Hemimegalencephaly (HME) is a rare congenital malformation of cortical development, usually associated with developmental delay and severe epilepsy. This condition has rarely been reported in adults. The aim of this study was to examine and compare neurological findings in adult patients with HME.
We retrospectively examined adult patients with HME by evaluating the presence of neurocutaneous disorders, current cognitive development, seizure control, and documentation of therapies for seizure management and outcomes.
Five patients were included in the study (three males, two females; mean age 23y 9mo [SD 6y 1mo], range 18–34y). Four patients had HME that was associated with neurocutaneous syndromes and the remaining patient had isolated HME. Two patients required surgical treatment for seizures in childhood. One patient had no intellectual disability, while one had mild, and three severe intellectual disability. All patients presented motor deficits ranging from mild hemiparesis in two patients to non-ambulation in one patient. Patients in whom seizure onset occurred after the 7 years of age had better seizure control and psychomotor development in adulthood than patients in whom seizure onset occurred in the first year of life.
In our small sample of adults with HME, age at seizure onset, cognitive disability, and seizure control were found to be associated.
This is the first study of the progression of hemimegalencephaly into adulthood.
Patients with late-onset epilepsy may exhibit better seizure control during adulthood.
Non-syndromic and/or less extensive hemimegalencephaly is associated with better outcomes.
Hemimegalencephaly (HME) is an uncommon congenital malformation of the brain characterized by the overgrowth of one hemisphere. The enlarged hemisphere exhibits hamartomatous characteristics with dysplastic and disorganized cell arrangements and atypical cell morphology.
The clinical picture varies depending on the severity of the malformation; however, HME patients typically exhibit refractory epilepsy. Other clinical manifestations include macrocephaly, colpocephaly, global developmental delay, intellectual disability, hemibody hypertrophy, and hemiparesis. HME may present alone or in association with neurocutaneous syndromes, such as epidermal naevus and its subtypes (i.e. linear naevus sebaceous syndrome and proteus syndrome), Klippel–Trénaunay–Weber syndrome, neurofibromatosis, or hypomelanosis of Ito.[1-4]
The pathogenesis of HME is probably related to erroneous cell signalling during fetal development,[1-3, 5] possibly due to genetic chimerism leading to discrepancy between the affected and the unaffected hemispheres.[6-8] Chimerism is a possible pathogeic model for isolated HME and neurocutaneous syndromes, given the similarities in clinical, neuroradiological, and histopathological presentation of both conditions. If two cell lineages arise from the neural crest progenitor cell line, one exhibiting normal cellular physiology and the other abnormal cellular physiology, then different migration patterns could be observed. This explains how skin lesions appear in neurocutaneous syndromes and an enlarged hemisphere in patients with HME. Additionally, overgrowth of a hemisphere and epileptogenesis might be present if the affected cell line exhibits mutations in the pathways regulating cell proliferation, such as the Wnt/β-catenin or phosphoinositide 3-kinase-AKT3-mTOR signalling pathway,[8, 10] or modified expression of phospho-S67 ribosomal protein, interleukin 1β, and neuropeptide Y.
While HME is well described clinically in infants and children, little has been reported on the long-term evolution of this disorder into adulthood. The aim of this case series was to examine and compare neurological findings in adult patients with HME.
All patients with HME were seen at the Adult Tertiary Epilepsy Centre at the Toronto Western Hospital, University of Toronto. Participants were selected based on the following inclusion criteria: (1) age over 18 years; and (2) HME diagnosis confirmed by magnetic resonance imaging (MRI) showing diffuse enlargement of one hemisphere. Patients were excluded if (1) they had not been assessed in the last 12 months; or (2) there was no clear documentation of seizure frequencies since onset, antiepileptic drugs, or neurosurgeries.
We conducted a retrospective chart review collecting demographic data, associated conditions, current seizure frequency, treatments, cognitive evolution, magnetic resonance reports and imaging, and neuropathology reports of patients who had undergone surgery. Cognitive evolution was determined by examining the patients' history for attention deficits, learning disabilities, or cognitive delay (according to neuropsychologist reports), and if they were following a modified academic curriculum, such as life skills or special education programmes. Positive cognitive evolution was defined as the absence of neurobehavioural disorders during adulthood or transition into a regular academic curriculum. This study was approved by the research ethics board of the University Health Network.
Out of 1750 patients in the Epilepsy Clinic Database, five qualified for the study (three males, two females, mean age 23y 9mo [SD 6y 1mo], range 18–34y). All but one patient presented global developmental delay in childhood. Three started having seizures within the first year of life, and two after 7 years of age. HME-associated conditions were hypomelanosis of Ito in three patients and linear naevus sebaceous syndrome in one patient. The diagnosis of HME was made after epilepsy onset through neuroimaging (computed tomography, MRI, and angiography), confirming the presence of an enlarged hemisphere with associated dilated ventricles to varying degrees. Other imaging findings included loss of grey matter–white matter differentiation, heterotopias, and cortical enlargement (Fig. 1). Neuropathological examination of resected sections from patients 3 and 4 revealed gross disorganization or loss of cortical lamination with immature balloon cells and disorganized dendrites (Table 1).
Table 1. Demographic statistics, clinical data, and magnetic resonance imaging and neuropathology reports in a series of adult patients with hemimegalencephaly
aCognitive evolution was determined by examining the patients' history for evidence of learning disabilities or cognitive delay (according to neuropsychologist reports), and/or modified academic curriculum, such as life skills or special education programmes. Mild intellectual disability: patients have the ability to profit educationally within a regular class with the aid of considerable curriculum modification and supportive services. Moderate intellectual disability: patients need considerable support in school, at home, and in the community in order to participate fully. They can learn simple health and safety skills, and they may work in a sheltered workshop. Severe intellectual disability: patients need more intensive support and supervision throughout their entire life. They may learn some activities of daily living and their IQ is below 35. bNo pathology reports are available since these patients have not undergone any resective surgery. cNo pre-surgical MRI available.
40–50 seizures per month; focal onset seizures + focal onset seizures with secondary generalization
30–60 seizures per month; focal onset seizures
Clusters of three or four seizures every 6mo; focal onset seizures + focal onset seizures with secondary generalization
Motor neurological deficits
Left mild hemiparesis with normal tone and deep tendon reflexes
Left mild hemiparesis with normal tone and deep tendon reflexes
Non-ambulatory, bilateral pyramidal signs, global hyperreflexia, and ankle clonus
Right hemiparesis with pyramidal signs
Left hemiparesis with pyramidal signs. Left-hand dystonic posture
Neurosurgical interventions performed
Right functional hemispherectomy; ventricle peritoneal shunt
Left functional hemispherectomy and subdural peritoneal shunt in childhood; recently, anatomical left hemispherectomy and callosotomy
Neuroimaging and/or neuropathology reports
MRI: mild pachygyria over right parietal and occipital cortex and ill-defined grey matter–white matter junction over the right temporal, parietal, and occipital lobesb
MRI: the right-side shows ill-defined grey matter–white matter junction in the parietal, frontal, and temporal lobes. The three described lobes exhibited hyperintensity of the white matter signalb
Neuropathology report: resected sections showed histological findings consistent with hemimegalencephaly; cerebral cortex containing large number of abnormally large neurons; chaotically neuronal organization with dendrites pointing in various directions and no cortical laminationc
MRI: left-sided hemimegalencephaly with extensive involvement of left hemisphere and relative sparing of the occipital lobe. Neuropathology report: resected sections showed histological findings consistent with hemimegalencephaly; disordered cortical lamination and neuronal orientation, balloon cells, giant neurons, abnormalities of neuronal shape and Nissl patterns, poor grey matter–white matter junction, gliosis, and neuronal heterotopia in the white matter
MRI: prominent sulcus in the right parietal lobe extending deeply to the periventricular region, coarsening of the gyral pattern, and a prominent primitive sylvian fissure; mild dilatation of the right lateral ventricle with heterotopic grey matter around the anterior horn; asymmetrical deep white matter in right cerebral hemisphere, grey matter–white matter differentiation is well maintainedb
Treatment with antiepileptic drugs did not result in complete seizure control, except in patient 2, who experienced a seizure-free period of 14 years before her seizures resumed at 22 years of age. At present, all patients are on antiepileptic drugs (mean number of drugs 2.2). Patients with syndromic HME required polytherapy to manage their seizures. Patients 3 and 4, with childhood seizure frequencies in excess of 15 seizures daily, underwent hemispherectomy at 9 and 2 years of age respectively. Although these patients continue to experience seizures, seizure control has significantly improved since surgical intervention.
Cognitive impairment in adulthood ranged from lower normal cognition to severe impairments (Table 1). Patient 1 has completed high school, albeit following a modified curriculum and is currently a volunteer; patient 2 was able to complete secondary school on a regular curriculum and is currently attending college. Patients 3, 4, and 5 require constant supervision for daily living activities; they understand only a few simple commands, and use few words to communicate.
Our sample of adult patients demonstrated that there might be an association between age at seizure onset, seizure control, and cognitive disability. Patients with less extensive brain abnormalities and seizure onset after 7 years of age (patients 1 and 2) had better cognitive development and seizure control during adulthood than patients with a seizure onset within the first year of life and extensive brain abnormalities (patients 3 and 4).
Patients 1 and 2 are able to perform simple work or volunteer duties, while those with early-onset epilepsy are totally dependent for activities of daily living. In addition, the patient who presented isolated HME (patient 2) exhibited the best prognosis in our sample, being the only one to experience a long seizure-free period.
On examination, all patients exhibited some form of motor defect. Patients 1, 2, 4, and 5 exhibited hemiparesis. Patient 3 was the only non-ambulatory patient in our cohort. This patient had a fractured left femur at 4 years of age, and subsequently experienced several orthopaedic complications, which may have contributed to his non-ambulatory state.
HME is a malformation of cortical development with pathological findings strongly suggestive of errors affecting all three phases of neuronal development: cell differentiation/proliferation, neuronal migration, and organization. The affected hemisphere usually demonstrates cytomegalic/balloon cells, disoriented axons and dendrites, heterotopic neurons, and indistinct/absent cortical lamination.[1, 11, 12] Interestingly, the contralateral, supposedly ‘normal’, hemisphere may also be atypical, and this fact may explain the lack of complete seizure control in our two patients who underwent hemispherectomy (Patient 3: Engel class IVA; Patient 4: Engel class IIIA). For instance, non-affected hemispheres were found to present cerebral hypoperfusion and hypometabolism, indicating that they might also have developed abnormalities in early development. Structurally, the supposedly ‘normal’ hemisphere can demonstrate atypical columnar cortical arrangement, possibly contributing to the persistence of seizures after hemispherectomy.
Long-term outcome in hemimegalencephaly
Early seizure activity may be indicative of the severity of the brain overgrowth/dysplastic nature. In turn, the severity of the structural abnormalities could explain the poorer outcome (regarding cognition and seizure control) of patients in whom seizure onset occurred in the first year of life, compared with those with seizure onset after 7 years of age, in our series. Undoubtedly, neuronal development defects are strongly associated with poor cognition and refractory epilepsy, as seen in patients with polymicrogyria and lissencephaly.[11, 14] Thus, maintaining proper neuronal migration and cortical lamination to some degree may be beneficial in facilitating cognitive development and attenuating seizure frequency. The effects of continuous seizures on a developing brain, however, may also contribute to cognitive problems in adulthood.
For instance, it has been found that, among children with temporal lobe epilepsy, neuropsychological function is poorer in those in whom onset occurred early than in those in whom onset was later, a finding attributed to prolonged exposure to seizures. Moreover, prolonged exposure to pharmacoresistant epilepsy can impair cognition. In a cohort study of 198 children, pharmacoresistant epilepsy was associated with lower performance on cognitive tests.
Review of the literature demonstrates that in the majority of patients with HME, seizure onset occurred between the first days of life and 2 years 6 months.[2, 5, 10, 17-20] In rare instances, however, individuals with HME have experienced seizure onset during adulthood. In such cases, seizures are usually mild and intelligence is normal.[21, 22] Indeed, one of our patients was able to complete high school on a regular curriculum, obtain a college-level degree, and achieve seizure control for 14 years with monotherapy. We believe her late seizure onset, isolated HME presentation, and less extensive brain abnormality resulted in her experiencing a better clinical outcome than our other patients.
Isolated versus syndromic hemimegalencephaly
HME may result from genetic chimerism tying neurocutaneous syndrome into the clinical picture of HME.[6-8] However, while chimerism and mutations regulating cell proliferation would explain the association between HME and neurocutaneous syndromes,[8-10] the differences in the clinical severity of isolated HME compared with syndromic HME have not been widely addressed. Flores-Sarnat[1, 3] found the same clinical neurological, neuroimaging, and neuropathological features in isolated and syndromic HME.
In our sample of adult patients, of the two patients with late-onset epilepsy, the one with isolated HME exhibited a better clinical outcome. Obviously, larger cohorts of adult patients must be studied to make any statistical association.
HME progression into adulthood has rarely been described. In our evaluation of five adult patients, a less favourable outcome was seen in those in whom seizure onset was earlier, probably reflecting the severity of the structural malformations. Of the two patients with late-onset epilepsy, the one with isolated HME exhibited a better clinical outcome than the patient with syndromic HME. In addition, despite a reduction in seizure frequency, hemispherectomy did not provide complete seizure control. This may be related to abnormalities on the supposedly ‘normal’ contralateral hemisphere. We recognize that our sample of patients is small, and further studies on adults with HME are necessary to better characterize the long-term evolution of this condition.