the medial geniculate nuclei that was similar to that seen in Patient 1,
though less striking.
Discussion
Before our report of Patient 1 1161, Drake 191
published neuropathological findings in a well-documented case of developmental dyslexia. He described
a thinned corpus callosum particularly involving the
parietal connections, abnormal cortical folding in the
parietal regions, and, on microscopical examination,
excessive numbers of neurons in the subcortical white
matter. The illustrations provided did not show the
parietal lobe, and the portion of the corpus callosum
that could be seen appeared normal. No mention was
made as to whether the anomalies were asymmetrically
distributed.
The case of another patient with developmental dyslexia on whom anatomical examination was performed
was published by Levine and co-workers 1371. The
patient suffered an intracranial hemorrhage at a young
age, before he learned how to read, and later developed intractable seizures. The child underwent a left
temporal lobectomy that involved the anterior half of
the lobe. He was later noted to be dyslexic. The pathological specimen showed the area of hemorrhage and
scarring in association with a vascular anomaly. A subsequent computed tomographic scan revealed the
presence of calcifications caudal to the area of resection in the temporal lobe.
The authors argued that the dyslexia witnessed in
their patient was the result of the operation, which in
their view had removed the language-dominant regions. They added that the opposite hemisphere did
Galaburda et
al:
Cortical Anomalies in Dyslexia 227
B
A
not compensate after the lobectomy carried out in
childhood, as there was marked asymmetry in favor of
the left side. This could not of course be demonstrated. An alternative explanation would be that the
left temporal speech areas were anomalously formed
during fetal life, and that dyslexia would have been
evident even without temporal lobectomy. First, abnormalities in the formation of the cortex almost invariably accompany intracortical vascular anomalies 12,
32); second, the computed tomographic scan provided
some evidence that the anomaly extended caudally
from the resected tissue and involved the classic temporal language heas; and third, we have seen patients
with an angiomatous anomaly located posteriorly in
the left hemisphere in association with developmental
dyslexia 1171. In other words, this patient was probably
similar to those described here.
The case of a patient with congenital aphasia with
pathological findings was published by Landau and associates C351. This patient had severe oral language
deficits and congenital heart disease in association with
porencephaly that involved both perisylvian regions. It
was argued that these lesions were acquired soon after
birth as a direct consequence of the severe anoxic
heart disease. This interpretation appears less likely in
view of the almost complete absence of elementary
neurological findings. An alternate explanation is that
the anoxic lesions, if they indeed existed, occurred in
previously anomalous perisylvian regions, which were
already relatively nonfunctional; this might account for
the absence of noteworthy neurological sequelae.
Veith and Ziegler 1541 have shown that developmental
brain anomalies are found at very high rates in patients
228 Annals of Neurology
Vol 18 No 2 August 1985
Fig 7. (A)Typical pattern of planurn temporale asymmetry. (B)
Brain showing symmetry of the planum temporale (see text for
explanation). (PT = planum temporale; H = HescbPs gyrus.)
with congenital cardiac anomalies. This may have been
such a patient.
Cerebral Asymmetry
The 4 patients showed alterations in the pattern of
brain asymmetry in the planum temporale and developmental anomalies of the cerebral cortex affecting
preferentially (but not exclusively) the perisylvian regions of the left hemisphere.
It has been shown in several studies on autopsy material that the majority of brains coming from subjects
free of any known neurological disease show asymmetry of the planum temporale in favor of the left side
(Fig 7 ) . This side is larger in roughly two-thirds of
brains; reverse asymmetry is present in about 1096,
whereas brains with symmetrical plana make up about
25% of the total C20, 34, 5 2 , 57, 601. The probability
of finding 4 consecutive brains with symmetrical plana
is close to '/4 to the fourth power, i.e., less than 0.004,
so it is not likely to be a chance occurrence. It probably
cannot be argued, however, that the presence of symmetrical plana is a sufficient condition for dyslexia, as
even by the most liberal estimates the prevalence of
the disability does not approach 25%, the figure for
the proportion of brains with symmetrical plana.
One possibility to consider is that symmetry of the
plana is causally related to dyslexia, but that a proportion of persons with this anatomical situation are able
to compensate. Even if dyslexia were as common as
some of the high estimates, i.e., 10 to 12% of the
population, this would mean that 13 to 15% with symmetrical plana can compensate. It is well known that
dyslexia is at least 2 to 3 times more common in males
than in females 1141. We have no data on the frequency of symmetrical plana in boys and girls. If they
were equally frequent, one could argue that the group
with symmetrical plana who are able to compensate is
composed mainly of girls. This interpretation would
suggest that similar anatomical substrates would have
different functional consequences in males and females. The distribution of planum symmetry may not,
however, be the same in males and females, a possibility that needs further study.
It is, however, important to consider another possibility. Our patients had not only symmetrical plana,
but also cortical anomalies. It is unlikely that cortical
anomalies are present in all brains with symmetrical
plana, as this would lead to the unlikely conclusion that
such anomalies are present in 25% of all brains, a
figure probably far above the correct one (as will be
discussed in the next section). It therefore appears
more likely that most patients have both changes. This
is not to exclude the possibility that a few persons may
lack one or the other; rather we suggest that, on the
whole, the pathogenetic process may be adequate to
produce dyslexia only when the process leads to both
types of change.
Cortical Anomalies
The second finding common to all the dyslexic brains
is the presence of developmental anomalies located
asymmetrically and affecting inferior frontal and
superior temporal regions predominantly on the left.
These anomalies consist mainly of neuronal ectopias in
layer I, often nodular in appearance (brain warts), and
seen in association with dysplasia of the underlying or
adjacent cortex. Frank micropolygyria was seen in 2
patients. The common cause of these anomalies was
suspected 181 and has now been confirmed by the experiments of Dvorak and collaborators 1121. Thus it
appears that in dyslexic brains the micropolygyria, ectopias, brain warts, and dysplasias are all the result of a
common pathogenetic effect, acting perhaps at different levels of severity.
The question can be raised as to whether the finding
of focal dysplasias and layer I ectopias in these dyslexic
brains is a chance occurrence. There have been several
studies reporting the incidence of similar changes in
unselected autopsy brains. It is unlikely that the figure
exceeds 10% in populations without noteworthy
neurological abnormalities, either elementary or behavioral, especially when one considers the specific topography of the lesions in the patients reported here
(see 13, 32, 38, 477). isolated verrucous dysplasia is
frequently seen in routine postmortem examinations.
Jacob 1321found them in 11 of approximately 50 cerebral hemispheres, and they showed a predilection for
the frontal lobes and slightly favored the right hemisphere. The number of dysplasias varied between 1
and 2 per hemisphere; in none of the brains were they
present in the numbers seen in the present dyslexic
brains. Veith and Schwindt 1531 found a much higher
figure (30%) in a population of derelicts, but their
detailed report shows a very high rate of other congenital anomalies in these individuals, and they carefully point out that the rate of anomalies found in these
brains far exceeded that of control populations. We
have carried out studies of cytoarchitectonic asymmetries in the cortical language areas in brains that were
processed in identical fashion to the dyslexic brains,
and only rarely did we encounter ectopias.
Employing an argument similar to that used for the
findings in the planum temporale, it is difficult in the
worst of cases to explain the anomalies in the dyslexic
brains as a chance occurrence. The probability of 4
consecutive cases would be close to 1/10 to the fourth
power, i.e., 1 in 10,000. But if we ask the more reasonable question, what is the probability that both
symmetrical plana and cortical anomalies would be
found in every case, the figure is less than 0.004 x
0.0001, i.e., less than 4 X 10 to the negative seventh
power, so chance appears to be exceedingly unlikely. It
seems reasonable to suggest, therefore, that the presence of anomalous cortex is meaningfully associated
with the manifestations of dyslexia.
The lesions seen in these brains are developmental
anomalies acquired some time before birth, probably
during the middle of gestation, a time that coincides
with peak rates of neuronal migration from the germinal zones to the cerebral cortex. Lesions with a similar histological appearance (though not of similar distribution) have been described in other congenital
disorders in which fetal death occurs shortly after that
period 14, 361. Furthermore, it is possible to produce
analogous anomalies in experimental animals by cresting lesions in the cortex before neuronal migration has
ended Ell, 127. Such experiments produce cortical
dysplasia, brain warts, and even micropolygyria. Abnormal blood vessels are often demonstrated in association with the cytoarchitectonic abnormalities.
The distribution of lesions of a developmental type
was not identical in all our patients. In Patient 1, except for 6 small ectopias, the cortical lesions were restricted to the left hemisphere. The other 3 patients
showed lesions bilaterally, although they were more
frequent on the left. Furthermore, the lesions did not
directly involve the posterior language zones in Patient
4; in the other patients the extent of involvement of
the language areas varied. The lesions, however, predominated on the left, were generally perisylvian, and
Galaburda et al: Cortical Anomalies in Dyslexia
229
in every instance affected portions of the left inferior
frontal and superior temporal gyri. The failure of the
topography to coincide exactly suggests that the lesions
played no’pathogenetic role, but this is highly unlikely
for the reasons already given. One must therefore
question the mechanisms by which the lesions impair
function. This is important not only for theoretical reasons but also because a clearer understanding of their
effect may suggest important methods of treatment.
One possibility is that the lesions lead to cerebral reorganization.
Cerebral Reorganization
Several authors have shown that lesions acquired early
in experimental animals are capable of greatly reorganizing the architecture of the cortex and its connections, even at a considerable distance from the area of
lesion. Goldman-Rakic and co-workers 1221, operating
on fetal monkeys, were able to show that lesions
placed unilaterally in the frontal cortex produced proliferation of visually related cortex in the occipital lobe
of both hemispheres. The implication was that the occipital cortex, as a result of the frontal lesion, underwent a reduced extent of cell death during the postmigrational period. In other observations they noted
the appearance of enhanced contralateral corticothalamic projections from undamaged frontal and parietal lobes [21, 231. These observations are compatible with the notion that lesions occurring at specific
stages of development may affect the architectonic and
connectional organization of areas directly involved by
the lesions and distant areas; they can also affect the
patterns of symmetry and asymmetry in the brain. It is
also possible that the lesions generated during gestation in dyslexic brains may also be capable of these
reorganizing effects. It would be possible to test this
hypothesis in experimental animals in which similar
lesions can be produced artificially or in those that
develop these lesions spontaneously (as will be discussed).
The major effects of disturbed neuronal migration
and assembly in the dyslexic brains may thus be to
produce anomalous patterns of growth and connectivity in the cortex, primarily in the posterior languagerelated regions. Direct lesions in these regions of
course necessarily impair the architecture and connectivity, but lesions farther away can also lead to similar
effects, as seen in the experiments of Goldman-Rakic
and Rakic 1231. Every one of our patients showed lesions in the inferior frontal gyrus, i.e., in areas that are
connectionally related to the temporal and parietal
perisylvian cortices involved in language. Effects at a
distance may therefore result from connectional relationships.
Findings in developmental neurobiological studies
show that the death of young neurons is determined in
230 Annals of Neurology Vol 18 No 2 August 1985
part by the availability of synaptic contacts [6]. We
have seen in all our patients that the planum temporale
is nearly symmetrical on the two sides. An additional
observation is that in these and other patients with
symmetrical plana 120, 57, 601, both plana are relatively large, i.e., they conform in size to the commonly
larger planum (see Fig 7).
It can be argued, therefore, that the bilaterally large
plana reflect increased survival of neurons during corticogenesis. One can also extend the argument to suggest that larger numbers of planum cells survive because their synaptic targets are likewise increased.
Some of these exuberant planum-related synaptic
targets may in fact be the ectopic neurons in the inferior frontal gyrus and the excessive numbers of cells
present in the underlying dysplastic cortex, as well as
connectionally related ectopic cells in other cortical
and in subcortical locations. A logical conclusion of
this argument would claim that the mechanism for
eliminating unwanted cells is at fault in dyslexia. This
mechanism may involve immunological processes, as
will be discussed.
Lesions can thus produce their effects by direct removal of all or part of necessary processing areas or by
the preservation of unwanted neuronal elements. They
may also lead to difficulty through what may be called
“miswiring,” i.e., improper connections. Finally, as
such lesions can have abnormal electrical properties,
they may interfere with normally functioning areas.
The notions of miswiring and interference will require
further study in appropriate animal models. They raise
important possibilities for therapy, which a simple
mechanism of loss of processing would not provide.
One must, however, also raise another possibility.
The lesions we have observed involve disorganization
of cell assemblies or misplacement of cells. We have
not described anomahes of single neurons. Scheibel
[46] showed that in the vicinity of the frontal speech
region there are more higher-order dendrites on the
left side than on the right. It is conceivable that the
same influences that lead to obvious defects of
neuronal migration and assembly also lead to impairment of dendritic development in parts of the
malformed cortex and in connectionally related areas
despite the absence of obvious architectonic anomalies. Further studies aimed at visualizing single neurons
and their components will be needed to investigate
these possibilities. In addition, there are cortical asymmetries in cholineacetyltransferase content in normal
brains ill, and similar methods can be employed to
search for possible histochemical anomalies in dyslexic
brains.
Immune Pathology
Beginning with the assumption that symmetry and developmental lesions are etiologically related to the
Fig 8. Ectopic collection of cells (arrows) in kayer I of the
somatosensory cortex of the autoimmune New Zeakand Black
mouse. (Bar = I00 JL.)
problem of dyslexia, the elucidation of the cause of the
anatomical changes is of primary importance for the
development of preventive and therapeutic measures.
An important clue to research on this subject may
come from the recent findings of Geschwind and Behan {18}. After studying more than 1,000 subjects,
they found a marked difference between strongly lefthanded and right-handed subjects in the frequency of
occurrence of learning disabilities and certain immunerelated illnesses. In 600 left-handed and 900 righthanded subjects with documented handedness scores
and either self-reported or hospital-confirmed medical histories, these authors found that left-handers
and their first- and second-degree relatives had a
significantly elevated incidence of immune diseases,
dyslexia, and stuttering. In a subsequent study C193,
left-handers were found significantly more often
among those with migraine, allergies, dyslexia, attention deficit disorders, skeletal anomalies, and immune
gut and thyroid disorders. More recently, Behan and
Geschwind [unpublished observations} found a high
rate of congenital cardiac anomalies in the families of
dyslexics and a high rate of antibodies against Ro antigen in their mothers. This antibody had been described previously only in patients with congenital
heart block 145, 481. It is noteworthy that in all the
patients reported here in whom the family history of
medical illnesses is known, instances of these types of
associations were found. Patient 1 had a family history
of nonrighthandedness, rheumatoid arthritis, and migraine; Patient 2 had a family history of juvenile
rheumatoid arthritis, thyroid disorder, asthma, food allergies, migraine, and mitral valve prolapse; Patient 3
showed left-handedness and twinning in the family;
and Patient 4 had a family history of left-handedness
and idiopathic thrombocytopenic purpura.
Geschwind and Behan 118) suggested that the same
factors that produced abnormal cortical development
also affected development of the thymus, thus setting
the stage for later immune disease. Because of the
male predominance of left handedness and the even
higher male predominance of childhood learning disorders, they advanced the hypothesis that intrauterine
testosterone played an important role in the cause of
these conditions. In view of their findings in immune
disorders, we decided to examine the brains of New
Galaburda et al: Cortical Anomalies in Dyslexia
231
Zealand Black mice and other mouse strains known to
develop autoimmune diseases [49]. We have found
that these animals exhibit cortical anomalies analogous
to those found in the dyslexic brains, i.e., predominantly unilateral ectopias and dysplasias in layer I of
the cortex (Fig 8). It is also interesting to note that
various behavioral disabilities have been reported in
New Zealand Black mice [27, 40, 517, although additional research will be needed to specify the types and
severity of the deficits and to determine the relationship between the presence of lesions and behavioral
function. It will also be important to ascertain whether
the presence of cortical ectopias and dysplasias in these
animals is associated with major reorganization of the
cortical architecture and connectivity, including reorganization of symmetry and asymmetry, as well as with
cellular, histochemical, and pharmacological alterations. One possible hypothesis, as suggested by Ohno
{41), is that immunological markers are involved in
determining the correct pattern of cell-to-cell contact
during ontogenesis. There may be direct immunologically mediated injury to the elements involved in
neuronal migration. Finally, as suggested above, immune mechanisms may be involved in the elimination
of unwanted elements. It is thus possible that immune
disturbances are directly involved in the production of
malformations of the cortex. In addition, the male predominance of the learning disorder suggests that hormonal effects in utero may enhance the immune
anomalies, whereas others may diminish them.
Supported in part by NIH grants 14018 and 0721 1, and by grants
from the Beth Israel Hospital, the Wm. Underwood Co., the Orton
Dyslexia Society, the Powder River Company, and the Essel Foundation. The Yakovlev Collection is supported by NIH 1-NS-4 2303.
The authors thank Mr Antis Zalkalns for valuable technical support
in the preparation of the human histological sections and Dr Deborah L. Levy for help with the interpretation of the cognitive tests.
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