Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery.

PURPOSE: We aimed to assess long-term seizure outcome and risk factors for seizure recurrence in a cohort of patients who have undergone extratemporal resection for management of refractory seizures. METHODS: Eighty-one patients underwent extratemporal resection at Austin Health, Melbourne, Australia (1991-2004). Seizure recurrence was any postoperative disabling seizure (complex partial seizure [CPS] ± secondary generalization). Multivariate Cox proportional hazards regression models examined potential preoperative and perioperative risk factors and the risk associated with early postoperative seizures (≤ 28 days postsurgery). The change between preoperative and postoperative seizure frequency was also measured. KEY FINDINGS: Median follow-up was 10.3 years (range 1-17.7). The probabilities of freedom from disabling seizures (on or off antiepileptic medication) were 40.7% (95% confidence interval [CI] 30-51) at 1 month, 23.5% (95% CI 15-33) at 1 year, and 14.7% (95% CI 8-23) at 5 years postoperative. Reduction of disabling seizures to at least 20% of preoperative frequency was attained by 57% of patients at 5 postoperative years. Of the preoperative/perioperative factors, focal cortical dysplasia (FCD) type 1 (hazard ratio [HR] 1.90, 95% CI 1.08-3.34, p = 0.025) and incomplete resection (HR 1.71, 95% CI 1.06-2.76, p = 0.028) were independent recurrence risks. After surgery, an early postoperative seizure was the only factor associated with higher risk (HR 4.28 [2.42-7.57], p = 0.00). SIGNIFICANCE: Distinction between subtypes of focal cortical dysplasia, which can be made using magnetic resonance imaging (MRI) criteria, may be useful for preoperative prognostication. Early seizures after surgery are not benign and may be markers of factors that contribute to seizure recurrence. Most patients achieve substantial reduction in seizure frequency. Further study of the significance of this reduction in terms of surgical "success" or otherwise is required.

Hippocampal sclerosis and a second focal lesion--how often is it ipsilateral?

PURPOSE: Hippocampal sclerosis (HS) is the most common pathologic finding in intractable temporal lobe epilepsy (TLE). In many patients, HS is accompanied by an extrahippocampal lesion (EHL). We sought to assess the lobar distribution and side of EHLs in relation to HS in a large consecutive series of patients presenting to our epilepsy surgery program. METHODS: The inclusion criterion was the presence of both definite HS and an unequivocal EHL on magnetic resonance imaging (MRI) studies in patients evaluated for potential epilepsy surgery at our tertiary epilepsy center. KEY FINDINGS: Fifty-eight patients were identified over a 7-year period. This represented about one-third of all patients with HS. The mean age was 32 years (SD 18.4), and the mean age of seizure onset 13 years (SD 16.4). Fifty-four percent of the EHLs could be classified as acquired and 36% as developmental. In 98% of patients HS was found on the same side as EHL. SIGNIFICANCE: Our findings support the hypothesis that HS may be a secondary event from seizures generated initially by another focal lesion. However, HS and EHL may also originate from the same insult to the brain.

Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients.

Polymicrogyria is one of the most common malformations of cortical development and is associated with a variety of clinical sequelae including epilepsy, intellectual disability, motor dysfunction and speech disturbance. It has heterogeneous clinical manifestations and imaging patterns, yet large cohort data defining the clinical and imaging spectrum and the relative frequencies of each subtype are lacking. The aims of this study were to determine the types and relative frequencies of different polymicrogyria patterns, define the spectrum of their clinical and imaging features and assess for clinical/imaging correlations. We studied the imaging features of 328 patients referred from six centres, with detailed clinical data available for 183 patients. The ascertainment base was wide, including referral from paediatricians, geneticists and neurologists. The main patterns of polymicrogyria were perisylvian (61%), generalized (13%), frontal (5%) and parasagittal parieto-occipital (3%), and in 11% there was associated periventricular grey matter heterotopia. Each of the above patterns was further divided into subtypes based on distinguishing imaging characteristics. The remaining 7% were comprised of a number of rare patterns, many not described previously. The most common clinical sequelae were epileptic seizures (78%), global developmental delay (70%), spasticity (51%) and microcephaly (50%). Many patients presented with neurological or developmental abnormalities prior to the onset of epilepsy. Patients with more extensive patterns of polymicrogyria presented at an earlier age and with more severe sequelae than those with restricted or unilateral forms. The median age at presentation for the entire cohort was 4 months with 38% presenting in either the antenatal or neonatal periods. There were no significant differences between the prevalence of epilepsy for each polymicrogyria pattern, however patients with generalized and bilateral forms had a lower age at seizure onset. There was significant skewing towards males with a ratio of 3:2. This study expands our understanding of the spectrum of clinical and imaging features of polymicrogyria. Progression from describing imaging patterns to defining anatomoclinical syndromes will improve the accuracy of prognostic counselling and will aid identification of the aetiologies of polymicrogyria, including genetic causes.

Small temporal pole encephaloceles: a treatable cause of "lesion negative" temporal lobe epilepsy.

Epilepsy due to encephaloceles of the temporal pole may be an under recognized, treatable cause of refractory temporal lobe epilepsy (TLE). We describe three adult patients initially labeled "lesion negative" TLE. In all, video­electroencephalography (EEG) revealed ictal theta in the left temporal region and positron emission tomography (PET) showed temporal lobe hypometabolism, but neuropsychology revealed preserved verbal memory. Close inspection of structural magnetic resonance imaging (MRI) suggested subtle abnormalities at the tip of the left temporal lobe. High resolution computed tomography (CT) confirmed bony defects in the inner table of the skull. 3T MRI with fine coronal and sagittal slices indicated cerebrospinal fluid (CSF) and brain tissue protruding into the defects. All proceeded to resection of the temporal tip and became seizure free. Patients with "lesion negative" TLE should have careful review of images covering the temporal pole. If encephalocele is suspected, further imaging with high-resolution CT and MRI can be helpful. Temporal polar resection, sparing mesial structures, appears to be curative.

Does registration of serial MRI improve diagnosis of dementia?

INTRODUCTION: We aimed to assess the value of a second MR scan in the radiological diagnosis of dementia. METHODS: One hundred twenty subjects with clinical follow-up of at least 1 year with two scans were selected from a cognitive disorders clinic. Scans were reviewed as a single first scan (method A), two unregistered scans presented side-by-side (method B) and a registered pair (method C). Scans were presented to two neuroradiologists and a clinician together with approximate scan interval (if applicable) and age. Raters decided on a main and subtype diagnosis. RESULTS: There was no evidence that differences between methods (expressed as relative odds of a correct response) differed between reviewers (p = 0.17 for degenerative condition or not, p = 0.5 for main diagnosis, p = 0.16 for subtype). Accordingly, results were pooled over reviewers. For distinguishing normal/non-progressors from degenerative conditions, the proportions correctly diagnosed were higher with methods B and C than with A (p = 0.001, both tests). The difference between method B and C was not statistically significant (p = 0.18). For main diagnosis, the proportion of correct diagnoses were highest with method C for all three reviewers; however, this was not statistically significant comparing with method A (p = 0.23) or with method B (p = 0.16). For subtype diagnosis, there was some evidence that method C was better than method A (p = 0.01) and B (p = 0.048). CONCLUSIONS: Serial MRI and registration may improve visual diagnosis in dementia.

Accuracy of dementia diagnosis: a direct comparison between radiologists and a computerized method.

There has been recent interest in the application of machine learning techniques to neuroimaging-based diagnosis. These methods promise fully automated, standard PC-based clinical decisions, unbiased by variable radiological expertise. We recently used support vector machines (SVMs) to separate sporadic Alzheimer's disease from normal ageing and from fronto-temporal lobar degeneration (FTLD). In this study, we compare the results to those obtained by radiologists. A binary diagnostic classification was made by six radiologists with different levels of experience on the same scans and information that had been previously analysed with SVM. SVMs correctly classified 95% (sensitivity/specificity: 95/95) of sporadic Alzheimer's disease and controls into their respective groups. Radiologists correctly classified 65-95% (median 89%; sensitivity/specificity: 88/90) of scans. SVM correctly classified another set of sporadic Alzheimer's disease in 93% (sensitivity/specificity: 100/86) of cases, whereas radiologists ranged between 80% and 90% (median 83%; sensitivity/specificity: 80/85). SVMs were better at separating patients with sporadic Alzheimer's disease from those with FTLD (SVM 89%; sensitivity/specificity: 83/95; compared to radiological range from 63% to 83%; median 71%; sensitivity/specificity: 64/76). Radiologists were always accurate when they reported a high degree of diagnostic confidence. The results show that well-trained neuroradiologists classify typical Alzheimer's disease-associated scans comparable to SVMs. However, SVMs require no expert knowledge and trained SVMs can readily be exchanged between centres for use in diagnostic classification. These results are encouraging and indicate a role for computerized diagnostic methods in clinical practice.

The Observer Memory Questionnaire-Parent Form: introducing a new measure of everyday memory for children.

Relatively little research has focused on everyday memory function in childhood, possibly reflecting the limited number of measures available. This study introduces the Observer Memory Questionnaire-Parent Form (OMQ-PF), which assesses parental beliefs about their child's everyday memory. The OMQ-PF and a selection of neuropsychological measures were administered to a cohort of healthy children in Study 1 (n = 376; 5-16 years old) and a temporal lobe epilepsy (TLE) group in Study 2 (n = 44; 6-16 years old). Study 1 found the OMQ-PF had sound internal consistency and was significantly correlated to a learning task. Study 2 found the TLE group was impaired on the OMQ-PF relative to the healthy cohort. Everyday memory ratings were related to a wider range of neuropsychological measures in this group. Findings are encouraging in terms of the properties of the OMQ-PF and suggest further development of the scale is warranted.

Spontaneous intracranial hypotension presenting as a reversible dorsal midbrain syndrome.

A 47-year-old woman with postural headache, episodic stupor, and vertical gaze palsy had brain imaging findings consistent with spontaneous intracranial hypotension (SIH), including severe descent of the mesodiencephalic structures and diffuse pachymeningeal enhancement. The source of the cerebrospinal fluid leakage was a ruptured dorsal perineural cyst. Clinical symptoms improved after a targeted epidural blood patch was performed. Dorsal midbrain syndrome has not been reported previously as a manifestation of SIH. Perhaps distortion of structures in this brain region can occur in SIH as it does in obstructive hydrocephalus.

Assessment of suitability of thrombolysis in middle cerebral artery infarction: a proof of concept study of a stereologically-based technique.

BACKGROUND: The extent of cerebral ischemia, assessed by the Alberta Stroke Program Early CT Score (ASPECTS) method and unaided visual determination of the CT Summit Criterion, correlates with increased risk of intracerebral hemorrhage following rt-PA administration. Concerns about the accuracy of the unaided visual assessment in the estimation of infarct size and the conservative nature of the ASPECTS method led us to develop a new method (MCAGrid) based on stereological grid counting and a digital atlas of the middle cerebral artery (MCA) infarct territory. METHODS: We tested the hypotheses that the stereological method increases the accuracy of infarct estimation and that the number of patients deemed eligible for thrombolysis is greater with this method than with existing methods. Four experienced radiologists with extensive neuroradiological experience examined the CT images of 19 patients with MCA territory stroke and determined patient eligibility for thrombolysis by: unaided visual determination of the CT Summit Criterion, MCAGrid, and the ASPECTS score. The chi(2) test was used to compare the differences in the number of patients deemed 'eligible' for thrombolysis by the 3 imaging methods. Further, the unaided visual assessment and MCAGrid were compared with volumes calculated following manual segmentation of infarct, and the sensitivity, specificity and positive and negative likelihood ratios for these techniques were calculated. RESULTS: In general, MCAGrid was better than unaided visual assessment in the prediction of >1/3 involvement of the MCA territory by infarct. The number of patients considered as 'eligible' for thrombolysis based on imaging criteria was significantly lower when ASPECTS criteria (15/76) were used than when unaided visual determination of the CT Summit Criterion (32/76; p < 0.01) or MCAGrid (59/76; p < 0.001) criteria were used. CONCLUSION: The choice of methods for rating infarct extent affects the number of patients 'eligible' for thrombolysis significantly. Furthermore, MCAGrid increased the accuracy with which infarct extent was estimated. These results provide justification for a prospective study of this technique in the setting of acute stroke.

The localization and lateralization of memory deficits in children with temporal lobe epilepsy.

PURPOSE: It is often reported that children with temporal lobe epilepsy (TLE) experience nonlateralized memory impairments. However, many of these studies have been exploratory and not based on memory theory. Further, differences between mesial and lateral subgroups have not been adequately examined. This study aimed to discern more specific patterns of memory impairment in children with TLE. METHODS: Forty-three children (5-16 years) with lesional TLE participated. Subjects were categorized in terms of lesion laterality (left, n = 21; right, n = 22) and intratemporal location (mesial, n = 31; lateral, n = 12). Verbal and nonverbal memory tasks were administered that reflected associative, allocentric and recognition paradigms. RESULTS: Facial recognition was poorer in right TLE (p = 0.03). There were no differences between left and right groups on any other memory task, even when comparisons were restricted to cases with mesial involvement. Irrespective of laterality, clear differences were observed between mesial and lateral lesion subgroups (arbitrary associative learning, p = 0.01; complex figure recall, p = 0.03). The lateral lesion subgroup displayed intact memory function relative to normative standards. CONCLUSIONS: Memory is more frequently impaired in children with mesial as opposed to lateral TLE. Tasks with an associative component discriminated between these subgroups, supporting an associative model of hippocampal function. With the exception of facial recognition, memory deficits were not lateralized. Therefore, the nature of memory impairment experienced by children with TLE cannot be extrapolated from adult models.

The ASPECTS template is weighted in favor of the striatocapsular region.

The extent of cerebral infarction correlates with increased risk of intracerebral hemorrhage (ICH) following recombinant tissue plasminogen activator (rt-PA) administration. The Alberta Stroke Program Early CT Score (ASPECTS) is a widely used, validated method which assesses involvement of 10 selected regions of the MCA territory. An ASPECTS score >7 is associated with a higher risk of ICH following thrombolysis than lower scores. To understand the internal structure of the ASPECTS template better, we estimated the infarct volume corresponding to each region. We hypothesized that, in the ASPECTS scoring system, the striatocapsular region is weighted disproportionally. Four experienced radiologists rated individual ASPECTS regions on subacute CT images (day 5-day 10) of 19 patients with MCA territory stroke. Infarct volume was determined from manual segmentation of infarcts on CT images. Linear regression was used to estimate the regional volume associated with each ASPECTS region. The ASPECTS regions are weighted unequally with the striatocapsular region accounting for 21% of the MCA territory infarct volume. Together, the 10 ASPECTS regions account for approximately 51% of the maximum MCA infarct territory volume. These findings should provide impetus for research to develop a scoring system explicitly based on regional hemorrhage risk as an aid to selecting patients for thrombolysis.

Early seizures after temporal lobectomy predict subsequent seizure recurrence.

Patients are understandably anxious if seizures occur immediately after temporal lobectomy. Such "neighborhood" seizures are commonly regarded as irrelevant to seizure outcome and discounted in outcome measurement. We conducted an in-depth examination of early postoperative seizures (<28 days) and outcome. The risk of recurrence at one postoperative year was calculated using Poisson regression, and statistical adjustments were made for preoperative pathology. Of 321 patients, 69 (22%) experienced early postoperative seizures. These early seizures were associated with subsequent seizure recurrence (rate ratio [RR] 5.9; 95% confidence interval [CI], 4.1-8.4). Among patients with early seizures, the only significant factor was the presence of seizure precipitants, which was associated with a lower recurrence risk. However, when compared with patients with no early seizures, those with precipitants to early seizures had a higher risk of recurrence (RR, 3.0; 95% CI, 1.8-5.2). The risk was higher again for patients without precipitants to early seizures (RR, 7.6; 95% CI, 5.0-11.5). Early seizures and other seizure recurrences in the first postoperative year did not differ in their effect on subsequent outcome (X(2) [3] = 3.4, p = 0.33). We conclude that early postoperative seizures are associated with subsequent seizure recurrence. These findings have implications for patient counseling and the measurement of outcome.

Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.

There is little information available relevant to long-term seizure outcome after anterior temporal lobectomy, particularly at extended postoperative periods. The aim of this study was an in-depth examination of patterns of longitudinal outcome and potential risk factors for seizure recurrence after lobectomy, utilizing a large patient sample with long follow-up. Included were 325 patients who underwent anterior temporal lobectomy between 1978 and 1998 (mean follow-up 9.6 +/- 4.2 years). Retrospective data were analysed using survival analysis and multivariate regression with Cox proportional hazard models. The probability of complete seizure freedom at 2 years post-surgery was 55.3% [95% confidence interval (CI) 50-61]; at 5 years, 47.7% (95% CI 42-53); and at 10 postoperative years it was 41% (95% CI 36-48). Patients with discrete abnormalities preoperatively (i.e. lesions and hippocampal sclerosis) had a significantly higher probability of seizure freedom than patients without obvious abnormality. The latter group had a pattern of recurrence similar to that in patients with lesions outside the area of excision. After adjustment for preoperative pathology, only the presence of preoperative secondarily generalized seizures had a significant association with recurrence [occasional preoperative generalized seizures, hazard ratio (HR) 1.6, 95% CI 1.1-2.3; frequent seizures, HR 2.0, 95% CI 1.4-2.9 compared with absence of preoperative generalized seizures]. Duration of preoperative epilepsy, age of seizure onset and age at surgery did not have an effect on outcome. Patients with two seizure-free postoperative years had a 74% (95% CI 66-81) probability of seizure freedom by 10 postoperative years. This late seizure recurrence was not associated with any identified risk factors. Specifically, patients with hippocampal sclerosis were not at higher risk. Surprisingly, complete discontinuation of anti-epileptic drugs (AEDs) after two postoperative years was not associated with an increased risk of recurrence (HR 1.03, 95% CI 0.5-2.1). This may be because selection of patients for AED discontinuation is biased towards those individuals perceived as 'low risk'. The results of this study indicate that the lack of an obvious abnormality or the presence of diffuse pathology, and preoperative secondarily generalized seizures are risk factors for recurrence after surgery. Late recurrence after initial seizure freedom is not a rare event; risk factors specific to this phenomenon are as yet unidentified.

Correlation between language organization and diffusion tensor abnormalities in refractory partial epilepsy.

PURPOSE: Atypical language organization is more frequently found in patients with refractory partial epilepsy than in healthy controls; however, the reasons for this are not well known. Here we assess the relation between language laterality index (LI) and white-matter tract changes. METHODS: Nine patients with refractory partial epilepsy were assessed with a 3-T GE scanner. Functional magnetic resonance imaging (fMRI) of language and diffusion tensor imaging (DTI) were acquired. For the fMRI, a noun-verb generation task was performed, all images were motion corrected, and activated pixels in classic language areas were counted. The DTI images were acquired in six standard directions with an initial non-diffusion-weighted scan. The "average anisotropy" was determined in a region of interest in the frontal lobe, temporal lobe, and parietal lobe white matter. An asymmetry index (AI) was calculated for language and DTI. Atypical language lateralization was diagnosed if the lateralization index (LI)-language was smaller than 0.4. RESULTS: Two of the nine patients had atypical language localization (LI-language, -0.6, and 0.3); both had left temporal DTI asymmetry (LI-DTI, -0.3 and -0.2). The remaining seven patients had typical language localization, and no marked DTI abnormalities. Asymmetry in temporal lobe DTI correlated with LI-language (r= 0.8; p = 0.006). CONCLUSIONS: Atypical language lateralization in patients with partial epilepsy may be associated with white-matter tract abnormalities.

Anterior temporal changes on MR images of children with hippocampal sclerosis: an effect of seizures on the immature brain?

BACKGROUND AND PURPOSE: Ipsilateral loss of anterior temporal gray-white matter definition, due mainly to white matter signal intensity abnormality, is frequently seen on MR images of patients with hippocampal sclerosis. Our aim was to determine the prevalence and clinical correlations of these anterior temporal changes in pediatric cases of hippocampal sclerosis and to determine whether cumulative damage from seizures is important for their development. METHODS: We reviewed the MR images and clinical details of 54 children (age range, 1.5-19 years) with typical hippocampal sclerosis. Specific imaging features noted included hippocampal sclerosis, anterior temporal changes, anterior temporal atrophy, and extra-hippocampal abnormality. RESULTS: Thirty-one (57%) of 54 children with hippocampal sclerosis had associated ipsilateral anterior temporal changes. Ipsilateral anterior temporal atrophy was associated with anterior temporal changes (P <.03). Children whose images showed anterior temporal changes were younger at onset of epilepsy (P <.01) and younger at antecedent cerebral insult (P <.03) than those with normal anterior temporal lobes. Most (84%) children whose images showed anterior temporal changes had experienced the onset of epilepsy or antecedent cerebral insult before the age of 2 years (P <.0009). Eighty-one percent of children with anterior temporal changes shown on their images experienced seizures at the time of antecedent insult. CONCLUSION: Ipsilateral anterior temporal changes identical to those observed in adult cases are seen on the MR images of young children with hippocampal sclerosis, with a similar prevalence, and are associated with either epilepsy onset or seizure-related cerebral insult before the age of 2 years. We suggest that the loss of gray-white matter definition may represent a persistent immature appearance, including an abnormality of myelin or myelination, possibly a result of seizures occurring during maturation of the temporal pole.

MR imaging of epilepsy: state of the art at 1.5 T and potential of 3 T.

Shortly after being introduced in the nineteen eighties, magnetic resonance imaging (MRI) became a key tool for the investigation of patients with epilepsy, due to its ability to acquire high quality images. The strength of the magnetic field of a scanner is measured in tesla (T). This review addresses the clinical and research potential in epilepsy of MR imaging at 1.5 T and 3 T. A typical clinical scanning protocol at 1.5 T for a patient with refractory epilepsy may include T1- and T2-weighted imaging, fluid-attenuated inversion recovery (FLAIR) imaging, and a 3D volume acquisition sequence. A research protocol may add quantification of structural imaging, such as volumetric assessment and T2-relaxometry, together with functional measures, such as MR-spectroscopy, functional MRI and diffusion weighted sequences. MR-spectroscopy assesses the metabolites of the seizure focus and other brain areas. Functional MRI allows localisation of cognitive and sensori-motor function and the ability to assess the spatial relationship of these functions to the seizure focus. Whereas these techniques can be performed at 1.5 T, particularly MR-spectroscopy and functional MRI benefit from increased magnetic field-strength. Higher magnetic field-strength is associated with a higher signal-to-noise ratio (SNR). The increased SNR can allow shorter imaging times for a given resolution, higher resolution for a given imaging time, or combination of both. The use of higher magnetic field-strengths is therefore indicated for the (fast) imaging of ill subjects, for long protocols, including structural, metabolic and functional imaging, and for novel applications, such as continuous EEG recording and functional MRI for the detection of the seizure focus. Disadvantages of MR imaging in epilepsy at a high field-strength of 3 T and above are, apart from engineering and technical challenges, the greater energy deposition into tissue and increased susceptibility to artefacts. So far, magnets of 3 T and above have been used mainly for research applications, however the benefits of high field-strength for MR spectroscopy and functional MRI, and the usefulness of these techniques for the investigation of epilepsy patients are obvious incentives for the use of 3 T systems in routine clinical investigations.

Ectopic posterior pituitary lobe and periventricular heterotopia: cerebral malformations with the same underlying mechanism?

BACKGROUND AND PURPOSE: Ectopic posterior pituitary lobe often occurs in children with growth hormone deficiency and is part of the spectrum associated with septo-optic dysplasia. Some cases of septo-optic dysplasia are caused by homozygous mutations in the homeobox gene HESX1, whereas heterozygous mutations are associated with milder phenotypes. To date, HESX1 is the only gene associated with ectopic posterior pituitary lobe. We describe an association between ectopic posterior pituitary lobe and periventricular heterotopia in four children without classic features of septo-optic dysplasia and suggest possible mechanisms on the basis of a review of pituitary embryology and recent molecular genetic advances. METHODS: Among 20 children with ectopic posterior pituitary lobe, four had associated periventricular heterotopia. We herein review the clinical and MR imaging findings of these four children. Mutation screening of HESX1 was performed in two. RESULTS: All four children had growth hormone deficiency. None had visual or neurologic disturbances. MR images showed a range of pituitary appearances, with scattered discrete periventricular heterotopia in each case. Other abnormalities were limited to small suprasellar lipomas and callosal dysgenesis. A heterozygous HESX1 mutation was present in one case. CONCLUSION: The coexistence of ectopic posterior pituitary lobe and periventricular heterotopia suggests they have a common underlying genetic basis that is due to gene expression at different locations and stages of development. The presence of a heterozygous HESX1 mutation in one case suggests this gene is important in the development of both ectopic posterior pituitary lobe and periventricular heterotopia and supports their place in the spectrum of septo-optic dysplasia. Further analysis of HESX1 and other genes in related developmental pathways will elucidate their roles in the development of both malformations.