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Keywords:

  • Epilepsy;
  • Neurocutaneous Syndromes;
  • Tuberous sclerosis;
  • Sturge-Weber syndrome;
  • Neurofibromatosis;
  • Pigmentation disorders;
  • Proteus syndrome

Abstract

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

Summary:  Epilepsy may be seen as a feature of many of the neurocutaneous syndromes. The challenge lies within the diagnosis of the specific disorder and ultimately control of the epilepsy. Tuberous sclerosis is the most common of the disorders with a frequency of 4.9/100,000. An autosomal-dominant condition, diagnostic features may be unclear under 2 years of age. Population studies suggest a prevalence of epilepsy of 78%, the majority presenting under the age of 12 months, with a high association between the occurrence of seizures and the presence of learning disability. Although an apparent multifocal disease, surgery may have a role to play where seizures are demonstrated to probably arise from a single tuber. Other less common neurocutaneous syndromes also have a high prevalence of epilepsy in association with cerebral malformations; unilateral or lobar malformations should be referred early for surgical consideration. Neurofibromatosis is the second most common of the disorders but the prevalence of epilepsy in this population is relatively low; in addition, a greater proportion may be easier to treat with medication.

The neurocutaneous syndromes are a group of disorders where characteristic skin lesions are seen in association with abnormalities of the central nervous system, and by consequence are at risk of presenting with epilepsy. Although the features of some disorders have included abnormalities of the cerebrum within diagnostic criteria, advances in imaging and genetics have further delineated some of the rarer forms and outlined associations with malformations of cerebral development. This has major implications for management as it is apparent that many, if drug resistant epilepsy is a feature, may be suitable for resective surgery. Although in some diagnostic criteria and/or genetics are clear, in others they may be more subtle and may present issues for diagnosis within the epilepsy clinic. Such diagnoses are important to guide prognosis and counseling for the individual, as well as determine possible merits of surgical referral.

TUBEROUS SCLEROSIS

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

Tuberous sclerosis (TS) is the most common of the neurocutaneous syndromes occurring in a frequency of 4.9/100,000. First described by Bourneville in 1880 as “tuberous sclerosis of the cerebral convolutions,” it was the triad of seizures, learning difficulty, and adenoma sebaceum (now facial angiomatosis) that became almost synonymous with the condition. It is now well established that individuals may have multisystem involvement and clinical diagnostic criteria have evolved (1) (Table 1). It is an autosomal condition with variable expression and high sporadic mutation rate (estimated at 66%). Recurrence in siblings of individuals with unaffected parents is rare. Two loci have been documented where mutations lead to the clinical phenotype; TSC1 located at 9q34 that codes for the protein hamartin, and TSC2 located at 16p13.3 responsible for the protein tuberin. The two proteins appear to function in the same complex, sharing a common biochemical pathway involved in cell differentiation and proliferation, so that mutation in either gene will lead to the clinical phenotype although differences are seen (2).

Table 1. Diagnostic criteria and features of tuberous sclerosis
Major featuresMinor features
  1. Diagnostic criteria:

  2. (a) Definite TS: −2 major or 1 major +2 minor.

  3. (b) Probable TS: −1 major +1 minor.

  4. (c) Possible TS: −1 major or 2 minor.

Facial angiofibromasDental pitting
Ungual/periungual fibromasHamartomatous rectal polyps
>3 hypopig maculesBone cysts
Shagreen patchWM radial migration lines
Retinal hamartomasGingival fibromas
Cortical tuberNonrenal hematoma
Subependymal noduleRetinal achromic patch
Giant cell astrocytomaConfetti skin lesions
Cardiac rhabdomyomasMultiple renal cysts
Lymphangiomatosis/renal angiomyolipoma 

Diagnostic issues

There appears to be an equal incidence of familial occurrence of TSC1 and TSC2 but mutations of TSC2 are more common amongst sporadic cases. Sporadic TSC2 mutations appear to lead to a more severe clinical phenotype, with an earlier presentation with seizures and higher frequency of infantile spasms, incidence of seizures and mental retardation, more subependymal nodules/cortical tubers, more severe renal involvement, retinal hamartomas, and facial angiofibromata (3,4). Although diagnostic criteria are obviously useful, 7% with either the TSC1 or TSC2 mutation do not meet them (and therefore the clinical phenotype appears wider than originally thought) and 15% meet the criteria but have no mutation. This is irrespective of the fact that the clinical diagnosis can be extremely difficult in the very young (particularly under the age of 2 years) as the cutaneous and visceral lesions are unapparent (5).

With regard to the neurological manifestations, cortical tubers and subependymal nodules are the major features seen on neuroimaging (Fig. 1). Such features may not be apparent on early imaging and tubers may “emerge” (i.e., become visible) with time. However, certain sequences for magnetic resonance imaging (MRI) such as fluid-attenuated inversion recovery (FLAIR) may be more useful for visualizing the abnormalities. Computed tomography (CT) scan must also not be forgotten for visualizing calcification. Subependymal giant cell astrocytomas may arise from subependymal nodules located near the Foramen of Munro in 6–15% (2), and although only locally invasive require watching in view of the risk of obstructive hydrocephalus.

image

Figure 1. CT scan (A) and T2 MRI (B) of a child with tuberous sclerosis; CT scan shows calcification of the right frontal tuber. MRI shows evidence of the tuber as well as periventricular nodules.

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Seizures in tuberous sclerosis

Epilepsy occurs in a high number of individuals but is not inevitable. Population-based studies suggest occurrence in 78% (6), which is lower than studies based in neurological clinics (96%) (5). The majority start under the age of 12 months (70%) with lesser occurrence with age: 16%, 1–4 years; 9%, 5–15 years; and only 4% presenting for the first time with seizures over the age of 16 years (6). Seizures in the context of tuberous sclerosis (TS) appear difficult to control; in one study following a 2-year follow-up, 46% were described as “good” control (seizure free for at least a year) and 25% as “poor” (daily or weekly seizures) (6). Sparagana et al. reviewed the rate of possible remission in 106 children with epilepsy in the context of tuberous sclerosis; 15 (14.2%) had entered a remission but this was unsustained in 11 giving an absolute relapse rate of 26.7% (7). However, many of these reports are dated prior to the use of the newer anticonvulsants.

The prevalence of learning disability ranges between 38% and 53% in population-based studies (6,8). The presence of learning disorder correlates with the presence of seizures, age at first seizure, type of seizure at onset (infantile spasms), and outcome for seizure control (6,9). Of note individuals may have seizures without learning difficulty, although IQ in individuals with TS is lower than unaffected siblings (9) and all individuals with learning difficulty have a history of seizures (6). There is now evidence also that learning disorder correlates with tuber load, even when controlled for the presence of infantile spasms (10).

Autistic spectrum disorders (ASDs) have a high representation amongst those with tuberous sclerosis, and is seen in 43–86% in epidemiological studies. Review of clinical and investigative findings in a group of 53 consecutive referrals with clinical diagnostic criteria for tuberous sclerosis complex (TSC) by Bolton and colleagues showed 19 having ASD (11). This was seen to be associated with the presence of tubers in the temporal lobe, temporal lobe epileptiform activity on electroencephalogram (EEG), as well as early onset seizures (<3 years) and a history of infantile spasms. ASD has been demonstrated to be associated with lesions in the temporal lobe with early onset epilepsy outside the context of tuberous sclerosis (12,13); so whether the findings of Bolton and colleagues are specifically related to this condition remains to be examined.

Treatment of seizures

Vigabatrin can be particularly useful in the treatment of seizures in association with tuberous sclerosis, particularly infantile spasms with a response rate of 95% compared to 54% of children with a non-TS etiology (14,15). In older children and adults there has been the concern about peripheral visual field defects with persistent use of vigabatrin. However, the risk of this has to be weighed against the risk of continuing spasms in the light of cognitive data, and recent evidence that the occurrence of such a side effect may be related to duration of treatment and cumulative dose (16). Other medical treatments have not been systematically tried; there is preliminary pilot data that suggest topiramate may be an useful agent where other antiepilepsy medications (AEDs) have failed (17).

The role of surgery

Although epilepsy associated with tuberous sclerosis may be presumed to be a multifocal disease with multiple structural abnormalities seen on MRI, it has become evident that surgery may benefit selected individuals with drug-resistant epilepsy. Resective surgery may be considered particularly where seizures are seen to be stereotyped and likely to arise from a single tuber. Several series have shown good outcome in such selected patients (18–22) with outcome at 1 month to 47 years of 22–69% seizure free. The challenge, however, in many is to determine the responsible tuber. Neuroimaging in the form of MRI will determine the location of tubers; optimized imaging may be required to do this, for example, the use of FLAIR sequences. CT may also reveal calcification; there is a suggestion that this may be associated with epileptogenicity (22). One study has suggested the use of diffusion-weighted imaging to determine the possible epileptogenic tuber, but this requires further evaluation (23).

Functional imaging may also help. Ictal single-photon emission CT has been shown to aid the detection of the responsible tuber with hyperperfusion of the relevant area; however, hyperperfusion directly over the area appears unlikely but more of a pattern anterior to the tuber (20). Spatial resolution may therefore preclude exact localization and a requirement for invasive EEG monitoring. The latter may also be required to determine proximity to functional cortex. Promising work has also been reported with the use of alpha methyl tryptophan positron emission CT, with increased uptake in tubers thought to be epileptogenic as determined by ictal recording (with ultimate removal) (24) or interictal spike activity (25). It is apparent, however, that as with all children undergoing presurgical evaluation, multimodality investigation is optimal (26). One study has suggested that localized noninvasive studies however, particularly with regard to EEG concordant with localized MRI abnormality, suggest a more favorable outcome with regard to seizures compared where there are multiple nonprominent tubers (27).

One major issue is counseling with regard to long-term seizure outcome following surgery—with multiple tubers present, there remains the possibility of other seizure foci arising in the future. Jarrar et al. reviewed the longer-term outcome of 22 patients undergoing resective surgery for epilepsy associated with tuberous sclerosis (28). Of 22, 13 (59%) were seizure free at 12 months, whereas this had fallen to 9 of 21(42%) at 5 years following surgery. Outcome with regard to behavior and cognition is also less certain with no systematic studies.

STURGE WEBER SYNDROME

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

Sturge Weber syndrome is characterized by the association of a facial capillary angioma involving the periorbital area, the forehead and possibly the scalp, and an underlying, usually unilateral, leptomeningeal angioma. In a proportion of cases there is also a choroidal angioma, and 15% of the leptomeningeal angiomas are bilateral (29). The condition is sporadic with no evidence of genetic determinants. Epilepsy occurs in around 80%, and in the majority (85%) it presents under the age of 2 years, and almost all under 5 years (30). The epilepsy is typically focal, difficult to treat, and with a high incidence of status epilepticus (seen in 50%) (31). It may also be characterized by periods of encephalopathy associated with frequent or prolonged seizures. During these periods increased degree of hemiplegia and cognitive plateau or decline may be noted. Exact mechanisms underlying this are unclear. However, there is evidence to suggest this may be neurovascular, with inadequate increases in cerebral flow in the affected hemisphere and venous hypertension. Low-dose aspirin has been advocated in view of the risk of venous stasis to prevent vascular episodes of hemiparesis (32). Retrospective series have suggested severe learning disability (IQ < 60) in 47%, with a normal range IQ seen in only 25–30% (33).

Although the skin lesion will be apparent, neuroimaging is diagnostic. CT will show abnormality although this will evolve with time, with progressive cortical atrophy and calcification. The extent of the angioma will be more apparent on gadolinium-enhanced MRI (34). Accelerated myelination may also be seen within the affected hemisphere (35). EEG may not be useful as attenuation may be seen over the area of angioma and contralateral spikes more prominently (Fig. 2). Spikes at the time of a seizure are rare, and it is more likely that slowing will be seen in association with ictal onset. Functional imaging is unlikely to lead to more than structural imaging; on single-photon emission CT hypoperfusion will be seen of the affected hemisphere although some studies have suggested initial hyperperfusion over the first year with a subsequent reduction after seizures (36,18). Fluorodeoxyglucose (FDG) positron emission tomography has been reported to show progressive hypometabolism of the affected hemisphere with seizures suggesting progressive dysfunction (37).

image

Figure 2. Gadolimium-enhanced MRI (A), interictal (B) and ictal (C) EEG of a child with Sturge Weber syndrome. The interictal EEG shows attenuation over the left cerebral electrodes while ictal recording shows slow activity over the left centrotemporal electrodes.

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With evidence of improved outcome with better seizure control, the aim is to strive for this. At the outset medical treatment is aimed at the treatment of focal epilepsy, with the use of standard anticonvulsants. However, early resective surgery is advocated. One retrospective series suggested better cognitive outcome in those operated at an earlier age (31). The difficulty is determining the appropriate timing of surgery. Not all children will show marked deterioration in neurological status and a method of early prediction of those who will otherwise have a poor outcome is required in order to select those children who might benefit from early surgery.

EPIDERMAL NEVUS SYNDROME

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

This is another sporadic neurocutaneous disorder that consists of the presence of epidermal nevi in association with anomalies involving the brain and/or the eye and skeletal systems. Epidermal nevi are congenital skin lesions that consist of slightly raised ovoid or linear plaques. The term epidermal nevus is used inclusively of several dermatological conditions including nevus sebaceous of Jadassohn, nevus unius lateris, ichthyosis hystrix, linear epidermal nevus, and inflammatory linear verrucous epidermal nevus (38).

There appears to be a high association with malformations of the cerebral cortex (Fig. 3); in the majority this is unilateral and a proportion suffer hemimegalencephaly (39). The exact prevalence of this association is unknown, however, as many reported cases do not report detailed neuroimaging. There also appears some confusion in the literature as to what is encompassed in the syndrome. However, although abnormalities of cortical development seem to be unilateral there is no relationship between the laterality of the malformation and that of the nevus. Gurecki reported 23 cases; 4 reported and 19 from a literature review (38). In 10 of 19 cases where data were available there was a history of mental retardation and 12 of 22 seizures, 10 of 12 described as “difficult.” All cases described as having neonatal seizures, infantile spasms, and “Lennox–Gastaut” variants had major hemispheric malformations (hemimegalencephaly, hemiatrophy, or gyral abnormalities). Such abnormalities were seen in only 4 of 10 children who did not have seizures. A similar principle to all children who may be surgical candidates should be applied here; early onset epilepsy in association with a unilateral malformation of cortical development should be referred early to an epilepsy surgery program for evaluation and possible resective surgery, with the aim of controlling seizures.

image

Figure 3. MRI scans of children with epidermal nevus syndrome: (A) Left hemimegalancephaly; (B) malformation of cortical development affecting the left posterior quadrant.

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HYPOMELANOSIS OF ITO

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

Ito first described in 1952, a woman with a distinctive pattern of whorls and streaks of pigmentation over the trunk and limbs (40). It has since been noted that the whorls of pigmentation follow Blashko's lines, which is a representation of the orderly migration of mesodermal and ectodermal precursors during embryogenesis. Although thought to be a sporadic condition, abnormalities of the karyotype are found in up to 50%. These abnormalities are predominantly mosaicism leading to the generation of two lineages of cells that produce the pattern of pigmented and hypopigmented skin. X chromosome alterations are not unusual. The occurrence of neurological abnormalities will vary in series between 40% and 70%, depending on whether the series was based on dermatology (40%) or neurology (70%) clinics; the proportion of associated neurological disease of course much higher in the latter. A total of 57–70% are reported as having learning difficulty and 37–53% as having seizures. Of a series of 76 patients referred to a neurology clinic with the disorder 37(49%) had seizures, 40% of which were controlled on medication. A few imaging studies have reported associated abnormality and hemimegalencephaly.

INCONTINENTIA PIGMENTI

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

Children with incontinentia pigmenti show characteristic linear cutaneous lesions that may show an evolution presenting with vesicular rash in the neonatal period, which then later become verrucous and ultimately pigmentary. This is an X-linked condition lethal in males. A locus has been mapped to Xq28. Other features beside the skin lesions include dental and skeletal dysplasia, ocular abnormalities, and nonprogressive central nervous system involvement. Neurological sequelae are seen in 10–30%, including developmental delay, microcephaly, and seizures. Seizures are reported to occur in 13%.

The underlying pathology to cerebral involvement has been unclear. One case is reported of a neonate presenting with seizures soon after birth in association with the characteristic vesicular rash and died on day 26; brain CT showed multiple low-density areas (41). Furthermore, a neonate has been reported who underwent serial MRIs that demonstrated evolution of acute microvascular hemorrhagic infarcts in the periventricular white matter, suggesting that evolution of brain lesions may follow the evolution of the skin lesions (42). Another study reported abnormalities on MRI only when neurological sequelae were seen (43). These included signal abnormalities as well as focal atrophy of the cerebrum, cerebellum, and corpus callosum.

NEUROFIBROMATOSIS TYPE I

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

Neurofibromatosis type I (NF1) the second most common neurocutaneous syndrome behind tuberous sclerosis affecting 1 in 3,000 individuals (44). However, although children with NF1 frequently are found to have specific learning difficulty, attention deficit disorder and abnormalities on MRI, the prevalence of epilepsy amongst this population is relatively low (45,46).

First described by Von Recklinhausen in 1882, it is characterized by café au lait spots, multiple neurofibromas, and Lisch nodules of the iris (47). It is an autosomal-dominant condition with a locus mapped to 17q11.2 (48). The gene is a member of the tumor suppressor gene family coding for the protein neurofibromin. NF1 inactivation in Schwann cells and astrocytes contributes to tumor formation in the peripheral and central nervous system.

Abnormalities are seen on MRI relatively frequently including megalencephaly, anomalies of the corpus callosum, and most frequently, areas of hyperintensity on T2-weighted images termed unidentified bright objects (UBOs). These are seen in about 64% individuals, located in the thalamus, brainstem, cerebellum, and basal ganglia (49). One study recently examined the relationship between the presence of UBOs and cognitive function (50). Learning problems occur in about 30% of individuals with NF1. The presence of UBOs in childhood appeared to be the best predictor of cognitive function in adulthood; however, their exact relevance is not understood. Malformations of cerebral development are not seen as frequently as in other neurocutaneous syndromes.

The prevalence of epilepsy has been quoted to range between 3% and 12%. Kulkantrakorn and Geller retrospectively identified 21 patients with active epilepsy from 499 patients with NF1 presenting to a clinic over a 7-year period and therefore determined a prevalence of 4.2%. Neuroimaging was available in 20 patients and abnormalities probably not relevant to the epilepsy seen in 10; 5 with UBOs (with which there was no relationship to EEG abnormalities) and 5 structural lesions including optic hypothalamic glioma, a frontal mass, encephalomalacia, hydrocephalus, encephalocele, and associated sphenoid wing hypoplasia. Vivarelli and colleagues reviewed 198 patients and found 14 (7%) to have epilepsy. Of the 14, 9 showed abnormalities on imaging thought to be relevant to the epilepsy; five had tumors, three cortical malformations, and one hippocampal sclerosis (45). However, alongside the relatively low occurrence of epilepsy, when it does occur it appears relatively easy to control, also in contrast to other neurocutaneous disorders. Kulkantrakorn and Geller found 6 of 21 patients to be in remission on or off medication, with 5 only being treated after one seizure, and 7 off medication (46). Vivarelli and colleagues found drug resistance in only 4 of 14 (29%), 3 of which had cortical malformations (45).

PROTEUS SYNDROME

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

This condition has previously probably been confused with other neurocutaneous syndromes, in particular a link to neurofibromatosis that had been misinterpreted and some reports of the literature of apparent epidermal nevus may in fact now be considered as proteus syndrome. Originally described by Cohen and Hadyn in 1979, Weidemann coined the term in 1983 after the Greek god meaning “change at will.” The condition is characterized by asymmetrical overgrowth of the trunk, extremities or digits, bony exostoses, tissue hamartomatous, linear epidermal nevi, and gyriform hyperplasia of the soles. The genetics are not fully elucidated. Links to chromosomes 16 and 1 have been postulated (51), whereas 20% of proteus and 50% of a proteus-like syndrome have been found to have germline PTEN tumor suppressor gene mutations on 10q23.3. Of relevance with regard to epilepsy is that despite the isolated case reports, there is a relatively high occurrence of proteus in reports of children with hemimegalencephaly (52,53). In one series, 8 of 41 children with hemimegalencephaly had an associated diagnosis of proteus syndrome (54). Certainly, such children with difficult epilepsy are suitable candidates for consideration for hemispherectomy.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES

Children presenting with epilepsy as part of a neurocutaneous syndrome can provide a challenge in management, both with regard to diagnosis of the syndrome as well as treatment of the epilepsy and associated morbidity. Many have a high association with difficult epilepsy, often the result of associated malformations of cerebral development. When such malformations are unilateral, then early consideration to surgery should be given. In tuberous sclerosis, surgery may still have a role where seizures are seen to arise from a predominant tuber, although long-term prognosis with regard to seizure control may be less certain.

REFERENCES

  1. Top of page
  2. Abstract
  3. TUBEROUS SCLEROSIS
  4. STURGE WEBER SYNDROME
  5. EPIDERMAL NEVUS SYNDROME
  6. HYPOMELANOSIS OF ITO
  7. INCONTINENTIA PIGMENTI
  8. NEUROFIBROMATOSIS TYPE I
  9. PROTEUS SYNDROME
  10. CONCLUSIONS
  11. REFERENCES
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