Epilepsy & Behavior 7 (2005) 133–142

www.elsevier.com/locate/yebeh

Review

Neurocutaneous syndromes: Behavioral features

Charles M. Zaroff *, Keren Isaacs
Comprehensive Epilepsy Center, New York University, 403 East 34th Street, New York, NY 10016, USA

Received 1 May 2005; accepted 5 May 2005

Available online 29 June 2005

Abstract

Neurocutaneous syndromes are disorders charactertized by a neurological abnormality and cutaneous manifestations. Three of
the more common neurocutaneous syndromes are Sturge–Weber syndrome, tuberous sclerosis, and neurofibromatosis. This review
focuses on the cognitive and behavioral features of these syndromes.
Ó 2005 Elsevier Inc. All rights reserved.

Keywords: Neurocutaneous; Tuberous sclerosis; Sturge–Weber; Neurofibromatosis; Epilepsy; Cognitive; Autism

1. Introduction patient with bilateral facial nevus and unilateral buph-

Neurocutaneous syndromes, or phakomatoses, were
first discussed as a clinical entity by the ophthalmologist
Van der Hoeve in 1932. Van der Hoeve included neuro-
fibromatosis, tuberous sclerosis, Sturge–Weber syn-
drome, and von Hippel–Landau syndrome. Currently,
20 to 30 disorders are grouped under the neurocutane-
ous rubric. The disorders typically consist of abnormal-
ities of the brain and skin, and may also involve the
peripheral nervous system and other organs. This review
focuses on the behavioral features of three of the more
common syndromes: Sturge–Weber syndrome, in which
a cutaneous vascular anomaly is associated with central
nervous system dysfunction, and tuberous sclerosis and
neurofibromatosis, which share hamartomatous forma-
tions as a disease mechanism.
2. Sturge–Weber syndrome
Schirmer probably provided the first report of
Sturge–Weber syndrome in 1860 when he described a
*
Corresponding author. Fax: +1 212 263 8342.
E-mail address: charles.zaroff@med.nyu.edu (C.M. Zaroff).
thalmos [1]. In 1879 Weber presented another case of
a 6-year-old girl with bilateral facial nevus. Prevalence
is currently estimated at one per 50,000 live births [2],
although identification of milder forms of the disease
will likely increase prevalence estimates. Males and fe-
males are equally affected. Familial cases are rare, and
the lack of clinical similarity in monozygotic twins has
pointed to somatic mutation as a possible means of dis-
ease transmission.
The vast majority of those with Sturge–Weber syn-
drome present with a cutaneous vascular abnormality
at birth, typically affecting the upper part of the face
(although most children with a facial cutaneous vascular
malformation do not have the disorder). The cutaneous
vascular malformation typically affects the face in a
manner consistent with the ophthalmic division of the
trigeminal nerve. The proximity of the portions of the
ectoderm destined to form the facial skin and the pari-
eto-occipital area of the brain has been postulated as
cause for the combination of the facial nevus and lepto-
meningeal angiomatosis [3,4].
The main cerebral finding in Sturge–Weber syndrome
is leptomeningeal angiomatosis, which can be diffuse
and bilateral but most often affects occipital and poster-
ior parietal lobes unilaterally [5]. Bilateral intracranial

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doi:10.1016/j.yebeh.2005.05.012
134 C.M. Zaroff, K. Isaacs / Epilepsy & Behavior 7 (2005) 133–142
involvement, which is uncommon, is associated with
poorer clinical outcome [6,7]. Calcifications in meninge-
al arteries and in cortical and subcortical veins underly-
ing the leptomeningeal angiomatosis are often
associated with cortical atrophy and severe hypometab-
olism [8]. In infants, accelerated myelination in tissue
underlying the leptomeningioma has been reported [8].
The etiology of the leptomeningeal angiomatosis is
unknown. It has been theorized that superficial cortical
veins fail to develop appropriately or thrombosis of such
veins early in development causes a redirection of blood
to the developing leptomeninges and into the deep ve-
nous system [9]. Progressive venous stasis and vessel
dilation due to insufficient drainage then lead to chronic
hypoxia.
Partial seizures, which may occur in up to 90% of
those with the disorder in early childhood, typically oc-
cur contralateral to the neurocutanous sequelae,
although infantile spasms are also observed. A general
pattern of worsening seizures with age is common, at
times necessitating surgical intervention. Headache and
transient ischemic phenomena such as hemiparesis are
also commonly reported. When present, hemiparesis
and hemianopia occur contralateral to the brain abnor-
mality. Hemiparesis may or may not be directly associ-
ated with seizures, as strokelike episodes can precede
seizure onset and hemiparesis can occur in the absence
of epileptiform activity on electroencephalography [10].
Few large studies of cognition and/or behavior in
Sturge–Weber syndrome exist. Mental retardation rates
of 50 to 60% have been reported [7,11]. In a sample of
40, 60% were mentally retarded and nearly one-third of
the sample fell in the severely mentally retarded range
[7]. Even in those without frank cognitive impairment,
intellectual skills are often lower than expected. Chapies-
ki and colleagues noted a mean intelligence quotient (IQ)
of approximately 75 and a range from 42 to 127 in 32
individuals for whom IQ scores were available [12]. In
a study of 15 children, all of whom had seizure onset in
the first year of life, none of the 6 individuals with normal
intelligence had an IQ score greater than 100 [13].
No prospective studies of development in Sturge–
Weber syndrome have been conducted. Studies of
development and cognition often investigate the role
of epilepsy factors. The presence of a seizure disorder
is associated with poorer clinical outcome [12]. Howev-
er, the correlation between age at seizure onset and
intellectual functioning is less clear in this population
than in others. Kramer and colleagues did not find a
correlation between cognitive level at follow-up and
the age at seizure onset, presence of ongoing seizures,
or degree of hemiparesis, although a connection between
seizure intensity and cognitive outcome was noted [13].
A study of families identified through the Sturge–Weber
Foundation used questionnaires and available medical
records [14]. All subjects without seizures had normal
intelligence, and 85% with seizure onset at 4 years of
age and older had normal intelligence. However,
whereas 25% of those with seizure onset before age 1
had normal intelligence, none of those with onset be-
tween 1 year and 3 years 11 months had normal intelli-
gence (although the latter group tended to do better
academically than the group with onset before age 1).
Thus, it is possible that the combination of vascular
and electrophysiological abnormalities may provide a
more detrimental impact on development at a later
age, in comparison with children with a more selective
electrophysiological deficit earlier in life.
Hemispherectomy is a common surgical approach in
individuals with Sturge–Weber syndrome and medically
refractory epilepsy, particularly in children. Reviews of
the literature have noted an overall 80% rate of seizure
freedom following hemispherectomy [15]. The effect on
cognitive and behavioral functioning has rarely been
studied in a systematic fashion. Kossoff and colleagues
used mailings to examine the effects of hemispherectomy
in a sample of 32 individuals with seizure onset before 1
year, the majority of whom had frequent seizures and
hemiparesis [15]. Surgery was performed at a mean age
of 2 years 7 months. Postoperatively, 2 patients were felt
to be normal cognitively, whereas 10 were noted to have
only circumscribed learning difficulties. Fourteen were
rated as ‘‘moderately disabled’’ and 6 were rated as ‘‘se-
verely disabled.’’ The percentage of children with no or
mild learning disability did not differ between those
operated before or after 1 year of age. However, inter-
pretation of the statistical significance of such results
may have been limited by sample size. The mean age
at surgery was just after 2 years of age for the group with
at most mild disability, compared with just after 3 years
of age for those with moderate to severe disability. Erba
and Cavazzuti noted a connection between later age at
surgery and mental retardation [16].
One area of concern in Sturge–Weber syndrome is
developmental deterioration. Ito et al. reported a pro-
gressive neurological syndrome that in at least one case
was not resolved with epilepsy surgery [17]. In some
individuals, an abrupt deterioration is temporally corre-
lated with worsening of seizures and EEG abnormalities
[18,19]. However, it is believed that venous occlusions
and hypoxia may be responsible for neurological deteri-
oration outside of overt seizure activity. Vascular and
electrophysiological factors may combine to cause great-
er damage then when either factor is operating indepen-
dently. Theoretically, a lack of increase in blood flow
during seizures would compromise an already ischemic
cortex. Additionally, the underlying brain abnormality
also plays a role in development. Mental retardation
has been correlated with the extent of unilateral calcifi-
cation and atrophy, and bilateral leptomeningeal angio-
matosis is associated with more seizures and focal
deficits [6,7].
 C.M. Zaroff, K. Isaacs / Epilepsy & Behavior 7 (2005) 133–142
Functional neuroimaging has provided information
about the relative contributions of structural and func-
tional abnormalities in Sturge–Weber syndrome. Lee
and colleagues studied a group of individuals with
Sturge–Weber syndrome with mostly left-sided cerebral
involvement using 2-[18F]fluorodeoxyglucose (FDG)
PET scan imaging [20]. Subjects with a higher IQ had
a larger area of severe cortical hypometabolism and a
greater degree of asymmetry than those with bilateral
EEG involvement. These results suggest that severely
hypometabolic cortex results in less functional impair-
ment in the remainder of the brain, and that functional
reorganization occurs more readily when cortex is
severely rather than mildly damaged. However, those
with higher intellectual scores also had seizures for a
shorter period.
Psychiatric symptoms have been reported in Sturge–
Weber syndrome, beginning with Falconer and
RushworthÕs mention of irritability [21]. On standard-
ized parent and teacher reports, significantly more social
problems have been noted in children and adolescents
with Sturge–Weber syndrome than in their unaffected
siblings, findings predicted by the presence of a seizure
disorder and hemiparesis [12]. Teachers, but not parents,
reported significantly higher rates of noncompliance
associated with inattentive, hyperactive, and opposition-
al behaviors, also predicted by the presence of a seizure
disorder. In one study, 85% of subjects with mental
retardation exhibited emotional or behavioral problems,
with the most commonly reported symptoms being
physical aggression directed at others and self-abuse,
and depression less common [6]. In contrast, half of
the 12 subjects with normal intelligence reported depres-
sion. Depression and paranoia have been reported in a
series of three subjects [22].
3. Tuberous sclerosis
First named by Bourneville for the resemblance of the
cortical brain lesions to potato tubers [23], tuberous scle-
rosis is an autosomal, dominantly inherited multisystem
disorder in which two-thirds of cases are due to sponta-
neous mutation. Genetic mutations in TSC1 (on chro-
mosome 9q34) and TSC2 (on chromosome 16p13.3)
lead to abnormalities in cell proliferation, differentia-
tion, and migration.
The prevalence of tuberous sclerosis is estimated at
one in 6000 to 9000 [24,25], although as less severely
affected individuals with the disease are discovered, this
number may increase. Structural abnormalities may in-
clude cortical tubers, cortical dysplasia, subcortical het-
erotopias, white matter abnormalities, subependymal
nodules, and subependymal giant cell astrocytomas.
Epilepsy is the most common presenting symptom in
tuberous sclerosis, with estimates as high as 80 to 90%.
135
Seizures typically develop in childhood, many in the first
year of life, manifesting as infantile spasms in one-third
of individuals.
Developmental disability was once considered a core
triad symptom. However, lack of adequate assessment
techniques and sampling bias likely confounded the
external validity of earlier studies. Interestingly, one ear-
lier study actually found a much lower rate of develop-
mental disability than had been previously reported
when subjects were those from a nonneurological sam-
ple [26]. To date, the most comprehensive measure of
abilities undertaken used psychometric assessment in a
sample of 108 individuals and their nonaffected siblings
[27]. Approximately 55% of individuals scored within
the normal range and 44% had an IQ below 70. About
31% of the sample obtained a developmental quotient
below 21, suggesting a bimodal distribution of abilities.
Even in those with normal intellectual skills, scores were
skewed toward the lower end of the average range and
were significantly lower than those of unaffected
siblings.
Cognitive and behavior deficits are common in tuber-
ous sclerosis regardless of developmental level. Problems
in attention and executive functioning predominate. In a
study of 20 children with normal or near-normal intelli-
gence and 20 unaffected siblings using standardized
tests, 50% met ICD-10 criteria for a hyperkinetic syn-
drome [28]. Even those not meeting diagnostic criteria
performed poorly on attention measures, particularly
in the area of sustained attention.
In studies examining individuals with tuberous scle-
rosis and normal intelligence, dyspraxia, speech delay,
visuospatial disturbance, memory impairment, and dys-
calculia have been reported [29]. In comparing individu-
als with tuberous sclerosis with a normal control group,
group means on cognitive testing were similar across
tasks, although five of seven individuals with tuberous
sclerosis scored in the range denoted to reflect impair-
ment, whereas none of the control group did [30]. Indi-
viduals with tuberous sclerosis performed in the
impaired range most often on tests assessing executive
functioning skills.
Humphrey and colleagues conducted a longitudinal
study of development in tuberous sclerosis [31]. They as-
sessed children between the ages of 11 and 37 months at
6-month intervals. All but one subject had a diagnosis
of epilepsy and/or an abnormal EEG. Age at onset of epi-
lepsy ranged from 1 to 21 months, with a mean onset age
of 4 months. Seven of the children had infantile spasms at
onset. While raw scores increased over time, representing
absolute development, the group declined relative to age-
appropriate normative data. The average composite score
for the group as a whole fell in the mentally retarded range
of functioning at all intervals. There was a decline, albeit
modest, in developmental quotient over time. At 12
months, an 5-month lag in development was noted com-
136 C.M. Zaroff, K. Isaacs / Epilepsy & Behavior 7 (2005) 133–142
pared with normative means, which increased to 13
months at 36 months of age. No particular area of exam-
ination from among language (receptive/expressive), mo-
tor (gross/fine), or visual reception function gained faster
than others. The only child in the average range of intelli-
gence for more than 6 months did not have seizures and
had a normal EEG. Notably, the developmental quo-
tients of those with infantile spasms were similar to those
with partial seizures. Also of note, two children had a de-
cline of more than 20 points in developmental quotient
following a worsening/onset of seizures. The one child
with an increase of 20 points or more exhibited this after
a period of seizure control.
Epilepsy is a risk factor for cognitive impairment in
tuberous sclerosis [32,33]. However, those without cog-
nitive impairment may vary widely in the severity and
frequency of seizures. Early onset of seizures, in partic-
ular infantile spasms, is associated with poor develop-
mental outcome [34–36]. Recently, a significant
relationship between infantile spasms and low IQ was
observed, even after controlling for tuber count [37].
Reduction of infantile spasms with vigabatrin has been
shown to improve development [38], whereas a lack of
seizure control is associated with a lack of developmen-
tal progression [39].
Surgery for medically refractory epilepsy in tuberous
sclerosis is increasingly recognized as a viable treatment
option. A review of 12 studies from 1991 to 2004 [40]
noted that, more than 50% of the subjects in each series
experienced greater than 50% reduction in seizure fre-
quency, and even higher rates of seizure freedom were
noted in specific series [41–44]. In individuals without
developmental delay, positive postoperative outcomes
occur on a long-term basis [45]. While most studies re-
port some improvement in outcome in at least a sub-
group of patients, the majority of studies lack
standardized assessment pre- and postoperatively.
Cognitive status in tuberous sclerosis has also been cor-
related with tuber number, size, and location, designated
tuber burden. Meta-analysis of five studies [46] correlated
cognitive status with median tuber number, although the
actual number varied across studies. Others have reported
similar results [29,47]. Jambaque and colleagues noted a
relationship between tuber number and number of lobes
involved and IQ [29]. However, there are also reports of
individuals with normal IQ and multiple tubers, so the
relationship is far from perfect. Additionally, tubers or
surrounding structural/functional abnormalities may be
responsible for epilepsy, complicating the relationship,
although an independent relationship between tuber
count and cognitive outcome has been reported, even
after controlling for epilepsy variables [37].
Genetic contributions to developmental outcome in
tuberous sclerosis are now recognized. There is an over-
representation of TSC2 in sporadic cases and lower
rates of mental retardation in TSC1 cases [48,49].
Higher rates of mental retardation in a sporadic group
versus a group in which the disorder was familial have
also been observed [28]. Dabora and colleagues exam-
ined 224 cases in which 28 were characterized by the
TSC1 mutation and 158 were characterized by the
TSC2 mutation. TSC1 cases had a lower frequency of
seizures [50]. Low IQ (<70 vs P70), a history of autism,
and infantile spasms were significantly more frequent in
those with TSC2 mutation than with TSC1 mutation in
one report [32]. Both a TSC2 mutation and a history of
infantile spasms increased the likelihood of a low IQ.
Less severe clinical involvement has been noted in those
with unidentified mutations [33].
Although rarely noted, medication effects may con-
tribute to the cognitive profile in tuberous sclerosis. In
those with medically refractory epilepsy, polytherapy is
common. Antiepileptic medications can impact process-
ing speed, sustained attention, and specific executive
functioning skills. Additionally, high rates of psychiatric
and behavioral disturbances, described below, may fur-
ther exacerbate preexisting cognitive weakness.
Behavior abnormalities are common in tuberous scle-
rosis, with perhaps the most widely investigated being
autism spectrum disorders. Rutter has postulated that
tuberous sclerosis provides the clearest link of any med-
ical disorder to autism [51]. Rates of prevalence of aut-
ism in tuberous sclerosis vary, due in part to discrepant
diagnostic criteria, assessment techniques, and samples
surveyed. While numbers ranging from 50% [52,53] to
60% [54] likely represent upper estimates when all disor-
ders along the spectrum are considered, there is a clear
need for further research. There is little evidence differ-
entiating autism in tuberous sclerosis from autism with-
out tuberous sclerosis. What is known is that tuberous
sclerosis with autism is not associated with the male pre-
ponderance commonly observed in idiopathic cases.
Additionally, it appears that individuals with tuberous
sclerosis with greater developmental delay are more
likely to have autism.
Both neurological and genetic substrates have been
postulated as responsible for autism in tuberous sclero-
sis. While autism has been noted in individuals with
tuberous sclerosis without mental retardation [52,54],
in general, the greater the degree of neurological impair-
ment, the higher the rate of autism. In one report, all
individuals with autism were mentally retarded [55]. In
another study, all profoundly mentally retarded individ-
uals with tuberous sclerosis were autistic [29]. Lower IQ
scores, either infantile spasms or secondarily generalized
seizures, and both frontal and posterior tubers have
been reported in an autistic group with tuberous sclero-
sis compared with a group without autism [36]. The risk
for autism in tuberous sclerosis is higher in those with
epilepsy than in those without, particularly when sei-
zures arise early in life and infantile spasms are observed
[53,56,57].
 C.M. Zaroff, K. Isaacs / Epilepsy & Behavior 7 (2005) 133–142
Several studies have pointed to temporal lobe pathol-
ogy as a possible mechanism for autism in tuberous scle-
rosis. For instance, in one series temporal lobe tubers
were found in eight of nine patients with an autism spec-
trum disorder, compared with none in nine nonspectrum
subjects [52]. Bolton and colleagues replicated their ear-
lier study and further added temporal lobe electroen-
cephalographic abnormality as a risk factor for autism
[56]. Seri and colleagues also found temporal lobe le-
sions in all subjects with autism and none in those with-
out [58]. Additionally, all autistic subjects had bilateral
lesions. These findings were of interest as the two groups
in the study had nearly an identical total tuber burden.
Evoked response potential (ERP) differences, the focus
of SeriÕs investigation, were also noted. Autistic subjects
with tuberous sclerosis had significantly prolonged-la-
tency and lower-amplitude N1 response than the non-
autistic group, and longer latency and global field power
was observed in those with autism.
Functional neuroimaging using PET reveals de-
creased glucose metabolism in the lateral temporal gyri
bilaterally, increased glucose metabolism in the deep cer-
ebellar nuclei bilaterally, and increased a-[11C]methyl-L-
tryptophan (AMT) in the caudate nuclei bilaterally in
those with tuberous sclerosis and autism [55]. Lateral
temporal hypometabolism and infantile spasms were
correlated with communication disturbances [55]. Glu-
cose hypermetabolism in the deep cerebellar nuclei and
increased AMT uptake in the caudate nuclei were relat-
ed to stereotypical behaviors and impaired social
interaction.
Temporal lobe abnormalities are not noted in all re-
ports concerning autism and tuberous sclerosis. For in-
stance, Walz and colleagues found no relation between
autism and either subcortical or cortical tuber topogra-
phy [59]. In another study, no tubers were found in the
temporal lobes in four individuals with tuberous sclero-
sis and autism [60]. Others have found a cerebellar, not
temporal lobe relation to autism in tuberous sclerosis
[61]; decreased abilities of daily living did not correlate
with total tuber number or number of lobes involved
but, instead, with the cerebellar tubers.
These findings, as a whole, indicate that specific vari-
ables that have been the subject of scrutiny require fur-
ther refinement and, in fact, may be too crude [62].
Genetic factors also need to be considered. In a pair
of monozygotic twins with tuberous sclerosis [63] only
one of the pair had a diagnosis of autism. However,
the other twin met autism criteria at 18 months (but
not thereafter) and was noted to have ‘‘social and com-
munication difficulties.’’ A larger number of tubers were
found in the twin without autism, who exhibited a high-
er developmental level, although the authors postulate
that the larger size of the tubers in the autistic twin
reflected greater brain involvement. Both twins had an
equal number of temporal lobe tubers. Interestingly,
137
the nonautistic twin suffered from infantile spasms,
whereas the autistic twin did not. Lewis et al. found
more frequent reports of autism in those with TSC2 ver-
sus TSC1 mutations [32].
In addition to autism, other problem behaviors are
common in tuberous sclerosis, including but not limited
to inattention, hyperactivity, anxiety, and depression.
Anxiety disorder was observed in 20 of 36 adults able
to complete a questionnaire, and depression was ob-
served in 7 of 56 [32]. In a comparison of individuals
with fetal alcohol syndrome, Prader–Willi syndrome,
fragile X syndrome, and tuberous sclerosis using stan-
dardized assessment methods [64], the subjects with
tuberous sclerosis had the lowest overall composite
score, reflecting less severe psychopathology. However,
the tuberous sclerosis group was reportedly chosen on
the basis of their ability to complete specific psychomet-
ric tasks, and none was rated as having an autistic disor-
der, suggesting a purposeful sampling bias. Nonetheless,
at least half of the tuberous sclerosis sample was rated as
impulsive, overly attention seeking, overactive, and dis-
tracted. Similar rates were found for the characteristics
of fearfulness and preferring the company of adults or
younger children. Attention-deficit/hyperactivity disor-
der (ADHD) was the most common comorbid diagnosis
(44%), followed by oppositional defiant disorder (25%)
and separation anxiety disorder (19%).
4. Neurofibromatosis
Neurofibromatosis is a disease of the skin, nervous
system, bones, endocrine glands, and at times other or-
gans, consisting of hamartomatous lesions. Hyperpig-
mented macules, freckling, dermal and plexiform
neurofibromas, optic nerve gliomas, Lisch nodules,
and skeletal abnormalities (scoliosis and pseudoarthro-
sis) are the most frequently encountered symptoms
[65]. The term neurofibromatosis (NF) refers to a group
of several disorders sharing autosomal dominant inher-
itance and clinical symptoms. NF-1 and NF-2 are the
most commonly reported, and with a prevalence of
one in 3000, NF-1 is one of the most common neuroge-
netic disorders. Von Recklinghausen, a pathologist in
the 1800s, reported on the skin lesions in neurofibroma-
tosis, believing that these arose from the fibrous tissue
surrounding peripheral nerves [66].
The disease has been localized to a mutation on chro-
mosome 17. Inheritance occurs in an autosomal domi-
nant fashion, although half the cases have no family
history [67]. NF1 has been theorized to serve as a tumor
suppressor gene, given the possibility of both benign and
malignant tumors occurring with the disorder.
In NF-1, the most common tumor is the benign
peripheral nerve sheath tumor (neufibroma), usually
first seen in puberty, which can form on spinal roots
138 C.M. Zaroff, K. Isaacs / Epilepsy & Behavior 7 (2005) 133–142
and cranial nerves. These lesions can be asymptomatic
for periods. However, in up to 13%, a subgroup called
plexiform neurofibroma can undergo transformation
to malignancy (malignant peripheral nerve sheath tu-
mor, MPNST) [68]. MPNSTs occur at a younger age
in those with NF-1 compared with the overall popula-
tion, and are associated with poor survival and poor
response to traditional cancer therapies. Additionally,
15–20% of children with the disorder develop low-grade
astrocytomas, usually involving the optic pathway, that
can result in vision loss or, if invasion of the hypothala-
mus occurs, endocrine dysfunction resulting in preco-
cious puberty [69]. Gliomas, when present, are usually
stable or progress very slowly. This is perhaps the reason
why a 5-year survival rate of 90% and 10-year survival
rate of 82% have been observed [70]. Mortality is asso-
ciated with extraoptic tumor location, symptomatic tu-
mors, and adulthood [70]. Brainstem gliomas are less
malevolent in NF-1 patients than in those without
NF-1 as etiology, although mortality in 5 of 12 adults/
children was observed in one study [71]. By use of mag-
netic resonance angiography, cerebrovascular abnor-
malities were detected in 8 of 316 children, with the
internal carotid artery and middle cerebral artery the
most commonly affected [72]. Macrocephaly, due to in-
creased brain volume [73], occurs in 30–50% of children
and adolescents [74,75]. Treatment of all tumors in NF-
1 is surgical excision or radiation.
The clinical course in NF-1 is variable. Café-au-lait
spots, plexiform neurofibromas, and tibial dysplasias
are usually recognized within the first year of life, while
freckling and optic pathway gliomas often occur be-
tween 3 and 5 years of age. Dermal neurofibromas are
usually first noted in adolescence.
Despite initial reports noting high rates of mental
retardation in NF-1, mean intellectual functioning is
generally reported to be in the average range, with only
a slight downward shift in some studies [76,77]. Rates of
mental retardation, while still higher than those of the
overall population, tend to be in the single digits [74],
although bimodal distribution of IQ scores has been
suggested [78]. While some studies note verbal intellectu-
al strengths relative to nonverbal intellectual strengths
[76,77], others have reported the opposite [79,80] pat-
tern. In a recent study containing a review of the extant
literature, no dominant discrepancy in either direction
was observed [81].
Learning disabilities occur in 30–60% of those with
NF-1 [82]. However, across studies, there is considerable
variability in the diagnostic criteria used to define a
learning disability. Additionally, some reports lack stan-
dardized assessment, while others omit mention of the
methodology employed. One common finding has been
a visual perceptual learning disability subtype not due
to visual acuity difficulties [83]. For instance, in an
NF-1 sample in which some individuals presented with
brain tumors, three subtypes of learning disability were
noted [79]. A primarily visual–perceptual subtype was
most common, occurring in 56%. A mixed type was not-
ed in 30%, compared with a primarily verbal type in
only 4%. In one study that excluded those with develop-
mental disabilities and used a large number of neuropsy-
chological tests, a greater incidence of visual–spatial
impairment was found in comparison to a control group
of unaffected siblings [76].
Although visual–perceptual deficits are commonly
reported in NF-1 [73,74,79,84], their diagnostic signifi-
cance is unclear. Lower reading and math scores in
NF-1 individuals relative to their unaffected siblings,
in addition to visual–perceptual deficits, have been
reported [85]. Similarly, higher rates of verbal learning
disorders (e.g., reading skills) have been observed in
individuals with NF-1, even when compared with a
group of individuals with a learning disability [86]. In
the study by Mazzocco and colleagues, significant corre-
lations between verbal and visual–spatial test scores oc-
curred in the NF-1 group but not the unaffected sibling
controls, supporting the authorsÕ view that such deficits
coexist in the NF population [85]. Brewer et al. used the
WRAT-R and observed poor performance on all three
subtests (word reading, spelling to dictation, and math),
although there was a subset who did poorly only on the
spelling subtest [87]. Further analysis toward a neuro-
psychological profile revealed an intact group, a general-
ly impaired group, and a relatively small group with
circumscribed deficits in visual–spatial/constructional
skills (10%). However, the last group shared deficits in
achievement testing and verbal skills relative to the in-
tact group, again arguing for a more generalized pattern
to the dysfunction.
ADHD behaviors are greater in individuals with NF-1
than in the general population [79,88–90], with an esti-
mated rate of 33% [81]. However, evidence has shown that
inattention and/or hyperactivity is not solely responsible
for the cognitive profile observed. For instance, a combi-
nation of visual–spatial tasks predicted membership in
the NF-1 versus nonaffected sibling control group, even
after covarying DSM-IV ADHD symptom ratings [90].
Speech articulation and motor coordination difficulties
also have been reported [77,91,92].
Developmental studies on NF-1 are lacking, and co-
hort studies produce mixed results. Riccardi found high-
er IQs in NF-1 adults than in NF-1 individuals below
the age of 17 [93]. However, others have found no signif-
icant difference between such groups [94]. Moore and
Slopis found no decline in performance over time in a
subset of their sample who underwent repeat testing in
a cohort study [95]. However, in the cohort aspect, lower
scores were observed in older individuals (ages 4
through 16), and negative correlations with age reached
significance on verbal IQ, academic achievement, mem-
ory, and attention tasks.
 C.M. Zaroff, K. Isaacs / Epilepsy & Behavior 7 (2005) 133–142
Hyman et al. studied cognitive outcome in two
groups at baseline (one between ages 8 and 10, one be-
tween 14 and 16) and again 8 years later [96]. Those with
brain tumors were excluded. Tests of IQ (WISC-R),
memory, attention, and executive functioning were used.
In areas in which significant changes were noted for
both groups (FSIQ, VIQ, and Part A of the Trail Mak-
ing Test), the older group showed greater increases than
the younger group. However, these changes were similar
to those observed in the control group, which numbered
only 11. The authors reference prior reports [97,98] cap-
turing normal IQ scores in younger age groups, and
emphasize the lack of data to support the notion that
average IQ scores in adulthood are indicative of a reso-
lution of childhood cognitive dysfunction.
Unidentified bright objects (UBOs) are areas of T2
hyperintensity that are observed in 64% of those with
NF-1 [99,100]. UBOs are theorized to result from white
matter abnormalities [101]. These signs are most
frequently observed in the optic pathways (66%), brain-
stem (17%), cerebral lobes (7%), basal ganglia (5%),
cerebellum (4%), and spinal cord (1%) [70]. Some
studies find no relationship between cognitive profile
and UBOs. However, accumulating evidence relates
cognitive status to the presence [84], number [102],
and location [89] of these findings. Cross-sectional data
indicate that UBOs disappear over time and are less
common when patients reach their twenties and thirties
[99,103]. In one study, a decrease in the number, size,
and intensity of UBOs on follow-up at 8 years was
found in 88% who initially presented with lesions
[96]. The prevalence of lesions fell with age, from a
mean of 63% at age 12.2 years to 44% at 19.8 years.
Lesions in the basal ganglia decreased in number, size,
and intensity, in contrast to lesions within the cerebral
cortex and deep white matter, which did not disappear.
Despite the decreases noted, the changes were not asso-
ciated with changes in general cognitive functioning or
any specific cognitive abilities. The best predictor of
current cognitive dysfunction at follow-up (15–25 years
of age) was whether patients had UBOs when younger.
The presence of UBOs at follow-up did not adequately
distinguish between patients with higher and lower
cognitive abilities.
Macrocephaly in NF-1 has not been found to corre-
late with neuropsychological status [94]. A relationship
between brain volume and neuropsychological func-
tioning has been noted in NF-1 [104]. Greater corpus
callosum volumes have been detected in those with
NF-1 than in controls, although differences in measure-
ments correlate to the presence or absence of ADHD
only [81].
The NFI gene on chromosome 17q11.2 encodes the
protein neurofibromin, expressed primarily in neurons,
Schwann cells, oligodendrocytes, astrocytes, leukocytes,
and the adrenal medulla. Neuofibromin has a role in
139
Ras GTPase-activating protein activity [105], adenylyl
cyclase modulation [106], and microtubule binding
[107]. Learning deficits in mice carrying a heterozygous
null mutation of the NF1 gene could be ameliorated
by genetic and pharmacological manipulations decreas-
ing Ras function [108], which also reverse increased
GABA-mediated inhibition and deficient long-term
potentiation. These findings implicate excessive Ras
activity as the cause of learning deficits.
Psychopathology, including social difficulties, has
been the focus of some NF-1 reports. Johnson and col-
leagues used teacher and parent versions of the Child
Behavior Checklist in those with NF-1 (n = 43) and
their unaffected siblings (n = 22) who were between 5
and 18 years of age [109]. Significantly more problems
were observed in the NF-1 group on the majority of
scales examined, including those assessing social prob-
lems, anxiety, depression, somatization, aggression,
unusual behaviors, and areas of competence. Church
et al. found that adolescents with NF-1 and learning
disabilities had greater difficulties with friendships than
those without learning difficulties, although the study
was limited by a small sample size [110]. Differences
have been noted in ratings of social skills by teachers
and parents in comparison to unaffected sibling con-
trols. Specifically, nearly 40% of NF-1 children had
scores in the borderline/clinical range [111]. However,
self-ratings were comparable across illness and control
groups. Similar to prior reports [112], the presence of
ADHD, and not IQ or academic achievement score,
proved to be the major risk factor for elevated symp-
tom ratings. It has been reported that social problems
may be in part due to isolation and alienation. For
instance, adults with NF-1 attribute difficulties in form-
ing friendships during school years to skin lesions and
frequent absences from school due to medical reasons
[113].
5. Conclusion
Sturge–Weber syndrome, tuberous sclerosis, and
neurofibromatosis are three of the more common neu-
rocutaneous disorders. All three disorders are defined
by greater than expected rates of mental retardation,
particularly in those with Sturge–Weber syndrome
and tuberous sclerosis. In individuals lacking gross
intellectual deficit, dysfunction in specific aspects of
cognition may occur, ranging from subtle weakness in
a circumscribed cognitive skill to more severe and
diffuse deficits in a range of cognitive abilities. Behav-
ioral disorders are also common. Problems in cognition
and behavior are thought to be due to the underlying
neurological etiology of the disorders, and in tuberous
sclerosis, there is evidence that genotype may contrib-
ute to clinical heterogeneity.
140 C.M. Zaroff, K. Isaacs / Epilepsy & Behavior 7 (2005) 133–142
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